AIM:To explore the effects of sex and baseline body mass index (BMI) on the efficacy and safety of survodutide in people with a BMI ≥27 kg/m2. MATERIALS AND METHODS:Totally 387 people (aged 18-75 years, BMI ≥27 kg/m2, without diabetes) were randomized 1:1:1:1:1 to once-weekly subcutaneous survodutide (0.6, 2.4, 3.6 or 4.8 mg) or placebo for 46 weeks (20-week dose escalation; 26-week dose maintenance). Participants were categorized according to sex and baseline BMI. Data were analysed descriptively for the full analysis set (FAS), according to dose assigned at randomization (planned treatment) using on-treatment data or all data censored for COVID-19-related treatment discontinuations. (ClinicalTrials.gov number: NCT04667377). RESULTS:After 46 weeks of survodutide treatment, females had greater reductions in bodyweight and waist circumference than males. Participants with a lower baseline BMI had greater proportional reductions in bodyweight than those with a higher baseline BMI; the trend was reversed for reductions in waist circumference. Rates of adverse events (AEs) were comparable between subgroups for sex and baseline BMI. Nausea was the most frequently reported gastrointestinal AE in all subgroups. CONCLUSIONS:In people with a BMI ≥27 kg/m2, survodutide was associated with clinically meaningful reductions in bodyweight and waist circumference when compared with placebo, in prespecified subgroups based on sex and baseline BMI, and was tolerated at all doses tested.

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors may be more effective than GLP-1 receptor agonism alone in reducing body weight, but the cardiovascular (CV) effects are unknown. The authors describe the rationale and design of SYNCHRONIZE-CVOT, a phase 3, randomized, double-blind, parallel-group, event-driven, CV safety study of survodutide, a dual glucagon and GLP-1 receptor agonist, administered subcutaneously once weekly compared with placebo in adults with a body mass index >= 27 kg/m2 and established CV disease or chronic kidney disease, and/or at least 2 weight-related complications or risk factors for CV disease. The primary endpoint of SYNCHRONIZE-CVOT is time to first occurrence of the composite adjudicated endpoint of 5-point major adverse CV events. This global CV outcomes trial is currently enrolling, with a target recruitment of 4,935 participants. SYNCHRONIZE-CVOT is the first trial that will determine the CV safety and efficacy of survodutide in people with obesity and increased CV risk. (A Study to Test the Effect of Survodutide [BI 456906] on Cardiovascular Safety in People With Overweight or Obesity. (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Abstract Disclosure: C.W. Le Roux: Consulting Fee; Self; Boehringer Ingelheim, Novo Nordisk, GI Dynamics, Herbalife, Johnson & Johnson, Eli Lilly, Keyron. O. Steen: Consulting Fee; Self; Eli Lilly & Company, Novo Nordisk, Sanofi. Grant Recipient; Self; Alnylam, Anji, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Janssen, Genzyme Corporation, Medacorp, Novo Nordisk, Medicago, Moderna, Novavax, Pfizer, Sanofi, Zucara Therapeutics, Gilead, ViaCyte, CRISPR Therapeutics, Kowa. Speaker; Self; Amgen Inc, AstraZeneca, Bausch Health, Janssen, LMC, Novo Nordisk. K.J. Lucas: None. E. Startseva: Employee; Self; Boehringer Ingelheim. A. Unseld: Employee; Self; Boehringer Ingelheim. A.M. Hennige: Employee; Self; Boehringer Ingelheim. Aim: To explore the effect of gender and BMI on weight loss and adverse events with survodutide in people living with overweight/obesity. Methods: In this double-blind, placebo (PBO)-controlled Phase II trial (NCT04667377), 387 adults with BMI ≥27 kg/m2 without diabetes were randomized 1:1:1:1:1 to weekly subcutaneous survodutide (0.6, 2.4, 3.6, 4.8 mg) or PBO over 46 weeks. Percentage change in body weight (primary endpoint), absolute change in body weight and waist circumference (secondary endpoints), and adverse events (AEs) were assessed in subgroups based on gender and BMI at baseline (BL). Data were analyzed descriptively for all participants who received ≥1 dose of study drug and had data for ≥1 efficacy endpoint (full analysis set [FAS]; planned treatment: n=384). Results: Of 384 participants, 68.2% (262) were female. At BL, 9.9% (38), 30.5% (117), 31.8% (122), and 27.9% (107) had a BMI of <30, 30-<35, 35-<40, and ≥40 kg/m2, respectively. Demographics and clinical characteristics at BL were similar between males and females and across BMI subgroups. At Week 46, mean percentage change in body weight from BL with survodutide 4.8 mg vs PBO was -11.9% vs -3.3% in males and -17.0% vs -3.2% in females, and -19.1% vs -1.7%, -15.8% vs -3.1%, -15.4% vs -5.8%, and -13.4% vs -0.8% across BL BMI categories. Mean absolute body weight loss from BL (survodutide 4.8 mg vs PBO) was -15.9 vs -4.2 kg in males and -22.0 vs -3.0 kg in females. Reductions in absolute body weight with survodutide 4.8 mg vs PBO were similar across BMI subgroups: -21.3 vs 1.4 kg, -16.2 vs -3.3 kg, -22.2 vs -7.5 kg, and -19.9 vs -1.6 kg. Mean absolute change in waist circumference from BL (survodutide 4.8 mg vs PBO) was -12.8 vs -1.7 cm in males and -17.9 vs -4.9 cm in females, and -8.4 vs -2.6 cm, -14.3 vs -6.4 cm, -17.5 vs -5.0 cm, and -17.2 vs 3.3 cm across BL BMI categories. A higher proportion of participants lost ≥15% of BL body weight with survodutide 4.8 mg vs PBO: 31.8% vs 9.5% in males and 66.7% vs 3.0% in females, and 75.0% vs 14.3%, 57.9% vs 4.5%, 52.0% vs 6.7%, and 50.0% vs 0.0% across BL BMI categories; respectively. All survodutide doses (pooled) were tolerated as expected across gender and BL BMI subgroups. In males vs females, respectively, rates of any AE (87.9% vs 92.4%), serious AEs (4.0% vs 4.3%), and discontinuations due to AEs (25.3% and 24.3%) were comparable. Gastrointestinal (GI) AEs with all survodutide doses were experienced by fewer males (65.7%) than females (79.5%); mild to moderate nausea was the most frequently reported GI AE in both subgroups. Conclusion: After 46 weeks of survodutide treatment, females appeared to lose more body weight and waist circumference than males. Participants with a lower vs higher BL BMI generally lost more proportional body weight, with an opposite trend observed for waist circumference. Presentation: 6/2/2024

Background Obesity is a widespread and chronic condition that requires long-term management; research into additional targets to improve treatment outcomes remains a priority. This study aimed to investigate the safety, tolerability, and efficacy of glucagon receptor-GLP-1 receptor dual agonist survodutide (BI 456906) in obesity management. Methods In this randomised, double-blind, placebo-controlled, dose-finding phase 2 trial conducted in 43 centres in 12 countries, we enrolled participants (aged 18-75 years, BMI >= 27 kg/m2, without diabetes) and randomly assigned them by interactive response technology (1:1:1:1:1; stratified by sex) to subcutaneous survodutide (0 center dot 6, 2 center dot 4, 3 center dot 6, or 4 center dot 8 mg) or placebo once-weekly for 46 weeks (20 weeks dose escalation; 26 weeks dose maintenance). The primary endpoint was the percentage change in bodyweight from baseline to week 46. Primary analysis included the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint) and was based on the dose assigned at randomisation (planned treatment), including all data censored for COVID-19-related discontinuations; the sensitivity analysis was based on the actual dose received during maintenance phase (actual treatment) and included on-treatment data. Safety analysis included all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov (NCT04667377) and EudraCT (2020-002479-37). Findings Between March 30, 2021, and Nov 11, 2021, we enrolled 387 participants; 386 (100%) participants were treated (0 center dot 6 mg, n=77; 2 center dot 4 mg, n=78; 3 center dot 6 mg, n=77; 4 center dot 8 mg, n=77; placebo n=77) and 233 (60 center dot 4%) of 386 completed the 46-week treatment period (187 [61%] of 309 receiving survodutide; 46 [60%] of 77 receiving placebo). When analysed according to planned treatment, mean (95% CI) changes in bodyweight from baseline to week 46 were -6 center dot 2% (-8 center dot 3 to -4 center dot 1; 0 center dot 6 mg); -12 center dot 5% (-14 center dot 5 to -10 center dot 5; 2 center dot 4 mg); -13 center dot 2% (-15 center dot 3 to -11 center dot 2; 3 center dot 6 mg); -14 center dot 9% (-16 center dot 9 to -13 center dot 0; 4 center dot 8 mg); -2 center dot 8% (-4 center dot 9 to -0 center dot 7; placebo). Adverse events occurred in 281 (91%) of 309 survodutide recipients and 58 (75%) of 77 placebo recipients; these were primarily gastrointestinal in 232 (75%) of 309 survodutide recipients and 32 (42%) of 77 placebo recipients. Interpretation All tested survodutide doses were tolerated, and dose-dependently reduced bodyweight. Funding Boehringer Ingelheim. Copyright (c) 2024 Elsevier Ltd. All rights reserved.

Glucagon receptor (GCGR) agonism increases energy expenditure and glucagon-like peptide 1 receptor (GLP-1R) agonism reduces energy intake; thus, dual GCGR/GLP-1R agonists, such as BI 456906, may be more effective at treating obesity than mono GLP-1R agonists. This dose-finding study tested efficacy and safety of BI 456906 in participants (pts) with overweight/obesity. This double-blind, placebo (PBO)-controlled study (NCT04667377) randomised adults with BMI ≥27 kg/m2 to weekly subcutaneous BI 456906 (0.6, 2.4, 3.6, 4.8 mg) or PBO for 46 weeks (thereof 20-week (W) rapid, bi-weekly dose escalation; 26-W maintenance). Primary endpoint was bodyweight (BW) change (%) from baseline (BL) at W46. Secondary endpoints included proportion of pts reaching ≥5, ≥10 or ≥15% BW loss from BL at W46. In total, 387 pts were randomised (treated set [TS], N=386; full analysis set [FAS], N=384; n≈77 per arm). At BL (FAS) mean age was 49.1 years, BW 105.7 kg and BMI 37.1 kg/m2; 31.8% of pts were male. BI 456906 therapeutic benefit vs PBO was shown by a non-flat dose response curve of BW change (%) from BL at W46. Mean BW reduced with dose over 46 weeks (FAS; 0.6 mg, −6.2%; 2.4 mg, −12.5%; 3.6 mg, −13.2%; 4.8 mg, −14.9%; vs PBO, −2.8%). At W46, BW loss (FAS) of ≥5, ≥10 and ≥15% was reached by 82.8%, 68.8% and 54.7% of 4.8 mg BI 456906 pts and 25.9%, 11.1% and 5.6% of PBO pts, respectively. Pts reaching and staying on 4.8 mg BI 456906 achieved BW loss of 18.7% at W46. Adverse events (AEs) were reported by 90.9% of BI 456906 pts (TS; 0.6 mg, 90.9%; 2.4 mg, 89.7%; 3.6 mg, 92.2%; 4.8 mg, 90.9%) and 75.3% of PBO pts, mainly gastrointestinal (TS; 0.6 mg, 57.1%; 2.4 mg, 85.9%; 3.6 mg, 75.3%; 4.8 mg, 81.8%; PBO, 41.6%); 24.6% of BI 456906 pts and 3.9% of PBO pts stopped treatment, mainly during dose escalation. Serious AE incidence was similar in BI 456906 and PBO pts (TS; 0.6 mg, 1.3%; 2.4 mg, 2.6%; 3.6 mg, 7.8%; 4.8 mg, 5.2%; vs PBO, 6.5%). Over 46 weeks, BI 456906 showed substantial BW loss efficacy with no unexpected safety concerns. Disclosure C.Le roux: Advisory Panel; Novo Nordisk, Boehringer Ingelheim Inc., Lilly, Herbalife International of America, Inc., Johnson & Johnson, Medtronic, GI Dynamics, Keyron Ltd. O.Steen: None. K.J.Lucas: None. E.Startseva: Employee; Boehringer Ingelheim International GmbH. A.Unseld: None. A.M.Hennige: Employee; Boehringer Ingelheim International GmbH. Funding Zealand Pharma A/S; Boehringer Ingelheim

Die kardiovaskuläre Endpunktstudie LEADER (NCT01179048) untersuchte Liraglutid vs. Placebo zusätzlich zu Standardbehandlung bei 9.340 Patienten mit Typ 2 Diabetes und hohem kardiovaskulärem Risiko (mediane Beobachtungszeit 3,8 Jahre). Unter Liraglutid zeigten sich niedrigere Raten für schwere kardiovaskuläre Ereignisse (MACE) und Hypoglykämie, eine verbesserte Kontrolle von Glykämie, Gewicht, systolischem Blutdruck und Lipiden.

Aim Glucagon-like peptide-1 receptor agonist (GLP-1RA) and insulin combination therapy is an effective treatment option for type 2 diabetes, but long-term data are lacking. The aim was to assess the long-term efficacy of the GLP-1RA liraglutide in subgroups by insulin use in the LEADER trial. Materials and Methods LEADER assessed cardiovascular (CV) safety and efficacy of liraglutide (1.8 mg) versus placebo (plus standard of care therapy) in 9340 patients with type 2 diabetes and high risk of CV disease, for up to 5 years. We analyzed CV events, metabolic parameters and hypoglycaemia post hoc in three subgroups by baseline insulin use (basal-only insulin, other insulin or no insulin). Insulin was a non-random treatment allocation as part of standard of care therapy. Results At baseline, 5171 (55%) patients were not receiving insulin, 3159 (34%) were receiving basal-only insulin and 1010 (11%) other insulins. Insulin users had a longer diabetes duration and slightly worse glycaemic control (HbA1c) than the no-insulin subgroup. Liraglutide reduced HbA1c and weight versus placebo in all three subgroups (P < .001), and severe hypoglycaemia rate in the basal-only insulin subgroup. The need for insulin was less with liraglutide. CV risk reduction with liraglutide was similar to the main trial results in the basal-only and no-insulin subgroups. Conclusions In patients on insulin, liraglutide improved glycaemic control, weight and need for insulin versus placebo, for at least 36 months with no increased risk of severe hypoglycaemia, while maintaining CV safety/efficacy, supporting the combination of liraglutide and insulin for management of type 2 diabetes.

Combining GLP-1 analogs and insulin has complementary benefits, but long-term data are sparse. In the LEADER cardiovascular (CV) outcomes trial (N=9340; median follow-up 3.8 years; NCT01179048), rates of major CV events and hypoglycemia were lower when liraglutide vs. placebo was added to standard care (frequently including insulin) in patients with type 2 diabetes (T2D) at high risk for CV disease, and there were improvements in control of glycemia, body weight, systolic blood pressure (SBP) and lipids. This post-hoc subgroup analysis assessed these outcomes by baseline insulin use: no insulin vs. basal-only vs. other. At baseline, 5171 (55%) patients were not on insulin treatment, 3159 (34%) were on basal-only insulin and 1010 (11%) were treated with other insulin regimens (9.7% premix). Insulin use at baseline was balanced overall between randomized treatment groups, but fewer patients randomized to liraglutide (29%) vs. placebo (43%) initiated in-trial insulin. In the basal-only subgroup, liraglutide reduced A1C vs. placebo (estimated treatment difference [ETD]: −0.48%, 95% CI: −0.57; −0.38), with a significant reduction in severe hypoglycemia rate (estimated rate ratio: 0.42, 95% CI: 0.26; 0.68). Liraglutide also reduced weight (ETD: −2.5 kg, 95% CI: −3.0; −2.1) and there were trends for reductions in SBP (ETD: −1.1 mmHg, 95% CI: −2.4; 0.1) and LDL cholesterol (ETD: -1.3 mg/dL, 95% CI: -3.6; 1.0). The CV risk reduction observed with liraglutide in the full trial population was similar in the basal-only subgroup (estimated hazard ratio: 0.84, 95% CI: 0.70; 1.00). Results were similar in the no-insulin subgroup. There was heterogeneity in the results for the smaller, other insulin subgroup with reductions in A1C and weight, but no significant differences in other endpoints. In conclusion, in basal insulin-treated patients with T2D and high CV risk, treatment with liraglutide improved glycemic control, reduced body weight and halved the severe hypoglycemia risk, with a similar CV risk reduction to patients not on insulin. Disclosure C. Tack: Advisory Panel; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S, AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; Novo Nordisk A/S. S. Jacob: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, AstraZeneca, Eli Lilly and Company. Board Member; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk Foundation. Advisory Panel; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K., Menarini Group, Roche Diabetes Care Health and Digital Solutions. C. Desouza: Consultant; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Merck & Co., Inc.. Advisory Panel; Self; Medscape. S.C. Bain: Research Support; Self; Novo Nordisk Inc., AstraZeneca. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Fractyl Laboratories, Inc., GlaxoSmithKline plc., Berlin-Chemie AG, Merck Sharp & Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim GmbH, Eli Lilly and Company, Berlin-Chemie AG, Merck Sharp & Dohme Corp., Medscape, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Berlin-Chemie AG, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, GlaxoSmithKline plc., Novo Nordisk A/S. Consultant; Self; Nordic Bioscience, Empros. J. Petrie: Advisory Panel; Self; Novo Nordisk A/S. Other Relationship; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Pfizer Inc.. Consultant; Self; Novo Nordisk A/S. Research Support; Self; Merck KGaA, Itamar Medical Ltd., Janssen Pharmaceuticals, Inc.. Other Relationship; Self; Diabetes UK, Applied Clinical Intelligence Ltd, Bayer AG, QuintilesIMS. N.R. Poulter: Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc.. Research Support; Self; Servier. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S, Amgen Inc., Servier. Other Relationship; Self; International Society of Hypertension. R.E. Pratley: Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., Sanofi-Aventis, Takeda Development Center Americas, Inc. H. Stegmann: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. H. Bosch-Traberg: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. E. Startseva: Employee; Self; Novo Nordisk A/S. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck & Co., Inc., Abbott.