Impact of microvascular disease on cardiovascular outcomes in type 2 diabetes: Results from the LEADER and SUSTAIN 6 clinical trials

Abstract

The randomized, double-blind, cardiovascular outcomes trials LEADER (NCT01179048) and SUSTAIN 6 (NCT01720446) showed cardiovascular risk reduction in patients with type 2 diabetes treated with liraglutide and semaglutide, respectively, compared with placebo. This post hoc analysis examined the impact of microvascular disease at baseline on cardiovascular outcomes in these trials, and the efficacy of liraglutide (1.8 mg) and once-weekly semaglutide (0.5-1.0 mg) in patients with and without microvascular disease. In total, 9340 patients from LEADER and 3297 patients from SUSTAIN 6 were included in this analysis; of these, 5761 and 2356 had a history of microvascular disease at baseline and 3835 and 1640 had a history of both microvascular and macrovascular disease, respectively. Patients with microvascular disease were shown to have an increased risk of major adverse cardiovascular events compared with patients without microvascular disease (hazard ratio [95% confidence interval] in LEADER: 1.15 [1.03; 1.29], P = .0136; SUSTAIN 6: 1.56 [1.14; 2.17], P = .0064). Liraglutide and semaglutide consistently reduced cardiovascular risk in patients with and without microvascular disease.

Keywords: cardiovascular disease; diabetic nephropathy; diabetic neuropathy; diabetic retinopathy; macrovascular disease; type 2 diabetes.

Conflict of interest statement

SV has received research grants and/or speaking honoraria from Boehringer Ingelheim/Eli Lilly, AstraZeneca, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Valeant and Amgen. SCB has received research grants (includes principal investigator, collaborator or consultant and pending grants/grants already received) from Healthcare and Research Wales (Welsh Government) and Novo Nordisk. He has received other research support from Healthcare and Research Wales (Welsh Government), honoraria from Novo Nordisk, Sanofi, Lilly, Boehringer Ingelheim and Merck, and has ownership interest in Glycosmedia (diabetes online news service). JBH, SR and MSR are full‐time employees of Novo Nordisk A/S. SR also holds stocks in Novo Nordisk A/S. JFEM has received speaker honoraria from Amgen, Astra, Boehringer Ingelheim, Braun, Fresenius, Gambro, Eli Lilly & Co, Medice, Novo Nordisk, Relypsa and Roche; research support from the European Union, Canadian Institutes of Health Research, Boehringer Ingelheim, Celgene, Novo Nordisk, Roche and Sandoz; and consulting fees from Astra, Bayer, Celgene, Fresenius, Eli Lilly & Co, Lanthio Pharma, Novo Nordisk, Relypsa, Sanifit and Vifor Pharma. MAN has served on advisory boards or consulted for AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., Fractyl, GlaxoSmithKline, Servier, Menarini/Berlin Chemie, Merck, Sharp & Dohme and Novo Nordisk. His institution has received grant support from AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., GlaxoSmithKline, Intarcia, Menarini/Berlin‐Chemie, Merck, Sharp & Dohme, Novartis Pharma and Novo Nordisk A/S. He has served on speakers' bureau of AstraZeneca, Boehringer Ingelheim, Eli Lilly & Co., GlaxoSmithKline, Menarini/Berlin Chemie, Sun Pharma, Merck, Sharp & Dohme and Novo Nordisk A/S. REP has received research grants from Gilead Sciences, Lexicon Pharmaceuticals, Ligand Pharmaceuticals Inc., Lilly, Merck, Novo Nordisk, Sanofi‐Aventis US LLC and Takeda; has acted as a speaker for AstraZeneca, Novo Nordisk and Takeda; and as 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 (AdventHealth). BZ has received consulting fees from Merck, Novo Nordisk, Sanofi‐Aventis, Eli Lilly, AstraZeneca, Janssen and Boehringer Ingelheim. JBB has been an advisor (all fees paid to the University of North Carolina) for Adocia, AstraZeneca, Dance Biopharm, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, vTv Therapeutics and Zafgen; and received grant support from Novo Nordisk, Sanofi and vTv Therapeutics. He is a consultant to Cirius Therapeutics, CSL Behring, Mellitus Health, Neurimmune AG, Pendulum Therapeutics and Stability Health, and holds stock options in Mellitus Health, Pendulum Therapeutics, PhaseBio and Stability Health. He is supported by a grant from the National Institutes of Health (UL1TR002489).

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

Figures

FIGURE 1

LEADER and SUSTAIN 6 patient populations by microvascular disease at baseline: Venn diagram of number (%) of patients according to microvascular diseases at baseline in LEADER and SUSTAIN 6

FIGURE 2

Cardiovascular (CV) events by history of microvascular disease in LEADER and SUSTAIN 6: Kaplan–Meier estimates (based on number of microvascular diseases at baseline) of A, time to first major adverse cardiovascular events (MACE, composite of CV death, non‐fatal myocardial infarction or non‐fatal stroke) and B, time to first expanded MACE (composite also including coronary revascularization, or hospitalization for unstable angina or heart failure), in LEADER and SUSTAIN 6