Background
The FDA required cardiovascular outcome trials (CVOTs) for all new diabetes drugs after 2008. SUSTAIN-6 was a preapproval CVOT for semaglutide, evaluating its cardiovascular safety and potential benefit in type 2 diabetes patients with high cardiovascular risk.
Methods
Phase 3b, double-blind, placebo-controlled trial. Participants had type 2 diabetes and established cardiovascular disease or chronic kidney disease, or were ≥60 years with cardiovascular risk factors. Randomized 1:1:1:1 to semaglutide 0.5 mg, 1.0 mg, or matching placebo (combined as one group for primary analysis).
Primary endpoint: MACE (cardiovascular death, nonfatal MI, nonfatal stroke).
Key Findings
| Outcome | Semaglutide | Placebo | HR (95% CI) |
|---|---|---|---|
| Primary MACE | 6.6% | 8.9% | 0.74 (0.58–0.95) |
| Nonfatal stroke | 1.6% | 2.7% | 0.61 (0.38–0.99) |
| Nonfatal MI | 2.9% | 3.9% | 0.74 (0.51–1.08) |
| HbA1c reduction | −1.1% (1.0 mg) | −0.4% | — |
| Weight loss | −3.6 kg (1.0 mg) | −0.7 kg | — |
Clinical Significance
SUSTAIN-6 was the first trial to demonstrate cardiovascular superiority for semaglutide (and one of the first for any GLP-1 agonist). The 26% relative risk reduction in MACE met the superiority threshold, leading to an FDA label update for cardiovascular risk reduction.
Notable: The stroke reduction was particularly pronounced (39% RRR), distinguishing semaglutide from liraglutide in the LEADER trial.
Limitations
- Not powered to evaluate individual MACE components separately
- Relatively short duration (2 years) for a CV outcome trial
- Open-label rescue medication use permitted