Applying REWIND cardiovascular disease criteria to SUSTAIN 6 and PIONEER 6: An exploratory analysis of cardiovascular outcomes with semaglutide

Abstract

In the REWIND trial, dulaglutide reduced cardiovascular (CV) risk versus placebo in patients with type 2 diabetes in both the "established CV disease" (CVD) and "CV risk factor" subgroups. The SUSTAIN 6 and PIONEER 6 trials of semaglutide used different criteria for established CVD from those used in REWIND. The present post hoc analysis assessed the effect of semaglutide on major adverse CV events (MACE) in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re-categorized into CV risk subgroups using the REWIND CVD criteria. In the pooled analysis (n = 6480), a lower percentage of patients were in the established CVD subgroup, when using the REWIND CVD criteria, compared with the original trial CVD criteria (66.5% vs. 83.8%, respectively). After re-categorization, the risk of MACE was significantly lower with semaglutide versus placebo in the established CVD subgroup (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.59, 0.92) and nonsignificantly lower in the CV risk factor subgroup (HR 0.84, 95% CI 0.55, 1.28) (P-interaction = 0.60). These results suggest that the CV effects of semaglutide may extend to patients with type 2 diabetes across the CV risk continuum.

Trial registration: ClinicalTrials.gov NCT01720446 NCT02692716.

Keywords: GLP-1 analogue; antidiabetic drug; cardiovascular disease; incretin therapy.

Conflict of interest statement

S.V. has received research grants and/or speaking honoraria from Boehringer Ingelheim/Eli Lilly, AstraZeneca, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Valeant and Amgen. U.F., S.R. and M.S.R. are full‐time employees of Novo Nordisk A/S. S.R. also holds stocks in Novo Nordisk A/S. M.H. has received personal fees from Boehringer Ingelheim and Janssen Inc. for advisory panel consultancy and speaker honoraria, grants and personal fees from AstraZeneca and Merck & Co for advisory panel consultancy and investigator‐initiated clinical trial grants, personal fees from Roche for advisory panel consultancy, and grants and personal fees from Novo Nordisk for advisory panel consultancy, speaker honoraria and investigator‐initiated preclinical study grants. L.R. reports grants from the Swedish Heart Lung Foundation, Stockholm County Council and Boehringer Ingelheim, and fees for consulting and speaking from Boehringer Ingelheim, Novo Nordisk, Eli Lilly, Merck and Bayer. J.B.B.'s contracted consulting fees and travel support for contracted activities 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. J.B.B. also reports grant support from AstraZeneca, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon, Medtronic, NovaTarg, Novo Nordisk, Sanofi, Theracos, Tolerion and vTv Therapeutics, is a consultant to Cirius Therapeutics Inc, CSL Behring, Fortress Biotech, Mellitus Health, Neurimmune AG, Pendulum Therapeutics, Stability Health and Zealand Pharma, holds stock/options in Mellitus Health, Pendulum Therapeutics, PhaseBio and Stability Health, and his effort here is also supported by grants from the National Institutes of Health (UL1TR002489, P30DK124723).

© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Primary and secondary endpoints with semaglutide versus placebo in patients from SUSTAIN 6 and PIONEER 6 re‐categorized as having established cardiovascular disease (CVD) or cardiovascular (CV) risk factors using REWIND criteria. Established CVD, n = 4310; CV risk factors, n = 2170. *Major adverse CV events (MACE) = death from CV causes, nonfatal myocardial infarction (MI), nonfatal stroke. †Expanded MACE = MACE plus coronary or peripheral revascularization and hospitalization for unstable angina (UA) or heart failure (HF). Established CVD = MI, ischaemic stroke, UA, coronary heart disease or asymptomatic cardiac ischaemia, arterial revascularization and >50% stenosis of coronary, carotid or lower extremity arteries. CV risk factors = microalbuminuria/proteinuria, hypertension and left ventricular hypertrophy, left ventricular dysfunction, ankle‐brachial index <0.9, chronic kidney disease, HF or transient ischaemic attack/haemorrhagic stroke. CI, confidence interval; IR, incidence rate (events/100 patient‐years of observation); n, number of patients with event