The effect of glucagon-like peptide-1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across baseline blood pressure categories: Analysis of the LEADER and SUSTAIN 6 trials

Abstract

It is unknown if the cardioprotective and renal effects of glucagon-like peptide-1 receptor agonists are consistent across blood pressure (BP) categories in patients with type 2 diabetes and at high risk of cardiovascular events. Using data from the LEADER (9340 patients) and SUSTAIN 6 (3297 patients) trials, we evaluated post hoc the cardiorenal effect of liraglutide and semaglutide on major adverse cardiovascular events (MACE) and nephropathy by baseline BP categories using a Cox proportional hazards model (treatment and subgroup as factors; adjusted for cardiorenal risk factors). Data from the two trials were analysed separately. In the LEADER and SUSTAIN 6 trials, the prevalence of stage 1 hypertension was 30% and 31%, respectively, and of stage 2 hypertension 41% and 43%, respectively. There was no statistical heterogeneity across the BP categories for the effects of liraglutide (P = .06 for MACE; P = .14 for nephropathy) or semaglutide (P = .40 for MACE; P = .27 for nephropathy) versus placebo. This implies that liraglutide and semaglutide may be beneficial for patients with type 2 diabetes, irrespective of their baseline BP.

Trial registration: ClinicalTrials.gov NCT01179048 NCT01720446.

Keywords: MACE; blood pressure; cardiovascular; liraglutide; semaglutide.

Conflict of interest statement

LAL reports consultant and speaker fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi and Servier; and research grant or support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Novo Nordisk and Sanofi. 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; and 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 and Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care and 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), and 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), and 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, and 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), and Svelte; Trustee: American College of Cardiology; and unfunded research: FlowCo, Merck, Novo Nordisk, and Takeda. 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 and U54DK118612), PCORI and ADA. CDM reports research grants to institution and/or consulting honoraria from Amgen, Boehringer Ingelheim, CSL Behring, OctaPharma and Quark Pharmaceuticals. REP reports research grants from Gilead Sciences, Lexicon Pharmaceuticals, Ligand Pharmaceuticals Inc., Lilly, Merck, Novo Nordisk, Sanofi‐Aventis US LLC and Takeda; is a speaker for AstraZeneca, Novo Nordisk and Takeda; and a consultant for AstraZeneca, Boehringer Ingelheim, Eisai, Inc., GlaxoSmithKline, Janssen Scientific Affairs LLC, Ligand Pharmaceuticals Inc., Lilly, Merck, Novo Nordisk, Pfizer and Takeda; all payments are made directly to his employer (Florida Hospital/AdventHealth). SR is an employee of and shareholder in Novo Nordisk. MSR is an employee of Novo Nordisk. HV was an employee of Novo Nordisk at the time of manuscript development. SV reports consultant and speaker fees from Boehringer Ingelheim, Eli Lilly, AstraZeneca, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Valeant, Amgen, HLS Therapeutics and Sun Pharma; and research support from Boehringer Ingelheim, Eli Lilly and Amgen.

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

Figures

FIGURE 1

Cardiorenal outcomes by baseline blood pressure (BP) category, adjusted for baseline variables related to cardiorenal risk, in the LEADER (A) and SUSTAIN 6 trials (B). †Primary major adverse cardiovascular events (MACE): composite of cardiovascular death, non‐fatal myocardial infarction (MI) and non‐fatal stroke. Analysis adjusted for baseline characteristics related to cardiorenal risk (age, antihyperglycaemic medications, diabetes duration, geographic region, history of MI or stroke, renal function as measured by estimated glomerular filtration rate, sex, and smoking status). ‡Nephropathy (new or worsening): new or persistent macroalbuminuria, doubling of serum creatinine, end‐stage kidney disease or death from kidney disease. §Analysis adjusted as for MACE, with the omission of smoking status because of a low number of events. BP categories were defined as follows: normal = systolic blood pressure (SBP) < 120 mmHg, diastolic blood pressure (DBP) 80 mmHg; elevated = SBP 120‐129 mmHg and DBP < 80 mmHg; stage 1 hypertension = SBP 130‐139 mmHg or DBP 80‐89 mmHg; stage 2 hypertension = SBP ≥ 140 mmHg or DBP ≥ 90 mmHg. CI, confidence interval; HR, hazard ratio

FIGURE 2

Quadratic spline regression treatment differences in time to first major adverse cardiovascular events (MACE), according to baseline systolic blood pressure (SBP) (A and B) and diastolic blood pressure (DBP) (C and D), in the LEADER (A and C) and SUSTAIN 6 (B and D) trials. Primary MACE: composite of cardiovascular death, non‐fatal myocardial infarction (MI) and non‐fatal stroke. Q1, one quarter of patients had a lower blood pressure (BP) value than this. Median, half of patients had a lower BP value than this. Q3, three‐quarters of patients had a lower BP value than this. BP categories were defined as follows: normal = SBP