Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials

Bo Ahrén, Stephen L Atkin, Guillaume Charpentier, Mark L Warren, John P H Wilding, Sune Birch, Anders Gaarsdal Holst, Lawrence A Leiter, Bo Ahrén, Stephen L Atkin, Guillaume Charpentier, Mark L Warren, John P H Wilding, Sune Birch, Anders Gaarsdal Holst, Lawrence A Leiter

Abstract

Aims: To assess the effect of baseline body mass index (BMI) and the occurrence of nausea and/or vomiting on weight loss induced by semalgutide, a once-weekly glucagon-like peptide 1 analogue for the treatment of type 2 diabetes. Semaglutide demonstrated superior reductions in HbA1c and superior weight loss (by 2.3-6.3 kg) versus different comparators across the SUSTAIN 1 to 5 trials; the contributing factors to weight loss are not established.

Materials and methods: Subjects with inadequately controlled type 2 diabetes (drug-naïve or on background treatment) were randomized to subcutaneous semaglutide 0.5 mg (excluding SUSTAIN 3), 1.0 mg (all trials), or comparator (placebo, sitagliptin, exenatide extended release or insulin glargine). Subjects were subdivided by baseline BMI and reporting (yes/no) of any nausea and/or vomiting. Change from baseline in body weight was assessed within each trial and subgroup. A mediation analysis separated weight loss into direct or indirect (mediated by nausea or vomiting) effects.

Results: Clinically relevant weight-loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. Overall, 15.2% to 24.0% and 21.5% to 27.2% of subjects experienced nausea or vomiting with semaglutide 0.5 and 1.0 mg, respectively, versus 6.0% to 14.1% with comparators. Only 0.07 to 0.5 kg of the treatment difference between semaglutide and comparators was mediated by nausea or vomiting (indirect effects).

Conclusions: In SUSTAIN 1 to 5, semaglutide-induced weight loss was consistently greater versus comparators, regardless of baseline BMI. The contribution of nausea or vomiting to this weight loss was minor.

Keywords: BMI; GLP-1 analogue; GLP-1 based therapy; gastrointestinal adverse events; nausea; type 2; vomiting; weight control; weight loss.

Conflict of interest statement

B. A. has received speaking or consultancy fees from GSK, MSD, Novartis, Novo Nordisk and Sanofi. S. L. A. has received consultancy fees from Novo Nordisk. G. C. has received consultancy fees from AstraZeneca, Beckton Dickinson, Boehringer Ingelheim, Lilly, Novo Nordisk and Sanofi. M. L. W. has received speaking or consultancy fees from AstraZeneca, Lilly, Merck, Novo Nordisk and Sanofi; research funding for clinical trials (all paid to the institution) from AstraZeneca, Boehringer Ingelheim, Lilly, Mannkind Corporation, Medtronics, Mylan Pharmaceuticals, Novo Nordisk and Sanofi; and travel funding from AstraZeneca, Lilly, Novo Nordisk and Sanofi. J. P. H. W. has received consultancy fees (all paid into University funds) from GW Pharma, Janssen, Lilly, Merck, Novo Nordisk, Orexigen and Takeda; research grants for clinical trials from Janssen, Novo Nordisk, Sanofi and Takeda; and travel grants for conference attendance from Janssen and Novo Nordisk. S. B and A. G. H. are both full‐time employees of Novo Nordisk. L. A. L. has received consultancy fees from AstraZeneca, Boehringer Ingelheim, Lilly, GSK, Janssen, Merck, Novo Nordisk, Sanofi and Servier; and grant funding for CME activity from AstraZeneca, Boehringer Ingelheim, Lilly, Janssen, Merck, Novo Nordisk and Sanofi.

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
Absolute change from baseline in body weight by BMI (A) and change in body weight from baseline by nausea or vomiting (B) across the SUSTAIN 1 to 5 trials
Figure 2
Figure 2
Mediation analysis of direct and indirect (gastrointestinal adverse events) effects on weight loss for subjects treated with semaglutide 0.5 and 1.0 mg

References

    1. Guh DP, Zhang W, Bansback N, Amarsi Z, Birmingham CL, Anis AH. The incidence of co‐morbidities related to obesity and overweight: a systematic review and meta‐analysis. BMC Public Health. 2009;9:88.
    1. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113:898‐918.
    1. Jung RT. Obesity as a disease. Br Med Bull. 1997;53:307‐321.
    1. Han TS, Tijhuis MA, Lean ME, Seidell JC. Quality of life in relation to overweight and body fat distribution. Am J Public Health. 1998;88:1814‐1820.
    1. Franz MJ, Boucher JL, Rutten‐Ramos S, VanWormer JJ. Lifestyle weight‐loss intervention outcomes in overweight and obese adults with type 2 diabetes: a systematic review and meta‐analysis of randomized clinical trials. J Acad Nutr Diet. 2015;115:1447‐1463.
    1. Wing RR, Espeland MA, Clark JM, et al. Association of Weight Loss Maintenance and Weight Regain on 4‐Year Changes in CVD Risk Factors: the Action for Health in Diabetes (Look AHEAD) Clinical Trial. Diabetes Care. 2016;39:1345‐1355.
    1. Look AHEAD Research Group . Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med. 2013;369:145‐154.
    1. Ryden L, Grant PJ, Anker SD, et al. ESC Guidelines on diabetes, pre‐diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre‐diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34:3035‐3087.
    1. American Diabetes Association . Standards of Medical Care in Diabetes‐2017. Diabetes Care. 2017;40:S1‐S135.
    1. Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care. 2015;38:1777‐1803.
    1. Madsbad S. Review of head‐to‐head comparisons of glucagon‐like peptide‐1 receptor agonists. Diabetes Obes Metab. 2016;18:317‐332.
    1. Trujillo JM, Nuffer W, Ellis SL. GLP‐1 receptor agonists: a review of head‐to‐head clinical studies. Ther Adv Endocrinol Metab. 2015;6:19‐28.
    1. Kapitza C, Nosek L, Jensen L, Hartvig H, Jensen CB, Flint A. Semaglutide, a once‐weekly human GLP‐1 analog, does not reduce the bioavailability of the combined oral contraceptive, ethinylestradiol/levonorgestrel. J Clin Pharmacol. 2015;55:497‐504.
    1. Marbury T, Flint A, Segel S, Lindegaard M, Lasseter K. Pharmacokinetics and tolerability of a single dose of semaglutide, a once‐weekly human GLP‐1 analog, in subjects with and without renal impairment. Clin Pharmacokinet. 2017;56:1381‐1390.
    1. Sorli C, Harashima SI, Tsoukas GM, et al. Efficacy and safety of once‐weekly semaglutide monotherapy versus placebo in patients with type 2 diabetes (SUSTAIN 1): a double‐blind, randomised, placebo‐controlled, parallel‐group, multinational, multicentre phase 3a trial. Lancet Diabetes Endocrinol. 2017;5:251‐260.
    1. Ahrén B, Masmiquel L, Kumar H, et al. Efficacy and safety of once‐weekly semaglutide versus once‐daily sitagliptin as an add‐on to metformin, thiazolidinediones, or both, in patients with type 2 diabetes (SUSTAIN 2): a 56‐week, double‐blind, phase 3a, randomised trial. Lancet Diabetes Endocrinol. 2017;5:341‐354.
    1. Ahmann AJ, Capehorn M, Charpentier G, et al. Efficacy and safety of once‐weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56‐week, open‐label, randomized clinical trial. Diabetes Care. 2018;41:258‐266.
    1. Aroda VR, Bain SC, Cariou B, et al. Efficacy and safety of once‐weekly semaglutide versus once‐daily insulin glargine as add‐on to metformin (with or without sulfonylureas) in insulin‐naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open‐label, parallel‐group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol. 2017;5:355‐366.
    1. Rodbard HW, Lingvay I, Reed J, et al. Semaglutide added to basal insulin in type 2 diabetes (SUSTAIN 5): a randomised, controlled trial. J Clin Endocrinol Metab. 2018. 10.1210/jc.2018-00070 [Epub ahead of print].
    1. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834‐1844.
    1. Pratley RE, Aroda VR, Lingvay I, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open‐label, phase 3b trial. Lancet Diabetes Endocrinol. 2018;6:275‐286.
    1. European Medicines Agency . International Conference on Harmonisation Guideline for Good Clinical Practice E6(R2). 2009. . Accessed May 29, 2018.
    1. World Medical Association . World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013;310:2191‐2194.
    1. Vansteelandt S, Bekaert M, Lange T. Imputation strategies for the estimation of natural direct and indirect effects. Epidemiol Methods. 2012;1:131‐158.
    1. Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION‐6): a randomised, open‐label study. Lancet. 2013;381:117‐124.
    1. Ji L, Onishi Y, Ahn CW, et al. Efficacy and safety of exenatide once‐weekly vs exenatide twice‐daily in Asian patients with type 2 diabetes mellitus. J Diabetes Investig. 2013;4:53‐61.
    1. Hamano K, Nishiyama H, Matsui A, Sato M, Takeuchi M. Efficacy and safety analyses across 4 subgroups combining low and high age and body mass index groups in Japanese phase 3 studies of dulaglutide 0.75 mg after 26 weeks of treatment. Endocr J. 2017;64:449‐456.
    1. Umpierrez GE, Pantalone KM, Kwan AY, Zimmermann AG, Zhang N, Fernández Landó L. Relationship between weight change and glycaemic control in patients with type 2 diabetes receiving once‐weekly dulaglutide treatment. Diabetes Obes Metab. 2016;18:615‐622.
    1. Umpierrez G, Tofe Povedano S, Perez Manghi F, Shurzinske L, Pechtner V. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD‐3). Diabetes Care. 2014;37:2168‐2176.
    1. Russell‐Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug‐naive patients with type 2 diabetes (DURATION‐4): a 26‐week double‐blind study. Diabetes Care. 2012;35:252‐258.
    1. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD‐3 Mono): a randomised, 52‐week, phase III, double‐blind, parallel‐treatment trial. Lancet. 2009;373:473‐481.
    1. Nauck MA, Stewart MW, Perkins C, et al. Efficacy and safety of once‐weekly GLP‐1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo‐controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetologia. 2016;59:266‐274.
    1. Nauck MA, Petrie JR, Sesti G, et al. A phase 2, randomized, dose‐finding study of the novel once‐weekly human GLP‐1 analog, semaglutide, compared with placebo and open‐label liraglutide in patients with type 2 diabetes. Diabetes Care. 2016;39:231‐241.
    1. MacKinnon D. An Introduction to Statistical Mediation Analysis. New York, NY: Lawrence Erlbaum Associates; 2008.
    1. Secher A, Jelsing J, Baquero AF, et al. The arcuate nucleus mediates GLP‐1 receptor agonist liraglutide‐dependent weight loss. J Clin Invest. 2014;124:4473‐4488.
    1. Campos CA, Bowen AJ, Schwartz MW, Palmiter RD. Parabrachial CGRP neurons control meal termination. Cell Metab. 2016;23:811‐820.
    1. Betley JN, Cao ZF, Ritola KD, Sternson SM. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell. 2013;155:1337‐1350.
    1. Edwards CM, Stanley SA, Davis R, et al. Exendin‐4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab. 2001;281:E155‐E161.
    1. Naslund E, Barkeling B, King N, et al. Energy intake and appetite are suppressed by glucagon‐like peptide‐1 (GLP‐1) in obese men. Int J Obes Relat Metab Disord. 1999;23:304‐311.
    1. Blundell J, Finlayson G, Axelsen MB, et al. Effects of once‐weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity. Diabetes Obes Metab. 2017;19:1242‐1251.
    1. Rolin B, Larsen MO, Christoffersen BO, Lau J, Knudsen LB. In vivo effect of semaglutide in pigs supports its potential as a long‐acting GLP‐1 analogue for once‐weekly dosing. Diabetes. 2015;64:1119.
    1. Horowitz M, Flint A, Jones KL, et al. Effect of the once‐daily human GLP‐1 analogue liraglutide on appetite, energy intake, energy expenditure and gastric emptying in type 2 diabetes. Diabetes Res Clin Pract. 2012;97:258‐266.
    1. Flint A, Raben A, Astrup A, Holst JJ. Glucagon‐like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998;101:515‐520.

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