A population-adjusted indirect comparison of cardiovascular benefits of once-weekly subcutaneous semaglutide and dulaglutide in the treatment of patients with type 2 diabetes, with or without established cardiovascular disease

Abstract

Introduction: Cardiovascular (CV) effects of once-weekly subcutaneous (s.c.) semaglutide 0.5 and 1 mg and dulaglutide 1.5 mg are reported in their respective placebo-controlled cardiovascular outcome trials (CVOTs), SUSTAIN 6 and REWIND. There is no head-to-head CVOT comparing these treatments and heterogeneity between their CVOTs renders conventional indirect comparison inappropriate. Therefore, a matching-adjusted indirect comparison (MAIC) was performed to compare the effects of s.c. semaglutide and dulaglutide on major adverse cardiovascular events (MACE) in patients with and without established cardiovascular disease (CVD).

Methods: Individual patient data from SUSTAIN 6 were matched with aggregate data from REWIND, using a propensity score method to balance baseline effect-modifying patient characteristics. Hazard ratios (HRs) for three-point (3P) MACE (CV death, non-fatal myocardial infarction, non-fatal stroke), anchored via placebo, were then indirectly compared between balanced populations. Sensitivity analyses were performed to test the robustness of the main analysis.

Results: After matching, included effect modifiers were balanced. In the main analysis, s.c. semaglutide was associated with a statistically significant 35% reduction in 3P MACE versus placebo (HR, 0.65 [95% confidence interval [CI]; 0.48, 0.87]) and nonsignificantly greater reduction (26%) versus dulaglutide (HR, 0.74 [95% CI; 0.54, 1.01]). Results were supported by all sensitivity analyses.

Conclusions: This study demonstrated a statistically significant lower risk of 3P MACE for s.c. semaglutide versus placebo, in a population with lower prevalence of pre-existing CVD than that in the pre-specified primary analysis in SUSTAIN 6. Reduction in 3P MACE with s.c. semaglutide was greater than with dulaglutide, although not statistically significant.

Keywords: GLP‐1 receptor agonist; cardiovascular risks; type 2 diabetes.

Conflict of interest statement

J.L. is an employee of Novo Nordisk A/S. P.J. and A.S. were employees of Novo Nordisk A/S during development of the manuscript. A.P. received consultancy fees for the statistical analyses presented in this manuscript; she has also received personal fees from Novo Nordisk, Sanofi and Ultragenyx. L.M.E. has received lecture fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk and research support from AstraZeneca and Novo Nordisk. Linda Mellbin has received lecture fees from Amgen, AstraZeneca, Bayer AB, Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk and Sanofi Aventis. She has also received consulting fees from or been involved in clinical trials funded by AstraZeneca, Bayer AG, Boehringer Ingelheim, Novo Nordisk and Sanofi Aventis.

© 2021 Novo Nordish A/S. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1

Summary of step‐by‐step MAIC process for the main analysis. Abbreviations: 3P MACE, 3‐point major adverse cardiovascular event; DULA, dulaglutide; PBO, placebo; SEMA, s.c. semaglutide

FIGURE 2

Forest plot for matching IPD from semaglutide trials with REWIND aggregate data—3P MACE† Abbreviations: 3P MACE, 3‐point major adverse cardiovascular event; CI, confidence interval; CVD, cardiovascular disease; DULA, dulaglutide; eGFR, estimated glomerular filtration rate; HF, heart failure HR, hazard ratio; IPD, individual patient data; MAIC, matching‐adjusted indirect comparison; MI, myocardial infarction; PAD, peripheral arterial disease; PBO, placebo; SEMA, semaglutide; UACR, urinary albumin‐to‐creatinine ratio. †Sensitivity analysis 1: SUSTAIN 6 + PIONEER 6, CVD effect modifiers (MI, stroke, HF, PAD), eGFR and UACR dichotomous (eGFR <60/eGFR ≥60 ml/min/1.73 m2; UACR <3.39 vs. ≥3.39 mg/mmol); Sensitivity analysis 2: SUSTAIN 6, CVD effect modifiers (MI, stroke, HF, PAD), eGFR and UACR continuous; Sensitivity analysis 3: SUSTAIN 6, CVD effect modifiers (MI, stroke, HF, PAD). References: 1. (Marso et al. 13 ); 2. (Husain et al. 13 ); 3. (Gerstein et al. 13 )