År 2017 Årgång 30 Nr 6-7 DIABETOLOGNYTT Medlemstidning För Svensk Förening För Diabetologi

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År 2017 Årgång 30 Nr 6-7 DIABETOLOGNYTT Medlemstidning för Svensk Förening för Diabetologi

År 2017 Årgång 30 Nr 6-7 Höstnumret Ordföranden har ordet 150 Redaktören har ordet 152

NDR-Nytt 153

Diabetesproil Claes-Göran Östensson 154

Sett & Hört 160

Ny ADA-standard för diabetesutbildning 162

Managing diabetes in pre-school ISPAD Guidelines 170

Better quick screening för monogenic diabetes 192

Sveriges första TV-Gala till förmån för diabetes 14/11 199

TLV kan lära av Frankrike kring implementering av Libre 202 Exercise Management in T1DM Consensus 215 ADA rapporter från amerikanska diabetesmötet 229 LCHF till T1DM barn är en livsfara 257 Recension böcker 265

Endo-diabetesmötet i Göteborg 7-9/3 2018 267

Res med SFD till ATTD, ADA, EASD, ISPAD 272

Kongress- och möteskalender 276

Redaktör Adress till redaktionen Internet Doc Stig Attvall Doc Stig Attvall www.diabetolognytt.com [email protected] Diabetescentrum, Blå Stråket 5 www.dagensdiabetes.se SU/Sahlgrenska med dagliga uppdateringar av Ansvarig utgivare 413 45 Göteborg diabetesnyheter David Nathanson VO internmedicin, Medlemsavgift Nästa nummer av DiabetologNytt Södersjukhuset 200:– per år Planerad utgivning 180215 Sjukhusbacken 10, Deadline för bidrag 180115 118 83 Stockholm Bankgiro 5662-5577 Tryck & layout Annonsansvarig Swishkonto Litorapid Media AB [email protected] 123 084 9125 Miljömärkt Trycksak 3041 0834 www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 149 Ordföranden har ordet

Övergången från sommar till höst Lund SUS är ny vetenskaplig se- För att bli ännu bättre på att brukar kännas lättare när de ar- kreterare i SFD. kommunicera viktiga händelser betsuppgifter som ligger framför Styrelsen hade en öppen dis- i svensk diabetesvård och forsk- oss är spännande och utvecklan- kussion om SFDs strategiska mål ning, så vill SFD satsa mer på de. Så är verkligen fallet i år med och kom fram till att från och strategisk kunskapsstyrning. Sty- EASD, höstmöte och världsdiabe- med 2019 endast ordna ett ve- relsen anser att detta är motiverat tesdag på agendan. tenskapligt möte per år. Detta eftersom kunskapsspridning är ett SFDs styrelse träfades i bör- för att kunna attrahera en stör- av SFDs huvudmål och vi tror att jan av september i Stockholm re publik och föreläsare med stor detta kan bli en framgångsfaktor för att lägga upp och planera det dragningskraft. Vår plan är att för att öka vårdgivares, patienters kommande årets aktiviteter. SFD dessa kommande möten blir något och allmänhetens medvetenhet kunde här introducera Niclas Ab- längre (tre dagar) där en dag viks om diabetesforskning och vård- rahamsson (Akademiska Sjukhu- åt kliniskt inriktade föreläsningar processer i Sverige. set, Uppsala) och Erik Schwarcz av typen ”meet the expert”, en dag Ett betydelsefullt instrument (Universitetssjukhuset, Örebro) i innehåller vetenskap och en dag är för en kvalitetsgranskad kun- styrelsearbetet. Niclas sitter även mer fokuserad på samhällsfrågor skapsspridning är en gemensam i styrelsen för Svenska endokrino- som är kopplade till diabetes. Vå- lärobok. En utmärkt sådan inns logföreningen (SED) vilket är en ren 2019 kommer det första mötet sedan 20 år i form av boken ”Dia- stor tillgång i SFDs kommande i detta format att hållas i Stock- betes” (LIBER) med redaktörskap samarbeten med SED. Magnus holm i samarbete mellan SFD och från Christian Berne och Carl-Da- Löndahl från diabetesenheten barnläkarföreningen. vid Agardh. SFD har nu fört sta-

150 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se fettpinnen för denna mycket lästa klubben att revidera inrapporte- Denna gala kommer att sändas bok vidare till Mona Landin Ols- ringen för retinopati i NDR. Den från Stockholm. Dagens medicin son som har tackat ja till att bli re- nya inrapporteringsmallen plane- arrangerar även tillsammans med daktör för en ny upplaga. ras att harmoniera med den gäl- det nationella diabetesteamet (där Under hösten kommer studien lande internationella klassiikatio- SFD, barnläkarföreningen, SFSD som går under namnet: Chang- nen och kommer att spikas under och dietisternas riskförbund in- ing Diagnostic Criteria for Ge- hösten. går) som ges på Operaterrassen i stational diabetes in Sweden att Agendan för höstmötet 12- Stockholm. Vi har denna dag valt startas upp (http://cdc4g.com/ 13/10 i Malmö www.jamlikvard. kommunikation och mångfald sv). Erik Schwarcz sitter i styr- org samarrangeras med SKL och som teman, då vi tycker att dessa gruppen för denna studie som Svenska Psykiatriska föreningen ämnen är angelägna att diskute- avser att studera efekterna av de och innehåller ett antal angelägna ra. Vi hoppas att inom kort kun- nya riktlinjer för gestationell di- teman som psykisk ohälsa hos dia- na presentera innehållet till detta abetes. Samtliga Sveriges regioner betespatienten, somatisk hälsa hos seminarium! kommer i denna studie att stegvis den psykiatriska patienten och en Vi går en spännande höst till lottas till de nya riktlinjerna som översikt av kommunala insatser. mötes med andra ord! både gäller diagnos och mer aktiv Världsdiabetesdagen kommer behandlingsstrategi. att få stor uppmärksamhet i år David Nathanson Ett annat arbete som pågår är på grund av den TV sända ga- Ordf SFD samordningen mellan NDR, SFD lan som arrangeras gemensamt och svenska medicinska retina- av MTG och Diabetesförbundet.

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 151 Redaktörspalten

Svensk Förening för Diabetologi av CGM vid typ 1 diabetes disku- deras pressrelease kring Libre. An- (SFD) fyller i år 30 år. Salvador teras på sid 247. Förutom HbA1c ders Lönnberg, regerings utredare, Dalis ”Minnets beständighet” med är vid typ 1 diabetes minst lika vill på sid 228 att Sverige ska vara skulpturen ”Nobility of Time”, en viktigt att ha så lång tid som möj- ett kraftfullt innovativt land, ock- smältande klocka, pryder framsi- ligt i normoglykemi - och mini- så med en öppenhet för medicin- dan av detta nummer. mera tiden med hyperglykemi res- teknik. pektive tiden med hypoglykemi. Som redaktör är det en glädje att I tidningen inns ISPADs Guideli- ha med rapporter från amerikan- LCHF risks for life diskuteras av nes om diabetes in pre-school på ska diabetesmötet ADA i juni i Carmel Smart på sid 257 utifrån sid 192, konsensus kring exercise San Diego, världens största dia- en studie med fallrapporter från management vid typ 1 diabetes sid beteskonferens, sid 229-248. Här Australien och Nya Zeeland. 215 och referat av en artikel kring inns både kliniska och veten- monogen diabetes på sid 192. skapliga studier vid typ 1 och 2 TLV kan lära mycket av Frankri- diabetes. DEVOTE en studie av ke då det gäller implementering Önskan om en in höst och vinter långverkande insulin som visar av Libre vid typ 1 och 2 diabetes. [email protected] att degludec är kardiovaskulärt Se sid 202. NT-rådets rekommen- Redaktör säkert. Studien CANVAS gör att dationer om Libre vid typ 2 dia- SGLT2-hämmare stärker sin roll betes inns på sid 210. Professor Hör av dig om du hört och läst inom typ 2 diabetes med 33% Jan Bolinder, Karolinska, ger på något du vill sprida vidare. mindre hjärtsvikt. Standardisering sid 214 sitt yttrande om TLV och

152 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se NDR-nytt www.ndr.nu

Typ 1-diabetes och vikten av god riskfaktorkontroll I en nyligen publicerad artikel i Circulation presenteras en studie där NDR undersöker sambandet mellan antalet riskfaktorer och ris- Swediabkids och NDR har alltid ande över sig att man inte ska ha ken för hjärt-kärlsjukdom och död haft drivkraften att vara verktyg dåliga värden kan skapa stress och hos individer med typ 1-diabetes i arbetet att förbättra vården och oro och det kan man behöva prata jämfört med matchade kontroller. nästa steg är att harmonisera de om med sin läkare eller diabetes- Fem traditionella och modiierbara två registren så att det går att följa sjuksköterska. NDR är ett redskap kardiovaskulära riskfaktorer val- personer med diabetes genom hela för diabetesvården att följa upp des ut; blodsockernivåer (HbA1c), livet. Detta kommer att underlätta den medicinska behandlingen och blodtryck, blodfetter (LDL-koles- utvärderingen av diabetesvården dess resultat, men fram till nu har terol), albuminuri och rökning. och syftet är en ännu bättre vård det inte funnits med i registret hur Efekten av att uppnå målnivåer för barn, ungdomar och vuxna personer med diabetes mår och för de fem utvalda riskfaktorer- med diabetes. Swediabkids ska hur deras vardag fungerar. na studerades för att ta reda på ingå i den webbaserade lösning Enkäten innehåller förutom frå- om en person med typ 1-diabetes som inns för vuxenregistret NDR gor om måendet även frågor som kan eliminera sin förhöjda risk för vilket innebär att även barn- och handlar om stödet från vården hjärt-kärlsjukdom och död genom ungdomsdiabetesmottagningar- och om patienten är nöjd med optimal riskfaktorkontroll. Alla na får möjlighet till direktöverfö- sin behandling och sina hjälpme- patienter, 18 år eller äldre, med ring från journal till registret. De del. Med enkäten får vården och typ 1 diabetes och som registre- sökfunktioner som redan inns i patienterna nu ett redskap för att rats i NDR från år 1998 till 2014 NDR ska anpassas för att också följa upp även dessa frågor. Läkar- inkluderades i studien. För varje kunna användas för Swediabkids na och diabetessjuksköterskorna individ med diabetes inkluderades och de blir värdefulla verktyg i har naturligtvis pratat med patien- fem ålders-, kön-, och regionmat- det lokala förbättringsarbetet även terna om de här viktiga frågorna chade kontroller utan diabetes, på barn- och ungdomsklinikerna. tidigare, men med hjälp av enkä- slumpmässigt utvalda från befolk- Dessutom kommer NDRs öppna ten blir det på ett mer systematiskt ningen. Jämförelse gjordes av 33 utdataverktyg ”knappen” nästa år sätt. Enkäten kan dels fungera 333 patienter med typ 1-diabetes också innehålla resultat från barn- som ett stöd i det enskilda vård- med 166 529 matchade kontrol- och ungdomsdiabetesvården. mötet men också då vården ut- ler. För varje riskfaktor som inte värderas på gruppnivå. Förutom nådde målvärdet ökade risken för NDRs diabetesenkät väcker de medicinkliniker som i nuläget död och kardiovaskulär händelse frågor om hur det är att leva testar enkäten så kommer den gradvis. Slutsatsen är att indivi- med diabetes introduceras på ett antal primär- der med typ 1-diabetes som upp- Hur det är att leva med diabetes vårdsenheter under hösten. Nästa når optimal riskfaktorkontroll av har uppmärksammats i media år blir det möjligt för alla diabe- fem utvalda riskfaktorer markant med anledning av att NDR tes- tesmottagningar som vill, att börja reducerar den förhöjda risken för tar diabetesenkäten på lera med- använda diabetesenkäten. hjärt-kärlsjukdom och möjligtvis icinkliniker i landet. Till exempel Vi vill passa på och än en gång även eliminerar sin förhöjda risk har SVT Nyheter Halland gjort tacka er för det fantastiska samar- för stroke och död. ett reportage från en av testklini- betet och för all värdefull input. kerna, se länk från NDRs hem- NDR utvecklas ständigt tack vare Diabetesregistren för barn sida. I reportaget tas upp att det det. Vi hörs och ses. och vuxna går ihop och får ställs höga krav på den som har di- gemensam hemsida abetes att ta hand om sin sjukdom Soia Gudbjörnsdottir, Från och med nästa år kommer på egen hand med till exempel registerhållare NDR och Swediabkids att in- blodsockerkontroller och dosering Pär Samuelsson, utvecklingsledare nas på samma webbsida. Både av insulin. Att hela tiden ha häng- Ebba Linder, utvecklingsledare www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 153 ”Spännande att gå från cell- till samhällsnivå”

Han blev doktorand som 20-åring och var bland de första att lyfta fram Claes-Göran sitter hemma i lägen- kafets förtjänster vid diabetes. För DiabetologNytt berättar professor heten i Solna, bara några minuters Claes-Göran Östenson om myndighetsuppdrag, japanska råttor och promenad från KI, där han alltså att aldrig bli färdig. fortfarande är anställd som forskare. I laboratoriet är han i regel lera Ett nytt kapitel i livet. Det började håller han på att avsluta årets re- gånger i veckan – om han inte är förra året när Claes-Göran Östen- videring. Ovanpå detta är han i sommarhuset i skärgården eller son efter närmare fyra decennier ordförande för Nationella pro- på något utlandsjobb. Vid sidan som diabetesdoktor på Karolinska gramrådet för diabetes vid Sveriges om sina nationella uppdrag le- Sjukhuset sade hej då till sina pa- Kommuner och Landsting (SKL) der Claes-Göran sedan många år tienter. Numera ägnar han sig åt och medlem i Läkemedelsverkets tillbaka forskningsprojekt i Viet- dem indirekt – i egenskap av se- vetenskapliga råd. Det senare nam, Malaysia, Uganda och Bo- niorprofessor inom diabetes typ 2 innebär heldagsmöten en gång i livia – länder där Sida har stöttat på Karolinska Institutet, KI, och månaden. forskarutbildningar. Syftet är att genom ett lertal myndighetsenga- – Jag inser att jag börjar bli en förbättra diabetesvården och före- gemang. Oiciellt jobbar han bara myndighetsperson, säger Claes- bygga den ökade förekomsten av halvtid, vilket ger lite mer tid åt Göran och skrattar. typ 2-diabetes. barnbarnen. Men börjar man rada – Det känns intressant och ro- – Diabetes ökar stort i länder upp alla uppdrag är det svårt att ligt att jag kan använda min erfa- i Asien och Afrika i och med att förstå när han egentligen är ledig. renhet och expertis på det sättet livsstilen håller på att förändras Vid sidan om forskningen på KI – myndighetsuppdragen syftar ju där, särskilt i städerna. Människor är han institutets diabetesrepre- också till att göra det bättre för pa- börjar få det bättre, de köper mat sentant i 4D-programmet – ett tienterna. Men det var på ett sätt som inte är så bra och skafar mo- samverkansprojekt mellan KI och tråkigt att lämna personer som jag torcyklar och bilar. Det är spän- Stockholms läns landsting med hade träfat ett par gånger om året nande att följa och att få vara med fokus på de vanligaste folksjukdo- i kanske 30 år. Samtidigt är ingen och försöka hitta lösningar, säger marna. Han jobbar också sedan människa oumbärlig. Jag har duk- Claes-Göran. 2006 för Socialstyrelsen i arbetet tiga kollegor som tar över. I början på juni i år kom han med att ta fram nationella riktlin- Det är en solig sommarför- hem från en tur i Uganda där jer för diabetes. I skrivande stund middag när vi hörs på telefon. en av utmaningarna är de be- gränsade möjligheterna att mäta Claes-Göran Östenson plasmaglukos. En annan är för- Ålder: 68 år. varingen av insulin; då många Bor: Lägenhet i Solna och sommarhus i Stockholms skärgård. saknar kylskåp kan insulinet som Familj: Fru (läkare och specialist i klinisk mikrobiologi), två döttrar och tre barnbarn. bäst förvaras ett par veckor ned- Jobbar som: Seniorprofessor och forskargruppsledare för diabetes typ 2 vid grävd i jorden. Universitetet i hu- Karolinska Institutet i Stockholm samt innehar lera myndighetsuppdrag, vudstaden Kampala har ett direkt bland annat ordförande för Nationella programrådet för diabetes och medlem samarbete med KI, vilket bidrog i Läkemedelsverkets vetenskapliga råd. Favoritmat: Vågar jag säga annat än isk och grönsaker? (men det är faktiskt till att Claes-Göran engagerade sant) sig just där. Hans doktorands stu- Gör på fritiden: Går gärna länge på konstmuseer och har sedan många år dier i Uganda har lärt honom vik- abonnemang på Stockholms Konserthus. Spelar piano, reser, plockar svamp ten av att förstå människors olika och bär i skogen på sommaren och åker långfärdsskridskor på vintern. Det visste du inte om Claes-Göran: Har tillsammans med vänner vandrat villkor och tankar för att kunna i bland annat Alperna, Dolomiterna, Västbengalen strax under Himalayas försöka påverka deras livsstil. toppar och i Yunnanprovinsen i sydvästra Kina. – Många som är överviktiga vill absolut inte gå ner i vikt eftersom

154 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se att de är rädda för att folk då ska Jag hade inga läkare i släkten. sockerkontrollen vid diabetes). tro att de är sjuka och har Aids. Egentligen hade jag ett större in- Dessförinnan hade han hunnit Att uppmana människor att mo- tresse vid sidan av naturvetenska- göra sin AT i Västerås och jobbat tionera genom att jogga väcker pen: konst och litteratur. Jag läste deltid som lärare i histologi och också motstånd, eftersom det i re- mycket, gick gärna på muséer och cellbiologi för medicinstudenterna gel bara är barn som springer om- anordnade några gånger föreställ- i Uppsala. Än idag tycker han att kring i värmen. ningar med samtida poeter på det är spännande med cellbiologi skolan. Men jag hade väl en aning och hur man kan koppla mikro- Det var inte självskrivet att om att läkaryrket skulle kännas skopiska och molekylära funktio- Claes-Göran skulle komma att bli viktigt och väsentligt. Och mina ner till människor och samhälle. en litigt resande diabetesdoktor föräldrar tyckte att det lät bra. – Jag har svårt att säga varför eller ens läkare. Han växte upp i Redan andra terminen gick det blev just diabetes. Kanske be- Linköping med sina föräldrar och han till institutionen för histolo- rodde det på den där artikeln som sin bror. Pappan arbetade inom gi, där man forskade om diabetes, min vän visade mig på gymna- spannmålshandeln och mamman och sade att han ville börja forska. siet. En annan orsak kan vara att var tandsköterska. Claes-Göran Han ick då i uppgift av professorn Claes Hellerström var en väldigt tyckte att det mesta i skolan var Claes Hellerström att skriva en trevlig, kunnig och stimulerande roligt men var särskilt intresserad uppsats om epifysen och tillbring- person med ett stort nätverk inom av kemi. På gymnasiet hade han ade timmar på biblioteket där han diabetesforskningen. en klasskompis som hade snöat slog i tjocka böcker och bläddrade Efter avhandlingen rekrytera- in sig på diabetes och en dag vi- i dammiga tidskrifter. Idag kom- des Claes-Göran direkt till Karo- sade han Claes-Göran en artikel mer Claes-Göran knappt ihåg vad linska i Stockholm. De sökte nå- av KI-forskaren Rolf Luft – då han skrev, men professorn gillade gon till kliniken och laboratoriet en av de internationellt främsta det och erbjöd den då 20-årige som hade disputerat inom diabe- inom sjukdomen. Artikeln väckte Claes-Göran att bli doktorand hos tes och på den tiden var det inte Claes-Görans nyikenhet – kanske honom. Tio år senare, 1979, dis- så många. Patientmässigt hade mer än han anade. Efter studenten puterade han på en avhandling om Claes-Göran inte mycket erfaren- sökte både Claes-Göran och hans det blodsockerhöjande hormonet het, men efter fem år på sjukhuset kompis till läkarlinjen i Uppsala. glukagon (som med tiden visa- blev han specialist i klinisk endo- –Det var nog inte så överlagt. de sig ha stor betydelse för blod- krinologi. I slutet på 80-talet bör- www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 155 jade han och hans chef, professorn nologi och diabetesvård och jag torand i Bolivia som presenterar en Suad Efendić, diskutera hur man är väldigt glad över det vi gjorde. avhandling på en ny substans näs- skulle kunna göra en mer omfat- Personligen har det gett mig större ta år. Men att gå från det till ett tande kartläggning över riskfakto- förståelse för hur livsstil och om- godkänt läkemedel är en lång resa. rerna för och förekomsten av typ givningsfaktorer samverkar med Vad tänker du om att du kom att 2-diabetes. Detta var startskottet genetiken vid utveckling av inte viga ditt liv åt just diabetes? till det som sedermera blev den så bara typ 2-diabetes utan även – Jag är jättenöjd. Arbetet har kallade Stockholmsstudien, Stock- obesitas. gett mig så mycket, bland annat holms diabetespreventiva program Under arbetet med studien blev många internationella kontakter. (SDPP), som Claes-Göran ledde. Claes-Göran chef för Karolinska 2010 var jag till exempel en av ar- I studien ingick 8 000 personer sjukhusets diabetespreventiva en- rangörerna till en stor europeisk i åldrarna 35–56 år, utspridda i het och totalt har han och hans diabeteskongress på Stockholms- fem kommuner i Storstockholm. kollegor publicerat 80-90 veten- mässan med 18 000 deltagare från När den drogs igång i början på skapliga artiklar baserade på pro- hela världen. Jag har aldrig haft 90-talet var det en av de största i jektet. Ett 15-tal personer har även någon tanke på att jag skulle vil- sitt slag, även internationellt sett, använt studien i sina doktorsav- ja jobba med något annat, säger och den första som visade att så- handlingar och Claes-Göran har Claes-Göran och tillägger: väl kafedrickande som minskad varit handledare till merparten. – Det är ju så när man håller stress och ett stort socialt nätverk Nyligen avslutades även en 20-års- på med forskning: man blir aldrig minskar riskerna för sjukdomen. uppföljning av deltagarna i SDPP. färdig. Man har alltid sökarljuset Cirka tio år efter starten gjordes – Det har varit jättespännande på och känner ett driv. en uppföljning av drygt 70 procent att gå från cell- till samhällsnivå. Hur har det funkat att kombinera av deltagarna. För Claes-Göran Uppgiften som forskare, att föra ut karriär med familjeliv? innebar arbetet med Stockholms- sin kunskap i samhället, tycker jag – Jag har ju jobbat mycket ge- studien en ny värld. Plötsligt hade är oerhört viktig. nom åren men om du frågar mina han medarbetare som var allt från två döttrar så tror jag inte att de gymnastikdirektörer och dietister Cellnivån har Claes-Göran fått har tyckt att det har varit så pestigt till tränare på Friskis & Svettis uppleva i laboratoriet på KI. Se- med en pappa som har varit läka- och chefer för restauranger och dan han började forska har han re – de är själva doktorer och fors- livsmedelsbutiker. Han var regel- varit engagerad i att hitta nya lä- kare idag. Det ser jag som ett gott bundet ute på informationsmöten kemedel mot typ 2-diabetes – en tecken, som att det jag har hållit där han träfade projektledarna i resa som pågår än. På 90-talet i på med måste ha verkat ganska kul respektive kommun. Där pratade Vietnam började han titta på in- – även om det förstås ibland har han om diabetes och varför det hemska växter som har använts för tagit tid från familjen. var viktigt att alla hjälpte till – att att lindra diabetes i över 2 000 år. Claes-Görans plan är att fort- matbutiker frontade grönsaker och Claes-Göran har haft lera dokto- sätta inom diabetesfältet på en restauranger erbjöd nyttig mat. rander, bland annat i Bolivia och regulatorisk nivå och med forsk- – Tyvärr såg vi inte någon efekt Malaysia, som har forskat på att ningen. Drömmen är att få hålla av arbetet som mer generellt upp- hitta den efektiva substansen i på så länge han får och orkar. Men lyste invånarna om vikten av att lokala naturläkemedel och försöka han ser också fram emot att till- motionera och äta rätt. De studier framställa den syntetiskt. Kliniska bringa ännu mer tid med sina tre vi har gjort där en mindre grupp studier har genomförts i Vietnam barnbarn – dem träfar han och personer i riskzonen för att få dia- och lera experiment har gjorts på hämtar på dagis så ofta han kan. betes erbjöds hjälp som personliga den koloni av råttor med spontan – Barnbarnen är en jätterolig tränare och dietister, har däremot typ 2-diabetes som Claes-Göran del av mitt nya liv. När jag är med gett efekt. Slutsatsen är att om tog hem till KI från Japan för snart dem minns jag roliga detaljer från man ska rekommendera preven- 30 år sedan. mina egna barns uppväxt, men tion så bör det vara på individnivå. – Utländska växtextrakt får slipper känna något ansvar för Hur kändes det att projektet inte man inte testa hur som helst i Sve- uppfostran. gav de efekter som du kanske hade rige, och att ta fram nya läkemedel hoppats på? är komplicerat, tidskrävande och Louise Fauvette –Även om det först blev en be- dyrt – det kan kosta miljarder. Frilansjournalist svikelse var det ju viktigt att få Naturligtvis vill alla forskare hitta På uppdrag för DiabetologNytt erfarenheten. Syftet var att koppla nya mediciner och jag hoppas att ihop socialmedicin med endokri- vi kommer lyckas. Jag har en dok-

156 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Forskare cyklar 250 mil, för bättre fothälsa vid diabetes

En reseberättelse

Med avhandlingen i cykelväs- kan gav jag mig, Ulla Hellstrand Tang, ut på Hoj17 för att full- göra högskolans tredje uppgift, att föra ut forskningsresultat för diskussion i samhället. Hoj17 är en klimatsmart aktion för bättre fothälsa organiserat av Göteborgs Diabetesförening. Under den 250 mil långa cykelturen arrangera- de diabetesföreningarna runt om i landet, från Jonsered i väst till Jokkmokk i norr, fotmöten för att diskutera varför det är så stora regionala skillnader i prevention och behandling av fotkomplikation vid diabetes. Politiker och vårdprofes- sion uppmanades att tillsammans med patientorganisationerna sam- Vid inalen av Hoj17 på Jonsereds Herrgård medverkade, från vänster, Stefan las kring en gemensam strategi för Hellstrand, Tekn. Dr.; Fredrik Löndahl, ordf. i Diabetesförbundet; Kent Olaisson, ordf. i Diabetesföreningen i VGR; Leif Sundberg, patientrepresentant, Cafégruppen; Conny minskade fotskador. Jalkegård, Erimed; Mirjana Vidicek, medicinsk fotterapeut i VGR; Christel Dahlström, Initiativet till Hoj17 togs den medicinsk fotterapeut, medicinmottagningen, Mölndals sjukhus, Sahlgrenska 16 april 2016 av mig, Monica Universitetssjukhuset; Margareta Jonsson, medicinsk fotterapeut i VGR; Ninni Jonsson, Ullbrandt, och Birgitta Kihlberg, Cinnamon samt Ulla Hellstrand Tang, Med. Dr. och leg. ortopedingenjör, Ortopedtek- nik, Sahlgrenska Universitetssjukhuset. båda aktiva i diabetesrörelsen. Från patientorganisationerna for- mulerades uppropet för Hoj17, adekvat prevention och vård för regionala skillnader i andelen am- nämligen ”Kolla min fot”. Kravet att främja god fothälsa som för- putationer vid diabetes2. Från Na- är i enlighet med Socialstyrelsens hindrar fotsår och amputation1. tionella Diabetesregistret presen- rekommendationer att alla perso- Flera källor pekar mot att vården teras att det beror på var i landet ner med diabetets bör fotunder- är ojämlik. Jämförelser från So- man bor ifall man som diabetiker sökas, riskgraderas och erbjudas cialstyrelsen visar att det är stora får sina fötter fotundersökta eller inte3. I Västra Götalandsregionen (VGR) inns skillnader i vilken Faktaruta utsträckning personer med typ 2 Ulla Hellstrand Tang, disputerade den 30 mars med avhandlingen ”The Diabetic diabetes remitteras till fotvård4. Foot – assessment and assistive devices” vid Institutionen för Kliniska vetenskaper, Avdelning för Ortopedi [4]. I avhandlingen föreslås ett strukturerat sätt att undersöka fötterna vid diabetes med hjälp av checklistan i webprogrammet Förberedelser D-Foot. Vidare framkommer att enklare prefabricerade inlägg kan användas Förberedelserna satte igång under för prevention av fotsår. Forskningsresultaten testas nu i klinisk vardag på Ullas sommaren 2016. Rutten plane- arbetesplats, Ortopedteknik, Område 3, Sahlgrenska Universitetssjukhuset. Hoj17 (www.hoj17.se) ick stöd av Diabetesförbundet, VGR och privata aktörer rades på cykelvänliga vägar med inom ortopedteknik och sårvård. hjälp av cykelkartor. Cykel, cykelvagn, packväskor, tält, sovsäck, www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 157 förening och fotterapeuter bokade in mötestid med politiker. Syftet var att till hösten diskutera strate- gier för bättre prevention och vård av fotkomplikation vid diabetes i Östergötland. Tre veckor efter starten cykla- de jag in till mötet i Stockholm. Politiker, patientföreträdare och vårdprofessionen bestämde att till hösten 2017 samlas för att diskutera vilka regionala fotproblem som Stockholm har att lösa. Färre fot- Vid paneldebatten i Jonsered deltog sjukhusdirektör Agnetha Folestad, Lundby sår, färre amputationer och bättre Capio Närsjukhus; Christel Dahlström, medicinsk fotterapeut, medicinmottagningen, Mölndals sjukhus, Sahlgrenska Universitetssjukhuset; Susanne Asteberg, sårsköterska, livskvalitet för personer med dia- ortopedmottagningen, Mölndals sjukhus, Sahlgrenska Universitetssjukhuset; Fredrik betes sattes upp som långsiktigt Löndahl, ordf. i Diabetesförbundet; Kent Olaisson, ordf. i Diabetesföreningen VGR; mål. Pär Samuelsson, Nationella Diabetesregistret; Ulla Hellstrand Tang, Med. Dr. och leg. På väg norrut sker möten i ortopedingenjör, Ortopedteknik, Sahlgrenska Universitetssjukhuset; Stefan Hellstrand, Västmanland, Hälsningland och Tekn. Dr. samt Leif Sundberg, Cafégruppen. Västernorrland. Efter nio veckors cykling kommer jag till mötet i gasolkök införskafades och verk- mötet med önskan att till hösten Piteå. Där krokar diabetesförbun- tygslådan gjordes iordning. Forsk- 2017 sitta ner vid samma bord som dets representant arm med fotte- ningsenkäter sammanställdes. I politiker för att lägga en plan för rapeuter och lokalföreningen för enkäterna fanns frågor om huruvi- minskade amputationer i VGR. att tillsammans verka för att alla da fotundersökning, fotvård, ort- Avsikten är att i gemensam aktion personer med diabetes ska fotun- opedtekniska hjälpmedel och vård verka för en fotsjukvård i topp- dersökas årligen, enhetligt en i multidisciplinära fotteam erbjuds klass, med och för patienten. förbestämd god struktur. Fötter vid diabetes. Aktiviteter pågick Men låt oss nu börja från bör- i riskzonen bör remitteras vidare runt om i landet. Lokalförening- jan. Den 29 april gick startskottet för åtgärder (ortopedteknik och arna bokade plats för möten, bjöd för Hoj17 från Jonsereds Herrgård specialistvård). in politiker och press, ordnade cy- under hejarop och salut. Sjukhus- På väg till mötet i Jokkmokk kelkortege och fotkontroller samt direktör Agnetha Folestad, Capio passerar jag det imponerande vat- spred information om fotmötena. Lundby Närsjukhus, lyckönskade tenfallet i Storforsen och Polcir- mig på färden mot Norrköpin. keln. Lappland imponerar. Debatt och möten I Jokkmokk samlades fot- Den 30 juli 2017, efter 90 dagar Strålande resultat terapeuter, representanter från och 250 underbara mil på cykel Det första mötet, i Norrköping Diabetesföreningen Jokkmokks- når jag målet, Jonsereds Herrgård. den 12 maj var framgångsrikt. Di- bygden med omnejd, Diabe- Vid inalen la Göteborgs Diabetes- abetesförbundets direktör Cecilia tesförbundet och Hoj17 för att förening upp fotfrågan på bordet. Gomez, Östergötlands Diabetes- tillsammans med politiker jobba Kalla fakta om den ojämlika fot- sjukvården för personer med diabetes i Västra Götalandsregionen presenterades. I paneldebatten gavs handfasta förslag till hur VGR kan halvera antalet fotsår och amputationer. Patientrepresentant Leif Sundberg berättade hur värdefullt det är att ha en fot fri från fotsår. Positivt utfall, i ekologiska, ekono- miska och sociala termer, vid en halvering av amputationer presenterades av Tekn. Dr. Stefan Hell- strand. Arrangörerna avslutade Ulla eskorterades till torgmötet i Norrköping.

158 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Polcirkeln passeras. Cykelturen gick från Jonsered i väster till Jokkmokk i norr. I åtta regioner ordnade lokala diabetesföreningar 13 debattmöten. för en bättre prevention och vård platser. Åsynen av björnspåret i kuterats i nio regioner. Tretton av fotkomplikation vid diabetes i granskogen ick min puls att öka. möten har arrangerats. Kravet på Norrbotten. Den röda älgkalven i björksnåret fotundersökningar för alla med var förtjusande. diabetes och insatser för de med Naturliv riskfot ick stor uppmärksamhet Trettionio nätter somnade och Resan söderut i media. Hoj17 renderade inslag vaknade jag till naturens ljud i Cykel, cykelvagn och tio packväs- i TV nyheter, fyra sändningar i mitt tält. Tranor, orrar, enkelbeck- kor färdades exotiskt på Inlands- lokalradio, 15 tidningsartiklar asiner och brölande råbockar gav banan söderut från Jokkmokk till och ick tusentals läsare i de so- krydda åt naturlivet. Det blev so- Värmland. Vid mötet i Kil presen- ciala medierna. Tvärprofessio- liga frukoststunder vid blänkande terades Värmlandsmodellen av di- nella nätverk för samverkan har vatten och annorlunda middags- abetesfotkoordinator Marie Bejmo. skapats. Patientorganisationerna, Hon fängslade publiken när hon fotterapeuter, ortopedingenjörer, berättade om ett 17 års arbete för fysioterapeuter, läkare, sjukskö- att halvera antalet amputationer i terskor har blivit inspirerade att länet. Tekn. Dr. Stefan Hellstrand tillsammans med politiker gå till visade värdet av en hållbar hälso- handling för bättre prevention och och sjukvårdssatsning, att minska vård av fotkomplikation vid diabe- antalet fotsår och amputationer. tes. Landsting som redan gjort en Efter 13 veckor på cykel når jag framgångsresa, att halvera antalet VGR och deltar i tvärprofessionel- amputationer, står med öppna ar- la möten i Uddevalla, Stenung- mar för att ta emot delegationer sund och Jonsered. Patienter gav från andra delar av landet. Här värdefulla berättelser, bl. a. om fö- kan nämnas Södermanland och rekomst av fotsår som ej behand- Värmland som kan visa föredöm- lats multidisciplinärt. liga till följd av decennier av strukturerat förbättringsarbete. Mission completed Under Hoj17, ett unikt klimats- Ulla Hellstrand Tang Lyckat fotmöte på Hotell Jokkmok mart projekt, har fothälsan dis- För DiabetologNytt

Referenser 1. Socialstyrelsen, Nationella riktlinjer för diabetesvård 2015. 2. Socialstyrelsen, Nationella riktlinjer - Utvärdering 2015. Indikatorer och underlag för bedömningar. 2015. 3. NDR, Nationella Diabetesregistret. Årsrapport. 2014 års resultat. 2015. 4. Hellstrand Tang, U., The Diabetic Foot - assessment and assistive devices. 2017. https://gupea.ub.gu.se/handle/2077/50860 www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 159 Sett & Hört

Gemensamt ansvar att svensk diabetesvård är av yttersta världsklass, då det gäller diabeteshjälpmedel. Debattinlägg. Alltsedan möjligheten att behand- Teknikutvecklingen har förbätt- På samma sätt behöver även den la personer med diabetes med in- rat diabetesvården och ger hopp mest erfarna person med diabetes sulin tillkom har vården och red- om ytterligare förbättringar inom ha tillgång till säkra hjälpmedel skapen för behandling utvecklats en snar framtid. Förbättringar av för att genomföra insulinbehand- avsevärt. Utvecklingen har skett tekniska hjälpmedel kan göras av lingen. Här behöver regelverk och i samarbete mellan vårdprofessio- många olika aktörer, vanligast är myndighetsfunktioner utvecklas ner, forskare, personer med dia- den kommersiella industrin men för att passa in i dagens snabba betes, anhöriga, vårdorganisatörer utvecklingen kan också drivas av teknikutveckling. När dagens re- och industri. Därför uppfattar andra såsom akademi eller använ- gelverk skrevs hade nog ingen trott vi att Sarkadi med lera i Dagens dare. Kraven på produkten måste att insulinpumpar skulle kunna Medicin försöker slå in öppna dör- dock vara desamma oavsett vem programmeras om. Vem bär an- rar när de skriver att vården behö- som utvecklar den. Därför inns svaret för att förhindra en olycka ver samskapas med personer med krav på CE-märkning och god- innan den sker? Den relevanta frå- diabetes. kännande av tillsynsmyndigheter. gan är inte om något barn ännu Beslutsfattarna, i form av regering, kommit till skada genom obehö- Som läkare i diabetesvården vet vi riksdag och myndigheter, har givit riga ingrepp i medicinteknisk ut- att företrädare för personer med vårdprofessionerna ansvaret att se rustning, utan hur vi ska förhindra diabetes, oftast representerade av till att vården bedrivs i enlighet att det sker. Diabetesförbundet, är en viktig med vetenskap och beprövad erfa- del i utformandet av diabetes- renhet. Vi har ett gemensamt ansvar att vården. Diabetesförbundet är en se till att svensk diabetesvård är självklar del av paraplyorganisa- Som förskrivare av hjälpmedel är av yttersta världsklass och att per- tionen Nationella diabetesteamet. vi ansvariga för att användaren får soner med diabetes i Sverige har Vården genomförs i samråd med säkra och välfungerande hjälpme- tillgång till moderna, säkra och personen med diabetes och, hos del samt att användaren har fått välfungerande hjälpmedel på jäm- barn med diabetes, i samråd också utbildning i och kunskap om hur lik basis. Tillsammans behöver med barnets familj. Vad som pas- dessa ska användas på ett säkert vi fortsätta arbetet med att skapa sar en familj är inte alltid bra för och ändamålsenligt sätt. Därför största möjliga nytta med tillgäng- en annan. vände vi barndiabetesläkare oss till liga godkända hjälpmedel. Läkemedelsverket och Inspektio- Det går inte att säga att vissa fa- nen för vård och omsorg och bad Skriven av: Frida Sundberg, Anna miljers lösningar är mer spetsbe- om råd för hur vi skulle förhålla Olivecrona och David Nathanson. tonade än andras då varje person oss till att anhöriga modiierar in- Från www.dagensmedicin.se är expert på sitt eget liv, och värd sulinpumpar, i synnerhet då pum- att respektera utifrån sitt enskilda panvändaren är ett barn som inte Nyhetsinfo 3 augusti 2017 val. Därför ser vi att den av Ek- på egen hand kan förväntas göra www red DiabetologNytt holm med lera lanserade titeln en riskanalys. ”spetspatienter” avviker från vår- dens humanistiska ideal och mo- En jämförelse kan göras med bilar. dern vårdideologi som baseras på Även en extremt duktig bilförare individualiserad vård, se Dagens är beroende av att kunna förlita Medicin. sig på att gas, broms, ratt och sä- kerhetsbälte fungerar som de ska.

160 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se NDRs expert Staffan Björck går emot Socialstyrelsen. T2D patienter ska ha bättre målblodtryck. Nu! Enligt Stafan Björck visar data från diabetesregistret även att patienter med typ 2-diabetes som går på specialistkliniker har bättre tryck än de som går i primärvården - och då går det bättre.

Socialstyrelsen är ute på tunn is efter 2008. Socialstyrelsen borde skriver och resonerat i relation till när den inte tar hänsyn till aktuell ha samlat expertis och värderat ny blodtryckssänkning i de nationella forskning kring blodtrycksgränser forskning, säger han. riktlinjerna för diabetesvård. Hör i de nationella riktlinjerna, anser Enligt Socialstyrelsen inns såklart av dig om du har ytterliga- kritiker, skriver Jens Key www.da- det dock inget i riktlinjerna som re frågor eller synpunkter. gensmedicin.se hindrar den behandlande läkaren – Det är rätt häftigt att säga att att sätta upp individuella blod- 1. Vi har i de nationella riktlinjerna man inte rekommenderar patien- trycksmål för sina patienter. för diabetesvård inga rekommen- ter med diabetes att ha normalt Antyder inte din kritik att dationer som säger vilket blod- blodtryck längre. Det ett stort den behandlande läkaren inte trycksmål som ska uppnås. Våra experiment med en halv miljon är tillräckligt insatt? Det är ju riktlinjer har i stor del ett styr- och människor som har diabetes, säger ändå den personen som har ledningsperspektiv och är inte ut- läkaren Stafan Björck, docent i behandlingsansvaret. formade att ge rekommendationer njurmedicin vid Sahlgrenska aka- – Jo, men vi har 1 200 vårdcen- om exempelvis blodtrycksmål uti- demien, Göteborgs universitet, till traler som alla behandlar typ 2 di- från olika förutsättningar. Dagens Medicin. abetes - och som dessutom har en a. Det vi säger i våra rekom- Fram till för några år sedan oändlig massa andra krämpor att mendationer är att blodtrycks- fanns normalt blodtryck som tyd- ta hand om. Så de vill ha robusta sänkande behandling av personer ligt målvärde i Socialstyrelsens rikt- riktlinjer. De håller sig vid de rät- med diabetes och högt blodtryck linjer för diabetsvården. Men kring tesnören som inns, det är inte lätt, har hög prioritet/angelägenhet- 2010-2011 började myndigheten säger Stafan Björck. sgrad (se utdrag ur tillstånd- och ändra uppfattning och 2015 för- Han förklarar att den tjocka åtgärdslistan nedan). svann det ur riktlinjerna, berättar lunta som utgör de nationella han. Samtidigt avstannade den för- riktlinjerna inte är något som lätt 2. I det vetenskapliga underlaget bättring av blodtrycket för patien- stoppas i ickan för att sedan an- skriver vi dock om behandlings- ter med diabetes som kunnat följas vändas i den kliniska vardagen. mål generellt inom diabetesvården i det nationella diabetesregistret se- Det som läkarna kommer ihåg är (se länk nedan). Huvudbudskapet dan starten. Något Stafan Björck de indikatorer som inns. Och i där är individanpassning utifrån anser har ett tydligt samband. riktlinjerna inns blodtrycksmålet olika förutsättningar. Vårat reso- – Ja rimligen. Det kom signaler 140/85 mm Hg angivet som even- nemang där skrevs inför publice- om att blodtrycksrekommenda- tuellt behandlingsmål. ringen 2015 och bygger på referen- tion skulle höjas runt 2010-2011 – Så riktlinjerna blir styrande ser från 2015. Jag har även stämt och det är där vi ser ett trendbrott. ändå. Det är inte det instilta som av de referenserna med senare ut- I jol publicerade Brittish Med- läses. givna internationella konsensus- ical Journal Stafan Björcks stora Han har fört fram sin kritik till dokument. Bedömning är att de studie över alla personer i diabetes- Socialstyrelsen men svaret är att är överensstämmande med hur vi registret. Den visade på ett linjärt riktlinjerna ligger fast. uttrycker oss. Ett utdrag (se länk samband mellan ökat blodtryck – Så det är skrivet i stjärnorna till fullständigt dokument längre och ökad risk för hjärt- kärlsjuk- när man tittar på detta igen. ner): domar. Stafan Björck hoppades att resultat skulle göra att Soci- http://www.bmj.com/content/354/ ”Ett riktvärde för behandlingsmål alstyrelsen ändrade uppfattning bmj.i4070 när det gäller blodtryck kan vara när myndigheten i år publicerade under 140/85 mm Hg. Målet bör nya riktlinjer. Men förhoppningen FRÅN SOCIALSTYRELSEN utformas utifrån en individuell be- kom på skam. dömning av nytta och risk. Lägre – Därför blir jag mycket be- Hej Stafan, blodtrycksmål kan övervägas för sviken när uppdaterade riktlinjer Jag har fått din fråga vidarebeford- unga patienter och för patienter inte har tagit hänsyn till litteratur rad och ska försöka klargöra hur vi med förhöjd albuminutsöndring ▶

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 161 i urinen (makroalbuminuri), eller Vi är medvetna om att nya som utgör uppdatering av se- förhöjd kardiovaskulär risk - för- ESH/ESC guidelines kommer naste och bästa vetenskapliga utsatt att behandlingen kan ges 2018 och att det inns de som ar- dokumentationen. utan besvär för patienten.” gumenterar för sänkta målvärden ... att patienter med typ 2 dia- Vilket får anses vara överens- på basen av SPRINT. Där fanns betes kan ha målblodtryck 130/80 stämmande med vad man ifrån ex ju dock inte diabetiker med varför för individer med hög kardio- ADA skriver 2017: betydelsen för utformning av dia- vaskulär risk, yngre patienter och …Most patients with diabetes betes-guidelines är osäker. Vi följer patienter med begynnande njurpå- and hypertension should be tre- såklart utvecklingen kontinuerligt verkan i form av mikroalbuminu- ated to a systolic blood pressure i vår förvaltning av riktlinjerna ri - och patienter som klarar detta goal of 140 mmHg and a diastolic och gör vid behov uppdateringar. målblodtryck utan biverkningar. blood pressure goal of 90 mmHg. I nuläget inns dock ingen plan att ... att patienter med typ 1 dia- A Lower systolic and diastolic ändra våra skrivningar angående betes har som tidigare målblod- blood pressure targets, such as behandlingsmål. tryck 130/80. 130/80 mmHg, may be appropriate for individuals at high risk of Kommentar Nyhetsinfo 1 augusti 2017 cardiovascular disease, if they can I avvaktan på Framtiden förefaller www red DiabetologNytt be achieved without undue treat- det rimligt ment burden...... att Sverige följer ADA 2017, Se också sid 249.

New ADA/AADE Standards Combine Diabetes Education. Diab Care The American Diabetes Association and the American Association of Diabetes Educators have combined the concepts of diabetes self-ma- While the standards deine nagement education and support for the irst time in their updated evidence-based DSMES services that meet or exceed Medicare’s guidelines published in Diabetes Care and the Diabetes Educator. diabetes self-management training Diabetes self-management separately. (DSMT) regulations, they don’t education (DSME) Today, the view is that ”dia- actually guarantee reimbursement. he document outlines 10 speciic betes self-management education ”he hope is that payers will view standards for DSMES programs, and support (DSMES) is a critical these standards as a tool for re- including individualization, qu- element of care for all people with viewing DSMES reimbursement ality improvement, evaluation of diabetes and those at risk for de- requirements and consider change population served, participant veloping the condition,” write task to align with the way their bene- progress and ongoing support force cochairs and certiied diabe- iciaries’ engagement preferences New recommendations from the tes educators Joni Beck, PharmD, have evolved,” the authors say. American Diabetes Association and Deborah A Greenwood, PhD, Currently, less than 5% of (ADA) and American Association RN, and colleagues. Medicare beneiciaries use the DS- of Diabetes Educators (AADE) DSMES is the ongoing pro- MES beneits that are covered. combine the concepts of diabetes cess of facilitating the knowledge, he standards apply to diabetes self-management education and skills, and ability necessary for educators in a variety of settings support for the irst time. prediabetes and diabetes self-ca- and within new and emerging mo- he document, published onli- re, as well as activities that assist dels of care, such as virtual visits, ne July 28 in both Diabetes Care a person in implementing and sus- accountable care organizations, and the Diabetes Educator, is an taining the behaviors needed to patient-centered medical homes, update from 2014, when guideli- manage his or her condition on an and value-based payment models. nes for diabetes self-management ongoing basis, beyond or outside hese same DSMES standards support and diabetes self-manage- of formal self-management trai- are used both for ADA recognition ment education had been outlined ning,” they explain. and AADE accreditation and also

162 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se can serve as a guide for nonaccre- Article every 5 years by key stakeholders dited and nonrecognized diabetes http://care.diabetesjournals.org/ and experts within the diabetes education providers. content/35/11/2393 education community. In the fall Although there is overlap of 2011, a Task Force was jointly between DSMES services and tho- By the most recent estimates, 18.8 convened by the American As- se of the National Diabetes Pre- million people in the U.S. have sociation of Diabetes Educators vention Program (National DPP) been diagnosed with diabetes and (AADE) and the American Diabe- lifestyle-change program, the two an additional 7 million are believed tes Association (ADA). Members are tailored to diferent audiences to be living with undiagnosed di- of the Task Force included experts (diabetes vs prediabetes) and have abetes. At the same time, 79 mil- from the areas of public health, diferent goals (diabetes manage- lion people are estimated to have underserved populations including ment vs prevention). Recognition blood glucose levels in the range of rural primary care and other rural of DPP programs is handled by the prediabetes or categories of incre- health services, individual practi- US Centers for Disease Control ased risk for diabetes. hus, more ces, large urban specialty practices, and Prevention. Centers providing than 100 million Americans are at and urban hospitals. hey also in- both types of services have been risk for developing the devastating cluded individuals with diabetes, shown successful, but they need to complications of diabetes (1). diabetes researchers, certiied dia- meet both sets of standards. Diabetes self-management educa- betes educators, registered nurses, he new document details 10 tion (DSME) is a critical element registered dietitians, physicians, speciic standards for DSMES of care for all people with diabetes pharmacists, and a psychologist. programs: internal structure, sta- and those at risk for developing the he Task Force was charged with keholder input, evaluation of po- disease. It is necessary in order to reviewing the current National pulation served, quality coordina- prevent or delay the complications Standards for Diabetes Self-Mana- tor overseeing DSMES services, of diabetes (2–6) and has elements gement Education for their appro- the DSMES team, curriculum, in- related to lifestyle changes that are priateness, relevance, and scientiic dividualization, ongoing support, also essential for individuals with basis and updating them based on participant progress, and quality prediabetes as part of eforts to pre- the available evidence and expert improvement. vent the disease (7,8). he National consensus. While previous standards have Standards for Diabetes Self-Mana- he Task Force made the de- used the term ”program,” the gement Education are designed to cision to change the name of the current terminology is ”services,” deine quality DSME and support Standards from the National Stan- which ”more clearly delineates the and to assist diabetes educators dards for Diabetes Self-Manage- need to individualize and identify in providing evidence-based edu- ment Education to the National the elements of DSMES appropri- cation and self-management sup- Standards for Diabetes Self-Ma- ate for an individual. port. he Standards are applicable nagement Education and Support. his revision encourages provi- to educators in solo practice as well his name change is intended to ders of DSMES to embrace a cont- as those in large multicenter pro- codify the signiicance of ongoing emporary view of the new com- grams—and everyone in between. support for people with diabetes plexities of the evolving healthcare here are many good models for and those at risk for developing the landscape,” the authors write. the provision of diabetes education disease, particularly to encourage Expect the next revision soo- and support. he Standards do behavior change, the maintenance ner than 3 years from now, they not endorse any one approach, but of healthy diabetes-related beha- say. ”Given the rapidly changing rather seek to delineate the com- viors, and to address psychosocial healthcare environment and the monalities among efective and ex- concerns. Given that self-mana- ever-growing ield of technology, cellent self-management education gement does not stop when a pa- the 2017 Standards Revision Task strategies. hese are the standards tient leaves the educator’s oice, Force recognizes the potential need used in the ield for recognition self-management support must be to review the literature for eviden- and accreditation. hey also serve an ongoing process. ce-driven updates more frequently as a guide for nonaccredited and Although the term “diabetes” in the future as advances in healt- nonrecognized providers and pro- is used predominantly, the Stan- hcare delivery are evolving.” grams. dards should also be understood Because of the dynamic nature to apply to the education and sup- Diabetes Care. Published online of health care and diabetes-rela- port of people with prediabetes. July 28, 2017. ted research, the Standards are re- Currently, there are signiicant From www.medscape.com viewed and revised approximately barriers to the provision of edu- ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 163 cation and support to those with pant’s health care teams is essenti- DEFINITIONS prediabetes. And yet, the stra- al to ensure high-quality, efective DSME. tegies for supporting successful education and support for people he ongoing process of facilitating behavior change and the healthy with diabetes and prediabetes. the knowledge, skill, and ability behaviors recommended for pe- In the course of its work on necessary for prediabetes and dia- ople with prediabetes are largely the Standards, the Task Force betes self-care. his process incor- identical to those for individuals identiied areas in which there is porates the needs, goals, and life with diabetes. As barriers to care currently an insuicient amount experiences of the person with di- are overcome, providers of DSME of research. In particular, there abetes or prediabetes and is guided and diabetes self-management are three areas in which the Task by evidence-based standards. he support (DSMS), given their Force recommends additional overall objectives of DSME are training and experience, are par- research: to support informed decision ma- ticularly well equipped to assist king, self-care behaviors, problem individuals with prediabetes in 1. What is the inluence of orga- solving, and active collaboration developing and maintaining be- nizational structure on the ef- with the health care team and to haviors that can prevent or delay fectiveness of the provision of improve clinical outcomes, health the onset of diabetes. DSME and DSMS? status, and quality of life. Many people with diabetes 2. What is the impact of using have or are at risk for developing a structured curriculum in DSMS. comorbidities, including both di- DSME? Activities that assist the person abetes-related complications and 3. What training should be requi- with prediabetes or diabetes in conditions (e.g., heart disease, li- red for those community, lay, or implementing and sustaining the pid abnormalities, nerve damage, peer workers without training behaviors needed to manage his hypertension, and depression) and in health or diabetes who are to or her condition on an ongoing other medical problems that may participate in the provision of basis beyond or outside of formal interfere with self-care (e.g., emp- DSME and to provide DSMS? self-management training. he hysema, arthritis, and alcoholism). type of support provided can be In addition, the diagnosis, pro- Finally, the Standards emphasize behavioral, educational, psychoso- gression, and daily work of mana- that the person with diabetes is cial, or clinical (11–15). ging the disease can take a major at the center of the entire diabetes emotional toll on people with di- education and support process. It STANDARD 1 abetes that makes self-care even is the individuals with diabetes Internal structure more diicult (9). he Standards who do the hard work of mana- he provider(s) of DSME will do- encourage providers of DSME and ging their condition, day in and cument an organizational structu- DSMS to address the entire pano- day out. he educator’s role, irst re, mission statement, and go- rama of each participant’s clinical and foremost, is to make that work als. For those providers working proile. Regular communication easier (10). within a larger organization, that among the members of partici- organization will recognize and support quality DSME as an integral component of diabetes care. Documentation of an organizational structure, mission statement, and goals can lead to eicient and efective provision of DSME and DSMS. In the business literature, case studies and case report investigations of successful management strategies emphasize the importance of clear goals and objectives, deined relationships and roles, and managerial support. Business and health policy experts and organizations emphasize written commitments, policies, support, and the importance of

164 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se outcomes reporting to maintain discussion in the program plan- age, as well as levels of formal ongoing support or commitment ning process is to foster ideas education, literacy, and nume- (16,17). that will enhance the quality of racy (28–31). It may also entail Documentation of an organi- the DSME and/or DSMS being identifying resources outside of zational structure that delineates provided, while building bridges the provider’s practice that can channels of communication and to key stakeholders (19). he re- assist in the ongoing support of represents institutional commit- sult is efective, dynamic DSME the participant. ment to the educational entity is that is patient centered, more re- • Identifying access issues and critical for success. According to sponsive to consumer-identiied working to overcome them. It he Joint Commission, this type needs and the needs of the com- is essential to determine factors of documentation is equally im- munity, more culturally relevant, that prevent individuals with portant for both small and large and more appealing to consumers diabetes from receiving self-ma- health care organizations (18). (17,19,20). nagement education and sup- Health care and business experts port. he assessment process overwhelmingly agree that do- STANDARD 3 includes the identiication of cumentation of the process of pro- Access these barriers to access (32–34). viding services is a critical factor he provider(s) of DSME will de- hese barriers may include in clear communication and pro- termine who to serve, how best to the socioeconomic or cultural vides a solid basis from which to deliver diabetes education to that factors mentioned above, as well deliver quality diabetes education. population, and what resources as, for example, health insuran- In 2010, he Joint Commission can provide ongoing support for ce shortfalls and the lack of en- published the Disease-Speciic that population. couragement from other health Care Certiication Manual, which Currently, the majority of people providers to seek diabetes edu- outlines standards and perfor- with diabetes and prediabetes do cation (35,36). mance measurements for chronic not receive any structured diabetes care programs and disease mana- education (19,20). While there are STANDARD 4 gement services, including “Sup- many barriers to DSME, one cru- Program coordination porting Self-Management” (18). cial issue is access (21). Providers A coordinator will be designated of DSME can help address this to oversee the DSME program. STANDARD 2 issue by: he coordinator will have over- External input sight responsibility for the plan- he provider(s) of DSME will seek • Clarifying the speciic popula- ning, implementation, and evalu- ongoing input from external sta- tion to be served. Understan- ation of education services. keholders and experts in order to ding the community, service Coordination is essential to en- promote program quality. area, or regional demographics sure that quality diabetes self-ma- For both individual and group is crucial to ensuring that as nagement education and support providers of DSME and DSMS, many people as possible are be- is delivered through an organized, external input is vital to maintai- ing reached, including those systematic process (37,38). As the ning an up-to-date, efective pro- who do not frequently attend ield of DSME continues to evol- gram. Broad participation of com- clinical appointments (9,17,22– ve, the coordinator plays a pivotal munity stakeholders, including 24). role in ensuring accountability individuals with diabetes, health • Determining that population’s and continuity in the education professionals, and community self-management education and program (39–41). he coordina- interest groups, will increase the support needs. Diferent indivi- tor’s role may be viewed as that program’s knowledge of the local duals, their families, and com- of coordinating the program (or population and allow the provider munities need diferent types education process) and/or as sup- to better serve the community. of education and support (25). porting the coordination of the Often, but not always, this exter- he provider(s) of DSME and many aspects of self-management nal input is best achieved by the DSMS needs to work to ensu- in the continuum of diabetes and establishment of a formal adviso- re that the necessary education related conditions when feasible ry board. he DSME and DSMS alternatives are available (25– (42–49). his oversight includes provider(s) must have a documen- 27). his means understanding designing an education program ted plan for seeking outside input the population’s demographic or service that helps the partici- and acting on it. characteristics, such as ethnic/ pant access needed resources and he goal of external input and cultural background, sex, and assists him or her in navigating the ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 165 health care system (37,50–55). instructors on the diabetes team physicians, and physician assis- he individual serving as the (69–72). Professionals serving as tants (68,74,87). coordinator will have knowledge instructors must document app- Individuals who serve as lay of the lifelong process of mana- ropriate continuing education or health and community workers ging a chronic disease and facilita- comparable activities to ensure and peer counselors or educators ting behavior change, in addition their continuing competence to may contribute to the provision to experience with program and/ serve in their instructional, trai- of DSME instruction and provide or clinical management (56–59). ning, and oversight roles (73). DSMS if they have received trai- In some cases, particularly in solo Relecting the evolving health ning in diabetes management, the or other small practices, the coor- care environment, a number of teaching of self-management skills, dinator may also provide DSME studies have endorsed a multidis- group facilitation, and emotional and/or DSMS. ciplinary team approach to diabe- support. For these individuals, a tes care, education, and support. system must be in place that ensu- STANDARD 5 he disciplines that may be invol- res supervision of the services they Instructional staff ved include, but are not limited provide by a diabetes educator or One or more instructors will pro- to, physicians, psychologists and other health care professional and vide DSME and, when applicable, other mental health specialists, professional back-up to address cli- DSMS. At least one of the in- physical activity specialists (in- nical problems or questions beyond structors responsible for designing cluding physical therapists, occu- their training (88–90). and planning DSME and DSMS pational therapists, and exercise For services outside the experti- will be a registered nurse, registe- physiologists), optometrists, and se of any provider(s) of DSME and red dietitian, or pharmacist with podiatrists (68,74,75). DSMS, a mechanism must be in training and experience pertinent More recently, health educators place to ensure that the individu- to DSME, or another professional (e.g., Certiied Health Education al with diabetes is connected with with certiication in diabetes care Specialists and Certiied Medi- appropriately trained and creden- and education, such as a CDE or cal Assistants), case managers, lay tialed providers. BC-ADM. Other health workers health and community workers can contribute to DSME and pro- (76–83), and peer counselors or STANDARD 6 vide DSMS with appropriate trai- educators (84,85) have been shown Curriculum ning in diabetes and with supervi- to contribute efectively as part of A written curriculum relecting sion and support. the DSME team and in provi- current evidence and practice gui- Historically, nurses and dieti- ding DSMS. While DSME and delines, with criteria for evalua- tians were the main providers of DSMS are often provided within ting outcomes, will serve as the diabetes education (3,4,60–64). In the framework of a collaborative framework for the provision of recent years, the role of the diabetes and integrated team approach, it DSME. he needs of the indivi- educator has expanded to other dis- is crucial that the individual with dual participant will determine ciplines, particularly pharmacists diabetes is viewed as central to the which parts of the curriculum will (65–67). Reviews comparing the team and that he or she takes an be provided to that individual. efectiveness of diferent disciplines active role. for education have not identiied Certiication as a diabetes Individuals with prediabetes and clear diferences in the quality of educator (CDE) by the National diabetes and their families and services delivered by diferent pro- Certiication Board for Diabetes caregivers have much to learn to fessionals (3–5). However, the lite- Educators (NCBDE) is one way become efective self-managers of rature favors the registered nurse, a health professional can demon- their condition. DSME can pro- registered dietitian, and pharmacist strate mastery of a speciic body of vide this education via an up-to- serving both as the key primary in- knowledge, and this certiication date, evidence-based, and lexible structors for diabetes education and has become an accepted credential curriculum (8,91). as members of the multidisciplina- in the diabetes community (86). ry team responsible for designing An additional credential that indi- he curriculum is a coordina- the curriculum and assisting in the cates specialized training beyond ted set of courses and educatio- delivery of DSME (1–7,68). basic preparation is board certii- nal experiences. It also speciies Expert consensus supports the cation in Advanced Diabetes Ma- learning outcomes and efective need for specialized diabetes and nagement (BC-ADM) ofered by teaching strategies (92,93). he educational training beyond aca- the AADE, which is available for curriculum must be dynamic demic preparation for the primary nurses, dietitians, pharmacists, and relect current evidence and

166 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se practice guidelines (93–97). Re- cent education research endorses the inclusion of practical problem-solving approaches, collaborative care, psychosocial issues, behavior change, and strategies to sustain self-management eforts (12,13,19,74,86,98–101). he following core topics are commonly part of the curriculum taught in comprehensive programs that have demonstrated successful outcomes (2,3,5,91,102–104):

1. Describing the diabetes disease process and treatment options- Incorporating nutritional management into lifestyleIncor- the development of action-orien- to diabetes, readiness to learn, lite- porating physical activity into ted behavioral goals and objectives racy level (including health litera- lifestyle (12–14,113). Creative, patient-cen- cy and numeracy), physical limita- 2. Using medication(s) safely and tered, experience-based delivery tions, family support, and inancial for maximum therapeutic ef- methods—beyond the mere ac- status (11,106,108,117,119–128). fectivenessMonitoring blood quisition of knowledge—are ef- he education and support plan glucose and other parameters fective for supporting informed that the participant and in- and interpreting and using the decision making and meaningful structor(s) develop will be rooted results for self-management de- behavior change and addressing in evidence-based approaches to cision making psychosocial concerns (114,115). efective health communication 3. Preventing, detecting, and tre- and education while taking into ating acute complicationsPre- STANDARD 7 consideration participant bar- venting, detecting, and treating Individualization riers, abilities, and expectations. chronic complications he diabetes self-management, he instructor will use clear 4. Developing personal strategies education, and support needs of health communication principles, to address psychosocial issues each participant will be assessed avoiding jargon, making infor- and concernsDeveloping perso- by one or more instructors. he mation culturally relevant, using nal strategies to promote health participant and instructor(s) will language- and literacy-appropria- and behavior change then together develop an individu- te education materials, and using alized education and support plan interpreter services when indica- While the content areas listed focused on behavior change. ted (107,129–131). Evidence-ba- above provide a solid outline for Research has demonstrated the sed communication strategies a diabetes education and support importance of individualizing di- such as collaborative goal setting, curriculum, it is crucial that the abetes education to each partici- motivational interviewing, cog- content be tailored to match each pant’s needs (116). he assessment nitive behavior change strategies, individual’s needs and be adapted process is used to identify what problem solving, self-eicacy en- as necessary for age, type of dia- those needs are and to facilitate hancement, and relapse preven- betes (including prediabetes and the selection of appropriate edu- tion strategies are also efective diabetes in pregnancy), cultural cational and behavioral interven- (101,132–134). Periodic reassess- factors, health literacy and nume- tions and self-management sup- ment can determine whether racy, and comorbidities (14,105– port strategies, guided by evidence there is need for additional or 108). he content areas will be (2,63,116–118). he assessment diferent interventions and future able to be adapted for all practice must garner information about the reassessment (6,72,134–137). A settings. individual’s medical history, age, variety of assessment modalities, Approaches to education that are cultural inluences, health beliefs including telephone follow-up interactive and patient centered and attitudes, diabetes knowledge, and other information technolo- have been shown to be efective diabetes self-management skills gies (e.g., Web based, text messa- (12,13,109–112). Also crucial is and behaviors, emotional response ging, or automated phone calls), ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 167 may augment face-to-face assess- can improve documentation and can be behavioral, educational, ments (72,87,138–141). may ultimately improve quality of psychosocial, or clinical (11–14). he assessment and education care (135,143–145). A variety of strategies are available plan, intervention, and outcomes for providing DSMS both within will be documented in the edu- STANDARD 8 and outside the DSME organiza- cation/health record. Documen- Ongoing support tion. Some patients beneit from tation of participant encounters he participant and instructor(s) working with a nurse case mana- will guide the education process, will together develop a persona- ger (6,86,146). Case management provide evidence of communi- lized follow-up plan for ongoing for DSMS can include reminders cation among instructional staf self-management support. he about needed follow-up care and and other members of the parti- participant’s outcomes and goals tests, medication management, cipant’s health care team, prevent and the plan for ongoing self-ma- education, behavioral goal setting, duplication of services, and de- nagement support will be commu- psychosocial support, and connec- monstrate adherence to guideli- nicated to other members of the tion to community resources. nes (117,135,142,143). Providing health care team. he efectiveness of provi- information to other members of While DSME is necessary ding DSMS through disease the participant’s health care team and efective, it does not in itself management programs, trained through documentation of edu- guarantee a lifetime of efecti- peers and community health cational objectives and personal ve diabetes self-care (113). Initi- workers, community-based pro- behavioral goals increases the li- al improvements in participants’ grams, information technolo- kelihood that all the members will metabolic and other outcomes gy, ongoing education, support work in collaboration (86,143). have been found to diminish after groups, and medical nutrition Evidence suggests that the deve- approximately 6 months (3). To therapy has also been established lopment of standardized proce- sustain the level of self-manage- (7–11,86,88–90,142,147–150). dures for documentation, training ment needed to efectively manage While the primary responsibility health professionals to document prediabetes and diabetes over the for diabetes education belongs to appropriately, and the use of long term, most participants need the provider(s) of DSME, partici- structured standardized forms ba- ongoing DSMS (15). pants beneit by receiving reinfor- sed on current practice guidelines he type of support provided cement of content and behavioral goals from their entire health care team (135). Additionally, many patients receive DSMS through their primary care provider. hus, communication among the team regarding the patient’s educational outcomes, goals, and DSMS plan is essential to ensure that people with diabetes receive support that meets their needs and is reinforced and consistent among the health care team members. Because self-management takes place in participants’ daily lives and not in clinical or educational settings, patients will be assisted to formulate a plan to ind community-based resources that may support their ongoing diabetes self-management. Ideally, DSME and DSMS providers will work with participants to identify such services and, when possible, track those that have been efective with patients, while communicating with providers of community-ba-

168 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se sed resources in order to better in- and engage in self-management. he Institute for Healthcare Im- tegrate them into patients’ overall DSME providers who account provement suggests three funda- care and ongoing support. for these diferences when colla- mental questions that should be borating with participants on the answered by an improvement pro- STANDARD 9 design of personalized DSME or cess (149): Patient progress DSMS programs can improve par- he provider(s) of DSME and ticipant outcomes (147,148). • What are we trying to accom- DSMS will monitor whether par- Assessments of participant out- plish? ticipants are achieving their perso- comes must occur at appropriate • How will we know a change is nal diabetes self-management go- intervals. he interval depends on an improvement? als and other outcome(s) as a way the nature of the outcome itself • What changes can we make to evaluate the efectiveness of the and the time frame speciied based that will result in an improve- educational intervention(s), using on the participant’s personal go- ment? appropriate measurement techni- als. For some areas, the indicators, ques. measures, and time frames will be Once areas for improvement are Efective diabetes self-manage- based on guidelines from professi- identiied, the DSME provider ment can be a signiicant contri- onal organizations or government must designate timelines and im- butor to long-term, positive health agencies. portant milestones including data outcomes. he provider(s) of collection, analysis, and presen- DSME and DSMS will assess each STANDARD 10 tation of results (150). Measuring participant’s personal self-manage- Quality improvement both processes and outcomes helps ment goals and his or her progress he provider(s) of DSME will to ensure that change is success- toward those goals (151,152). measure the efectiveness of the ful without causing additional he AADE Outcome Stan- education and support and look problems in the system. Outcome dards for Diabetes Education for ways to improve any identiied measures indicate the result of a specify behavior change as the gaps in services or service quality process (i.e., whether changes are key outcome and provide a use- using a systematic review of pro- actually leading to improvement), ful framework for assessment and cess and outcome data. while process measures provide in- documentation. he AADE7 lists Diabetes education must be re- formation about what caused tho- seven essential factors: physical ac- sponsive to advances in knowled- se results (144,150). Process mea- tivity, healthy eating, taking med- ge, treatment strategies, education sures are often targeted to those ication, monitoring blood glucose, strategies, and psychosocial in- processes that typically impact the diabetes self-care–related problem terventions, as well as consumer most important outcomes. solving, reducing risks of acute trends and the changing health and chronic complications, and care environment. By measuring References psychosocial aspects of living with and monitoring both process and See 154 references on diabetes (93,153,154). Diferences outcome data on an ongoing basis, http://care.diabetesjournals.org/ in behaviors, health beliefs, and providers of DSME can identify content/35/11/2393 culture as well as their emotional areas of improvement and make response to diabetes can have a adjustments in participant engage- Nyhetsinfo 31 juli 2017 signiicant impact on how parti- ment strategies and program ofe- www red DiabetologNytt cipants understand their illness rings accordingly.

EU-kommissionen godkänner utökad indikation för Victoza (liraglutide). ”motverkar kardiovaskulära händelser vid T2DM” EU-kommissionen har godkänt vaskulära händelser som en del i tion och diet, när metformin anses utökad indikation för Novo Nord- behandlingen mot diabetes typ 2. otillräcklig isk Victoza (liraglutide) så att den Victoza är sedan tidigare god- relekterar att behandling med känt för behandling av vuxna med Nyhetsinfo 28 juli 2017 läkemedlet förbättrar blodsock- otillräckligt kontrollerad typ 2-di- www red DiabetologNytt ernivåer och motverkar kardio- abetes, som monoterapi med mo-

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 169 Managing diabetes in preschool children ISPAD Guidelines. Pediatric Diabetes. 2017;1–19. 1 | EXECUTIVE SUMMARY • For preschool children using in- preschool children may necessitate AND RECOMMENDATIONS tensive insulin therapy, preprandi- diluting insulin for precise dosing he target hemoglobin A1c al administration of bolus insulin (E). (HbA1c) for all children with type given for correction if blood glu- • Syringes with ó unit marking 1 diabetes, including preschool cose is high and for at least part and pens with at least ó unit do- children, is recommended to be of the meal is preferable to giving sing increments should be used to <7.5% (<58 mmol/mol) (B). the whole dose during or after the facilitate more accurate insulin do- meal (C). Greg Dooley is parent of sing if a pump is not used (or as a his target is chosen with the aim a child with type 1 diabetes diag- back-up to pump use) (E). of minimizing hyperglycemia, se- nosed at age 2, cofounder of the • Continuous glucose monitoring vere hypoglycemia, hypoglycemic type 1 diabetes blog Inspired by (CGM) can be helpful as an app- unawareness, and reducing the Isabella (www. inspiredbyisabella. roach to adjusting insulin doses likelihood of development of long- com); Jef Hitchcock is parent of (E). Some CGM devices are app- term complications (B). a child with diabetes diagnosed roved for this use. If CGM is not at age 2, founder and president available, 7 to 10 plasma glucose Intensive insulin therapy, i.e. as of Children with Diabetes (www. checks per day are usually needed close to physiological insulin re- childrenwithdiabetes.com) for satisfactory glucose control (E). placement as possible with pre- • Injection, infusion, and CGM prandial insulin doses and basal his article is a new chapter in the sites should be properly prepared insulin, should be used, with fre- ISPAD Clinical Practice Consen- and regularly rotated in order to quent glucose monitoring and me- sus Guidelines Compendium. he reduce the likelihood of lipohyper- al-adjusted insulin regimens. (C). complete set of guidelines can be trophy, scarring, infection, rashes, found for free download at www. skin reaction, and dry skin (E). • Insulin pump therapy is the pre- ispad.org. he evidence grading • Injection, infusion, and CGM ferred method of insulin adminis- system used in the ISPAD Gui- sites should be inspected by diabe- tration for young children (aged delines is the same as that used by tes team members at every clinic <7 years) with type 1 diabetes (E). the American Diabetes Associa- visit to detect and treat any skin If pump therapy is not available, tion. problems, such as skin reactions, multiple daily injections (MDIs), lipohypertrophy, or lipohypotrop- with consideration of use of an in- Carbohydrate counting is best in- hy (E). jection port, should be used from troduced at onset of diabetes (E). • he use of pumps and CGM are the onset of diabetes (E). • he small insulin doses of often limited by skin reactions to the adhesive. A skin moistener that preserves water can be used to prepare the site a few days prior to insertion. Topical corticosteroid (group I or II) can be used to treat skin reactions and to manage itching after removal (E).

Life style interventions designed to reduce the risk of subsequent cardiovascular disease in children with type 1 diabetes are needed, and should be directed toward the entire family and not just the individual child with type 1 diabetes (C). Family-centered meal routines with restrictions on continuous eating habits (grazing) are important

170 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se to ensure dietary quality and opti- reducing the likelihood of acute treatment, including their need mize glycemic control in preschool and chronic complications impe- for counseling and sleep, is essen- children (C). rative from the time of diabetes tial to promote and maintain the Diabetes education should be pro- onset. Optimizing glycemic con- health and well-being of the child. vided to staf at preschools and trol for children in this age group It is also important to support the schools where children with type often requires treatment using parents to involve the child in dia- 1 diabetes are enrolled, in order to strategies that difer from those betes-related tasks such as helping ensure that equal participation in employed for older children and to select a inger for monitoring, all preschool/school activities oc- adolescents with type 1 diabetes. site for injection/infusion, and to curs and is safely managed (E). hese strategies need to take into encourage age-appropriate positive consideration the cognitive, motor, problem solving strategies when Optimal glycemic control, invol- and social immaturity of preschool diabetes-related problems occur. ving the minimizing of both hy- children as well as their small body Screening and promotion of op- poglycemia and hyperglycemia size and growth pattern. In addi- timal health-related quality of life will give the child the best oppor- tion to their dependence on oth- should be regularly undertaken tunity to concentrate, participate, ers for insulin administration and in preschool children with type 1 and learn while at preschool and glucose monitoring, preschool diabetes as in any child with type school (C). Weight, height (or children are also dependent on 1 diabetes. It is important to use length if <18 months), and Body others for aspects of their life- validated parent and parent-proxy Mass Index Standard Deviation style related to healthy eating and screening questionnaires to captu- Score (or percentiles) should be engagement in physical activity. re factors important to the quality monitored on growth charts in all Lifestyle choices and preferences of life of children and their parents children with type 1 diabetes (E). established during early childhood as both are important and im- provide a window of opportunity pactful on diabetes management. 2 | INTRODUCTION for ingraining healthy habits that Children younger than 7 years his chapter focuses on compo- will be perpetuated throughout with type 1 diabetes constitute a nents of care unique to toddlers the child’s life. he early establish- minority of the population of all and preschool-aged children with ment of positive behaviors is ne- pediatric patients with type 1 di- type 1 diabetes. hese guidelines cessary to ameliorate the high risk abetes. In small centers, this will are written in particular for child- of cardiovascular disease that is as- make the number of very young ren with type 1 diabetes aged 6 sociated with diabetes. Providing patients small and the time needed months to 6 years. Children <6 adequate education and support to gain experience in care of this months of age at diagnosis should of lifestyle changes requires that patient group will be longer. Clo- be suspected of having diabetes the multi-disciplinary diabetes se collaboration between centers is other than type 1 including mo- team uses a family-based approach necessary in order to optimize qu- nogenic diabetes, and their ma- to ensure that the whole family ality of care for preschool children nagement is discussed in the In- is appropriately supported. Sup- with type 1 diabetes. ternational Society for Pediatric porting the family is necessary for and Adolescent Diabetes (ISPAD) promoting health in the preschool 3 | GROWTH AND DEVE- guidelines on “he diagnosis and child with type 1 diabetes. Early LOPMENT IN THE FIRST management of monogenic diabe- childhood is important for esta- YEARS OF LIFE tes in children and adolescents”.1 blishing the “salutogenic” (health Growth and development in the Preschool children are dependent promoting) capacity needed for irst years of life are characterized on others for all aspects of their a long life with type 1 diabetes.2 by an intricate interplay between care. For the families (primari- he core aspect of a person’s salu- genetic, metabolic, hormonal, and ly parents) of preschool children togenic capacity is a good “sense of environmental factors. “Growth” with type 1 diabetes, their diabe- coherence”, consisting of an eve- is an increase in size of the body tes teams, and other caregivers, ryday perception of comprehen- and its constituent organs. “De- including school and day care staf sibility, manageability, and mea- velopment” is the diferentiation members and babysitters, treat- ningfulness of health promoting of the form and function of the ment is a constant challenge. Yet, actions taken in everyday life. he organs, and refers to not only so- despite this hurdle, it is important main sources of the child’s saluto- matic development but also neuro- to strive for normoglycemia, as genic capabilities are the parents. cognitive, and psychosocial deve- current knowledge about the im- Supporting the parents to endure lopment. Rapid changes in growth plications of dysglycemia makes the burden of intensiied insulin and development occur in the irst ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 171 years of life. In the irst year of life intracerebral pathways.9 Brain de- diabetic ketoacidosis (DKA), seve- children grow 25 to 30 cm, in the velopment requires diferent nutri- re hypoglycemia and hyperglyce- second year approximately 12 cm, ents to support the 5 key processes: mia, all being detrimental for the (comparable to the growth spurt (1) neuron proliferation, (2) axon health of the preschool child. in puberty) and in years 3 to 6 and dendritic growth, (3) synapse When reviewing these indings, around 6 to 8 cm/y. Weight trip- formation, pruning, and function, it is important to distinguish les in the irst year of life, increases (4) myelination, and (5) neuron between statistically signiicant by approximately 2.5 kg in the se- apoptosis. Regional and tempo- group diferences vs clinically sig- cond year, followed by an increase ral variation in glucose utilization niicant indings. Statistically sig- of around 2 kg/y in the next 3 to suggests that glucose is essential niicant group diferences may or 4 years. A peak in subcutaneous not only for energy production in may not translate into a functional tissue mass is observed around 9 the brain, but potentially for cellu- impact on the daily life of a child, months of age, which subsequent- lar proliferation and synaptogene- which has not been fully explored ly decreases until 6 years of age. sis as well.10 In the neonatal and in children with type 1 diabetes. In order for preschool children to infant brain, alternative energy However, we know that early brain experience normal growth and de- sources may be identiied such as and cognitive development are im- velopment, it is essential that they ketone bodies, which are transpor- portant for later success in school maintain near normoglycemia, ai- ted over the blood-brain barrier and beyond. Glucose uptake by ming to increase glucose time in in times of glucose shortage. he the brain is insulin-independent range, and are provided with suf- ketone bodies are a substrate for and mainly driven by the concen- icient nutrients.3–6 Restrictive lipid synthesis, although not es- tration of glucose. his directly diets or lack of food make it dii- sential.11 exposes the neuronal cells of the cult to provide essential nutrients In addition to somatic growth, brain to oxidative stress and gluco- for growth and development, and preschool children experience ra- toxicity in hyperglycemia, and to should be avoided. It is essential to pid cognitive development. Child- lack of fuel in hypoglycemia. monitor weight, height (or length ren start by investigating objects he maturation of gray matter in if <18 months), and BMI-SDS (or in their immediate environment, the brain is intense throughout the percentiles) on growth charts in eventually expanding to exploring toddler and preschool years. Gray all children with type 1 diabetes anything within reach. Mobility matter development slowly cur- at every clinic visit. his require- and thus physical activity increa- tails over time beginning around ment of suicient nutrition is in ses with age. puberty. In contrast, white matter part due to the brain’s high meta- Multiple risk factors have been as- maturation (that is necessary for bolic expenditure in infancy and sociated with potential suboptimal processing speed and coordinated, childhood (3 times higher than in cognitive and ine motor develop- luid movements) continues until adults). Body proportion at birth is ment in children and adolescents early adulthood.18,19 characterized by a large head and with type 1 diabetes. hese factors prominent abdomen. After birth, include early onset of disease (typi- During toddler and preschool the brain and the cranium conti- cally deined as <5 years of age),12 years, the brain is highly sensiti- nue to grow and reach 4/5 of the disease duration, history of mo- ve to metabolic disturbances, and adult size by the end of the second derate to severe ketoacidosis (in- potential abnormalities have repe- year, growing much faster than cluding those at diagnosis),13,14 atedly been identiied in magnetic many other body parts including severe hypoglycemia (including resonance imaging (MRI) studies the extremities.7 seizures or unconsciousness),15 of young brains exposed to gly- cumulative exposure to hyperglycemic extremes, as in type 1 dia- 4 | THE BRAIN AND COG- cemia, and possibly, the sex of the betes.20–23 he mechanisms by NITIVE DEVELOPMENT IN child.16 A meta-analysis showed which early brain development is CHILDREN WITH EARLY that the risk of cognitive disrup- afected by type 1 diabetes are not ONSET TYPE 1 DIABETES tion is largest for children with clearly understood. Long-term ex- he brain is metabolically highly early-onset diabetes and that the posure to hyperglycemia as well as demanding, accounting for 20% efect is detectable after a mean hypoglycemia (especially with se- of the total energy requirement diabetes duration of 6 years.17 izures) and oxidative stress caused in adults.8 In the adult, the brain he mean efect size is moderate by glycemic variability have been depends on a continuous supply but might not be large enough to suggested as contributing factors. of glucose as fuel. In the neonate, afect school performance. Clini- he main efects seem to occur in glucose is essential for diferent cians should be concerned about the early phase of the disease. It

172 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se internalizing mood disorders. re, both with respect to acute and Longitudinal follow-up of these longtime diabetes complications children is ongoing and may reveal as well as their neurocognition, how these diferences change with brain structure, and health-related time, further exposure to diabetes quality of life (HRQoL). ISPAD (including hypoglycemia and hy- published glycemic targets for perglycemia), and brain develop- hemoglobin A1c (HbA1c; <7.5%, ment.27 (<58 mmol/mol) and for self measured blood glucoses (SMBGs) A young child who has executive (from optimal to high risk) in functioning diiculties, language/ the latest guidelines 2014 (Table literacy deicits, slowed processing 1).30 he targets are applicable speed, or ine motor coordination to all pediatric age groups, inclu- diiculties will likely require pro- ding preschool children, and the fessional attention at some point in aim should be to achieve optimal their youth. Typically, these child- glycemic control. he American ren are referred to a neuropsycho- Diabetes Association31 in 2014 logist or other learning specialist redeined blood glucose targets for has been suggested that metabolic during the early elementary years. all pediatric age groups to be at the conditions such as hyperglycemia hese children can require specia- same level as ISPAD.32 In United and ketoacidosis at diagnosis can lized tutoring, small group instruc- Kingdom, glycemic targets for all be predisposing events that makes tion, support in the classroom, or pediatric age groups are recom- the brain more vulnerable to sub- other assistance. For all children mended in the National Institute sequent metabolic insults.13,16 with cognitive development issues, for Clinical Excellence (NICE) Some, but not all, studies investi- early identiication and remedia- guidelines, recently updated to an gating cognition in childhood tion are crucial to avoid poor out- even lower HbA1c level of ≤6.5% onset type 1 diabetes, report de- comes. Optimal glycemic control (≤48 mmol/mol; the numbers are crements in the domains of intel- will give young children with type based on the published studies).33 ligence quotient (IQ) (verbal IQ 1 diabetes the best opportunity to It is important that the diabetes in particular), executive functions concentrate, participate, and learn team and family share the same (attention, working memory, and while at preschool and school. By target HbA1c and glucose rang- response inhibition), delayed me- achieving good glycemic control, es. Otherwise, there is a high risk mory (episodic recall), and proces- including mitigating prolonged of discrepancy that can go both sing speed (paper-pencil); however, exposure to hyperglycemia, and ways. Sometimes parents strive these diferences are generally not by providing early identiication for lower glucose levels than the reported until the children are stu- and intervention of academic, diabetes team, who at times may died later in childhood.24,25 One cognitive, or motor issues, health articulate that the family is too possibility is that chronic exposure care professionals are best able to strict and take too many gluco- to diferent aspects of dysglycemia help children avoid any negati- se checks, especially at night. At is additive, and that brain and cog- ve impact of type 1 diabetes on other times, the parents have their nitive changes only become appa- everyday function. For further own set of higher glucose targets rent over time. reading, the ISPAD guidelines that they feel it better with their Studies that speciically target the on psychological care of children daily life, inding the targets set youngest children with type 1 di- and adolescents with type 1 dia- by the health care team unachie- abetes have found only modest betes comprehensively addresses vable. When evaluating glycemic diferences in cognitive function this subject.28 See also the ISPAD targets together with the family, it compared with peers. Among a Guidelines on hypoglycemia.29 might be useful to express them as large group (n = 144) of children time spent within target and time aged 4 to 7 years, small diferences 5 | GLYCEMIC TAR- below or above target. It is impor- in the following areas were repor- GETS AND CONTROL IN tant that both the diabetes team ted: IQ, especially verbal, execu- PRESCHOOL CHILDREN and the families consequently use tive functions, and internalizing WITH TYPE 1 DIABETES a language that tells the child that mood disorders.26 he cognitive Optimizing glycemic control for a glucose value can be high, low or diferences remained when con- preschool children with type 1 normal, and that the glucose level ▶ trolled for parental IQ and level of diabetes is crucial for their futu- is never “bad”. he knowledge of a www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 173 glucose value often calls for action, but never for blaming or punish- ing the child. Parents express that diabetes management style can make a diference. A positive, non-judgmental, attitude will likely have a positive inluence on the way a young child views and manages his/her type 1 diabetes as he/she gets older. Parents should be encouraged to adopt a “matter-of-fact” approach to the routines (injections/ pump site changes, inger pricks, and meal times), treating numbers as just numbers/data points, and not apologizing for aspects get 4.0-8.0 mmol/L (70-145 mg/ tion plays a key role in achieving of care such as inger pricks, site dL) 5.0-7.2 mmol/L (90-130 mg/ metabolic targets, together with changes, and injections that can- dL) 4.0-7.0 mmol/L (72-126 mg/ lexible insulin regimens, gluco- not be avoided. Maximizing the dL) Postprandial glucose target se monitoring, and carbohydrate amount of time glucose values are (2 h post meal) 5.0-10.0 mmol/L (CHO) counting.30,34,44 Hy- in range needs to be the target for (90-180 mg/dL) 5.0-9.0 mmol/L perglycemia is a major risk factor multi-disciplinary diabetes teams, (90-162 mg/dL) Bedtime 6.7-10 for (recurrent) ketoacidosis45 and as well as the family/caregivers. mmol/L (120-180 mg/dL) 5.0- microvascular complications later Diabetes education34,35 and a 8.3 mmol/L (90-150 mg/dL) in life.46,47 Long-term tracking clearly set glycemic target36 are Overnight 4.5-9.0 mmol/L (80- of glycemic control from child- very important.37,38 Age-speciic 162 mg/dL) HbA1c target <58 hood until adulthood has been challenges need to be considered mmol/mol (<7.5%) <58 mmol/ reported.48–52 here is a correla- and age-appropriate actions taken mol (<7.5%), a lower target of <53 tion between the HbA1c achieved to achieve these. mmol/mol (<7%) can be set if it within the irst few months after As discussed above, there are can be achieved without hypogly- diabetes diagnosis, the glycemic detrimental efects of hyperglyce- cemia ≤48 mmol/mol (≤6.5%) control later in life, and the risk mia; yet it is an existing practice Abbreviations: HbA1c, hemoglo- for cardiovascular complications. to allow glucose levels to reach bin A1c; ISPAD, International So- A lower HbA1c achieved at an the hyperglycemic range in the ciety for Pediatric and Adolescent early phase of life with diabetes youngest age group in order to av- Diabetes, NICE, National Institu- is associated with a lower HbA1c oid hypoglycemia at all costs. his te for Clinical Excellence. later on.48–52 Long-term studies, is unsafe, and treatment should for example, the Diabetes Control instead aim to minimize both It might not just be the HbA1c and Complications Trial-Epide- hyperglycemia and hypoglyce- level that is important. Glycemic miology of Diabetes Interven- mia in the efort to achieve (near) variability may play a role in the tions and Complications (DC- normoglycemia. If the diabetes development of diabetic compli- CT-EDIC), describe a prolonged team is inexperienced in treating cations,39,40 but the long-term efect of prior glycemic levels on preschool children with type 1 di- impact of glycemic variability diabetic complications, called abetes, support and advice should remains controversial.41,42 In glycemic memory. his efect is be sought from more experienced adults using continuous glucose independent of more recent glyce- colleagues. monitoring (CGM), glycemic va- mic control. he DCCT showed riability was signiicantly lower in a signiicant diference of around TABLE 1 Glycemic targets in those without complications com- 2% in HbA1c between the intensi- preschool children with type 1 di- pared with those with complica- ve and conventional groups, but 1 abetes according to ISPAD, ADA tions (Standard Deviation SD 3.4 year after the closeout of the study, and NICE guidelines ISPAD30 vs 4.1 mmol/L), despite compara- HbA1c levels were approximate- American Diabetes Association31 ble HbA1c values.43 Age-speciic, ly the same (around 8%).46,47 NICE33 Preprandial glucose tar- family-centered diabetes educa- Nevertheless, the intensive group

174 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se showed fewer microvascular com- for many of these children,” in- not experienced enough in pump plications, with a risk reduction jection, injection therapy is used treatment of preschool children, in retinopathy even 18 years after in many centers in the following advice should be sought from a the end of the study.53 he DC- instances: early in the course of the more experienced center to opti- CT-EDIC results have led to the disease in their remission period; mize quality of care. recommendation of early tight gly- children who were using an in- cemic control to reduce the risk for sulin pump but have experienced 6.2 | Basal insulin diabetic microvascular and macro- pump failures “or skin reactions”, When using injections for insu- vascular complications.47,54,55 “inexperience of the diabetes team lin treatment, the special diurnal he ISPAD guidelines on micro- in using pumps in this young age pattern of insulin requirements vascular and macrovascular com- group,” and if living in limited in preschool children should be plications provides a more detailed resource settings where insulin taken into consideration in desig- discussion.56 Early onset of diabe- pumps are unavailable. Approval ning an individualized basal do- tes at a very young age will lead to of insulin analogs in diferent age sing scheme. he low requirement a longer duration, which in itself groups is regulated by authorities. of insulin and tendency toward is associated with a higher lifelong Two examples are the European low glucose risk of complications, compared Medicines Agency (EMA) (www. with persons with later onset type ema.europe.eu) approvals and the TABLE 2 Approved insulin ana- 1 diabetes. 57 So far, conlicting US Food and Drug Administra- logs in diferent age groups accor- data exist to whether the prepu- tion (FDA) (www.fda.gov) as of ding to EMA and FDA Approved bertal years contribute to the same June 2017 (Table 2). When using by EMA from age Approved by degree as the pubertal years for injections for insulin delivery, pain FDA for (studied from age) the development of microvascu- can be reduced by usage of sub- Insulin lispro “Adults and child- lar complications.58 Suboptimal cutaneous catheters changed every ren” (2 y) metabolic control in children with third day (Insulon; Unomedical, “Adults and children” (3 y) early prepubertal diabetes onset Lejre, Denmark or I-port: Medtro- Insulin aspart ≥2 y “Adults and may further contribute to the risk nic MiniMed, Northbridge CA, children” (2 y) of complications.59–61 Persons USA).64 Insulin glulisine ≥6 y “Adults and with poor glycemic control during children” childhood have a high risk of long- 6.1 | Insulin dosing (4 y) Insulin detemir ≥1 y “Adults term complications, even if sub- Preschool children with optimal and children” (2 y) stantial improvement is achieved glycemic control usually need so- Insulin glargine ≥2 y Adults and as young adults,62 and NICE mewhat less insulin than older pediatric patients” (6 y) emphasizes the need to reduce the children. he total insulin dose Insulin degludec ≥1 y ≥1 y risk of long-term complications of has been reported to be 0.4 to 0.8 Abbreviations: EMA, European type 1 diabetes in a population U/kg/d (median 0.6 U/kg/d) in Medicines Agency; FDA, Food that will have a long duration of preschool children with well con- and Drug Administration. diabetes because the condition trolled type 1 diabetes after the levels are often most obvious starts before adulthood. remission phase.65 Insulin pumps during the night and especially ofer both greater lexibility in in- between 3 and 6 AM. Preschool 6 | INSULIN THERAPY IN sulin dosing and a better means children often need much more PRESCHOOL CHILDREN to deliver very small, precise doses insulin late in the evening between Insulin treatment guidelines for of insulin than when using injec- 9 PM and 12 midnight.67–69 preschool children are essential- tions,66 and are thus considered his creates typical patterns when ly similar to older children and the preferred method for insulin programming the basal rates of an adolescents, but age-dependent delivery in infants, toddlers, and insulin pump used by a preschool aspects have to be taken into preschoolers with diabetes, alt- child. With MDIs, a basal insulin consideration. See the ISPAD hough earlier randomized studies analog can reduce hypoglycemia, guidelines for further reading on have failed to show an efect on including nighttime hypoglyce- insulin and insulin analogs in pe- glycemic control.63 If pump the- mia, compared with NPH insu- diatric use.63 Worldwide, most rapy is not available due to lack of lin.70–72 preschool children with diabetes economic resources, multiple daily use insulin injections to manage injections (MDIs), with conside- he combination of the low body their diabetes. Although insulin ration of use of an injection port, weight, and thus low total insulin pump use should be considered can be used. If the diabetes team is dose, demands special conside- ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 175 ration when using commercially carefully monitored and parents studies show that preprandial bo- available insulin pumps. A pump need constant access to support lus insulin is preferable to insulin with a very high precision in deliv- from the diabetes team. administered during or after the ering very small basal rates should meal and should thus be routi- be chosen for a preschool child. 6.3 | Bolus dosing nely advised for all toddlers and Sometimes further reduction in Although still often used, twice preschoolers, even the most unpre- the dose is needed, necessitating daily insulin dosing in this age dictable eaters. However, the dose dilution of the current U-100 in- group does not give the lexibi- can be split into 1 preprandial and sulin,65,73,74 or an intermittent lity needed in adapting doses to 1 during the meal when eating is basal rate of 0 U/h for limited peri- varying situations in daily life. It erratic or new foods are ofered. ods, i.e. every second hour during is diicult to ine-tune, and dii- the night. Use of these approaches cult for the family to understand he dose given during the meal may help to meet the needs of the and adjust on their own, which can be based on what the parent young child and the planning of is a necessity for a successful in- estimates the child will eat of the the child’s insulin treatment has sulin treatment. A glucose and remaining meal, taking into consi- to be carefully discussed (with ad- meal-adjusted basalbolus insulin deration the food that has just been vantages and disadvantages) with regimen (delivered by injections eaten and the child’s remaining the parents so that they are well or pump) can be adapted to the appetite. Small inaccuracies in cal- aware of the beneits and risks of preschool child’s daily activities, culation of up to 5 to 7 g CHO the chosen strategy. he given in- and is the preferred type of insulin will usually not be problematic.78 sulin should always be prescribed treatment. Larger inaccuracies may result and documented in normal units in possible hypoglycemia or hy- to avoid hazardous misunderstan- Preschool children often need pro- perglycemia 2 to 3 hours after ea- dings regarding insulin dosing, portionally larger bolus doses than ting, but not immediately.79 he- especially if the child is admitted older children, often constituting se can be anticipated and treated to hospital. A pump containing 60% to 80% of the total daily in- with additional CHO or a small diluted insulin should be labeled sulin dose (TDD). he often used correction dose of insulin. With a with information regarding the rule of 500 (500/TDD = how pump, a combination bolus (also currently contained concentration many grams of CHO is covered called combo or dual wave bolus) of insulin (Table 3). by 1 U of insulin) for bolus calcu- can be helpful, i.e. part of the bo- A glucose and meal-adjusted lations, as detailed in the ISPAD lus is given before the meal and the basal-bolus insulin regimen (de- guidelines on insulin therapy63 remainder over 20 to 40 minutes. livered by injections or pump) rarely its the youngest children If the child stops eating before the requires that the basal rate can be as it often underestimates the in- meal is inished, the remainder of ine-tuned by the parents in accor- sulin dose.70,75,76 Diferent stra- the bolus can be suspended. When dance with the child’s current in- tegies can be used; either use a giving these relatively large bolus sulin sensitivity. 330 or 250 rule (gives 50%-100% doses, one must remember that Insulin sensitivity can be incre- more insulin) instead of 500, or, they interact with the need for ba- ased after very active days, such which is preferable, to observe and sal insulin in the following hours. as a day at the beach or out in the calculate the correct proportion hus, the total basal rate can be re- snow (decreased insulin resistan- between insulin and CHO from latively low, around 20% to 40% ce). he overnight basal might real life meals. To calculate the in- of TDD. In preschool children, it then be reduced by 10% to 30% sulin to CHO ratio from a given is often estimated that the efect of when using a pump or a similar meal, divide the CHO content in a subcutaneous bolus of rapid-ac- decrease in bedtime long-acting the meal (in grams) by the insulin ting insulin analogs (eg, as lispro, insulin. Insulin sensitivity can be dose in units that gives an app- aspart, or glulisine) lasts for only 2 markedly reduced (increased insu- ropriate glucose proile after the to 3 hours (active insulin time in lin resistance) for example during meal. he need for insulin at bre- pumps).75 fever when the basal rate might akfast is often very high, and one need to be increased by 20% to might consider using 150/TDD in At breakfast there is often some 100% according to glucose levels the calculation, or calculate from degree of insulin resistance, and when using a pump, or a similar real life meals as above. it is common to experience a mar- increase in dose of long-acting in- he timing of the prandial bo- ked glucose peak after breakfast in sulin. Under these circumstances, lus is important. As outlined in spite of an adequate insulin dose glucose levels have to be extremely the review by Bell et al,77 several taken before the meal. he nutri-

176 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se 7 | NUTRITIONAL NEEDS OF THE PRESCHOOL CHILD WITH TYPE 1 DIABETES Breastfeeding should be encouraged for all infants, including infants with diabetes (World Health Organization [WHO] recommendation, www.who.int). Comple- mentary foods, preferably iron- rich, should be commenced from 4 to around 6 months of age.80 If breastfeeding is not possible, an iron-fortiied infant formula should be given as the main milk drink until 12 months of age. A routine regarding breast- or formula-feeding is important for infants tional content of the breakfast has TABLE 3 Diferent strategies for with diabetes as this enables app- to be discussed and planned by the delivering minute basal rates. No ropriate interpretation of glucose dietitian together with the parents. pumps that are available today levels and basal and bolus insulin Increasing the insulin dose (lower can be adjusted to the insulin adjustments. his may involve 3 insulin-to-CHO ratio) too much concentration. hus, if using dil- to 4 hourly feeds (of approxima- can risk hypoglycemia before uted insulin, recommended doses tely 150-240 mL) during the day lunch. In this situation, it may be from the bolus calculator must be with complementary solids. Con- helpful to give the prandial insulin recalculated to the diluted concen- tinuous or hourly breastfeeding is 10 to 20 minutes before breakfast. tration Advantages Disadvantages discouraged as this makes insulin he need for a large bolus dose of Diluted insulin (i.e. 10 or 50 U/ dosing diicult. Breast milk has insulin to cover breakfast might mL) Fine tuning of basal rates is approximately 7.4 g CHO per 100 necessitate a very low or suspended possible. All technical features of mL; so for infants 6 months and basal rate during the following 3 the pump can be used, such as older it is possible to bolus before hours. For some children, a small temporary basal rate changes and the feed for at least 5 to 7 g CHO amount of fruit (5-10 g of CHO) bolus calculations. Possible to set and 15 g CHO in older babies (>9 may be given 2 hours after break- extremely low basal rates and make months). fast (without insulin) to avoid hy- changes in small increments. Risk Optimal nutrition is requi- poglycemia, but it is preferable not of mistakes due to the delivered red to provide suicient energy to establish a practice that necessi- insulin dose not being the same as and nutrients to meet the rapidly tates skipping a bolus as this may that displayed on the screen. Pain changing needs of children at this continue as the child gets older. can occur when large volumes are stage of life. Dietary recommenda- given as bolus doses. Impractical tions are based on healthy eating When using MDIs with frequent to prescribe doses with diluted in- principles suitable for all preschool glucose checking and mealadju- sulin More expensive insulin. children, with the aim of esta- sted insulin dosing, one possible “Empty” hours without basal rate blishing family based meal-time strategy is to give a rapid-acting • he pump gives exactly the do- routines that promote glycemic insulin analog for all meals, with ses displayed on the screen, de- control and reduce cardiovascu- the exception of the last meal of creased risk of mistakes in dosing lar risk factors. CHO counting is the day when short-acting regular for instance when insulin is given important to permit the matching insulin can be used to meet the in- temporarily with pen. Use of more of insulin dose to CHO intake on crease in glucose before midnight. stable commercially available in- intensive insulin regimens,44 and Part of the dose can be given as ra- sulins is possible. Increased risk should be taught to the family at pid-acting analog insulin to avoid of occlusion in tubing due to low the onset of diabetes. needing to give the dose 30 minu- low rate. Increased risk of keto- Nutritional advice must be in- tes before the meal; the insulins sis due to planned hours without dividualized and adapted to cul- can be mixed in a syringe or given insulin. Some of the pumps’ tech- tural and family traditions. A pe- as separate injections (if an injec- nical features (as temporary basal diatric diabetes dietitian should tion aid is used). dose changes) cannot be used. provide education, monitoring, ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 177 vegetables daily between 1 and 3 years.86 400 g of fruits/vegetables are recommended each day from 4 years of age.87 Research has shown the dietary quality of preschool children with diabetes is poorer than their healthy peers.88Studies have shown that preschool children with type 1 diabetes consume less fruit and vegetables and have higher saturated fat intakes than peers89 and than recommendations would advise.90,91 Poor food intake may increase the risk of cardiovascular disease. Eating habits in young children can inluence food choi- and support at regular intervals this age group; adequate consump- ces later in life,92 so early inter- throughout the preschool years, as tion of lean meat or alternatives is vention with increased attention parents of preschool children with important and should not be over- to an increase in fruit and vegeta- diabetes report meal-times as one looked because of the increased ble intake and decrease in satura- of the most diicult components focus on CHO. ted fat is needed. Just like healthy of their child’s care.81 Preschoo- A guide to the macronutrient children, children with diabetes lers require more frequent review distribution of the total daily en- may require up to 10 exposures to than older children,44 with a ergy intake in preschool children a new food before it is accepted.93 suggestion for reassessment twice is as below. However, this should Several studies show that children annually until the age of 6. he- be based on an individualized as- with type 1 diabetes are more over- re is international agreement that sessment. Carbohydrates: 45 to 55 weight compared with children in CHO should not be restricted in Energy (E) %.44,82 Average in- the general population,91,94 with children with type 1 diabetes as takes 150 g/d in children aged 1ó the youngest children (<6 years) it may result in deleterious efects to 3 years; 200 g/d in children 4 being the most overweight.95,96 on growth. Care should be taken to 10 years.83 Protein: 15 to 20 E It is important to plot the growth when giving dietary education, so % (decreasing with age from app- chart including assessments of that methods of quantifying CHO roximately 1.5 g/kg body weight/ weight for length or height regu- do not increase total fat and/or sa- day in 6-month-old infants to 1 g/ larly to identify excessive weight turated fat intake.44 Although ca- kg body weight/day in preschoo- gain, in order to commence inter- regivers may prefer highfat snacks lers)84 Fat: 30 to 35 E % (less than ventions that involve the whole fa- to avoid afecting glucose levels, 10 E% saturated fat, less than 10 mily. Encouraging participation in this should be discouraged as they E% polyunsaturated fat, and more family meals has been recommen- will provide unnecessary calories, than 10 E% mono-unsaturated ded to promote dietary quality97 an unhealthy fat intake, and nega- fat). Infants less than 12 months and social interaction. Age-app- tively impact dietary quality. may consume up to 40% energy ropriate inger foods should be Preschool children with type 1 di- from fat. encouraged for self-feeding, and abetes should consume a diet that It is important to encourage all the reintroduction of a bottle as an emphasizes fruit, vegetables, who- children, including children with easy method of CHO intake dis- le grain bread and cereals, dairy type 1 diabetes, to eat plenty of couraged. Bottles can lead to over- foods and appropriate types and fruit and vegetables. Examples of consumption of luids, increasing amounts of fats. Low fat diets are recommendations from Austra- CHO intake and placing other not suitable for children under 2 lia,85 United States,86 and the nutrients at risk. years of age. Lower glycemic index Nordic countries87 are expressed (GI) choices, such as wholegrain in diferent ways but consistent in 8 | ESTABLISHING POSITI- bread and cereals can be introdu- content, and state 180 g vegeta- VE FOOD BEHAVIORS AND ced as substitutes for higher GI bles (2ó servings) and 150 g fruit MEAL-TIME ROUTINES food choices from 2 years of age. (1 serving) daily from 2 years of Establishing positive food behavi- Iron deiciency can be a concern in age85; or 1ó serving of fruit and ors and meal-time routines are im-

178 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se portant for preschool children with inadequate CHO consumption. titian throughout childhood and type 1 diabetes, as these behaviors Parents should be adviced that adolescence is essential for optimal impact glycemic control81,98 and postprandial bolus insulin is pro- care. encourage life-long nutrition prac- blematic as it can become an esta- In parental experience, it can be tices.92 Normal early childhood blished habit and also reinforces diicult at times to give prepran- development, including seeking anxiety about the child under-ea- dial bolus doses of insulin due to independence, transient food pre- ting. Fear of hypoglycemia can the fear of food refusal and resul- ferences, variable appetite, food lead to under-bolusing for meals, tant hypoglycemia. Strategies to refusal, and behavioral resistance resulting in inadequate bolus do- handle this need to be discussed often make meal times challeng- ses given over the day and subse- with the parents (as above) and all ing for parents and carers. Parents quent hyperglycemia. Continuous aspects of the risk of dysglycemia of children with type 1 diabetes eating (grazing) makes interpreta- following postprandial bolus do- report more disruptive meal beha- tion of glucose levels and insulin ses need to be explored. Should a viors, including longer meal dura- dose adjustments diicult. A re- child have a high plasma glucose tion and more frequent food refu- gular meal pattern with 1 small because of eating something un- sal compared with controls99,100; snacking episode between meals planned, a calm explanation of the even for children using insulin (7-15g CHO preceded by an app- need to cover food with insulin is pump therapy.101 Research has ropriate insulin dose) will assist necessary. demonstrated positive correla- with preventing food refusal as tions between suboptimal dieta- the child will be hungrier at main 9 | LIFESTYLE FACTORS IN ry adherence and higher glucose meals. A dietitian should advise PRESCHOOL CHILDREN levels.81,89,101,102 Caregivers’ regarding age appropriate CHO he American Heart Associa- fear of hypoglycemia associated amounts as it is necessary to ensu- tion (AHA) has identiied certain with food refusal or unpredictable re the anticipated CHO intake is childhood conditions (including dietary patterns can result in force reasonable based on age, growth, type 1 diabetes) associated with feeding, grazing continually over and the child’s previous intake. extremely high risk of cardiovascu- the day, and postprandial insulin Unreasonable expectations of a lar disease, calling for treatments administration, causing prolonged child’s intake may result in food to minimize this risk.105 Lifestyle periods of hyperglycemia. refusal and subsequent hypoglyce- habits, such as nutritional pre- Family-centered meals are impor- mia. Food refusal should generally ferences,92 physical activity,106 tant to model eating practices and be dealt with efectively and simi- and time spent sedentary,107 that to encourage new foods. For small larly to toddlers without diabetes. are established in childhood have children, meal times should be Preschool children becoming in- a great propensity to follow into limited to approximately 20 mi- creasingly independent can recog- adulthood. hus, lifestyle factors nutes per meal.103 Conventional nize parental stress and quickly in early childhood have a dual im- insulin regimens require adheren- learn to use their diabetes as a way pact on later cardiovascular risk, ce to a structured plan of CHO in- of getting their favorite foods. It is observable both as early markers take, and parents frequently report important to emphasize parental of atherosclerosis during adole- problems with this approach.81 patience and to encourage parents scence108 and also as a set of be- Intensive insulin management of- not to use food bribes. haviors that inluences the child’s fers greater lexibility in meal ti- risk of cardiovascular disease as ming and CHO quantities. To as- All diabetes team members should an adult and even into senescen- sist the reliable intake of CHO at provide the family with clear and ce. Children tend to follow the meal-times and to minimize food consistent messages regarding lifestyle habits of their parents refusal, the following strategies food and meal-time behaviors. and entire family regarding phy- should be adviced: Distractions such as the television sical activity,109 TV watching110 structured meal-times avoidance and toys should be removed at me- and food choices,97,111,112 and of continuous eating habits small altimes. Research has demonstra- this has been found to inluence snacks including limits on low ted that disruptive child behaviors children´s food habits throughout CHO foods as these ill the child can be reduced by establishing their lives.92 Lifestyle supporting up limits on the time spent at the speciic rules and consequences for interventions should thus be di- table avoidance of force feeding mealtimes and teaching parents rected toward the parents and en- reassurance by all team members behavioral strategies for meals.104 tire family and not the individual regarding the usual nonseverity of here is consensus that continua- child with type 1 diabetes mellitus hypoglycemic episodes related to tion of support by a pediatric die- (T1DM). ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 179 here is no contradiction outdoor playing environments are reason for erroneously high blood between population-based inter- associated with increased physical glucose levels. he child should be ventions to promote increased activity in preschool children.122 introduced to checks glucose moni- physical activity or healthier food Asking families about the amount toring and interpretation according choices in all children and inter- of time spent playing outdoors to age appropriate and individual ventions that are routinely part of can be a useful way to quantify capabilities, as the development of the diabetes care delivered by the the physical activity of a preschool the mathematical understanding of diabetes team. Preschool children child with type 1 diabetes. numbers and time is gradual. with type 1 diabetes can beneit Physical activity should be pro- Most children with type 1 diabetes from both eforts, but targeted in- moted in all children with type 1 can by the age of 7 be capable of terventions are necessary to meet diabetes. taking blood glucose checks and the speciic needs of children with Both having diabetes and being performing some basic interpreta- type 1 diabetes. a girl has been reported to be asso- tion of glucose levels under super- ciated with lower levels of physical vision. However, this should always 10 | PHYSICAL ACTIVITY activity in preschool children with be overseen by a parent or other Physical activity confers many type 1 diabetes, indicating that caregiver, as independent self-care health beneits for all children. A particularly young girls with type is not expected from any preschool strong graded inverse cross-sectio- 1 diabetes are at high risk of being child with type 1 diabetes. nal association has been observed too physically inactive.123 General advice on SMBG mo- between physical activity, insulin nitoring is available in the ISPAD resistance,113,114 and body fat.115 11 | PRACTICAL MONITO- guidelines on Assessment and mo- Spending more time in moderate RING OF GLYCEMIC CON- nitoring of glycemic control.29 In and vigorous physical activity is as- TROL children younger than 7 years of sociated with decreased cardiome- In this section, “blood glucose” age, the recommended checking tabolic risk factors in children. 116 values refer to glucose values me- frequency of 4 to 6 times per day is When designing physical activity asured by capillary blood check rarely suicient when striving for interventions to reduce the risk of (“inger prick” and “blood gluco- target glucose and HbA1c levels. cardiovascular disease in children, se monitoring”) although meters Even with a higher monitoring fre- including children with type 1 di- generally display plasma glucose. quency of 7 or 10 checks per day, abetes, it is important to focus on Since plasma glucose is 11% hig- the number of undetected hypogly- high-intensity physical activity to her than whole blood glucose, this cemia and hyperglycemic events in be most efective.116 Engaging in term is used when exact numbers insulin treated preschool children regular physical activity is also ne- are mentioned. are high.124,125 Observational cessary in order to acquire and im- studies from diferent countries prove gross motor skills.117 Many 11.1 | Blood glucose checking show that a common frequency of countries recommend at least 60 Glycemic control is often evalu- SMBG in preschool children with min/d of moderate and vigorous ated with blood glucose monito- type 1 diabetes is 7 to 10 checks physical activity for all child- ring (SMBG). All families with per day.125,126 Nighttime SMBG ren,118 and WHO recommends a child with diabetes should be is recommended by many diabetes this at least from 5 years of age.119 taught how to measure and in- teams, and performed by most fa- Some countries have changed terpret plasma glucose values. A milies with preschool children.127 their recommendations for phy- high precision glucometer (error Preschool children with diabetes sical activity in preschool child- less than 10%) should be used in can spend a long time in the hy- ren from 60 minutes of moderate preschool children, both when re- poglycemic range without detec- and vigorous physical activity to lying on SMBG for glycemic mo- tion, despite nighttime monito- 180 minutes of any intensity of nitoring and when using the glu- ring of SMBG.125 Many parents physical activity per day.120,121 cometer for calibration of CGM. are sleep-deprived due to night- his change of recommendation Accuracy in everyday monitoring time checking of plasma gluco- has been questioned because the situations should be ensured by se.127,128 he normal activities reduction in the risk of cardio- follow-up with the diabetes team. of the child have to be interrupted vascular and metabolic problems his shall include education on the in order to measure a blood glu- might be too low with lower in- importance of ensuring that the cose value during daytime. hus, tensity of physical activity.115,116 ingertips are clean and dry before SMBG has several limitations as It has been shown that outdoor monitoring blood glucose, as su- a method of monitoring glycemic playing and especially spacious gar on the ingertips is a common control.

180 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se 11.2 | Continuous glucose mo- for parents/caregivers who rely on infusion sets/sensors) over the nitoring others for part-time care of their past few years make these thera- CGM can provide an efective child with diabetes, for example, pies more acceptable for preschool mode of monitoring for low and while at day care or preschool. children. he safety of insulin high glucose levels, allowing for CGM enables deepened ana- pump and CGM use in this popu- eicacious insulin adjustment. lysis and understanding of glyce- lation appears to be similar to that When available, CGM with mic patterns (such as postprandial seen in other age groups.130,134 alarms is generally the preferred glycemic excursions), and down- It is essential for the family to have method for monitoring of glucose loading data from the device is a access to blood ketone checking to levels in children younger than 7 pedagogic tool for the team when detect problems with the supply of years of age with type 1 diabetes. discussing solutions to various insulin from the pump. See the se- CGM should be available and uti- problems with the parents of a ction on ketone monitoring below lized as a tool for adjusting insu- child with diabetes. Downloading and the ISPAD guidelines on sick lin doses. Parent experience from at home by parents should be en- days.135 Regular downloading of Children with diabetes (CWD) couraged, and can form a basis for data from the pump (and CGM if conferences: “I have seen many self-adjustment of insulin doses for used), both at home and in clinic, young children in the age group experienced families. allows patterns of dosing136 and of 5 to 6 who understand both the glucose levels to be recognizable. numbers and trend arrows on their 12 | USE OF INSU- Always give extra insulin with a CGM”. We also know from perso- LIN PUMPS WITH AND pen or syringe in case of suspicion nal experience that children who WITHOUT CGM IN of problems with insulin delivery are diagnosed young sometimes PRESCHOOL CHILDREN from the pump. If the child is pro- grasp ‘the numbers’ of diabetes Preschool children are unique ne to ketosis, replacing part of the very quickly. Data on CGM use consumers of novel insulin de- overnight basal (30%-40%) with in preschool children are limited, livery and device technologies, as a small dose of long-acting insu- but suggest low overall rates of they are dependent on caregivers lin (detemir, glargine or degludec) use,126,129 often due to inancial for all aspects of device use. Re- may help, but might also reduce constraints. Parental satisfaction cent technologies, such as pumps the lexibility in basal insulin ad- with CGM use is high, in large and CGM, can be particularly ministration by temporary basal part because the technology can helpful to parents and caregivers rates. decrease the likelihood of severe of preschool children who are ex- Parents of preschool children hypolycemia.130 When parents/ tremely dependent on ine-tuning who switch from MDI to insu- caregivers share their thoughts and of small insulin doses, both with lin pumps report more lexibility interpretations, real-time CGM regard to size and timing of insu- and freedom, as well as less stress information, including a co- lin doses. and anxiety related to their child’s lor-coded screen with arrows, and An insulin pump system is av- care.137 Data suggest a decrea- alarms can often be understood by ailable that can suspend insulin se in HbA1c129,134 and reduc- preschool children from around delivery when glucose levels, as tions in rates of severe hypoglyce- age 5 to 6 years. Talking with the measured by CGM, are predicted mia95,134 after implementation child in an age-appropriate way to become low, and thus reduce of insulin pumps in preschool about actual CGM information the risk and duration of hypogly- children. Insulin pump features gradually increases the child´s un- cemia. 133 On the other hand, that enable automatic bolus cal- derstanding and participation in insulin pumps and CGM are asso- culations based on insulin sensi- their insulin treatment. ciated with increased cost and may tivity factors and insulin to CHO Even if children can have some increase the provider burden; in- ratios can aid caregivers in insulin understanding of this, interpreta- sulin pumps may also carry addi- administration. tion and necessary steps of action tional risks associated with pump Insulin pump therapy may be are always the responsibility of the and infusion set malfunctions. efective in helping to manage parent/caregiver. Use of CGM de- Insulin doses in preschool child- toddlers’ eating behaviors by fa- vices in preschool children can be ren need to be modiied frequently cilitating split bolus dosing. he hampered by issues of adhesion as children of this age are growing pump calculates “insulin on bo- and skin irritation.131,132 rapidly and have changing pat- ard”, i.e. how many units from a he ability of some CGM de- terns of eating and sleeping. he previous dose of insulin that still vices to remotely transmit glucose decrease in size of insulin pumps exerts a glucose-lowering efect. A values to a phone can be of beneit and CGM devices (including the phone app that can calculate “in- ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 181 sulin on board” can be used for early, in order to treat promptly. low glucose levels indicates com- calculation of bolus doses of insu- he use of pumps and CGM are bined lack of CHO and insulin, lin when on injection therapy. often limited by skin reactions to commonly associated with gastro- Although CGM provides an the adhesive. Prepare the site a few enteritis in preschool children. overwhelming amount of data, it days prior to insertion by the use his can most often be treated is important to look for daily pat- of a skin moistener that preser- at home with ingestion of sugary terns (eg, the “modal day” when ves water. Topical corticosteroid luids and administration of extra downloading data), and adjust in- (group I or II) can be used to treat insulin subcutaneously. sulin-to-CHO ratios and correc- skin reactions and break the vicio- See the ISPAD Guidelines on tion factors only after a repeated us circle of itching after removal. Sick days for further advice.135 pattern has been identiied. he Ketoacidosis is a life-threatening frequency of insulin pump and 14 | KETONE MONITORING acute complication of diabetes that CGM use varies between centers. Measuring ketone bodies in blood demands care at a skilled hospi- Barriers to the use of these treat- (betahydroxybutyrate, BOHB) tal unit. Six percent of children ment options in preschool child- should be recommended as the younger than 6 years in the Uni- ren need to be explored. primary method of detecting and ted States and 4% of children in monitoring ketosis in preschool Germany/Austria (from data from 13 | SKIN CARE children with type 1 diabetes; see the Type 1 Diabetes Exchange here are very few data on speci- the ISPAD Guidelines on Sick clinic registry and the Prospecti- al considerations regarding skin days.135 Measurement of acetoa- ve Diabetes Follow-up Registry: care in preschool children with cetate in urine can be used as an DPV) have sufered from ketoaci- type 1 diabetes but CGM-related alternative, but gives less precise dosis during the past year.45 Edu- skin problems seem to be most information. As preschool child- cation of families on prevention of common in very young users.132 ren do not urinate on command, ketoacidosis is an essential part of CGM-related skin problems are especially when sick, results from diabetes care.140 See the ISPAD not associated with atopy.138 In blood ketone monitoring will be Guidelines on Diabetic Ketoaci- general, recommendations for site more easily available both for the dosis for further advice.140 use (including site selection, site child and parent. Blood ketone preparation, and site rotation) are checking also gives the health care 15 | HYPOGLYCEMIA similar as for older children. Many professional much better infor- Hypoglycemia, including fear of preschool children receive insu- mation to provide advice over the hypoglycemia, is a limitation to lin injections and insert infusion phone or in the emergency room. striving for normoglycemia. he sets and CGM sensors in their Ketones should be monitored risk of hypoglycemia presents a ma- buttocks, an area often covered when there is a suspicion of lack of jor physiological and psychological by a diaper. he abdomen, upper insulin raised either by high blood barrier to achieving optimal glyce- arm, and upper thigh regions are glucose (2 values above 14 mmol/L mic control, and may result in sig- also commonly used. For children within 2 hours that do not decline niicant emotional morbidity for under the age of 6 using insulin on a correction insulin dose) or patients and caregivers.29,141,142 pumps, data suggest that rates of when the child shows symptoms Young age is traditionally regarded scarring and lipohypertrophy are suggestive of ketosis (vomiting, as a marker of high risk of severe high (50% and 45%, respective- nausea, stomach pain, fever, or un- hypoglycemia during insulin tre- ly) but not diferent than in older clear illness). Elevated glucose le- atment. 29he frequency of severe children.139 vels and ketone levels suggest lack hypoglycemia has decreased over Injection, infusion, and CGM of insulin and should promptly be time in all children.29,35,143,144 sites should be properly prepared treated with injection of insulin In Germany and Austria, fewer and regularly rotated in order to 0.1 U/kg (or 10% of TDD) every than 2% of children younger than reduce the likelihood of lipohy- second hour until BOHB is below 6 years with type 1 diabetes have pertrophy, supericial scarring, in- 0.5 mmol/L. If levels are above 3.0 experienced a severe hypoglycemic fection, rashes, skin reactions, and mmol/L, the family should seek event with seizures/unconscious- dry skin. guidance by phone or in person ness during the previous year; in Injection, infusion, and CGM immediately, possibly in an emer- the United States this igure is less sites should be inspected by dia- gency room, due to the high risk than 3%.126 betes team members at every vi- of ketoacidosis. Slightly elevated he erratic daily life of a sit to the clinic to detect any skin BOHB (usually <1.0 mmol/ mol) preschool child (food intake, acti- problem or lipo-hyper/hypotrophy in combination with normal or vity, sleep, and sick days) has been

182 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se younger than 7 years most frequently have the lowest HbA1c. In Sweden, 74% of insulin-treated children younger than 7 years have HbA1c < 7.4% (<57 mmol/ mol), and the overall frequency of severe hypoglycemia (seizures/unconsciousness) in the pediatric age (0-18 years) is 2.5%.152 For deinitions and further information see the ISPAD Guideli- nes on Hypoglycemia.29

15.1 | Treatment of mild hypoglycemia in infants and preschool children Oral glucose as tablets, gel, or a drink (0.3 g glucose/kg bodyweight) is the preferred method of hypoglycemia treatment.29,153 his dose will raise plasma glucose approximately 2.5 to 3.6 mmol/L (45- 64 mg/ dL).29 It is important not to give too much CHO when treating hypoglycemia, in order to avoid subsequent hyperglycemia. Giving something that contains fat (ie, milk and chocolate) will slow down the gastric emptying, and cause a regarded as the explanation for the ask about thoughts and feelings slower rise in plasma glucose.154 historically high risk of severe hy- during and after the hypoglycemic Sucrose sweetened confectionary poglycemia in preschool children event. Fear of nocturnal hypogly- should not be routinely used to with type 1 diabetes. Preschool cemia is a particular challenge.142 treat hypoglycemia, as it can lead children are not yet able to iden- Fear is not correlated with the to increased risk of dental caries tify and articulate their symptoms numbers of hypoglycemic episo- and food refusal if the child learns and it can be very diicult for ca- des, but is related to their severity, that sweets are substituted for un- regivers to detect these symptoms. especially in mothers of children consumed food. It is important Prolonged nocturnal hypoglyce- who have experienced a hypogly- that hypoglycemia is not over-tre- mia is not uncommon in children cemic seizure. he use of insulin ated, as 5 to 7 g CHO is usual- younger than 7 years with type pumps and CGM has been repor- ly adequate in raising the plasma 1 diabetes as detected in CGM ted to decrease the risk of hypogly- glucose to normal levels for small studies,125,145–147which is asso- cemia.148,149 Insulin pumps children using intensive therapy. ciated with a higher risk of severe with low glucose suspend features To treat hypoglycemia in bre- hypoglycemia.146 appear to further reduce the time ast- or formula-fed infants, CHO he fear of an hypoglycemic spent in hypoglycemia.150,151 gel, diluted juice, or a glucose po- event, rather than the frequency he comparison of data lymer from a spoon or bottle can of hypoglycemic events, is associ- between the United States T1D be ofered. Honey should not be ated with higher HbA1c and poo- Exchange and German/Austri- given to infants younger than 1 rer HRQoL.141 he role of fear an DPV registries showed that year due to risk of botulism. of hypoglycemia cannot be unde- an HbA1c of <7.5% (<58 mmol/ restimated for parents of children mol) can frequently be achieved in 16 | SCREENING FOR AS- with type 1 diabetes.142 Asking children younger than 6 years with SOCIATED DISEASES about frequency and severity of type 1 diabetes without an incre- Early onset of type 1 diabetes is hypoglycemia is typical in a clinic ased risk of severe hypoglycemia. associated with a higher frequ- ▶ visit, and it may also be helpful to 126 In many countries, children ency of celiac disease compared www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 183 with older children, which afects misconceptions about diabetes. those tasks and assignments invol- the treatment situation of the Parents are an integral part of the ved in daily life with diabetes. It is child,155–157 and may inluence diabetes team and have the most important to engage both fathers the risk of complications and qua- important supportive role to play and mothers in diabetes care from lity of life. Repeated screening for over the years as their children the onset, and to keep them both celiac disease, thyroid disease, and eventually learn to self-mana- involved in everyday diabetes care other autoimmune disorders is es- ge their diabetes. Providing this throughout the childhood years. sential.158 support can be diicult when pa- Parents express that it is impor- rents have their own stressors to tant to explain to their child in 17 | LIVING WITH DIABETES deal with, and struggle with the very simple and clear terms what IN THE FAMILY constant vigilance needed to ensu- type 1 diabetes involves. here are For people living with type 1 di- re the safety of their child. Dashif certain aspects of diabetes ma- abetes and their families, the et al160 report that parents of ol- nagement that are not negotiable management of the condition der children with type 1 diabetes (glucose checking, insulin injec- is complex and individual. Da- experience an ongoing struggle, tions/pump site changes, CGM ily challenges imposed by type worry, and frustration about their use, etc), and the child needs to 1 diabetes include cognitive and parenting role. During young begin to understand that as early emotional burdens that can take childhood, parents take responsi- as possible. It is important to in- the form of increased vigilance bility for all diabetes-related tasks volve the child in diabetes mana- to dietary intake, symptom mo- such as insulin administration, gement as soon as possible so they nitoring, and frustrations with dosing calculations, blood glucose can begin to develop a sense of glucose excursions. For caregivers checking, and so It is important ownership/management of their of preschool children with type 1 that they do this in a way that is own disease. Reinforcing such an diabetes, additional complexities neither threatening nor frighte- attitude early on will help to shape are encountered, including the ning for their child. Involving the the child’s attitude and approach necessity to adapt to developme- child in aspects of diabetes ma- to diabetes in the future. ntal changes to ensure adequate nagement as soon as possible (eg, Parents report that diabetes will psychological adjustments for the inger pricks and CHO counting) often initially disrupt the normal child and themselves, and to faci- is recommended, so the child can parent-child relationship, as dia- litate care in the context of other begin to develop a sense of ow- betes frequently comes irst in the care providers such as preschool nership/management of their own mind of the parent in response to a staf.159 Clinicians need to be health. A supportive and emotio- child’s requests. It is important for aware of the overwhelming sense nally warm parenting style is im- parents to ask themselves, “If my of responsibility and worry which portant for promoting improved child didn’t have type 1 diabetes, parents of preschool children with quality of life for children with would I say no to this request?”, type 1 diabetes can feel. Parents type 1 diabetes.161 and thus strive to reestablish the who have access to a supportive Establishing good habits in normal parent-child relationship. network (relatives and/or friends) the early years will form the basis have lower risk of diabetes-rela- for optimal diabetes self-mana- 18 | SCREENING CHILDREN ted stress and burnout. 128 It is gement during adolescence and FOR PSYCHOSOCIAL DIST- important to educate secondary into adulthood. 2,92,106,107 In RESS caregivers about type 1 diabetes order to create an environment in Regular screening of children for and insulin treatment. Attention which parents feel conident and psychosocial distress is impor- should be given to the needs of the comfortable, it is crucial that they tant to ensure that diiculties are siblings of a child with type 1 di- are appropriately supported by all identiied early, and appropriate abetes. members of their multi-disciplina- support and treatment plans esta- As children grow, they under- ry team and that they have adequ- blished as soon as possible. Most stand more about health and ill- ate access to appropriate support children are not able to complete ness. When appropriate, it needs when they need it. he way that questionnaires or report on their to be explained that diabetes is not parents model diabetes-related own level of emotional distress caused by eating too much sugar, tasks will have a direct impact on in a reliable manner until they and that you cannot catch diabetes the way their children learn. Sup- are approximately 7 to 8 years of from another person. his needs to porting parents toward a positive age. herefore, either talking with be actively taught to friends and adjustment to living with diabetes them directly about how they feel, relatives as well to avoid common will help them to efectively model or asking their parents to report

184 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se on their children’s psychosocial so we recommend assessing anx- ration between the preschool, the well-being is recommended. For iety separately from depression. family, and the diabetes team. An children who are older, there are se- he Center for Epidemiological individually written diabetes ma- veral pediatric measures of depres- Studies-Depression Scale (CESD) nagement plan is helpful in this sive symptoms that are validated is often used as a measure of de- cooperation to help the child with and reliable for use with children pressive symptoms in adults, and type 1 diabetes,167 and should in- as young as 7 years of age, varying the Beck Depression as well as the clude information about and prac- in length and depth of detail. he- Beck Anxiety scales are also often tical training for the use of diabe- se include the Children’s Depres- used. Worries about diabetes im- tes-related technologies.168 Both sion Inventory (CDI)162 and the pact on glycemic control in child- the parents and the diabetes team Center for Epidemiologic Studies ren, should be acknowledged and need to share the responsibility for – Depression (CES-D) scale.163 addressed. educating the preschool institu- Both measures are self-reported tion, especially when the child is questionnaires containing items 19 | PRESCHOOL CARE newly diagnosed with diabetes or on types of symptoms (eg, sadness Many preschools provide excel- when additional diagnosis such and low self-esteem) and functio- lent care for children with type 1 as celiac disease occurs. Preschool nal areas (eg, not having friends, diabetes. Parents and health care staf often ind CHO counting schoolwork is not as good as it was professionals should work together helpful as it gives them a tool to as- before, and arguing with others). to overcome any diiculties and sess the dose of insulin to be given Pediatric quality of life can be ensure the safety and well-being in relation to the food intake and addressed by speciic questionn- of the child with type 1 diabetes current glucose level. In countries aires such as the Pediatric Quality when cared for outside the home where there are no regulations to of Life Inventory (PedsQL) generic setting. It is crucial that every support the child with diabetes, and Type 1 Diabetes modules.164 child is supported efectively to the diabetes team together with hese measures ofer a child achieve their full potential. Legi- the parent organizations should self-report for youth ages 5 to 7 slation protects children with type advocate for improved regulations. and also for youth ages 8 to here 1 diabetes in many countries. One Parents express that while regu- are also PedsQL parent proxy re- example is the Equality Act 2010 lations certainly help to ensure ports for children ages 2 to 18.164 (England, Scotland, and Wales) documentation and agreements Diabetes-speciic emotional dist- which dictates that schools must on daily care, maintaining a close ress can be assessed in children make reasonable adjustments to relationship with the school (staf, ages 8 to 11 Problem Areas in Di- ensure that children with disabi- teachers, etc) is equally if not more abetes Survey-Children (PAIDC) lities are not put at a substantial important to ensure efective daily and teens Problem Areas in Dia- disadvantage compared with their management of their child’s diabetes Survey-Teens (PAID-T) and peers. For diabetes, this means betes. Parents can be in very close parent’s diabetes-speciic emotio- schools ensuring they have eno- contact with the school, including nal distress can also be assessed ugh staf trained so that the child ofering training sessions, educa- (PPAID- C and P-PAID-T) in with diabetes can take part in all tional materials for other parents measures developed by Weissberg- aspects of preschool and school etc, which will lead to better and Benchell and colleagues. Similarly, life. Contingency plans must be more efective diabetes manage- diabetes-speciic emotional dist- in place to train replacement staf ment. his helps them to feel more ress from age 8 can be assessed by quickly. he Kids and Diabetes comfortable/ less stressed when the PAID-Parent (PAID-PR) scale in Schools (KiDS) program of sending their child to preschool. and from age 8 in youth with the the International Diabetes Fede- PAID-Peds scale, both developed ration (IDF) ofers education and 20 | ALTERNATIVE AND by Markowitz et al.165,166 Paren- guidance for families and school COMPLEMENTARY THERA- tal anxiety can have a direct and staf on ways to help children with PIES negative efect on diabetes ma- type 1 diabetes manage in school. At times families try alternati- nagement and health outcomes. KiDS information is available in ve indigenous remedies and even here can often be a comorbidity 10 languages (as of June 2017) and discontinue insulin. his can be of depression; however, they are 2 can be accessed online at http:// avoided if parents are counseled separate conditions and should be www. idf.org/education/kids. In regarding the absolute necessity treated separately. hey may act in addition to ensuring the rights of of insulin for the child’s survival. opposite directions with regard to the child with diabetes, it is im- Alternative therapies may be tole- diabetes management and control, portant to create trust and coope- rated if important for the family as ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 185 long as they do not interfere with infection, genital tract infection jection at school. It is very impor- the regular diabetes care, inclu- (candidiasis), enuresis, and ma- tant to motivate and explain this ding insulin doses, glucose moni- laria. Parents may take longer to to the school staf as the alternative toring and healthy food choices, come to terms with the diagnosis of giving a twice daily mixture of or impact the child’s growth or and the need for life-long insulin regular and NPH does not result development or deplete economic therapy. he inancial implica- in a physiological insulin proile. resources needed for insulin treat- tions of the condition add to the In a situation where food availa- ment. psychological distress brought bility is unpredictable, a child on about by the diagnosis. Risk of twice daily injections will expe- 21 | CARE FOR THE acute and chronic complications, rience hypoglycemia, while the PRESCHOOL CHILD WITH as well as mortality, is higher in child on multiple injections can TYPE 1 DIABETES IN LIMI- these children due to suboptimal adjust mealtime doses accordingly. TED RESOURCES SETTINGS management. 169 In the United Few patients are able to aford ana- Whenever possible, the guidelines States, young people of African log insulin and pen devices. described above in the preceding descent have increased risk of he use of insulin pumps is only sections should be followed. It is short-term complications (ketoa- afordable by a low percentage of important to remember that buil- cidosis and severe hypoglycemia) the population. Administration ding a good rapport with the fa- when adjusted for socioeconomic of small doses is therefore a prac- mily and providing comprehensive status,170 and higher HbA1c even tical challenge. In young infants, diabetes education are inexpensi- when adjusted for mean glucose parents may be taught to dilute ve, and remain the most efective levels.171 HbA1c was higher even insulin with normal saline (avai- strategies to improve diabetes ma- when fasting glucose is <7 mmol/L lable in 10 mL vials). he use of nagement by the family.37 Know- in black individuals both with and 0.3 mL insulin syringes (100U/ml, ledge about the efects of insulin, without diabetes compared with 30 U in total) allows an accurate food, and physical activity on glu- white, but the prognostic value of administration of half units, app- cose levels are essential to protect HbA1c for predicting cardiovas- ropriate for most preschool child- the child from acute and chronic cular disease, nephropathy and re- ren. Similarly, use of CGM rema- complications of diabetes under tinopathy were similar.172 ins unavailable for most children all circumstances. he irst few he inancial issues need to be with type 1 diabetes in the resour- visits of the family are the most addressed upfront by the treating ce-limited scenario, and frequent crucial in this regard. Initial app- team. he challenge of inding self-monitoring of blood glucose roach to diagnosis and treatment ways to support the families lies is the only method for monitoring is based upon staing and facilities chiely with the care providers. glycemia. However, even this may at specialized centers for the care he team should be familiar with not be feasible for some families of young children with diabetes, the governmental and non-govern- due to the high cost of blood glu- with many centers recommending mental agencies in the area that cose strips. If possible, the child hospitalization. may provide inancial assistance can be recommended a meal plan Parents should be counseled for procuring insulin and glucose with a relatively consistent CHO and educated in detail. he chal- strips, and ensure that parents have intake at meal and snack times lenges in managing type 1 diabe- access to these before the child is during the day to match the in- tes in the preschool child are seve- discharged home. Most preschool sulin regimen. he family can be ral-fold higher in resource limited children in resource-limited set- taught to have a high index of sus- settings. Awareness, health infra- tings remain on regular and NPH picion for hypoglycemia and trea- structure, and number of medical insulin administered by insulin ting it on suspicion, relying mostly professionals trained in the mana- syringes. With only regular and on urinary glucose monitoring for gement of childhood diabetes are NPH available (as in the DCCT insulin dosing, and to use SMBG inadequate for a signiicant pro- study), a multiple injection thera- at least on sick days if available.173 portion of the population in many py with regular insulin for meals With limited number of strips, the countries in South East Asia and and NPH insulin at bedtime can family can, for example, measure sub-Saharan Africa. he diagnosis be efective in teaching the fami- before and 2 hours after lunch 1 is often delayed, and may even be ly the relationship between insu- week, and before and after din- missed in some cases, resulting in lin dose and CHO content of the ner the next to get a more string- death before diagnosis. Common meal. CHO counting can be used ent picture of the day compared misdiagnoses are gastroenteritis, in this situation. he challenge to with random checks. Urine strips pneumonia, asthma, urinary tract overcome will be the lunchtime in- should be available for ketone mo-

186 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se and others who play a role in their daily care” (Daneman).174 he addition of new tools should enable families living with type 1 diabetes to provide incre- asingly efective therapy and support for preschool children with diabetes. he cognitive, motor and social immaturity, as well as the small body size of preschool children must be considered when designing new equipment, including sensors, insulin pumps, and (hybrid) closed-loop solutions for insulin delivery. It is important to include children younger than 7 years in both nitoring during sick days. sought immediately in the absen- epidemiological and clinical stu- Another issue that may com- ce of knowledge and diagnostic dies regarding treatment strategies pound the challenge in resourceli- measurements. and tools (both technical equip- mited settings is that some parents If the child is not feeling well ment and pharmacological) and may have low levels of literacy and with other symptoms, the irst line outcomes; moreover, when the health literacy, meaning thereby of treatment should be something youngest children with type 1 dia- that they cannot read the num- containing sugar to treat impen- betes are included in these studies, bers on the insulin syringe and on ding hypoglycemia. his should be data regarding children with ear- the glucometer. For example, in well known by all the older child- ly-onset diabetes must be presen- India, literacy rate is 74.04% ac- ren and adults who are close to ted separately to enable subgroup cording to the 15th oicial census the child with diabetes, and they analysis. Children younger than in 2011 (http://www.census2011. should know where to readily ind 7 years with type 1 diabetes con- co.in/literacy.php). In such cases, a source of sugar. To conclude, the stitute only approximately 10% it is helpful to identify a suitably goals of management of type 1 di- of the population of all children literate relative, friend or neigh- abetes in resource-limited settings and adolescents with type 1 diabe- bour who can undergo diabetes must be situated in the context of tes,126,152 but in many countries education along with the parents the resource-limited environment the incidence in this subgroup is and assist them in the domiciliary and based on the family’s educa- increasing most quickly. Collabo- management. he parents should tional and inancial status. Av- ration between centers is thus ne- also be encouraged to learn the oidance of acute life-threatening cessary in order to conduct studies basics of reading and writing. In complications and continuation that are suiciently powered. the case of low literacy, a simpler of regular treatment and follow-up insulin regime such as twice daily are the immediate goals. REFERENCES 1-174 and better dosing with premixed insulin can tables from www.ispad.org be given. Hearing the number of 22 | FUTURE NEEDS OF clicks from an insulin pen can ob- PRESCHOOL CHILDREN How to cite this article: Sundberg viate the need to read the number WITH TYPE 1 DIABETES F, Barnard K, Cato A, de Beaufort of units. Teaching the parents to “Diabetes during early childhood C, DiMeglio LA, Dooley G, Hers- recognize “Hi” and “Lo” on gluco- creates a psychosocial challenge to hey T, Hitchcock J, Jain V, Weiss- meter, to treat hypoglycemia based the families of these children. Suc- berg-Benchell J, Rami-Merhar B, on symptoms alone, and to recog- cessful management of infants and Smart CE, Hanas R. Managing nize hyperglycemia and ketonuria toddlers with diabetes depends on diabetes in preschool children. Pe- by urinary strips is also useful to a well functioning and educated diatr Diabetes. 2017;0:1–19. htt- prevent lifethreatening episodes. family, the availability of a diabe- ps://doi.org/10.1111/pedi.12554 Vomiting in a child with dia- tes health care team experienced in betes should always be regarded the treatment of these youngsters, Nyhetsinfo 25 juli 2017 as imminent ketoacidosis, and and the involvement of the exten- www red DiabetologNytt appropriate treatment should be ded family, child care personnel

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 187 HTA-rapport och DN-Debatt: Använd Avastin i stället för Lucentis Frågan om användning av läkemedel utanför godkänd indikation har blossat upp igen. I dag skriver Dagens Nyheter om en utvärdering av läkemedlen bland andra Lucentis (ranibizumab) och Avastin (bevacizu- mab), som gjorts av HTA-centrum vid Sahlgrenska universitetssjukhuset i Göteborg. HTA-centrumet anser att båda av åldersförändring i gula läcken. läkemedlen kan användas för be- En ny rapport visar att landsting- handling av åldersförändringar en skulle spara mångmiljonbelopp välfungerande ögonläkemedel på av gula läcken, trots att endast om man började använda läke- marknaden. Men till skillnad från Lucentis är godkänd för den indi- medlet Avastin mot sjukdomen cancerläkemedlet Avastin som kationen. Det inns inga mätbara – ett läkemedel som fungerar lika numera kostar ett par hundralap- och kliniskt relevanta skillnader bra som de betydligt dyrare alter- par per dos, kostar Lucentis drygt mellan de båda läkemedlen, anser nativen. Men frågan är kontrover- 9 000 kronor per dos. professor Henrik Sjövall, vid Sahl- siell eftersom Avastin inte är god- HTA-centrum vid Sahlgrenska grenska universitetssjukhuset, och känt för ändamålet. universitetssjukhuset i Göteborg, stödjer sig på utvärderingen som – Du blir inte blind men du för- som har uppdraget att granska publicerats i en rapport. lorar ditt centralseende. Du tappar och utvärdera nya behandlings- ”Det inns inget stöd för att ru- förmågan att se färger och detal- metoder, publicerade nyligen en tinmässigt använda det dyrare jer. Du kan orientera dig, se saker rapport där man undersökt efek- Lucentis i stället för Avastin, säger i periferin men i mitten ser du en ten och biverkningarna av de två Henrik Sjövall till tidningen. mörk läck. läkemedlen. I DN av Kerstin Wickström, kli- Så beskriver läkaren Per Po- – Vi har gått igenom ett massivt nisk expert på Läkemedelsverket. hjanen ögonsjukdomen våt ma- forskningsmaterial av studier gjor- ”Det är inte så att vi avråder kuladegeneration eller så kallad da enligt konstens alla regler. Det läkare från att använda Avastin, åldersförändring i gula läcken, vi hittade var väldigt intressant, vi värnar den fria förskrivnings- den vanligaste orsaken till syn- det inns inga mätbara och kli- rätten som läkare har. Men vi kan nedsättning hos äldre i Sverige och niskt relevanta skillnader mellan bara förorda användningen av ett västvärlden. de två läkemedlen över huvud ta- godkänt läkemedel”, säger Kerstin Länge fanns inget bra funge- get. Helhetsbilden är för mig kris- Wickström. rande läkemedel mot sjukdomen. tallklar – det inns inget stöd för Enligt HTA-utvärderingen Men i början av 2000-talet upp- att rutinmässigt använda det dy- skulle Västra Götalandregionen täckte läkare att vissa cancerpa- rare Lucentis i stället för Avastin, kunna spara upp till 85 miljoner tienter som behandlades med läke- säger Henrik Sjövall, professor och kronor per år om det billigare Av- medlet Avastin upplevde att de ick universitetsöverläkare vid Sahl- astin skulle användas i stället för bättre syn. Det visade sig att just grenska universitetssjukhuset och Lucentis. Ungefär hälften av alla dessa cancerpatienter även hade ål- en av författarna till rapporten. landsting och regioner använder dersförändringen i gula läcken – Det inns inga mätbara och kli- Avastin utanför godkänd indika- och att efekten av läkemedlet var niskt relevanta skillnader mellan tion i dag. orsaken till synförbättringen. de två läkemedlen i över huvud ta- Lucentis marknadsförs av Läkemedelsbolaget bakom Av- get. Helhetsbilden är för mig kris- Novartis. Avastin marknadsförs astin, amerikanska Genentech, tallklar – det inns inget stöd för av Roche. Avastin är ett läkemedel tog då fram ett nytt snarlikt lä- att rutinmässigt använda det dyra- som anävänds vid cancer och pa- kemedel – Lucentis – som registre Lucentis i stället för Avastin. tentet är utgånget. rerades som ett ögonpreparat hos HTA-centrum räknade också Läkemedelsverket. på hur mycket pengar Västra Gö- Från lakemedelsvarlden.se Henrik Sjövall, professor och talandsregionen skulle spara om universitetsöverläkare vid Sahl- ögonsjukvården gick över till att PUBLICERAD 2017-07-16 grenska universitetssjukhuset och använda det billigare läkemedlet DN Debatt en av författarna till rapporten. Avastin. Exakt vad landstinget be- Varje år drabbas tusentals personer Plötsligt fanns det ett godkänt, talar för läkemedlet vet man inte

188 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se eftersom det är en afärshemlighet, Att Avastin skulle godkännas inom bara några veckor. Vanliga men vanligtvis får landstingen en för behandling av åldersföränd- symptom är att man börjar se raka viss rabatt på det oiciella listpri- ringar i gula läcken är heller inte linjer som krokiga, att ansikten ser set. Enligt HTA-centrums beräk- troligt, säger Kerstin Wickström. förvrängda ut och att det centrala ningar handlar det om besparingar Läkemedelsföretaget måste näm- synfältet går förlorat. I stället ser på 46–85 miljoner kronor per år ligen ansöka till myndigheten personen en suddig, mörk läck i beroende på läkemedelsrabatt. om att få läkemedlet godkänt mitten. Ungefär hälften av Sveriges för ögonbehandling. Och det är Våta förändringar behand- landsting använder sig redan av samma företag som tillverkar den las med läkemedel som sprutas Avastin. Redan 2012 presentera- aktiva substansen i det billigare in i ögats glaskropp. Läkemedlet des en stor amerikansk studie som icke-godkända Avastin och det dy- bromsar bildandet av blodkärl visade att de två läkemedlen hade rare godkända Lucentis. under gula läcken och gör så att samma efekt och därefter valde – Företaget har alltså inte nå- mindre vätska läcker ut. Behand- lera landsting och regioner att got incitament att ansöka om ett lingen botar inte sjukdomen, men byta till det billigare preparatet. godkännande för Avastin, säger kan bromsa den. – Vi sparar 7–8 miljoner per år Kerstin Wickström. Källa: Vårdguiden 1177 genom att använda Avastin. Men Läs mer: ”Det handlar om att vi räknar inte så, vi räknar på hur skapa jämlik vård.” Fakta. Läkemedlens pris många ögon vi kan behandla. För Lucentis och Eylea kostar ungefär varje öga som vi behandlar med ett Fakta. Åldersförändring 9 000 kronor per dos enligt listpris. dyrare läkemedel får 15–20 ögon i gula fläcken Avastin kostar i sin tur omkring stå tillbaka, säger Per Pohjanen, Gula läcken kallas det område 3 300 kronor per förpackning. En överläkare inom Ögonsjukvård som inns i mitten av näthinnan. förpackning räcker till cirka 30 Norrbotten. Det inns två typer av åldersför- doser dvs kostnad 110 SEK istället Men det inns de som har in- ändringar i gula läcken, torra el- för 9000 SEK per patient. vändningar mot att använda det ler våta. Torra förändringar är den billigare alternativet Avastin efter- vanligaste formen av sjukdomen När landstingen upphandlar får de som läkemedlet inte är godkänt för och synen förändras långsamt. rabatt på läkemedlen och vad varje ändamålet. Mot det inns ingen efektiv be- landsting faktiskt betalar för res- – Det är inte så att vi avråder handling. pektive preparat är en afärshem- läkare från att använda Avastin, Våta förändringar är ovanligare. lighet. vi värnar den fria förskrivnings- Våta förändringar beror på att det Källa: Tandvårds- och läkemedels- rätten som läkare har. Men vi kan bildas blodkärl under gula läcken förmånsverket bara förorda användningen av ett som läcker blod och vätska, vilket Från www.dn.se godkänt läkemedel, säger Kerstin gör att gula läcken svullnar och Wickström, klinisk expert på syncellerna försämras. Nyhetsinfo 18 juli 2017 Läkemedelsverket. Synen kan försämras snabbt, www red DiabetologNytt

20% Reduction in Total Mortality 12 Years Prospective Study With Greater Diet Quality. N Engl J Med BACKGROUND sionals Follow-up Study from 1998 pants who had the greatest impro- Few studies have evaluated the re- through 2010. Changes in diet qu- vement in diet quality (13 to 33% lationship between changes in diet ality over the preceding 12 years improvement), as compared with quality over time and the risk of (1986–1998) were assessed with the those who had a relatively stable death. use of the Alternate Healthy Eating diet quality (0 to 3% improve- Index–2010 score, the Alternate ment), in the 12-year period were METHODS Mediterranean Diet score, and the the following: 0.91 (95% coni- We used Cox proportional-hazards Dietary Approaches to Stop Hy- dence interval [CI], 0.85 to 0.97) models to calculate adjusted hazard pertension (DASH) diet score. according to changes in the Alter- ratios for total and cause-speciic nate Healthy Eating Index score, mortality among 47,994 women RESULTS 0.84 (95 CI%, 0.78 to 0.91) accor- in the Nurses’ Health Study and he pooled hazard ratios for ding to changes in the Alternate 25,745 men in the Health Profes- all-cause mortality among partici- Mediterranean Diet score, and ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 189 0.89 (95% CI, 0.84 to 0.95) ac- ciated with reductions of 8% to follow-up period.20,21 In both cording to changes in the DASH 22% in the risk of death from any studies, follow-up rates exceeded score. cause15,16 and reductions of 19% 90% in both cohorts.22 A 20-percentile increase in diet to 28% in the risk of death from For the present study, the initi- scores (indicating an improved qu- cardiovascular disease and 11% to al cycle was set at 1986, baseline ality of diet) was signiicantly as- 23% in the risk of death from can- was set at 1998 (changes in diet sociated with a reduction in total cer.2-4,17 quality were calculated from 1986 mortality of 8 to 17% with the use Given such consistent evidence, through 1998), and the end of of the three diet indexes and a 7 to the 2015 Dietary Guidelines for follow-up was 2010. We excluded 15% reduction in the risk of death Americans recommended the Al- participants who had a history of from cardiovascular disease with ternate Healthy Eating Index, the cardiovascular disease or cancer at the use of the Alternate Healthy Alternate Mediterranean Diet, and or before baseline in 1998, missing Eating Index and Alternate Med- DASH as practical, understanda- information regarding diet and iterranean Diet. ble, and actionable diet plans for lifestyle covariates, or very low or Among participants who ma- the public.18 Such guidelines are high caloric intake (<800 kcal or intained a high-quality diet over important in the United States >4200 kcal per day in men and a 12-year period, the risk of death and globally because unhealthy <500 or >3500 kcal per day in from any cause was signiicantly diets have been ranked as a major women). We also excluded partici- lower — by 14% (95% CI, 8 to 19) factor contributing to death and pants who died before 1998. he when assessed with the Alternate health complications.19 Evalua- inal analysis included 47,994 wo- Healthy Eating Index score, 11% tion of changes in diet quality over men and 25,745 men. (95% CI, 5 to 18) when assessed time in relation to the subsequent with the Alternate Mediterranean risk of death would be important. CONCLUSION Diet score, and 9% (95% CI, 2 to Here, we evaluated the association In the present study, we found 15) when assessed with the DASH between 12- year changes (from consistent associations between score — than the risk among par- 1986 through 1998) in the three improved diet quality over 12 ticipants with consistently low diet diet-quality scores noted above years as assessed by the Alternate scores over time. and the subsequent risk of to- Healthy Eating Index, Alternate tal and cause-speciic death from Mediterranean Diet, and DASH CONCLUSIONS 1998 through 2010 among parti- scores and a reduced risk of de- Improved diet quality over 12 cipants in the Nurses’ Health Stu- ath in the subsequent 12 years. A years was consistently associated dy and the Health Professionals 20-percentile increase in dietqua- with a decreased risk of death. Follow-up Study. We also exami- lity scores was associated with an Funded by the National Institutes ned shortterm changes (baseline 8 to 17% reduction in mortality. of Health. to 8-year follow-up, 1986–1994) In contrast, worsening diet qu- and long-term changes (baseline ality over 12 years was associated FROM THE ARTICLE to 16-year follow-up, 1986–2002) with an increase in mortality of BACKGROUND in diet quality in relation to total 6 to 12%. he risk of death from Some epidemiologic studies of and cause-speciic mortality. any cause was signiicantly lower nutrition focus on dietary pat- (by 9 to 14%) among participants terns rather than single nutrients Methods who maintained a high-quality or foods to evaluate the associa- Study Population and Design he diet than among those who had tion between diet and health out- Nurses’ Health Study, a prospec- consistently low diet scores over comes.1 Accumulated evidence tive study that was initiated in time. Our results are consistent supports an association between 1976, enrolled 121,700 registered with those of recent meta-analyses healthy dietary patterns and a de- nurses who were 30 to 55 years of showing that higher dietquality creased risk of death.2-11 Results age. he Health Professionals Fol- scores measured with the Alterna- from recent studies suggest that low-up Study, a prospective study te Healthy Eating Index, Alternate improved diet quality, as assessed that was initiated in 1986, enrolled Mediterranean Diet, DASH, and by means of the Alternate Healt- 51,529 U.S. health professionals the Healthy Eating Index–2010 hy Eating Index–2010 score,12 who were 40 to 75 years of age. were associated with a 17 to 26% the Alternate Mediterranean Diet Baseline and follow-up question- reduction in the risk of death from score,10,13 and the Dietary App- naires were sent to participants any cause.15,16 We found a do- roaches to Stop Hypertension every 2 years to update medical se-dependent relationship between (DASH) diet score,14 was asso- and lifestyle information over the changes in diet quality over 12

190 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se associated with a reduction in the risk of death from cardiovascular disease,21,35 and this component is not included in the DASH score. Although some studies have shown a signiicantly reduced risk of death from cancer with good adherence to some dietary patterns,4-6 other studies have not shown such associations.2,8,32 years and total mortality. consumption of red and processed Our study did not provide hese results underscore the con- meats from 1.5 servings per day to consistent evidence that impro- cept that moderate improvements little consumption will result in an ving diet quality had a substantial in diet quality over time could improvement of 20 points in the efect on overall mortality from meaningfully decrease the risk of score. hese indings are broadly cancer. death, and conversely, worsening consistent with those of previous he strengths of our study diet quality may increase the risk. meta-analyses of the association include the prospective design, he change in the risk of death between consumption of nuts30 large sample sizes, high rates of was more pronounced when long- and red meat31 and mortality. follow-up, repeated assessment of er-term (16 years) rather than shor- In line with other studies, diet and lifestyle, and use of mul- ter-term (8 years) changes in diet stronger associations were seen tiple diet-quality scores. quality were considered. when overall deaths and deaths However, the study has certain Taken together, our indings from cardiovascular causes were limitations. Because dietary data provide support for the recom- analyzed, and null or weaker as- were reported by the participants, mendations of the 2015 Dietary sociations were observed for death measurement errors were inevita- Guidelines Advisory Committee from cancer.2,3,8,12,32 Our re- ble. However, our food frequency that it is not necessary to conform sults with respect to improvement questionnaires were extensively to a single diet plan to achieve in the Alternate Healthy Eating validated against diet records and healthy eating patterns.18 hese Index and a reduction in the risk biomarkers. Although we were three dietary patterns, although of death from cardiovascular di- able to adjust for many potential diferent in description and com- sease were expected, given that confounders, residual and unme- position, capture the essential ele- the Alternate Healthy Eating In- asured confounding could not be ments of a healthy diet. Common dex is based on current knowled- completely ruled out. We did not food groups in each score that ge of dietary factors contributing examine the association of each contributed most to improvements to cardiovascular disease.12 Evi- component of the scores and mor- were whole grains, vegetables, fru- dence supports the inverse asso- tality because we considered that a its, and ish or n− 3 fatty acids. ciation between higher scores in high diet quality is a combination To improve our comparison the Alternate Healthy Eating In- of multiple components that act of associations between the three dex2-4,6,8,16 or the Mediterra- synergistically. Finally, generaliza- scores that difer in scoring crite- nean-style diet10,11,13,32-34 and bility may be limited because par- ria and range, we evaluated the a lower risk of death from cardio- ticipants were mostly white health association with mortality using vascular disease in various popula- professionals and we only included a 20-percentile increase in each tions. We did not ind signiicant one third of the initial popula- score as a common unit for im- associations between changes in tion because of our study design. proving diet. For example, if we the DASH score and death from However, our indings are broadly assume a causal relationship, a cardiovascular causes. Although consistent with those from other person with an increase of 22 of the DASH score shares some food populations. 110 points in the Alternate Healt- and nutrient components with the In conclusion, among U.S. hy Eating Index score over a 12- two other scores, it does not in- adults, we observed consistent as- year period could reduce his or clude ish or speciic fatty acids, sociations between increasing diet her risk of death by nearly 20% which have been consistently asso- quality over 12 years and a redu- in the subsequent 12 years. An ciated with a reduced risk of car- ced risk of death. increase in consumption of nuts diovascular disease.21,33 In addi- and legumes from no servings to 1 tion, previous indings have shown Nyhetsinfo 14 juli 2017 serving per day and a reduction in that moderate alcohol intake is www red DiabetologNytt www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 191 Better Quick Screening pathway could aid and speed up in diagnosis of monogenic diabetes (MODY), 98% sens, 85% spec. Diab Care A biomarker-based screening method assessing levels of C-peptide fold increase in probability over and islet autoantibodies in patients with diabetes is an efective, inex- the background prevalence alone.” pensive approach to identify patients with monogenic forms of the he strength of the pathway, the researchers wrote, is in the in- disease, including maturity-onset diabetes of the young, according to tegration of both C-peptide and indings from a population-based assessment conducted in Britain. islet autoantibodies, rather than “Identifying patients with mono- no known genetic cause for their relying on clinical features. genic diabetes, particularly [matu- diabetes, 34 had conirmed mo- “his ofers a simple approach rity-onset diabetes of the young], nogenic diabetes at baseline and that does not require speciic cli- can be challenging,” Beverley M. eight had cystic ibrosis-related di- nician interpretation or complex Shields, PhD,senior lecturer in abetes. After urinary C-peptide to algorithms of diferent combina- medical statistics with the Insti- creatinine testing, 979 (76%) had tions of features,” the researchers tute of Biomedical and Clinical minimal endogenous insulin se- wrote. “By combining the two Science at the University of Exeter cretion, indicating type 1 diabetes, biomarkers, we increase the dis- Medical School, United Kingdom, and received no further testing. criminatory ability and allow the and colleagues wrote. Of the 386 patients then tested clinician to pick up even atypical “Monogenic diabetes is conir- for GAD or IA-2A autoantibodi- cases and rarer forms of monoge- med by molecular genetic testing, es, 170 (44%) tested positive, also nic diabetes, which traditional cri- but this is expensive, so testing all indicating type 1 diabetes, and re- teria may miss. he use of clinical patients is not feasible. An app- ceived no further testing. features, however, results in fewer roach that could be used to enrich he remaining 216 patients cases being sent for genetic testing for monogenic diabetes, increasing underwent sequencing for the th- that are negative, which clearly has the proportion identiied in tho- ree most common MODY-related cost implications.” se who undergo genetic testing, genes; eight tested positive, accor- he most cost-efective app- would be helpful.” ding to researchers. Of the 208 roach will likely involve a com- Shields and colleagues tested who tested negative for common bination of both biomarkers and a screening pathway using both MODY genes, additional testing clinical features, they noted, and C-peptide (via urinary C-peptide by targeted, next-generation se- further research is needed to de- to creatinine ratio) and glutamic quencing identiied mutations in termine whether the pickup rate acid decarboxylase (GAD) and genes associated with monogenic could be improved by integrating insulinoma-associated-2 autoan- diabetes in eight more patients. the pathway with clinical features, tibodies (IA-2A) to exclude type One additional patient had a MO- such as the MODY calculator. 1 diabetes in two populations DY-related mutation identiied with previously high pickup rates through exome sequencing. he http://www.diabetesgenes.org/ of maturity-onset diabetes of the results suggested a prevalence of content/mody-probability- young (MODY) — patients di- 3.6% (95% CI, 2.7-4.7) among calculator agnosed before age 30 years and the 1,407 recruited participants. currently younger than 50 years “A total of 199 out of 1,348 Disclosures: he authors report no from the areas surrounding Royal (15%) patients were put forward relevant inancial disclosures. Devon and Exeter NHS Founda- for genetic testing who were not From https://www.healio.com tion Trust (n = 716) and Ninewells found to have monogenic diabetes Hospital (n = 702), both in the (ie, 15% false-positive rate, so 85% United Kingdom. For all patients speciicity),” the researchers wrote. negative for antibodies with signi- “Assuming a 98% sensitivity and icant endogenous insulin, DNA 85% speciicity, the [positive pre- sequencing was performed for dictive value] for the pathway is known MODY-related mutations. 20%, suggesting a 1-in-5 pickup Within the cohort, 1,365 had rate for monogenic diabetes, a 5.6-

192 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Abstract genetic cause, 34 with mono- 2 diabetes misclassified as type 1 Population-Based Assessment genicdiabetes,and8withcystic diabetes will be treated with in- of a Biomarker-Based Screening fibrosis–relateddiabetes).Atotalo- sulin, whereas noninsulin therapy Pathway to Aid Diagnosis of Mo- f386outof 1,365 (28%) patients would be more appropriate. Diet nogenic Diabetes in Young-Onset had a UCPCR ‡0.2 nmol/mmol, and metformin are the treatment Patients. https://doi.org/10.2337/ and 216 out of 386 (56%) were ne- of choice in young type 2 diabe- dc17-0224. Beverley M. gative for GAD and IA2 and un- tes (5). Patients with MODY be- Shields,1,2 Maggie Shepherd,1,2 derwent molecular genetic testing. cause of mutations in the HNF1A Michelle Hudson,1 Timothy J. Seventeen new casesofmonoge- or HNF4A genes respond well to McDonald,1,3 Kevin Colclough,4 nicdiabetes werediagnosed(8com- low-dose sulphonylureas (6,7), and Jaime Peters,5 Bridget Knight,1,2 monMaturityOnset Diabetesof those with MODY because of mu- Chris Hyde,5 Sian Ellard,1,4 the Young [Sanger sequencing] tations in the GCK gene require Ewan R. Pearson,6 and Andrew and 9 rarer causes [next-generation no pharmacological treatment (8). T. Hattersley,1,2 on behalf of the sequencing]) in addition to the 34 Getting a correct diagnosis for all UNITED study team. known cases (estimated preva- forms of monogenic diabetes has lence of 3.6% [51/1,407] [95%CI important implications for mana- OBJECTIVE 2.7–4.7%]). he positive predic- gement of an individual’s diabetes, Monogenicdiabetes, a young-onset tive value was 20%, suggestinga a prognosis, and recognition of form of diabetes, is often misdiag- one-in-five detection rate for the associated clinicalf eatures; it also nosed a stype1 diabetes, resulting pathway. he negative predictive allows appropriate counseling of in unnecessary treatment with value was 99.9%. other family members regarding insulin. A screening approach for likely inheritance (4). monogenic diabetes is needed to CONCLUSIONS Identifying patients with mo- accurately select suitable patients hebiomarker screeningpathway- nogenic diabetes, particularly for expensive diagnostic genetic for monogenic diabetes isanefec- MODY, can be chal-lenging. Mo- testing. We used C-peptide and is- tive,cheap,and easily implemented nogenic diabetes is confirmed by let autoantibodies, highly sen-sitive approach to systematically screen- molecular genetic testing, but this and specific biomarkers for discri- ing all young-onset patients. he is expensive, so testing all patients minating type 1 from non–type 1 minimum prevalence of monoge- is not feasible. An approach that diabetes, in a biomarker screening nic diabetes is 3.6% of patients di- could be used to enrich for mo- pathway for monogenic diabetes. agnosed aged 30 years or younger. nogenic diabetes, increasing the proportion identified in those who RESEARCH DESIGN AND From the article undergo genetic testing, would METHODS be helpful. Clinical features can We studied patients diagnosed BACKGROUND aid identification of those who aged 30 years or younger, current- Correct classification of a patient’s may have an alternative diagno- ly younger than diabe-tes is important to ensure sis, and a prob-ability calculator 50 years,intwoU.K. regions he or she re-ceives the most app- has been developed to help deter- with existinghighdetectionofmo- ropriate treatment and ongoing mine which patients are likely to nogenicdiabetes. he biomarker management. he most common have the most common forms of screening pathway comprised form of diabetes in children and MODY (9). However, this will not three stages:1) assessment of en- young adults is type 1 diabetes, pick up other forms of monoge- dogenous insulin secretion using ac-counting for .90% of cases nic diabetes, and its performance urinary C-peptide/creatinine ra- (1,2). Other forms of diabetes in is weaker for detecting MODY in tio (UCPCR); 2) if UCPCR was this age group, such as monoge- insulin-treated patients com-pared ‡0.2 nmol/mmol, measurement nic diabetes (including Matu-ri- with non–insulin-treated patients. of GAD and IA2 islet autoanti- ty Onset Diabetes of the Young An alternative approach to bodies; and 3) if negative for both [MODY]), or young-onset type 2, enrich for monogenic diabetes autoantibodies, molecular genetic are not often con-sidered. It is esti- is to use biomarkers that have diagnostic testing for 35 mono-ge- mated that at least 80% of patients been shown to discriminate well nic diabetes subtypes. with MODY are misdiagnosed (3), between type 1 and other forms of and other rarer forms of monoge- young-onset diabetes. Type 1 dia- RESULTS nic diabetes often go unrecogni- betes is characterized by autoim- A total of 1,407 patients parti- zed because of lack of awareness mune destruc-tion of the b-cells in cipated (1,365 with no known (4). Patients with MODY or type the pancreas, leading to absolute ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 193 insulin deficiency, so two tests that and absence of islet autoantibodi- highlighting the importance of could be used to diagnose type 1 es. his allowed us to deter-mine looking for monogenic diabetes in di-abetes are is let autoantibodies the prevalence of all monogenic adult diabetes clinics. his may ex- (markers of the autoimmunepro- di-abetes subtypes in those diag- plain why the prevalence we find cess) and C-peptide (a marker of nosed at 30 years or younger and is higher thananyofthepreviouspe- insulin deficiency). C-peptide has to calculate the positive predic- diatricstudies. he strength of our been shown to be ahighly sensiti- tive values (PPVs) and neg-ative pathway is the in-tegration of two veand specific biomarker for dis- predictive values (NPVs) for the biomarkers (C-peptide and islet criminating be-tween type 1 and pathway. autoantibodies [both GAD and type 2 diabetes and MODY 3–5 IA2]), rather than relying on cli- years after diagnosis (10,11). CONCLUSIONS nical fea-tures. his ofers a simple Urine C-peptide/creatinine he biomarker screening pathway approach that does not require ratio (UCPCR) canbeusedtore- for monogenic diabetes is a syste- specific clinician inter-pretation movetheneedforblood samples, matic, cheap (U.K. UCPCR cost or complex algorithms of diferent which may be of particular con- of £10.80 and antibodies cost of combinations of features.Wes- cern in the pediatric population, £20), and easily imple-mented howed that by using clinical fea- and means that the sample can approach to screening all pa-tients tures alone, over half of the cases easily be taken at home and po- with young-onset diabetes in a cli- of monogenic diabetes would be sted to the labora-tory (12). GAD nic or population that helps iden- missed. and IA2 islet autoanti-bodies also tify suitable patients for molecular By combining the two biomar- discriminate well between type 1 diagnostic genetic testing. he kers, we increase the discrimi- and MODY, with cross-sectional pathway picked up new cases of na-tory ability and allow the clini- studies showing they are present monogenic diabetes, even in areas cian to pick up even atypical cases in 80% of patients with type 1 di- of existing high detection be-cause and rarer forms of monogenic diabetes and in ,1% of patients with of research interests in the regions. abetes, which tra-ditional crite- MODY (13). We found 3.6% of patients diag- ria may miss. he use of clin-ical hese biomarkers have been nosed at younger than 30 years of features, however, results in fewer used to screen for MODY in other age have monogenic diabetes. In cases being sent for genetic testing studies (14,15), but have been limi- areas in which no cases have been that are negative, which clearly has ted to pediatric cases only. Given identified, we estimate that 1 in 5 cost impli-cations.hemostcost-ef- the median age at diagnosis for patients referred for genetic testing fectiveapproach is likely to involve MODY is 20 years (from U.K. because of the pathway will have a combination of bio-markers and refer-rals data [3]), and there is on monogenic diabetes, which is a clinical features. Further studiesa- average a delay of 13 years from 5.6-fold higher detection rate than reneeded to determinewhether the diabetes diag-nosis to a confirmed if all patients in this age range re- pickup rate could be further im- genetic diagnosis (16), it is crucial ceived genetic testing. he high proved by integrating the pathway to study adults as well. NPV of 99.9% indicates it is an with clini-cal features, such as the Furthermore, the combined di- extremely efective approach for MODY calcula-tor, or whether agnostic performance of the two ruling out monogenic diabetes. this would result in moremissed- biomarkers as a screening pathway here have been relatively few patientsbecause ofreduced testing. has not been formally assessed. studies that have systematically In this study, we also systema- By excluding those with type1 screened whole populations for tically tested all known genes for diabetes using these two bio- monogenic diabetes. he majority monogenic diabetes, rather than markers, we can obtain a smaller of studies have been in pediatric just the most com-mon MODY percentage of patients in whom populations only (14,15,22–26), genes (GCK, HNF1A, and HN- diagnostic molecular testing for with only two studies that have F4A).Nineout of17 (53%) of the monogenic diabetes could be screened adults (27,28).Noother cases identified as part of our co- per-formed. We tested a screen- studyhas systematically screened hort had mu-tations identified ing pathway using both C-peptide a whole population of both adults through additional testing on and islet autoanti-bodies to exclu- and children together. Only 8 out the targetedcapture,and17outof de type 1 diabetes in two popula- of 51 (16%) of patients with a ge- 51 (33%) of all of the monogenic tions with previously high pickup netic diagnosis of monogenic dia- diabetes cases found in total had rates of MODY (3) and performed betes in our cohort were in the pe- mutations in other genes, high- genetic testing on all patients with diatric age range (younger than 20 lighting the advantage of further significant en-dogenous insulin years) at the time of recruitment, testing using targeted next-genera-

194 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se tion sequencing. for monogenic diabetes (99% for screening represent a PPV at the Health economic evaluation UCPCR [10,11] and .99% for islet background prev-alence rate of of the path way for detecting the auto-antibodies [13]), and by using 3.6%), misses fewer cases than common forms of MODY (GCK, both of these markers in a pathway, using clinical features alone, and HNF1A, and HNF4A) has been the number of missed cases should is at a level that has been shown carried out as a separate project, be minimal at a population level to be cost-efective (20,21). Fur- which has shown the pathway to (2% of 3.6% = 0.07%, reflected thermore, the screening pathway be cost-saving(20,21).hecost-ef- in the NPV of 99.9%). Although still provides useful test results fectiveness of additional testing there have been reports of MODY for this age group that of-fer ad- for other forms of monogenic di- pa-tients who are positive for islet ditional information to support abetes has not been as-sessed. Be- autoanti-bodies (reviewed in Ref. patient care. Patients with severe cause of the rarity of other mono- 13), these are rare and likely to be insulin deficiency, as determi- genic diabetes, there are few data cases with coinciden-tal type 1 di- ned by very low C-peptidevalues, available to inform such analyses. abetes. Previous studies re-porting will not respond to non-insulin Treat-ment change from insulin high prevalence of positive au- therapy (33). Positive C-peptide to sulphonylur-easisstillpossiblein- toantibodies in their cohort have and negative antibody results are casesdiagnosedwith ABCC8 and in-cluded clinically defined, rather impor-tantclinicallytohighlighta- KCNJ11 (29,30), and for other than ge-netically confirmed, typical casesof type1diabetesori- genes for which treatment change MODY (31) or use low cutofs for nwhichother forms of diabetes, is not an option, a confirmed di- antibody positivity, which can be such as young-onset type 2 di-abe- agnosis can still help with ma- inappropriate (32), and are likely tes, should be considered. Patients nagement, prognosis, and advice to represent an overestimate. he- with very high endogenous insulin on risk to other family members re is also the potential for missed with out is let auto antibodies and- (4). he decision whether to pay cases based onUCPCR,butaga- nomutations in monogenic diabe- for the more expensive, but more in,thenumberofthese patients will tes genes are likely to have type 2 comprehen-sive, next-generation be small, and as they have insulin diabetes and may be able to mana- sequencing, rather than Sanger levels suggestive of type 1 dia- ge on noninsulin treatment. sequencing for MODY genes only, be-tes (33), they are unlikely to be Finally, this study comprised a would depend on assessing the able to transfer of insulin even if a 98% white population and asses- tradeofs of additional costs with genetic diag-nosis is made. ses patients at a median of 14 years long-term benefits to the patient. A further limitation is that after diagnosis. Assessment of the he pres-ence of additional clini- despite screening using C-pepti- pathway in other racial groups and cal features (e.g., renal cysts associ- de and antibody testing, the PPV in patients close to diagnosis is ated with HNF1B) may also point is still fairly low at 20%, indi- needed. to specific monogenic diagno-ses cating four out of five screened In conclusion, we have demon- and increase the likelihood of a will not have a monogenic cause strated a simple, cheap, efective posi-tive genetic test result. identified on diagnostic molecu- screening path-way that could be A limitation of our study was lar genetic testing. However, the implemented at a pop-ulation level that we had small numbers of pa- aim of our screening path-way is to help correctly diagnose patients tients with monogenic diabetes on that it is used purely as a tool to with monogenic diabetes. which to evaluate the sensitivity of narrow down those individuals the pathway. Consider-ably larger who would be more appropriate Nyhetsinfo 14 juli 2017 studies have shown the biomarkers for genetic testing. his approach www red DiabetologNytt individually to be highly sen-sitive is a vast improve-ment over no www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 195 Swedish Diabetes Summit will take place November 21-22 in Gothenburg. See Program and More Info. No Cost for Registration, Free he Second Swedish Diabetes Welcome! Wednesday Summit will take place November On behalf of the organisers led 07.45–08.00 Cofee available 21-22 in Gothenburg. by Associate Professor Charlotta 08.00–10.10 Genetics his is a unique national diabe- Olofsson, University of Gothen- 08.00–08.40 Steve O’Rahilly, tes research meeting with speakers burg. Please, spread the word! University of representing as many as 8 dife- Cambridge rent Swedish universities as well as Preliminary programme 08.40–09.10 Charlotte Ling, guest speakers from abroad. Second Swedish Diabetes Summit Lund University he preliminary programme 21st –22nd November 2017, 09.10–09.40 Anders Rosengren, with the conirmed speakers is at- Gothenburg Lund University/ tached (presentation titles TBA). University of his symposium is targeted to Tuesday Gothenbur basic and clinical diabetes resear- 09.00–09.30 Registration, cofee 09.40–10.10 Carina Ämmälä, chers, researchers from industry, 09.30–09.40 Welcome address AstraZeneca, clinically active medical doctors/ 09.40–11.50 Treating metabolic Mölndal health care personnel and patient disease 10.10–10.40 Cofee organization representatives. 09.40–10.20 Roy Taylor, 10.40–11.40 Nutrition and We welcome abstracts to the Newcastle University exercise poster session. Two abstracts sub- 10.20–10.50 Fredrik Bäckhed, 10.40–11.10 Christian A mitted to the poster session will be University of Drevon, selected for a short (10 min) oral Gothenburg University of Oslo. presentation. 10.50–11.20 Lena Carlsson, 11.10–11.40 Anna Krook, Karo- http://neurophys.gu.se/english/ University of linska Institutet Research/second-swedish- Gothenburg 11.40–12.40 Lunch diabetes-summit/abstract-posters 11.20–11.50 Olov Andersson, 12.40–14.40 Islets Abstract submission to the pos- Karolinska Institutet 12.40–13.10 Helena Edlund, ter session - Institute of Neurosci- 11.50–13.00 Lunch, poster setup Umeå university ence and Physiology, University of 13.00–15.00 Type 1 diabetes 13.10–13.40 Per‐Olof Berggren, Gothenburg, Sweden neurophys. 13.00–13.30 Knut Dahl‐ Karolinska gu.se Jörgensen, Institutet University of Oslo 13.40–14.10 Patrik Rorsman, Abstract - Poster 13.30–14.00 Johan Jendle, University of Ox- Registration to the event is free of Örebro University ford/University of charge on a irst come irst serve 14.00–14.30 Daniel Espes, Gothenburg basis. Registration to the Second Uppsala University 14.10–14.40 Sebastian Barg, Swedish Diabetes Summit. 14.30–15.00 Helena Fadl, Uppsala University Conference delegates must care Örebro University 14.40 –15.10 Cofee for their own lodging. A list of 15.00 –15.30 Cofee 15.10–16.10 Neural Control of recommended hotels where subsi- 15.30–17.00 Adipose tissue metabolism dized prizes will be ofered can be 15.30–16.00 Peter Strålfors, 15.10–15.40 Tore Bengtsson, found on the symposium website Linköping University Stockholm University below. 16.00–16.30 Ingrid Dahlman, 15.40–16.10 Karolina Skibicka, http://neurophys.gu.se/english/ Karolinska Institutet University of Research/second-swedish- 16.30–17.00 Ingrid Wernstedt Gothenburg diabetes-summit/accommodation Asterholm, Univer- 16.10–16.40 Closure of meeting sity of Gothenburg (including 2x10min More information: http:// 17.00–19.00 Bufet dinner with poster presentations) neurophys.gu.se/english/ poster viewing Research/second-swedish- Nyhetsinfo 11 juli 2017 diabetes-summit www red DiabetologNytt

196 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Diabetes Mellitus More Prevalent In Psychiatric Patients Than General Population, Meta-analysis 32 Studies. Journal of Gen Hosp The prevalence of diabetes and disorders, with little variation in RELATED ARTICLES impairment in glucose meta- prevalence of unspeciied DM by Mental Health, Behavioral Scre- bolism are noticeably higher in psychiatric category (11% across enings Vital for Pediatric Pa- all inpatient disorders, 95% CI, tients With T1DOSA Linked psychiatric patients. 10-12). to Sight-hreatening Diabetic Diabetes mellitus (DM) appears Retinopathy in Type 2 Diabetes- to be more prevalent in the psychi- he etiology of this increased pre- Concomitant Use of Antidepres- atric setting than in the general po- valence was not clear, although the sants, Antipsychotics Linked to pulation, according to the results investigators suggested that links T2D Risk Antipsychotics Have of a recent meta-analysis from the to antipsychotic medication use in Few Negative Long-term Efects United Kingdom published ear- these patients could be a factor.4,5 on Schizophrenia OutcomesSchi- lier this year in General Hospital “he study did not set out to exa- zophrenia Symptoms May Beneit Psychiatry.1 Both inpatients and mine the etiology of abnormal glu- From Speciic Kind of Talk he- outpatients with psychiatric con- cose metabolism in these patients, rapy ditions were more likely to have a but to document its prevalence in diagnosis of DM, or to have im- these settings,” study co-investiga- References paired fasting glucose (IFG) or tor, Emmert Roberts, MA, BM- Roberts E, Jones L, Blackman A, et al. he prevalence of diabetes mellitus and abnor- impaired glucose tolerance (IGT) BCh, MRCP (UK), MRCPsych, mal glucose metabolism in the inpatient than patients without a psychiatric DFSRH, of the Institute of Psychi- setting: a systematic review and meta-ana- condition.2,3 atry, Psychology and Neuroscience lysis[published online January 11, 2017]. at King’s College London, in the Gen Hosp Psychiatrydoi:10.1016/j.gen- he investigators evaluated 36 stu- hosppsych.2017.01.003. United Kingdom, told Psychiatry Global status report on noncommuni- dies from Europe, Asia, and North Advisor. cable diseases 2014. Geneva:World Health America involving 42 psychiatric Organization; 2012. www.who.int/nmh/ cohorts for the prevalence of mul- he study indings indicated a publications/ncd-status-report-2014/en/. tiple impairments of glucose me- need for psychiatrists to give at- Accessed June 30, 2017.Vancampfort D, Correll CU, Galling B, et al. tabolism. Unspeciied DM was tention to their patients’ glucose Diabetes mellitus in people with schi- reported in 10% of all patients metabolism status. “We would re- zophrenia, bipolar disorder and major de- evaluated from 31 studies (95% commend that routine screening pressive disorder: a systematic review and CI, range 9-12), while the preva- take place in psychiatric inpatient large scale meta-analysis. World Psychi- lence of type 1 DM was 1% (0-1) atry. 2016;15(2):166-174. doi:10.1002/ settings for not only DM but also wps.20309Galling B, Roldán A, Nielsen and type 2 DM was 9% (613) re- pre-diabetic states of abnormal RE, et al. ported in 5 and 13 studies, respec- glucose metabolism,” Dr. Roberts Type 2 diabetes mellitus in youth ex- tively. he prevalence of IFG was said. he researchers contend that posed to antipsychotics: a systematic re- 18% (8-28, 7 studies), and of IGT such screening would present op- view and meta-analysis. JAMA Psychi- at 2016;73(3):247-259. doi:10.1001/ 22% (16-28, 3 studies). portunities for timely intervention jamapsychiatry.2015.2923.Leslie DL, Ro- with metabolic issues that might senheck RA. his meant that 1 of every 10 be contributing to psychiatric Incidence of newly diagnosed diabe- psychiatric patients studied was illnesses. “A prevalence of 1 in 5 tes attributable to atypical antipsycho- diagnosed with DM, 1 in 5 with tic medications. Am J Psychiatry for IFG or IGT is higher than es- 2004;161(9):1709-1711. doi:10.1001/ja- IFG, and 1 in 5 with IPG. he timates for number of inpatients mapsychiatry.2015.2923. prevalence rates did not vary by with bipolar afective disorder and continent or by type of inpatient some personality disorders across From wwww.psychiatryadvisor. setting. all inpatient settings, suggesting com/ that abnormal glucose metabo- he range of psychiatric diag- lism should be an essential part of Nyhetsinfo 11 juli 2017 noses included schizophrenic or psychiatric postgraduate examina- www red DiabetologNytt schizoafective disorders, mood tion, training and expertise,” they disorders, and substance abuse concluded.

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 197 ADA Report. Metformin particularly effective in those with history of GDM, 41% reduced risk for T2DM after 15 years. Dpp diabetes prevention program SAN DIEGO — Long-term use mass index (BMI) and impaired Nathan pointed out. of metformin shows a particular- glucose tolerance. hey were ran- At 15 years, the diferences ly strong efect in preventing the domized to one of three groups: between the subgroups in the be- development of type 2 diabetes intensive lifestyle interventions neits of metformin also waned, among women who’ve had gesta- with diet and exercise, 850-mg so that the efects of metformin tional diabetes, according to data metformin twice a day, or place- were for the most part no longer presented at the American Diabe- bo. DPP ran through 2002 and signiicantly diferent in these sub- tes Association (ADA) 2017 Scien- compared the incidence of diabe- groups, with the exception of the tiic Sessions. tes — deined as a fasting plasma women with a history of gestatio- hese latest indings come from glucose of 126 mg/dL or greater, nal diabetes. the Diabetes Prevention Program or a 2-hour oral glucose tolerance (DPP) and its extension phase. test of 200 mg/dL or more — in Clinical Implications After 15 years from the start of each of the groups. When considering which of their DPP, women with a history of ge- As has already been reported, patients should receive metformin, stational diabetes taking metformin those in the placebo group deve- clinicians should now ”be more li- still had a 41% reduced risk of type loped diabetes at a rate of 11% per kely to prescribe it” to women with 2 diabetes, compared with an 11% year, while the lifestyle interven- a history of gestational diabetes, reduction in parous women with no tion was associated with a 58% ”who were shown in this study to history of gestational diabetes. decrease in the risk of diabetes and have the biggest impact in terms of his contrasts with an overall metformin was linked to a 31% re- diabetes reduction,” said Dr Jaga- efect of metformin in reducing duction in risk. sia. the risk of type 2 diabetes by 18% In that original analysis, met- ”hese are the patients in whom in the study cohort as a whole. formin reduced the risk of future we would be more likely to go the ”he overall results reinforce diabetes by 51% in women with metformin route if for any reason the long-lasting eicacy of metfor- a history of gestational diabetes. intensive lifestyle modiication or min in reducing the development Two other subgroups of patients a 5% to 10% reduction in body of diabetes and support its more also seemed to gain greater beneit weight is not possible,” she added. widespread use as a prevention from metformin — those young- However, lifestyle modiica- measure in those at high risk,” said er than 60 years of age and those tion should always be tried irst, David M Nathan, MD, director with a BMI >35 kgm2. she stressed to Medscape Medi- of the Diabetes Center at Massa- At the conclusion of the DPP, cal News. ”Whenever clinicians chusetts General Hospital, Bos- the placebo was stopped, and all prescribe medication for diabetes, ton, the study chair of DPP, who patients were ofered a slightly dif- it is always in addition to lifestyle presented these latest results at the ferent lifestyle intervention. In ad- changes.” conference. dition, metformin continued to be Dr Nathan reports no relevant Asked for comment, Shubhada provided to the people in the origi- inancial relationships. Disclosures Jagasia, MD, professor of medicine nal metformin group. his exten- for the coauthors are listed in the and vice chair of clinical afairs in sion phase — known as the Diabe- abstract. Dr Jagasia disclosed no the department of medicine, Van- tes Prevention Program Outcomes relevant inancial relationships. derbilt University Medical Center, Study (DPPOS) — was started American Diabetes Association Nashville, Tennessee, told Meds- in 2003 and is still ongoing, with 2017 Scientiic Sessions. June 11, cape Medical News that these new 88% of the original volunteers still 2017; San Diego, California. Ab- data should help doctors to target participating. stract 169-OR metformin treatment to those who Over time, the 31% reduction will beneit most. in diabetes risk initially seen with From www.medscape.com metformin waned to 18% by 10 DPP: An Ongoing Investigation years and has remained stable, so Nyhetsinfo 7 juli 2017 DPP started in 1996 and followed ”an 18% reduction is the overall www red DiabetologNytt individuals who were at high risk result, compared with people in of diabetes on the basis of body the original placebo group,” Dr

198 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Diabetesutbildningar i höst i Sverige för läkare och sjusköterskor. När? Var? Hur? - Inkretiner tivitet och maten. Glukoskon- diabeteshandboken.se i samar- – Insuliner, för diabetesteam, troll-mål-tablettbehandling bete med distriktsläkare.com 1 dag Stockholm 19 - 20 oktober Göte- http://www.fokusdip.se/utbild- Steg 2 (Heldag) borg 9 - 10 november Malmö 23 ningar-moten/dip-nar-var-hur Insulin och kombinationsbehand- - 24 november ling samt patientinformation vid Dagen bygger på aktivitet från insulinbehandling. Produktinfor- Lilly Academy deltagarna med diskussioner mation om våra insuliner. https://www.lillyacademy.com/se/ och grupparbeten. Utbildning- news/news.aspx Utbildningar mm en innehåller därför praktiska Steg 3 (Heldag) från Lilly övningar och verkligheten: Bak- Kardiovaskulära komplikationer, Uppdatering diabetes för all- grund och patofysiologi, Behand- retino-, neuro- och nefropati och mänläkare anställda i Närhälsan lingsarsenalen, Målvärden, Inkre- diabetesfoten. samt ST. tiner Kontakta utbildningsansvarig https://www.narhalsan.se/ Novo Nordisk Trollhättan 23 maj Annelie Jörnvik Karlsson, om-narhalsan/for-vardgivare/ Skövde 31 maj e-post: annelie.jornvik.karlsson@ KursDoktorn/kurser2/kurser/ Karlstad 28 sep sanoi.com. uppdatering-diabetes/ Västerås 11 oktober DIP Öppen inns kurstilfällen be- Uppdatering diabetes typ 2 Kurs i första hand typ-2-diabe- slutad för läkare tes och utgår ifrån verkliga pri- https://distriktslakare.com/utbild- märvårdsfall som allmänläkaren Sanofi Balans ning/ träfar i sin kliniska vardag. Ut- En interaktiv utbildning för dia- En praktisk klinisk inriktad redning, diagnostik, utformning betesteam. 3 heldagar vid 3 olika utbildning för distriktsläkare. 2 av individualiserad behandling, tillfällen dagar vanliga komplikationer och före- http://www.sanoi.se/l/se/sv/ Hur ska vi individualisera dia- byggande arbete. layout.jsp?scat=35E60207-9B1F- betesbehandlingen, Nyheter, In- 4427-83D1- sulin, ”nya” läkemedel, Njuren, Nyhetsinfo 7 juli 2017 Fotsår, Lipider. Utbildningen ut- www red DiabetologNytt Steg 1 (Heldag) går mycket från patientfall. Den Diagnostik och klassiikation, är oberoende av producent och screening, prevention, fysisk ak- läkemedelsindustri.

Sveriges första tv-gala till förmån för diabetes 14/11 TV3 Diabetes är en av våra stora folksjukdomar, ändå får sjukdomen inte den uppmärksamhet som de drabbade förtjänar. Därför kan vi nu stolt avslöja att vi sänder Sveriges första direkt- sända TV-gala till förmån för diabetes, den 14 november kl. 20.00 på TV3, Viafree och Viaplay. Galan sänds direkt från Vin- terträdgården på Grand Hôtel i Stockholm och görs i samarbete Från www patientföreningen Nyhetsinfo 1 juli 2017 med MTG. Svenska Diabetesförbundet www red DiabetologNytt

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 199 Many people with type 1 diabetes still make some insulin surprising finding hints at potential future therapy. Swedish Study, Diab Care Almost half of people with type 1 despite their long-standing type ily needs. To survive, people with diabetes are still producing some 1 diabetes had higher levels of a type 1 diabetes must replace that insulin more than a decade after protein called interleukin-35. his lost insulin through multiple daily being diagnosed with the disease. protein appears to play an impor- injections or through a tiny tube he new indings challenge tant role in the immune system. inserted under the skin every few previous assumptions that people Past research had shown that days and then attached to an insu- with type 1 diabetes lose the abi- both newly diagnosed people with lin pump. lity to produce any insulin -- a type 1 diabetes and those who’ve he Uppsala researchers have hormone that helps usher sugar to had the disease for some time had launched a new study to see if they cells to be used as fuel -- over time. lower average levels of interleuk- may be able to boost insulin pro- Researchers at Sweden’s Uppsa- in-35 compared to healthy people. duction in those people with type la University, led by post-doctoral Type 1 diabetes is an autoim- 1 diabetes who are still making researcher Daniel Espes, reached mune disease that causes the bo- insulin. their conclusions after studying dy’s immune system to mistakenly he study appears in the June more than 100 patients with type attack healthy cells in the pancreas issue of Diabetes Care. 1 diabetes. that make insulin. he investigators found that his leaves people without eno- Nyhetsinfo 7 juli 2017 people who still produced insulin ugh insulin to meet the body’s da- www red DiabetologNytt

Marcus Lind, Sahlgrenska Akademin, får hedervärt Jubileumspris från Sv Läkaresällskapet för sin forskning kring diabetes typ 1 och 2. 150 000 SEK I år går Svenska Läkaresällskapets stora Jubilemspris till forskare inom diabetesområdet. Det händer kanske vart 5:e år - och nog nu framöver än mer ofta. Priset delas ut på Svenska Läkare- nationella och internationella epi- sällskapet 14/11. Av en händelse är demiologiska studier i världsklass det samtidigt Världsdiabetesdagen för att bättre förstå prognosen vid med events world wide, i Sverige, typ 1- och typ 2-diabetes och hur nationellt, regionalt och nationellt, sjukdomarna bör behandlas för att för awareness-kampanj och upp- minska risken för organskador och märksamma diabetes uppnå normal livslängd. Foto Anette Juhlin - Jag är oerhört glad och känner Press release Svenska Läkaresäll- mig mycket hedrad att få ta emot ning bidragit till kunskap och ut- skapet 170629 09.45 detta ina pris. Det känns mycket veckling av så kallad kontinuerlig unikt då det går till en pristagare blodsocker-mätning, en subkutan ”Behandling mot diabetes, inom hela det medicinska området sensor som många patienter med inte om utan när!” och det inns så många discipliner. typ 1-diabetes idag använder för Diabetesforskare Marcus Lind, Jag känner mig oerhört stimule- behandling av sin sjukdom. Göteborgs universitet, får Svens- rad för framtida forskningspro- Behandlingen innebär att blod- ka Läkaresällskapets Jubileums- jekt. Priset är mycket anrikt med sockret blir bättre och riskerna för pris, 150 000 kronor, för banbry- dess långa tradition ända sedan låga blodsockervärden mindre. tande kliniska prövningar inom 1800-talet. Jag hoppas det kommer Den leder också till ökad livskva- typ 1- och typ 2-diabetes i syfte ge spin-of-efekter inom diabetes- litet och trygghet i behandlingen. att förbättra behandlingarna för vården och diabetesforskningen” Inom typ 2-diabetes har Marcus dessa sjukdomar. Han har utfört Marcus Lind har med sin forsk- Lind utfört studier inom bland

200 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se annat inkretinbaserad behandling. nås för att få en bättre prognos. PRISUTDELNING Han var till exempel den förste att Vidare var han en av de första att Priset kommer att delas ut vid Lä- i en placebo-kontrollerad studie studera efekter på hjärtsvikt vid karesällskapets Årshögtid den 14 visa att patienter med svårbehand- typ 1-diabetes i populationsbase- november 2017. lad typ 2-diabetes, som behöver rade studier. Svenska Läkaresällskapet är lä- lera insulininjektioner per dag, Marcus Linds studier har un- karkårens oberoende vetenskapli- har nytta av denna behandling. der de senaste åren publicerats i ga och professionella organisation Inom det epidemiologiska samtliga av världens ledande kli- och arbetar för en förbättrad häl- området har Marcus Lind utfört niska vetenskapliga tidskrifter som sa och sjukvård i samhället. Vi är nyckelstudier såväl i Sverige som New England Journal of Medici- en politiskt och fackligt obunden i andra länder, däribland Kanada ne, Lancet, Journal of American ideell förening med cirka 10 500 och Storbritannien för att bättre Medical Association (JAMA) och medlemmar. Vi arrangerar kon- förstå prognosen vid typ 1- och British Medical Journal (BMJ).för ferenser, seminarier och debatter typ 2-diabetes. frågor om hans forskning. och stödjer medicinsk forskning. Han har bland annat visat hur Marcus Lind är lektor och do- Mer information hittar du på dödligheten skiljer sig vid typ 1- cent i Diabetologi, Sahlgrenska www.sls.se och typ 2-diabetes jämfört med Akademin, Göteborgs Universi- övriga befolkningen och vilka ni- tet, samt överläkare i Diabetologi, Nyhetsinfo 7 juli 2017 våer på riskfaktorer som behöver NU-Sjukvården, Uddevalla. www red DiabetologNytt

Vilket bröd ska vi helst äta? Avhandling Pernilla Sandvik, Uppsala Brödvalet en klassfråga smak och hälsosamhet, och vad de konsumenttestet. I konsument- Vilket bröd vi väljer att äta som själva väljer att äta. 398 personer testet provsmakades bröden blint, vuxna påverkas av både utbild- alla mellan 18 och 80 år var med det vill säga utan information ningsnivå och vilket bröd vi ick och provsmakade bröden. om vilket bröd det var. Smaken när vi var barn. Yngre personer fö- på de mest hälsosamma bröden redrar mindre hälsosamt bröd och Smaktest stick i stäv med den yngre grup- äldre föredrar hälsosammare bröd. I provsmakningen användes fär- pens smakpreferenser. Personer Det visar en ny avhandling om råg digpackade bröd från stora bage- mellan 18 och 44 år föredrar bröd från Uppsala universitet. rier som säljs i livsmedelsbutiker med en mild smak, lågt tuggmot- Det är känt att rågbröd på över hela Sverige. stånd, utan fullkorn och med ett många sätt är hälsosammare än Smaken på 24 bröd kartlades lågt innehåll av råg, medan den bröd bakat på vete. Rågbröd ger en med hjälp av en tränad sensorisk äldre (45-80 år) oftare föredrog jämnare blodsockernivå, en läng- panel, sedan valdes ett represen- smaken av bröden med mycket re mättnad, skapar viktkontroll, tativt urval av 9 olika bröd ut till fullkornsråg. motverkar typ 2-diabetes och är positivt för tarmloran. Ändå äter vi i Sverige mycket mindre råg jämfört med andra nordiska län- der, bara drygt 11 kg per person och år jämfört med Finlands 16 kilo per person och år. Men viktigast när vi väljer vilket bröd vi ska äta är ändå att det sma- kar gott. Men gott är inte alltid det mest hälsosamma, skriver Pernilla Sandvik, forskare vid institutionen för kostvetenskap vid Uppsala universitet, i sin nya avhandling. Hon har undersökt hur människor uppfattar olika bröd när det gäller ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 201 - I båda åldersgrupperna var den visar att även om det står råg tycka om nya smaker även i vux- det tydligt att de som i större ut- eller surdeg på förpackningen kan en ålder, visar studien på vikten av sträckning föredrog ljust, mjukt innehållet vara lågt. Idag inns att tidigt vänja sig vid olika sma- bröd med mer sötma hade en lägre inte heller några godkända märk- ker men också på potentialen för utbildningsnivå och hade i större ningar som hjälper konsumenten brödindustrin att utveckla bröd utsträckning ätit vitt bröd under välja till exempel ett bröd som bi- med en hög andel siktad råg. Det uppväxten, säger Pernilla Sandvik. drar till en jämn blodsockernivå. ger en mildare smak, mjukare textur och kan samtidigt stabili- Ska vara bra för magen Tuggmotstånd sera blodsockerhalten. En ökad I avhandlingen tycker konsumen- En studie av mjukt bröd i Sveri- rågbrödkonsumtion skulle kunna terna att ett hälsosamt bröd ska ge, innehållande 15-100 procent ha en positiv efekt på folkhälsan vara bra för magen, bidra till ett råg visar att vi kan ta hjälp av vårt men först måste de vara tillgäng- balanserat blodsockersvar och vara smaksinne för att hitta det häl- liga och smaka gott, säger Pernilla mättande. Råg och surdeg uppfat- sosammare rågbrödet. Bröd som Sandvik. tas som hälsosamt i bröd. Många bidrog till mer jämna blodsocker- upplever att det är svårt att veta nivåer karaktäriserades av en kom- Källa: Pressmeddelande från Upp- vilket bröd som är hälsosamt, men pakt textur, ett högt tuggmotstånd sala universitet tycker att ett rågbröd ska innehålla och eller en tydligt syrlig smak. 70 procent råg. Om brödet är mörkt eller ljust spe- Nyhetsinfo 28 juni 2017 En kartläggning av 24 mjuka lar mindre roll. www red DiabetologNytt rågbröd på den svenska markna- - Även om man kan lära sig

TLV kan lära av Frankrike. Se utvärdering och konklusion av Libre. Nationell reimbursement T1DM och T2DM med flerdosinsulin Haute Autorité De Santé HAS veral times a day (≥ 3 per day). Se nedtill hur TLVs motsvarighet i National Committee for the he FREESTYLE LIBRE sys- Frankrike arbetar Evaluation of Medical Devi- tem is especially designed for pa- Kanske kan TLV lärdom hur ces and Health Technologies tients who have received therapeu- en motsvarande process kring CNEDiMTS Review 12th July tic education and speciic training medicinteknik i Sverige kan ske. 2016 Following the inspection da- on the use of the lash interstitial ted 28th June 2016, CNEDiMTS glucose monitoring system. Frankrikes har fokuserat på den adopted the draft review on 12th behandling patienterna faktiskt July 2016 Actual Benefit (AB): behöver. Suicient, due to: Conclusions · he diagnostic value of the FRE- 1. Först gjorde man en en HTH- FREESTYLE LIBRE Flash Glu- ESTYLE LIBRE system analys via Haute Autorité De cose Monitoring System · he interests of public health due Santé. Applicant: ABBOTT France to the seriousness of complications S.A.S. Manufacturer: ABBOTT caused by type 1 or type 2 diabetes 2. Sedan gjorde man en nationell (USA) prisförhandling. Retained Comparator: Retained Indications: Self-monitoring of blood glucose 3. Utfallet blev estimerat 300 000 Measuring interstitial glucose le- using a single capillary blood glu- individer med diabetes dvs ler- vels in the treatment of patients cose meter dosbehandlade T1 och T2 DM. with type 1 or type 2 diabetes Added Clinical Value (ADV) (adults and children aged at least ASA Level III Nyhetsinfo 4 years) undergoing intensiied www red DiabetologNytt insulin therapy (using an external Type of Inclusion on Reim- insulin pump or ≥ 3 injections per bursement List: day) and performing self-monito- Brand name ring of blood glucose (SMBG) se- Duration of Inclusion: 5 years

202 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Analyzed Data: must be ensured by a diabetologist ning is provided by a pump center - Two prospective non-randomi- or a pediatric diabetologist. or any other center that provides zed, multi-center studies to evalu- care for diabetic patients and is ate the performance of the FRE- Initiation phase: involved in therapeutic education ESTYLE LIBRE system in terms Before issuing a long-term pres- programs validated by the Regio- of accuracy and precision, com- cription, the arrangements shall nal Health Agencies (ARS)[1]. It is pared to the values of capillary allow the provision of the FRE- essential to plan this SMBG with blood glucose on 75 patients, and ESTYLE LIBRE system for: the patient and/or his caregivers, 89 adult patients aged 4-17 years, - A trial period of a minimum by determining its frequency, the treated with insulin. of one month for every patient targets and therapeutic decisions - A randomized controlled stu- candidate of the FREESTYLE to be taken based on results. dy, to evaluate, in 239 patients LIBRE system. his period should with type 1 diabetes on insulin allow patients who are capable of Terms of reimbursement : pumps or on multiple daily injec- using the FREESTYLE LIBRE FREESTYLE LIBRE includes tions (IMPACT study), the impact and wearing the Sensor to be a capillary blood glucose me- of using FREESTYLE LIBRE on selected. ter. Terms of reimbursement for the time spent in hypoglycemia (< he criteria for termination of this device does not include any 70 mg/dl), compared to a control the trial may in particular be re- other capillary blood glucose me- group performing capillary blood lated to the patient’s own choice ter. Terms of reimbursement of glucose monitoring. and/or that of his caregivers, poor the FREESTYLE LIBRE system - A randomized controlled stu- skin tolerance to the Sensor, and should allow the provision of the dy to compare, in 224 patients the inability to wear a Sensor at all FREESTYLE LIBRE system ele- with type 2 diabetes on insulin times. ments, as a part of a long-term (REPLACE study), the level of - Towards the end of the trial prescription: a Reader and Sensor HbA1c at 6 months in the FRE- period, patients who continue to (wearing time 14 days), following ESTYLE LIBRE group, compa- use the FREESTYLE LIBRE sys- a 3-month initial period. red to the clinical control group tem should undergo an evaluation · he wearing time of the Sen- performing capillary blood gluco- at 3 months to assess whether or sor being 14 days, the total num- se monitoring. not to continue to use the system. ber of Sensors to maintain per year his assessment is based on the and per patient is limited to 28 Factors Determining the aforementioned criteria, in addi- Sensors. Actual Benefit: tion to a clinical assessment pertai- · In clinical situations, where Technical Specifications: ning to the objectives set a priori the manufacturer recommends No additional requirements pro- (severe hypoglycemia, ketoacidosis measuring blood glucose, the ca- posed by the manufacturer with decompensation, time spent abo- pillary blood glucose meter test respect to the technical speciica- ve or below a certain hypoglyce- strips and lancets must be limited tions. mic threshold), and/or biological to 100 test strips and 100 lancets, (HbA1c). per patient, per year. Warranty period: - he FREESTYLE LIBRE Renewal: Terms of Use: Reader: 4 years Renewal is ensured by any doctor. Measuring interstitial glucose - he FREESTYLE LIBRE Sen- Patient-speciic education and/or using the FREESTYLE LIBRE sor: 14 days their caregivers: system requires patient interven- Prior to prescription, patients tion via a scan of the Reader over In case of the product failing should receive speciic education the Sensor to get a current glucose within the warranty period, the to provide them with the necessary reading. In the case of occasion- defective Reader shall be replaced skills and knowledge to apply the al scanning (> 8 hours), the irst with a new one within 3 working Sensor and to interpret and use the values become lost. he device is days. information provided by the FRE- designed to replace the capillary ESTYLE LIBRE system to opti- blood glucose measurement, ex- Prescription and Terms of mize their treatment. he patient cept in the cases listed below whe- Use: should also be informed of the re the manufacturer recommends Prescription: lower reliable results of the FRE- the use of a capillary blood glucose he initial prescription of the ESTYLE LIBRE system 1st day meter to check the results of the FREESTYLE LIBRE system after sensor application. his trai- glucose levels. ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 203 The different cases are as he Reader Kit includes: food or exercising. follows: 1 Freestyle libre reader 1 usb he Reader also allows the me- - In the case of rapidly chang- cable 1 power adapter quick start asurement of blood glucose and ing glucose levels, the level of in- guide user manual blood ketones of capillary blood terstitial glucose, as measured by he sensor kit includes: sampling. It works using the glu- the Sensor and reported as actual, 1 Sensor pack 1 sensor applica- cose and blood ketone electrodes may not accurately relect blood tor 1 alcohol wipe product lealet FREESTYLE OPTIUM. sugar levels. When glucose levels 01.3. Claimed indication - A Sensor that is inserted by are rapidly dropping, the results Measuring interstitial glucose the patient subcutaneously on of interstitial glucose levels mea- levels for the treatment of patients the back of the upper arm with sured with the Sensor may be hig- with type 1 or type 2 diabetes a simple applicator unit (only); it her than the blood glucose levels. (adults and children aged at least 4 measures and stores interstitial Conversely, when glucose levels years) undergoing intensiied insu- glucose levels. are rapidly increasing, interstiti- lin therapy (using an external in- It comprises a sterile, lexible al glucose results measured with sulin pump or multiple injections). ilament (0.4 mm thick), which is the Sensor may be lower than the 01.4. Claimed comparator inserted 5 millimeters under the blood glucose levels. Self-monitoring of blood gluco- skin, into the interstitial luid. he - In order to conirm hypogly- se by capillary sampling (reference ilament is connected to a small, cemia, or impending hypoglyce- method). 5 mm high and 30 mm diame- mia, as reported by the Sensor. 02 Reimbursement history ter round disc and held in place - If symptoms do not match his is the irst application for on the skin with a small medical the FREESTYLE LIBRE system inclusion on the lppr for freestyle adhesive. readings. Symptoms that may be libre. he Sensor can be worn for up caused by hypoglycemia or hy- 03 Characteristics of the to 14 days. It is water-resistant up to perglycemia should not be ignored. product 1 meter (3 feet) of water for a maxi- No on-call duty 24/7 is requi- 03.1. Ce marking mum of 30 minutes. No calibration red in case of system failure. Class iib, notiication by the is recommended by the manufactu- No preventive maintenance is british standards institution (no. rer within 14 days of usage. required for the FREESTYLE LI- 597686), United kingdom. he manufacturer also indica- BRE system. 03.2. Description ted that the Sensor can be used to he Flash Interstitial Glucose check the glucose level 60 minutes Renewal Conditions: Monitoring System FREESTYLE after start-up. Updating data as recommended LIBRE consists of two main parts: he Sensor automatically me- by the practice guidelines for in- - A Reader that is used to get the asures and continuously stores clusion in the reimbursement list interstitial glucose readings from glucose readings and stores up to of products and services. the Sensor by scan (scan of the 8 hours of glucose readings at 15 Reader above the Sensor). Scan- minute intervals. herefore, in or- Target Population: ning can be done over clothing der to obtain all glucose data over Approximately 300,000 patients. and requires a maximum distance a typical day, the patient should of 4 cm between the Reader and scan over the Sensor at least every Definitive Review 1 Sensor to obtain readings. 8 hours. In the event of scans spa- EVIDENCE REVIEW With every scan, the user re- ced apart over a longer period (> 8 01 NATURE OF THE APPLI- ceives a reading of the current in- hours), the initial data is lost. CATION terstitial glucose level, the last 8 he operating temperature Application for inclusion on hours of glucose data and an arrow (Sensor and Reader) is between 10 the list of products and services indicating the direction and rate and 45 degrees Celsius. qualifying for reimbursement, of the glucose change. A glucose 03.3. Functions provided mentioned under article L 165-1 pattern and variability report can Interstitial glucose of the Social Security Code (refer- be generated. measurement. red to as LPPR in the rest of the he Reader holds up to 90 04 Expected beneit of the pro- document). days of data, providing a histori- duct or service 01.1. Models and references cal snapshot of glucose levels over 04.1. Beneit of the product 01.2. Packaging time; as well as the notes entered 04.1.1. Data analysis: assess- he system comes in a Reader by the user about his daily activi- ment of the therapeutic efect /ad- Kit and a Sensor Kit. ties, such as taking insulin, eating verse efects and risKS

204 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se LINKED TO USE Survey) and the DDS (Diabetes atment Satisfaction Questionnai- 04.1.1.1. Specific data Distress Screening) scores. re) and the treatment satisfaction he IMPACT Study, unpublis- With respect to the number of score in the DQoL (Diabetes Qu- hed[2], was an open, multicenter tests in the intervention group, ality of Life) questionnaire. (23 centers) randomized control- the mean number self-monitoring Other dimensions of the DQoL led study. he purpose of the stu- blood glucose (SMBG) jumped and the DDS (Diabetes Distress dy was to assess the impact, after from 5.5 ± 2 tests per day (between Screening) scale showed no dife- completion of 6-months use of 0 and 15 days) to 0.6 ± 0.1 tests per rence between the groups. FREESTYLE LIBRE on the time day at 6 months. he mean num- With respect to the number of spent in hypoglycemia [number of ber of scans decreased from 18.5 ± tests in the intervention group, hours per day <70 mg/dL], compa- 9.4 tests per day to 14.5 ± 9.8 tests the mean number self-monitoring red to a control group performing per day at 6 months. blood glucose (SMBG) was 0.3 self-monitoring of blood glucose In the control group, the mean ± 0.7 tests per day and the mean (SMBG) by capillary sampling. frequency of self-monitoring of number of scans 8.3 ± 4.3 tests he patients analyzed were dia- blood glucose (SMBG) went from per day (between day 15 and day betic adults with type 1 diabetes, 5.8 ± 1.7 tests per day (between 208). In the control group (N = using intensive insulin treatment 0 and 15 days) to 5.6 ± 2.2 test 51), the mean number self-moni- with either an insulin pump or per day at 6 months. he Sensor toring blood glucose (SMBG) was multiple daily injections, (N= wearing time in the FREESTYLE 3.0 ± 1.1 tests per day. he Sensor 239) with an HbA1c level of 6.74 ± LIBRE (between day 15 and day wearing time in the FREESTYLE 0.56% (144/239 patients (60.3%) 208) was between 40% and 99%, LIBRE group (between day 15 had an HbA1c <7.0%). with an average of 92.8 ± 7.3%. and day 208) was between 48% he time spent in hypoglyce- he study is explained in detail and 99%, with an average of 88.7 mia was signiicantly lower in the in the Appendix. ± 9.2%. FREESTYLE LIBRE group com- he REPLACE Study, unpu- he study is explained in detail pared to the control group (mean blished[3], is an open, multicen- in the Appendix. diference -1.24 ± 0.239 hours per ter (26 centers), randomized con- he BAILEY et al. Study is day (p <0.0001), at 6 months). trolled study. he purpose was to a prospective, non-randomized, he results obtained after the compare the HbA1c (glycated he- multicenter (involving 4 centers completion of multiple analyses moglobin A1c) level at 6 months in the US) study using the FRE- in favor of FREESTYLE LIBRE between FREESTYLE LIBRE ESTYLE LIBRE device in hidden tackled the time spent in the tar- group (N.of patients = 149) and mode. get range (70 to 180 mg/dL) with a a control group (N. of patients= he purpose of this study was mean diference of 1 ± 0.30 hours 75), performing self-monitoring of to evaluate the performance and per day (p = 0.0006) between the blood glucose (SMBG) by capilla- usability of the FREESTYLE LI- groups at 6 months; time spent ry sampling. Patients included in BRE Flash glucose monitoring in hyperglycemia (> 240 mg/dL) the study were adults with type system compared with capillary with a diference of -0.37 ± 0.163 2 diabetes on insulin (N= 5/224 blood glucose (BG) results. hours per day (p = 0.0247); max- (2.2%), either treated with pran- In total, 75 adult patients with imum satisfaction score [in the dial insulin alone, N= 207/224 type 1 or 2 diabetes treated with Diabetes Treatment Satisfaction (92.4%), or with prandial and ba- insulin were selected; the fol- Questionnaire (DTSQ)]; and the sal insulin; and 12 patients (5.4%) low-up period was 14 days. treatment satisfaction score in the treated by insulin pump, with an he primary endpoint was the [Diabetes Quality of Life ques- HbA1c level between 7.5% and percentage of paired points (FRE- tionnaire (DQoL)]. 12.0% (average 8.68%). ESTYLE LIBRE / SMBG) found he results did not show any he results indicated no sta- within Consensus Error Grid diference between the FRE- tistically signiicant diference Zone A. (zone corresponding to ESTYLE LIBRE group and the between both groups in terms of clinically accurate readings, which control group tackled concerning reducing HbA1c at 6 months (av- is clariied as having “no efect on the mean reduction in HbA1c at erage of 0.03% ± 0.114, p = NS). clinical action.”). 3 and 6 months; the time spent With respect to the quality he analysis indicated that in hyperglycemia > 180 and 300 of life questionnaires, the results 86.7% of the results achieved by mg/dL; the other dimensions of were in favor of FREESTYLE LI- the FREESTYLE LIBRE devi- the DTSQ and DQoL scores, the BRE on the maximum satisfaction ce were found within Consensus HFS scores (Hypoglycemia Fear score in the DTSQ (Diabetes Tre- Error Grid Zone A[4], compared ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 205 with the results obtained by capil- he application is based on or their consequences. However, lary sampling. On the irst day of two speciic randomized, control- the decrease of time spent in hy- use, 72% of the results were within led clinical studies (one speciic to poglycemia (<70 mg/dL) and in- Consensus Error Grid Zone A. type 1 diabetics and the other to creased time spent in the target he BEAGLE, Edge et al. Stu- type 2 diabetics) and two accura- range are likely to protect the pa- dy, unpublished[5], is a prospecti- cy studies. he data highlights the tient from the occurrence of severe ve, non-randomized, multicenter feasibility of usage of the FRE- hypoglycemia. Interpretation of (involving 9 centers in the UK), ESTYLE LIBRE device in terms the results obtained from the se- using the FREESTYLE LIBRE of accuracy. condary endpoints of the studies device in hidden mode. he irst study (IMPACT) was limited, given the multiplicity he objective of this study evaluates the clinical beneit of of the criteria being evaluated. was to assess the accuracy of the the FREESTYLE LIBRE device he National Professional readings on the FREESTYLE LI- in adult patients with type 1 dia- Council for Endocrinology, Dia- BRE device on children in ambu- betes using intensive insulin treat- betes and Metabolic Diseases and latory use. ment with either an insulin pump the Federation of Associations of A total of 89 patients were in- or multiple daily injections, with patients with diabetes in France cluded in the study. Patients were an average HbA1c level of 6.74 were interviewed by the Commis- aged 4-17 years, with type 1 or 2 %. he time spent in hypoglyce- sion. hey conirmed the actual diabetes and were treated with mia (<70 mg/dL) was signiicantly beneit of the FREESTYLE LI- insulin. lower in the FREESTYLE LIBRE BRE system in the indications he primary endpoint was the group compared to the control and deined the conditions for its percentage of paired points (FRE- group (average diference -1.24 prescription and use. Reliable re- ESTYLE LIBRE / SMBG) found hours per day at 6 months. here sults of the FREESTYLE LIBRE within Consensus Error Grid was no diference in terms of the system as of the irst day of set-up Zone A (zone corresponding to mean reduction in HbA1c levels have however been brought to the clinically accurate readings, which between the groups. attention of the Commission. is clariied as having “no efect on he second clinical study (RE- clinical action”). PLACE) targets a population of 04.1.2. ROLE IN THE DIAG- he analysis indicated that adult patients with type 2 diabe- NOSTIC STRATEGIES 83.8% of the results achieved by tes using insulin with an average Glycemic control is the main ob- the FREESTYLE LIBRE device HbA1c level of 8.68%. his stu- jective of medical care for patients were found within dy did not reveal any diference with diabetes to prevent long-term Consensus Error Grid Zone A, in terms of HbA1c reduction at 6 vascular complications and acute compared with the results obtai- months. he study was not speciic metabolic complications. ned by capillary sampling. to patients using intensive insulin Pharmacological treatment of therapy. glycemic control in insulin-depen- 04.1.1.2. MATERIOVIGILANCE In these two clinical studies, the dent type 1 and type 2 diabetes is FREESTYLE LIBRE has been results from the diabetes quality of based on an insulin therapy that marketed and distributed since life questionnaire (DQoL) were in mimics the normal physiologic September 2014. 17 materiovigi- favor of the FREESTYLE LIBRE, pancreatic insulin secretion due to lance (post-market surveillance) in terms of patient satisfaction. a basal/ bolus regimen, obtained statements have been received by With respect to safety and to- either by multiple injections or by the National Agency for the Safety lerance data, adverse events in cli- pump. of Medicines and Health Products nical trials were primarily related he choice between intensive (L’Agence Nationale de Sécurité to reactions around the Sensor in- insulin treatment with either an du Médicament et des Produits de sertion site (skin rash, infections, insulin pump or multiple daily in- Santé or ANSM) between 2014- allergies, erythemas and necrosis). jections is primarily based on pa- 2015. he number of incidents reported tient preferences. Materiovigilance statements in- in the context of a materiovigilan- Self-monitoring of blood gluco- cluded skin reactions (N = 9) and ce (post-market surveillance) state- se is essential in insulin-treated pa- result discrepancies between the ment was low. tients. It should be performed da- scan and capillary blood glucose (N he available data does not al- ily using a capillary blood glucose = 8). he number of Readers sold is low assessment of the impact of the meter (at least 4 times per day). 17,174, including samples (between FREESTYLE LIBRE device on his reading would allow patients September 2014 to May 2016). the frequency of prevented events to adjust treatment and is an am-

206 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se bulatory reference method. cemia or impending hypoglycemia sional Council for Endocrinology, Continuous measurement of as reported by the Sensor. Diabetes and Metabolic Diseases interstitial glucose constitutes a - If symptoms do not match and the Federation of Associations new tool in the therapeutic arse- the FREESTYLE LIBRE system of Patients with Diabetes in Fran- nal against the disease. It comple- readings. Symptoms that may be ce, the Committee underscores ments conventional monitoring of caused by hypoglycemia or hy- the beneit of the FREESTYLE capillary blood glucose but not a perglycemia should not be ignored. LIBRE device for the self-monito- substitute. Systematic monitoring of ring of interstitial glucose, within Measuring interstitial glucose HbA1c concentrations should be the provided indications and con- using the FREESTYLE LIBRE done 4 times per year. Measure- ditions for use. system requires patient interven- ment of fasting blood glucose car- tion via a scan of the Reader over ried out in a medical laboratory, 04.2. PUBLIC HEALTH BE- the Sensor to get a current glucose allows self-monitoring of blood NEFIT reading. In the case of occasional glucose (SMBG) and should be 04.2.1. SEVERITY OF THE scan (> 8 hours), the irst values be- carried out once a year. PATHOLOGY come lost. he device is designed to Continuous measurement of Diabetes is a serious condition due replace the capillary blood glucose glucose levels (3 -5 days test) using to the associated complications. measurement, except in the cases li- a Continuous Glucose Monitoring Acute complications of dia- sted below where the manufacturer System (CGMS) Holter-style Sen- betes are metabolic emergenci- recommends the use of a capillary sor system, provides a posteriori es (discomfort or coma) due to blood glucose meter to check the analysis by the doctor of glycemic hyperglycemia, ketoacidosis or results of the glucose levels. excursions; it can be used to com- hypoglycemia. he diferent cases are as plement capillary blood glucose. Chronic and degenerative com- follows: hese last two readings are use- plications of diabetes are the le- -In the case of rapidly changing ful to the doctor to check the pa- ading cause of morbidity and de- glucose levels, the level of intersti- tient’s glycemic control. ath with this disease. hey include tial glucose, as measured by the Given the data, the Committee the microvascular complications Sensor and reported as actual, may considers that the FREESTYLE (retinopathy, glomerular disease not accurately relect blood sugar LIBRE system is beneicial in the and neuropathy) and macrovascu- levels. When glucose levels are ra- management of diabetes and con- lar complications (coronary heart pidly dropping, results of intersti- stitutes a new tool in the self-mo- disease, cerebrovascular and perip- tial glucose levels measured with nitoring of blood glucose, accor- heral artery disease [PAD]). the Sensor may be higher than the ding to interstitial glucose data, Diabetes is a serious disease due blood glucose levels. Conversely, but does not completely replace it. to complications that may occur when glucose levels are rapidly but are preventable when the me- increasing, the interstitial glucose 04.1.3. CONCLUSION ON tabolic control of blood sugar is results measured with the Sensor THE BENEFIT OF THE permanently achieved. may be lower than blood glucose PRODUCT levels. Given the available data and 04.2.2. EPIDEMIOLOGY OF - In order to conirm hypogly- according to the National Profes- THE PATHOLOGY ▶

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 207 Results of the 2007-2010 Entred products and services qualifying the selection of patients who are survey have estimated that 2.4 for reimbursement mentioned un- capable of using the FREESTYLE million adults in France sufer der article L 165-1 of the Social LIBRE and wearing the Sensor. from diabetes. In 2013, the French Security Code. he criteria for termination of Institute for Public Health Sur- he Commission recommends the trial may in particular be re- veillance (InVS) estimated that inclusion of the product under lated to the patient’s choice and/or over 3 million patients are being brand name and retains the fol- his caregivers, poor skin tolerance treated for diabetes. lowing indications: to the Sensor, or the inability to Type 2 diabetes is the most Measurement of interstitial wear a Sensor at all times common form (92%, or 2.76 glucose levels for the treatment - Towards the end of the trial million people in France). Pa- of patients with type 1 or type 2 period, patients who continue to tients with type 2 diabetes treated diabetes (adults and children aged use the FREESTYLE LIBRE sys- with insulin account for 17% of 4 years) undergoing intensiied tem should undergo an evaluation type 2 diabetes patients (469,200 insulin therapy (using an external at 3 months to assess whether or patients). insulin pump or ≥ 3 injections per not to continue to use the system. Patients with type 1 diabetes day) and performing the self-mo- his assessment is based on account for 5.6% of diabetic pa- nitoring of blood glucose (SMBG) the aforementioned criteria, in tients, i.e. approximately 168,000 several times a day (≥ 3 per day). addition to a clinical assessment patients. he FreeStyle Libre System is pertaining to the objectives set a According to Entred, there are especially designed for patients priori (Severe hypoglycemia, ke- approximately 12,000 children who have received therapeutic toacidosis decompensation, time with diabetes; they mainly sufer education and speciic training on spent above or below a certain hy- type 1 diabetes. the use of the lash interstitial glu- poglycemic threshold), and/or bio- he total number of diabetic cose monitoring system. logical (HbA1c). patients who have type 1 diabetes account for 170,000 patients. he 05 FACTORS DETERMINING Renewal: total number of patients with type THE ACTUAL BENEFIT Renewal is ensured by any doctor. 2 diabetes treated with insulin is 05.1. MINIMUM TECHNICAL Patient-specific education estimated at 470,000. SPECIFICATIONS and/or their caregivers: 04.2.3. IMPACT No additional requirements Prior to prescription, patients are Blood glucose monitoring is provi- with respect to the technical supposed to receive speciic edu- ded by capillary blood glucose me- speciications proposed by the cation to provide them with the ters. No interstitial blood glucose manufacturer. necessary skills and knowledge to scanner is currently listed on the Warranty period: apply the Sensor and to interpret LPPR. - he FREESTYLE LIBRE and use the information provided his type of medical device con- Reader: 4 years by the FREESTYLE LIBRE sys- stitutes a new tool in the arsenal of - he FREESTYLE LIBRE tem to optimize their treatment. diabetes self-monitoring devices. Sensor: 14 days he patient should also be infor- 05.2. TERMS OF USE AND med of the lowest reliability of 04.2.4. CONCLUSION ON PRESCRIPTION the FREESTYLE LIBRE system’s PUBLIC HEALTH BENEFITS results upon installation. his trai- Due to the expected reduction of Prescription: ning is provided by a pump cen- the occurrence of long-term com- he initial prescription of the ter any other center that provides plications from diabetes and severe FREESTYLE LIBRE system care for diabetic patients and is hypoglycemia; and given the seve- must be ensured by a diabetologist involved in therapeutic education rity of the pathology, the Com- or a pediatric diabetologist. programs validated by the Regio- mittee estimates that the FRE- Initiation phase: nal Health Agencies (ARS)[6]. It is ESTYLE LIBRE system provides Before issuing a long-term pres- essential to plan this SMBG with a public health beneit. cription, the arrangements shall the patient and/or his caregivers, In conclusion, the National allow the provision of the FRE- by determining its frequency, the Committee for the Evaluation ESTYLE LIBRE system for: targets and therapeutic decisions of Medical Devices and Health - A trial period of a minimum to be taken based on results. Technologies (CNEDiMTS) be- of one month for every patient lieves that Actual Beneit is suf- eligible for FREESTYLE LIBRE Conditions for support: icient for inclusion on the list of system. his period should allow FREESTYLE LIBRE includes a

208 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se capillary blood glucose meter. Pro- lower than blood glucose levels. mated based on analysis of indivi- viding support and maintenance - In order to conirm hypogly- dual data on the reimbursement of for this device does not include cemia or impending hypoglycemia healthcare expenses.[7] any other capillary blood glucose as reported by the Sensor. he selection criteria were as meter. he conditions for support - If symptoms do not match follows: of the FREESTYLE LIBRE sys- the FREESTYLE LIBRE system - At least one insulin treatment tem should allow the provision of readings. Symptoms that may be reimbursed during 2015 (ATC the FREESTYLE LIBRE system caused by hypoglycemia or hy- code: A10A) elements, as a part of a long-term perglycemia should not be ignored. Associated to prescription: a Reader and Sensor No on-call duty 24h/24h is re- - At least one capillary blood (wearing time 14 days), following quired in the case of system failure. glucose meter strip reimbursed a 3-month initial period. No preventive maintenance is during 2015 (LPPR code: 1173487, he wearing time of the Sensor required for the FREESTYLE LI- 1136894, 1186722, 1180441, being 14 days, the total number of BRE system. 1187408, 1177611, 1179337 and Sensors to maintain per year and 1172861). per patient is limited to 28 Sen- 06 ADDED CLINICAL VALUE Results indicated that the num- sors. In clinical situations, where (ACV) ber of individuals treated with in- the manufacturer recommends 06.1. RETAINED COMPARA- sulin and using testing strips for measuring blood glucose, the ca- TOR capillary blood glucose meter in pillary blood glucose meter test Self-monitoring of blood glucose 2015 was: strips and lancets must be limited using a single capillary blood glu- - 288,963 based on a minimum to 100 test strips and 100 lancets, cose meter. of 1,095 strips reimbursed (which per patient, per year. relects a mean daily consumption 06.2. ACV LEVEL of 3 strips or more). Terms of Use: he Commission emphasizes -136,127 based on a minimum Measuring interstitial glucose that patient comfort and impro- of 1,460 strips reimbursed (which using the FREESTYLE LIBRE ved quality of life due to lower relects a mean daily consumption system requires patient interven- capillary blood glucose by inger of 4 strips or more). tion via a scan of the Reader over prick test improved with the FRE- - 72,540, based on a minimum the Sensor to get a current glucose ESTYLE LIBRE system. of 1,825 strips reimbursed (which reading. In the case of occasional he Commission decided on relects a mean daily consumption scanning (> 8 hours), the initial a moderate Added Clinical Value of 5 strips or more). values will become lost. he device (ACV III) of the FREESTYLE Bearing in mind that individu- is designed to replace the capillary LIBRE versus Self-Monitoring of al reimbursement relects the actu- blood glucose measurement, ex- Blood Glucose (SMBG) by capil- al use of the product and that the cept in the cases listed below whe- lary blood glucose Reader alone. frequency of use of capillary blood re the manufacturer recommends glucose meter strips is linked to in- the use of a capillary blood glucose 07 CONDITIONS OF RE- sulin injections, it is estimated that meter to check the results of the NEWAL AND DURATION OF the number of patients performing glucose levels. INCLUSION at least 3 insulin injections per day he diferent cases are as would be approximately 300,000 follows: 07.1. RENEWAL CONDI- per year. - In the case of rapidly changing TIONS glucose levels, the level of intersti- Updating data, as recommended ANNEX 1 tial glucose as measured by the by the practice guidelines for in- CLINICAL DATA Sensor and reported as actual may clusion in the reimbursement list All studies published in detail with results not accurately relect blood sugar of products and services. and conclusions [1] Two decrees (D2010-904 and D2010- levels. When glucose levels are ra- 906) and two bylaws dated 2nd August pidly dropping, results of intersti- 07.2. DURATION OF INCLU- 2010, setting the authorization procedures tial glucose levels measured with SION of patient education by the regional health the Sensor may be higher than the 5 years. agencies and the skills required to deliver these programs, have been published in the blood glucose levels. Conversely, Oicial Gazette on 4th August 2010. when glucose levels are rapidly in- 08 TARGET POPULATIONS According to these texts, any implemented creasing, interstitial glucose results he population using the FRE- therapeutic education program must sub- measured with the Sensor may be ESTYLE LIBRE device was esti- mit for authorization from the Regional ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 209 Health Agencies (ARS). Blood Glucose; Diabetes Care’ 23:1143- [7] According to the Inter-scheme [2] IMPACT Study Report ‘Randomized 1148,2000. Consumption Data (données de consom- Controlled Study to Evaluate the Impact [5] Edge J.A., Acerini C., Campbell F., mation inter-régimes [DCIR]) database of of Novel Glucose Sensing Technology on Hamilton-Sheild J., Moudiotis C. ‘Clinical Health Insurance; which compiles data on Hypoglycemia in Type 1 Diabetes’ – 25th Accuracy Evaluation of the FREESTYLE healthcare expenses paid to beneiciaries in January 2016. LIBRE Flash Glucose Monitoring System France. [3] REPLACE Study Report ‘Randomized When Used by Children and Young People [8] Diabetes Treatment Satisfaction Ques- Controlled Study to Evaluate the Impact with Diabetes’. tionnaire : 8 questions on a scale of 0 to 6, of Novel Glucose Sensing Technology on [6] Two decrees (D2010-904 and D2010- highest score = high satisfaction HbA1c in Type 2 Diabetes’- 23rd October 906) and two bylaws dated 2nd August [9] Diabetes Quality of Life: 46 items (on a 2015. 2010, setting the authorization procedures scale of 0 to 5). 4 Bailey T., Bode B., Christiansen M., of patient education by the regional health [10] Diabetes Distress Screening Scale Klaf L., Alva S. et al. ‘he performance agencies and the skills required to deliver [11] Hypoglycemia Fear Survey and Usability of a Factory-Calibrate Flash these programs, have been published in the Glucose Monitoring System.’ ‘Diabetes Oicial Gazette on 4th August 2010. Nyhetsinfo 25 juni 2017 Technol he.’ 2015; 17(11). According to these texts, any implemented [4] Parkes JL et al, ‘A New Consensus Error therapeutic education program must apply www red DiabetologNytt Grid to Evaluate the Clinical Signiican- for authorization from the Regional Health ce of Inaccuracies in the Measurement of Agencies (ARS).

NT-rådets rekommendation angående Freestyle Libre vid diabetes typ 2: ”NT-rådet rekommenderar lands- drag påbörjades, har företaget Ab- För NT-rådet, tingen - att avstå från att använda bot valt att inte häva sekretessen Gerd Lärfars, ordförande lashglukosmätaren Freestyle Li- gällande hälsoekonomiska beräk- Referenser: bre vid typ 2-diabetes” ningar och resultat och därmed https://www.tlv.se/Medicintek- NT-rådet (Nya Terapi-Rådert), kan inte FreeStyle Libre längre ut- nik/Medicinteknikuppdraget/ SKL, Sveriges Kommuner och värderas inom medicinteknikupp- Landsting draget, vilket TLV kommunicerat. https://www.tlv.se/press/ov- NT-rådets yttrande till lands- riga-nyheter/Ingen-utvarde- tingen gällande kontinuerlig glu- NT-rådets bedömning ring-av-FreeStyle-Libre/ kosmätning med FreeStyle Libre För att en fullständig bedömning vid typ 2-diabetes av behandlingens värde med hän- Om NT-rådets beslut visning till den etiska plattformen http://www.janusinfo.se/Natio- Bakgrund ska kunna göras krävs en utvärde- nellt-inforande-av-nya-lakemedel/ Enligt önskemål från landstingens ring av kostnadsefektivitetet. Nationellt-inforande-av-nya- lake- hälso- och sjukvårdsdirektörsnät- Det är NT-rådets förhoppning medel/NT-radets-rekommenda- verk ska kontinuerliga glukosmä- att företaget kan tillgängliggöra tioner-grunder-till-beslut/ tare och lashglukosmätare för ett hälsoekonomiskt underlag till diabetiker, inom ramen för ett TLV och bidra till att en sådan be- Närvarande vid beslut: Gerd Lär- pilotförsök, genomgå samma pro- dömning kan göras. fars, ordförande NT-rådet; Lars cess för nationellt ordnat införan- I avsaknad av underlag för be- Lööf, Uppsala/Örebro sjukvårds- de som nya läkemedel. dömning, rekommenderar NT-rå- region; Johannes Blom, sjuk- TLV uppdrogs därför att inom det landstingen att avstå från vårdsregion Stockholm/Gotland; sitt medicinteknikuppdrag göra använda lashglukosmätaren Fre- Anna Lindhé, Västra regionen; en bedömning av kostnadsefek- estyle Libre vid typ 2-diabetes. Maria Landgren, Södra regionen; tiviteten för lashglukosmätaren Eftersom FreeStyle Libre sedan Mårten Lindström, Sydöstra sjuk- FreeStyle Libre, som skulle ligga tidigare är införd vid diabetes typ vårdsregionen; Anders Bergström, till grund för en rekommendation 1 ger NT-rådet ingen rekommen- Norra regionen från NT-rådet. Uppdraget omfat- dation, men uppmärksammar Jäv: Ingen ledamot deklarerade tade både användning vid diabetes landstingen på att ingen bedöm- någon intressekonlikt för det ak- typ 1, vid vilken FreeStyle Libre ning av kostnadsefektiviteten tuella ärendet. sedan tidigare används, samt vid gjorts varför en noggrann klinisk diabetes typ 2, där FreeStyle Libre värdering av vilka patienter som Nyhetsinfo 21 juni 2017 ännu inte är införd. har det största behovet av produk- www red DiabetologNytt Omkring år efter att detta upp- ten bör göras innan den sätts in.

210 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se TLV tar semester utan att leverera hälsoekonomiskt dokument för FGM Ett års arbete Syftet med rekommendationen var ligga till grund för NT-rådets re- Publicerad 13 juni 2017. Ingen ut- att ge förutsättningar för en jämlik kommendation. Företaget har nu värdering av FreeStyle Libre. Ned- tillgång till FreeStyle Libre. valt att inte bidra med materialet an är utlagt på TLVs www från ansökan och TLV kan där- ”TLV har inte möjlighet att Bakgrund för inte publicera den utvärdering publicera en hälsoekonomisk ut- TLV påbörjade en hälsoekono- som gjorts. värdering av den kontinuerliga misk utvärdering av FreeStyle För att TLV ska kunna återupp- glukosmätaren FreeStyle Libre, ef- Libre sommaren 2016. På hösten ta arbetet krävs att företaget bidrar tersom företaget som marknadsför samma år ansökte företaget som till en utvärdering.” produkten valt att inte bidra med marknadsför produkten om att nödvändigt underlag. den skulle ingå i läkemedelsför- https://www.tlv.se/press/ov- I dag använder minst 27.000 pa- månerna och utvärderingen till riga-nyheter/Ingen-utvarde- tienter i Sverige FreeStyle Libre och NT-rådet avbröts. ring-av-FreeStyle-Libre/ merkostnaden för den användning- I mars 2017 återkallade företa- en är minst en kvarts miljard kronor get sin ansökan och TLV återupp- Nyhetsinfo 21 juni 2017 per år. FreeStyle Libre har introdu- tog då utvärderingen som skulle www red DiabetologNytt cerats utan ordnat införande vilket lett till ojämlik tillgång beroende på var i landet patienten bor. – Det är viktigt att rätt patienter får FreeStyle Libre så det är olyckligt att vi nu inte har möj- lighet att publicera en hälsoeko- nomisk utvärdering, säger Malin Blixt, enhetschef. TLV:s utvärdering inom medicinteknikuppdraget skulle legat till grund för en nationell rekommendation från landstingens NT-råd.

FDA panel supports cardiovascular indication for Novo’s diabetes drug Victoza for T2DM, Can Lower CV Risks in High-Risk Patients Following a daylong meeting on cebo. he Novo drug reduced car- has shown a “highly reliable and Tuesday, an FDA expert panel diovascular deaths by 22%, any statistically strong evidence of an voted to recommend a label up- deaths by 15%, and advanced dia- important clinical beneit, such as date for Novo’s blockbuster diabe- betic kidney disease by 22%. an efect on survival, and a con- tes drug Victoza stating the med Ahead of the committee’s vote, irmatory study would have been can lower cardiovascular risks for FDA reviewers published brie- diicult to conduct on ethical high-risk Type 2 diabetes patients. ing documents raising no major grounds.” By a 17-2 vote, the panel con- qualms about those results. he Further, the reviewers poin- cluded that an outcomes trial dub- FDA doesn’t have to follow panel ted out that the agency approved bed Leader provides signiicant recommendations, but it typically a CV indication for Eli Lilly and evidence demonstrating the CV does. Boehringer Ingelheim’s SGLT-2 beneit for Novo’s blockbuster’s While the FDA reviewers noted drug Jardiance on a single study, GLP-1 diabetes medication. that two clinical studies are usu- Empa-Reg. In that trial, Victoza redu- ally needed in order to approve a FDA committee members ced major adverse cardiovascular new indication, the agency can took two votes on Tuesday, one ▶ events by 13% compared to pla- rely on one study when the trial on whether the Leader trial esta- www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 211 blishes that use of Victoza in Type of liraglutide in both primary and in patients with high cardiovascu- 2 diabetes patients isn’t associated secondary cardiovascular preven- lar risks. In its document, Novo with excess CV risks, and the se- tion.” Liraglutide is the generic said the new indication would cond on whether the trial shows name for Victoza, a GLP-1 med “provide important guidance to that Victoza reduces CV risks. that was irst approved in 2010. prescribers considering their op- he committee voted “yes” unani- Victoza is already approved in tions to treat” patients. mously on the irst question. Type 2 diabetes in combination In its own brieing document with diet and exercise, but the Da- From www.iercepharma.com published ahead of the meeting, nish drugmaker wants an addition Novo touted the data as sup- to the label stating its med can Nyhetsinfo 21 juni 2017 porting ”a cardiovascular beneit lower the risk of major CV events www red DiabetologNytt

Antioxidant i broccoli vid T2DM? Science Translational Medicine. Forskning Lund, Göteborg Nya forskningsresultat ger hopp åt patienter med diabetes typ 2 Lantmännen har genom sin forskningsstiftelse kunnat bidra till forskning som visar positiva efekter hos patienter med typ 2-diabetes. I fokus står en vanlig grönsak som odlas på de svenska åkrarna. Genom ett forskningsprojekt som inansieras av Lantmännen har forskare vid Lunds Universi- tet och Sahlgrenska akademin nu lyckats identiiera en naturlig substans som har en positiv efekt på patienter med diabetes typ 2. Det aktiva ämnet - en antioxidant som inns i broccoli – har visat sig ge lägre blodsockernivåer hos vissa personer med diabetes typ 2. Den mängd av antioxidan- Diabetesstudien har pågått – Forskning är viktigt för Lant- ten som behövs dagligen motsva- under tolv veckor och resultaten männen och för våra ägare. Vår rar 4-5 kg broccoli och dosen ges publiceras nu i tidskriften Science forskningsstiftelse är central för därför som ett koncentrat. Translational Medicine. I studien oss, och vi är stolta över att se Typ 2-diabetes är redan idag ingick 100 patienter med diabetes, så tydliga och ina resultat, som ett gigantiskt hälsoproblem och resultatet visar att en viss an- på sikt kan göra verklig skillnad och Världshälsoorganisationen tioxidant i broccoli kan motverka för konsumenten, säger Per Olof WHO uppskattar att 500 mil- leverns förhöjda produktion av Nyman, vd och koncernchef på joner människor kommer att ha glukos – och därmed bli ett viktigt Lantmännen. typ 2-diabetes år 2030. I Sve- tillskott för diabetiker. rige står sjukdomen för 10% av – Mycket talar för att det här Läs mer om studien på vårdkostnaderna. kan bli ett värdefullt tillägg till ex- – Diabetes är en aktuell och isterande läkemedel, säger Anders http://www.gu.se/omuniversitetet/ global utmaning. Att ta ansvar är Rosengren, docent vid Sahlgren- aktuellt/nyheter/detalj//brocco- viktigt för Lantmännen, som har ska akademin. li-i-fokus-nar-ny-substans-mot-di- ett stort fokus på hälsosamma livs- Planen är att livsmedelsproduk- abetes-identiierats.cid1475132 medelsprodukter och en ambition ter innehållande den aktiva anti- att bidra till ett bättre hälsoläge i oxidanten skall innas tillgängligt Nyhetsinfo 21 juni 2017 världen, säger Mats Larsson, forsk- på marknaden så snart utveck- www red DiabetologNytt ningsdirektör på Lantmännen. lingsarbetet är klart.

212 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Artificiell intelligens ska göra diabetesvården vid T2DM bättre – och mer kostnadseffektiv. I Skåne. Christina Bjartell och Mattias verktyget samlar in och tolkar pa- Europa, USA och andra delar av Jönsson verksamhetschef på tientdata. Patienten kan med sin världen. Capio i Malmö deltar i projektet app få större möjlighet att förstå och följa sin behandling, och där- som leds av Damon Tojjar . Fakta/Diabetes igenom få bättre kontroll över sin Diabetes är den snabbast växan- Kan artiiciell intelligens bidra till diabetes. de folksjukdomen i världen. År smartare användning av sjukvår- Lösningen bygger på artii- 2040 beräknas ler än 640 miljo- dens resurser och leda till en bättre ciell intelligens vilket innebär ner människor vara drabbade. Typ diabetesvård? Tillsammans med att behandlingsrekommendatio- 2-diabetes utgör 90 procent av alla Region Skåne tar Lunds univer- nerna som presenteras bygger på fall. Utan behandling leder sjuk- sitet täten i en satsning på e-hälsa en kombination av en ansenlig domen till svåra följdsjukdomar och diabetes. mängd data och variabler som den och kan leda till njursvikt, blind- – Vinnare är både patienten enskilda läkaren normalt sätt inte het, amputationer, hjärtinfarkt och samhället, säger Damon Toj- kan hantera. och stroke. jar som leder projektet. Efter att ha fått diagnosen typ Trettiotal vårdcentraler Möt oss i Almedalen! 2-diabetes väntar för det mesta en Under 2017 deltar ett trettiotal Medverkande på seminariet i Al- krokig väg till bästa behandlingen vårdcentraler i projektet med Re- medalen: Göran Hägglund (mo- kantad av många olika läkemedel. gion Skåne som huvudman. derator), Johan Assarsson (Inera), I dagens riktlinjer saknas speciik – Detta kan innebära en stor Heidi Stensmyren (Sveriges läkar- vägledning i vilket preparat som vinst och ökad trygghet för patien- förbund), Anders Åkesson (Region bäst passar den enskilde patienten. ten samtidigt som det löser en vik- skåne), Niklas Eklöf (eHälsomyn- Samtidigt har såväl antalet patien- tig utmaning för sjukvården, säger digheten), Janeth Leksell (Uppsa- ter som nya godkända produkter Mattias Jönsson verksamhetschef la universitet) och Damon tojjar ökat i antal de senaste åren. Resul- vid Capio citykliniken i Malmö (Lunds universitet). tatet är att allt ler läkemedel skrivs som deltar i projektet. Intresserad av att veta mer? Väl- ut till allt ler patienter, utan adek- Professor Patrik Midlöv vid kommen till vårt seminarium i vat uppföljning och utvärdering. Centrum för primärvårdsforsk- Almedalen onsdagen den 5 juli kl ning är koordinerande prövare: 16-17, Hästgatan 13, Visby Ger rekommentationer - Det är mycket på gång inom Ett intelligent digitalt beslutsstöd e-hälsa men det är viktigt att dessa Hur kan artificiell intelligens ger läkare behandlingsrekom- innovationer utvärderas veten- bidra till en bättre, mer jämlik mendationer anpassade till varje skapligt i en rigorös klinisk studie och personcentrerad diabe- enskild patient. Detta genom att såsom vi gör i detta projekt innan tesvård? de införs på bred front. Utvecklingen inom e-hälsa går rasande fort och nya evidensbase- ”Först i världen” rade lösningar som kan förbättra – Vi är först i världen med denna läkemedelsbehandlingen och livs- lösning, tack vare vårt fantastis- kvaliteten för personer med diabe- ka team av experter från klinik, tes är redan här. På vilket sätt bi- akademi och industri, inom både drar de till en bättre diabetesvård? medicin och teknik. Vi bygger Hur tar vi vara på dessa initiativ lösningar som löser sjukvårdens och hur kan de implementeras? utmaningar och är på god väg att bygga ut systemet mot lera andra Läs mer om seminariet viktiga folksjukdomar i närtid, http://www.almedalsveckan. säger Damon Tojjar som är forsk- info/event/user- ande läkare vid Lunds universitets view/47364?redir=%23eidx_2 Christina Bjartell (tv) och Mattias Jönsson Diabetescentrum som själv varit verksamhetschef på Capio i Malmö (i mitten) deltar i projektet som leds av med om att framgångsrikt ut- Nyhetsinfo 20 juni 2017 Damon Tojjar (th). Foto: www.med.lu.se veckla och få godkänt läkemedel i www red DiabetologNytt

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 213 TLV beslutar att Fiasp, mer snabbverkande än Novorapid, i beredningsform Fiasp Flextouch Snabbverkande Novorapid, Fiasp, sulin. 11,8 min snabbare i pump läkemedelsförmånerna. inns nu i beredningsformen Flex- mot 8 min snabbare i penna jäm- Tandvårds- och läkemedels- touch, till engångspenna, och till fört med Novorapid. förmånsverket, TLV, beslutar att samma pris som för Humalog och Fiasp i beredningsformen och Apidra. Tandvårds- och läkemedelsför- styrkan nedan ska ingå i läke- Förhoppningsvis kan TLV och månsverket, TLV, avslår ansökan medelsförmånerna från och med Novo Nordisk komma överens om att Fiasp injektionsvätska lös- 2017-06-16 till i tabellen angivna om, efter sommaren, också ett pris ning i cylinderampull, 5 x 3 ml ska priser. TLV fastställer det alterna- för Fiasp som penil och laska till få ingå i läkemedelsförmånerna. tiva försäljningspriset till samma insulinpump. Tandvårds- och läkemedelsför- belopp som AIP. Det är framförallt sprut-Fiasp månsverket, TLV, avslår ansökan till insulinpump, som är intres- om att Fiasp injektionsvätska, lös- Nyhetsinfo 21 juni 2017 sant, ett extra snabbverkande in- ning laska, I x IO ml ska få ingå i www red DiabetologNytt

TLV har diskvalificerat sig själv som hälsoekonomisk utredare. Debattinlägg, Jan Bolinder, prof, Karolinska Det bidde inte ens en tumme. TLV tar semester utan att grund för en nationell rekommen- Efter att under lång tid ha för- leverera hälsoekonomiskt dation från landstingens NT-råd. halat en önskvärd nationell sam- dokument för FGM. Syftet med rekommendationen var ordning för användning av FGM Ett års arbete. Ingen utvärdering att ge förutsättningar för en jämlik kastar nu TLV in handduken. av FreeStyle Libre. Nedan är ut- tillgång till FreeStyle Libre. Ett minst sagt märkligt och lagt på TLVs www. uppseendeväckande agerande, Bakgrund som nu riskerar att bidra till fort- ”TLV har inte möjlighet att TLV påbörjade en hälsoekono- satt ojämlik subvention och för- publicera en hälsoekonomisk ut- misk utvärdering av FreeStyle skrivning i landet med stora regi- värdering av den kontinuerliga Libre sommaren 2016. På hösten onala olikheter. glukosmätaren FreeStyle Libre, ef- samma år ansökte företaget som Detta trots att lera länder i tersom företaget som marknadsför marknadsför produkten om att Europa – senast i raden Frankri- produkten valt att inte bidra med den skulle ingå i läkemedelsför- ke – beslutat om obegränsad sub- nödvändigt underlag. månerna och utvärderingen till vention för alla med typ 1 diabetes I dag använder minst 27.000 NT-rådet avbröts. och typ 2 diabetes med multipel patienter i Sverige FreeStyle Libre I mars 2017 återkallade företa- insulin-behandling. och merkostnaden för den använd- get sin ansökan och TLV återupp- Man frågar sig om inte TLV nu ningen är minst en kvarts miljard tog då utvärderingen som skulle diskvaliicerat sig själv i sin själv- kronor per år. FreeStyle Libre har ligga till grund för NT-rådets re- påtagna roll som hälsoekonomisk introducerats utan ordnat införan- kommendation. Företaget har nu utredare; i den uppgiften borde de vilket lett till ojämlik tillgång valt att inte bidra med materialet väl rimligen ingå att i egen regi ta beroende på var i landet patienten från ansökan och TLV kan där- fram nödvändiga underlag, och bor. för inte publicera den utvärdering samverka med motsvarande organ – Det är viktigt att rätt patien- som gjorts. inom EU. ter får FreeStyle Libre så det är För att TLV ska kunna återupp- olyckligt att vi nu inte har möj- ta arbetet krävs att företaget bidrar Jan Bolinder. Professor/överläkare lighet att publicera en hälsoeko- till en utvärdering.” Kliniken för Endokrinologi, nomisk utvärdering, säger Malin Metabolism och Diabetes Blixt, enhetschef. Nyhetsinfo 18 juni 2017 Karolinska Universitetssjukhuset TLV:s utvärdering inom medi- www red DiabetologNytt Huddinge cinteknikuppdraget skulle legat till

214 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Exercise management in type 1 diabetes: a consensus Statement. The Lancet jan 2017. Peter Adolfsson m fl Michael C Riddell, Ian W Gallen, Introduction patients who were categorised as Carmel E Smart, Craig E Taplin, Despite tremendous advances sin- being most physically active (exer- Peter Adolfsson, Alistair N Lumb, ce the discovery of insulin almost cising two or more times per week) Aaron Kowalski, Remi Raba- 100 years ago, management of had better HbA1c concentrations, sa-Lhoret, Rory McCrimmon, type 1 diabetes remains challen- a more favourable BMI, less dys- Carin Hume, Francesca Annan, ging.1,2 he majority of patients lipidaemia and hypertension, and Paul A Fournier, Claudia Graham, living with type 1 diabetes do not fewer diabetes-related complica- Bruce Bode, Pietro Galassetti, Ti- have a healthy body weight (about tions (retinopathy and microalbu- mothy W Jones, Inigo San Millan, 60% are overweight or obese), minuria), than those who were less Tim Heise, Anne L Peters, Andre- about 40% have hypertension, habitually active. he study also as Petz, Lori M Lafel about 60% have dyslipidaemia,3 showed that patients with type 1 and most do not engage in enough diabetes who are more active tend Abstract regular physical activity.4 Regular to have less diabetic ketoacidosis Type 1 diabetes is a challenging exercise can help patients achieve and a reduced risk of developing condition to manage for various several goals: it improves the car- severe hypoglycaemia with coma.3 physiological and behavioural re- diovascular disease risk proile in However, older women who are asons. Regular exercise is impor- paediatric patients5 and reduces physically active have higher ra- tant, but management of diferent HbA1c by about 0.3% in the pa- tes of severe hypoglycaemia (with forms of physical activity is par- ediatric population.6 Body com- coma) than those who are inac- ticularly diicult for both the in- position, cardiorespiratory itness, tive.3 Several barriers to exercise dividual with type 1 diabetes and endothelial function, and blood might exist, including a fear of the health-care provider. People lipid proile (ie, triglycerides and hypoglycaemia, loss of glycae- with type 1 diabetes tend to be at total cholesterol) all improve with mic control, insuicient time, least as inactive as the general po- regular physical activity in child- access to facilities, an absence of pulation, with a large percentage ren and young people with type 1 motivation, issues around body of individuals not maintaining a diabetes.6 hese cardiometabolic image, and a general scarcity of healthy body mass nor achieving improvements are all important, knowledge around exercise ma- the minimum amount of modera- given that cardiovascular disease is nagement.12–14 For all adults te to vigorous aerobic activity per the leading cause of morbidity and living with diabetes, including week. Regular exercise can impro- mortality in young people with those living with type 1 diabe- ve health and wellbeing, and can type 1 diabetes.7,8 In adults, both tes, 150 minutes of accumulated help individuals to achieve their retinopathy and microalbuminu- physical activity is recommended target lipid proile, body compo- ria are less common in those who each week, with no more than two sition, and itness and glycaemic are physically active than in those consecutive days of no physical ac- goals. However, several additional who are not.9 Active adults with tivity.15 Resistance exercise is also barriers to exercise can exist for a type 1 diabetes tend to have better recommended two to three times person with diabetes, including chance of achieving their HbA1c a week.15 Getting this much exer- fear of hypoglycaemia, loss of and blood pressure targets, and a cise is diicult for many patients; glycaemic control, and inadequate healthier BMI, than do inactive results from a large cross-sectional knowledge around exercise ma- patients.3 Regular exercise also de- study showed that less than 20% nagement. his Review provides creases total daily insulin needs.10 of patients manage to do aerobic an up to date consensus on exer- Having a high exercise capacity exercise more than two times per cise management for individuals in adulthood is associated with week, and about 60% of patients with type 1 diabetes who exercise a reduced risk of coronary artery do no structured exercise at all.3 regularly, including glucose tar- disease, myocardial ischaemia, For children and young people, gets for safe and efective exercise, and stroke, regardless of whether at least 60 minutes of physical ac- and nutritional and insulin dose a person has diabetes or not.11 In tivity should be done per day.16 adjustments to protect against ex- a large cross-sectional study of 18 Physical inactivity and prolonged ercise-related glucose excursions. 028 adults with type 1 diabetes,3 sitting times increase gradually ▶

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 215 with age and are linked to high exercise using free weights, weight the working body. Although the HbA1c concentrations in young machines, body weight, or elastic main determinant of glucose pro- people with type 1 diabetes,17 resistance bands that rely primari- duction during aerobic exercise is and physical inactivity appears to ly on anaerobic energy-producing an increase in glucagon concentra- be more common in women than systems. High intensity inter- tions, neural control of glucose re- in men.3 Regular exercise should val training involves alternation lease and other counter-regulatory be encouraged and supported by between brief periods of vigorous hormones also have a supportive health-care professionals for many exercise and recovery at low to mo- role.23 An extended duration of reasons, but primarily because the derate intensity (eg, from 20 s to 4 exercise leads to reduced reliance overall cardiometabolic beneits min intervals of exercise and rest, on muscle glycogen as fuel and in- outweigh the immediate risks if for up to ten cycles).18 Both aero- creased reliance on lipid oxidation certain precautions are taken. In bic and anaerobic activities are re- and glucose derived from plas- this Review, the basic categories of commended for most people living ma.24 If insulin concentrations do exercise are described from a phy- with diabetes,15,16 and guidelines not fall during prolonged aerobic siological perspective, as are the now also incorporate high inten- exercise (eg, walking, jogging, or starting points for nutritional and sity interval training as a training cycling), the rise in counter-re- insulin dose adjustments to keep modality with established beneits gulatory hormones is less efecti- patients in a targeted glycaemic for individuals with prediabetes or ve than when they do fall in the range. his Review summarises type 2 diabetes.15 In some studies, promotion of hepatic glucose pro- the authors’ consensus on the av- high intensity interval training has duction.21 When the intensity of ailable strategies that help incor- been shown to be more efective exercise increases above 50–60% porate exercise safely into the daily than continuous aerobic training of maximal oxygen consumption management plan for those adults in improvement of cardiovascular (VO2max), fat oxidation decrea- with type 1 diabetes who are regu- itness and various parameters re- ses, particularly in those who are larly engaging in exercise, sports, lated to glucose metabolism, inclu- untrained, and carbohydrates be- or competitive events. We hope ding insulin sensitivity and glyca- come the preferred fuel.25 Pro- these new guidelines for exercise emic control in type 2 diabetes.19 longed high intensity exercise is management will improve glyca- At present, it is unclear what the supported by use of both muscle emic control and encourage more most efective forms of exercise for glycogen and blood glucose, with individuals with type 1 diabetes to improvement of cardiometabolic minimal contributions from lipid increase their physical activity. control in type 1 diabetes are.20 and protein.26 During predominantly anaerobic activities such as Physiology of physical activi- Neuroendocrine and metabo- springing,27 and during a high in- ty and exercise lic responses to exercise tensity interval training session,28 Modalities of exercise Individuals without diabetes circulating insulin concentrations An understanding of the metabo- he metabolic responses to dife- do not decrease as markedly as in lic and neuroendocrine responses rent forms of exercise are distinct. purely aerobic activities, in part to the various types of exercise However, in almost all forms of because the duration of activity done by people with type 1 diabe- exercise, regardless of the intensity is typically shorter. High rates of tes is essential for determination of or duration, blood glucose concen- external power output during high appropriate nutritional and insulin trations are normally held within intensity interval training increase management strategies. Exercise is a tight range (4–6 mmol/L). reliance on muscle phosphagens generally classiied as aerobic or During aerobic exercise, insulin and glycogen, with lactate con- anaerobic, depending on the pre- secretion decreases and glucagon centrations rising markedly in the dominant energy systems used secretion increases in the portal circulation.28 Insulin concentra- to support the activity, although vein to facilitate release of glucose tions increase above baseline con- most exercise activities include a from the liver to match the rate of centrations in early recovery from combination of energy systems. glucose uptake into the working a high intensity interval training Aerobic exercise (eg, walking, muscles.21 Exercise can increa- session to ofset the rise in glucose cycling, jogging, and swimming) se glucose uptake into muscle by caused by the elevations in coun- involves repeated and continuous up to 50 times—a phenomenon ter-regulatory hormones and other movement of large muscle groups that occurs independently of in- metabolites.27 that rely primarily on aerobic en- sulin signalling—22 so the de- ergy-producing systems. Resistan- crease in circulating insulin does Dysglycaemia during exercise in ce (strength) training is a type of not restrict glucose provision to individuals with type 1 diabetes In

216 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se type 1 diabetes, the glycaemic responses to exercise are inluenced by the location of insulin delivery, the amount of insulin in the circulation, the blood glucose concentration before exercise, the composition of the last meal or snack, as well as the intensity and duration of the activity29 (igure 1).

During aerobic exercise, blood glucose concentrations fall in most individuals with type 1 diabetes , unless they ingest carbohydrates, because insulin concentrations cannot be decreased rapidly enough at the start of the activity and reduction, or both, for prolonged weight lifting, and some compe- might rise in the systemic circula- aerobic exercise. High intensity in- titive sports),42,46 or during high tion,30 perhaps because of incre- terval sprint training promotes the intensity interval training,28 glu- ased blood low to subcutaneous increased oxidative capacity of ske- cose concentrations typically rise. adipose tissue during exercise.31 letal muscle in type 1 diabetes and Dysglycaemia after exercise in Even if basal insulin infusion ra- attenuates the rates of glycogen individuals with type 1 diabetes tes are halved 60 min before the breakdown,37 which might, in Glucose uptake into muscle de- start of exercise in patients on theory, protect against hypoglyca- creases immediately after aerobic continuous subcutaneous insulin emia after exercise. Perhaps in line exercise, but overall glucose dis- infusion, circulating free insulin with this, individuals who are ae- posal remains elevated for several concentrations do not decrease robically conditioned have lower hours in recovery from exercise to suiciently upon commencement glucose variability than do those help replenish glycogen stores.47 of exercise and concentrations who are unconditioned.38 Low he risk of hypoglycaemia is ele- tend to increase transiently during insulin concentrations due to ag- vated for at least 24 h in recovery the activity.32 Increased insulin gressive reductions in insulin ad- from exercise, with the greatest concentrations in the circulation ministration or a skipped insulin risk of nocturnal hypoglycaemia during exercise promote increased dose can cause hyperglycaemia be- occurring after afternoon activi- glucose disposal relative to hepatic fore and during aerobic exercise,39 ty.48 As mentioned above, weight glucose production, and might de- and even mild activity could lead lifting, sprinting, and intense lay lipolysis—another feature that to development of ketosis.40 aerobic exercise can promote in- increases the reliance of muscles crease in glycaemia that could last on glucose as a fuel. Hypoglyca- Resistance exercise is associated for hours in recovery. Although emia develops in most patients with better glucose stability than a conservative insulin correction within about 45 min of starting continuous moderate intensity after exercise might be prudent in aerobic exercise.33–35 Trained aerobic exercise,41 although re- some situations,49 over-correction individuals with type 1 diabetes sistance exercise could cause a with insulin can cause severe noc- have greater reductions in blood modest rise in glycaemia in some turnal hypoglycaemia and lead to glucose concentrations during ae- individuals.42 Compared with death.50 High intensity interval robic exercise than do individuals aerobic exercise, a high intensity training has been associated with with reduced physical itness,36 interval training session attenu- a higher risk of nocturnal hy- possibly because the overall work ates the decrease in glycaemia,43 poglycaemia than continuous ae- rate is higher in those who are as does resistance exercise done robic exercise in some51—but not more aerobically conditioned than before aerobic exercise,44 possibly all—52,53 studies. those who are not. As such, both because of increased concentra- trained and untrained individu- tions of counterregulatory hor- Exercise goals and als with type 1 diabetes typically mones and various metabolites glycaemic targets require an increased carbohydrate that restrict glucose disposal.45 Individuals with type 1 diabetes intake [A: before commencing ae- In situations of brief and intense should engage in exercise for vario- robic exercise?] or an insulin dose anaerobic exercise (eg, sprinting, us health reasons. he evidence on ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 217 whether regular exercise improves and maintaining circulating glu- (ie, relativity euglycaemic but ke- metabolic control in adults with cose concentrations in this range totic; see panel 1). [A:OK?] he type 1 diabetes is somewhat scar- is challenging. he glycaemic re- cause of elevated ketone concen- ce,20,54 although exercise appears sponse to exercise is variable and trations should be identiied (ill- to be helpful in young people with based on several factors, including ness, diet manipulation, a recent type 1 diabetes.6 Exercise readi- the duration and intensity of ex- bout of prolonged exercise, insulin ness questionnaires, such as Phy- ercise,45,56 the starting level of omission, etc). Prolonged enduran- sical Activity Readiness Medical glycaemia,34 the individual’s ae- ce type activities (eg, marathons Examination (ePARmed-X+) and robic itness,36 and the amount of and trekking) and diets very low Physical Activity Readiness Ques- insulin in circulation57,58 (igure in carbohydrate can elevate blood tionnaire for Everyone (PAR-Q+), 1). Anaerobic exercise and a high ketone concentrations in patients are available online for adults with intensity interval training session and blood glucose might not be diabetes who might be at increased can be initiated with a lower star- markedly elevated. he health-ca- risk of developing adverse events. ting glucose concentration (5–7 re professional should therefore Patient goals for exercise (eg, me- mmol/L) because glucose concen- deine appropriate protocols for tabolic control, prevention of trations tend to remain relatively ketone monitoring and strategies complications, itness, weight loss, stable and fall to a lesser extent for what to do when blood or urine or competition and performance) than with continuous aerobic ex- ketones are elevated. Blood ketone should be considered before deci- ercise, or rise slightly (igure 1). concentrations of 3.0 mmol/L or sions on diabetes management are Strategies to cope with a range of more should be managed imme- made. his is an important ele- glucose concentrations before the diately by a qualiied health-care ment of the diabetes management start of exercise are provided in pa- professional (eg, a hospital emer- plan. For example, exercise for nel 1, bearing in mind that for ae- gency department or physician). weight loss requires strategies that robic activities lasting longer than focus on reduction of insulin con- 30 min, additional carbohydrates Recent hypoglycaemia centrations during and after exer- are likely to be needed (table 1). Severe hypoglycaemia (deined here cise, as opposed to consumption If glucose concentrations are too as blood glucose ≤2.8 mmol/L or a of additional carbohydrates. By high because of insulin omission, hypoglycaemic event requiring as- contrast, if maximisation of sports ketosis and further hyperglycae- sistance from another individual) and exercise performance is the mia can occur,40 and perceived within the previous 24 h is a con- primary goal, then nutritional gui- exercise or work efort probably traindication to exercise, because dance speciic to the sporting acti- increases. Although it is unclear of the substantially increased risk vity is needed and a modiied in- if there is an optimal glycaemic of a more serious episode during sulin plan to match the increased range for exercise performance, exercise.63 In situations where mi- nutritional requirements should clinical experience and data from nor hypoglycaemia (blood glucose be considered.55 For all patients, a ield study in adolescents62 sug- 2.9–3.9 mmol/L, with the ability blood glucose monitoring before, gest that maintenance of a concen- to self-treat) has occurred, the in- during, and after exercise is essen- tration of about 6.0–8.0 mmol/L creased risk of recurrence must be tial to inform strategies and main- might be ideal. taken into account.64 Vigilance tain stable and safe glycaemia. around monitoring should be stres- Contraindications and sed and exercise should be avoided he appropriate blood glucose cautions for exercise if the setting is deemed particular- concentration at the start of exer- Although few exercise restrictions ly unsafe (eg, Alpine skiing, rock cise should be tailored to the indi- should be placed on patients, some climbing, swimming or trekking vidual. Based on our consensus, a considerations are important, and alone). reasonable starting range for most are highlighted below. patients doing aerobic exercise las- Diabetes-related ting up to an hour is 7–10 mmol/L. Elevated ketones complications his range balances performance Elevated blood ketones (≥1.5 Overall, the health beneits of be- considerations against the risk of mmol/L) or urine ketones (2+ or ing physically active outweigh the hypoglycaemia. Concentrations 4.0 mmol/L) [A:OK?] before a risks of being sedentary for people higher than 7–10 mmol/L might bout of exercise should be addres- with diabetes. hose with compli- be acceptable in some situations sed before the start of the session cations can derive several health where added protection against hy- via insulin administration with beneits from low intensity physi- poglycaemia is needed. Achieving carbohydrate feeding if necessary cal activities, with little risk of any

218 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se adverse events.65 In individuals carbohydrate intake should relate indicated for individuals wanting with long-standing disease or with to the fuel cost of training in the to lose weight.71 he major nutri- HbA1c concentrations well above athletic subpopulation and ensure ents required to fuel performance the target, vigorous exercise, ac- prevention of hypoglycaemia for are carbohydrates and lipids, while tivities involving lifting of heavy all active people. Balancing insu- the addition of protein is needed to weights, and competitive enduran- lin dose to carbohydrate intake help foster recovery and maintain ce events are contraindicated, par- during exercise is essential. Various nitrogen balance.59,72 Protein re- ticularly if the patient has unstable carbohydrate and insulin adjust- quirements range from 1.2 to 1.6 proliferative retinopathy, severe ment strategies can be used, such g per kg body weight per day, and autonomic dysfunction, or renal as reduction of the pre-exercise bo- will vary with training type and failure.65 lus insulin dose by 30–50% up to intensity, and carbohydrate availa- 90 min before aerobic exercise,67 bility.59,73 Higher intakes might Inadequate preparation for consumption of carbohydrates with be needed for recovery from injury exercise-associated a high glycaemic index during sport or for individuals on energy-restric- hypoglycaemia (30–60 g/h), or replacement of car- ted diets74 to maintain lean body In preparation for exercise, indivi- bohydrates after anaerobic exercise. mass. duals with type 1 diabetes should Personal tolerance of ingested car- be aware of their starting glucose bohydrate, particularly during ex- Carbohydrate needs before, concentrations, and should also ercise, is a key factor in tailoring of during, and after exercise have blood glucose monitoring recommendations. he distribution A distinction should be made equipment and snacks to treat of macronutrient intake over the between carbohydrate needs for hypoglycaemia. hey should also day should take into account the performance and carbohydrate be advised to wear or carry some timing of exercise so that liver and intake required for hypoglyca- form of diabetes identiication. muscle glycogen stores are maximi- emia prevention (table 1). Car- sed before the activity and replenis- bohydrate requirements will alter Nutritional management hed in early recovery.59 his stra- insulin management strategies Goals for nutritional management tegy should include carbohydrate and vice versa. Most studies in Nutritional management for pe- feeding well before exercise (~4 h) type 1 diabetes have investigated ople with type 1 diabetes should and early in recovery.59,68Daily the amount and distribution of incorporate strategies that opti- energy and macronutrient balan- carbohydrate required to prevent mise glycaemic control while proce Athletes with type 1 diabetes hypoglycaemia rather than to moting long-term health.66 he need suicient energy to meet the optimise performance, although main strategies around nutrition demands of their daily activities. the two might be at least parti- for exercise and sport discussed hese demands will vary with age, ally related.34,67,75,76 For ex- in this section primarily aim to sex, body composition, and activity ample, although only 15–20 g/h maximise athletic performance type.69 Total energy requirements of carbohydrate might be requi- and are based largely on studies difer with individual aims. Predic- red to prevent hypoglycaemia in done in highly trained healthy tive equations can be used to esti- people who reduce their insulin individuals without diabetes,59 mate resting energy expenditure;70 concentrations in anticipation of with few studies done in people however, they should serve only as a exercise, this amount of carbohy- with type 1 diabetes. Application guide, as they could overestimate or drate could be insuicient for of these strategies to people with underestimate actual requirements. performance. Implementation of type 1 diabetes must consider the An appropriate macronutrient ba- increased carbohydrate supple- individual’s insulin management lance and micronutrient intake,59 mentation (up to 75 g/h) is pos- plan and include speciic advice coupled with a glycaemic control sible for prolonged activity lasting focused on nutrition for both ath- strategy, is required to maximise longer than 2.5 hours (eg, marat- letic performance and glycaemic performance. he optimal ma- hons and other endurance type management. A registered dieti- cronutrient distribution will vary races) without having an adverse tian with specialist diabetes and depending on the individualised efect on glycaemia, as long as the sports knowledge is the most qu- assessment and exercise goals. A insulin dose is titrated appropri- aliied to help active people with guide to the nutritional distribu- ately.55 In general, carbohydrate type 1 diabetes. An individualised tion of the total daily energy intake requirements during shorter, in- meal planning approach is central is as follows: 45–65% carbohydra- termittent, high-intensity, and to improvement of performance te, 20–35% fat, and 10–35% pro- anaerobic activities can be consi- and glycaemic outcomes. Daily tein, with higher protein intakes derably decreased (table 1). ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 219 dration and optimisation of performance.68 Water is the most efective drink for low-intensity and short-duration sports (ie, ≤45 min), as long as glucose concentrations are 7 mmol/L or higher. Sports beverages containing carbohydrate (6–8%) and electrolytes are useful for athletes with type 1 diabetes exercising for a longer duration; they are also useful as a hydration and fuel source for higher intensity exercise, and for prevention of hypoglycaemia.34,81 However, overconsumption of these beverages can result in hy- Nutritional needs for recovery could sustain carbohydrate availa- perglycaemia. Milk-based drinks Nutrition requirements to maxi- bility and maintain euglycaemia, containing carbohydrate and pro- mise muscle recovery and muscle whereas consumption of meals tein can assist with recovery after protein synthesis after exerci- and snacks with a high glycaemic exercise and prevent delayed hy- se have been well studied in the index after exercise could enhan- poglycaemia.76Low-carbohydrate athletic population without di- ce recovery. Snacks with a low or high-fat diets and exercise People abetes.77 For replenishment of moderate glycaemic index could with type 1 diabetes can choose a glycogen content after exercise, also be preferred for long-distan- low carbohydrate high fat diet for carbohydrate intake is essential.59 ce activities such as trekking and various reasons. A review on low For athletes with type 1 diabetes, long-distance cycling at low to mo- carbohydrate high fat diets and rapid and adequate replenishment derate workloads. Consumption of sports performance in individuals of muscle and liver glycogen sto- a carbohydrate with a low glycae- without type 1 diabetes concluded res is essential to help prevent mic index (isomaltose) 2 hours be- that, despite increasing the abi- late onset hypoglycaemia. Glyco- fore a high intensity run in adults lity of muscles to utilise fat over gen replacement strategies could with type 1 diabetes showed better time, no evidence was available to also be important in prevention blood glucose responses during suggest performance beneits.82 of euglycaemic ketosis in exercise exercise than did consumption of Long-term studies have yet to be recovery.78 Ingestion of protein a carbohydrate with a high glyca- done on the health, glycaemia, or (~20–30 g) in addition to carbohy- emic index (dextrose).79 In adults performance efects of low car- drate in the period after exercise is with type 1 diabetes, consumption bohydrate high fat diets in people beneicial for muscle protein synt- of a meal and bedtime snack with with type 1 diabetes. A concern hesis, but protein ingestion does a low glycaemic index after mid- with these diets is that they could not appear to facilitate glycogen day exercise prevented postprandi- impair the capacity for high-in- replenishment in athletes who do al hyperglycaemia more efectively tensity exercise.83 Variation in not have diabetes.59 Role of high than consumption of a meal and carbohydrate intake (ie, periodi- and low glycaemic index foods for snack with a high glycaemic in- sation throughout the training maintenance of euglycaemia he dex after exercise, with both meal cycle according to fuel needs and glycaemic index of a carbohydra- types being protective against hy- performance) has been suggested te-rich food can be used to assist poglycaemia for about 8 h.80 [A: by some researchers as a way to with the selection of the carbohy- OK as edited?] he protection help promote adaptation of ske- drate type for exercise; sports provided by a snack was not sus- letal muscle to training.84 Addi- drinks and energy gels with a high tained beyond 8 h, and the risk of tionally, various exercise-nutrient glycaemic index provide rapidly hypoglycaemia remained high for protocols are used to manipulate released carbohydrate to increa- at least 24 h.80 carbohydrate availability, such se blood glucose concentrations as training in a fasting state or during endurance events and can Fluid replacement withholding carbohydrate intake treat or prevent hypoglycaemia. Adequate luid intake before, at a meal before or after exercise. Consumption of foods with a low during, and after exercise is ne- hese approaches have not been glycaemic index before exercise cessary for prevention of dehy- studied in individuals with type 1

220 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se diabetes, in whom manipulation and carbohydrate intake during centrations can ameliorate this of dietary carbohydrate as part of and after planned exercise are pre- risk. For patients on multiple daily training presents unique challeng- sented in table 2 and table 3. insulin injections, clinical obser- es for insulin therapy and requires vations and limited experimen- careful glucose monitoring. Sports Insulin adjustment for pro- tal data106 show that reduction nutritional aids and type 1 diabe- longed activities: bolus of long-acting basal (as well as tes he use of ergogenic aids is a insulin approaches prandial) insulin concentrations widespread performance enhan- Reductions in the bolus insulin before exercise reduces the risk of cement strategy used by athletes, dose accompanying the meal befo- hypoglycaemia during and after but little evidence is available on re exercise or consumption of ad- the activity, but might promote their use in athletes with type 1 ditional carbohydrate during exer- hyperglycaemia at other points diabetes. Cafeine intake in ath- cise are typically needed to avoid during the day. herefore, reduc- letes without diabetes has shown hypoglycaemia during prolonged tion in the basal insulin dose for improvements in endurance capa- exercise (>30 min).34,56,67,102– patients on multiple daily insulin city and power output.85 Cafeine 104 Bolus dose reductions require injections should not be routinely intake (5–6 mg per kg body mass) planning in advance and are pro- recommended but can be a thera- before exercise attenuates decrease bably only appropriate for exercise peutic option for those engaging in glycaemia during exercise in in- with a predictable intensity per- in considerably more planned dividuals with type 1 diabetes, but formed within 2–3 h after a meal. activity than usual (eg, camps or it might increase the risk of late As shown in table 3, the extent of tournaments). In general, basal in- onset hypoglycaemia.86 Recom- a mealtime dose reduction is pro- sulins with a short half-life, such mendations for management of portional to both the intensity and as NPH insulin or insulin detemir, glycaemia Blood glucose responses duration of the physical activity. seem to lead to less hypoglycaemia to the various forms and intensi- his approach is safe and efecti- in conjunction with exercise than ties of exercise show high variabili- ve; even reducing the bolus insulin do basal insulins with a longer ty between and within individuals dose by as much as 75% does not half-life, such as insulin glargi- (igure 1). Glycaemic management appear to increase ketone produc- ne,107 although the mechanism is therefore based on frequent tion during exercise.104 Another through which this occurs is un- glucose monitoring, adjustments strategy is to combine a 75% re- clear. Although ultra-long-acting to both basal and bolus insulin duction of the bolus insulin dose insulins (eg, insulin degludec, with dosing, and consumption of car- before exercise with ingestion of a a 25 h half-life) pose similar risks bohydrates during and after ex- snack or meal with a low glycae- of hypoglycaemia with endurance ercise. hese recommendations mic index.105 his method also exercise to those of insulin glargi- are intended to serve as a starting reduces the risk of hyperglycae- ne,108 dose reductions for exercise point for insulin adjustments and mia before exercise. However, this would have to be implemented at carbohydrate intake that can then approach will not protect against least 48 h before planned exercise. be individualised (igure 2). Clini- hypoglycaemia if the exercise is We do not recommend this, as it cal management strategies should performed an hour or more after would compromise overall glycae- be built around exercise types and consumption of the snack.105 mic control. individual aims, and implementa- As such, this combined approach tion of these strategies should take might be preferable only for post- Continuous subcutaneous insu- into account the factors summari- prandial exercise done soon after a lin infusion ofers the lexibility sed in panel 2. Generally, sustained meal. to modify basal infusion delivery aerobic exercise requires more sub- and obtain a quick efect (within stantial reductions in insulin dose Basal insulin approaches ~1–2 h).109 Suspension of basal and a higher carbohydrate intake Late postprandial hypoglycaemia insulin infusion at the onset of 60 than a short-term high intensity (>4 h after a meal) following ae- min exercise reduces the risk of interval training session. By con- robic exercise is driven partly by hypoglycaemia during the activi- trast, brief anaerobic exercise (eg, circulating basal insulin concen- ty, but it could increase the risk of sprinting or weight lifting) could trations. Elevated insulin sensiti- hyperglycaemia after exercise.110 require increased insulin delivery, vity after exercise, and possibly a Moreover, glucose concentra- which is typically given in early re- blunting of glucose counter-regu- tions could still decrease by 2–3 covery rather than before exercise lation, appear to place individuals mmol/L over 30–60 min even for obvious safety reasons.49 Stra- at risk for at least 12 h. Reduction when basal insulin is dramatical- tegies for insulin dose adjustments of circulating basal insulin con- ly reduced (or completely suspen- ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 221 ded),67,110,111 because of the lag cise.48,115 Immediate increases in of the insulin pump (for example, time in the change in circulating insulin sensitivity after exercise can combat sports, diving, and some insulin concentrations. Where be addressed through a reduction team sports such as football, soc- practical, a basal rate reduction, of about 50% in the bolus insulin cer, ield hockey, or basketball).118 rather than suspension, should be dose administered at meal after Continuous subcutaneous insulin attempted 60–90 min before the exercise, along with consumption infusion could also contribute to a start of exercise. An 80% basal of a snack with a low glycaemic in- greater sense of being diseased and reduction at the onset of exercise dex at bedtime.80 In one study of social stigma in some individuals helps mitigate hyperglycaemia af- 16 young people using an insulin by drawing undue attention to ter exercise more efectively than pump, a temporary basal rate re- their condition.118 Prolonged dis- does basal insulin suspension, and duction of about 20% at bedtime connection of the pump (>60 min) appears to be associated with a re- for 6 h reduced the risk of noctur- should be managed by reconnec- ducedrisk of hypoglycaemia both nal hypoglycaemia.113 Similarly, ting, testing, and reconnection of during and after the activity.67 in another study of ten men on the pump if necessary, or by swit- multiple daily insulin injections, ching to basal insulin provision However, the optimal timing of a 20% basal rate reduction on the by needle. Continuous glucose basal rate reductions for aerobic day of exercise along with provi- monitoring provides comprehen- and high intensity exercise activi- sion of a free carbohydrate snack sive information on blood glucose ties and the maximal safe duration at bedtime (0.4 g carbohydrate per concentrations, real-time trends, for insulin pump suspension have kg body mass) reduced the risk of and rates of change, which can be yet to be determined and remain nocturnal hypoglycaemia.106 In- used to prevent low concentrations open to debate. To limit the risk dividuals at high risk ofsevere noc- during exercise,119 even in unique of compromised glycaemic control turnal hypoglycaemia (eg, those settings where self-monitoring of and ketosis, we propose a time li- with recurrent hypoglycaemia and blood glucose is diicult.120 Exis- mit of less than 2 h on the basis those sleeping alone) should take ting sensors are reasonably accura- of rapid-acting insulin pharma- additional preventive measures, te for exercise;96,121 however, the cokinetics.109 Hyperglycaemia including blood glucose checks at lag time in glucose equilibrium commonly occurs in patients after 0200 h or 0300 h, or the use of a with the interstitial space and the intense exercise, particularly if in- real time continuous glucose mo- rapid turnover in glucose during sulin concentrations are reduced. nitoring system with alarms and exercise might afect accuracy (ie, Continuous subcutaneous insulin automatic pump suspension.116 overestimate blood glucose when infusion seems to ofer advanta- Consumption of a snack alone, concentrations are dropping and ges over multiple daily insulin without changing basal insulin underestimate it when concentra- injections in the management of therapy, does not appear to entire- tions are rising).97,122 Structured early onset112 and late onset hy- ly eliminate the risk of nocturnal educational sessions can be imple- poglycaemia after exercise,113 be- hypoglycaemia,80 and alcohol in- mented by downloading data on cause of the increased lexibility take might increase the risk.98 self-monitoring of blood glucose, around basal insulin adjustments. continuous glucose monitoring, Overcorrection of hyperglycaemia Emerging tools for exercise and continuous subcutaneous in- after exercise via repeated insulin management sulin infusion.123 Continues glu- dose administration results in an Several treatment regimens exist cose monitoring systems now ofer increased risk of severe late onset for people with type 1 diabetes. the option to add followers who hypoglycaemia, which could even Continuous subcutaneous insulin can view glucose concentrations be fatal.50 Strategies to reduce infusion ofers better lexibility in real time and potentially alert the risk of late onset hypoglycae- in basal insulin adjustments and the patient while they are playing mia after exercise Increased insu- management of exercise-associ- sports. hreshold suspension of lin sensitivity lasts up to 24–48 h ated hyperglycaemia than other insulin delivery in continuous sub- following exercise.47 Few studies methods of insulin delivery.117 cutaneous insulin infusion could have tested various nutrient or in- Continuous subcutaneous insulin ofer additional protection against sulin dose adjustments to prevent infusion is associated with redu- exercise-associated hypoglycae- hypoglycaemia after exercise. Noc- ced hyperglycaemia after exercise mia, according to some data.124 turnal hypoglycaemia after exerci- compared with multiple daily in- he development of a fully artiici- se commonly occurs in individuals sulin injections,112 but can create al pancreas for exercise remains an with type 1 diabetes,114 with an frustrating challenges for sports elusive goal.125 increased risk after afternoon exer- that might require disconnection

222 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Conclusion can help ameliorate the risk of dL) and monitor closely for hy- Regular physical activity should hypoglycaemia, as can increasing poglycaemia Starting glycaemia be a routine objective for patients carbohydrate intake to 60 g per near target (5–6·9 mmol/L) Ing- with type 1 diabetes, for various h or more. For anaerobic exercise, est 10 g of glucose before starting health and itness reasons. Consi- conservative insulin dose correc- aerobic exercise Anaerobic exer- derable challenges remain for tions might be required, although cise and high intensity interval people with type 1 diabetes, and this too might increase the risk of training sessions can be started their health-care team, in ma- nocturnal hypoglycaemia, parti- Starting glycaemia at target levels nagement of exercise and sports. cularly if the exercise is performed (7–10 mmol/L) Aerobic exercise Several small observational stu- late in the day. In all instances, can be started Anaerobic exercise dies and a few clinical trials have additional vigilance around glu- and high intensity interval trai- been published to date that help to cose monitoring is needed before, ning sessions can be started but inform the consensus recommen- during, and after the physical ac- glucose concentrations could rise dations presented here. More stu- tivity. Starting glycaemia slightly above dies are needed to determine how target (10·1–15·0 mmol/L) Aero- to best prevent exerciseassociated Panel 1: Blood glucose con- bic exercise can be started Anae- hypoglycaemia with basal rate in- centrations before exercise robic exercise can be started but sulin dose adjustments and how to commencement and recom- glucose concentrations could rise manage glycaemia in the recovery mended glucose manage- Starting glycaemia above target period after exercise. In general, ment strategies (>15 mmol/L) If the hyperglycae- aerobic exercise is associated with he carbohydrate intakes shown mia is unexplained (not associated reductions in glycaemia, whereas here aim to stabilise glycaemia at with a recent meal), check blood anaerobic exercise might be as- the start of exercise. Blood gluco- ketones. If ketones are modestly sociated with a transient increase se at the start of exercise must also elevated (up to 1·4 mmol/L), exer- in glucose concentrations. Both be viewed within a wider context. cise should be restricted to a light forms of exercise can cause delay- Factors to consider include direc- intensity for only a brief duration ed-onset hypoglycaemia in recove- tional trends in glucose and insu- (<30 min) and a small corrective ry. A sound understanding of the lin concentrations, patient safety, insulin dose might be needed be- physiology of diferent forms of and individual patient preferences fore starting exercise. If blood ke- exercise and the variables that can based on experience. Carbohydra- tones are elevated (≥1·5 mmol/L), inluence glycaemia during exer- te intake will need to be higher if exercise is contraindicated and cise and sport should underpin circulating insulin concentrations glucose management should be in- the implementation of safe and are high at the onset of exercise. itiated rapidly as per the advice of efective glycaemic management Starting glycaemia below target the health-care professional team. strategies. For aerobic exercise, re- (<5 mmol/L) Ingest 10–20 g of Mild to moderate aerobic exerci- ductions in insulin administration glucose before starting exercise se can be started if blood ketones before the activity (ie, reductions Delay exercise until blood glucose are low (<0·6 mmol/L) or the uri- in basal or bolus insulin, or both) is more than 5 mmol/L (90 mg/ ne ketone dipstick is less than 2+ (or <4·0 mmol/L). [A: OK as edited?] Blood glucose concentrations should be monitored during exercise to help detect whether glucose concentrations increase further. Intense exercise should be initiated only with caution as it could promote further hyperglycaemia

Panel 2: Factors that to consider before adjustments are made for exercise in individuals with type 1 diabetes Subcutaneous insulin injection and its adjustments Diferences in the site and depth of insulin injection afect absorption charac- ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 223 teristics87,88 Lipodystrophy can References 13 Jabbour G, Henderson M, Mathieu lead to increased luctuation in 1 Mayor S. Insulin pumps improve glucose ME. Barriers to active lifestyles in child- control in children with type 1 diabetes, ren with type 1 diabetes. Can J Diabetes blood glucose and unpredictable study inds. BMJ 2015; 351: h5998. 2016; 40: 170–72. 14 Lascar N, Kennedy hypoglycaemia Inadequate under- 2 McKnight JA, Wild SH, Lamb MJE, et A, Hancock B, et al. Attitudes and barriers standing of insulin pharmacokin- al. 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Avhandling kring socioekonomiska konsekvenser av typ-1 diabetes. Sofie Persson, Lund 8/6 försvarade IHE:s Soie Persson conomic Consequences of Child- Hela vhandlingen som free sin avhandling kring socioekono- hood Onset Type 1 Diabetes – a https://lup.lub.lu.se/search/publi- miska konsekvenser av typ-1 dia- case study of the impact of an early cation/2fdf7492-311e-4a0c-bf94- betes. life health shock” och undersöker 3fa2b8456d51 Disputationen ägde rum vid de socioekonomiska konsekvenser- Ekonomihögskolan, Lunds uni- na av typ-1 diabetes och hur en häl- Nyhetsinfo 17 juni 2017 versitet, den 8 juni 2017. sochock tidigt i livet kan påverka www red DiabetologNytt Avhandlingens titel är “Socioe- socioekonomisk status som vuxen.

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 227 Sverige ett innovativ land. Regeringens utredare Anders Lönnberg säljer in Sverige i USA som bioteknik intressant Sverige behåller andraplatsen i global innovationsrankning De fem nordiska länderna inns der, enligt GII 2017 (förra årets väl överens med mitt eget intryck bland de 25 högst rankade länder- placering inom parentes). från andra internationella events na i Global Innovation Index 2017, som jag deltagit i. Jag har där fun- Sverige behåller sin position 1. Schweiz (1) nit att det inns ett stort intresse som världens näst mest innovativa 2. Sverige (2) för svensk life science och för vårt land, enligt Global Innovation In- 3. Nederländerna (9) sjukvårdssystem”, säger Anders dex 2017, 4. USA (4) Lönnberg. Schweiz är för sjätte året i rad 5. Storbritannien (3) Under bioteknikkonferensen det mest innovativa landet. Neder- 6. Danmark (8) – som enligt Business Sweden är länderna är i år rankat som num- 7. Singapore (6) världens största i sitt slag – disku- mer tre, och har avancerat fem 8. Finland (5) teras beintliga och nära föreståen- positioner framför allt tack var de 9. Tyskland (10) de teknologiska genombrott och insatser som gjorts för att öka till- 10. Irland (7) hur dessa kan bidra till bättre kva- gängligheten till data i landet. litet samt kostnads- och tidsbespa- Sverige har förbättrat sin pla- Lönnberg säljer in svensk life ringar inom vården. cering i lera av rankningens un- science på Bio i San Diego dergrupper. I gruppen länkade I samband med den internationel- Andra ämnen som kommer innovationer (innovation linkage) la bioteknikkonferensen Bio i San att diskuteras: avancerade Sverige elva positio- Diego i USA 19–22 juni kommer * Hur kan digitalisering hjälpa pa- ner, i gruppen kunskapspåverkan svensk life science att företrädas av tienterna att aktivt bidra till bättre (knowledge impact) tio positioner Anders Lönnberg, regeringens na- behandlingsresultat? och sju positioner i gruppen infor- tionella samordnare på området. * Hur behöver det regulatoriska mations- och kommunikations- Anders Lönnberg är en av talar- ramverket för godkännande av teknik, IKT. na under ett seminarium med te- nya läkemedel förändras, så att Generellt inns Sverige med mat ”Är vi redo att digitalisera kli- digitaliseringens alla fördelar kan bland de tio högst rankande län- niska prövningar” (Are we ready utnyttjas? derna i de olika undergrupperna, for clinical trials to go digital?), med undantag för gruppen krea- enligt ett pressmeddelande från Business Sweden har tagit fram en tiva resultat (creative output) där organisationen Business Sweden i broschyr och en webbplats för att Sverige är rankat elva. dag. lyfta fram Sveriges komparativa Samtliga nordiska länder ”Ett av mina deluppdrag hand- fördelar inom life science. Infor- inns bland de 20 högst rankade lar om att främja förutsättningar mationsmaterialet inns här länderna. för att innovationer omsätts i nya http://lifescience.business-sweden. Bland de kluster som rankats produkter och tjänster som leder com/?utm_campaign= för sin innovationsförmåga ligger till nya exportintäkter. Jag är över- Läkemedelsmarknaden_170615_ Stockholm på plats 13, Malmö tygad om att Sverige har en hel Sverige%20behåller%20 på plats 62 och Göteborg på plats del att erbjuda när det gäller nya andraplatsen%20i%20global%20 69. De högst rankade klustren är lösningar och samarbeten, inte innovationsrankning&utm_ Tokyo–Yokohama i Japan, Shenz- minst inom digitalisering i vården medium=email&utm_ hen–Hongkong i Kina, San Jose– men även när det gäller utveckling source=Eloqua&elqTrackId= San Francisco i USA och Seoul i av nya läkemedel och jag ser fram ebe65877f4346508066a307f7 Sydkorea. emot en givande diskussion”, säger b4dd6e&elq=f2e151cd8ecd Rapporten presenteras i dag i Anders Lönnberg i en presskom- 42d4acc70563d49e77e0& Genève av Cornell University, he mentar. Han refererar till en nyli- elqaid=8507&elqat=1&elq Business School for the World (In- gen publicerad studie i tidskriften CampaignId=5999 sead) och världspatentorganisatio- Lancet och där svensk sjukvård nen World Intellectual Property rankas på järde plats bland 195 Nyhetsinfo 17 juni 2017 Organization (Wipo). undersökta länder. www red DiabetologNytt Världens mest innovativa län- ”Den höga rankingen stämmer

228 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se ADA Report. DEVOTE full text free article N Engl J Med DEVOTE: Tresiba as Safe as Glar- ludec rather than glargine to avert data were not collated on events gine With Less Severe Hypoglyce- one severe hypoglycemic event was when blood glucose was 54 mg/dL mia 40, the DEVOTE paper indicates. (3mmol/L) or lower, ”so impact Hypoglycemia: What’s the on the development of impaired SAN DIEGO — For the treat- Signiicance? awareness of hypoglycemia” again ment of type 2 diabetes, the ult- ”here’s always been this theo- could not be assessed, she noted. ra-long–acting, once-daily basal ry, demonstrated over and over And inally, because investi- insulin degludec (Tresiba, Novo again, that severe hypoglycemia gators in DEVOTE could modi- Nordisk) is as safe in cardiovascu- is a big risk for subsequent cardio- fy the titration process based on lar terms as insulin glargine and is vascular events,” Dr Buse explai- clinical judgment, ”it isn’t clear associated with much lower rates ned to Medscape Medical News. if this modiication process was of severe hypoglycemia, new data ”Whether it’s related to the fact applied equally in both arms.” conirm. that the people who have severe Any diferential application of this Full results from the Trial hypoglycemia are also people who process could have afected the hy- Comparing Cardiovascular Safety have cardiovascular events — be- poglycemia outcomes. of Insulin Degludec versus Insulin cause they are frail and have lots Glargine in Patients with Type 2 of comorbidities — or whether DEVOTE Details Diabetes at High Risk of Cardio- there is a causal relationship is still he US FDA insisted that Novo vascular Events (DEVOTE) were uncertain.” Nordisk conduct the DEVOTE reported by a number of investiga- Asked by Medscape Medical trial before it would approve insu- tors here at the American Diabetes News why — if there is a rela- lin degludec, despite the fact that Association (ADA) 2017 Scientiic tionship between hypoglycemia the product was already approved Sessions and were simultaneous- and CVD — would he not have in the European Union. In the ly published in the New England expected the rate of CVD to be end, the US agency approved in- Journal of Medicine, with lead au- signiicantly lower with degludec sulin degludec in November 2015 thor Steven P Marso, MD, of the than with glargine in DEVOTE, on the basis of interim results from Research Medical Center, Kansas Dr Marso said: ”he short answer DEVOTE. City, Missouri. is no. here may well be a causal In the trial, 7637 patients with he top-line results of DEVO- relationship between hypoglyce- type 2 diabetes were randomized TE had already been reported by mia and CV mortality, but in my to receive either insulin degludec the company in November last opinion, if true, it’s a small part of (n = 3818) or insulin glargine U100 year, and it recently applied to the what drives cardiovascular events (n = 3819) once daily between din- Food and Drug Administration in people with diabetes. ner and bedtime in a double-blind, (FDA) to update the Tresiba label ”As cardiologists, we tend to be treat-to-target fashion. with these data. focused on the [atherosclerotic] Dr Buse explained that insulin ”For me, this is a robust de- plaque, I think too much focused, glargine was chosen as the com- monstration of the cardiovascular and I think in the diabetes world parator insulin because of the safety of degludec — and a drama- they tend to be too much focused ORIGIN trial, which indicated tic and unimpeachable demonstra- on the hypoglycemia, and I think no increased risk of cardiovascular tion of the relatively lower rate of it’s going to be much more compli- events with glargine, ”so that’s why severe hypoglycemia” with deglu- cated than just one or the other.” we picked it as a comparator.” dec compared with glargine, seni- Meanwhile, discussant of the Of the patients in DEVOTE, or investigator of DEVOTE, John trial at ADA, Elizabeth R Se- 85.2% had established cardiovas- B Buse, MD, PhD, of University aquist, MD, from the University cular disease, chronic kidney di- of North Carolina School of Med- of Minnesota, Minneapolis, said sease, or both. Mean age was 65 icine, Chapel Hill, told Medscape there remain some unanswered years, the mean duration of dia- Medical News. questions in DEVOTE. betes was 16.4 years, and mean ”he former is of regulatory sig- For instance, ”data on mode- HbA1c was 8.4% niicance and the latter is of mea- rate hypoglycemia were not col- he primary composite outco- ningful clinical signiicance,” he lected, so the impact on the most me was the irst occurrence of an added. common type of hypoglycemia adjudicated major cardiovascu- he number of patients who experienced by patients cannot lar event (death from CV causes, would need to be treated with deg- be addressed,” she observed. And nonfatal myocardial infarction, or ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 229 nonfatal stroke). Severe hypogly- in 187 patients (4.9%) in the de- a clinician, he’s in the dark. cemia, as deined by the ADA, gludec group and in 252 (6.6%) He also questions whether in- was the prespeciied secondary in the glargine group, for an ab- sulin is even ”the ideal drug” for outcome. solute diference of 1.7 percentage the treatment of type 2 diabetes. he primary outcome occurred points (rate ratio, 0.60; P < .001 ”It’s probably not. It is an accepta- in 325 patients (8.5%) in the deg- for superiority). ble drug, its cardiovascular safety ludec group and in 356 (9.3%) in Rates of adverse events did not is well established, but it’s not em- the glargine group (hazard ratio, difer between the two groups. paglilozin, it’s not liraglutide.” 0.91; 95% CI, 0.78 — 1.06; P < Is Insulin the Right Treatment N Engl J Med. Published onli- .001 for noninferiority). for Type 2 Diabetes? ne June 12, 2017. Article At 2 years, the mean HbA1c It is almost impossible to as- http://www.nejm.org/doi/ was 7.5% in each group, but the sess how the cost of diferent in- full/10.1056/NEJMoa1615692?- mean fasting plasma glucose le- sulins compare with each other, query=featured_home#t=article vel was signiicantly lower in the both within one country and from degludec group than in the glar- country to country. From www.medscape.com gine group (128 vs 136 mg/dL; P In the United States, there has < .001). been an uproar about the cost of Nyhetsinfo 17 juni 2017 Severe hypoglycemia occurred insulin, and Dr Buse said that, as www red DiabetologNytt

ADA Report. More about CANVAS - the article in N Engl J Med in full text free. Dagens Medicin Björn Eliasson SAN DIEGO — he sodium– both all-cause and cardiovascular warning for canaglilozin from the glucose cotransporter 2 (SGLT2) death among high-risk patients US Food and Drug Administra- inhibitor canaglilozin (Invokana, taking empaglilozin (Jardiance, tion, and a warning on the labels Janssen Pharmaceuticals) redu- Boehringer Ingelheim/Lilly) in of all SGLT2 inhibitors by the Eu- ces cardiovascular events by 14% September 2015. ropean Medicines Agency. and cuts the rate of renal decline Now, the CANVAS data sug- In addition, cardiovascular de- by 40% but also doubles the risk gest that cardiovascular and renal ath was not signiicantly reduced for lower-limb amputation, new beneits are a class efect, lead in- in CANVAS, as it was in both cardiovascular-outcomes trial data vestigator Bruce Neal, MB, ChB, EMPA-REG and the Liragluti- indicate. PhD, professor of medicine, Uni- de Efect and Action in Diabe- Combined results from the versity of New South Wales Syd- tes: Evaluation of Cardiovascular Canaglilozin Cardiovascular As- ney, and senior director, the Ge- Outcome Results—A Long Term sessment Study (CANVAS) and orge Institute for Global Health, Evaluation (LEADER) trial of the the CANVAS renal-end-points Sydney, Australia, told Medscape glucagonlike peptide-1 (GLP-1) trial (CANVAS-R) were presen- Medical News. agonist liraglutide (Victoza, Novo ted here at the American Diabetes ”Here’s a second drug with Nordisk) Association (ADA) 2017 Scientiic clear protection. hings bounce ”Prescribers and patients will Sessions today and were simul- around in terms of the individual need to balance the positive and taneously published in the New outcomes, as you’d expect with re- negative events from the CAN- England Journal of Medicine. latively small numbers, but I think VAS trial in clinical decision-ma- hese data represent the se- it will be viewed — and should be king. Certainly it is a more com- cond time cardiovascular beneit viewed — as a big piece of new plicated calculus than with the has been demonstrated in a US evidence that basically says this is a results of the EMPA-REG trial,” Food and Drug Administration– great class of drugs for people with LEADER principal investigator mandated cardiovascular outco- diabetes.” John Buse, MD, of the University mes trial for an SGLT2 inhibitor, However, the CANVAS data of North Carolina, Chapel Hill, with the irst being the landmark also revealed a signiicant doubling told Medscape Medical News. Empaglilozin Cardiovascular in the risk for amputations, prima- Cardiovascular Protection, but Outcome Event Trial in Type 2 rily of the toe or metatarsal (6.3 vs at a Cost? Diabetes Mellitus Patients (EM- 3.4 cases per 1000 patient-years; he so-called ”CANVAS pro- PA-REG OUTCOME), which hazard ratio, 1.97). hat risk, al- gram” combined data from two demonstrated a major reduction in ready identiied, led to a boxed trials, CANVAS and CANVAS-R,

230 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se involving a total 10,142 patients ”It’s fair to say we’re clearly ra komplikationer bland patienter with type 2 diabetes and high car- preventing more major cardiovas- med typ 2-diabetes, enligt en ny diovascular risk. he CANVAS cular events than we’re going to studie som presenterades på diabe- patients were randomized 1:1:1 to be causing amputations. I think tesmötet ADA som pågår i USA. canaglilozin 300 mg or 100 mg the balance of beneits vs risks is or placebo, and the CANVAS-R going to fall pretty heavily in favor Maria Gustavsson www.dagens- patients to 100 mg (with option to of SGLT2 inhibition, even with medicin.se increase to 300 mg after week 13) an amputation risk,” Dr Neal told or placebo. Mean follow-up was Medscape Medical News. Björn Eliasson är adjungerad pro- 188 weeks (median, 126.1 weeks). Whether the amputation risk is fessor vid Sahlgrenska universi- Unlike EMPA-REG and LE- a class efect is still an open ques- tetssjukhuset i Göteborg. ADER, in which all subjects had tion. Amputation data weren’t re- – Fynden är i linje med förvänt- established cardiovascular disease, ported in EMPA-REG, although a ningarna. Det här blir ytterligare in CANVAS two-thirds did and post hoc analysis has not detected en bekräftelse på att det inns en the rest did not. a signal with empaglilozin com- kardiovaskulär nytta med läke- pared with placebo, according to medelsgruppen. Kanaglilozin ser CANVAS Program Primary and the study’s lead investigator Silvio även ut att ha gynnsamma efek- Secondary Outcomes Inzucchi, MD, of Yale University, ter på njurfunktionen, säger Björn Outcome Canaglilozina(n=5795) New Haven, Connecticut. Eliasson som är adjungerad profes- Placeboa(n=4347) Hazard ratio But Dr Neal pointed out that sor vid Sahlgrenska universitets- 95% CI P it’s a relatively infrequent compli- sjukhuset i Göteborg. Primary outcome (CV death, non- cation and ”certainly something Resultaten är även publicerade fatal MI, or nonfatal stroke 26.9 under intense scrutiny.” He also i tidskriften New England Jour- 31.5 0.86 0.75–0.97 0.02 for supe- said that ”there might be challeng- nal of Medicine. Fynden kommer riorityb es collecting the data retrospecti- från två studier som sammantaget All-cause death 17.3 19.5 0.87 vely” from EMPA-REG. inkluderar ler än 10 000 personer 0.74–1.01 In February 2017, the Europe- med typ 2-diabetes samt hög risk CV death 11.6 12.8 0.87 0.72– an Medicines Association said in för kardiovaskulär sjukdom. De 1.06 a statement: ”An increased [am- lottades till att antingen få placebo Hospitalization for heart failure putation] risk has not been seen eller kanaglilozin (Invokana), som 5.5 8.7 0.67 0.52–0.87 in studies with other medicines in är en så kallad SGLT2-hämmare. Albuminuria progression 89.4 the same class, dapaglilozin and Deltagarna följdes i snitt i 188 128.7 0.73 0.67–0.79 empaglilozin. However, data av- veckor och det primära utfalls- Renal composite (40% eGFR re- ailable to date are limited and the måttet var en kombination av duction, renal replacement thera- risk may also apply to these other död i kardiovaskulär sjukdom, py, or death) 5.5 9.0 0.60 0.47– medicines. Further data are ex- icke-dödlig stroke eller icke-dödlig 0.77 pected from ongoing studies with hjärtinfarkt. Amputationsc 6.3 3.4 1.97 1.41– canaglilozin, dapaglilozin, and Någon av dessa händelser in- 2.75 Not tested empaglilozin.” träfade för 31,5 personer per 1 New Engl J Med. Published 000 personer och år i placebo- Number of participants per online June 12, 2017. Article in gruppen. Motsvarande sifra var 1000 patient-yearP< .001 for non- full text free lägre bland deltagare på kanag- inferiority Primarily at the toe or http://www.nejm.org/doi/ lilozin, 26,9 per 1 000 patienter metatarsal level full/10.1056/NEJMoa1611925?- och år. Forskarna skriver även att Dr Neal presented an analysis query=featured_home läkemedlet kan ha en skyddande indicating that use of canaglilozin efekt på njurfunktionen och ex- reduces the risk of major cardio- LÄS DAGENS MEDICIN empelvis minska risken att prote- vascular adverse events (MACE) DIABETES VETENSKAP iner läcker ut i urinen. per 1000 patients over 5 years by HJÄRTA-KÄRL Till skillnad från tidigare stu- 23, risk of hospitalization for heart dier av läkemedlet fann dock fors- failure by 17 per 1000, and renal Kardiovaskulärt skydd av karna att patienter på kanaglilo- events by 16. ytterligare ett diabetesläke- zin drabbades av amputationer i At the same time, amputations medel högre utsträckning – främst av will occur in 15 more patients per Läkemedlet kanaglilozin fötter och tår. 1000 over 5 years. minskar risken för kardiovaskulä- – Frågan är om det är en ef- ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 231 fekt av läkemedlet i sig eller av år gamla och majoriteten var män. forskningsnyhet. läkemedelsklassen. Det är något Studien är sponsrad av läkeme- Just nu pågår ytterligare en som kommer att diskuteras vidare delsföretaget Janssen. studie med ett annat läkemedel framöver. För studien Empa-reg Tidigare har det inte gått att av klassen SGLT2-hämmare som antydde inte problem med am- visa om blodsockersänkande lä- kallas Forxiga (dapaglilozin) på putationer, säger Björn Eliasson. kemedel mot typ 2-diabetes även patienter med typ 2-diabetes. Det Empa-reg är en studie som be- sänker risken för så kallade makro- resultatet förväntas komma om rör en annan SGLT2-hämmare vaskulära komplikationer av di- något år. som heter Jardiance (empaglilo- abetessjukdomen. Men efter att Bruce Neal med lera. Canag- zin). Även här sågs en minskad risk resultaten för ovan nämnda stu- lilozin and cardiovascular and re- att dö i hjärt-kärlsjukdom bland die Empa-reg publicerades 2015 nal events in type 2 diabetes. he patienter med typ 2-diabetes. har en motsvarande efekt också New England Journal of Medici- SGLT2-hämmare är en läkeme- visats för två läkemedel i klassen ne, publicerad online den 12 juni. delsklass som sänker glukoshalten GLP1-analoger. DOI: 10.1056/NEJMoa1611925 i blodet genom att öka utsöndring- År 2016 utsåg Dagens Medicin en av glukos i urinen. Deltagarna i kardiovaskulär efekt av diabete- Nyhetsinfo 13 juni 2017 den aktuella studien var i snitt 63 släkemedel som det årets främsta www red DiabetologNytt

ADA Report. A New Era for SGLT2-I in the Treatment of T2DM. CANVAS. 14% mindre risk för CVD, hjärtsvikt 33%, njurskada 40%. Kommentar Peter Nilsson. Studien CANaglilozin cardioVas- Dock måste man även beakta Invokana® mest. I Sverige förskrivs cular Assessment Study (CAN- att risken för amputation fördubb- mest Jardiance® empa och på plats VAS) har idag just presenterats på lades i CANVAS, och detta kan 2 Forxiga® dapa. Fynden publicer- American Diabetes Association betyda att försiktighet bör iakttas as idag i N Engl J Med. (ADA) mötet. för förskrivning till patienter med Det är en stor randomiserad svår perifer artärsjukdom. Comment studie som testade två doser av Svenska riktlinjer från Social- Professor Neal: We do not know canaglilozin, SGLT2-hämmare, styrelsen 170529 har redan idag why there was an increased risk of mot placebo hos patienter med typ en positiv skrivning om nyttan amputation, but further work is 2 diabetes, både med och utan ti- med empagllozin Jardiance® med needed in this area. But now we digare kardiovaskulär sjukdom. prio vid T2DM med etablerad urge caution in prescribing this hjärt- och kärlsjukdom - och det- drug to people at increased risk of Resultaten anger ta kommer sannolikt framöver sufering amputations • att den samlade risken för kar- även att gälla för närbesläktade he study of more than diovaskulära händelser minska- canaglilozin. 10 000 patients with T2DM in 30 de med 14%, Dock väntar vi ännu på studie- countries also found that the drug • risken för hjärtsvikt minskade data av liknande slag för ett tredje ofered protection not just for pe- med 33% läkemedel inom gruppen, dapag- ople already sufering cardiovascu- • risken för att få allvarlig njurska- lilozin”, säger Peter M Nilsson, lar disease, but for all with T2DM da pga diabetes minskade med professor och överläkare vid SUS 40% i Malmö. Nyhetsinfo 12 juni 2017 I USA förskrivs canalilozin www red DiabetologNytt ”Detta är i linje med resultaten från den tidigare publicerade EM- PA-REG OUTCOME studien (N Engl J Med 2015) och antyder klinisk nytta med SGLT2-hämning, således mera av en klassefekt, sä- ger prof Peter Nilsson. Detta öppnar dörren för vidgad behandling.

232 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se ADA Report. DEVOTE trial. Tresiba versus Lantus. No increased risk of major cardiovascular events. Reduction in severe hypoglycemia. Tresiba® demonstrated no incre- analyses showed: similar levels of patients in the insulin glargine ased risk of major cardiovascular glycaemic control with an end of U100 arm), medication errors le- events and signiicant reduction trial HbA1c estimated treatment ading to serious adverse events and in rates of severe hypoglycaemia diference of 0.01% (p=0.779) adverse events related to technical compared to insulin glargine between the two treatment groups complaints. U100 in the DEVOTE trial and signiicantly lower fasting *Severe hypoglycaemia was San Diego, US, 12 June 2017 plasma glucose levels with Tresiba® deined as an episode requiring - Novo Nordisk today announced after 2 years vs. insulin glargine assistance of another person, the primary results from DEVO- U100 (estimated treatment dife- and nocturnal severe deined as TE - the irst randomised, double- rence -7.2 mg/dL, p<0.001).1 between the hours of 00:01-05:59, blind, treat-to-target, event-driven ”In the DEVOTE trial deglu- inclusive.1 trial comparing two basal insulins, dec demonstrated no increase in Tresiba® (insulin degludec injec- the risk of major cardiovascular About DEVOTE tion 100 U/mL) and insulin glar- events and signiicant reductions DEVOTE is a long-term, multi-na- gine U100, in adults with type 2 in the rates of severe and noctur- tional, randomised, double-blind diabetes at high risk of cardiovas- nal severe hypoglycaemia com- and event-driven trial conducted cular (CV) disease. he trial de- pared to insulin glargine U100,” to conirm the CV safety of Tresi- monstrated that Tresiba® met the said Dr Bernard Zinman of the ba® (insulin degludec) compared to primary endpoint of non-inferiori- Lunenfeld-Tanenbaum Research insulin glargine U100. In the trial, ty compared with insulin glargine Institute, Mount Sinai Hospital, 7,637 people (Tresiba®: n=3,818, in- U100 for major adverse CV events Toronto, Canada and member of sulin glargine U100: n=3,819) with (MACE) with a hazard ratio (HR) the DEVOTE Steering Commit- type 2 diabetes at high risk of CV of 0.91 (95% conidence interval tee. ”Risk of cardiovascular disease disease were randomised to treat- [CI]: 0.78; 1.06, p=0.209). Addi- and hypoglycaemia are important ment with either Tresiba® or insulin tionally, the indings for each com- concerns for those with type 2 dia- glargine U100 in vial in addition ponent of MACE were consistent betes and the results from DEVO- to standard of care.1 he primary with the primary endpoint, inclu- TE add to the mounting evidence endpoint in DEVOTE was time ding irst occurrence of CV death that will play an important role in from randomisation to the irst (HR=0.96, 95% CI: 0.76; 1.21, treatment decisions.” occurrence of a three-component p=0.714), non-fatal myocardial in- he safety proile of Tresiba® in composite CV outcome compri- farction (HR=0.85, 95% CI: 0.68; DEVOTE was generally consis- sing CV death, non-fatal myocar- 1.06, p=0.150) or non-fatal stroke tent with previous Tresiba® clinical dial infarction or non-fatal stroke. (HR=0.90, 95% CI: 0.65; 1.23, trials.1 In DEVOTE, systematic Secondary endpoints included p=0.502).1 collection of adverse events was severe hypoglycaemia, nocturnal Results from the trial, involving limited to serious adverse events, severe hypoglycaemia, HbA1c and 7,637 people with type 2 diabetes adverse events leading to perma- fasting plasma glucose.1 followed for approximately two nent discontinuation of investiga- years, were presented at the Ame- tional product (5.2% of patients Nyhetsinfo 12 juni 2017 rican Diabetes Association’s 77th in the Tresiba® arm and 5.8% of www red DiabetologNytt Scientiic Sessions (ADA 2017) and also published simultaneous- ly in the New England Journal of Medicine.1 Results from the secondary endpoints of the trial showed a signiicant reduction in the rate of severe (40%) and nocturnal severe (53%) hypoglycaemia with Tresi- ba® vs. insulin glargine U100 (both p<0.001).* Additionally, post hoc www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 233 ADA Report. T1DM Prevention; Trial.Net Org with Oral Insulin and DiAPREV-iIT-trial with Alum-GAD. No positive effects in prevention Delaying T1DM is important. way and is a step towards targeted young children with mulltiple islet It means a longer period of time therapies. autoantibodies, we found it is safe without the day to day extra job or T1DM Diabetes TrialNet has to use, living with T1DM. 3 other ongoing studies to deter- he results shows that Alun- his is the largest trial ever per- mine whether we can delay or stop GAD given alone coukld not formed using oral insulin. Oral in- disease progression. ”Since rela- in the current doseing, delay or sulin did not delay clinical diagno- tiuves hav a 15x increased risk of prevent T1DM in their cohort. sis of T1DM in the main strata of disiease we urge relatiuves of those Other dosing or combination 389 peiple, or when all the strata with T1DM to stop T1DM trial- with immunomodulatiory agents were combined. Net.org or other antigens may be tested. However, in a secondary ana- Immunological samples will be lysis of the subgroup of 55 people DIAPREV-it trial with Alunm- analysed to further investigate the there was a 31 month delay in me- GAD Helena Elding Larsson, mechanisms. dian time to clinical T1DM. his Lund university, Sweden further supports that not everyo- In this irst study of antigen-spe- Nyhetsinfo 12 juni 2017 ne develops T1DM in the same ciic therapy with Alumn-GAD in www red DiabetologNytt

ADA Report. Many CV-Outcomes Trials in T2DM Must Drive Guideline Change Rapid SAN DIEGO — he recent re- dibly important.” heart disease or diabetes [or both], sults of large outcomes trials he past few years have illustra- is to keep them alive,” Dr Nissen showing cardiovascular beneit ted ”a triumph of evidence-based asserted. with type 2 diabetes drugs must medicine,” he stressed, ”and now But if the results of these tri- be properly incorporated into tre- it’s very important for changes in als are not rapidly translated into atment guidelines, such as those the guidelines to relect contem- changes in guidelines, there is a issued by the American Diabetes porary knowledge, but we will still danger that the same thing that Association and other national have a way to go with that. We’ve happened with statins will happen guidelines all over the world, im- got to overcome clinical inertia,” in diabetes, he said, noting, ”It plores one expert. he stressed. took years for the adoption of the ”his is a very big deal. I think Referring speciically to land- pivotal trial results with statins, it it’s time now to apply the evidence mark results with the sodium-glu- was just too slow.” and incorporate it into the guideli- cose cotransporter-2 (SGLT-2) em- And he stressed that, since sta- nes for cardiologists, and endocri- paglilozin (Jardiance, Boehringer tins, ”it’s been hard to come up nologists and professional societies Ingelheim) in EMPA-REG OUT- with therapies that reduce cardio- have to take the lead,” cardiologist COME and the glucagonlike pep- vascular death. And now we have Steve Nissen, MD, of the Cleve- tide-1 (GLP-1) agonist liraglutide the most robust results with diabe- land Clinic, Ohio, told a packed (Victoza, Novo Nordisk) in LE- tes drugs on the end point that is auditorium here at the American ADER — which both showed toughest to achieve — death.” Diabetes Association (ADA) 2017 impressive reductions in cardio- CV-Outcomes Trials Show Not Scientiic Sessions yesterday. vascular end points in patients All Drugs in Class Are the Same And, he emphasized, for this with type 2 diabetes at high risk Dr Nissen explained how, prior to to happen, ”we need close colla- of cardiovascular events, he said the current crop of CV-outcomes boration between cardiologists that the most important outcome trials, there had historically been and diabeto-endocrinologists. We seen in both of these trials was the little progress in preventing diabe- take care of the same patients, so reduction in cardiovascular death. tes patients from dying from car- coming together to determine how ”he one thing we want to do diovascular disease — the biggest best to treat these patients is incre- for our patients, whether they have killer in this condition.

234 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se While nondiabetic patients saw fects, he said. end, said Dr Nissen. tumbling death rates from CVD For example, with the dipepti- ”We always had an ambitious in past decades, the rate had stag- dyl peptidase-4 (DPP-4) inhibitor agenda and we [eventually] got nated among diabetes patients and class of drugs, when these were in- some really big bonuses. EM- even increased in women with dia- troduced, ”people said it’s going to PA-REG is, in my opinion, a bre- betes, he explained. be a revolution. Every single [prior akthrough study.” ”It’s taken some shock waves analysis] suggested DPP-4 inhibi- However, as people wait with to wake the medical community tors would lower CV outcomes,” bated breath here for the results from a 50-year slump — the reali- he told the audience. he efect of the second CV-outcomes trial zation that merely lowering blood was on glucose and neutral efects with a SGLT2 inhibitor, CAN- glucose is not a guarantee of im- on CVD. VAS with canaglilozin, he reite- proving health outcomes [in dia- But this didn’t turn out to be rated that it’s always important betes],” he added. the case. to wait for the results from each He then went on to outline In fact, the results of the irst study. the history behind the cardiovas- CV-outcomes trials with the DPP- For example, whereby LE- cular-outcomes trials for diabetes 4 inhibitors saxagliptin (Onglyza, ADER with liraglutide showed drugs, which were mandated by AstraZeneca) and alogliptin (Ne- cardiovascular beneit (as did the FDA in 2008 as a result of the sina, Takeda) — SAVOR-TIMI SUSTAIN-6 with the investiga- rosiglitazone debacle — in which 53 and EXAMINE — ”actually tional GLP-1 agonist semagluti- Dr Nissen played a key role. showed a signiicantly increased de), another trial, ELIXA, with ”here was a lot of pushback, a risk for hospitalization for heart the GLP-1 agonist lixisenatide, lot of whining, when we irst sug- failure with the respective drugs, was neutral. gested these CV-outcomes trials,” a completely unexpected inding,” ”When you do large outcomes he noted. ”But we’ve gotten some he noted. trials, you get surprises. he most really big bonuses from doing ”We would never have found important message I can give you them. hese drugs are not all out this problem had we not done [for each agent] is wait for the the same. and before we label so- the trials,” he asserted. data.” mething as a ’class efect,’ we have And a third outcomes trial American Diabetes Associa- to look carefully. We only ind out with the DPP-4 inhibitor sitag- tion 2017 Scientiic Sessions. June what they actually do when we liptin (Januvia, Merck), TECOS, 11, 2017; San Diego, California. study them.” while not showing any increase in Presentation 1-AC-SY13 And while he acknowledged heart-failure hospitalization, did that the aim of the cardiovascu- not improve CV outcomes — it From www.medscape.com lar-outcomes trials was initially was neutral — and so ”that was a to demonstrate lack of CV harm third disappointment for DPP-4 Nyhetsinfo 12 juni 2017 with diabetes drugs, there was inhibitors.” www red DiabetologNytt some anticipation of positive ef- But patience paid of in the

ADA Report. Sexual Dysfunction in Diabetes: Underrecognized and Neglected SAN DIEGO — Treatment op- mechanisms underlying the dys- his is because research indi- tions for sexual dysfunction in function is needed, said Hunter cates that sexual dysfunction can diabetic patients are surprising- Wessells, MD, of the department occur in those with diabetes years ly limited, and new therapeutic of urology, University of Washing- earlier than it afects those in the targets are needed for both sexes, ton School of Medicine, Seattle, general population, he stressed. according to new data presented during a symposium on urologic Asked for comment, Aruna V here at the American Diabetes As- complications and sexual dysfunc- Sarma, PhD, research assistant sociation (ADA) 2017 Scientiic tion in diabetes. professor of urology, Universi- Sessions. Clinicians should start asking ty of Michigan School of Public To enable this, more informa- about sexual function when dia- Health, Ann Arbor, said sexual tion on who with diabetes is at betes patients are still in their 40s dysfunction may not be as lethal highest risk of developing sexu- and intervene as soon as the irst as neuropathy or nephropathy, but ▶ al dysfunction and the speciic symptoms occur, said Dr Wessells. ”these are conditions that matter www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 235 to the participants, they are both- of sexual dysfunction on quali- start with risk stratiication, be- ersome, and they impact quality of ty of life equals or exceeds that cause ”better knowledge of the life. of neuropathy, nephropathy, or risks may lead to earlier interven- ”We have an opportunity to retinopathy. tion,” Dr Wessells explained. motivate individuals to impro- here is some evidence that ve their diabetes care, because an A Multifactorial Problem better glycemic control in men is 18-year-old or 30-year-old type 1 Treatments have been diicult associated with a lower risk of de- diabetic may be more motivated to to develop in part because of the veloping erectile dysfunction, for try to prevent erectile dysfunction multifactorial nature of sexual example. that may occur in their 40s, rather function, Dr Wessells said. But the picture is more compli- than perhaps a more abstract no- For men, most of the emphasis cated than that, he added. Data tion of what may occur with neu- has been placed on erectile dys- from the DCCT for example, ropathy later in life. So there may function, but problems may also have shown that, while some men be an opportunity here to try to take the form of diminished libi- develop permanent erectile dys- improve sequelae that may occur do or ejaculatory or orgasmic dysfunction, others may have it for in the future.” function. Women similarly may a while, then go into remission, experience low desire, impaired and continue this back-and-forth Accelerated Aging: Sexual arousal, or diiculty with orgasm. pattern until age catches up with Dysfunction Manifests Early ”We know almost nothing them. in Diabetes about how diabetes afects central In addition, some men may For example, erectile dysfunction nervous system control of sexual smoke or have terrible glycemic will afect 50% of men with dia- behavior or about its impact on control yet never develop erectile betes by the time they are 50 years other components of sexual tissue dysfunction, while a few who fol- of age, with a mean age of onset of such as endothelial cells, smooth- low doctor’s orders to the letter ne- 45 years, Dr Wessells said. muscle cells, and the autonomic vertheless become impotent while ”Is that abnormal? Absolutely.” nerves involved in arousal in both still in their 40s. Among men in the general popu- sexes,” he pointed out. ”We have to learn what is lation, the rate of erectile dysfunc- First-line treatment options for protective in some men and see tion does not reach 50% until they men include phosphodiesterase 5 whether we can use that to help are in their 70s, so ”this represents inhibitors such as sildenail (Vi- others.” a 20-year acceleration of the aging agra, Pizer) and tadalail (Cialis, here is also evidence that in- process” for diabetic men, he Lilly). tensive lifestyle interventions may explained. hese are efective ”but they improve sexual function in people For women, data from the Dia- are still not good enough, because with type 2 diabetes, Dr Wessells betes Control and Complications these patients have more severe er- said. Trial(DCCT) in type 1 diabetes ectile dysfunction, so will they im- Weight loss has been associated suggest that two of the biggest prove enough to be normal? hat with an improvement of erectile risk factors for sexual dysfunction is the question.” dysfunction in men and a slight are being married and a history Second-line therapies include decrease in sexual dysfunction in of depression or treatment with vacuum erection devices, injection women. antidepressants. of vasoactive substances into the Neither Dr Wessells nor Dr ”We think of diabetes as im- penis, and penile implants. Sarma disclosed any relevant i- pacting blood vessels and nerves, For premenopausal women, nancial relationships. but there are all these other aspects libanserin (Addyi, Sprout Phar- American Diabetes Association that need exploration so we can maceuticals), approved in the US 2017 Scientiic Sessions. June 9, understand how we can better in- in 2015, may restore some sexual 2017; San Diego, California. Pre- tervene to help these patients,” Dr desire, but its exact mechanism sentation 1-AC-SY06 Wessells explained. of action is unknown, and it is Adding to the urgency of the associated with side efects inclu- Nyhetsinfo 12 juni 2017 problem is that as they live longer, ding hypotension and syncope, Dr www red DiabetologNytt men and women alike are seeking Wessells warned. to prolong their sexual function as much as possible. Future Directions here is evidence that, for pe- An efective approach to the sexual ople with diabetes, the impact complications of diabetes should

236 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se ADA Report. Alirocumab PCSK9-I Underwhelming in ODYSSEY Trials in T2 Diabetes SAN DIEGO — First data on use FOURIER was a large outco- Most patients (80%) continued on of a proprotein convertase subti- mes trial conducted with a dife- their starting alirocumab dose. lisin kexin 9 (PCSK9) inhibitor rent PCSK9 inhibitor, evolocumab At 24 weeks, compared with speciically in patients with diabe- (Repatha, Amgen) in more than patients in the placebo group, tho- tes failed to excite here at the Ame- 27,000 participants with athero- se who received alirocumab had rican Diabetes Association (ADA) sclerotic disease already receiving a greater percentage decrease in 2017 Scientiic Sessions . statins, which was reported at the LDL cholesterol — the primary Alirocumab (Praluent, Sanoi/ ACC meeting to great fanfare ear- eicacy outcome — by 48.2%, vs Regeneron Pharmaceuticals) met lier this year. a 0.8% reduction, for a mean dif- its primary eicacy end points of But the absolute risk reduction ference between the two treatment reducing LDL cholesterol in the was modest, at 1.5%, and the au- arms of 49% (P < .0001). ODYSSEY DM-Insulin study and thors estimated that 74 patients Patients who received aliro- reducing non-HDL cholesterol in would need to take evolocumab cumab also had an improved the ODYSSEY DM-Dyslipidemia to prevent a cardiovascular event. overall lipid proile, including sig- study, both out to 24 weeks. he Furthermore, evolocumab did not niicantly reduced non-HDL cho- therapy was also safe, as assessed reduce cardiovascular death or de- lesterol, apolipoprotein B (apoB), at 32 weeks. ath from any cause. and triglycerides. But ”I think the data to some And most important, the cost Treatment emergent adverse extent are underwhelming,” ses- of this class of drugs is currently events were similar in both groups sion chair Robert H Eckel, MD, approaching $15,000 a year and and included nasopharyngitis, University of Colorado, Anschutz ”we can’t aford PCSK9 inhibito- myalgia, arthralgia, and cough. Medical Campus, Aurora, told rs at their current price,” said Dr here was no new safety signal Medscape Medical News. ”he Mandrola at the time the FOU- with the concomitant use of aliro- results that were presented were RIER results were reported. cumab and insulin. kind of what was expected and ODYSSEY DM-Insulin: Aliro- And ”Importantly, alirocumab the [short-term] safety issue was cumab Did Not Afect HbA1c did not afect HbA1c,”Dr Leiter fulilled.” Results from 441 patients with said. Although long-term eicacy type 2 diabetes who were part of and safety is unclear, ”it’s presu- the ODYSSEY DM-Insulin trial ODYSSEY DM-Dyslipidemia med that eicacy would continue,” were presented by Lawrence Leiter Meanwhile Robert Henry, MD, he noted. ”I think an outcome tri- MD, from St Michael’s Hospital, from the University of California, al now in patients with diabetes, Toronto, Ontario. he trial also San Diego, presented results from meeting the criteria of entrance included 76 participants with type the ODYSSEY DM-Dyslipidemia here, would be important.” 1 diabetes, but data for these pa- study in patients with type 2 dia- A cardiologist who blogs for tients were not presented. betes and mixed dyslipidemia. theheart.org on Medscape, John At baseline, all the type 2 dia- hat trial randomized 413 pa- Mandrola, MD, of Baptist Med- betes patients were on insulin and tients with type 2 diabetes and ical Associates, Louisville, Ken- had LDL cholesterol ≥70 mg/dL mixed dyslipidemia at high car- tucky, agrees. he ODYSSEY re- on maximum tolerated statin the- diovascular risk who did not have sults ”simply show something we rapy (some were unable to tolerate not adequately controlled lipids already know: that PCSK9 inhibi- statins at all), and they also had with maximally tolerated statins. tors improve lipid proiles.” established cardiovascular (CV) Patients were randomized in a ”What would be better is to disease or at least one additional 2:1 ratio to receive alirocumab or show a reduction of hard outco- CV risk factor. usual care (which included statin, mes. But it took many thousands hey were randomized 2:1 to 24 ezetimibe, fenoibrate, or other li- of patients in the Further Cardio- weeks of alirocumab 75 mg sub- pid-lowering therapy). vascular Outcomes Research With cutaneously every 2 weeks or pla- he primary end point was per- PCSK9 Inhibition in Subjects With cebo. Alirocumab-treated patients centage change in non-HDL cho- Elevated Risk (FOURIER) trial to who still had LDL cholesterol ≥70 lesterol [total cholesterol minus show a small decrease in nonfatal mg/dL at week 8 were titrated up HDL cholesterol] from baseline to events,” Dr Mandrola pointed out. to double the dose at week 12. week 24. ▶

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 237 At 24 weeks, non-HDL cho- Third-Party Payer Makes milial hypercholesterolemia (LDL lesterol was lowered more among Final Decision cholesterol consistently above 190 patients in the alirocumab group Expanding upon his thoughts, Dr mg/dL) or for those who have than those in the usual-care group Eckel said whether this class of atherosclerotic cardiovascular di- (37.3% lower vs 4.7% lower, for PCSK9 inhibitor drugs — aliro- sease (such as a previous heart a mean diference of 32.5%; P < cumab or its ”kissing cousin” evo- attack or stroke) and LDL choles- .0001). locumab — are going to be efecti- terol that is insuiciently lowered Similarly, LDL cholesterol was ve in reducing cardiovascular risk by current therapy, he noted. he lowered more in the alirocumab over time remains to be seen. patient could be on a maximum group (43.3% vs 0.3%, P < .0001). And ”the idea of additional mo- statin dose or no statin at all if he most frequent treatment diication of lipoprotein in diabe- they are intolerant. emergent adverse events were uri- tes is an unanswered question,” he ”But the inal decision is made nary-tract infection, diarrhea, and added. by the third-party payer, because nasopharyngitis. Moreover, ”I’m always con- these drugs cost [around] $14,000 As in the other trial, fasting cerned when you’re modifying to $15,000 dollars a year in US plasma glucose and HbA1c levels multiple lipoproteins at the same or in Europe 6000 US dollar per remained stable in both treatment time....Is it really the additional year,” he reiterated. groups. LDL lowering, or is it in fact these American Diabetes Association ”hese studies demonstrate no other particles that are remnants 2017 Scientiic Sessions; June 11, new safety signal” and ”superiority and/or VLDL-cholesterol-carry- 2016. in reducing non-HDL cholesterol ing particles that are contributing From www.medscape.com vs usual care, as well as an impro- to the beneit?” vement in levels of other lipids vs PCSK9 inhibitors are currently Nyhetsinfo 12 juni 2017 usual care,” Dr Henry said. approved for patients who have fa- www red DiabetologNytt

ADA Report. 2017 Diabetic Nurses are Diabetologists Outstanding Educator in Diabetes Scientiic Sessions. “Even as late as 1976, nurses Award recipient trumpets value of “By the time I had graduated were expected to stand when a team-based care from nursing school, my grand- doctor entered the room. hat he Diabetes Control and mother and her children had all wasn’t going to happen,” she joked. Complications Trial (DCCT) did been diagnosed with diabetes,” she he Detroit Visiting Nurses more than conirm that intensi- recalled. “It was no surprise that I Association had a diferent out- ve glucose control can reduce the wanted to work on diabetes.” look on patient care. Nurses didn’t complications and mortality asso- Kruger’s irst nursing job was work alone with patients, they ciated with diabetes. It also esta- with the Detroit Visiting Nurses worked in teams with dieticians, blished the role of a diabetes team Association. Working in a hospital social workers, therapists, and in patient care. was not an option, she said. other specialists as needed. “We didn’t just learn that it takes a team to manage diabetes, we learned that the patient is the most important member of the team,” said Davida F. Kruger, MSN, APRN-BC, BC-ADM, a nurse practitioner at the Henry Ford Health System. “Much of our current expertise in diabetes care, as well as our experts, came out of the DCCT.” Kruger is one of those experts. She received this year’s ADA Out- standing Educator in Diabetes Award and presented her award lecture Saturday morning at the

238 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Nurses were expected to coor- “hat wasn’t the most impor- she added. NPs and physicians dinate the other nonphysician tant change during the trials,” produce equivalent diagnostic re- specialists and advocate for the she said. “When the trial began, sults in diabetes, but nurse practi- patient. It was an experience that the principal investigators [PIs] tioners are far more likely to pro- shaped Kruger’s involvement in sat around a table and the clinical vide prevention counseling, health the DCCT and diabetes care. coordinators sat at the back of the promotion, and more personalized “My mother did not receive any room. he PIs spent so much time therapies, Kruger said. type of education or medical nut- turning around asking us ques- “here’s a signiicant and rition therapy for her T1DM” she tions that we found ourselves at growing gap between the need explained. “he technology and the table with them. he DCCT for diabetes care and the supply of knowledge of the time might not didn’t just establish the clinical ef- adult and pediatric endocrinolo- have extended her life, but it could fects of intensive glucose control, gists,” she said. have made a signiicant diference it established the clinical utility “Nurse practitioners have now in her quality of life.” of the team approach to diabetes, the knowledge and the expertise Kruger was recruited to the and the positive impact of diabetes to ill that gap. Nurse practitioners DCCT as one of 12 clinical coor- education.” are diabetologists.” dinators. By the end of the trial, Diabetes education can have she was the National Chair of the even greater impact when delive- Nyhetsinfo 11 juni 2017 Trial Coordinators Committee. red by a nurse practitioner [NP], www red DiabetologNytt

ADA Report. EMPA reduce nephropathy by 39% in T2DM NEW ORLEANS — New data ses of empaglilozin employed (10 that the EMPA-REG trial lasted from the EMPA-REG OUTCO- mg and 25 mg once daily). only 3 years, ”so we are certainly ME trial with the sodium-gluco- ”Empaglilozin reduced clini- looking to the future for more on se cotransporter-2 (SGLT2) in- cally relevant renal events when this.” hibitor empaglilozin (Jardiance, added to standard of care in pa- And both he and discussant of Boehringer Ingelheim) show that tients with type 2 diabetes and the indings at ADA, endocrinolo- the drug signiicantly reduced the high cardiovascular risk,” he anno- gist and epidemiologist, William incidence of worsening nephro- unced, adding that this efect was Herman, MD, MPH, of the Uni- pathy by 39% in the population primarily driven by a reduction in versity of Michigan, Ann Arbor, of type 2 diabetes patients studied new-onset macroalbuminuria (ha- stressed that the results are appli- (ie, those who were at high cardio- zard ratio [HR], 0.62 for those tre- cable only ”to the population stu- vascular risk). ated with empaglilozin compared died in the EMPA-REG trial” (ie, he results were received to with placebo; P < .001). older patients with type 2 diabetes spontaneous applause here today He pointed out that kidney at high cardiovascular risk). at the American Diabetes Associ- disease is ”a growing concern” in Currently, about a third of the ation (ADA) 2016 Scientiic Ses- patients with type 2 diabetes, with population of type 2 diabetes fall sions when presented by nephro- 35% of patients eventually deve- into that category, Dr Herman logist Christoph Wanner, MD, of loping it, and noted that almost said. the Würzberg University Clinic, half (44%) of the renal-dialysis Nevertheless, Dr Wanner ob- Germany; they were also simul- population at any current time is served in his presentation: ”here taneously published in New Eng- made up of those with diabetes, have been no new diabetic kid- land Journal of Medicine with Dr primarily type 2. ney-disease–speciic treatments in Wanner as lead author. ”In the placebo group you see the past 15 years, until today.” he assessment of renal out- the natural progression of kidney And he hinted that the agent comes in EMPA-REG was a pre- disease [as would be expected in may well be used in those who speciied outcome of the trial, Dr type 2 diabetes] whereas the [es- don’t yet have overt cardiovascular Wanner noted, and he added that timated glomerular iltration rate] disease (CVD). ”Nephrologists are the beneicial efects on the kidney eGFR in the empaglilozin group waiting for this drug for patients observed in the trial ”were there remained stable,” he observed. with albuminuria,” he told Meds- early and continued for the whole Important Addition to Original cape Medical News. of the study.” Moreover, these ef- Findings, but More Work Needed hey and endocrinologists fects were observed with both do- Dr Wanner noted, however, ”maybe will not wait until the pa- ▶

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 239 tient has survived a myocardial in- [GLP-1] agonists, and insulin ana- of a combination of progression to farction — there are some patients logues) —are expensive, costing, macroalbuminuria, a doubling of without cardiovascular disease but in the US, in the region of $500 serum creatinine, the start of re- already with nephropathy, so I per month, as compared with a nal-replacement therapy, or renal think we are all going to use this few dollars for metformin, the death. drug in the nephropathy patients recommended irst-line agent for However, the beneit was pri- with albuminuria.” type 2 diabetes and some other marily driven by the reduction in But Dr Herman pointed out in generically available drugs, such as new-onset albuminuria, which oc- his talk that ”the absolute diferen- sulfonylureas and pioglitazone. curred in 459 of 4091 patients ta- ces are relatively small” in EM- Another trial with one of the- king empaglilozin compared with PA-REG and the number needed se newer agents, the GLP-1 ago- 330 of 2033 patients on placebo to treat with empaglilozin to nist liraglutide (Victoza, Novo (11.2% vs 16.2%; HR, 0.62; P < achieve the renal beneits was 200. Nordisk), stole the headlines here .001). In addition, it’s possible that the yesterday with the results of the Kidney dialysis was also redu- indings ”had to do with medica- LEADER trial indicating that ced by more than half among tho- tions not administered,” he said. it signiicantly reduced the rates se taking empaglilozin, although ”So it may not be a beneit of em- of major adverse cardiovascular the absolute numbers afected paglilozin but the fact that those events in a patient population si- were small (HR, 0.45; P = .0409). in the empaglilozin group did not milar to those in EMPA-REG, In an editorial accompanying receive medications causing harm type 2 diabetes patients at elev- the renal indings in the publis- [as patients in the trial were also ated cardiovascular risk. his has hed paper, Julie R Ingelinger, allowed certain other standard prompted some experts to predict MD, from Massachusetts General therapies for diabetes].” ”a new era” in the management of Hospital, Boston, Massachusetts, Overall, as well as the demon- type 2 diabetes. and Cliford J Rosen, MD, from strated renal efects, empaglilo- Dr Riddle, however, believes the Center for Clinical and Tran- zin is ”moderately efective” at this is a premature conclusion to slational Research, Maine Medical lowering HbA1c and results in a 2- draw: ”I don’t think the regulato- Center Research Institute, Scar- to 3-kg reduction in body weight, ry agencies’ and the professional borough, say: ”his new report with no issue with hypoglycemia, societies’ recommendations are indicates that empaglilozin was as- although it does increase the risk going to change immediately; we sociated with a slower progression of genitourinary infections, Dr are going to have to digest these of kidney disease and lower rates of Herman surmised. indings,” he told Medscape Med- clinically relevant renal events than He concluded that empaglilo- ical News. was placebo when added to stan- zin is ”a reasonable therapy, but we dard care in [type 2 diabetes] pa- still don’t know its exact role or ex- Drilling down into tients at high cardiovascular risk.” act mechanisms of action.” renal outcomes And commenting on both EM- Chair of the session in which In the overall EMPA-REG trial, PA-REG overall and LEADER, the EMPA-REG renal indings irst reported last September to ”We are left with diferences that were presented at ADA, Matthew much acclaim, more than 6000 are encouraging yet are not a home Riddle, MD, from Oregon Health patients with type 2 diabetes at run with regard to the manage- & Science University, Portland, high risk of cardiovascular events ment of diabetes,” they point out. said the renal outcomes from were randomly assigned to one of EMPA-REF are ”an important two doses of empaglilozin or pla- Is empagliflozin a renal drug? addition to the original indings,” cebo on top of standard therapy. here was also some discussion which nevertheless require further Empaglilozin reduced the risk of at the ADA meeting about the analysis. cardiovascular deaths by 38% re- mechanism of action of empagli- lative to placebo. lozin, both in lowering cardiovas- Cost Is an Issue In this new analysis of micro- cular risk and now with regard to Of key importance, said both vascular outcomes, incident or these renal beneits. Drs Herman and Riddle, is the worsening nephropathy occurred Most newer agent for diabetes fact that empaglilozin and other in 525 of 4124 patients taking em- will require dose adjustment in di- SGLT2 inhibitors — like the other paglilozin and 388 of 2061 in the abetic kidney disease because the newer agents for type 2 diabetes placebo group (12.7% vs 18.8%; majority are renally excreted; this (dipeptidyl peptidase-4 [DPP-4] HR, 0.61; P < .001). includes DPP-4 inhibitors other inhibitors, glucagonlike peptide-1 his renal end point consisted than linagliptin, most GLP-1 ago-

240 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se being speciically tested in a diabetic kidney-disease population in the large multicenter randomized Evaluation of the Efects of Canaglilozin on Renal and Car- diovascular Outcomes in Partici- pants With Diabetic Nephropathy (CREDENCE) trial. his will enroll 3000 patients with stage 2 or 3 chronic kidney disease and macroalbuminuria already receiving standard of care. hey will be randomized to canaglilozin 100 mg daily or placebo for 5 years, and results are not nists with the exception of liraglu- despite being metabolized by the expected until 2019. tide, and the SGLT2 inhibitors. kidney. It is not known whether the he latter, including empagli- ”he efect of empaglilozin on latest caution from the Food and lozin, have required dose adjust- renal outcomes was there early and Drug Administration, strengthe- ment in patients with diabetic kid- continued for the whole of the stu- ning the warning regarding acute ney disease. he current licenses dy, with both doses showing an ef- kidney injury for canaglilozin and for most SGLT-2 inhibitors preclu- fect. Empaglilozin works at lower dapaglilozin, will afect this trial. des their use in patients with renal stages of kidney function too,” Dr his states that healthcare provi- failure (eGFR < 60 mL/min/1.73 Wanner stressed. ders should consider factors that m2 in some cases or < 45 mL/ Silvio Inzucchi, MD, of Yale might predispose patients for ex- min/1.73 m2 in others). University, New Haven, Con- ample gastroenteritis to acute kid- Dr Wanner said that 25% of the necticut, the lead investigator of ney injury prior to starting them patients in EMPA-REG had eGFR EMPA-REG, added also that, re- on canaglilozin or dapaglilozin. < 60 mL/min/1.73 m2, more than garding the overall cardiovascular a third already had albuminuria, beneit of empaglilozin seen in N Engl J Med. Published online and almost a third already had the trial, ”there was no hetero- June 14, 2016. Article, Editorial prevalent kidney damage. geneity of efect based on eGFR; http://www.nejm.org/doi/ Yet, paradoxically, they seem cardiovascular disease was redu- full/10.1056/NEJMoa1515920?- to provide some renal protection. ced even in stage 3b renal-disease query=featured_home#t=article- hese newest indings from EM- [eGFR 30–45 mL/min/1.73 m2] Top PA-REG bolster excitement about patients.” the potential for SGLT2 inhibitors Another SGLT2 inhibitor, ca- Nyhetsinfo 11 juni 2017 to provide a renoprotective efect, naglilozin (Invokana, Janssen) is www red DiabetologNytt

ADA Report. New era of type 2 diabetes treatment after EMPA, LEADER etc NEW ORLEANS — Details of he study is the second such another GLP-1 agonist, ELIXA, the Liraglutide Efect and Action mandated FDA cardiovascular were neutral. in Diabetes: Evaluation of Car- safety study for a diabetes drug to Experts here said that LE- diovascular Outcome Results—A show cardiovascular beneit, rather ADER and EMPA-REG may now Long Term Evaluation (LEADER) than just lack of harm, on top of begin to change the landscape of trial of the glucose-lowering drug standard therapy in type 2 diabe- diabetes therapy, giving doctors a liraglutide (Victoza, Novo Nord- tes patients at high cardiovascular somewhat clearer choice when de- isk), showing that it signiicantly risk after the EMPA-REG trial, ciding which drug to use second reduced the rates of major adverse and the irst with an agent from line after metformin in type 2 cardiovascular events in type 2 di- the glucagonlike peptide 1 (GLP- diabetes. abetes patients at elevated cardio- 1) receptor agonist class. he results from the multicen- ▶ vascular risk, were reported today. Results of a previous trial with ter, international study were pre- www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 241 sented June 13, 2016 here at the sodium glucose cotransporter-2 United Kingdom, told Medscape American Diabetes Association (SGLT-2) inhibitor empaglilozin Medical News, ”I think we are in a (ADA) 2016 Scientiic Sessions (Jardiance, Boehringer Ingelheim/ diferent era now. People die from and were published online simul- Lilly) in the EMPA-REG trial, the hypoglycemia, whether by insulin taneously in the New England LEADER indings have experts or sulfonylureas. We shouldn’t for- Journal of Medicine, by Steven P talking about a ”new era” in the get that. Marso, MD, of University of Tex- management of type 2 diabetes. ”hese drugs [liraglutide and as Southwestern Medical Center, While most agree that metfor- empaglilozin] don’t cause hy- Dallas, and colleagues. min remains the irst-line drug of poglycemia and have other efects LEADER began in 2010 and choice, these new landmark study that may be beneicial. I agree ab- followed 9340 high-risk adults data are starting to better inform solutely we need to conirm with with type 2 diabetes for 3.5 to 5 the clinical choice of second drug other studies, but I think we’re de- years, who were randomly assig- based on characteristics beyond initely going to see a shift toward ned to receive either a subcuta- their glucose-lowering capaci- modern therapies.” neous injection of liraglutide 1.8 ty, speakers said during the press Beneits Seen for Multiple Car- mg once daily (or the maximum brieing. diovascular End Points tolerated dose) or placebo along ”In type 2 diabetes, most of us he LEADER trial included with standard treatment. agree that under most circumstan- patients with type 2 diabetes who he primary end point was the ces metformin is the drug of choi- had HbA1c levels of 7.0% or hig- irst occurrence of the three-point ce,” brieing moderator Robert H her. Entry criteria were either age major adverse cardiac event Eckel, MD, of the University of 50 and above with established (MACE) components: cardiovas- Colorado, Denver, said, noting that cardiovascular disease or chronic cular death, nonfatal myocardial additional potential cardiovascular renal failure or age 60 and older infarction (MI), or nonfatal stroke. and also anticancer beneits have with CVD risk factors. he degree of risk reduction been seen with that drug as well. Dr Robert H Eckel on podium; for MACE was 13% (occurring in However, he said, ”It’s interes- left to right, Drs Simon Heller, 608 of 4668 patients taking lirag- ting, with LEADER the beneit John Buse, Steven P Marso, and lutide) vs 14.9% (in 694 of 4672 for cardiovascular death is very Bernard Zinman taking placebo) (P = .01 for su- similar to what statins do. I think Patients could be drug-naive or periority), including a 22% lower with validation, it could potential- taking oral agents or basal insulin rate of cardiovascular death (4.7 ly change practice. I’d like to see but not other GLP-1 agonists or vs 6.0%, P = .007), Dr Marso re- second and third trials for both [li- DPP-4 inhibitors, pramlintide, or ported in a press brieing held at raglutide and empaglilozin]. Keep rapid-acting insulin. In both treat- the ADA meeting in advance of a in mind there are 25 or 30 trials ment and placebo groups, current special 2-hour symposium devoted for statins showing beneit,” said standards of care were targeted for to the indings. Dr Eckel, who was not involved in HbA1c, blood pressure, lipids, and he number of patients who LEADER or EMPA-REG. antiplatelet therapy. would be needed to treat to pre- Senior investigator of LEADER, Subjects had a mean baseline vent one event in 3 years was 66 John Buse, MD, of the University age of 64 years, diabetes duration for the MACE composite and 98 of North Carolina, Chapel Hill, 13 years, and HbA1c 8.7%. for death from any cause. added: ”I think this changes the At 36 months’ postrandomi- Liraglutide also reduced conversation with patients. Now, zation, HbA1c levels were 0.40 HbA1c, body weight, and hy- instead of just saying we’re giving percentage points lower in the li- poglycemia, and its safety proile you this drug to manage your hy- raglutide group, a signiicant dife- was similar to what has been seen perglycemia in diabetes, [we can rence (P < .001). Body weight also in previous trials, with gastroin- say] this drug also has the potential dropped signiicantly, by 2.3 kg (P testinal adverse events and incre- to modify your risk for cardiovas- < .001). ases in heart rate being the most cular disease and death. Overall, results for each of the common. ”It was beyond our expecta- components of the composite pri- tions that we would be able to de- mary MACE outcome were in New Trials Inform Clinical monstrate cardiovascular eicacy,” favor of liraglutide, with a 22% Choice of Second Drug for he told the press brieing. reduction in cardiovascular death Type 2 Diabetes Asked to comment, Simon (4.7% vs 6.0%, P = .007), which Coming on the heels of the car- Heller, MD, professor of clinical was signiicant, and a nonsigni- diovascular beneit seen for the diabetes, University of Sheield, icant 12% reduction in nonfatal

242 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se MI (6.0% vs 6.8%, P = .11) and an here were two cases of chronic LEADER gives a hint of the same 11% lower rate of nonfatal stroke pancreatitis, both in the placebo kind of modiication Everything is (3.4% vs 3.8%, P = .30). group. kind of changing modestly in the Also signiicant were a 15% re- However, acute gallstone di- right direction.” duction in all-cause death (8.2% sease was more common with li- But the LEADER investigators vs 9.6%, P = .02) and an expanded raglutide, 3.1% vs 1.9% (P < .001). note some diferences in how the composite CV outcome that in- Hypoglycemia was more com- drugs may be working. cluded coronary revascularization, mon in the placebo group, both ”he pattern of cardiovascular unstable angina, or hospitalization with overall conirmed cases of beneits that were associated with for heart failure (20.3% vs 22.7%, blood glucose levels below 56 liraglutide in our trial appears to P = .005). mg/dL (43.7% with liraglutide difer from that with the SGLT- Hospitalization for heart failure vs 45.6% with placebo, P < .001) 2 inhibitor empaglilozin in the itself was 13% less frequent in the and in severe hypoglycemia requi- previously reported EMPA-REG liraglutide group (4.7% vs 5.3%, P ring assistance (2.4% vs 3.3%, P OUTCOME trial.” = .14). Although not statistically = .016). he likely reason for this, he time to beneit emerged signiicant in terms of beneit, the Dr Eckel noted, is that the place- earlier in EMPA-REG than in lack of any signal for concern with bo patients may have been treated LEADER, they note, and the va- regard to heart failure is notewort- more intensively with insulin in riability of the direction and mag- hy, Dr Marso said. ”here has attempt to achieve HbA1c targets. nitude of the efects on the com- been a lot of discussion in the in- Neoplasms were not diferent ponents of the composite primary cretin space about whether agents between the groups except for a outcome in that trial ”contrasts such as SGLT2 inhibitors, DPP-4 46% reduction in prostate cancer with the consistency of efect in inhibitors, or GLP-1 receptor ago- (0.9% vs 1.6%) and a lower rate of the present trial.” nists are neutral, hazardous, or be- leukemias (0.1% vs 0.3%) in the he observed beneits in EM- neicial for heart failure.” liraglutide group. PA-REG ”may be more closely He added: ”What’s striking here was a numeric increase in linked to hemodynamic changes, is the consistency in the relative the number of pancreatic-cancer whereas in the present trial, the risk reduction in all of the major cases with liraglutide (13 vs ive) observed beneits are perhaps rela- cardiovascular end points that we for a higher rate of pancreatic can- ted to the modiied progression of measured in LEADER.” cer in the liraglutide group (0.3% atherosclerotic vascular disease,” he prespeciied primary mi- vs 0.1%), but four more cases were they conclude. crovascular outcome in LEADER identiied on imaging in the pla- Dr Marso reports grants and was a composite of nephropathy cebo group that did not have pat- personal fees from Novo Nordisk and retinopathy outcomes, and hology to establish the diagnosis, during the conduct of the study there was a beneit with liraglu- so the two groups were not signi- and personal fees from Abbott tide over placebo: time to irst icantly diferent, Dr Buse noted. Vascular and AstraZeneca outside renal event was 22% longer with the submitted work. Disclosures liraglutide, a signiicant diference. Everything Changing Modest- for the coauthors are listed on the However, this latter efect drove ly, but in the Right Direction journal website . the beneit, as there was no sig- Dr Eckel said that the results of Leader trial. N Engl J Med . niicant diference in retinopathy LEADER follow in the same vein Published online June 13, 2016. events between the two groups. as those of EMPA-REG. Article ”In EMPA-REG, many things Safety profile shows no signals related to CVD risk were modi- Nyhetsinfo 11 juni 2017 Overall adverse events occurred ied in a modest but favorable way. www red DiabetologNytt in two-thirds of both treatment groups and were not signiicantly diferent (P = .12). Serious adverse events occurred in 50% of both groups and severe events in a third of both (P = .51). Adjudicated cases of acute pancreatitis occurred in 0.4% of patients taking liraglutide compared with 0.5% on placebo (P = .44). www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 243 ADA Report. Sulfonylureas in T2DM, low cost but risks for hypoglycemia and weight increase. New better drugs coming in SAN DIEGO — A talk on have a question,” he noted, imply- tes(GRADE) study. GRADE is whether sulfonylureas still have ing that if cost were not a factor, he comparing four commonly used a role in the contemporary treat- would choose a second-line agent diabetes medications — the sul- ment of type 2 diabetes garnered other than a sulfonylurea. fonylurea glimepiride, the DPP- much interest here at the Ameri- Session chair Neda Rasou- 4 inhibitor sitagliptin (Januvia, can Diabetes Association (ADA) li, MD, University of Colorado, Merck), the glucagon peptide-1 2017 Scientiic Sessions. Aurora, told Medscape Medical (GLP-1) receptor agonist liragluti- Speaking to a large audience in News that with many newer class de (Victoza, Novo Nordisk), and a packed room, Kamlesh Khunti, of medication to treat type 2 dia- insulin glargine — head to head, MD, from the University of Lei- betes coming to the market, ”some when added to metformin. Pa- cester, United Kingdom, presen- leaders in the diabetes ield are say- tients will be followed for 4 to 5 ted a fast-paced overview of the ing that maybe there is no room years, and ”that study will help us history of the use of sulfonylure- for sulfonylureas.” to decide what the best medication as, randomized controlled trials vs But ”it’s hard to let them go be- is after metformin,” Dr Khunti observational data, mechanism of cause of the low cost,” she acknow- noted. action, novel insights, and practi- ledged, adding, ”Everybody wants Both studies are expected to cal considerations. to make sure that they are using a complete their data collection for While there is universal agre- medication that is safe, and that’s primary outcomes in February ement that metformin should be why I think there is great interest.” 2019 and August 2020, respecti- the treatment of irst choice in However, ”if cost were not a vely, and the results will help gui- type 2 diabetes, there is still much factor, probably people wouldn’t de clinical practice, Dr Rasouli debate about which and how use sulfonylureas,” she also agreed. many of the many classes of drugs acknowledged. However, GRADE does not in- should be used second line, when CAROLINA and GRADE clude sodium-glucose cotranspor- metformin alone isn’t suicient to Will Help Inform Choice ter 2 (SGLT2) inhibitors, and control blood glucose. And if SU he extensive review presen- one of these agents, empaglilozin should be on the list ted by Dr Khunti at the ADA (Jardiance, Boehringer Ingelheim) ”I don’t think you can throw meeting showed that there are was the irst type 2 diabetes med- away sulfonylureas (SU) complete- concerns about side efects such ication to show cardiovascular ly; there are a lot of data showing as hypoglycemia and weight gain protection in the landmark EM- that they can be beneicial for with sulfonylureas, but the data PA-REG OUTCOME study re- many countries, the low price, and were inconclusive about potential ported in September 2015. a lot of it comes down to aforda- cardiovascular harm, Dr Rasouli Two glucagon peptide-1 (GLP- bility,” Dr Khunti told Medscape noted. 1) agonists have since also shown Medical Newsfollowing his talk. Dr Khunti said: ”We really this, liraglutide in LEADER here is extensive experience in need to [see] the head-to-head and the investigational agent se- using them, and the risks and be- comparisons that we are all eagerly maglutide (Novo Nordisk) in neits are reasonably well-under- waiting for.” SUSTAIN-6. stood, he stressed. hese include data from the ”It will be interesting to see if While the larger database stu- cardiovascular-outcome study of other SGLT2 inhibitors and GLP- dies may show that sulfonylureas the dipeptidyl peptidase-4 (DPP- 1 receptor agonists are cardiopro- are not as good as other type 2 4) inhibitor linagliptin (Tradjen- tective,” Dr Rasouli commen- diabetes drugs, in the randomi- ta, Lilly/Boehringer Ingelheim) ted to Medscape Medical News. zed controlled trials, the data on vs the sulfonylurea glimepiride ”hen you might consider them as eicacy, safety, and durability ”are in patients with type 2 diabetes a second agent, but if [trials] don’t pretty reasonable. here is still a (CAROLINA). conirm it, then we go back to the place for sulfonylureas and in the And indings from the Compa- costs of the medication.” UK, we still use them,” he added. rative Efectiveness Study of Major She also noted that ”right now, On the other hand, ”If afor- Glycemia-lowering Medications in the ADA guideline, basal insu- dability is not a problem, we don’t for Treatment of Type 2 Diabe- lin can be used after metformin,

244 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se but there is clinical inertia, and with diabetes in the United States, are not using them in a timely not everybody is comfortable with and rates of use are even higher in manner, and we are waiting far starting an injectable therapy as a Europe — 41% to 45% of patients too long to intensify therapy in second agent, and ity is also the in the United Kingdom and 47% patients.” risks of hypoglycemia.” of patients in the Netherlands use ”We should be getting these a sulfonylurea, he added. patients on whatever therapy we Can’t ignore cost when here may however be diferen- can aford, bringing HbA1c down considering diabetes ces between countries in the type to control from diagnosis, keeping therapies of sulfonylurea that is used, Dr the HbA1c down for as long as Stressing the importance of cost, Khunti explained. possible, as safely as possible, with Dr Khunti said: ”Worldwide, ”In the UK, gliclazide is the whatever therapy is available and 415 million people have diabetes, [sulfonylurea] that is used the afordable to the patient.” hat is and 80% live in low–middle-in- most,” he said, noting that it does more likely to generate better outcome countries.” And price is an seem to have a better proile than comes for the patients in the long- important consideration even for other sulfonylureas in the AD- er term, he explained. developed countries, he emphasi- VANCE trial. ”here’s good eicacy and du- zed. Diabetes UK has said that the And ”over time we have impro- rability. here’s a bit lower risk of costs of treating diabetes threaten ved and use a lower dose” of glicla- hypoglycemia with the second-ge- to bankrupt the National Health zide, he said. neration sulfonylureas. We’ve Service, for example. Gliclazide is not available in the established long-term beneit with here ”is a massive diference” United States, Dr Rasouli noted, decreased risk of micro- and to in cost for an annual supply of but glimepiride and glipizide are a certain extent macrovascular antidiabetic agents, which, in the available. complications from randomized United States, ranges from $96 controlled trials.” And sulfonylu- US for glipizide and $192 for gly- Get Patients on Whatever reas are afordable for the 80% of buride — both sulfonylureas — to Therapy They Can Afford diabetes patients worldwide who $1243 for generic metformin to Summarizing, Dr Khunti said: reside in low- to middle-income around $5000 for DPP-4 inhibito- ”What I’ve shown you is there are countries, he reiterated. rs and around $5400 for SGLT2 controversial issues in terms of inhibitors, he noted. whether we use sulfonylureas or From www.medscape.com A recent study reported that not, and a lot of it comes down to sulfonylureas are still used by too afordability.” Nyhetsinfo 11 juni 2017 many patients, 31% of patients ”We have great drugs, but we www red DiabetologNytt

SGLT2 Inhibitors Double the Risk for Diabetic Ketoacidosis. N Engl J Med he risk of developing diabetic and Women’s Hospital, Boston, And he advises that patients be ketoacidosis (DKA) among type Massachusetts. monitored for signs of DKA or full 2 diabetes patients initiating a ”We found a doubling in the information to thew patients of sodium–glucose cotransporter 2 risk of DKA, which sounds frigh- the symtoms of DKA to seek help (SGLT2) inhibitor medication is tening, but the absolute risk is qui- if DKA appears after starting on about double that seen among pa- te small....I still think this is a very SGLT2 inhibitors, noting, ”his tients starting a dipeptidyl pepti- good class of medications and for is something that can happen re- dase-4 (DPP-4) inhibitor, but the certain patients will continue to latively quickly, so that’s why I overall risk is still low, new resear- be. Now we just have a little more think it’s important right after ch suggests. information to add to the discus- patients are started on these drugs Findings from the largest study sion when the risks and beneits that they’re closely monitored and conducted to date to investigate are being considered,” Dr Fralick the clinician considers ordering the issue were published as a rese- told Medscape Medical News. bloodwork.” arch letter in the June 8 issue of He estimates that between 5 But overall, Dr Fralick, a gene- the New England Journal of Med- and 8 patients per 1000 initiating ral internist, supports use of the icine by Michael Fralick, MD, SGLT2 inhibitors will develop SGLT2 inhibitor class for selec- ▶▶ and colleagues at the Brigham DKA. ted patients with type 2 diabetes, www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 245 given the recent results from the he primary outcome was Physicians and Surgeons of Ca- Empaglilozin Cardiovascular hospitalization for DKA — the nada, outside the submitted work. Outcome Event Trial in Type 2 unadjusted rate within 180 days Disclosures for the coauthors are Diabetes Mellitus Patients (EM- of SGLT2 inhibitor initiation was listed on the journal website. PA-REG OUTCOME) study 4.9 per 1000 person-years, com- showing reduction in cardiovascu- pared with 2.3/1000 person-years From www.medscape.com lar deaths, as well as renal protec- following DPP-4–inhibitor initiation, with empaglilozin (Jardian- tion (hazard ratio, 2.1). N Engl J Med. 2017;376:2300- ce, Boehringer Ingelheim/Lilly). After propensity score matching 2302. ”I completely agree that these with 38,045 patients in each arm medications have signiicant bene- to account for confounders such Article to the editor: its,” he commented. as age, comorbidities, use of other http://www.nejm.org/doi/ All eyes will be on the results medications, and healthcare utili- full/10.1056/NEJMc1701990 from another cardiovascular-out- zation, the hazard ratio for hospi- comes trial with a diferent SGLT2 talization for DKA with SGLT2 Inhibitors of sodium–glucose inhibitor, canaglilozin (Invokana, inhibitors vs DPP-4 inhibitors was cotransporter 2 (SGLT2) decrea- Johnson & Johnson) to be repor- still signiicant at 180 days (4.9 se plasma glucose by blocking ted on Monday at the American vs 2.2/1000 person-years; HR, the reabsorption of glucose at the Diabetes Association (ADA) 2017 2.2), as well as at 30 days (7.5 vs proximal tubule.1,2 Case reports Scientiic Sessions. 3.3/1000 person-years; HR, 2.3) have suggested that SGLT2 inhi- Results from the Canaglilozin and 60 days (5.6 vs 2.3; HR, 2.5). bitors may be associated with an Cardiovascular Assessment Stu- he DKA risk at 180 days increased risk of diabetic ketoaci- dy(CANVAS) program will reveal was also signiicantly higher with dosis, which led to a warning from whether the cardiovascular protec- SGLT2 inhibitors among patients the Food and Drug Administra- tion observed with empaglilozin not taking insulin (2.5 vs 1.0; HR, tion (FDA) in May 2015.3,4 he in EMPA-REG OUTCOME is a 2.5). objective of our study was to assess class efect or not. the risk of diabetic ketoacidosis And the indings will further ”Still so much work to be after the initiation of an SGLT2 inform on some of the side efects done” inhibitor. so far associated with this drug Once the investigators had the Using a large claims database class, including DKA, as well as data, they strove to get them of commercially insured patients fracture risk and a doubling of published as quickly as possible in the United States (Truven Mar- amputations of the lower limb, al- — hence in a research letter rather ketScan), we identiied a cohort of ready identiied with canaglilozin than a full paper, Dr Fralick told adult patients (≥18 years of age) compared with placebo in CAN- Medscape Medical News, ad- who had newly started treatment VAS, which resulted in the Food ding, ”here’s still so much work with either an SGLT2 inhibitor or and Drug Administration adding to be done to identify speciic risk a dipeptidyl peptidase-4 (DPP4) a boxed warning to this efect to factors.” inhibitor between April 1, 2013, the product label. Meanwhile, the group is using and December 31, 2014 (before the same database to examine the the FDA warning). DPP4 inhibi- Largest study of its kind risk of amputations with canagli- tors were chosen as the compara- For the current study, Dr Fralick lozin; results are expected in a few tor medication because they are and colleagues used a claims data- weeks. similarly used as a second-line base of commercially insured US he study was supported by the treatment for diabetes but have no patients (Truven MarketScan) and division of pharmacoepidemiology known association with diabetic identiied 50,220 type 2 diabetes and pharmacoeconomics, depart- ketoacidosis. We excluded patients patients who had received a new ment of medicine, Brigham and with human immunodeiciency prescription for an SGLT2 inhibi- Women’s Hospital, Harvard Med- virus infection, end-stage renal tor and 90,132 initiating a DPP-4 ical School, Boston. Dr Fralick disease, cancer, type 1 diabetes, inhibitor (chosen as the compara- reports grants from the Universi- or past diabetic ketoacidosis. Our tor class because it is used similarly ty of Toronto Clinician Scientist primary outcome was hospitali- to SGLT2 inhibitors, as second-li- Program and Clinician Investiga- zation for diabetic ketoacidosis ne after metformin for type 2 di- tor program and grants from the (using the primary position code abetes, but has no known link to Detweiller Traveling Fellowship of the International Classiica- DKA). funded by the Royal College of tion of Diseases, Ninth Revision)

246 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se within 180 days after the initiation tion for an SGLT2 inhibitor and propensity-score matching, the of an SGLT2 inhibitor or a DPP4 90,132 who had received a new hazard ratio was 2.2 (95% CI, 1.4 inhibitor. We censored data for prescription for a DPP4 inhibi- to 3.6) (Table 2TABLE 2Primary patients at the time that they dis- tor. Patients who were receiving and Other Outcomes.). he re- continued the initial medication, SGLT2 inhibitors were younger sults were robust across sensitivity had the outcome, lost insurance and had fewer coexisting illnesses analyses. coverage, or died. than those receiving DPP4 inhibi- In conclusion, shortly after ini- We used 1:1 propensity-score tors but were more likely to recei- tiation, SGLT2 inhibitors were as- matching to balance 46 characte- ve insulin. After propensity-score sociated with approximately twice ristics of the patients and Cox re- matching was performed, these the risk of diabetic ketoacidosis as gression to estimate hazard ratios diferences were well balanced were DPP4 inhibitors, although and 95% conidence intervals for (Table 1TABLE 1Characteristics cases of diabetic ketoacidosis le- diabetic ketoacidosis within 180 of the Patients at Baseline.). Befo- ading to hospitalization were in- days after treatment initiation. re propensity-score matching, the frequent. he increased risk of Predeined sensitivity analyses unadjusted rate of diabetic ketoa- diabetic ketoacidosis with SGLT2 included shorter durations of fol- cidosis within 180 days after the inhibitors is among the factors to low-up (30 days and 60 days). All initiation of an SGLT2 inhibitor be considered at the time of pres- statistical analyses were performed was about twice the rate after the cribing and throughout therapy if with the use of the validated Ae- initiation of a DPP4 inhibitor (4.9 patients present with symptoms tion platform and R software, ver- events per 1000 person-years vs. suggestive of diabetic ketoacidosis. sion 3.1.2.5 2.3 events per 1000 person-years) We identiied 50,220 patients (hazard ratio, 2.1; 95% coniden- Nyhetsinfo 10 juni 2017 who had received a new prescrip- ce interval [CI], 1.5 to 2.9). After www red DiabetologNytt

ADA Report. Researchers call for standardizing CGM Continuous glucose monitoring may have other detrimental efects. cial Pancreas Clinical Trials: A (CGM) outcomes provide mea- Consensus Report; and results ningful metrics for clinical trials Richard M. Bergenstal, MD from the Helmsley/IDC Stan- and diabetes care, but the beneits “CGM has the potential to be a dardized Glucose Reporting Ex- can’t be demonstrated without a critical tool in clinical trials to pert Working Group. standard set of deinitions, accor- evaluate and compare new med- ding to a panel of experts who spo- ications and new technologies hey also highlighted the in- ke at a Friday symposium. to see which is more efective at dings of three soon-to-be publis- he researchers outlined three obtaining more control and mini- hed CGM consensus statements: published and three forthcoming mizing hypoglycemia and variabi- Improving the Clinical Value and CGM metric statements, and cal- lity,” said Richard M. Bergenstal, Utility of CGM Systems: led for combining those into one MD, Executive Director of the • Issues and Recommendations, international consensus during the International Diabetes Center at • ADA-EASD Diabetes Techno- session Reaching an Internatio- Park Nicollet. “But with no stan- logy Working Group; Priority nal Consensus on Standardizing dard deinition, every trial might Outcome Measures for Type 1 Continuous Glucose Monitoring use a diferent deinition of what’s Diabetes: (CGM) Outcomes—Aligning high and what’s low, so we can’t • Consensus Statement of JDRF, Clinicians, Researchers, Patients, easily compare the data. We need Helmsley Charitable Trust, and Regulators. A uniied set of to get everyone to agree.” • AACE, Endocrine Society, PES, deinitions would aid in the deve- AADE, T1D Exchange and lopment of new drugs and devices, he researchers reviewed three ADA; and the International the researchers said. published CGM consensus state- Consensus Statement on CGM Key metrics derived from CGM ments: Outcomes: ATTD. data include time in range of glu- • he International Hypoglycae- cose levels, time above range, time mia Study: A key point repeated often during below range, and glucose variabi- • A Joint Position Statement of the symposium is the fact that the- lity, which may impact both hy- ADA and EASD; re’s only a slight diference in the perglycemia and hypoglycemia and • Outcome Measures for Artii- suggested values for many CGM ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 247 metrics. For example, in the six dence whether or not a particular of the University of Southern Cali- CGM consensus statements noted insulin formulation, new techno- fornia Clinical Diabetes Program. in the session, hypoglycemia was logy for insulin delivery, or an inn- deined as: 70 mg/dL, ovative patient-centered approach Anne Peters, MD Simon Heller, FRCP, MD, Pro- to care was an important factor in “It increases the complexity of fessor of Clinical Diabetes at the helping individuals with diabetes analysis and can lead to errors in University of Sheield, England, reach optimal glycemic control,” interpretation and dose adjust- argued that there needs to be three Dr. Danne said. ments,” Dr. Peters said. “A com- standard glucose levels to manage Aaron J. Kowalski, PhD, Chief mon set of standards would lead to hypoglycemia. Mission Oicer for the JDRF, said an easier way to interpret research “If you’re going to have glucose the diabetes community needs to trial results, as well as data viewed levels that are relevant to hypogly- recognize that although important, in a clinical setting.” cemia, you can’t have one or two. A1C has limitations. Dr. Kowalski Drs. Peters and Heller urged We have argued for three,” he said. has been working with the T1D industry and developers to create “You don’t want a patient to go Outcomes Program, a community one default reporting system or down as low as 54 mg/dL. By that to develop better ways to deine cli- way to visualize CGM proiles and time, they’re already in trouble. nically meaningful type 1 diabetes patterns. People need to be aware that hy- outcomes beyond A1C. If the diabetes community— poglycemia has consequences that Dr. Bergenstal agreed with Dr. clinicians, researchers, patients, aren’t captured by current classii- Kowalski’s assessment of A1C. developers, and regulators—can cations and in research studies and agree oxn a consensus for CGM in clinical trials.” Simon Heller, FRCP, MD metrics and visualization, it will “A1C doesn’t tell you where you help everyone with the end goal: Thomas Danne, MD, PhD were high or where you were low, or Helping people with diabetes homas Danne, MD, PhD, Di- how you should adjust your med- self-manage their condition more rector of the Department of Gene- ication,” Dr. Bergenstal said. “If efectively, Dr. Heller said. ral Pediatrics and Endocrinology/ you’re doing it for research, it tells “We’re beginning to have tech- Diabetology at Kinderkrankenhaus you your risk for complications, but nologies that can [help with that auf der Bult in Hannover, Ger- it doesn’t tell you if you have more goal], but the trouble is they’re ex- many, outlined the levels he, and or less hypoglycemia. CGM adds pensive,” he said. other experts in the room, believed important information to the A1C. “Governments and health insu- should be the “standard” metrics. Instead of getting in a ight with rance companies are unwilling to Dr. Danne said time out of the A1C, CGM adds value and gi- pay this money because they don’t range has two components: mode- ves you the whole picture, or tells see the potential beneit. We’ve rate and serious hypoglycemia. For you the patient’s story.” got to do something about that. reasons of conformity, the terms Unlike blood glucose meters, Technology and people’s abilities ‘alert hypoglycemia’ and ‘serious CGM devices have the ability to use them efectively have to be a hypoglycemia’ are recommended to measure 96 to 288 blood su- major focus for assisting people to to be used analogously for CGM gars every day and allow patients live with this incredibly burdenso- and self-monitoring blood glucose to monitor their glucose “conti- me condition. If people can get it (SMBG) threshold ranges, he said. nuously” to help avoid reaching right, people with diabetes can live Levels hypoglycemia, Dr. Danne said. with both improved quality of life Dr. Danne added that a key me- Other CGM hurdles include and a normal life expectancy.” asure of glycemic variability is the technology software and data vi- coeicient of variation (CV), which sualization. Companies that make Nyhetsinfo is independent of mean glucose CGM devices have proprietary At the Meeting the audience was concentration. Stable glucose levels software that makes it diicult to told that there is an internatione- are deined as a CV 50 percent, compare data across systems or al harmony in nomenclature of and intermediate stability as CV companies, Dr. Heller said. CGM, it should include both GM between 33 and 50 percent, he said. From a clinician’s perspective, with and without alarms, dexcom “A composite goal of lash glu- it’s diicult to look at data from and Medtronic enlite as well as cose monitoring or CGM, repor- diferent devices that use diferent Abbott´s Libre ted in a standardized way and in target ranges and standards for conjunction with an A1C value, hyperglycemia and hypoglycemia, Nyhetsinfo 10 juni 2017 could establish with more coni- agreed Anne Peters, MD, Director www red DiabetologNytt

248 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Reducing SBP targets below current guidelines cuts risk reducing SBP to 120 to 124 mm Hg linked to reduced risk of cardiovascular disease, all-cause mortality. J42 trials. 144220 patients. JAMA Cardiology For adults with hypertension tre- and Risk of Cardiovascular Di- mature deaths. However, the opti- ated with antihypertensive med- sease and MortalityA Systematic mal target for reduction of systolic ication, reducing systolic blood Review and Network Meta-ana- blood pressure (SBP) is uncertain. pressure (SBP) levels to 120 to 124 lysis mm Hg is associated with reduced Objective risk of cardiovascular disease and Joshua D. Bundy, MPH1; To assess the association of mean all-cause mortality, according to a Changwei Li, MD, PhD1; Patrick achieved SBP levels with the risk review published online May 31 in Stuchlik, MS1; et alXiaoqing Bu, of cardiovascular disease and JAMA Cardiology. MD1,2; Tanika N. Kelly, PhD1; all-cause mortality in adults with Joshua D. Bundy, M.P.H., from Katherine T. Mills, PhD1; Hua hypertension treated with antihy- the Tulane University School of He, PhD1; Jing Chen, MD1,3; pertensive therapy. Public Health and Tropical Med- Paul K. Whelton, MD1,3; Jiang icine in New Orleans, and colle- He, MD, PhD1,3. Author Aili- Data Sources agues examined the correlation of ations Article Information. JAMA MEDLINE and EMBASE were mean achieved SBP levels with the Cardiol. Published online May searched from inception to De- risk of cardiovascular disease and 31, 2017. doi:10.1001/jamacar- cember 15, 2015, supplemented by all-cause mortality in adults with dio.2017.1421 manual searches of the bibliograp- hypertension. Data were inclu- hies of retrieved articles. ded from 42 trials, with 144,220 Key Points patients. Question What is the optimal tar- Study Selection he researchers observed li- get for reduction of systolic blood Studies included were clinical tri- near associations between mean pressure among patients with hy- als with random allocation to an achieved SBP and risk of cardio- pertension? antihypertensive medication, con- vascular disease and mortality; the Findings In this systematic trol, or treatment target. Studies lowest risk was seen at 120 to 124 review and network meta-analy- had to have reported a diference mm Hg. For randomized groups sis of 42 trials, including 144 220 in mean achieved SBP of 5 mm with a mean achieved SBP of 120 patients, linear associations were Hg or more between comparison to 124 mm Hg, the hazard ratios seen between mean achieved groups. for major cardiovascular disease systolic blood pressure and risk of were 0.71 compared with SBP of cardiovascular disease and morta- Data Extraction and Synthesis 130 to 134 mm Hg, 0.58 compa- lity, with the lowest risk at a systo- Data were extracted from each red with SBP of 140 to 144 mm lic blood pressure of 120 to 124 study independently and in du- Hg, 0.46 compared with SBP mm Hg. plicate by at least 2 investigators of 150 to 154 mm Hg, and 0.36 according to a standardized pro- compared with SBP of 160 mm Meaning tocol. Network meta-analysis was Hg or more. he corresponding Reducing systolic blood pressu- used to obtain pooled randomized hazard ratios for all-cause morta- re below currently recommended results comparing the association lity were 0.73, 0.59, 0.51, and 0.47, targets with commonly used an- of each 5–mm Hg SBP category respectively. tihypertensive medications may with clinical outcomes after adjus- ”hese indings support more signiicantly reduce the risk of car- ting for baseline risk. intensive control of SBP among diovascular disease and all-cause Main Outcomes and Measu- adults with hypertension,” the au- mortality. res Cardiovascular disease and thors write. all-cause mortality. Abstract Results Forty-two trials, in- From http://www.physiciansbrie- Importance cluding 144 220 patients, met ing.com Clinical trials have documented the eligibility criteria. In gene- that lowering blood pressure redu- ral, there were linear associations Systolic Blood Pressure Reduction ces cardiovascular disease and pre- between mean achieved SBP and ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 249 risk of cardiovascular disease and a strong, independent, and log-li- hough concerns remain regarding mortality, with the lowest risk at near association between usual its generalizability to populations 120 to 124 mm Hg. Randomi- systolic blood pressure (SBP) and at large with hypertension. zed groups with a mean achieved mortality from CVD and all cau- Finding the optimal SBP target SBP of 120 to 124 mm Hg had a ses, with no evidence of a threshold could have far-reaching implica- hazard ratio (HR) for major car- down to at least 115 mm Hg.3 tions for the reduction of CVD diovascular disease of 0.71 (95% Randomized clinical trials have and premature death in general CI, 0.60-0.83) compared with documented that lowering blood populations. By using a network randomized groups with a mean pressure (BP) with commonly meta-analysis to combine availa- achieved SBP of 130 to 134 mm used regimens reduces the risk of ble data from randomized clinical Hg, an HR of 0.58 (95% CI, 0.48- CVD and all-cause mortality.4,5 trials, we compared the association 0.72) compared with those with a However, post hoc analyses based of diferent levels of SBP reduction mean achieved SBP of 140 to 144 on achieved BP in some clinical with the risk of major CVD, st- mm Hg, an HR of 0.46 (95% CI, trials, in which the results were roke, CHD, CVD mortality, and 0.34-0.63) compared with those not analyzed according to the ran- all-cause mortality. with a mean achieved SBP of 150 domized treatment assignment, to 154 mm Hg, and an HR of 0.36 identiied a J-shaped association Methods (95% CI, 0.26-0.51) compared between achieved BP and risk of Data Sources and Searches with those with a mean achieved CVD and all-cause mortality, es- We searched MEDLINE and EM- SBP of 160 mm Hg or more. Li- pecially between achieved BP and BASE using the following search kewise, randomized groups with a coronary heart disease (CHD).6,7 terms as medical subject headings mean achieved SBP of 120 to 124 he uncertainty of optimal go- and key words: (antihypertensive mm Hg had an HR for all-cause als for treatment for patients with agents OR blood pressure lowering mortality of 0.73 (95% CI, 0.58- hypertension has resulted in in- OR antihypertensive treatment) 0.93) compared with randomi- consistent recommendations for AND (cardiovascular disease OR zed groups with a mean achieved BP targets in clinical practice gui- coronary disease OR myocardial SBP of 130 to 134 mm Hg, an delines.4,8,9 For example, compa- infarctionOR stroke OR heart fai- HR of 0.59 (95% CI, 0.45-0.77) red with the 2003 Seventh Report lure OR mortality). he searches compared with those with a mean of the Joint National Committee were conducted without language achieved SBP of 140 to 144 mm on Prevention, Detection, Evalu- or date restriction, from inception Hg, an HR of 0.51 (95% CI, 0.36- ation, and Treatment of High to December 15, 2015. We limited 0.71) compared with those with a Blood Pressure,4 the 2014 Eviden- searches to randomized clinical mean achieved SBP of 150 to 154 ce-Based Guideline for the Mana- trials in human adults. Additional mm Hg, and an HR of 0.47 (95% gement of High Blood Pressure in trials were identiied by hand-se- CI, 0.32-0.67) compared with Adults8 raised the recommended arching bibliographies from in- those with a mean achieved SBP SBP treatment goal from less than cluded studies, reviews, and me- of 160 mm Hg or more. 130 mm Hg to less than 140 mm ta-analyses. Hg for patients with type 2 diabe- Conclusions and Relevance tes or chronic kidney disease and Study Selection his study suggests that reducing from less than 140 mm Hg to less Titles and abstracts of retrieved ar- SBP to levels below currently re- than 150 mm Hg for individuals ticles were independently screened commended targets signiicantly 60 years of age or older. Recently, by at least 2 of us (J.D.B., C.L., reduces the risk of cardiovascu- the Systolic Blood Pressure Inter- P.S., and X.B.). Articles deemed lar disease and all-cause morta- vention Trial (SPRINT) reported potentially eligible by either re- lity. hese indings support more that intensive treatment (targeting viewer were retrieved for full-text intensive control of SBP among an SBP of <120 mm Hg), as com- review. Disagreements on full-text adults with hypertension. pared with standard treatment review were resolved by discussion (targeting an SBP of <140 mm and consensus. The Article Hg), signiicantly reduced CVD Studies were included if they Introduction and all-cause mortality among met the following criteria: (1) par- Hypertension is the leading global adults with hypertension who were ticipants were randomly allocated preventable risk factor for cardio- at high risk for CVD, but without to an antihypertensive medica- vascular disease (CVD) and prediabetes or stroke.10 he data tion, control, or treatment target; mature death.1,2 Observational from SPRINT support a more (2) the allocation to antihyperten- epidemiologic studies have shown intensive SBP treatment goal, alt- sive treatment was independent

250 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se of other treatment regimens; (3) tion-to-treat analysis, and other all randomized SBP comparisons the sample size was 100 patients sources of bias. Disagreement was in the network. In addition, we or more in each treatment group; resolved by consensus. conducted the following 2 sensi- (4) trial duration was 6 months or tivity analyses: the irst excluding more; (5) one or more events for an Data Synthesis and Analysis SPRINT10 to assess its inluen- outcome of interest were reported Network meta-analysis allows ce on the results, given its large in each treatment group; (6) mean pooling of results derived from di- sample size and treatment efects, achieved SBP level was reported rect and indirect evidence across and the second excluding trials for each treatment group, and the multiple diferent treatments whi- with 4 or more categories deemed diference in mean achieved SBP le preserving the beneits of ran- at “high” or “unclear” risk of bias. between the comparison groups domized comparisons within each To account for trial heteroge- was 5 mm Hg or more; and (7) trial.12 We constructed network neity in the intervention duration outcomes included major CVD, diagrams for each outcome and the and baseline risk of CVD or mor- stroke, CHD, CVD mortality, or overall network to visualize direct tality, we adjusted for trial length all-cause mortality. Clinical trials and indirect comparisons between and event rate (or mortality) of the with mean achieved SBP of 160 SBP treatment levels. Treatment reference groups for each trial in mm Hg or more in both compari- nodes were deined by categori- the model.14 he median of the son groups were excluded because zing SBP into the following 10 posterior distribution was selected they do not contribute informa- separate treatment levels: less than as the point estimate, bounded by tion to the optimal target for SBP 120, 120 to 124, 125 to 129, 130 the 2.5th and 97.5th percentiles to treatment. For studies with mul- to 134, 135 to 139, 140 to 144, 145 form a 95% CI. Heterogeneity was tiple publications, data from the to 149, 150 to 154, 155 to 159, and assessed by monitoring the poste- article with the longest trial fol- 160 mm Hg or more. We used a rior between-trial SD. We used in- low-up time were included. Bayesian hierarchical random-ef- consistency models, design-by-tre- fects model with a binomial like- atment interaction models, and the Data Extraction and Quality lihood and complementary log-log node-splitting method to evaluate Assessment link function to model the proba- the diferences between direct and Data abstraction was conducted bility of events.13 Hazard ratios indirect comparisons.15,16 by 2 of us (J.D.B., C.L., P.S., and (HRs) for each possible compari- Finally, publication bias was as- X.B.) who independently used a son were calculated using Markov sessed using funnel plots and the predeined, standardized protocol Chain Monte Carlo simulation. Egger test for direct comparisons and data collection instrument. For an individual trial, each with 4 or more studies. All ana- Information was recorded on randomization group was assigned lyses were conducted using Win- sample size, demographic charac- to 1 category of achieved SBP ac- BUGS, version 1.4.3 (Medical Re- teristics, and medical history of cording to the group’s mean SBP search Council Biostatistics Unit), the trial participants; BP measure- level during the trial, irrespecti- R, version 3.2.1 (R Project for ment methods; mean achieved BP ve of medications used or initial Statistical Computing), and Stata, during treatment; follow-up time; treatment target. hus, each trial version 12.1 (StataCorp LP). A de- outcome ascertainment methods; contributed to 2 distinct achieved tailed description of the methods and number of events for each out- SBP categories based on rando- is available in the eAppendix in come. he predeined outcomes mization groups. Hazard ratios the Supplement. were major CVD events (inclu- comparing the lower vs higher ding CHD, stroke, heart failure, achieved SBP categories from each Results and CVD deaths), stroke, CHD, trial using intention-to-treat ana- Searches of MEDLINE and EM- CVD mortality, and all-cause lysis results within speciic SBP BASE yielded 2721 records, and mortality. comparison groups (eg, 120-124 manual searches of bibliographies Risk of bias was assessed by 2 vs 130-134 mm Hg) were pooled. of reviews, meta-analyses, and of us (J.D.B., C.L., P.S., and X.B.) herefore, randomized compari- other trial publications identiied using the Cochrane Collabora- sons within each trial were pre- an additional 26 articles (Figure tion’s risk of bias tool, based on served. he pooled HR for a given 1). After removal of duplicates, 7 domains11: random sequence comparison is composed of direct 2371 titles and abstracts were scre- generation, allocation conceal- evidence obtained from trials ened for eligibility, and 449 article ment, blinding of participants and comparing the 2 SBP randomiza- texts were reviewed in full. outcome assessment, incomplete tion groups and indirect evidence A total of 42 trials were included data, selective reporting, inten- obtained from the association of in the analyses, with a combined ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 251 sample size of 144 220 individuals with a mean achieved SBP of 130 of 0.67 (95% CI, 0.40-1.22) com- (eTable 1 in the Supplement). he to 134 mm Hg, an HR of 0.58 pared with randomized groups mean achieved SBP levels ranged (95% CI, 0.48-0.72) compared with a mean achieved SBP of 130 from 114 to 171 mm Hg among with those with a mean achieved to 134 mm Hg, an HR of 0.55 treatment groups. he trials were SBP of 140 to 144 mm Hg, an (95% CI, 0.30-1.07) compared conducted in diverse study popu- HR of 0.46 (95% CI, 0.34-0.63) with those with a mean achieved lations with various comorbidities, compared with those with a mean SBP of 140 to 144 mm Hg, an HR and 30 trials included participants achieved SBP of 150 to 154 mm of 0.43 (0.22-0.93) compared with with type 2 diabetes. Trial dura- Hg, and an HR of 0.36 (95% CI, those with a mean achieved SBP of tion ranged from 6 months to 0.26-0.51) compared with those 150 to 154 mm Hg, and an HR more than 8 years, with a mean with a mean achieved SBP of 160 of 0.34 (0.17-0.76) compared with follow-up of 3.7 years across all mm Hg or more (Figure 3; eTable those with a mean achieved SBP trials. Most trials used standar- 5 in the Supplement). Randomized of 160 mm Hg or more (eFigure 2 dized BP measurement methods groups with a mean achieved SBP and eTable 7 in the Supplement). (eTable 2 in the Supplement) and of 120 to 124 mm Hg had an HR In a sensitivity analysis exclu- had a low risk of bias (eTable 3 in for stroke of 0.69 (95% CI, 0.40- ding SPRINT, HRs and 95% CIs the Supplement). 1.07) compared with randomi- were consistent with results from he network of included trials zed groups with a mean achieved the main analyses for major CVD, was well connected, with many SBP of 130 to 134 mm Hg, an CHD, and all-cause mortality, indirect comparisons across the ca- HR of 0.51 (95% CI, 0.26-0.87) dicating the lowest risk at an SBP tegories of mean achieved SBP compared with those with a mean of 120 to 124 mm Hg for these out- levels (Figure 2; eFigure 1 in the achieved SBP of 140 to 144 mm comes (eTables 8-10 in the Supple- Supplement). he group with an Hg, an HR of 0.36 (95% CI, 0.17- ment). However, in the sensitivity SPB of 130 to 134 mm Hg deined 0.68) compared with those with a analysis, the lowest-risk group for the center of the network, with 21 mean achieved SBP of 150 to 154 stroke was the group with an SBP trials directly comparing a mean mm Hg, and an HR of 0.27 (95% of 120 to 124 mm Hg, and the achieved SBP of 130 to 134 mm CI, 0.12-0.51) compared with tho- lowest-risk group for CVD morta- Hg with 7 other mean achieved se with a mean achieved SBP of lity was the group with an SBP of SBP groups. A total of 31 trials 160 mm Hg or more (eFigure 2 less than 120 mm Hg. In the main contributed to network compari- and eTable 5 in the Supplement). analyses, the lowest-risk group for sons for major CVD, 27 trials for A similar but weaker association stroke was the group with an SBP stroke, 27 trials for CHD, 41 tri- between mean achieved SBP and of less than 120 mm Hg, and the als for all-cause mortality, and 33 CHD was observed (eFigure 2 and lowest-risk group for CVD mor- trials for CVD mortality. Descrip- eTable 6 in the Supplement). tality was the group with an SBP tions of outcomes are available in Randomized groups with a of 120 to 124 mm Hg. A second eTable 4 in the Supplement. mean achieved SBP of 120 to 124 sensitivity analysis excluding trials In general, there were linear as- mm Hg had an HR for all-cause with 4 or more categories deemed sociations between mean achieved mortality of 0.73 (95% CI, 0.58- at “high” or “unclear” risk of bias SBP levels and the risk of major 0.93) compared with randomi- did not substantively change the CVD, stroke, CHD, all-cause zed groups with a mean achieved results compared with the main mortality, and CVD mortality SBP of 130 to 134 mm Hg, an analyses (eTables 11-13 in the (Figure 3 and Figure 4; eFigure HR of 0.59 (95% CI, 0.45-0.77) Supplement). 2 and eTables 5-7 in the Supple- compared with those with a mean Model it for all outcomes was ment). he lowest risks for major achieved SBP of 140 to 144 mm adequate according to the Bayesi- CVD, CHD, all-cause mortali- Hg, an HR of 0.51 (95% CI, 0.36- an deviance information criterion, ty, and CVD mortality were at a 0.71) compared with those with a and the baseline risk covariate did mean achieved SBP of 120 to 124 mean achieved SBP of 150 to 154 not signiicantly alter the models mm Hg, whereas the lowest risk mm Hg, and an HR of 0.47 (95% (eTables 14-18 in the Supplement). for stroke was at a mean achieved CI, 0.32-0.67) compared with Heterogeneity was present for SBP of less than 120 mm Hg. those with a mean achieved SBP each outcome, with random-ef- Randomized groups with a of 160 mm Hg or more (Figure fects models itting better than mean achieved SBP of 120 to 124 4; eTable 7 in the Supplement). ixed-efects models according to mm Hg had an HR for major Randomized groups with a mean the Bayesian deviance information CVD of 0.71 (95% CI, 0.60-0.83) achieved SBP of 120 to 124 mm criterion. he magnitude of hete- compared with randomized groups Hg had an HR for CVD mortality rogeneity was low to moderate,

252 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se with a between-trial SD of 0.081 cant 25% reduction in the prima- mm Hg to achieve the treatment for major CVD and an SD ran- ry composite outcome of CVD goal of 120 to 124 mm Hg, the ging from 0.103 to 0.248 for the events (HR, 0.75; 95% CI, 0.64- risk of CVD was reduced by 29% other outcomes (eTables 14-18 in 0.89; P < .001) and a 27% reduc- (95% CI, 17%-40%), by lowering the Supplement). tion in all-cause mortality (HR, SBP by 20 mm Hg, the risk of here was no network-wide evi- 0.73; 95% CI, 0.60-0.90; P = .003) CVD was reduced by 42% (95% dence of inconsistency between were reported. CI, 28%-52%), by lowering SBP direct and indirect comparisons In our network meta-analy- by 30 mm Hg, the risk of CVD in any of the outcomes based on sis, compared with randomized was reduced by 54% (95% CI, inconsistency models and de- groups with a mean achieved SBP 37%-66%), and by lowering SBP sign-by-treatment interaction ana- of 130 to 134 mm Hg, CVD was by 40 mm Hg or more, the risk of lyses (eTables 19-23 in the Supp- reduced by 29% (HR, 0.71; 95% CVD was reduced by 64% (95% lement). However, inconsistency CI, 0.60-0.83), and all-cause mor- CI, 49%-74%). hese data support was present in a few individual tality was reduced by 27% (HR, a more intensive SBP management comparisons based on node-split- 0.73; 95% CI, 0.58-0.93), among approach to achieve a lower SBP ting analyses (major CVD, 125- randomized groups with a mean goal. 129 vs 130-134 mm Hg; CHD, achieved SBP of 120 to 124 mm Several meta-analyses have 125-129 vs 130-134 mm Hg; and Hg. his agreement persisted examined the association with CVD mortality, 120-124 vs 130- even after excluding SPRINT in CVD and mortality of more in- 134 mm Hg, and 120-124 vs 135- a sensitivity analysis. he indings tensive vs less intensive treatment 139 mm Hg). here was no evi- from SPRINT10 and our network of BP.18,19 Recently, Xie and dence of publication bias. meta-analysis suggest that a more colleagues18 reported an updated intensive treatment target than meta-analysis of 19 clinical trials, Discussion currently recommended (eg, SBP including 44 989 participants, on his network meta-analysis of ran- of 120-124 mm Hg) provides ad- the association of intensive BP domized clinical trials documen- ditional beneits for prevention of reduction with CVD outcomes. ted signiicant and linear associa- CVD complications and all-cause he mean achieved SBP was 133 tions between mean achieved SBP mortality. mm Hg (range, 118-144 mm Hg) and the risk of CVD and all-cau- Our study contributes ad- in the more intensive treatment se mortality. he lowest risks for ditional information on SBP group and 140 mm Hg (range, CVD and all-cause mortality were management strategies beyond 124-154 mm Hg) in the less inten- among randomized groups with a SPRINT.17 First, our study in- sive treatment group. Intensive BP- mean achieved SBP of 120 to 124 cluded 42 clinical trials condu- lowering treatment was associated mm Hg. hese indings support cted for 144 220 patients with with a reduction of 14% (95% CI, recently published results from various comorbidities (including 4%-22%) for major CVD, 13% SPRINT10 and suggest a beneit diabetes and stroke), age ranges, (95% CI, 0%-24%) for myocardi- of reducing SBP below the cur- and mean BP levels at baseline. al infarction, and 22% (95% CI, rently recommended target among herefore, these results are gene- 10%-32%) for stroke. However, adults with hypertension.8 ralizable to populations at large more intensive treatment had no he SPRINT trial randomly with hypertension. Second, our signiicant association with CVD assigned 9361 persons 50 years of study compared multiple levels of mortality (9%; 95% CI, –11% to age or older with an SBP of 130 to achieved SBP on the risk of CVD 26%) or all-cause mortality (9%; 180 mm Hg who had an increased and all-cause mortality and found 95% CI, –3% to 19%). Another risk of CVD, but without diabe- positive and linear associations recent meta-analysis conducted by tes or stroke, to receive intensive between achieved SBP and clini- Ettehad and colleagues19 sugge- treatment or standard treatment cal outcomes. Our indings do not sted that every 10–mm Hg reduc- of SBP.10 Blood pressure was me- support the existence of a J-shaped tion in SBP, including to levels less asured in accordance with a pre- association between achieved SBP than 130 mm Hg, signiicantly re- speciied, standardized protocol. and the risk of CVD and all-cause duced the risk of major CVD and he mean achieved SBP was 121.5 mortality. Furthermore, our study CHD. Our network meta-analysis mm Hg in the intensive-treatment indicates that there is a linear as- results complement and expand group and 134.6 mm Hg in the sociation between the magnitudes on the indings from these tradi- standard-treatment group during of SBP reduction and the risk of tional meta-analyses. Our analy- the intervention. During a median CVD and all-cause mortality. For ses, based on many achieved SBP follow-up of 3.26 years, a signii- example, by lowering SBP by 10 categories while maintaining ran- ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 253 domized treatment assignments, parison of multiple achieved SBP ducted in this topic area. First, we show a beneicial linear association levels on clinical outcomes while had limited sample size in some between more intensively reduced preserving trial-level treatment mean achieved SBP comparisons. mean achieved SBPs and clinical randomization and its associa- For example, only 3 trials achieved outcomes, and identify the lowest ted protection against bias. Our mean SBP levels below 120 mm risk at a mean SBP of 120 to 124 study allowed for comparisons of Hg, with a combined sample size mm Hg. a wider range of mean achieved of 7333. hus, most of the eviden- he association of intensive tre- SBP levels than has been possible ce in our analyses is based on tri- atment in subgroups of patients in traditional meta-analyses, with als treating participants to achieve with certain comorbidities, especi- a spread from less than 120 mm SBP levels above 120 mm Hg. ally type 2 diabetes, have been of Hg to more than 160 mm Hg, Second, few trials reported heart particular interest.18,20- 23 he and identiied the lowest risks for failure outcomes, which resul- Action to Control Cardiovascular CVD and all-cause mortality at a ted in an insuiciently connected Risk in Diabetes trial examined mean achieved SBP of 120 to 124 network to analyze this outcome. the association of an intensive mm Hg. Another strength of our Similarly, we were unable to as- SBP target (<120 mm Hg) com- network meta-analysis is that it sess the association of intensive pared with a standard SBP target uses all available information (di- SBP reduction with kidney disease (<140 mm Hg) for patients with rect and indirect comparisons) to outcomes, dementia, or adverse diabetes, inding a nonsigniicant compare the association of each events such as hypotension or fal- beneit on reducing risk for CVD mean achieved SBP level with cli- ling, which have been concerns events, which could be a consequ- nical outcomes. herefore, it was with intensive treatment of BP.18 ence of reduced statistical power possible to base the comparisons Furthermore, we were unable to or use of a factorial design.20,21 A between various SBP levels on a conduct subgroup analyses by age, 2012 meta-analysis conducted by much larger number of clinical race/ethnicity, history of CVD, McBrien and colleagues22 repor- trials compared with similar me- stroke, chronic kidney disease, ted a small reduction in the risk of ta-analyses limited to trials exa- or diabetes owing to insuicient stroke associated with more inten- mining more intensive compared data. Finally, we deined treat- sive BP reduction in adults with with less intensive therapy; our ment nodes according to the mean type 2 diabetes but found incon- study included 42 trials compared achieved SBP in each randomiza- clusive results for mortality and with the traditional analysis from tion group, which does not consi- CHD. Another recent meta-analy- Xie et al18 that included 19 trials. der the distribution of individual sis by Brunström and Carlberg23 Our data indicate that there was SBP levels within groups. hus, reported increased risk of CVD no signiicant diference between mean achieved SBP groups may mortality among patients with di- direct and indirect comparisons represent a range of SBPs. In ad- abetes who had a baseline SBP of at the network level. In addition, dition, analysis of mean achieved less than 140 mm Hg and reduced we used a systematic and compre- SBP does not guide treatment de- their level of SBP via treatment, hensive search strategy to identify cisions regarding diastolic BP. suggesting a J-shaped association. a wide coverage of available anti- here are several implications We were able to include many tri- hypertensive clinical trials. Most for clinicians based on indings als of patients with diabetes and of the included trials had low risk from SPRINT,10 other meta-ana- other comorbidities. Our indings of bias; a sensitivity analysis in- lyses, and our network meta-ana- do not support the existence of a dicated that trials with unclear lysis. First, data suggest that tre- J-shaped association among popu- risk of bias did not substantially atment to achieve an SBP below lations at large with hypertension. inluence our results. Finally, our currently recommended guidelines analyses included a large number reduces the risk for major CVD Strengths and Limitations of trials conducted in diverse pa- and all-cause mortality in adults here are several strengths in this tient populations and were adju- with hypertension. However, the- network meta-analysis compared sted for diferences in intervention re may be a tradeof between these with the previous meta-analy- duration and baseline risk among beneits and potential adverse ef- ses that used traditional analysis trials, which increases the genera- fects of intensive SBP reduction, methods. Network meta-analysis lizability of our indings. including hypotension, electroly- methods ofer a unique advan- Our indings should be inter- te abnormalities, and kidney in- tage compared with traditional preted in light of several limita- jury.10,18 hus, clinicians should meta-regression techniques by tions, most of which have been continue to monitor acute adverse allowing the simultaneous com- common to all meta-analyses con- efects in individual patients and

254 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se make treatment decisions based a meta-analysis of individual data for one projects/mpes/mtc/. Accessed September on accurate BP measurements, ac- million adults in 61 prospective studies. 25, 2015. Lancet. 2002;360(9349):1903-1913.Pub- 14.Achana FA, Cooper NJ, Dias S, et cording to standardized protocols MedArticle al. Extending methods for investigating similar to those used in clinical 4.Chobanian AV, Bakris GL, Black HR, the relationship between treatment efect trials. Second, although our ana- et al; Joint National Committee on Preven- and baseline risk from pairwise meta-analysis suggests that intensive SBP tion, Detection, Evaluation, and Treatment lysis to network meta-analysis. Stat Med. reduction reduces risk for major of High Blood Pressure. National Heart, 2013;32(5):752-771.PubMedArticle Lung, and Blood Institute; National High 15.Jackson D, Barrett JK, Rice S, White CVD and all-cause mortality in Blood Pressure Education Program Coor- IR, Higgins JPT. A design-by-treatment populations at large with hyper- dinating Committee. Seventh report of the interaction model for network meta-analy- tension, including in those with Joint National Committee on Prevention, sis with random inconsistency efects. Stat diabetes, the outcomes of inten- Detection, Evaluation, and Treatment of Med. 2014;33(21):3639-3654.PubMedAr- High Blood Pressure. Hypertension. ticle sive SBP reduction for patients 2003;42(6):1206-1252.PubMedArticle 16.Dias S, Welton NJ, Caldwell DM, with diabetes warrant further ex- 5.Turnbull F; Blood Pressure Lowering Ades AE. Checking consistency in mixed ploration. Clinicians should be Treatment Trialists’ Collaboration. Ef- treatment comparison meta-analysis. Stat particularly vigilant when treating fects of diferent blood-pressure-lowering Med. 2010;29(7-8):932-944.PubMedAr- patients with comorbidities, inclu- regimens on major cardiovascular events: ticle results of prospectively-designed over- 17.Jones DW, Weatherly L, Hall JE. ding diabetes. Finally, the most views of randomised trials. Lancet. SPRINT: what remains unanswered and efective strategies for implemen- 2003;362(9395):1527-1535.PubMedArtic- where do we go from here? Hypertension. ting more intensive SBP reduction le 2016;67(2):261-262.PubMed in general clinical practice remain 6.Messerli FH, Panjrath GS. he J-cur- 18.Xie X, Atkins E, Lv J, et al. Efects ve between blood pressure and coronary of intensive blood pressure lowering on to be established. Future research artery disease or essential hypertension: cardiovascular and renal outcomes: upda- should consider the best practices exactly how essential? J Am Coll Cardiol. ted systematic review and meta-analysis. for treating patients to reduce SBP 2009;54(20):1827-1834.PubMedArticle Lancet. 2016;387(10017):435-443.Pub- levels below current guidelines in 7.Mancia G, Grassi G. Aggressive blood MedArticle the routine clinical management pressure lowering is dangerous: the J-curve: 19.Ettehad D, Emdin CA, Kiran A, et pro side of the argument. Hypertension. al. Blood pressure lowering for prevention of hypertension. 2014;63(1):29-36.PubMedArticle of cardiovascular disease and death: a sys- 8.James PA, Oparil S, Carter BL, et al. tematic review and meta-analysis. Lancet. Conclusions 2014 Evidence-based guideline for the ma- 2016;387(10022):957-967.PubMedArticle Our study indicates that treating nagement of high blood pressure in adults: 20.Cushman WC, Evans GW, Byington report from the panel members appointed RP, et al; ACCORD Study Group. Ef- patients to reduce SBP below cur- to the Eighth Joint National Committee fects of intensive blood-pressure control in rently recommended targets may (JNC 8). JAMA. 2014;311(5):507-520. type 2 diabetes mellitus. N Engl J Med. signiicantly reduce risk of CVD PubMedArticle 2010;362(17):1575-1585.PubMedArticle and all-cause mortality. hese in- 9.Weber MA, Schifrin EL, White WB, 21.Margolis KL, O’Connor PJ, Morgan dings support more intensive SBP et al. Clinical practice guidelines for the TM, et al. Outcomes of combined cardio- management of hypertension in the com- vascular risk factor management strategies control among adults with hyper- munity: a statement by the American in type 2 diabetes: the ACCORD randomi- tension and suggest the need for Society of Hypertension and the Inter- zed trial. Diabetes Care. 2014;37(6):1721- revising the current clinical gui- national Society of Hypertension. J Clin 1728.PubMedArticle delines for management of hyper- Hypertens (Greenwich). 2014;16(1):14-26. 22.McBrien K, Rabi DM, Campbell N, PubMedArticle et al. Intensive and standard blood pressure tension. 10.Wright JT Jr, Williamson JD, Whel- targets in patients with type 2 diabetes mel- ton PK, et al; SPRINT Research Group. litus: systematic review and meta-analysis. References A randomized trial of intensive versus Arch Intern Med. 2012;172(17):1296- 1. Kearney PM, Whelton M, Reynolds K, standard blood-pressure control. N Engl 1303.PubMedArticle Muntner P, Whelton PK, He J. Global bur- J Med. 2015;373(22):2103-2116.Pub- 23.Brunström M, Carlberg B. Efect of den of hypertension: analysis of worldwide MedArticle antihypertensive treatment at diferent data. Lancet. 2005;365(9455):217-223. 11.Higgins JPT, Altman DG, Gøtzsche blood pressure levels in patients with di- PubMedArticle PC, et al; Cochrane Bias Methods Group; abetes mellitus: systematic review and 2.GBD 2013 Mortality and Causes of Cochrane Statistical Methods Group. he meta-analyses. BMJ. 2016;352:i717.Pub- Death Collaborators. Global, regional, Cochrane Collaboration’s tool for assessing MedArticle and national age-sex speciic all-cause and risk of bias in randomised trials. BMJ. cause-speciic mortality for 240 causes of 2011;343:d5928.PubMedArticle death, 1990-2013: a systematic analysis 12.Lu G, Ades AE. Combination of Nyhetsinfo 6 juni 2017 for the Global Burden of Disease Study direct and indirect evidence in mix- 2013. Lancet. 2015;385(9963):117-171. ed treatment comparisons. Stat Med. www red DiabetologNytt PubMedArticle 2004;23(20):3105-3124.PubMedArticle 3.Lewington S, Clarke R, Qizilbash N, 13.Multi-parameter Evidence Synthesis Se också sid 161. 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www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 255 Nyupptäckt sjukdomsmekanism för typ 2-diabetes. Betaceller blir omogna. Djurstudie. Anders Rosengren, Göteborg. Nature Communcations Publicering i Nature Communi- betes typ 2, ringade forskarna in Anders Rosengren. Troligen inns cations i dag klockan 11:00. Arti- vilka genförändringar i cellerna de redan i form av mediciner som keln nu synlig hos tidskriften efter som påverkade sjukdomsförloppet används vid andra sjukdomar. viss fördröjning. mest. En analys som Anders Ro- Samtidigt betonar han vikten sengren beskriver med en bild från av hälsosamma levnadsvanor vid Nyupptäckt sjukdomsmeka- lygets värld. diabetes typ 2. Den aktuella forsk- nism för typ 2-diabetes – Alla lygplatser är förbundna i ningen visar att SOX5 minskar Nu presenteras en nyupptäckt ett stort nätverk, men en störning om man äter onyttigt och rör sig mekanism bakom den minskade på Frankfurts lygplats är mycket för lite. insulinproduktionen vid diabetes allvarligare än en störning i Gö- – Det är viktigt att inte dra alla typ 2. I en artikel i Nature Com- teborg. Vi letade upp hubbarna, över en kam. Vissa klarar sig länge munications beskriver forskare vid nyckelgenerna, och de stora för- trots ohälsosamma levnadsvanor, Sahlgrenska akademin hur insu- bindelselänkarna. Av nästan 3 000 för andra tippar det över tidigare. linproducerande celler backar i sin gener som var förändrade vid dia- Men oavsett genetiska förutsätt- utveckling, blir omogna, och inte betes var 168 så kallade Frankfur- ningar har man en möjlighet att fungerar som de ska. Ett fynd som tgener, och det var dem vi fokuse- göra något år sin sjukdom, säger öppnar för nya kliniska behand- rade på, säger han. Anders Rosengren. lingar. Den fortsatta analysen visade – Om man kan påverka på att genen SOX5, tidigare okänd Länk till artikeln: https://www. cellnivå, och återställa kroppens i diabetessammanhang, påverkar nature.com/articles/ncomms15652 egen sekundsnabba reglering, får sjukdomen. Läs artikeln i sin helhet utan man en bättre ininställning av lösenord i fulltext blodsockret än vad insulinspru- tor kan ge, säger Anders Rosen- ABSTRACT gren, docent i metabol fysiologi, Sox5 regulates beta-cell phenotype och verksam vid Institutionen för and is reduced in type 2 diabetes neurovetenskap och fysiologi och A. S. Axelsson, T. Mahdi[...]A. H. Wallenbergcentrum för molekylär Rosengren och translationell medicin vid Gö- teborgs universitet. Nature Communications 8, Article Det har länge varit känt att de number: 15652 (2017)doi:10.1038/ insulinproducerande cellerna svik- – Om man artiiciellt under- ncomms15652Download tar vid typ 2-diabetes. Kroppen trycker och stänger av SOX5 så Type 2 diabetes (T2D) is cha- får inte tillräckligt med insulin försämras funktionen hos de 168 racterized by insulin resistance och blodsockret stiger. generna och cellerna backar i and impaired insulin secretion, En teori har gjort gällande att mognadsgrad. Om man sedan till- but the mechanisms underlying de insulinproducerande cellerna för SOX5 skruvas de 168 generna insulin secretion failure are not blir färre, en annan att deras funk- upp och insulinförsättningen kan completely understood. tion försämras. normaliseras, förklarar Anders Here, we show that a set of Den nya förklaringen, som för- Rosengren. co-expressed genes, which is en- enar de omdebatterade teorierna, – Det var väldigt spännande riched for genes with islet-selective går ut på att de insulinproduceran- att se. Det var nästan som en vo- open chromatin, is associated with de cellerna går tillbaka i utveck- lymkontroll där mognadsgraden T2D. hese genes are perturbed in ling och blir omogna. På så sätt kunde dras upp och ner i de insu- T2D and have a similar expression minskar antalet funktionsdugliga linproducerande cellerna. pattern to that of dediferentiated celler. islets. Befintliga läkemedel We identify Sox5 as a regulator Genen som driver Läkemedel som återställer mog- of the module. Sox5 knockdown Med hjälp av 124 vävnadsprover, naden hos insulinproducerande induces gene expression chang- varav 41 från personer med dia- celler är inte långt borta, menar es similar to those observed in

256 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se T2D and diabetic animals and model of T2D, increases the ex- of dediferentiation and highlight has profound efects on insulin pression of key β-cell genes and SOX5 as a regulator of β-cell phe- secretion, including reduced de- improves glucose-stimulated insu- notype and function. polarization-evoked Ca2+-inlux lin secretion in human islets from and β-cell exocytosis. SOX5 over- donors with T2D. Nyhetsinfo 6 juni 2017 expression reverses the expression We suggest that human islets in www red DiabetologNytt perturbations observed in a mouse T2D display changes reminiscent

LCHF to T1DM Children. Risks For Life. Pediatric Diabetics. Carmel Smart Low carbohydrate diets for the management of type 1 diabetes have been popularised by social media. he promotion of a low carbohy- and National Institute for Health adopting a low carbohydrate diet,1 drate diet in lay media is in con- and Care Excellence (NICE)2 there are no published data to sup- trast to published pediatric di- Paediatric guidelines recommend port this. Fur-thermore, substitu- abetes guidelines that endorse a that ~50%-55%, <35%, and 15%- tion of carbohydrate with other balanced diet from a variety of 20% of energy should be derived energy sources such as saturated foods for optimal growth and de- from carbohydrate, fat, and prote- fat, can lead to an increased risk velopment in children with type 1 in, respectively.1 with an individu- of developing cardiovascular di- diabetes. his can be a source of alized assessment required. At the sease.6,7To address this gap in the conlict in clinical practice. same time, alternative diets such literature, pediatric endocrinolo- We describe a series of 6 cases as low carbohydrate 30%-40% gists, and dietitians across Austra- where adoption of a low carbohy- energy from carbohydrate) and lia and New Zealand were invited drate diet in children impacted very low carbohydrate diets (21-70 to describe type 1 diabetes cases growth and cardiovascular risk g/d)3 are promoted for the mana- where adherence to a restricted factors with potential long-term gement of type 1 and type 2 dia- carbohydrate diet was believed to sequelae. betes in various media forums in result in endocrine and metabolic hese cases support current cli- order to optimise glycaemic con- consequences. Publica-tion of each nical guidelines for children with trol. While there is some evidence case was approved by the local diabetes that promote a diet where that low carbohydrate diet can be ethics committee from the contri- total energy intake is derived from efective for weight loss in obese buting centre. Nutrient Referen- balanced macronutrient sources. adults,4 and improve glycemia in ce Values for Australia and New adults with type 2 diabetes,5 there Zealand8 were used to determine CASE REPORT is no supportive scientiic literatu- recommended intakes for each in- Endocrine and metabolic conse- re in children with type 1 diabetes, dividual. Anthropometry utilised quences due to restrictive carbohy- and there are concerns that any the CDC reference growth charts drate diets in children with type 1 cardi-ovascular beneits of weight in all cases.9 diabetes: An illustrative case series loss using a low carbohydrate diet in adults may be countered by an 2 | CASES From Pediatric Diabetes. 2017;1– unfavourable lipid proile.4 2.1 | Case 1 9. wileyonlinelibrary.com/journal/ A nutrient-rich diet that meets Patient A was diagnosed with type pedi 1 individual energy, vitamin, and 1 diabetes aged 12 years 1 month. mineral requirements is important On initial presentation A had hy- 1 | INTRODUCTION for normal growth and develop- perglycemia and mild dehydra- Nutritional management is a core ment in children. Adherence to a tion, with no history of polyuria, aspect of diabetes care. Interna-ti- low carbohydrate diet in a bid to polydipsia, or reported weight loss. onal clinical guidelines on the ma- reduce glycemic excur-sions and During diagnosis, his HbA1c was nagement of type 1 diabetes uni- insulin requirements has the po- 10.3% (89 mmol/mol) and thy- ver-sally describe the requirement tential to result in a low total calo- roid function tests were normal. for a healthy diet based on a varie- ric intake, mineral deiciencies and Type 1 diabetes was subsequently ty of nutritious foods. he Inter- lead to suboptimal growth. While conirmed with positive diabe-tes national Society for Paediatric and clinical guidelines note the poten- autoantibodies. Patient A com- Adoles-cent Diabetes (ISPAD)1 tial for poor growth in children menced multiple daily injection ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 257 2.2 | Case 2 Patient B was diagnosed with type 1 diabetes at age 8 years 7 months after a classical 3 week pro-drome of polyuria and polydipsia, and conirmatory diabetes autoantibodies. Born to Egyptian parents, her mother had a history of gestational diabetes, her father had type 2 diabetes (on insulin) and a paternal grandmother had type 2 diabe-tes. he mid-parental height, deined as the genetic height potential based on the parental height, was reported as 162.5 cm (−0.13 SDS). Patient B transitioned to insulin pump therapy at the age of 9 therapy with meal-time insulin a cycling team and began training years. She was academically high to carbohydrate ratios. Patient A sessions for 1 to 2 hours on 4 oc- achieving and required a high le- lived with both parents and was casions per week. Between 13 and vel of counselling support to ma- involved in numerous sporting ac- 15 years, patient A attended clinic nage diabetes related and social tivities. less regularly than recommended. anxieties. After diagnosis for 3 months During this time his weight fell From age 10 years, patient B his HbA1c had fallen to 6.1% (43 from −1.22 to −1.88 SDS (Figure expressed concern about her body mmol/mol). Eight months after 1). Investigations for coeliac and weight and a strong desire to lose diagnosis, aged 12 years 9 months, thyroid disease were normal. weight. By age 12 years, patient B his HbA1c was 5.8% (40 mmol/ At 15 years 3 months, patient con-tinued to identify her main mol) with his height 149 cm (−0.67 A requested a dietary review as he concern as being her weight and SDS) and weight 34.9 kg (−1.21 was hungry and becoming very had a irm goal to reach a desired SDS). At this time his parents ex- fatigued during and after cycling. weight of 50 kg and be more ath- pressed concern about patient A’s His fam-ily were also concerned letic. At this time, she was 59.2 blood glucose levels increasing about glucose excursions noted af- kg (1.99 SDS) and had a body above the normal range particu- ter high fat, high protein meals. A mass index (BMI) of 23.7 kg/ m2 larly following his afternoon recess 24 hour dietary recall showed an (1.31 SDS) (Figure 2). Menarche at school. Patient A was advised average intake of 60 g of carbohy- had occurred at age 11 years 10 to eat more at lunchtime in accor- drate per day with <70% RDI of months. dance with appetite and to cover calcium and thiamin. He reported At the age of 12, patient B and this with additional insulin, as that he was inding the dietary her parents reported extensive li- the family were reluctant to give restrictions diicult, and asked his festyle changes made within the an additional insulin injection at family during the interview “Can family unit following her father’s recess. I please have milk after training?” own attempts to manage his type After 3 months, at 13 years His usual post-exercise intake 2 diabetes and weight loss fol- of age, patient A and his parents consisted of eggs, sausages, bacon, low-ing bariatric surgery. He en- imple-mented a lower carbohydra- and salad. Annual blood tests re- couraged patient B to join him te diet in an efort to control his vealed an elevated fasting choleste- in following a low carbohydrate blood glucose excursions. A 3-day rol level of 5.5 mmol/L. diet. Her parents reported that she food record showed an average da- From this time onwards pa- was exercising more regularly and ily intake of ~90 g of carbohydrate. tient A increased his carbohy- insulin pump downloads revea- His energy intake was an estima- drate intake to 150 g/d with car- led an average daily carbohydrate ted 8200 kj/d with 20% energy bohydrate pre- and post-training intake of ~50 g/d. HbA1c at this from carbohydrate, 30% from sessions. time was 7.0% (53 mmol/mol). protein, and 50% from fat. Calci- At 16 years his calcium intake Her dairy intake was noted to be um intake was less than 30% re- met 80% RDI, weight had recove- minimal and calcium intake less commended dietary intake (RDI). red to −1.31 SDS and his HbA1c than 50% of daily requirements. At the same time patient A joined was 6.3% (45 mmol/mol). Concurrently, patient B reported

258 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se poor concentration levels but was anxiety. rements and food preferences prior willing to pursue the low carbohy- From age 14 years onwards, her to diagnosis. drate eating plan as she had started diet started to become less restric- At his second review appoint- to achieve some weight loss (BMI tive, as she herself identiied that ment 2 months after diagnosis, 1.26 SDS) and her parents conti- “it was not the right diet for me” patient C had lost further 0.6 kg nued to encourage and pro-vide and concern over the disruption to (weight 20.3 kg, −0.55 SDS) and this diet in the family home. At her menstrual cycle was high. was still eating only salad at school age 12 years 7 months, elevated She increased her carbohydra- with lean meat or ish despite the fasting total cholesterol of 5.7 te intake to 120 to 140 g\d, her previous recommendation. he mmol/L and low vitamin D were men-strual cycle resumed and en- lunch-time injection and often noted. Systolic blood pressure was ergy levels improved enough to en- the dinner injection were omit- at the 95th percentile for age. gage in regular physical activities. ted. A diet history showed his At age 13 years, carbohydrate At this time, her BMI was 24.3 kg/ carbohy-drate intake was reduced intake was restricted further, to an m2 (0.84 SDS). further to 60 g/d, providing an average intake of 22 g carbohydra- estimated 20% of his daily ener- te per day. Patient B reported low 2.3 | Case 3 gy intake. His diet met ~70% of energy levels and lack of enjoyment Patient C was diagnosed with type his expected energy needs, with when playing sport. Fear of hy- 1 diabetes aged 6 years 3 months. calcium intake providing only 200 poglycemia was expressed, impac- He presented with hyperglycae- mg/d, 28% of his requirement for ting upon her sleep, engagement mia, polyuria, polydipsia, ketosis, age. he multi-disciplinary team in sport and normal daily activi- and bed wetting. His weight on recommended that a minimum ties, fear of entering carbohydrate diagnosis was 20.9 kg (−0.22 SDS) of 30 g carbohydrate were inclu- into the insulin pump, frequently and height was 124.8 cm (1.32 ded at both lunch and dinner to decreasing the recommended bo- SDS). Positive autoantibodies for meet nutritional needs and also lus dose for meals and disconnec- type 1 diabetes were conirmed. assist with patient C’s self-reported tion of the insulin pump from 1 He started multiple daily injection hunger. to 3 AM. here was an increase in ther-apy using insulin-to-carbohy- On review 3 months later, pa- her HbA1c from 6.0% (42 mmol/ drate ratios for meals and long ac- tient C had lost further weight mol) to 8.1% (65 mmol/mol). ting insulin before bed. A 24-hour (400 g). hyroid function tests Patient B then developed se- diet recall based on pre-diagnosis were normal and a coeliac screen condary amenorrhoea. She un- intake showed a wide variety of negative. He was continuing to fol- der-went numerous investigations, foods which met Nutrient Refe- low a low carbohydrate meal plan including magnetic resonance rence Value requirements1 for age. with ~50 g carbohydrate/d, with imaging (MRI) of the brain and His mother showed a good dieta- less than 7 g carbohydrate at lunch pituitary, laboratory tests for pu- ry knowledge; however, his father and dinner. Insulin injections bertal hor-mones, coeliac and was unable to attend education were not being given at school. His thyroid serology, folate and iron ses-sions despite eforts made by HbA1c at this time was 7.9% (63 studies, all of which were normal. the diabetes team. mmol/mol). Patient C’s mother ex- Her BMI continued to decrease Two weeks following diagno- pressed the opinion that a very low over this time (Figure 2), despi- sis patient C was commenced by carbohydrate diet would achieve te frequent dietetic interventions his family on a low carbohydrate, the best results for her son’s ove- that aimed to sup-port the family high-fat diet in an attempt to av- rall health and diabetes. his was in achieving a balanced, nutritio- oid mealtime insulin injections. related to information provided by us diet. Concerns regarding the Carbohydrate intake was limited social media. A hospital admission development of disordered eating to 75 g daily, with tinned ish, for re-stabilisation of his diabetes were raised when she was 13 years and green salad replacing his usual was recommended but refused by of age, primarily due to self-repor- sandwich at school. he mid-mor- his mother. ted fear of includ-ing additional ning fruit break was restricted to At the time of his next ap- carbohydrate in her diet because low carbohy-drate fruit only. At pointment, the diabetes team were it may lead to weight gain. his this time, it was noted that pa- con-tacted by staf at patient C’s was coupled with obsessively weig- tient C had only gained 500 g in school. hey reported patient C hing herself every day. Extensive weight since diagnosis (see Figure was hun-gry and asking for food psychological counselling conti- 3) so a carbohy-drate intake of at from other children and staf. His nued to help patient B man-age least 40 g was recommended at teachers noted he had only salad these persistent feelings of high school in accord-ance with requi- and tins of ish, with protein balls ▶ www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 259 in his lunch-box. During a visit to regivers thereafter. events resulting in coma or seizu- the school by the Diabetes team, Four weeks after diagnosis re. Her poor growth was extensi- there was a dis-cussion of the im- her height was 93.5 cm (−2.0 vely investigated; she had normal portance of a healthy diet at school SDS) and weight 13.5 kg (−1.49 thyroid function, coeliac screen, inclusive of fruit, wholegrains and SDS). he mid-parental height growth hormone testing, and nor- dairy foods and patient C’s mother was 154 cm (−1.6 SDS). Within mal female karyotype. Her bone seemed prepared to begin to inclu- 4 months of diagnosis a reduced age was delayed by 2 years. She de carbohydrate foods at school. carbohy-drate diet had been im- was screened for an eating disorder However, later it emerged that pa- plemented (less than 40% energy and this was discounted. tient C’s mother was angry with from carbo-hydrate), and there the advice given and expressed the was weight loss to 12.85 kg. For 2.5 | Case 5 desire to have a diferent multi-dis- the next 8 years while followed at Patient E was diagnosed with type ciplinary team. the clinic, her growth continued 1 diabetes aged 2 years, after a Nevertheless, at his subsequent to be poor (Figure 4). Patient D classical history of polyuria and appointment a diet history showed continued a diet low in carbohy- polydipsia. He did not present a much less restrictive dietary in- drate with a pro-portionally high with diabetic ketoacidosis. His take of 150 g carbohydrate with 45 amount of energy derived from HbA1c at diagnosis was 12.6% to 60 g eaten at school. Patient C fat. For example, based on a 3-day (114 mmol/ mol). He was the irst had gained 1.8 kg in weight (22.3 food record at the age of 11 years, born child of his parents, and there kg, −0.35 SDS). His carbohydra- she was reach-ing 76% of expec- was no family history of type 1 di- te intake was an esti-mated 35% ted energy requirement, with 39% abetes. Two weeks after diagnosis of his current energy intake with coming from car-bohydrate, 42% his height was 84 cm (−1.36 SDS) an excessive fat intake >40% en- from fat (48% saturated), and and his weight was 14.2 kg (1.31 ergy. Laboratory results revealed 19% from protein. his food re- SDS). he mid parental height was an elevated fasting choles-terol cord reached 47% of the calcium, recorded 182 cm (1.15 SDS). 6.3 mmol/L (reference range <5.5 70% of the phosphorous, and 74% After 18 months of diagno- mmol/L); LDL cholesterol of the magnesium recommended sis, at the age of 3.5 years, a low 3.04 mmol/L (reference range daily intake, respectively. She had car-bohydrate diet was introduced <2 mmol/L) and triglycerides 1.66 elevated fasting total cholesterol by the parents. Two months after mmol/L (reference range <1.59 of 5.2 mmol/L while adher-ing to commencing this diet, HbA1c had mmol/L). Lower fat alternatives to this diet. improved from 6.1% (43 mmol/ achieve <10% energy from satura- Patient D was last seen aged mol) to 5.3% (34 mmol/mol) with ted fat and ish oil supplementa-ti- 11.3 years; height 123.9 cm (−3.28 no severe hypoglycaemia. Patient on were recommended. SDS), weight 27 kg (−1.77 SDS). E was not growing well, with In subsequent visits, with a At this point her HbA1c was 8.6% height now 92.4 cm (−2.16 SDS) more liberalized carbohydrate in- (71 mmol/mol), on 0.7 U/kg/d and weight 15.3 kg (−0.54 SDS) take patient C’s growth improved of insulin, using a twice daily in- (Figure 5). A strict low carbohy- with weight 24 kg (−0.1 SDS) and jection insulin regimen. Subsequ- drate and high fat diet continued height 131.8 cm (1.32 SDS) centile ently, the family refused to attend to be adhered to, and 6 months (Figure 3). Food seeking behavio- clinic due to conlict between the later patient E had not gained ur ceased at the school. clinical team and her grandparents signiicant weight (15.5 kg, −0.86 regarding the diet implemented in SD). Dietetic eval-uation from a 2.4 | Case 4 the household. She was lost to fol- 3-day food record revealed that Patient D was diagnosed with low up despite eforts from social total energy intake reached 86% type 1 diabetes aged 4 years. She services. Her inal adult height is of estimated energy requirements. pre-sented with classical sympt- not available. Energy derived from carbohydra- oms of polyuria, polydipsia, and a Patient D had a mean HbA1c te was 6%, protein 27%, fat 67% 1-2 kg weight loss over a 4-week over her entire paediatric follow (saturated fat 36%). He had 406% period. She was not in diabetic up of 8.1% (65 mmol/mol) (range: of recommended daily sodium in- ketoacido-sis. Her HbA1c at di- 6.4-10.4%, 46-90 mmol/mol). She take. Calcium was 50% of recom- agnosis was >14% (>130 mmol/ had no admissions for diabetic ke- mended daily intake. mol). Her father also had type 1 toacidosis, and while she experien- he poor weight gain and short diabetes, but died 9 months after ced frequent mild and moderate stature were investigated. hy-roid patient D was diag-nosed. Her hypoglycaemia, there were no do- function and coeliac screen were grandparents were the primary ca- cumen-ted severe hypoglycaemic normal. IGF1 was very low (<25

260 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se mcg/L). Other laboratory investi- to insulin pump therapy at age 3.5 After 3 months, patient F’s gations showed an elevated total years and at this time, her parents parents decided to cease the diet cholesterol of 4.7 mmol/L, with decided to commence Patient F again due to their concerns that normal triglycerides and normal on a low carbohydrate diet in or- she looked unwell and tired most HDL (1.9 mmol/L). Serum mag- der to achieve less excursions in of the time, describing her as “de- nesium, vitamin B1, and folate the blood glucose readings. hey lated” and lacking in energy. She were normal. cited pop-ular literature and used was reportedly very irritable, was He proceeded to growth hor- other internet-based blog sites to always hungry and never satiated mone testing, initially with an support this change, including low by the foods that were ofered. She argi-nine stimulation test which carbohydrate recipes. However, had lost weight, now weighing failed. Peak growth hormone was they were only able to maintain 20 kg (−0.89 SDS) but her linear 4.3 mU/L (normal >19 mU/L). their daughter on a restricted car- growth was tracking (121.5 cm At this stage after negotiation with bohydrate intake of 40 g/d for 1 [−0.08 SDS]) (Figure 6). Labora- the family, more carbohydrate was month as they could not ind an tory investigations showed normal introduced into the diet. adequate variety of low carbohy- thy-roid function and a negative Two months later, average dai- drate foods that their child would coeliac screen. ly carbohydrate intake was 45 g/d, accept. At aged 6 years 9 months Patient F returned to a normal total insulin dose was 0.31 U/kg/d of age, patient F was placed on a family diet that contained on aver- (on insulin pump therapy), and the low carbohydrate diet again by her age 130-140 g of carbohydrate per HbA1c was 4.9% (30 mmol/mol). parents. he carbohydrate content day. he family continue to ofer he patient showed signiicant hy- of her diet was reduced to ~40 g/d predominantly foods of a low gly- poglycemia with 2 weeks of con- for 3 months by following a plan cemic index. After 3 months she tinuous glucose sensor data show- that provided 12 g of carbohydra- regained 3.7 kg to return to her ing 20% of sensor glucose values te for each main meal and 6 g of pre-low carbohydrate diet weight less than 3.9 mmol/L and 3% of carbohydrate for 1 midmeal, with percentile. his trend was sustai- time spent with a sensor glucose other carbohydrate free foods also ned at her subsequent follow-up below 2.9 mmol/L. A total of 47% ofered. he goal in doing this visit 6 months after returning to of hypoglycemic events occurred was to help improve glycaemia normal carbohydrate intake (Fi- between 11 PM and 5 AM. here stabil-ity, as although she conti- gure 6). were no episodes of hypoglycemic nued to have an average HbA1C seizures. Poor height velocity was of 7.6% (60 mmol/mol) [range 3 | DISCUSSION continuing with height now 95.9 7.3%-7.8% (56-62 mmol/mol)] his case series illustrates that car- cm (−2.36 SDS), and weight 16.6 her parents hoped to alleviate the bohydrate restriction in growing kg (−0.55 SDS). Further labora- spikes in her blood glucose levels. children can lead to anthropome- tory investigations demonstrated At this point patient F weighed 21 trical deicits and a higher cardio- an improvement in IGF-1 (28 kg (−0.31 SDS) and measured 120 vas-cular risk metabolic proile. mcg/L). Pituitary growth hormone cm (−0.31 SDS). Further, fatigue and low enjoy- secre-tion was tested again with an Adherence to the low carbohy- overnight growth hormone proi- drate diet was challenging. Her le, which showed only 1 overnight mother described the daily chal- peak of 20 mU/L. Other pituitary lenge of inding an adequate va- hormones, and a brain MRI, were riety of acceptable foods for her normal. daughter to eat as annoying and relent-less, made more diicult by 2.6 | Case 6 the fact that her daughter’s school Patient F was diagnosed with type was egg and nut-free. Patient F 1 diabetes at the age of 22 months quickly tired of the limited num- after presenting with a 1 month ber and repetitive ofering of low history of polyuria, polydipsia, and carbohydrate foods and would of- a 2.0 kg weight loss. Four months ten demand more food at bedtime after diagnosis she was 95.1 cm or wake during the night, com- tall (−0.18 SDS) and weighed 14.7 plaining of hunger. She did conti- kg (0.07 SDS). he mid-parental nue dance and swimming classes height was recorded as 170 cm despite her reports that she was (1.1 SDS). Patient F transitioned hungry all the time. www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 261 ment of sports was reported. type 1 diabetes are not conined or after the meal20 or inaccurate To our knowledge, this is the to the physical domain. Common insulin to carbohydrate ratios21 irst time that cases have been col- themes in these illustrative cases will cause marked deviations in lated which illustrate the publis- are anxiety, fatigue, subjection to blood glucose levels following car- hed guidelines that warn to this unnecessary medical investi-ga- bohydrate containing meals. Low efect.1,10 he likely mechanism tions and in some cases, clinical carbohydrate diets are also fashio- is that carbohydrate restriction, conlict, and loss to follow up nable for weight control and are without compensatory energy in- which can have long-term implica- promoted as healthy in lay media. take through other macronutrients tions. he families who adopt low hese issues should be carefully (fat and protein), leads to a deicit carbohydrate diets, as in this case addressed by the clinical team. in total energy intake. his occurs series, are often well educated, yet Contributing to this is the variety more easily in children than adults rely on personal blogs from social of media, including popular tele- as children have additional energy media as evidence that such a diet vision, books, magazines articles, needs for growth. A similar obser- is in the best interest of their child. and personal internet blogs, that vation for growth has been obser- Furthermore, while under-re- have popularised restrictive diets ved when a very low carbohydrate porting of food intake should be in type 1 and type 2 diabetes. (ketogenic) diet has been applied considered in any assessment of Such media exploit the intuition to children with intractable epi- the nutritional intake of children that if carbohydrate is the cause lepsy.11,12 Fur-thermore, when and adolescents with diabetes,18 of glycemic excursion, then the dietary fat becomes the principle families who follow restricted car- reduction of carbohydrate intake source of energy, this can result in bohydrate diets often fastidious- provides a solution for families de- a high proportion of saturated fat ly monitor carbohydrate intake. aling with the frustration of daily intake, and lead to a lipid proile Health professionals face a predi- glycemic variability. Further, the that raises cardiovascular disease cament between trying to main- notion that ‘less insulin is better’ risk13 as seen in cases 1, 2, 4, and tain a positive patient relationship, is a commonly expressed theme by 5. High fat diets have also been while trying to convince the fami- families and necessary for the mul- shown to blunt pituitary growth ly that the diet may be detrimental ti-disciplinary team to respectfully hormone release,14 which may ex- to their child’s health. discuss. plain the poor growth hor-mone It is well documented that Health care professionals wor- response shown in case 5. children and adolescents with type king in a multi-disciplinary team A number of studies have ex- 1 diabetes are at a greater risk for may use a variety of strategies amined the association of car- psychological disorders, including to encourage maintenance of a bohy-drate intake with glycemic a 2-fold risk of experiencing a bal-anced diet when families ex- control in people with type 1 di- psychiatric disorder and 2.4 times press the desire to adopt a low abetes.13,15–17 Delahanty et al15 more likely to develop an eating carbohy-drate diet to control gly- explored the dietary intakes of 532 disorder.19 Adoption of restric- cemic excursions. For example, intensively treated participants in ted eating behaviour can further postprandial glycemic excursions the Diabetes Control and Com- contribute to the social isolation due to delayed administration of plications Trial and reported that that patients with type 1 diabetes insulin boluses should be check- diets lower in carbohydrate and already experience, and feasibly ed for, and reassurance given that higher in fat were associated with add to psycho-social burden. Fur- postprandial glyce-mic targets worse glycemic outcomes. his ther, the diet may become an ad- can be met without carbohydrate inding has been supported by stu- ditional source of conlict within restriction when insulin to car- dies in children and adolescents the family as the child approaches bohydrate ratios are optimized. using intensive insulin therapy adolescence. Further, substitution of lower gly- that found higher total fat16 and he decision made by families cemic index (GI) for higher GI lower carbohydrate17 intakes were to adopt a restrictive diet is like- carbohydrates,22 and enhancing associated with higher hemoglobin ly to be multi-factorial. Increasing die-tary quality by decreasing A1c levels. hese studies conclu- use of newer technologies such as foods high in saturated fat and in- ded that improving dietary quality continuous glucose monitoring creasing ibre intake,16,17 can as- by increasing consumption of fruit has enabled parents of children sist in improving glycemic control. and wholegrain bread and cereals with type 1 diabetes to observe Encouraging meal-time routines, may enhance metabolic proiles in excursions resulting from food whilst minimising snacking episo- young people with type 1 diabetes. contribut-ing to anxiety. Behavio- des, is also important.23 Utilizing he efects of restrictive diets in urs such as giving insulin during continuous glucose monitoring

262 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Diabetes. 2009;10:389-394. can be an efec-tive tool to reinfor- REFERENCES ce that pre-prandial insulin dosing 1. Smart C, Annan F, Bruno L, Higgins 14. Galassetti P, Larson J, Iwanaga K, Sals- L, Acerini C. ISPAD clinical prac-tice berg SL, Eliakim A, Pontello A. Efect of and improved dietary quality can a high-fat meal on the growth hormone achieve better glycemic control, consensus guidelines 2014; nutritional management. Pediatr Dia-betes. 2014;15:135- response to exercise in children. J Pediatr as well as facilitat-ing insulin dose 153. Endocrinol. 2006;19:777-786. optimization. 2. National Institute for Health and Care 15. Delahanty LM, Nathan DM, Lachin Currently, there is a lack of ba- Excellence. Diabetes (type 1 and type 2) in JM, et al. Association of diet with glycated hemoglobin during intensive treatment lanced lay information warning children and young people: diagnosis and manage-ment. NICE Guideline. Publis- of type 1 diabetes in the diabetes control against the dangers of restricted hed August 2016. Last updated November and complications trial. Am J Clin Nutr. carbohydrate diets in growing 2016, nice.org.uk/guidance/ng18. Acces- 2009;89(2):518-524. chil-dren with type 1 diabetes. sed 7th March 2017. 16. Katz ML, Mehta S, Nansel T, Quinn 3. Wheeler ML, Dunbar SA, Jaacks LM, et H, Lipsky LM, Lafel LM. Associa-tions Published diabetes guidelines, and of nutrient intake with glycemic control in the societies that commission and al. Macronutrients, food groups, and eating patterns in the management of diabetes a youth with type 1 diabetes: diferences by endorse them are not visible in sys-tematic review of the literature, 2010. insulin regimen. Diabetes Technol her. the popular media with respect to Diabetes Care. 2012;35:434-445. 2014;16(8):512-518. their dietary recommendations, 4. Nordmann AJ, Nordmann A, Briel M, 17. Nansel TR, Lipsky LM, Liu A. 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Pediatr www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 263 Metformin joins forces with gut microbes to improve blood sugars, new study finds from Gothenburg. Nature Medicine Researchers at the University of lay of about two months in how tolerance readily improved. Gothenburg and the Institute of long it took for communities of One proposed mechanism for Biomedical Investigation of Giro- gut microbes to normalise, the pa- the efects has to do with the way na have found that gut microbial per showed that the microbiome the newly formed communities of shifts under metformin treatment of participants evidently adapted microbes process certain nutrients, contribute to improved blood su- to the treatment. like lavonoids. hese compounds gar control. Speciically, there appears to have been associated with a redu- hey believe that the drug ef- be common metformin treatment ced risk of type 2 diabetes. fects on blood glucose may result signatures in the gut microbiome, Overall, the results suggest that from normalising the dysbiosis or with an increase in abundance of metformin response is intrinsically imbalance of the gut lora that has beneicial gut microbe species and linked with the gut, but there are been previously linked with type 2 a decrease in less favourable ones. many more questions that remain diabetes. Metformin acts like a growth about the nature of this relationship Earlier research has found that factor for raising the bacteria and the correct way to look at it. metformin is distinctly diferent count of species that have been For example, researchers are from other types of diabetes med- shown to lower blood sugar levels, also considering the possibility ication in that it caused profound decrease visceral and total body that these efects may be media- changes in the gut microbiome of fat, dampen inlammation and gut ted through changes in functions users. permeability as well as improve in- of genes in the gut microbio- In the new indings, published sulin resistance. me, which constitute our second in the journal Nature Medicine, Furthermore, when researchers genome. the authors suggest that these dif- transplanted (through fecal trans- ferences may inluence both met- fers) the gut microbes of metfor- Nyhetsinfo 5 juni 2017 formin’s eicacy and side efects. min-treated participants to germ- www red DiabetologNytt Although there was a lag or de- free mice, the animals’s glucose

264 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Driften att veta, Mitt kunskaps Mitt veta, att Driften sidor, kapitel: uppdelad isex Jarrick att skriva boken. den berömda droppen som ick vara förefaller presidentval, USA:s i seger till gick ändå för sanning förakt som med sitt uttalade Trump, Donald falskt. och sant mellan för skillnaden de respekt över och fallan för kunskap tresse liksom liksom självmordshistoria” ga svensk –en frå ”Hamlets tårar”, och makt kens w.aesibtss ibtlgyt 07 råg3 N - 265 Nr 30 6-7 2017 Årgång DiabetologNytt www.dagensdiabetes.se som så sig, bakom böcker lera omskrivna har sakademin, Vetenskap av Kungliga ledamot Universitet Stockholms vid och professor ihistoria Jarrick, Arne nätet.via 195 ibokhandeln, den 269 kr kr Utgiven 2017 inbun kostar och av Jarrick Arne Recension av ”Det finns inga häxor bok –en om kunskap” Den är på strax under 190 strax på Den är Jarrick oroas över vikande in över oroas vikande Jarrick ”Behovet att behövas”. att ”Behovet ”Kärle ------

kunskap och betydelsen av lusten betydelsen och kunskap Vad är kunskapssam-hälle? i ett vi Lever det? är –vad skapssamhälle själv, mig kun Ett till uppdrag att förvärva den samt den samt förvärva att Kunskapspolitik. dissonans; när man man när dissonans; kognitiv begreppet blir varse uppfatt varse blir ningar eller sakför eller ningar hållanden som stri hållanden der mot det man der mot man det håller för sant. för sant. håller Människor har oli ka sätt att förhålla förhålla att sätt ka sig till detta. Oron detta. sig till inne i våra huvu ivåra inne den har sin grund grund sin den har i två omständig i två Han tar bl.a. upp bl.a. tar Han tiv och en social. en social. och tiv kogni en heter; Det kognitiva är är kognitiva Det vad vi faktiskt faktiskt vi vad tror och det so det tror och ciala vår benä vår ciala medlemmarna medlemmarna gen-het tro att på samma sätt sätt samma på som de andra som de andra ------hypotesen fel. är d.v.s. för den egna att bevis söka fel, få försöka sig att tvinga i stället och rätt få att impulsen motstå att vikten betonade skapsteoretiker Denne veten författare. för vår föredöme ett är förhållningssätt PoppersSir (1902 Karl –1994) tro! verkar tror –eller grupp av vår skapsbredd och överblick. och skapsbredd kun saknas en av dessa och var men hos experterna, till lämnas besluten – och information undan sig drar komplex så blir några att världen Jarrick; enligt med detta, risker inns Det ökar. kunskaperna nej till, säga att svårt väl är hälle läsaren att relektera. relektera. att läsaren få önskar Han erfarenheter. liga person och objektiva fakta mellan 1500-talet nutid, och mellan fritt rör ur. sigösa Han att källa en rik har han där monolog, böljande en liknar skrivna det och historia han några förslag på hur man kan kan hur på man förslag några han ger boken av slutet I hopplöshet. med lika inte är detta –menad att Att vi lever i ett kunskapssam lever iett vi Att Arne Jarrick kan sin kunskaps sin kan Jarrick Arne Författaren säger att han är oro är han att säger Författaren Foto © Marcus Marcetic ©Marcus Foto ------▶ BOKRECENSION minska kunskapsmotståndet. Fle- Vit färg; Neutral, faktabaserad värt med metoden och att genom- ra av för-slagen handlar om insat- och rationell. Vilken information förbarheten och nöjdheten med ser i tidig skolålder så våra skolpo- har vi redan? Hur väl underbyggd besluten har varit god. litiker borde ta del av dem. Men… är den? Vilken ytterligare kun- är dessa mottagliga? I boken inns skap/information behövs? Längtar du efter att någonsin få se ett exempel på faktaresistans; i tio Röd hatt; tänk eld, passion, en TV-debatt där någon av debat- år ledde Jarrick panelsamtal där känsla. Att lita på sin intuition har törerna ändrar sin ståndpunkt? forskare skulle presentera för po- i forskning visat sig vara avgörande Har Du deltagit i möten där du litiker relevanta vetenskapliga rön för att ta bra beslut. Känslan behö- frustrerad konstaterat att var och inom områden där politiska beslut ver inte motiveras. en kör i sina gamla hjulspår; den skulle tas. Vid en efterföljande en- Svart hatt; Svarta tanka, pes- negative är som vanligt emot alla kät visade det sig att ingen enda simisten. Det kritiska tänkan- förslag, den känslosamme verkar i politiker hade ändrat uppfattning det med varningar och risk-be- vanlig ordning helt tappat förmå- om någonting, den nya kunskapen dömningar. Var inns hindren, gan till logik etc. – du kan nästan

BOKRECENSION till trots… svagheterna? gissa i förväg vad respektive per- Gul hatt; solsken och opti- son kommer att säga? Jag kan därför inte motstå att re- mism. Att se möjligheter och för- Då är det här boken för Dig! kommendera också en annan, helt delar med förslagen. Läs och låt dig inspireras – och annorlunda bok. Hade Jarrick an- Grön hatt; grön växtlighet, nästa möte blir ett äventyr! vänt sig av den metod som beskrivs kreativitet. Att tänka utanför i den hade dialogsamtalen kanske ramarna, kläcka nya idéer med Marie Insulander lett till andra resultat? brainstorming. Leg. psykolog, specialist i Blå hatt; himlen, överblick, klinisk psykologi Edward de Bono: ser helheten, analyserar, söker Leg. psykoterapeut, handledare Six Thinking Hats samband och mönster. Under blå – run better meetings, hatt sätts dagordningen, bestäms make faster decisions. vilken ordning hattarna skall an- Penguin Life. Reviderad och om- vändas. Intar ett arbetad version från 1999. Häftad metaperspektiv; 114 kr. tänker om tän- Boken har funnits på svenska, kandet. Summerar men är slut på förlaget. De 177 diskussionen. sidorna är mycket lättillgängliga. Edward de Bono är brittisk lä- Metoden är främst kare och författare som framförallt tänkt som ett har fokuserat på kreativitet, ofta verktyg för att med barn. Han ligger bakom be- höja kvaliteten på greppet lateralt tänkande, till skill- diskussionen när nad från vertikalt tänkande. en grupp skall Författaren utgår från tänkan- komma fram till det som en viktig mänsklig förmå- en lösning på ett ga. Ett problem är att vi försöker speciikt pro- greppa för mycket på en gång och blem (som dei- blandar därmed känslor, fakta, nieras av den blå önskningar, logik och kreativitet hatten). Oftast när vi diskuterar. är det att före- De sex ”tänkarhattarna” är dra att alla del- mera tänkta som symboler än som ger sina tankar konkreta hattar (utom möjligen inom varje in- när barn arbetar enligt metoden, riktning. Erfa- vilket går utmärkt). Syftet är att renhetsmässigt endast använda ett tänkesätt åt har det visat sig gången. att mötestiden Varje hatts färg representerar en fram till beslut viss inriktning i tänkandet. förkortats avse-

266 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se Vårmöte svensk förening för diabetologi tillsammans med endokrinföreningen VÄLKOMMEN TILL GÖTEBORG OCH ENDODIABETES 7-9 MARS 2018

Quality Hotel 11, Göteborg

Mötet arrangeras tillsammans med Svenska Endokrinologföreningen och många gemensamma intresseområden kommer att diskuteras

Programmet kommer att ligga på https://www.endodiabetes.se

ORGANISATIONSKOMMITTÉ FÖR MÖTET Katarina Eeg-Olofsson [email protected] Oskar Ragnarsson [email protected] Jörgen Isgaard [email protected] Johan Svensson [email protected] Ragnhildur Bergthorsdottir [email protected] Björn Eliasson [email protected]

PREL PROGRAM OMFATTAR: • Transition från barn och ungdomar med endokrina diagnoser till vuxenvården • Bästa kosten och behandlingsriktlinjer för kost • Transgender • Kognition vid endokrina sjukdomar • PCSK9 - mekanismer och efekter av dess hämning • Hypoparathyroidism • Aggressiva hypofystumörer • Kardiovaskulär sjukdom vid diabetes: omfattning, behandlingsstudier och riktlinjer • Postrar och fria föredrag Mötet vänder sig till specialister i allmänmedicin, diabetologi/endokrinologi, internmedicin och närliggande specialiteter liksom programpunkter för diabetes- och endosköterskor liksom hela diabetesteamet Hjärtligt välkommen!

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 267 Berzelius symposium no 96 23–25 MAY 2018 IN MALMÖ, SWEDEN Diabetes and the cardiovascular risk challenge – mechanisms, epidemiology and treatment aspects

Organising Committe: Peter M Nilsson, Professor, MD, PhD, Lund University (chair) Margrét Leosdottir, MD, PhD, Lund University Lars Rydén, Senior Professor, MD, PhD, Karolinska Institute (co-chair) Linda Mellbin, MD PhD, Karolinska Institute Carl Johan Östgren, Professor, MD, PhD, Linköping University Stig Attvall, Associate Professor, MD, PhD, Sahlgrenska Academy

More information and registration: http://www.sls.se

268 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se WELCOME TO THE SYMPOSIUM ON Diabetes and the cardiovascular risk challenge – mechanisms, epidemiology and treatment aspects he Berzelius symposia are the most prestigious sci- PRELIMINARY PROGRAM entiic meetings organised by the Swedish Society WEDNESDAY MAY 23RD, 2018 for Medicine (SSM), this time in collaboration with 11.00–13.00 Registration at Jubileumsaulan, Malmö Lunds Universitet (LU) and Karolinska Institutet 13.00 Opening of symposium (KI). he symposium will focus on mechanisms and Stefan Lindgren, President, the Swedish clinical aspects of the relationship between diabetes Society of Medicine Jan Nilsson, and cardiovascular disease in the light of new studies President, HLF Foundation Mona and trial data that expand our understanding of this Landin-Olsson, President SFD, Lund relationship and new treatment possibilities. An ab- Peter M Nilsson, Chair, Organizing stract book and proceedings will be published. committee, Malmö he conference is open to all clinicians and basic science representatives from the Nordic area, interna- Session 1 Deinition of diabetes and origins of car- tional guests and lecturers, as well as representatives diovascular complications from pharma and device manufacturers. Chair: Lena Jonasson, Linköping We hope that you will join us for the Berzelius 13.10–13.30 Diabetes – a disease with many faces. symposium on 23–24th May 2018 and look forward Leif Groop, Malmö to your active participation. here will be a number 13.30–13.50 Lifestyle interventions in the context of oral presentations but also a possibility to submit of precision medicine. Paul Franks, abstracts for poster presentation. Malmö 13.50–14.10 he red blood cell in diabetes. John Welcome to Malmö in May 2018! Pernow, Stockholm 14.10–14.30 he gene-diet-microbiota-metabolism Organising Committee: link. Marju Orho-Melander, Malmö Peter M Nilsson, Professor, MD, PhD, Lund Univer- 14.30 –15.00 Cofee, Posters sity (chair) Margrét Leosdottir, MD, PhD, Lund University Session 2 Epidemiology and trends Lars Rydén, Senior Professor, MD, PhD, Karolinska Chair: Annika Rosengren, Göteborg Institute (co-chair) 15.00–15.20 Life course perspectives. he Finnish Linda Mellbin, MD PhD, Karolinska Institute experience. Johan Eriksson, Helsinki, Carl Johan Östgren, Professor, MD, PhD, Linköping Finland University 15.20–15.40 Early life programming of cardiome- Stig Attvall, Associate Professor, MD, PhD, Sahl- tabolic disease – Global perspectives. grenska Academy Chittaranjan Yajnik, Pune, India 15.40–16.00 Global trends in diabetes and prediabe- Contact information: tes – A threatening scenario. William Peter M Nilsson (chair), [email protected], Knowler, Phoenix, USA phone +46-40-33 24 15 16.00–16.20 Global trends in cardiovascular di- Lars Rydén (co-chair), [email protected], phone +46- sease – increased disease burden, but 70-7292171 not everywhere. Helena Nordenstedt, Camilla Key, Symposium secretariat, camilla.key@ Stockholm med.lu.se, phone +46-40-33 23 01 Annie Melin, Symposium secretariat, annie.melin@ sls.se, phone: +46-8-440 88 78 Session 3 State-of-the-Art 1 Chair: Leif Groop, Malmö 16.20–16.50 Personalized medicine to treat patients with diabetes. Andrew Hattersley, Exe- ter, UK 16.50 –17.00 Best poster abstract 1. 19.00 Welcome Reception at Malmö Town Hall (“Rådhus”)hosted by the Malmö City Council. www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 269 THURSDAY MAY 24RD, 2018 Session 8 The role of guidelines for prevention of Session 4 Diabetes – the clinical spectrum cardiovascular complications Chair: Anna Norhammar, Stockholm Chair: Lars Rydén, Stockholm 08.30–08.50 Micro- and macrovascular complica- 15.10–15.30 European perspective. Francesco Co- tions. John Petrie, Glasgow sentino, Stockholm 08.50–09.10 Importance of postprandial hyperglyca- 15.30–15.50 Transatlantic perspective. William M emia. Antonio Ceriello, Milano Herman, USA 09.10–09.30 Risk factors, omics and the heart in 15.50–16.10 Swedish perspective. Carl Johan Öst- diabetes. Martin Magnusson, Malmö gren, Linköping 09.30–09.50 Lipid disorders in diabetes. Olle Melan- der, Malmö Session 9 State-of-the Art 3 09.50–10.20 Cofee, Posters Chair: Martin Ridderstråle, Malmö 16.10–16.40 Integration of basic and clinical science Session 5 State-of-the-Art 2 for prevention of diabetes complications Chair: Marju Orho-Melander, Malmö – focus on the incretin system. Eber- 10.20–10.50 Lifestyle as the irst step for prevention hard Standl, Germany and treatment of diabetes. Mai-Lis 16.40 –17.00 Best poster abstract 2 and 3 Hellenius, Stockholm 19.00 Symposium Dinner in Malmö (pre-registration is necessary). Session 6 Primary prevention of CVD complications in diabetes FRIDAY MAY 25TH, 2018 Chair: Peter Rossing, Copenhagen Session 10 Quality Assessment and Developments, 10.50–11.10 Glycaemic control. Registers Katarina Eeg-Olofsson, Göteborg Chair: Emil Hagström, Uppsala 11.10–11.30 Lipid control. 08.30–08.50 he National Diabetes Register, Mats Eriksson, Stockholm Sweden. Soia Gudbjörnsdottir, Göte- 11.30–11.50 Blood pressure control. borg Karin Manhem, Göteborg 08.50–09.10 SWEDEHEART, Sweden. Tomas 11.50–12.10 Cardio-renal protection. Per-Henrik Jernberg, Stockholm Groop, Helsinki, Finland 09.10–09.30 SEPHIA Register, Sweden. Margrét 12.10–13.00 Lunch, Posters Leosdottir, Malmö 09.30–09.50 EUROASPIRE . Viveca Gyberg, Stock- Session 7 Secondary prevention of CVD complica- holm tions in diabetes 09.50–10.20 Cofee, Posters Chair: Linda Mellbin, Stockholm 13.00–13.20 he importance of a target driven Session 11 The role of Patients, Relatives and the multifactorial approach. Lars Rydén, Health Care Organisation Stockholm Chair: Mona Landin-Olsson, Lund 13.20–13.40 New lipid-lowering treatment and 10.20–10.40 Swedish Diabetes Association. Fredrik goals. Olov Wiklund, Göteborg Löndahl, Helsingborg 13.40–14.00 Arterial stifness – A new treatment 10.40–11.00 Patient centered health care. Åsa Hörn- target? Peter M Nilsson, Malmö sten, Umeå 11.00–11.20 Primary Health Care. Carl Johan Öst- Pro-Pro debate gren, Linköping 14.00–14.40 Second-line treatment for type 2 dia- 11.20–11.40 he Steno Diabetes Centre Concept. betes – incretin active drugs or SGLT2 Allan Flyvbjerg, Copenhagen, Den- inhibitors as irst choice?! Pro incretin mark Panel debate: Quality of diabetes drugs: Jens Juul Holst, Copenhagen Pro care – New challenges for 2020! Chair: SGLT2 drugs: Jan Eriksson, Uppsala Anders Frid, Malmö 14.40 –15.10 Cofee, Posters 11.40–12.30 Panelists: Karin Wikblad, Fredrik Löndahl, Carl Johan Östgren, Allan Flyvbjerg, Soia Gudbjörnsdottir, Vive- ca Gyberg, Stig Attvall 12.30–12.40 Closing remarks. Lars Rydén and Peter M Nilsson

270 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se POSTERS ague, this can be done at no charge, but please contact You are most welcome to submit a poster abstract to the congress secretariat no later than one week before the meeting! Please register for the meeting before the congress (before 16 May 2018). you send in the abstract! Max length 44 lines with Ti- mes New Roman 12 p. A limited number of abstracts Accommodation will be selected for an oral presentation in the poster Please book your room through this on-line service: sessions. Please send your abstract to annie.melin@ http://bookskane.malmotown.com/en/accommodation sls.se, no later than 15 April, 2018. Poster boards at Your hotel costs are to be settled directly with the ho- the meeting: approx size of 90 cm wide x 120 cm. If tel. All major credit cards are accepted. you already have a poster in larger size, two boards can be used. To and from the airport International lights: Copenhagen (Kastrup) Airport WHEN & WHERE, PAYMENT? is located 10 km west of Malmö. here are trains re- Venue gularly from the airport and the trip to Malmö takes 23–25 May 2018 at the Jubileumsaulan, Medicinskt 20 minutes by train. Step of the train at the second forskningscentrum, SUS Malmö at Jan Waldenströms stop from Copenhagen Airport ”Triangeln”, and take gata 1 in Malmö, Sweden. Registration 10 April 2018, the escalators located at the end of the platform that is deadline for registration. your train arrived at, and you will be 200 m from the entrance to Jubileumsaulan. When & Where, Payment? Domestic lights: Malmö Airport is located nearly 30 Registration for the meeting will start on Wednesday km east of Malmö and the Airport bus takes just over 23rd May 2018 at 11.00. a half an hour to get to the heart of Malmö. http:// www.malmotown.com/en/travel/ Registration fees SEK 2 500 (members of the SSM) SEK 3 000 (non-member) SEK 1 000, students After 10 April, 2018: Late registration: SEK 4500 Symposium dinner on hursday May 24th: SEK 500

The registration fee includes: - Lunch, cofee (Aug 31st and Sept 1st) and the welcome reception on Wednesday May 23rd (pre-reser- Jubileumsaulan – the conference hall vation is necessary). he symposium dinner on hursday May 24th costs SEK 500/person.

Payment he registration fee must be paid before 10 April, 2018, at the latest. Registration after this date may be possible, but at extra cost, as outlined above. Please pay via PayPal or we can send you an invoice for the fee (please state the correct invoice address, reference/ kostnadsställe).

Cancellation Cancellation of your participation has to be made in writing and sent to [email protected] before 10 April, 2018. For cancellations received before 10 Malmö University Hospital Emergency April, 2018, a cancellation fee of SEK 500 will be centre charged. After this date, no refund will be possible. More information and registration Transfer of registration In the event that you are unable to attend the meeting http://www.sls.se/diabetes and would like to transfer your registration to a colle- www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 271 Res med SFD på Diabetes Konferens 2018 - Enkelt Smidigt Tryggt

ATTD i Wien den 13–17 februari 2018

Res med oss till ATTD i Wien! Hotell: Vi erbjuder: Hotel Stefanie • Bokning av hotell med bra läge och standard www.schick-hotels.com/en/hotel-stefanie/index.html • Bokning av reguljärlyg och tåg 3 stationer med U-bahn till Austria Center Vienna • Bästa möjliga pris – valuta för pengarna! • Kongressregistrering – slipp alla krångliga registre- Pris 1.330:-/rum/natt inkl. frukost – Kan avbokas ringssidor! utan kostnad fram till den 09/2, därefter debiteras • Möjlighet att förlänga din vistelse i samband med 100% kongressen • Vi hjälper dig med bokning av medföljande resenär Vi håller inga rum i dagsläget. OBS! det är hög belägg- t ex. sambo/make/maka ning på hotellen under kongressen så vi råder Dig att • Alla kostnader samlade på en och samma faktura vara ute i god tid! eller uppdelade – en del till arbetsgivaren och en del privat om så önskas. Kongressregistrering: • Vi erbjuder avbeställningsförsäkring samt reseför- Early Brird fram till den 19/12 495 € säkring genom Europeiska ERV eller Gouda Regular fee fram till den 31/1 590 € • Vi skräddarsyr din resa utefter just Dina behov Onsite from den 01/2 675 € • Vid frågor eller bokning är kontaktperson Camilla Stattin. Kontakt sker i första hand per mejl camilla. Arvode kongressregistrering 350:- [email protected] Linné Travel Service AB Exempel på lygtider med Austrian Airlines - Box 19097 Arlanda: 104 32 Stockholm 13 feb OS314 Stockholm – Wien 16.50-19.05 Tel: 08-459 16 60 17 feb OS313 Wien – Stockholm 12.50-15.15 Fax: 08-662 08 85 www.linnetravel.se Prisexempel från 2.846:- inkl. skatter, bränsletillägg & bagage

272 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se ADA i Orlando den 21–26 juni 2018

Res med oss till ADA i Orlando! Hotell: Vi erbjuder: DoubleTree by Hilton Orlando at SeaWorld • Bokning av hotell med bra läge och standard http://www.hiltonhotels.com/sv_SE/forenta-staterna/ • Bokning av reguljärlyg och tåg doubletree-by-hilton-hotel-orlando-at-seaworld/ • Bästa möjliga pris – valuta för pengarna! Det tar ca 17 minuter att promenera till Orange • Kongressregistrering – slipp alla krångliga registre- County Convention Center. ringssidor! • Möjlighet att förlänga din vistelse i samband med Pris 2.950:-/ enkelrumt/natt inkl. frukost - kan avbo- kongressen kas utan kostnad fram till den 10/5 därefter debiteras • Vi hjälper dig med bokning av medföljande resenär 100% av kostnaden t ex. sambo/make/maka • Alla kostnader samlade på en och samma faktura Vi håller inga rum i dagsläget. OBS! det är hög belägg- eller uppdelade – en del till arbetsgivaren och en del ning på hotellen under kongressen så vi råder Dig att privat om så önskas. vara ute i god tid! • Vi erbjuder avbeställningsförsäkring samt reseför- säkring genom Europeiska ERV eller Gouda Kongressregistrering: • Vi skräddarsyr din resa utefter just Dina behov Det inns inga uppgifter om kongressregistrering i • Vid frågor eller bokning är kontaktperson Camilla dagsläget. Stattin. Kontakt sker i första hand per mejl camilla. [email protected] Arvode kongressregistrering 350:-

Exempel på lygtider Lufthansa - Arlanda: Linné Travel Service AB 21 juni LH801 Stockholm - Frankfurt 09.55-12.05 Box 19097 21 juni LH464 Frankfurt – Orlando 13.50-17.50 104 32 Stockholm 26 juni LH465 Orlando - Frankfurt 20.05-10.55 Tel: 08-459 16 60 27 juni LH6226 Frankfurt - Stockholm 12.50-14.50 Fax: 08-662 08 85 www.linnetravel.se Prisexempel från 7.750:- inkl. skatter, bränsletillägg & bagage - Mat ingår

www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 273 EASD i Berlin den 01–05 september 2018

Res med oss till EASD i Berlin! Hotell: Vi erbjuder: Louisa´s Place • Bokning av hotell med bra läge och standard www.louisas-place.de/ • Bokning av reguljärlyg och tåg Det tar ca 18 minuter att resa med kommunaltraik • Bästa möjliga pris – valuta för pengarna! till Messe Berlin • Kongressregistrering – slipp alla krångliga registre- ringssidor! Pris 2.170:-/svit deluxe/natt inkl. frukost • Möjlighet att förlänga din vistelse i samband med Kan avbokas utan kostnad fram till den 27/9 därefter kongressen debiteras 100% av kostnaden. • Vi hjälper dig med bokning av medföljande resenär t ex. sambo/make/maka Vi håller inga rum i dagsläget. OBS! det är hög belägg- • Alla kostnader samlade på en och samma faktura ning på hotellen under kongressen så vi råder Dig att eller uppdelade – en del till arbetsgivaren och en del vara ute i god tid! privat om så önskas. • Vi erbjuder avbeställningsförsäkring samt reseför- Kongressregistrering: säkring genom Europeiska ERV eller Gouda Det inns inga uppgifter om kongressregistrering i • Vi skräddarsyr din resa utefter just Dina behov dagsläget. • Vid frågor eller bokning är kontaktperson Camilla Stattin. Kontakt sker i första hand per mejl camilla. Arvode kongressregistrering 350:- [email protected] Linné Travel Service AB Exempel på lygtider - Arlanda:: Box 19097 13 feb OS314 Stockholm – Wien 16.50-19.05 104 32 Stockholm 17 feb OS313 Wien – Stockholm 12.50-15.15 Tel: 08-459 16 60 Fax: 08-662 08 85 Prisexempel från 2.095:- inkl. skatter, bränsletillägg www.linnetravel.se

274 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se ISPAD i Hyderabad den 10–15 oktober 2018

Res med oss till ISPAD i Hyderabad! Hotell: Vi erbjuder: he Westin Hyderabad Mindspacel • Bokning av hotell med bra läge och standard http://www.westinhyderabadmindspace.com/ • Bokning av reguljärlyg och tåg Det tar ca 15 minuter med taxi eller 30 minuter till • Bästa möjliga pris – valuta för pengarna! Hyderabad International Convention Centre (HICC) • Kongressregistrering – slipp alla krångliga registre- ringssidor! Pris 1.710:-/ enkelrumt/natt inkl. frukost • Möjlighet att förlänga din vistelse i samband med Kan avbokas utan kostnad fram till den 8/10 därefter kongressen debiteras 100% av kostnaden. • Vi hjälper dig med bokning av medföljande resenär t ex. sambo/make/maka Vi håller inga rum i dagsläget. OBS! det är hög belägg- • Alla kostnader samlade på en och samma faktura ning på hotellen under kongressen så vi råder Dig att eller uppdelade – en del till arbetsgivaren och en del vara ute i god tid! privat om så önskas. • Vi erbjuder avbeställningsförsäkring samt reseför- Kongressregistrering: säkring genom Europeiska ERV eller Gouda Det inns inga uppgifter om kongressregistrering i • Vi skräddarsyr din resa utefter just Dina behov dagsläget. • Vid frågor eller bokning är kontaktperson Camilla Arvode kongressregistrering 350:- Stattin. Kontakt sker i första hand per mejl camilla. [email protected] OBS! Pass och visum till Indien För att få visum till Indien gäller: Passet måste vara Exempel på lygtider Quatar - Arlanda: giltigt i minst sex månader från ankomstdatum i In- 10 okt QR170 Stockholm – Doha 09.30-16.35 dien. Passet måste även ha minst 2 tomma sidor för 10 okt QR500 Doha – Hyderabad 19.45-02.20 myndigheternas stämplar. Du ansöker själv via denna 15 okt QR501 Hyderabad - Doha 03.30-05.25 länk: https://indianvisaonline.gov.in/evisa/tvoa.html 15 okt QR167 Doha - Stockholm 20.20-22.35 Linné Travel Service AB Prisexempel från 8.519:- inkl. skatter och bränsletillägg Box 19097, 104 32 Stockholm Tel: 08-459 16 60, Fax: 08-662 08 85 www.linnetravel.se www.dagensdiabetes.se DiabetologNytt 2017 Årgång 30 Nr 6-7 275 Kongress- och möteskalender

2017

18-21/10 ISPAD Innsbruck, Austria. www.ispad.org

12-13/10 SFDs höstmöte tillsammans med Svensk Förening för Psykiatri. Malmö. www.jamlikvard.org För info: [email protected]

2018

7-9/3 SFDs vårmöte tillsammans med Svensk Förening för Endokrinologi. Göteborg.

14-17/2 ATTD, Wien, www.attd.kenes.com/2018/keep-me-update

22-26/6 ADA, Orlando, www.diabetes.org

2-5/10 EASD, Berlin, www.easd.com

10-15/10 ISPAD, Hyderabad, Indien www.ispad.org

2019

13-15/3 SFD vårmöte tillsammans med Barndiabetes, Stockholm

REKRYTERA NY MEDLEM TILL SVENSK FÖRENING FÖR DIABETOLOGI Medlemsavgift 200 kr per år. 2017 ingen kostnad. Sänd namn, yrke och adress per e-post till: [email protected]

276 DiabetologNytt 2017 Årgång 30 Nr 6-7 www.diabetolognytt.se