Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Abstract

Aim To investigate the effects of semaglutide versus comparators on major adverse cardiovascular events (MACE: cardiovascular [CV] death, nonfatal myocardial infarction [MI] and nonfatal stroke) and hospitalization for heart failure (HF) in the SUSTAIN (subcutaneous semaglutide) and PIONEER (oral semaglutide) trials across subgroups of varying CV risk. Methods Post hoc analyses of individual patient‐level data combined from SUSTAIN 6 and PIONEER 6 were performed to assess MACE and HF. MACE were analysed in subjects with and without: established CV disease and/or chronic kidney disease; prior MI or stroke; and prior HF. MACE in the SUSTAIN and PIONEER glycaemic efficacy trials were also assessed. Results In SUSTAIN 6 and PIONEER 6 combined, the hazard ratio (HR) for effect of semaglutide versus placebo on overall MACE was 0.76 (95% CI 0.62, 0.92), which was mainly driven by the effect on nonfatal stroke (HR 0.65 [95% CI 0.43, 0.97]). The HR for hospitalization for HF was 1.03 (95% CI 0.75, 1.40). The HRs for MACE were <1.0 in all subgroups, except for those with prior HF (HR 1.06 [95% CI 0.72, 1.57]); P‐values for interaction of subgroup on treatment effect were >0.05, except for HF (0.046). In the combined glycaemic efficacy trials, the HR for effect of semaglutide versus comparators on MACE was 0.85 (95% CI 0.55, 1.33). Conclusions In SUSTAIN and PIONEER combined, glucagon‐like peptide‐1 analogue semaglutide showed consistent effects on MACE versus comparators across varying CV risk. No effect of semaglutide on MACE was observed in subjects with prior HF.

Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials

“…Our results are consistent overall with a post hoc analysis of pooled SUSTAIN and PIONEER data, which also showed that the effect of semaglutide vs comparators on MACE was largely consistent across different CV subgroups [35]. Furthermore, a meta-analysis including CVOTs for all GLP-1 receptor agonists found no significant heterogeneity in the effect of these therapies in subgroups with a history of CVD vs those with no history of CVD [36].…”

Oral semaglutide in patients with type 2 diabetes and cardiovascular disease, renal impairment, or other comorbidities, and in older patients

“…The HR for the expanded MACE outcome (consisting of the primary outcome plus unstable angina resulting in hospitalization or heart failure resulting in hospitalization) was similar to that of the primary outcome (HR: 0.82 [95% CI: 0.61, 1.10]) [25]. PIONEER 6 demonstrated that oral semaglutide did not result in an increase in CV risk compared with placebo [25], a finding that is supported by a post-hoc analysis of CV events across the PIONEER glycemic efficacy trials [39]. The trial was an event-driven trial designed and powered to assess noninferiority of oral semaglutide to placebo, and continued until at least 122 MACE occurred, with no predefined minimum duration.…”

“…The trial was an event-driven trial designed and powered to assess noninferiority of oral semaglutide to placebo, and continued until at least 122 MACE occurred, with no predefined minimum duration. This design differs to that of other GLP-1RA CVOTs [30], such as SUSTAIN-6 with subcutaneous semaglutide, LEADER with liraglutide, and REWIND with dulaglutide, which reported significant reductions in risk of MACE with these agents versus placebo [18][19][20] (for an in-depth overview of the designs and outcomes of PIONEER 6 and SUSTAIN-6, see Husain et al, 2020 [39]). Like PIONEER 6, SUSTAIN-6 and LEADER were conducted primarily to establish noninferiority; however, these trials were both time-and event-driven and conducted for longer than PIONEER 6, accruing more MACE than originally planned (for example, MACE occurred in 254 patients in SUSTAIN-6, versus 137 in PIONEER 6), and therefore had greater power to evaluate the potential superiority of the study drug to placebo [18,19].…”

Type of diabetes mellitus: Does it matter to the clinician?

“…However, guidelines for glucose-lowering therapy take into account only general considerations of patient phenotype and comorbidities ( Table 2) rather than actual pathophysiologic mechanisms. [45][46][47][48][49][50][51][52] After studies of monozygotic twins and other evidence indicated that type 2 diabetes was a genetic disorder, there was hope that genetic information might be directly associated with specifi c pathophysiologic mechanisms Diabetes mellitus is a syndrome HOOGWERF involved in the development of hyperglycemia. These relationships might use genetic profi les to guide pharmacotherapy.…”

“…Some glucagon-like peptide 1 receptor agonists (liraglutide,48 dulaglutide,49 and semaglutide,50 but not lixisenatide51 or exenatide [weekly formulation])52 reduce risk of major adverse cardiovascular events…”