Effects of once-weekly semaglutide on major adverse cardiovascular events in patients with type 2 diabetes and polyvascular disease: a post hoc analysis of the SUSTAIN 6 trial

Abstract

Abstract Background The presence of polyvascular disease (defined as atherosclerosis involving ≥2 distinct vascular territories) is a strong, independent predictor of subsequent cardiovascular (CV) events in patients with type 2 diabetes (T2D). In the SUSTAIN 6 trial, the glucagon-like peptide-1 receptor agonist once-weekly (OW) subcutaneous semaglutide reduced major adverse cardiovascular events (MACE; a composite of death from CV causes, non-fatal myocardial infarction and non-fatal stroke) in patients with T2D at high CV risk. Purpose This analysis of SUSTAIN 6 assessed the effect of OW semaglutide on MACE in patients with T2D, stratified by the number of atherosclerotic vascular territories at baseline. Methods Patients in SUSTAIN 6 were randomised to receive 0.5 or 1.0 mg OW subcutaneous semaglutide or placebo. The median follow-up was 2.1 years. In this post hoc analysis, the SUSTAIN 6 population was stratified according to documented atherosclerosis: polyvascular disease (≥2 vascular territories), single vascular disease (1 vascular territory) or no atherosclerotic cardiovascular disease (ASCVD). Time to first MACE was analysed using a stratified Cox proportional hazards model, with pooled treatment by vascular risk group as fixed factors. Results In SUSTAIN 6, 640 patients (19.4%) had polyvascular disease, 1821 patients (55.2%) had vascular disease in one arterial bed and 836 patients (25.4%) had no ASCVD at baseline. Demographic and clinical characteristics at baseline are presented in the Table. In the total population, the presence of polyvascular disease and single vascular disease was associated with a greater risk of MACE, compared with no ASCVD (hazard ratio [HR]: 2.25 [95% confidence interval – CI: 1.47;3.52] and HR: 1.64 [95% CI: 1.11;2.48], respectively). In the SUSTAIN 6 trial, OW semaglutide significantly reduced the risk of MACE vs placebo (HR: 0.74 [95% CI: 0.58;0.95]). In this analysis, the risk of MACE was consistently lower with OW semaglutide vs placebo across those with polyvascular disease, single vascular disease and no ASCVD (pinteraction=0.98) (Figure). The absolute risk reductions for OW semaglutide vs placebo at 2 years were 3.37% [95% CI: –1.28;8.02] (number needed to treat [NNT] 30) in patients with polyvascular disease, 2.02% [95% CI: –0.30;4.34] (NNT 50) in patients with single vascular disease and 0.78% [95% CI: –1.96;3.52] (NNT 128) in patients with no ASCVD. Conclusion Patients with polyvascular disease in the SUSTAIN 6 trial population are at over two times greater risk of MACE than those without ASCVD. The MACE risk reduction with OW semaglutide vs placebo is consistent across people with T2D and polyvascular disease, single vascular disease or no ASCVD. However, patients with T2D and polyvascular disease may derive greater absolute benefit from semaglutide treatment owing to their higher risk.