Extended Commentary from the American Diabetes Association

MEETING REPORT

Extended commentary from the American Diabetes Association 2015 meeting Dr Mike Gwilt1 and Dr Caroline Day2 take a closer look at the 75th Annual Scientific Sessions of the American Diabetes Association, Boston, MA, June 4–9, 2015

Introduction ...... 1 Table 1 Awards at ADA 2015 Cardiovascular safety...... 1 Award Recipient PDE5 inhibitors and myocardial National Scientific & Health Care Achievement Awards infarction ...... 2 Banting Medal for Scientific Achievement Award Philipp E Scherer, Texas, USA Outstanding Scientific Achievement Award Pere Puigserver, Massachusetts, USA PCSK9 inhibitors...... 2 Albert Renold Award Richard N Bergman, California, USA DPP4 inhibitors...... 2 Outstanding Achievement in Clinical Diabetes GLP-1 receptor agonists ...... 2 Research Award David M Nathan, Massachusetts, USA Outstanding Physician in Clinical Diabetes Novel insulins ...... 3 Research Award Lori Lafel, Massachusetts, USA Devices ...... 4 Outstanding Educator in Diabetes Award Linda M Delahanty, Massachusetts, USA SGLT2 inhibitors –the newest class ...... 5 Harold Rifkin Award for Distinguished International Service in the Care of Diabetes Karl Eric Morgensen, Denmark Novel antidiabetic mechanisms ...... 5 Kelly West Award for Outstanding Achievement Looking back…and looking ahead ...... 6 in Epidemiology K M Venkat Narayan, Georgia, USA

Professional Interest Group Award Lectures Introduction Edwin Bierman Award (Complications) George L King, Massachusetts, USA The world’s largest diabetes congress Norbert Freinkel Award (Pregnancy) Elisabeth R Mathiesen, Denmark The 75th Annual Scientific Sessions of the Roger Pecorara Award (Foot care) Karel Bakker, The Netherlands American Diabetes Association was held in Richard R Rubin Award (Behavioural Medicine the Boston Convention and Exhibition Center, & Psychology) Robert Anderson, Michigan, USA close to the city’s harbour. The meeting, at- tended by some 18,000 delegates and ac- Association Officers Leadership and Service Recognition claimed as the world’s largest diabetes Charles H Best Medal Janel L Wright congress, opened with 17 ‘Meet The Expert’ Rachmiel Levine Medal for Service David G Marrero sessions, followed by a multiplicity of sym- Banting Medal Samuel Dagogo-Jack posia, oral sessions, and major award lectures Charles Kopke Medal Richard Farber (Table 1). There were also presentations and displays of posters and more than 3000 Administration (FDA) – have been conducted with dulaglutide also offers reassurance abstracts were published in association with over a relatively short time period with regard (1127-P), as do sub-analyses from the meeting.1,2 The abstracts themselves are to opportunity to observe potential cardiovas- SAVOR/TIMI-53 and EXAMINE. available at www.abstractsonline.com/ cular benefit (in the UKPDS it took 6 years for But how representative are these trials for pp8/#!/3699 and most posters can be viewed the cardiovascular benefit of metformin to people with diabetes seen in routine practice? at www.ada.apprisor.org. become apparent). Thus, it is no surprise that An analysis of the eligibility of the general US Check out the data all the cardiovascular outcomes trials pre- population for cardiovascular outcomes trials In the following commentary the references sented to date have shown non-inferiority (as with incretin agents showed that only 28% cited refer to the numbers of the abstracts, opposed to superiority) for major adverse of the current US population with diabetes which also denotes presentation format: for cardiovascular events (MACE). ELIXA and would have qualified for any of the trials example, 1-OR was an oral presentation, 386- TECOS, which were granted an afternoon of (1201-P). In the routine care setting the pro- P was a poster and 2374-PO shows that the back-to-back symposia, also reassuringly portion of patients who would have been material was in published-only format1 whilst showed non-inferiority for MACE. Neither eligible are: 21% for SAVOR (saxagliptin), 9% 1-LB describes a Late Breaking poster.2 For trial demonstrated any suggestion of adverse for CARMELINA (linagliptin), 5% for CAR- ease of reading we have not spelt out trial cardiovascular outcomes, either on their pre- OLINA (also linagliptin), 4% for TECOS acronyms in the text and you can find these specified primary and secondary composite (sitagliptin) and 0.5% for EXAMINE in Table 2. endpoints, the single-outcome components (alogliptin). This is due to the selection of of the composites, or any other exploratory patients at high cardiovascular risk to provide Cardiovascular safety outcomes, including pancreatic cancer, pan- a timely conclusion to an event-driven trial The so-called cardiovascular outcomes trials – creatitis and infection. The cardiovascular and to ensure adequate power to exclude the a requirement of the US Food and Drug outcomes meta-analysis of phase 2/3 trials possibility of adverse cardiovascular outcomes

1 PUBLISHED ONLINE ONLY THE BRITISH JOURNAL OF DIABETES & VASCULAR DISEASE MEETING REPORT

lowering efficacy of evolocumab in patients Table 2 Trial acronyms regardless of glycaemic status and recorded CARMELINA Cardiovascular and Renal Microvascular Outcome Study With Linagliptin in no notable changes in glycaemic status, new Patients With Type 2 Diabetes Mellitus onset diabetes (a concern with statin use) or other key safety issues (258-OR). CAROLINA Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes DPP4 inhibitors DECARTES Durable Effect of PCSK9 Antibody Compared with Placebo Study Sub-analyses explored the effects of saxagliptin or alogliptin on outcomes in sub- DECLARE– Dapagliflozin Effect on CardiovascuLAR Events–Thrombolysis in Myocardial populations from SAVOR (cancer [11-OR], TIMI58 Infarction Study group 58 race/ethnicity [15-LB], lymphocyte count [1239-P], liver enzymes [1227-P]) and EXAM- ELIXA Evaluation of LIXasenatide in Acute coronary syndrome INE (ACE inhibitor use [12-OR], ischaemic outcomes and hospitalisations [13-OR]). There EXAMINE EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome was no cancer signal for DPP4 inhibition and we now know that a lower lymphocyte count SAVOR– Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes is a risk factor for adverse cardiovascular out- TIMI53 mellitus–Thrombolysis in Myocardial Infarction Study group 53 comes. Otherwise, none of these analyses revealed a subgroup with outcomes different SCALE Satiety and Clinical Adiposity – Liraglutide Evidence from the main analyses of the trials. Interest- ingly, data from SAVOR suggested that TECOS Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin sulphonylurea treatment did not promote ad- UKPDS UK Prospective Diabetes Study verse cardiovascular outcomes (504-P), which has long been a source of controversy in diabetes pharmacotherapy. in high-risk patients. Nevertheless, this poster Men receiving testosterone therapy (long- Vildagliptin provided better overall daily raises the question of just how representative acting testosterone undecoanoate) showed a glucose control (as measured by continuous are these trials of the general patient popula- 62% reduction in mortality, despite being at glucose monitoring [CGM]) than sitagliptin tion seen in routine clinics. greater cardiovascular risk at baseline and (942-P) or saxagliptin (1230-P), although DECLARE-TIMI58 is the ongoing cardio- twice as likely to be taking a PDE5 inhibitor vildagliptin and sulphonylureas exerted similar vascular outcomes trial of the SGLT2 inhibitor, (9-LB). Analysis of 42 primary care records effects on glucose variability (1286-P). dapagliflozin. A previously described pooled identified 7,860 men with type 2 diabetes Little was presented this year on analysis (21 phase 2b/3 trials in type 2 dia- diagnosed before 2007. Follow up in 2014 sitagliptin, the first-in-class, but a 12 week betes patients treated with dapagliflozin for showed that PDE5 inhibitor use in men at study showed that this agent given at 50 ≤4 years) demonstrated no excess of MACE high cardiovascular risk was associated with a mg/day reduced circulating CD4+ T cells – with dapagliflozin. New research presented significant reduction in overall mortality and especially the proportion of Th17 and Tregs here showed that there was also no increase the risk of death was reduced by 50% in 432 cells, but numerical data were not provided in cardiovascular events with this agent in a men who had an incident myocardial infarc- (1252-P). With regard to DPP4 inhibition in subgroup of older patients (≥65 years) with tion (7-LB). general, large database studies or meta-analy- cardiovascular disease and hypertension ses provided further evidence of a lack of (15-OR). PCSK9 inhibitors association of DPP4 inhibition with pancreati- A cardiovascular outcome trial with the These drugs represent the next major step for- tis (1703-P). Addition of a DPP4 inhibitor to GPR40 agonist fasiglifam was terminated ward in the management of dyslipidaemia, insulin therapy has again been shown to early due to undue risk of liver toxicity. At reducing in LDL-C in excess of 50%, even improve glycaemic control without additional study termination (mean drug exposure was added to intensive statin treatment. hypoglycaemia or weight gain (1245-P). 221 + 134 days), 3,207 subjects at high car- Evolocumab and alirocumab are the agents New agents in development include diovascular risk had been enrolled and the most advanced in development, and each has gemigliptin (127-LB), retagliptin (1188-P), study’s primary endpoint (composite cardio- received positive opinions from both the teneligliptin (1251-P) and gosogliptin (1269- vascular death, nonfatal myocardial infarction European Medicines Agency and the FDA, so P). Omarigliptin, the first once weekly DPP4 and stroke or hospitalisation for angina) had marketing authorisation is pending. inhibitor improved glycaemic control in Japan- occurred in 40 subjects (2.5%) in each group In a pooled analysis of four phase 3 trials ese patients with type 2 diabetes when used (111-LB). in patients with or without type 2 diabetes, as add-on therapy to metformin, a sulphonyl- treatment for 12 weeks with evolocumab urea, a meglitinide, a thiazolidinedione or an PDE5 inhibitors and myocardial (given by either 2-weekly or monthly injec- α-glucosidase inhibitor (1231-P). infarction tions) induced reduced LDL-C by 57–62% Analysis of five primary care diabetes registers (257-OR). Alirocumab (2-weekly injections) GLP-1 receptor agonists identified 857 men with total testosterone of similarly induced reductions in LDL-C of Duration of action and effects on heart ≤12 nmol/L and free testosterone ≤0.25 59–63% in people with or without type 2 rate nmol/L who were followed for a mean of 5.8 diabetes in the Odyssey Long Term trial It would appear that the GLP-1 agonist class years. Increased mortality was observed in (1296-P). Reassuringly, 12 month data from contains at least two subdivisions, based on men with untreated low testosterone levels. the DESCARTES study affirmed the lipid duration of action: shorter acting agents are

VOLUME 15 ISSUE 3 l JULY/AUGUST/SEPTEMBER 2015 PUBLISHED ONLINE ONLY 2 MEETING REPORT more effective on postprandial glycaemia and GLP-1 agonist plus insulin at baseline in the SCALE Diabetes Trial longer acting agents tend to be more effec- When the GLP-1 agonists were introduced it (307-LB) and improved patient-reported out- tive on fasting plasma glucose. Also, in- was generally thought that they would only comes vs. placebo in this population (2219-P). creased heart rate has always been a concern be effective early in the course of diabetes, Liraglutide may be useful for non-responders with the GLP-1 agonist class. Shorter-acting due to their enhancement of glucose-depen- to bariatric surgery (2233-P, 2560-PO). agents (lixisenatide, exenatide BID) induced dent insulin release. Today, we know that Dual peptide receptor agonists smaller (1–3 bpm) and relatively transient adding a GLP-1 agonist to insulin for a patient HM12525A is a dual GLP-1-glucagon agonist, (1–12 h) increases in heart rate, while longer- with advanced type 2 diabetes will markedly and uses the LAPS technology (described ear- acting agents (liraglutide, exenatide QW and improve glycaemia (especially postprandially), lier) to link versions of these peptides together dulaglutide) exerted larger increases permit substantial reductions in the dose of via a human immunoglobulin Fc protein. (6–9 bpm) that lasted into the night (2566- insulin, limit insulin-induced weight gain (and Phase I data show that the pharmacokinetic PO). A head-to-head comparison of lixisen- often induce weight loss) and reduce the fre- properties of this agent support the once- atide versus liraglutide showed that the latter quency of hypoglycaemia. GLP-1 agonists weekly dosing schedule of its GLP-1 agonist increased sympathetic activation in line with might reduce glucose variability when given relatives (173-OR). MOD-6031, a long-acting effects on heart rate throughout the day, with insulin in patients with type 2 diabetes, preparation of oxyntomodulin (a peptide co- whereas the increase in heart rate and sym- as shown by studies with GLP-1 agonists in- secreted with glucagon that activates both pathetic drive with lixisenatide only occurred volving CGM (167-OR, 1110-P). glucagon and GLP-1 receptors) is in preclinical transiently after dosing (282-OR). There were 25 clinical reports on combi- development, where it has been shown to Efpeglenatide, a very long-acting GLP-1 nations of a GLP-1 agonist with insulin, in- inhibit food intake and induce weight loss agonist, induced smaller increases in heart cluding the fixed-dose combinations (FDCs), (1136-P). rate than liraglutide (278-OR), so there may LixiLan® (lixisenatide + glargine; e.g. 169-OR, Attaching long fatty acid chains to deriv- yet prove to be subdivisions within the longer- 107-LB), and IDegLira® (degludec + liraglu- atives of GLP-1 and GIP can generate full co- acting GLP-1 agonists. Increased heart rate tide) and reports on exenatide QW and BID, agonists at these peptides’ receptors, in mice, was identified as a risk factor for adverse and dulaglutide. It would appear that the sig- with a half-life of about 4–20 hours (2086-P). cardiovascular outcomes many years ago. nal transduction mechanisms following acti- Linking GLP-1 and GIP to Fc proteins also pro- Whether this proves to be an issue with the vation of insulin (glargine in this case) and GLP duces a dual agonist which is effective in pre- longer acting agents (in particular) remains to 1 receptors (lixisenatide) remain entirely sep- clinical models (2350-P). ZP-DI-70 is another be seen. arate, with no cross talk between them dual GLP-1/GIP dual agonist in preclinical Long-acting GLP-1 receptor agonists (1113-P). investigation (2061-P). PB119 has a half-life about 50–70 h, permitting Most presentations on currently approved at least a QW dosing regimen. This long dura- GLP-1 agonists concerned data cuts in special Novel insulins tion of action is due to addition of a long poly- populations, although dulaglutide may have Basal insulins ethylene glycol chain to exenatide (275-OR). modestly improved renal function in type 2 Comparison of the ultra long-acting insulin Efpeglenatide (née HM11260C or LAPSEx- diabetes (1114-P). degludec with glargine was the subject of endin-4) is essentially exenatide attached to GLP-1 receptor agonists in type 1 several presentations which supported the two non-glycosylated immunoglobulin Fc frag- diabetes current usage of degludec. A number of pre- ments, via a flexible polyethylene glycol linker. In insulin-treated type 2 diabetes, addition of sentations focused specifically on Asian This agent has a half-life of about 150 h and is a GLP-1 agonist has reduced weight gain and patient populations. One presentation con- effective weekly (278-OR) or even monthly insulin dose, so that there may be merit in cluded that U200 degludec had a larger effect (105-LB). Efpeglenatide can be co-formulated GLP-1 agonist usage in type 1 diabetes. In the on FPG and a lower incidence of hypogly- with LAPSinsulin (insulin115, based on glargine) LIRA-1 trial liraglutide (1.8mg QD) reduced caemia than standard U100 glargine to make LAPSCombo (172-OR). A “superago- body weight (~ 6 kg versus placebo over 6 (1040-P) – hardly surprising and a comparison nist” mechanism of efpeglenatide involves months) and daily insulin requirement in over- with U300 glargine may have been more retaining GLP-1 receptors on the cell surface for weight, poorly controlled patients with equitable. added efficacy (1116-P) and this agent is diabetes. There was no change in the hypo- The snappily-named ‘Basal insulin lispro thought to have potential as an anti-obesity glycaemia rate or in HbA1c compared with pegylated’ (BIP), was the subject of at least 17 agent in obese non-diabetic people (303-LB). placebo (277-OR). These observations were oral or poster presentations. This agent has a Attachment of elastin-like polypeptides to consistent with those of a similar trial (with liver-preferential action; suppressing endoge- bioactive proteins provides a further way to liraglutide 1.2mg QD) in normal weight nous hepatic glucose production similarly to enhance their duration of action. The length patients (279-OR). However, in another study glargine, but showing less peripheral activity of the polypeptide determines the precise in type 1 diabetes, the addition of liraglutide (89-LB). BIP also elevated some liver enzymes temperature at which a phase transition (1.8mg QD) reduced insulin dose by 20% and during treatment (989-P), which will be a note occurs that causes the molecule to drop out HbA1c by 0.45% (1141-P). Liraglutide has of caution for the future. of solution. Thus, a stable, clear solution in a also been shown to reduce glucose variability Other presentations on BIP included vial at 25°C becomes a slowly-dispersing, under closed loop conditions (220-OR). demonstrations of larger effects on glycaemia long-acting depot in the warmer environment GLP-1 receptor agonists as anti-obesity than glargine in insulin-naïve type 2 diabetes of the subcutaneous tissue. PE1039 is a agents patients (93-OR), type 2 diabetes patients on “super long-acting” analogue of human Liraglutide 3.0 mg is now approved for ther- background oral therapies (984-P), type 2 insulin and PB1023 is a once weekly GLP-1 apeutic use within the management of diabetes patients using a basal-bolus regimen agonist, each based on this technology and obesity. This dose of liraglutide reduced body (985-P) or in type 1 diabetes patients (95-OR, which can be co-administered (168-OR). weight irrespective of body mass index (BMI) 986-P). A pooled analysis revealed a lower in-

3 PUBLISHED ONLINE ONLY THE BRITISH JOURNAL OF DIABETES & VASCULAR DISEASE MEETING REPORT cidence of nocturnal hypoglycaemia with BIP ability for use in pumps and mechanistic loop conditions in type 2 diabetes patients than glargine (988-P). BIP was more effective studies focusing on the contribution of (956-P). PixoTest does away with the need at reducing glycaemic variability than glargine nicotinamide to the therapeutic profile). for a meter entirely, as the patient simply (94-OR), but counter-regulatory hormonal re- The concentrated rapid insulin BIOD-531 uses their smartphone camera to read a test sponses to BIP and glargine were similar (993- was studied in type 2 diabetes patients strip contained within a box physically at- P). Other studies focused mainly on binding (92-LB, 977-P) and pump users (1016-P). tached to the lancet (176-OR). kinetics, pharmacokinetic/pharmacodynamic Other new rapid insulins featured were Previous studies (e.g. STAR-3) have shown studies, dosing flexibility and effects on lipids. Ultra-Rapid BioChaperone Insulin Lispro (BC optimising sensor-augmented pump (SAP) The therapeutic effect of glargine U300 LIS), which was faster acting than lispro therapy requires patients to wear a glucose was the subject of 10 presentations, including (979-P), and it was reported that the sensor for most of the time, and a recent demonstrations of better sustained glycaemic biosimilar, SAR342434, showed bioequiva- study in newly diagnosed type 1 diabetes pa- control with less hypoglycaemia compared lence with Humalog insulin (1022-P). tients has added further confirmation, with with U100 glargine (98-OR, 987-P) or NPH or Inhaled insulins frequent users of CGM having significantly BID glargine (1021-P). Meta-analyses sup- The limited long-term safety data for the lower HbA1c (1.1%) at 1 year than infrequent ported a superior therapeutic profile of U300 newly-approved Technosphere® insulin CGM users (355-OR). The Medtronic Thresh- glargine versus U100 glargine, premix or NPH (Afrezza®) led the authors of a meta-analy- old Suspend feature, an important intermedi- insulin (99 OR, 1030-P). Other studies strati- sis to conclude that this product should be ate technology between SAP and closing the fied datasets for age, gender, BMI or diabetes reserved for “non-pregnant, non-smoking, loop, suspends insulin delivery for up to 2 duration. adult patients with diabetes, free of pul- hours if hypoglycaemic blood glucose levels Several weekly basal insulins are in devel- monary disease, who are needle-phobic and are imminent. Frequent use of Threshold Sus- opment, including Insulin115 (also known as would otherwise delay initiating or intensi- pend increased blood glucose during the day HM14270) which reported preclinical and fying insulin” (96LB). However it would ap- by about 4 mg/dL in the Aspire In-Home pharmacokinetic modelling data (96-OR, 86- pear unnecessary to restrict its use in people study, which was considered a small price to LB). PE0139, which is insulin attached to an with upper respiratory tract infections, as pay for the reduced frequency of hypogly- elastin-like polypeptide, displayed a peakless these do not affect the absorption of this caemia reported with this feature (1053-P). weekly profile in type 2 diabetes patients inhaled insulin (94-LB). A cohort of 250 pump users was very sat- (100-OR). AB101 (a microsphere formulation Dance-501 is an aerosolised human in- isfied with this technology (most patients of pegylated human insulin) produced a slow sulin with similar within-subject variability to were using SAP) and most found CGM useful. onset and sustained insulin levels in several lispro (978-P). Variations in particle size within Interestingly, very few of 350 pump users species and did not cause acute hypogly- the aerosol do not influence within-subject found smartphone (<10%) or (especially) web caemia (97-OR). The glargine analogue, Elin- variability in the response to this novel insulin apps (<6%) useful (1739-P). However, in a H, is comprised of glargine with a histidine (1028-P). 12 week uncontrolled study in poorly con- moiety attached to the B chain; this modifica- Oral insulin trolled type 2 diabetes, use of a smartphone- tion has extended the duration of action to at Ingestion of the oral insulin ORMD-0801 by based diabetes care system (Bluetooth least 36 hours, compared with 20–24 hours type 1 diabetes patients before meals re- connection to a meter, digital food diary and with glargine (84-LB). duced prandial insulin requirements and activity monitor) reduced HbA1c by about Biosimilar insulins positively impacted on fasting glucose, 0.5%, but the magnitude of improved gly- Of 19,600 insulin-treated Asian patients in though no benefit was reported for post- caemic control correlated with the frequency 11 countries, 7% were using biosimilar in- prandial glucose (1058-P). Oral insulin is hy- of glucose monitoring (174-OR). sulin, with usage ranging from 6.5% in pothesised to partially restore insulin Closing the loop Vietnam to 60% in India. These patients signalling in the liver, before dilution of the In a randomised crossover study, 12 pump- were mainly younger, heavier and poorly insulin in the general circulation. treated adolescents with type 1 diabetes controlled. Biosimilar use was associated completed 7 days of free living under closed with higher insulin dose and HbA1c in a Devices loop or SAP conditions (using a bolus calcu- multivariate analysis (1023-P). Meters and pumps lator for self administration of prandial Studies of the in vitro properties of the A comparison of 17 blood glucose meters boluses). Closed loop control was more glargine biosimilar LY glargine (LY LY2963016) found wide variations in performance with effective than SAP (p<0.001) at increasing did not show any significant differences with seven meeting the ISO15197: 2003 criteria the time within glycaemic target range, glargine itself (1033-P) and antibody and only two meeting the updated 2013 time in the hypoglycaemic range was low responses in people with type 1 and type 2 criteria. There was no correlation between and similar with both devices, daily insulin diabetes were also similar to those receiving accuracy and cost of test strip (72-LB). A dose was similar, but there was a small glargine (1029-P). In euglycaemic clamp stud- comparison of six meters drew similar con- increase in daily basal insulin dose (p<0.001) ies in non-diabetic subjects, the glargine clusions but suggested that the magnitude in patients using closed loop (221-OR). biosimilar MK-1293 showed bioequivalence of variation may not be clinically significant, Nineteen children aged 6-11 years at a with glargine (1026-P). according to their performance on the Con- diabetes camp were treated for 5 days using Prandial insulins sensus Error Grid (944-P). Elsewhere, the a bihormonal insulin:glucagon closed loop Most of the interest surrounding rapid act- Contour® Next USB, Freestyle InsuLinx® and system and 5 days with an insulin pump with ing insulin related to the absorption prop- OneTouch® Verio™ IQ systems met the monitoring using CGM (220-OR). Subjects erties of Faster Acting Insulin Aspart ISO15197: 2013 criteria (938-P). The Ab- selected their own meals and participated in (general pharmacodynamic studies, effects bott Navigator® II and Dexcom G4® meters all camp activities. The closed loop system de- in young people with type 1 diabetes, suit- performed identically under open or closed livered lower mean glucose values, greater

VOLUME 15 ISSUE 3 l JULY/AUGUST/SEPTEMBER 2015 PUBLISHED ONLINE ONLY 4 MEETING REPORT time within the target glycaemic range and appeared to reduce insulin levels by increasing diabetes with the presentation of seven reduced frequency of oral carbohydrate insulin clearance, as shown by increased cases of euglycaemic (blood glucose 90– for hypoglycaemia (once in 1.1 versus 1.8 C-peptide:insulin ratio, in patients with type 233 mg/dL 10.6–12.9 mmol/L) DKA in days). 2 diabetes (1223-P). women, aged 22–33 years. Other cases of In adults with type 1 diabetes, setting a The clinical development of luseogliflozin euglycaemic DKA in type 1 diabetes have closed loop system to establish normogly- (e.g. 948-P) and ipragliflozin (e.g. 1203-P, been reported with canagliflozin but this caemia before wake-up time improved day- 1236-P) continues, with an appearance from was associated with failure of an insulin in- time glucose control and reduced the the even newer agents, henagliflozin (1229- fusion system (932-P), and in a patient for frequency of hypoglycaemia compared with P) and ertugliflozin (2605-PO). New, and un- whom dapagliflozin plus liraglutide was SAP in both outpatients and home settings named, dual SGLT1/SGLT2 inhibitors were added to insulin (130-LB). In the sympo- (224-OR). The Zone-MPC closed loop control described, but with preclinical data only sium similar cases were presented for two system also demonstrated positive results in (2073-P, 2610-PO). men and a woman, all with insulin–treated outpatients, with increased time in range and Fixed-dose combinations of SGLT2 in- type 2 diabetes who had undergone recent less time at <70 mg/dL (225-OR). A number hibitors are coming and a number of presen- surgery. of other studies explored different aspects of tations supported the use in combination of It is perhaps noteworthy that glycaemic closed loop control, such as the benefits of dapagliflozin + saxagliptin, linagliptin + em- control improved with a SGLT2 inhibitor while using the system overnight only for 2 months pagliflozin. The use of lower doses in these treatment insulin doses were reduced. These (940-P), or the benefit for dual- versus single- combinations appears to reduce the risk of agents lower glycaemia via an insulin-inde- hormone closed loop devices in reducing genital infections (1208-P). pendent mechanism, but insulin is necessary hypoglycaemia risk during exercise (1059-P). SGLT2 inhibitors in type 1 diabetes for the normal metabolism of glucose and Patients were generally impressed with the The insulin independent mechanism of ac- much more. Therefore, assessment for ke- closed loop, noting that it is “a game tion of SGLT2 inhibitors has led to interest tones should be undertaken in insulin-requir- changer” (66-LB). in their use in type 1 diabetes. The EASE-1 ing euglycaemic patients who present with Other devices trial showed that empagliflozin (2.5mg; any symptoms suggestive of DKA. A discus- Devices intended to improve insulin delivery 10mg; 25mg) for 28 days in type 1 diabetes sion of euglycaemic DKA by Peters et al, fea- include InsuPad®, an injection site warming reduced HbA1c and body weight and re- turing the cases described above, has now device and Paq®, is a subcutaneous insulin duced insulin doses (1213-P), and use of been published.3 infusion device that delivers pre- CGM showed that addition of empaglifozin programmed basal rates and boluses at the reduced glucose exposure and variability Novel antidiabetic mechanisms push of a button. (1241-P). Several novel glucose lowering agents are InsuPad® has been shown to improve in- According to a retrospective analysis, the advanced in development. Those not dis- sulin kinetics and pharmacodynamics in the addition of dapagliflozin to liraglutide and in- cussed previously are noted below and controlled conditions of clinical trials (1069-P), sulin in type 1 diabetes reduced HbA1c, promising agents in preclinical development and more recently it demonstrated similar plasma glucose and weight; carbohydrate in- are shown in Table 3. performance in the ‘real world’ (1057-P). In take was increased but insulin dose was un- Saroglitazar, a dual PPARα/γ activator, type 2 diabetes patients, 12 weeks’ use of changed (130-LB). An algorithm was has been approved in India for the treatment Paq®, delivering insulin as intended, reduced proposed for adapting insulin doses in da- of type 2 diabetes patients in whom it has ® HbA1c by ~1.7% from the pre-Paq values pagliflozin-treated patients with type 1 dia- shown improvements in glucose and lipid me- when patients were receiving multiple daily betes, by using observed urinary glucose tabolism (703-P, 704-P, 126-LB). It has also injections (1062-P). excretion to estimate the insulin:carbohydrate shown benefit in people with non-alcoholic Endobarrier® is an implantable (and ratio (1279-P). fatty liver disease (NAFLD), improving liver en- removable) liner that prevents upper intestinal Sotagliflozin (LX4211), a dual SGLT1/2 in- zymes and indices of glycaemia (712-P). food absorption. One year of Endobarrier® hibitor which has previously been shown to Combination treatment with saroglitazar and use in obese patients with poorly controlled benefit type 2 diabetes, has now shown exenatide appears promising for the manage- type 2 diabetes reduced weight (by about 13 promise in the treatment of type 1 diabetes. ment of NAFLD (134-LB). kg) and improved multiple indices of gly- Sotagliflozin (400mg QD) reduced post- A dose-ranging study of imeglimin, a re- caemic control (967-P). prandial hyperglycaemia and HbA1c and storer of mitochondrial function which im- mealtime insulin dosage and body weight. proves insulin secretion and action, in obese SGLT2 inhibitors – the newest class CGM throughout the study also showed that type 2 diabetes patients has identified 1500 The evidence base deepens patients spent 62% more time within their mg BID as the optimum dose for phase 3 The volume of data is increasing for this target glucose range and 25% less time with trials. Imeglimin was well tolerated and did newest class of oral antidiabetic agents. hyperglycaemia and did not increase the inci- not promote hypoglycaemia or weight gain Weight loss with dapagliflozin is maintained dence of hypoglycaemia. Mild nausea was the (1169-P). during up to 4 years of treatment (103-OR) commonest side-effect, all without additional LEZ763, a GPR119 agonist, increased and no increased risk of MACE has been hypoglycaemia. glucagon (p<0.05), active GLP-1 (p<0.05), GIP Full? seen in a pooled analysis of trials of da- SGLT2 inhibitors and euglycaemic (p<0.05) and PYY (p<0.05) following a test pagliflozin for ≤4 years (15-OR, see earlier). diabetic ketoacidosis (DKA) meal after 4 weeks of treatment in this dose Evidence is now emerging that long-term A symposium presentation on glycaemic ranging study in type 2 diabetic patients. treatment with a SGLT2 inhibitor may be control in women drew to attention the off- Postprandial glucose was not significantly renoprotective in diabetes (e.g. 107-OR). label use of canagliflozin (the first SGLT2 in- decreased (122-LB). Dapagliflozin (combined with saxagliptin) hibitor to be approved in the USA) in type 1 HMS5552, a glucokinase activator

5 PUBLISHED ONLINE ONLY THE BRITISH JOURNAL OF DIABETES & VASCULAR DISEASE MEETING REPORT

duration of action. In addition, we will soon Table 3 Summary of novel compounds with glucose-lowering efficacy in preclinical see how the new class of PCSK9 inhibitors im- studies pacts on cardiovascular outcomes in at-risk Agent Proposed mechanism of action Abstract populations, including people with diabetes. These agents have the potential to finally CmpdA A dual SGLT1/SGLT2 inhibitor 2073-P answer the question of just how low should Unnamed A novel dual SGLT1/SGLT2 inhibitor 2610-PO we go with LDL-C? LGLS120-A A GPR120 agonist 1284-P Another theme has been the steady ad- vance of pharmacotherapy normally associ- KBP-042 A dual amylin-calcitonin receptor agonist 1098-P ated with type 2 diabetes into type 1 diabetes PBI-4547 An antifibrotic compound 552-P populations. Incretin drugs and SGLT2 inhibitors potentially bring a range of beneficial PBI4050 An antifibrotic/inflammatory compound 1166-P effects on glucose control, insulin doses and AJS1669 A muscle glycogen synthase activator 2016-P body weight in this population. But, the un- welcome appearance of euglycaemic DKA BTI-320 A glucommanan-based inhibitor of carbohydrate digestion 974-P will provide a note of caution with regard to MTBL0036 A mitochondrial uncoupler in the liver 1190-P the extent of lowering of the insulin dosage when adding-in SGLT2 inhibitors. TP70 A tricyclic pyrone compound with acyl CoA-cholesterol acyltransferase inhibitor activity 1205-P Looking further ahead, there are plenty of novel mechanisms making their way through JWU-A021 A TRPA1 calcium channel activator which stimulates late preclinical development, and into phase GLP-1 release 112-LB 1 and 2 trials. These drugs will provide plenty GMC-252 A conjugate of an anti-inflammatory and an antioxidant of interest at future meetings and perhaps the (diflunisal + N-acetylcysteine) 2601-PO next leaps forward in diabetes pharmacotherapy. CNX-013-B2 A heterodimer selective rexinoid (also has potential to reduce progression of diabetic complications) 120-LB Conflict of interest and disclaimer Unnamed An insulin degrading enzyme inhibitor 1101-P The authors have previously provided med- X-MetA An allosteric anti-insulin receptor antibody 1103-P ical communications/education services to some of the companies whose products are Unnamed A monoclonal anti-aP2 antibody (with particular benefit for described in this report. No funding has treating fatty liver disease) 108-LB been received for preparation of this report. 2,4- dintrophenol A controlled-release mitochondrial protonophore; also has This report reflects the authors’ personal (CRMP) potential in NAFLD, NASH and severe lipodystrophy 113LB impressions of the meeting and does not necessarily reflect those of the presenters or the ADA. targeting both pancreas and liver, has been Looking back…and looking ahead References shown to enhance glucose-stimulated insulin As we look back on this large and hugely 1. American Diabetes Association, 75th Scien- secretion and suppress hepatic glucose pro- varied meeting, it is time for a few final re- tific Sessions. Abstracts. Diabetes 2015; duction in phase 1 studies in patients with flections. Perhaps the “positive negative” 64 suppl 1:A1-900. (http://diabetes.dia- type 2 diabetes. The drug was well tolerated cardiovascular outcomes with sitagliptin betesjournals.org/content/64/Supplement_1) and did not produce any serious or severe ad- (TECOS) and lixisenatide (ELIXA) will have 2. American Diabetes Association, 75th Scien- verse events (1165-P, 1167-P). the greatest impact on how we see the field tific Sessions. Late Breaking Abstracts. Three glucagon receptor antagonists evolving. Was this the time that many of us Diabetes 2015;64 suppl 1A:LB113. (http://di- have yielded data which support further devel- realised that these are cardiovascular safety abetes.diabetesjournals.org/content/suppl/20 opment. LGD-6972 has shown promise in 15/06/03/64.Supplement_1.DC1/2015_ADA studies, first and foremost, and were never _LB_Abstracts.pdf) non-diabetic subjects (1193-P); and PF-0629187 designed to show the way forward to an 3. Peters AL, Buschur EO, Buse JB et al. (1202-P) and LY2786890 (106-LB) both re- improved cardiovascular outlook in type 2 Euglycemic diabetic ketoacidosis: a potential duced plasma glucose in phase 1 trials in type diabetes? Will a new generation of trials complication of treatment with sodium- 2 diabetes patients, producing pharmacokinetic explore the potential of these novel drugs glucose cotransporter 2 inhibition. Diabetes parameters that support once-daily dosing. to prevent adverse cardiovascular out- Care, ahead of print, June 15; 2015. A vaccine against interleukin-1β in- comes, once the safety-driven needs of the http://dx.doi.org/10.2337/dc15-0843 tended for use in the management of type 2 FDA have been met? diabetes has demonstrated glucose-lowering Elsewhere, we saw some reassuring data 1 Submissions Editor, BJDVD. efficacy in a phase 1 trial (1100-P). for other incretin-based agents. The absence 2 Visiting Fellow, Diabetes Group, The ApoA-I Inducer, RVX-208, increased of new safety concerns with these drugs was Aston University, Birmingham, B4 7ET, UK HDL particle size and reduced both hepatic certainly welcome, and there are still more Correspondence to: [email protected] glucose production and peripheral glucose outcomes trials to look forward to with the http://dx.doi.org/10.15277/bjdvd.2015.037 disposal whilst delaying the appearance of newer agents. Indeed, there is a long list of Br J Diabetes Vasc Dis 2015;15:1-6 online only glucose in the circulation of subjects with new incretin-based agents in advanced devel- impaired glucose tolerance (1189-P). opments, including agents with a very long

VOLUME 15 ISSUE 3 l JULY/AUGUST/SEPTEMBER 2015 PUBLISHED ONLINE ONLY 6