PDF: SUSTAIN-6
(2016)Objective
Semaglutide - To assess cardiovascular safety of once-weekly semaglutide in patients with type 2 diabetes at high cardiovascular risk.
Study Summary
• Nonfatal stroke: 1.6% vs 2.7%, HR 0.61 (95% CI 0.38–0.99), p=0.04
• CV death: 2.7% vs 2.8%, HR 0.98 (NS); nonfatal MI: 2.9% vs 3.9%, HR 0.74 (NS)
• Retinopathy complications were increased with semaglutide: 3.0% vs 1.8%, HR 1.76 (95% CI 1.11–2.78), p=0.02
Intervention
Randomized, double-blind, placebo-controlled trial at 230 sites in 20 countries. 3297 patients with type 2 diabetes were assigned to semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. Patients were ≥50 years with established CVD, CKD, or ≥60 years with risk factors. The primary endpoint was time to first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke.
Inclusion Criteria
Type 2 diabetes with HbA1c ≥7%. Either established cardiovascular disease, stage 3+ CKD, or ≥60 years with ≥1 CV risk factor.
Study Design
Arms: Semaglutide (0.5 mg or 1.0 mg weekly) vs. Placebo
Patients per Arm: Semaglutide: 1648; Placebo: 1649
Outcome
• Nonfatal Stroke: 1.6% vs. 2.7%; HR 0.61 (95% CI, 0.38–0.99); P=0.04
• Nonfatal MI: 2.9% vs. 3.9%; HR 0.74 (95% CI, 0.51–1.08); P=0.12
• CV Death: 2.7% vs. 2.8%; HR 0.98 (95% CI, 0.65–1.48); P=0.92
• New or worsening nephropathy: 3.8% vs. 6.1%; HR 0.64 (95% CI, 0.46–0.88); P=0.005
• Retinopathy complications: 3.0% vs. 1.8%; HR 1.76 (95% CI, 1.11–2.78); P=0.02
Bottom Line
In patients with type 2 diabetes at high cardiovascular risk, once-weekly semaglutide significantly lowered the composite rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke versus placebo (HR 0.74; 95% CI 0.58–0.95), confirming noninferiority. The nominal superiority finding (P=0.02) was NOT prespecified and was driven mainly by a 39% reduction in nonfatal stroke; the cardiovascular-death component was unchanged (HR 0.98).
Major Points
- Trial enrolled a high-risk population: 83% had established cardiovascular disease, chronic kidney disease, or both at baseline (2,735/3,297 patients); 17% had CV risk factors only.
- Semaglutide significantly lowered the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 26% compared to placebo.
- This reduction was primarily driven by a significant (39%) decrease in nonfatal stroke and a nonsignificant (26%) decrease in nonfatal myocardial infarction.
- There was no significant difference in the rate of cardiovascular death between the semaglutide and placebo groups.
- Semaglutide was associated with significant and sustained reductions in glycated hemoglobin levels (0.7 percentage points lower for 0.5 mg, 1.0 percentage point lower for 1.0 mg) and body weight (2.9 kg lower for 0.5 mg, 4.3 kg lower for 1.0 mg) compared to placebo.
- Patients treated with semaglutide had a lower risk of new or worsening nephropathy but a higher risk of diabetic retinopathy complications.
- Gastrointestinal disorders were more frequent in the semaglutide group, leading to more treatment discontinuations.
- The study confirmed the noninferiority of semaglutide and also showed a significantly lower risk of the primary outcome among patients in the semaglutide group.
- Retinopathy complications were specifically broken down: retinal photocoagulation 2.3% vs 1.2%, intravitreal agent 1.0% vs 0.8%, vitreous hemorrhage 1.0% vs 0.4%, diabetes-related blindness 0.3% vs 0.1% (semaglutide vs placebo).
- Systolic blood pressure was modestly reduced with semaglutide (−1.3 mm Hg at 0.5 mg, P=0.10; −2.6 mm Hg at 1.0 mg, P<0.001 vs placebo), while pulse rate increased by 2.0–2.5 bpm.
- The trial was conducted at 230 sites across 20 countries and was designed to exclude a noninferiority margin of 1.8 on the upper bound of the hazard-ratio 95% CI; superiority testing was not prespecified.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 3297
- Follow-up
- 104-week treatment period with a 5-week follow-up period; median observation time was 2.1 years
- Centers
- 230
- Countries
- Denmark, Germany, Italy, Canada, United Kingdom, United States, Spain, Brazil
Primary Outcome
Definition: First occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 8.9% (146 of 1649 patients) | 6.6% (108 of 1648 patients) | 0.74 (0.58 to 0.95) | <0.001 for noninferiority; 0.02 for superiority |
Limitations & Criticisms
- The trial was powered as a noninferiority study to exclude a preapproval safety margin of 1.8, not specifically to show superiority.
- Patients were followed for a relatively short duration (2.1 years).
- The generalizability of these findings to other populations and a longer duration of treatment is unknown.
- The extent to which greater glycated hemoglobin reductions in the semaglutide group contributed to the results is unknown.
- The unexpected higher rate of retinopathy complications in the semaglutide group warrants further investigation, as its applicability to rapid glucose lowering is unclear, and a direct effect of semaglutide cannot be ruled out.
- Superiority testing was not prespecified and was not adjusted for multiplicity, so the significant superiority P-value (0.02) should be interpreted as nominal/exploratory rather than confirmatory.
- No significant difference in cardiovascular death (HR 0.98) or all-cause death (HR 1.05); the composite benefit was driven almost entirely by nonfatal stroke reduction, with a non-significant trend for nonfatal MI.
- Retinopathy signal: the observed excess (HR 1.76) occurred predominantly in patients with preexisting retinopathy at baseline (84% of events), and a direct causal mechanism versus rapid glycemic lowering cannot be disentangled from this trial.
Citation
N Engl J Med 2016;375:1834-44.