SUSTAIN-6 Trial Summary: Semaglutide Cardiovascular Outcomes

Design

Randomized, double-blind, placebo-controlled cardiovascular outcomes trial (CVOT) enrolling 3,297 patients with type 2 diabetes and established cardiovascular disease, chronic kidney disease, or both. Participants were randomized 1:1:1:1 to semaglutide 0.5 mg once weekly, semaglutide 1.0 mg once weekly, or volume-matched placebo for each dose. The trial was designed as a pre-approval regulatory requirement to demonstrate cardiovascular safety (non-inferiority to placebo for major adverse cardiovascular events), with a pre-specified analysis for superiority if non-inferiority was met. Median follow-up was 2.1 years. Standard-of-care diabetes management was continued in all groups, with investigators permitted to adjust background medications as needed.

Primary result

The primary composite endpoint of major adverse cardiovascular events (MACE) — cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke — occurred in 6.6% of semaglutide-treated patients versus 8.9% of placebo-treated patients. The hazard ratio was 0.74 (95% CI, 0.58-0.95), representing a 26% relative risk reduction. Non-inferiority was confirmed (p < 0.001 for non-inferiority) and superiority was demonstrated (p = 0.02 for superiority). The cardiovascular benefit was driven primarily by reductions in non-fatal stroke (HR 0.61) and non-fatal myocardial infarction (HR 0.74). Cardiovascular death was numerically but not statistically significantly reduced (HR 0.98).

Secondary outcomes

Mean HbA1c reduction was 1.1% with semaglutide 0.5 mg and 1.4% with semaglutide 1.0 mg versus 0.4% with placebo. Body weight decreased by 3.6 kg (0.5 mg) and 4.9 kg (1.0 mg) versus 0.7 kg with placebo. Semaglutide reduced the need for initiation of insulin therapy and new or worsening nephropathy (HR 0.64), primarily driven by reductions in new-onset macroalbuminuria. Systolic blood pressure decreased by 1.3-2.6 mmHg more with semaglutide than placebo.

Adverse events

Gastrointestinal adverse events were the most common reason for treatment discontinuation: nausea, vomiting, and diarrhea occurred more frequently with semaglutide. Treatment discontinuation due to adverse events was 13.4% with semaglutide 0.5 mg and 12.1% with semaglutide 1.0 mg versus 7.6% with placebo. Retinopathy complications (vitreous hemorrhage, blindness, or need for treatment with an intravitreal agent or photocoagulation) occurred more frequently with semaglutide (3.0%) than placebo (1.8%), an unexpected finding attributed to the rapid improvement in glycemic control rather than a direct drug effect. Rates of pancreatitis were low and not significantly different between groups. Neoplasms were balanced between treatment and placebo groups.

Interpretation

SUSTAIN-6 exceeded its regulatory mandate of demonstrating cardiovascular safety by establishing cardiovascular benefit — semaglutide was the second GLP-1 receptor agonist (after liraglutide in the LEADER trial) to demonstrate reduced MACE in patients with type 2 diabetes at high cardiovascular risk. The 26% relative risk reduction in MACE positioned semaglutide as both a glucose-lowering and cardioprotective therapy. The retinopathy signal prompted further investigation and monitoring recommendations, though subsequent analyses suggested the finding was related to the magnitude and rapidity of HbA1c reduction in patients with pre-existing retinopathy rather than a direct toxic effect. SUSTAIN-6 was a pivotal trial in transforming semaglutide from a diabetes medication into a cardiometabolic intervention, and its cardiovascular findings were later reinforced and extended by the SELECT trial in patients with obesity without diabetes.