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MRIGTEAIS RG N REGIMENS AND DRUGS THERAPIES: EMERGING

Diabetes Care 1

fi W. Timothy Garvey,1 Ef cacy and Safety of Liraglutide Andreas L. Birkenfeld,2,3,4 Dror Dicker,5,6 Geltrude Mingrone,4,7,8 Sue D. Pedersen,9 3.0 mg in Individuals With AltynaiSatylganova,10 DortheSkovgaard,10 Danny Sugimoto,11 Camilla Jensen,10 and Overweight or and Type 2 Ofri Mosenzon12 Diabetes Treated With Basal : The SCALE Insulin Randomized Controlled Trial https://doi.org/10.2337/dc19-1745

1Department of Nutrition Sciences, The Univer- sity of Alabama at Birmingham and the Birming- ham VA Medical Center, Birmingham, AL 2Department of Diabetology, Endocrinology, and OBJECTIVE Nephrology, Eberhard Karls University Tubingen,¨ Tubingen,¨ Germany Most individuals with also have obesity, and treatment with some 3Institute for Diabetes Research and Metabolic diabetes medications, including insulin, can cause further weight gain. No approved Diseases, Helmholtz Centre Munich at the Uni- chronic weight-management medications have been prospectively investigated in versity of Tubingen,¨ Tubingen,¨ Germany 4Division of Diabetes and Nutritional Sciences, individuals with overweight or obesity and insulin-treated type 2 diabetes. The Faculty of Life Sciences and Medicine, King’s primary objective of this study was to assess the effect of liraglutide 3.0 mg versus College London, London, U.K. placebo on weight loss in this population. 5Internal Medicine D, Hasharon Hospital, Rabin Medical Center, Petah Tikva, Israel RESEARCH DESIGN AND METHODS 6Sackler School of Medicine, Tel Aviv University, d Tel Aviv, Israel Satiety and Clinical Adiposity Liraglutide Evidence (SCALE) Insulin was a 56-week, 7Fondazione Policlinico Universitario Agostino randomized, double-blind, placebo-controlled, multinational, multicenter trial in Gemelli IRCCS, Rome, Italy individuals with overweight or obesity and type 2 diabetes treated with basal insulin 8Universita` Cattolica del Sacro Cuore, Rome, Italy 9 and less than or equal to two oral antidiabetic drugs. C-ENDO Diabetes and Endocrinology Clinic, Calgary, Alberta, Canada 10 RESULTS A/S, Søborg, Denmark 11Cedar Crosse Research Center, Chicago, IL Individuals were randomized to liraglutide 3.0 mg (n 5 198) or placebo (n 5 198), 12Diabetes Unit, Department of Internal Medi- combined with intensive behavioral therapy (IBT). At 56 weeks, mean weight cine, Hadassah Hebrew University Hospital, Jer- change was 25.8% for liraglutide 3.0 mg versus 21.5% with placebo (estimated usalem, Israel treatment difference 24.3% [95% CI 25.5; 23.2]; P < 0.0001). With liraglutide Corresponding author: W. Timothy Garvey, [email protected] 3.0 mg, 51.8% of individuals achieved ‡5% weight loss versus 24.0% with placebo P < Received 30 August 2019 and accepted 13 Feb- (odds ratio 3.41 [95% CI 2.19; 5.31]; 0.0001). Liraglutide 3.0 mg was associated ruary 2020 with significantly greater reductions in mean HbA , mean daytime values, 1c reg. no. NCT02963922, clinicaltrials and less need for insulin versus placebo, despite a treat-to–glycemic target protocol. .gov. More hypoglycemic events were observed with placebo than liraglutide 3.0 mg. No This article contains Supplementary Data online at new safety or tolerability issues were observed. https://care.diabetesjournals.org/lookup/suppl/ doi:10.2337/dc19-1745/-/DC1. CONCLUSIONS © 2020 by the American Diabetes Association. In individuals with overweight or obesity and insulin-treated type 2 diabetes, Readers may use this article as long as the work is liraglutide 3.0 mg as an adjunct to IBT was superior to placebo regarding weight loss properly cited, the use is educational and not for profit, and the work is not altered. More infor- and improved glycemic control despite lower doses of basal insulin and without mation is available at https://www.diabetesjournals increases in hypoglycemic events. .org/content/license. Diabetes Care Publish Ahead of Print, published online March 5, 2020 2 Liraglutide and Insulin: SCALE Insulin Trial Diabetes Care

Obesity is a chronic, progressive disease 1.8 mg and 3.0 mg in individuals with Participants (1) associated with multiple complications overweight or obesity and diabetes trea- Eligible individuals were aged $18 years that, individually and in combination, con- ted with less than or equal to two oral with a BMI of $27 kg/m2, stable body fermorbidityand mortalityrisk(2).Therisk antidiabetic drugs (OADs) but excluded weight (maximum 5 kg self-reported of developing type 2 diabetes increases insulin-treated individuals. In this previ- weight change within 90 days before with adiposity and increasing BMI (3,4), ous study, weight loss of 4.7% and 6.0% screening), diagnosed with type 2 dia- and the global rise in the prevalence of this was observed with liraglutide 1.8 mg and betes with an HbA1c $6.0 to #10% (42–86 diseasecloselyfollowsthatofobesity(5,6). 3.0 mg, respectively, versus 2.0% with mmol/mol) at screening and receiving In turn, obesity in individuals with type 2 placebo (19). While liraglutide 1.8 mg is stable treatment with any basal insulin diabetes can exacerbate deterioration of indicated in combination with insulin for ($90 days; no requirement for minimum glycemic control (7). diabetes treatment, liraglutide 3.0 mg or maximum dose), and lessthan or equal There is substantial evidence that combined with insulin for weight man- to two OADs. Individuals were excluded if weight-loss interventions can lower blood agement has not previously been stud- they had type 1 diabetes, recurrent se- glucose (BG) levels, and, although weight ied. Furthermore, to our knowledge, no vere hypoglycemic episodes within the loss remains a key recommendation in medications approved for chronic weight last year, or use of dipeptidyl peptidase-4 diabetes guidelines (8–10), it is frequently management have been prospectively inhibitors, GLP-1 receptor agonists, bolus poorly implemented (11). Type 2 diabe- investigated in individuals with over- insulin, or medications known to induce tes is a progressive disease, and despite weight or obesity and insulin-treated significant weight change in the previous improved oral and injectable glucose- type 2 diabetes. 90 days. Other exclusion criteria included a lowering agents available today, many Thecurrentstudyaimedtoevaluatethe recent history of cardiovascular event, his- individuals with long-standing type 2 di- efficacy and safety of liraglutide 3.0 mg tory of medullary thyroid carcinoma or abetes eventually require insulin (12). for in individuals multiple endocrine neoplasia type 2, preg- Weight gain following initiation of in- with overweight (BMI $27 kg/m2)or nancy, breast-feeding, or intention to be- sulin or (SUs) is common, obesity (BMI $30 kg/m2) and type 2 di- come pregnant, or a history of . with increases of ;4 kg often observed abetes treated with basal insulin and up to with insulin and ;2 kg with SUs (13). two OADs. Study Design Given that insulin use is associated with SCALE Insulin was a 56-week, random- weight gain (14), weight management in RESEARCH DESIGN AND METHODS ized,double-blind,placebo-controlled,mul- individuals with coexistent obesity and Study Overview tinational, multicenter trial (Supplementary type 2 diabetes requiring insulin is par- SCALE Insulin (NCT02963922) was con- Fig. 1). A total of 396 individuals were ticularlychallenging.Thispopulationwould ducted from February 2017 to September randomized centrally using an interactive benefit from greater availability of phar- 2018 at 53 sites globally. The trial protocol voice/web response system, to receive macotherapeutic agents that address obe- was approved by local ethics committees either liraglutide 3.0 mg or placebo (1:1) sity. Accordingly, the American Association or institutional review boards, and the as adjunct to IBT. Individuals treated with of Clinical Endocrinologists diabetes guide- trial was conducted in accordance with SUs were stratified between the two lines, Endocrine Society obesity guidelines, the principles of the Declaration of Hel- arms. Liraglutide 3.0 mg or placebo was and the latest European Association for the sinki and International Council for Har- administered once daily by subcutane- Study of Diabetes/American Diabetes As- monisation of Technical Requirements for ous injection. During the first 4 weeks sociation (ADA) consensus advise that Pharmaceuticals for Human Use (ICH) postrandomization, the dose was esca- the effect on weight should be consid- Good Clinical Practice guidelines (20). lated by 0.6 mg weekly to reach the ered when choosing diabetes treatment The sponsor, Novo Nordisk A/S, devel- maintenance dose of 3.0 mg. A 4-week (8–10,15), and given their glucose- and oped the study protocol, planned and follow-up period was included after the weight-lowering effects, -like performed the statistical analyses, pro- 56-week treatment period. To promote 1 (GLP-1) receptor agonists have vided editorial and writing assistance, individual retention and improve data an advantage over many glucose-lowering and provided the trial medications. quality, individuals were permitted to agents in this regard. stop and restart the study drug, without Liraglutide is an analog of GLP-1 and in Study Objective re-escalating the dose, or with re-escalation doses up to 1.8 mg is approved for use in The primary objective was to confirm if three consecutive doses had been missed. combination with insulin (16). It is also superiority of liraglutide 3.0 mg versus approved as a fixed-ratio combination placebo, as an adjunct to intensive be- IBT with (17), as an adjunct havioral therapy (IBT), on weight-loss IBT consisted of a hypocaloric diet, in- to diet and exercise for type 2 diabetes efficacy in individuals with overweight or creased physical activity, and behavioral treatment. Liraglutide 3.0 mg (18) is ap- obesity and type 2 diabetes treated with therapy delivered in frequent counseling proved for chronic weight management basal insulin and less than or equal to two sessions and is described in detail else- in individuals with overweight or obesity OADs. Secondary objectives aimed to where (21) and the Supplementary Data. and has been investigated in individuals investigate the liraglutide 3.0 mg effects Individuals attended a total of 23 individ- with type 2 diabetes as part of the Satiety on other relevant efficacy end points and ual or group counseling sessions during and Clinical AdipositydLiraglutide Evi- to establish the safety and tolerability of the 56-week period, deliveredbyaregis- dence (SCALE) phase 3a program. SCALE liraglutide 3.0 mg versus placebo, as an tered dietitian or similarly qualified health Diabetes was a 56-week trial of liraglutide adjunct to IBT. care professional. care.diabetesjournals.org Garvey and Associates 3

Concomitant baselinetoweek56inwaistcircumference, To estimate the intervention effect, the It was recommended that, after random- HbA1c, fasting plasma glucose (FPG), SF-36 treatment policy estimand (primary esti- ization and at the investigator’s discre- version 2.0 acute, physical functioning score, mand) was defined for each efficacy end tion, individuals should reduce their dose and Impact of Weight on Quality of Life-Lite point. The treatment policy estimand eval- of SUs by 50% to lower the likelihood of for Clinical Trial Version (IWQOL-Lite for CT), uated the effect of liraglutide 3.0 mg versus SU-induced . In individuals physical function domain (five-items) score. placebo at week 56 for all randomized with HbA1c #8% (64 mmol/mol) at ran- Key supportive end points were change individuals, regardless of premature dis- domization, it was recommended to re- from baseline to week 56 in total daily continuation of trial product. This estimand duce the dose of basal insulin by 15–20% insulindose(units),meandaytimeglucose reflects the intention-to-treat principle as owing to anticipated glycemic improve- value (based on seven-point SMBG val- definedintheICHE9.Missingvaluesat ments. Insulin doses were adjusted based ues), systolic and diastolic blood pressure, week 56 were imputed from the placebo on self-measured BG (SMBG) values to lipids, the SF-36 physical component sum- arm using a jump-to-reference multiple- ensure that similar levels of fasting glu- mary, mental component summary and imputation approach based on 100 itera- cose were maintained between the two subdomains, the IWQOL-Lite for CT sub- tions of the data set (23). arms, regardless of background medica- domains, and the weight-related sign and For the coprimary end points and con- tion (Supplementary Table 1). In individ- symptom measure total score. Addition- firmatory secondary end points, the trial uals using once-daily basal , weekly ally, two composite end points of HbA1c product estimand (secondary estimand), adjustments were based on the mean of ,7% (53 mmol/mol) plusweight loss $5% based on a mixed model for repeated three prebreakfast SMBG values with a and HbA1c ,7% (53 mmol/mol) plus weight measurements, evaluated the treatment target range of 4 to 5 mmol/L (71–90 loss $5% plus no documented symptom- effect of liraglutide 3.0 mg versus placebo mg/dL). In individuals using twice-daily basal atic hypoglycemia were prespecified. A at week 56 for all randomized individuals insulins, adjustment was based on the post hoc analysis of the change in the seven- with the assumption that all individuals mean of three prebreakfast and predinner point SMBG profile was also carried out. had remained on trial product for the SMBG measurements. Basal insulin dose Safety was assessed by adverse events entireplanned trial duration, using assess- was not to exceed the entry dose within (AEs)andhypoglycemicepisodes,physical ments only from individuals who were the first 5 weeks. Furthermore, the initi- examination, resting pulse, electrocardio- taking the randomized treatment until ation of bolus insulin was permitted after gram, andlaboratory measurements. Two end of trial or at first discontinuation (see the 5-week period and only after optimi- different observation periods were used: Supplementary Data for detailed descrip- zation of basal insulin dose. The type and the on-drug period, used for all safety end tion). The treatment policy and trial prod- dose of other OADs were kept constant points, with the exception of neoplasms, uct estimands correspond to the updated throughout the trial, unless unacceptable for which the in-trial period was used. The ICH GoodClinicalPracticeregulatoryguide- hypoglycemia occurred that could not be in-trial period included time from ran- lines on quantifying treatment effects of managedbyareductionofbasalinsulin. domization to the final follow-up visit (or medications (24). date of last contact) regardless of trial Continuous primary and secondary end Hypoglycemia Classification product discontinuation. On-drug safety points were analyzed using ANCOVA with Hypoglycemia was defined using the ADA was assessed from the first treatment day randomized treatment, BMI and sex as classification (22). Severe hypoglycemia to 14 days after the last treatment day, factors, and baseline end point as a co- was defined as an episode requiring excludingpotentialoff-drugtimeintervals variate.TheestimatesandSDswerepooled assistance of another person to actively triggered by at least 2 weeks of consec- using Rubin’s formula. All categorical end administer carbohydrate or glucagon or utive missed doses. points were assessed at week 56 and takeothercorrectiveactions.Documented analyzed using logistic regression with the symptomatic and asymptomatic hypogly- Statistical Considerations samefactorsandcovariateasthecontinuous cemia were defined as a plasma glucose The planned sample size for this trial of end point analysis. concentration #70 mg/dL (3.9 mmol/L) 400 participants, along with a 1:1 random- For analyses of end points, the estimated with and without typical symptoms of ization and assuming a 30% discontinua- treatment difference (ETD) for continuous hypoglycemia, respectively. Hypoglycemia tion rate, resulted in a combined power of and the estimated odds ratio (OR) for the wasalsoassessedusingNovoNordisk’s 95.2%,whichwasestimatedtobeade- categorical end points are reported with classification, which, together with ADA quate to evaluate the two coprimary end the associated two-sided 95% CI and cor- criteria, is included in the Supplementary points.Powerforthecontinuousendpoint, responding P value. All analyses were un- Data. percentage weight change, was calculated dertaken using UNIX SAS (version 9.4) on with a two-group Satterthwaite test; the the Statistical Computing Environment. Study End Points power for the categorical end point, $5% Coprimary end points were change in responders, was calculated using a Pearson RESULTS 2 body weight (percentage) from baseline x test, both at a 5% significance level. The Trial Population to week 56 and proportion of individuals two coprimary end points were tested in A total of 551 individuals were screened, losing $5% of baseline body weight at hierarchal order with change in body and 396 were randomized: 198 to lira- week 56. Confirmatory secondary end weight at week 56 as a percentage of glutide 3.0 mg combined with IBT and points included the proportion of indi- baseline body weight first, followed by 198 to placebo combined with IBT. Base- viduals losing .10% of baseline body proportion of individuals losing $5% of line demographics were similar between weight at week 56 and the change from baseline body weight at week 56. treatment arms (Table 1). 4 Liraglutide and Insulin: SCALE Insulin Trial Diabetes Care

A high proportion of individuals re- no significant difference in the reduction with liraglutide 3.0 mg and 6.2% with turned for the final evaluation at week of mean FPG (mmol/L) between the placebo (OR 3.28 [95% CI 1.66; 6.48]; 56 (96.5% in the liraglutide 3.0 mg arm liraglutide 3.0 mg (21.0 mmol/L) and P 5 0.0006). and 97.5% in the placebo arm) and the placebo group (20.6 mmol/L; ETD remainedonstudydruguptoweek 20.4 [95% CI 20.9; 0.1]; P 5 0.1502) Safety 56 (83.8% and 84.8%, respectively). (Table 2), in keeping with the trial design Liraglutide 3.0 mg in combination with Two individuals on liraglutide 3.0 mg to target the same FPG in both groups. IBT was generally well tolerated, with no and four on placebo were lost to follow- Change in FPG over time is shown in Sup- new safety signals identified. Safety data up (Supplementary Fig. 2 and Supple- plementary Fig. 5. Liraglutide 3.0 mg was are summarized in Table 3. AE incidence mentary Table 2). associated with lower pre- and postpran- was similar for liraglutide 3.0 mg and Primary, confirmatory, and supportive dial glucose values over the course of placebo, except for gastrointestinal AEs, secondary end points relating to the the day, as evident in the mean daytime which had a greater incidence with lir- treatment policy estimand are presented glucose value (Supplementary Fig. 6A) aglutide 3.0 mg (62.1% vs. 46.7%). AEs in Table 2. Corresponding trial product and the seven-point SMBG profile at reported by $5% of participants and estimand end points are presented in week 16 and week 56 (Supplementary more frequently by participants in the SupplementaryTable3whereapplicable. Fig. 6B–D). Relative to placebo, there was liraglutide arm than the placebo arm asignificantly smaller increase in insulin included nausea, nasopharyngitis, diar- Body Weight and Waist Circumference dose required to achieve target fasting BG rhea, headache, and upper respiratory Figure 1A shows observed mean weight (13 units with liraglutide 3.0 mg vs. 118 tract infection (Supplementary Table 4). loss over time in the two groups. For the units with placebo; ETD 215.0 [95% CI The incidence of nausea was greater with treatment policy estimand (intention- 222.0; 28.0]; P , 0.0001) (Fig. 1C). A total liraglutide 3.0 mg (29.7%) than with to-treat principle), mean weight loss at of 24 individuals who had completed the placebo (11.7%), and most events were 56 weeks was 25.8% with liraglutide 3.0 trial (21 with liraglutide and 3 with placebo) mild or moderate in severity. There was mg and 21.5% with placebo (ETD 24.3% were no longer using insulin at the study nosignificantdifferenceinchangeinheart [95% CI 25.5; 23.2]; P , 0.0001) (Table 2 end. rate for liraglutide versus placebo. The and Supplementary Fig. 3A). For the trial proportion of individuals reporting a se- product estimand (if-all-adhered princi- Cardiometabolic Parameters and rious AE was 8.2% (23 events in 16 in- ple), estimated mean weight change at Quality of Life dividuals) with liraglutide 3.0 mg and 56 weeks was 26.4%forliraglutide3.0mg Mean systolic blood pressure decreased 9.6% (25 events in 19 individuals) with and 21.3% for placebo (ETD 25.1% [95% significantly with liraglutide 3.0 mg (25.6 placebo. There were no AEs with fatal CI 26.3; 23.9]; P,0.0001) (Supplementary mmHg) versus placebo (21.6 mmHg; outcomes in the trial. Table 3 and Supplementary Fig. 3B). For ETD 24.0[95% CI 26.4; 21.5],P50.0014), Using ADA criteria, greater than or equal individuals on trial product at 56 weeks, and changes in diastolic blood pressure to one episode of hypoglycemia occurred in mean observed change in weight was were not significant (Table 2). There 71.8% (742.3 events per 100 patient-years) 26.5% (n 5 163) with liraglutide 3.0 mg was a trend for improved lipids with of the liraglutide 3.0-mg group, compared and 21.7% (n 5 168) with placebo (Fig. liraglutide 3.0 mg versus placebo, al- with 71.1% (937.9 events per 100 patient- 1A). though with the exception of total cho- years) of the placebo group (Table 3). The proportion of individuals who lesterol, no significant differences between Documented symptomatic hypoglyce- achieved $5% weight loss was 51.8% treatmentarmswereobservedat56weeks. mia occurred at rates of 336.1 and 441.7 with liraglutide 3.0 mg and 24.0% with Individuals on liraglutide 3.0 mg and pla- events per 100 patient-years of exposure placebo (OR 3.41 [95% CI 2.19; 5.31]; P , cebo both reported increased physical with liraglutide 3.0 mg and placebo, re- 0.0001). The proportion who lost .10% functioning at week 56 as determined by spectively. There were three severe hy- was 22.8% and 6.6%, respectively (OR the SF-36 physical functioning domain poglycemic episodes (requiring assistance 4.21 [95% CI 2.2; 8.2]; P , 0.0001) score (Supplementary Fig. 7A) and the of another person) with liraglutide 3.0 mg (Supplementary Fig. 4). A significant IWQOL-Lite for CT Physical Function do- versus two episodes with placebo. Rates decrease was observed in waist circum- main score (Supplementary Fig. 7B), but of hypoglycemia determined by Novo- ference at 56 weeks in the liraglutide there were no significant differences Nordisk criteria are shown in Supple- 3.0-mg group versus placebo (25.28 cm between treatment groups. mentary Table 5. A greater number of vs. 22.56 cm [ETD 22.71 (95% CI 23.90; hypoglycemic episodes occurred in in- 21.53); P , 0.0001]) (Table 2). Composite End Points dividuals treated with SUs in both arms The proportion of individuals achieving (Supplementary Table 6). Glycemic Parameters $5% weight loss plus ADA HbA1c target Three acute gallstone disease events Figure 1B shows observed changes in HbA1c of ,7% (53 mmol/mol) was 39.0% with occurred in the trial, two with liraglutide over time in the two groups. For the treat- liraglutide 3.0 mg and 13.9% with pla- 3.0 mg (both cholelithiasis) and one with ment policy estimand at 56 weeks, a signif- cebo (OR 3.94 [95% CI 2.38; 6.53]; placebo (gallbladder disorder); none of icantly greater reduction in mean HbA1c was P , 0.0001). The proportion of individ- these were serious AEs. Two cases of observed with liraglutide 3.0 mg (21.1% uals achieving $5% weight loss plus ADA pancreatitis in one individual (acute pan- [211.9 mmol/mol]) versus placebo (20.6% HbA1c target of ,7% (53 mmol/mol) plus creatitis and pancreatitis, both serious) [26.0 mmol/mol]; ETD 20.5% [95% who did not report any documented were reported with placebo. A similar num- CI 20.8; 20.3]; P , 0.0001). There was symptomatic hypoglycemia was 17.8% ber of neoplasm events were reported care.diabetesjournals.org Garvey and Associates 5

Table 1—Baseline demographics and medications overweight or obesity and type 2 diabe- Liraglutide 3.0 mg Placebo tes goes beyond glucose control in favor (n 5 198) (n 5 198) of a more holistic approach addressing the full range of complications and un- Male sex, n (%) 90 (45.5) 99 (50.0) derlying pathophysiological mechanisms Mean age, years (SD) 55.9 (11.3) 57.6 (10.4) driving weight gain. Recently published Race, n (%) European Association for the Study of White 174 (87.9) 180 (90.9) Black 17 (8.6) 11 (5.6) Diabetes/ADA guidelines recommend Asian 3 (1.5) 5 (2.5) considering the effect on weight when Ethnicity: not Hispanic or Latino, n (%) 155 (78.3) 169 (85.4) choosing diabetes treatment (8,9), and the Mean body weight, kg (SD)* 100.6 (20.8) 98.9 (19.9) American Association of Clinical Endocri- Mean BMI, kg/m2 (SD) 35.9 (6.5) 35.3 (5.8) nologists obesity guidelines regard the Mean waist circumference, cm (SD) 114.8 (13.7) 114.2 (13.2) objective of weight-loss therapy to be prevention and treatment of weight- Mean HbA , % (SD) 7.9 (1.1) 8 (1.0) 1c related complications, including type 2 Mean HbA , mmol/mol (SD) 63.0 (11.5) 63.6 (11.3) 1c diabetes (10). Weight-loss medications Mean FPG, mmol/L (SD) 7.8 (2.2) 8.1 (2.5) have been shown to have a highly favor- Mean FPG, mg/dL (SD) 141 (40) 146 (46) able therapeutic profile in individuals Mean diabetes duration, years (SD) 11.4 (6.8) 12.8 (6.9) with obesity/overweight and type 2 di- † Mean heart rate, bpm (SD) 74.0 (10.0) 75.0 (11.0) abetes; however, efficacy has not been Mean SBP, mmHg (SD) 129.0 (14.0) 132.0 (16.0) examined in all subgroups of individuals Mean DBP, mmHg (SD) 78.0 (9.0) 78.0 (9.0) with diabetes as a function of specific Mean total cholesterol, mmol/L (SD) 4.5 (1.0) 4.4 (0.9) concomitant diabetes medication. Mean total cholesterol, mg/dL (SD) 172 (39) 171 (36) To our knowledge, SCALE Insulin is the Mean LDL cholesterol, mmol/L (SD) 2.4 (0.9) 2.4 (0.8) first randomized clinical trial to specifi- Mean LDL cholesterol, mg/dL (SD) 94 (33) 94 (29) cally investigate the efficacy and safety of Mean HDL cholesterol, mmol/L (SD) 1.2 (0.3) 1.2 (0.3) an approved antiobesity medication in Mean HDL cholesterol, mg/dL (SD) 45 (12) 45 (11) individuals with overweight or obesity Mean VLDL cholesterol, mmol/L (SD) 0.9 (0.4) 0.8 (0.4) and type 2 diabetes treated with basal Mean VLDL cholesterol, mg/dL (SD) 33 (16) 32 (15) insulin. Our findings demonstrate supe- Mean triglycerides, mmol/L (SD) 2.0 (1.2) 1.9 (1.0) riority of liraglutide 3.0 mg versus pla- Mean triglycerides, mg/dL (SD) 174 (105) 168 (89) cebo regarding both percentage of weight Mean free fatty acids, mmol/L (SD) 0.6 (0.2) 0.6 (0.3) loss (ETD 24.3% [95% CI 25.5; 23.2]; Mean free fatty acids, mg/dL (SD) 15.9 (6.9) 15.5 (7.3) P , 0.0001) and proportion of individuals $ Antidiabetic medications at screening, n (%) reaching a clinically relevant 5% weight 175 (88.4) 176 (88.9) loss at week 56 (liraglutide 3.0 mg: 51.8%; SUs 68 (34.3) 71 (35.9) placebo: 24.0%; P , 0.0001). Thus, the SGLT-2i 44 (22.2) 44 (22.2) two primary objectives of the trial were 4 (2.0) 6 (3.0) met. Combination BG-lowering drugs (oral) 4 (2.0) 3 (1.5) The weight-loss findings in the SCALE a-Glucosidase inhibitors 2 (1.0) 0 (0.0) Other BG-lowering drugs, excluding insulins 1 (0.5) 5 (2.5) Insulin trial are in line with those ob- served in the previously described SCALE Insulins/analogs (injection), n (%) Long-acting 180 (90.9) 184 (92.9) Diabetes trial, in which insulin-treated Intermediate-acting 18 (9.1) 14 (7.1) individuals were excluded (19). In SCALE Diabetes, placebo-adjusted weight loss DBP,diastolicbloodpressure; SBP,systolicbloodpressure;SGLT2-i,sodium–glucosecotransporter 2 inhibitor. *Body weight measurements include both fasting and nonfasting measures. †Safety in individuals with overweight or obesity analysis set; liraglutide, n 5 195; placebo, n 5 197. and type 2 diabetes was 2.7% and 4.0% with liraglutide 1.8 mg and 3.0 mg, re- spectively. Similarly, the proportion of with liraglutide 3.0 mg (23 events in medullary thyroid carcinoma with liraglu- individuals reaching $5% weight loss 19 individuals) and placebo (21 events in tide 3.0 mg. There were a similar number with liraglutide 3.0 mg and placebo in 17 individuals) during the in-trial period. of cases of depression and suicidal idea- SCALE Insulin was also comparable to Six neoplasm events with liraglutide tion/behavior AEs with liraglutide 3.0 mg SCALE Diabetes (liraglutide 3.0 mg, 54.3%; 3.0 mg and two with placebo were se- and placebo (eight events in seven indi- placebo, 21.4%, respectively) (19). No- rious (Supplementary Table 7). With the viduals vs. eight events in eight individuals tably, the placebo arm in SCALE Insulin exception of one case of thyroid ade- with placebo). demonstrated greater weight loss than noma, all serious neoplasm events were in the SCALE Diabetes trial, despite the assessed as malignant; all remaining CONCLUSIONS fact that the trial population was older, neoplasm events were benign. There Weight-loss therapy as a primary treat- had a greater number of complications, were no reports of breast cancer or ment approach in individuals with and was on weight-promoting insulin. 6 Liraglutide and Insulin: SCALE Insulin Trial Diabetes Care

Table 2—Change in primary and secondary end points from baseline to week 56: treatment policy estimand Liraglutide 3.0 mg Placebo ETD/OR* (n 5 198) (n 5 198) (95% CI) P value Primary end points Change in body weight from baseline, % 25.8 21.5 24.3 (25.5; 23.2) ,0.0001 Proportion of individuals achieving $5% weight loss,* % 51.8 24.0 3.4 (2.2; 5.3) ,0.0001 Secondary confirmatory end points Proportion of individuals achieving .10% weight loss,* % 22.8 6.6 4.2 (2.2; 8.2) ,0.0001 Change in waist circumference from baseline, cm 25.3 22.6 22.7 (23.9; 21.5) ,0.0001

Change in HbA1c from baseline, % 21.1 20.6 20.5 (20.8; 20.3) ,0.0001 Change in HbA1c from baseline, mmol/mol 211.9 26.0 25.8 (28.3; 23.4) ,0.0001 Change in FPG from baseline, mmol/L 21.0 20.6 20.4 (20.9; 0.1) 0.1502 Change in FPG from baseline, mg/dL 218.4 211.5 26.9 ( 216.4; 2.5) 0.1502 Change in SF-36 Physical Functioning score from baseline 2.7 2.3 0.4 (21.0; 1.8) 0.5716 Change in IWQOL-Lite for CT Physical Function domain score from baseline 8.2 5.7 2.5 (21.5; 6.4) 0.2218 Secondary supportive end points Change in total daily insulin dose from baseline, units 2.8 17.8 215.0 (222.0; 28.0) ,0.0001 Change in mean daytime glucose value from baseline, mmol/L 22.2 21.5 20.7 (21.1; 20.2) 0.0032 Change in mean daytime glucose value from baseline, mg/dL 239.6 227.3 212.4 (220.6; 24.1) 0.0032

Individuals achieving $5% weight loss and HbA1c ,7% at week 56* 39.0 13.9 3.9 (2.4; 6.5) ,0.0001

Individuals achieving $5% weight loss, HbA1c ,7%, and no documented symptomatic hypoglycemia at week 56* 17.8 6.2 3.3 (1.66; 6.48) 0.0006 Change in systolic blood pressure from baseline, mmHg 25.6 21.6 24.0 (26.4; 21.5) 0.0014 Change in diastolic blood pressure from baseline, mmHg 22.3 20.9 21.4 (23.0; 0.2) 0.0905 Total cholesterol† 0.97 1.01 0.97 (0.94; 1.00) 0.0463 LDL cholesterol† 0.97 1.01 0.96 (0.91; 1.01) 0.1027 HDL cholesterol† 1.04 1.02 1.02 (0.99; 1.04) 0.2778 VLDL cholesterol† 0.89 0.94 0.94 (0.88; 1.01) 0.0830 Triglycerides† 0.88 0.94 0.94 (0.87; 1.01) 0.0715 Free fatty acids† 0.79 0.84 0.95 (0.85; 1.07) 0.3936 Baseline to week 56 vs. placebo. Full analysis set. Statistical analysis is ANCOVA with jump-to-reference multiple imputation. *The end point is analyzed in a logistic regression model. †Data are treatment ratios (liraglutide 3.0 mg/placebo).

This is most likely attributable to a more designs, the studies demonstrate that and mean daytime glucose values de- intensive lifestyle intervention. Improve- basal insulin combined with liraglutide spite lower basal insulin requirements. ments in several cardiovascular risk fac- can result in clinically significant weight Given the broad range of baseline HbA1c tors such as waist circumference, systolic loss relative to treatment with insulin (6–10% [42–86 mmol/mol]), these gly- bloodpressure,andtotalcholesterolwere alone. cemic improvements are likely the result also in line with findings of the SCALE Di- Regarding the parameters of glycemic of the preferential effects of liraglutide abetes trial. Direct comparisons between control in SCALE Insulin, individuals in the on postprandial, rather than preprandial, these two trials should take into account liraglutide 3.0-mg group achieved statis- glucose (as indicated by daily seven-point differences in trial designs and statistical tically significant and clinically meaning- SMBG profiles) (Supplementary Fig. 6) analyses, including the more intensive ful improvements from baseline to week combined with the significantly greater lifestyle intervention in the current trial 56 in HbA1c and mean daytime glucose weight loss versus placebo. (IBT). values. At 56 weeks, there was no sig- Although treatment with insulin often In the Dual Action of Liraglutide and nificant difference between treatment results in weight gain, the extent towhich Insulin Degludec (DUAL) II trial, the con- groups concerning improvements in FPG. the weight loss observed with liraglutide tribution of liraglutide in a fixed-ratio Given that all individuals were actively 3.0 mg in the present trial was the result combination with insulin degludec was treated with basal insulin to achieve the of the direct action of liraglutide on investigated regarding efficacy and safety same glycemic targets in both treatment feelings of hunger and satiety and pos- (25). The trial demonstrated that insulin arms (Supplementary Table 1), this was sible delay in gastric emptying (26,27), or degludec alone had a minimal effect on expected. Importantly, however, similar the result of indirectly reducing insulin weight; however, when combined with fasting glucose levels were achieved with requirements and use of SUs, requires liraglutide, it resulted in an ETD of 22.5 kg an average of 15 units/day lower insulin further investigation. Furthermore, while (95% CI 23.2; 21.8; P , 0.0001). While requirement in the liraglutide group com- individuals on SUs were stratified be- comparisons of these findings to SCALE pared with placebo. Superiority with lir- tween the two treatment arms and in- Insulin should be cautious given the aglutide 3.0 mg versus placebo was sulindosesweretitratedtoachievesimilar differences in liraglutide doses and study confirmed for reductions in mean HbA1c levels of glycemic control, we are unable care.diabetesjournals.org Garvey and Associates 7

Figure 1—Change in body weight and glycemic control over time. A: Change in body weight (percentage); observed mean data 6 SEM. n values refer to all individuals who attended visit regardless of treatment status; on-drug n values refer to individuals who are still on active treatment at time of visit. B: Change in HbA1c; observed mean data 6 SEM. n values refer to all individuals who attended visit regardless of treatment status; on-drug n values refer to individuals whoarestillonactivetreatmentattimeofvisit.C: Change in total daily insulin dose; graph shows observed mean data 6 SEM. n values refer to all individuals who attended visit regardless of treatment status; on-drug n values refer to individuals who are still on active treatment at time of visit. U, units. to quantify the effect of other OADs on placebo,bothgroupsrequired anincrease standing type 2 diabetes, given the trial weight. Despite the marked reduction in in total daily insulin dose, as evident at duration and the purposeful titration of insulin dose needed to meet glycemic week 56. This was expected in these basal insulin to achieve the same gly- targets with liraglutide 3.0 mg versus actively treated individuals with long- cemic targets in all individuals. Given the 8 Liraglutide and Insulin: SCALE Insulin Trial Diabetes Care

Funding. The study was sponsored by Novo Table 3—Safety data (on-drug) Nordisk A/S and is registered with ClinicalTrials Liraglutide 3.0 mg Placebo .gov (NCT02963922). n (%) E R n (%) E R DualityofInterest. W.T.G.reportsinstitutionally sponsored research grants from Merck/Pfizer, dd dd Number of individuals 195 197 AstraZeneca, Sanofi, Novo Nordisk, and Lexicon Total AEs 180 (92.3) 1,139 578.3 175 (88.8) 1,053 531.2 Pharmaceuticals, Inc. and consulting fees and/or Serious AEs 16 (8.2) 23 11.7 19 (9.6) 25 12.6 honoraria for advisory board participation from Novo Nordisk, American Medical Group Associa- Fatal AEs 0 (0.0) 0 0.0 0 (0.0) 0 0.0 tion, BOYDSense, Gilead Sciences, Inc., Amgen, Events leading to treatment and Sanofi. A.L.B. reports funds to conduct the discontinuation 15 (7.7) 17 8.6 6 (3.0) 6 3.0 trial, global panel honoraria, and travel expenses GI AEs 121 (62.1) 408 207.1 92 (46.7) 202 101.9 for meetings from Novo Nordisk during the con- Nausea 58 (29.7) 105 53.3 23 (11.7) 27 13.6 duct of the study, and personal fees for educa- Constipation 28 (14.4) 36 18.3 17 (8.6) 21 10.6 tional talks from Sanofi, AstraZeneca, Eli Lilly and Diarrhea 45 (23.1) 77 39.1 30 (15.2) 54 27.2 Company, and Novo Nordisk. D.D. reports con- Vomiting 32 (16.4) 53 26.9 12 (6.1) 13 6.6 sulting fees and/or honoraria for advisory board Abdominal discomfort 11 (5.6) 17 8.6 8 (4.1) 11 5.5 participation and speaking from Merck Sharp & Dohme, Boehringer Ingelheim, Novo Nordisk, Hypoglycemic episodes 140 (71.8) 1,462 742.3 140 (71.1) 1,859 937.9 Sanofi, AstraZeneca, and Teva Pharmaceutical ADA classified Industries Ltd. and institutionally sponsored re- Severe 3 (1.5) 3 1.5 2 (1.0) 2 1.0 search grants from Boehringer Ingelheim. G.M. Asymptomatic 116 (59.5) 742 376.7 116 (58.9) 988 498.4 has received grants from Novo Nordisk and con- Documented symptomatic 92 (47.2) 662 336.1 102 (51.8) 816 411.7 sulting fees and/or honoraria for advisory board Pseudohypoglycemia 17 (8.7) 42 21.3 14 (7.1) 31 15.6 participation and speaking for Fractyl Laboratories Probable symptomatic 8 (4.1) 10 5.1 18 (9.1) 22 11.1 Inc. and Johnson & Johnson. S.D.P. reports grants, Unclassifiable 2 (1.0) 3 1.5 0 (0.0) 0 0 personal fees, and nonfinancial support from Novo Nordisk during the conduct of this study, personal fi Safety analysis set. Hypoglycemic episodes were classi ed using ADA criteria and recorded in fees and nonfinancial support including advisory individual diaries. Data are from individuals on-drug. E, number of events; GI, gastrointestinal; n, boards participation, speaker fees, and travel fees number of individuals experiencing at least one event; %, percentage of individuals experiencing from Novo Nordisk and Bausch Health/Valeant at least one event; R, event rate per 100 patient-years of exposure. Pharmaceuticals International, Inc., personal fees and nonfinancial support from Janssen Pharma- fi superior weight loss and beneficial gly- the higher insulin dose required to ceuticals, grants, personal fees, and non nancial support from Eli Lilly and Company, AstraZeneca, cemic effects of liraglutide 3.0 mg, this achieve glycemic targets in the placebo Boehringer Ingelheim, and Sanofi,personal treatment group experienced a substan- group when compared with those ran- fees from Merck, Prometic BioTherapeutics fi tially reduced need for exogenous insulin domized to liraglutide 3.0 mg and/or the Inc., and P zer, and grants and personal fees compared with placebo-treated individu- from Abbott Laboratories. A.S., D.Sk., and C.J. ability of liraglutide to reduce glycemic are employees of Novo Nordisk. D.Su. reports als. It is of interest to consider that being variability (28). Taken together, liraglu- research grants from Novo Nordisk. O.M. accustomed to treatment with injectable tide 3.0 mg had a favorable therapeutic reports fees related to advisory boards from insulins may have had a positive influ- Novo Nordisk, Eli Lilly and Company, Sanofi, profile; namely, greater weight loss with ence on treatment adherence in this trial Merck Sharp & Dohme, Boehringer Ingelheim, better glycemic control, with less need (84.3% of individuals were on drug at Novartis, and AstraZeneca; grants paid to in- for basal insulin, and without any in- stitution as study physician from AstraZeneca week 56). and Bristol-Myers Squibb; research grant sup- In SCALE Insulin, no new safety signals crease in hypoglycemia. port through Hadassah Hebrew University Hos- were observed, and the safety profile pital from Novo Nordisk; and speaker bureau observed with liraglutide 3.0 mg was in Conclusion participation for AstraZeneca, Bristol-Myers Squibb, In individuals with overweight or obesity Novo Nordisk, Eli Lilly and Company, Sanofi,No- line with that reported in previous trials, and basal insulin-treated type 2 diabetes, vartis, Merck Sharp & Dohme, Boehringer Ingel- with the most common AEs being gas- liraglutide 3.0 mg was superior to pla- heim, and Teva Pharmaceutical Industries Ltd. No trointestinal in nature. As trial partici- other potential conflicts of interest relevant to this cebo with respect to mean and categor- pants were informed about possible articlewerereported. ical weight loss at 56 weeks, as well as gastrointestinal side effects related to Author Contributions. All authors were in- improvements in glycemic control despite volved in the analysis of the data, the preparation treatment prior to the start of the trial, a lower need for basal insulin. No new of the manuscript, and the decision to submit it we cannot exclude the possibility of a safety or tolerability issues were observed for publication and verify the accuracy and “precebo effect” having been observed. completeness of the data and analyses. W.T.G. is during the trial, and fewer hypoglycemic Gastrointestinal AE findings are also sub- the guarantor of this work and, as such, had full events were observed with liraglutide access to all of the data in the study and takes ject to limitations of self-reporting used 3.0 mg versus placebo. responsibility for the integrity of the data and in current and other SCALE trials. Fewer the accuracy of the data analysis. serious AEs occurred in the liraglutide Prior Presentation. Parts of this study were presented at the 26th European Congress on 3.0-mg group compared with placebo. Acknowledgments. The authors thank the Obesity 2019, Glasgow, U.K., 28 April–1 May people who participated in this study and Jamie Improvements in glycemic outcomes in 2019. the present trial were achieved with Cozens, Watermeadow Medical, an Ashfield com- fewer hypoglycemic events per 100 pa- pany, part of UDG Healthcare plc (supported by Novo Nordisk), for writing assistance. 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