Effects of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: Results of the LEADER and SUSTAIN 6 trials

Abstract

Associations between body mass index (BMI) and the cardiovascular (CV) and kidney efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) are uncertain; therefore, data analysed separately from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) were examined. These international, randomized, placebo-controlled trials investigated liraglutide and semaglutide (both subcutaneous) in patients with T2D and at high risk of CV events. In post hoc analyses, patients were categorized by baseline BMI (<25, ≥25-<30, ≥30-<35 and ≥35 kg/m2 ), and CV and kidney outcomes with GLP-1 RA versus placebo were analysed. All baseline BMI data from LEADER (n = 9331) and SUSTAIN 6 (n = 3290) were included (91% and 92% of patients with overweight or obesity, respectively). In SUSTAIN 6, nominally significant heterogeneity of semaglutide efficacy by baseline BMI was observed for CV death/myocardial infarction/stroke (major adverse CV events, primary outcome of both; Pinteraction = .02); otherwise, there was no statistical heterogeneity for either GLP-1 RA versus placebo across BMI categories for key CV and kidney outcomes. The lack of statistical heterogeneity from these cardiorenal outcomes implies that liraglutide and semaglutide may be beneficial for many patients and is probable not to depend on their baseline BMI, but further study is needed.

Trial registration: ClinicalTrials.gov NCT01179048 NCT01720446.

Keywords: body mass index, cardiovascular, liraglutide, major adverse cardiovascular events, semaglutide.

Conflict of interest statement

SV reports personal fees and other from Boehringer Ingelheim, Eli Lilly, AstraZeneca, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Valeant, Amgen, Sun Pharma and HLS Therapeutics. DKM reports consultancy fees for clinical trial leadership from AstraZeneca, Sanofi Aventis, Janssen, Boehringer Ingelheim, Merck & Co, Pfizer, Lilly US, Novo Nordisk, Lexicon, Eisai, GlaxoSmithKline and Esperion; consultancy fees from AstraZeneca, Sanofi Aventis, Lilly US, Boehringer Ingelheim, Merck & Co, Novo Nordisk, Applied Therapeutics, Afimmune and Metavant. SCB reports personal fees and other from Abbott, AstraZeneca, Boehringer Ingelheim, BMS, Cellnovo, Diartis, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi‐Aventis, Schering‐Plough, Servier and Takeda; other from Cardiff University, Doctors.net, Elsevier, Onmedica, Omnia‐Med, Medscape, All‐Wales Medicines Strategy Group, National Institute for Health and Care Excellence (NICE) UK and Glycosmedia. DLB discloses the following relationships: advisory board: Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; board of directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; chair: American Heart Association Quality Oversight Committee; data monitoring committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health Research Institute; honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Vice‐Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE‐DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS‐II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Medtelligence/ReachMD (CME steering committees), Level Ex, MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co‐leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); other: Clinical Cardiology (Deputy Editor), NCDR‐ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); research funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald's Heart Disease); site co‐investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; trustee: American College of Cardiology; unfunded research: FlowCo, Merck, Novo Nordisk, Takeda. LAL reports consultant and speaker fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi and Servier; research grant or support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Novo Nordisk and Sanofi. CDM reports research grants to institution and/or consulting honoraria from Amgen, Boehringer Ingelheim, CSL Behring, OctaPharma and Quark Pharmaceuticals. TMF and SR are employees of and shareholders in Novo Nordisk. HV was an employee of Novo Nordisk during the development of this manuscript. REP reports research grants from Gilead Sciences, Lexicon Pharmaceuticals, Ligand Pharmaceuticals Inc., Lilly, Merck, Novo Nordisk, Sanofi‐Aventis US LLC and Takeda; speaker for AstraZeneca, Novo Nordisk and Takeda; consultant for AstraZeneca, Boehringer Ingelheim, Eisai, Inc., GlaxoSmithKline, Janssen Scientific Affairs LLC, Ligand Pharmaceuticals Inc., Lilly, Merck, Novo Nordisk, Pfizer and Takeda. All payments made directly to his employer (Florida Hospital/AdventHealth). BZ reports personal fees from Merck, Sanofi‐Aventis, Eli Lilly, AstraZeneca and Janssen; personal fees and other from Novo Nordisk and Boehringer Ingelheim. JBB's contracted consulting fees are paid to the University of North Carolina by Adocia, AstraZeneca, Dance Biopharm, Dexcom, Eli Lilly, Fractyl, GI Dynamics, Intarcia Therapeutics, Lexicon, MannKind, Metavention, NovaTarg, Novo Nordisk, Orexigen, PhaseBio, Sanofi, Senseonics, vTv Therapeutics and Zafgen; he reports grant support from AstraZeneca, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon, Medtronic, Novo Nordisk, Sanofi, Theracos, Tolerion and vTv Therapeutics; he is a consultant to Cirius Therapeutics Inc, CSL Behring, Mellitus Health, Neurimmune AG, Pendulum Therapeutics and Stability Health; he holds stock/options in Mellitus Health, Pendulum Therapeutics, PhaseBio and Stability Health; and he is supported by grants from the National Institutes of Health (UL1TR002489, U01DK098246, UC4DK108612, U54DK118612), PCORI and ADA.

© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Cardiovascular outcomes by baseline body mass index category in A, LEADER and B, SUSTAIN 6. Primary and expanded MACE analyses adjusted for sex, smoking status, antihyperglycaemic treatments, prior cardiovascular (CV) events, geographic region, age, diabetes duration, estimated glomerular filtration rate. Smoking status was not adjusted for in the SUSTAIN 6 analysis for CV death because of low event numbers. †Primary major adverse cardiovascular events (MACE): composite of CV death, non‐fatal myocardial infarction (MI) and non‐fatal stroke. ‡Expanded MACE: components of primary MACE plus revascularization (coronary only in LEADER; coronary or peripheral in SUSTAIN 6) or hospitalization for unstable angina pectoris or heart failure. BMI, body mass index (in kg/m2); CI, confidence interval; HR, hazard ratio

FIGURE 2

Renal outcomes by baseline body mass index category in A, LEADER and B, SUSTAIN 6. LEADER analysis adjusted for sex, smoking status, antihyperglycaemic treatments, prior cardiovascular events, geographic region, age, diabetes duration, estimated glomerular filtration rate. SUSTAIN 6 analysis adjusted for sex, antihyperglycaemic treatments, prior cardiovascular events, geographic region, age, diabetes duration, estimated glomerular filtration rate (smoking status was omitted because of low event numbers). †Nephropathy: new or persistent macroalbuminuria, doubling of serum creatinine, creatinine clearance of less than 45 mL/min/1.73m2, end‐stage kidney disease or death from kidney disease. BMI, body mass index (in kg/m2); CI, confidence interval; HR, hazard ratio