SUSTAIN-6 deep-dive: semaglutide MACE outcomes in T2D (Marso 2016 NEJM)
Last verified 2026-05-28 · Phase 3 · Completed (results published November 2016) · NCT01720446 ↗
SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) was a multicenter, double-blind, placebo-controlled, event-driven phase 3 non-inferiority trial sponsored by Novo Nordisk. It enrolled 3,297 adults with type 2 diabetes who were either at least 50 years old with established cardiovascular disease, chronic kidney disease, or chronic heart failure, or at least 60 years old with cardiovascular risk factors. Participants were randomized 1:1:1:1 to weekly subcutaneous semaglutide 0.5 mg, semaglutide 1.0 mg, or volume-matched placebo for either dose, all on top of standard care. The primary endpoint was the first occurrence of a three-point major adverse cardiovascular event composite (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). Marso and colleagues published the results in the New England Journal of Medicine on November 10, 2016. The trial achieved both pre-specified non-inferiority and superiority on the primary endpoint and became the regulatory basis for Ozempic's cardiovascular-risk-reduction indication in adults with T2D and established cardiovascular disease.
- Enrollment
- 3,297
- Duration
- Median observation time 2.1 years (median follow-up 104 weeks); planned treatment period 104 weeks plus 5-week follow-up
- Drug
- Semaglutide 0.5 mg and 1.0 mg (subcutaneous)
- Population
- Adults with type 2 diabetes and HbA1c ≥7.0% who were either aged ≥50 years with established cardiovascular disease, chronic kidney disease (eGFR <60 mL/min/1.73 m²), or chronic heart failure (NYHA class II-III), or aged ≥60 years with cardiovascular risk factors only. Mean age 64.6 years, 39.3% female, mean BMI 32.8 kg/m², mean HbA1c 8.7%, mean diabetes duration 13.9 years. 83% had established cardiovascular disease, chronic heart failure, or chronic kidney disease at entry. Background therapy included metformin (73%), insulin (58%), sulfonylureas (43%), and antihypertensives, statins, and antiplatelet agents per standard of care.
Primary endpoint
Three-point MACE: first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (time-to-first-event, pooled semaglutide 0.5 mg + 1.0 mg vs pooled placebo)
Treatment arm
108 of 1,648 (6.6%)
Comparator
146 of 1,649 (8.9%)
Treatment difference: Hazard ratio 0.74 (95% CI 0.58–0.95); P<0.001 for non-inferiority; P=0.02 for superiority
26% relative reduction in three-point MACE with pooled semaglutide vs pooled placebo over a median 104 weeks. Absolute risk reduction 2.3 percentage points; number needed to treat ≈45 over roughly two years. The trial pre-specified non-inferiority as the primary regulatory question and pre-specified superiority as a secondary hypothesis-testing step; both were met.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Nonfatal myocardial infarction (component of MACE) 26% directional reduction in nonfatal MI; confidence interval crossed 1.0 but the point estimate aligns with the MACE result. | 47 of 1,648 (2.9%) | 64 of 1,649 (3.9%) | Hazard ratio 0.74 (95% CI 0.51–1.08); P=0.12 |
| Nonfatal stroke (component of MACE) 39% relative reduction in nonfatal stroke — the single largest component contributor to the MACE win. Direction-of-effect is opposite to liraglutide's LEADER result, where MI rather than stroke dominated the benefit. | 27 of 1,648 (1.6%) | 44 of 1,649 (2.7%) | Hazard ratio 0.61 (95% CI 0.38–0.99); P=0.04 |
| Cardiovascular death (component of MACE) No reduction in cardiovascular mortality; the MACE win was driven entirely by nonfatal events. This contrasts with LEADER (liraglutide), which showed a clear CV-death reduction. | 44 of 1,648 (2.7%) | 46 of 1,649 (2.8%) | Hazard ratio 0.98 (95% CI 0.65–1.48); P=0.92 |
| Death from any cause (all-cause mortality) Neutral on all-cause mortality at median 2.1 years; reinforces that SUSTAIN-6 was not powered to show a survival benefit and any such inference would have to come from larger or longer trials. | 62 of 1,648 (3.8%) | 60 of 1,649 (3.6%) | Hazard ratio 1.05 (95% CI 0.74–1.50); P=0.79 |
| New or worsening nephropathy composite (persistent macroalbuminuria, persistent doubling of serum creatinine with eGFR ≤45, need for continuous renal replacement therapy, or renal death) 36% relative reduction in the nephropathy composite, driven mainly by fewer new cases of persistent macroalbuminuria. Foreshadowed the kidney-focused FLOW trial reported in 2024. | 62 of 1,648 (3.8%) | 100 of 1,649 (6.1%) | Hazard ratio 0.64 (95% CI 0.46–0.88); P=0.005 |
| Diabetic retinopathy complications (vitreous hemorrhage, blindness, or need for treatment with intravitreal agent or photocoagulation) 76% relative increase in diabetic retinopathy complications on semaglutide — the most-cited safety signal from the trial. Largely concentrated in participants with pre-existing retinopathy and rapid HbA1c lowering, consistent with the long-recognized 'early worsening' phenomenon described in the DCCT. | 50 of 1,648 (3.0%) | 29 of 1,649 (1.8%) | Hazard ratio 1.76 (95% CI 1.11–2.78); P=0.02 |
| HbA1c change at week 104 (estimated treatment difference vs placebo) Dose-dependent glycemic effect from a mean baseline of 8.7%. The 1.0 mg dose became the higher-strength T2D label and the foundation for later titration to Ozempic 2.0 mg. | −1.1 percentage points (0.5 mg arm); −1.4 percentage points (1.0 mg arm) | −0.4 percentage points (pooled placebo) | Estimated treatment difference −0.7 percentage points (0.5 mg) and −1.0 percentage points (1.0 mg) vs placebo; P<0.001 for both |
| Body weight change at week 104 (estimated treatment difference vs placebo) Weight reduction was modest relative to obesity-dose semaglutide 2.4 mg (Wegovy, STEP-1) because SUSTAIN-6 used the T2D doses; the result helped seed the case for a higher-dose obesity program. | −3.6 kg (0.5 mg arm); −4.9 kg (1.0 mg arm) | −0.7 kg (pooled placebo) | Estimated treatment difference −2.9 kg (0.5 mg) and −4.3 kg (1.0 mg) vs placebo; P<0.001 for both |
| Expanded cardiovascular composite (CV death, nonfatal MI, nonfatal stroke, revascularization, or hospitalization for unstable angina or heart failure) 26% relative reduction in the broader composite; consistent with the primary MACE result and adds revascularization to the picture. | 189 of 1,648 (11.5%) | 237 of 1,649 (14.4%) | Hazard ratio 0.74 (95% CI 0.62–0.89); P=0.002 |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Discontinuation due to adverse events (pooled semaglutide vs pooled placebo) Gastrointestinal events were the dominant reason for stopping, peaking during dose-escalation. | 13.5% (0.5 mg: 11.5%; 1.0 mg: 14.5%) | 8.0% (pooled placebo) |
| Nausea Most common adverse event; mostly mild-to-moderate and concentrated in the first weeks of treatment. | 21.6% (0.5 mg); 23.8% (1.0 mg) | 8.4% (pooled placebo) |
| Diarrhea | 12.6% (0.5 mg); 14.1% (1.0 mg) | 7.5% (pooled placebo) |
| Vomiting | 10.5% (0.5 mg); 11.5% (1.0 mg) | 5.5% (pooled placebo) |
| Acute pancreatitis (adjudicated) No increased risk of pancreatitis vs placebo. Cases were balanced or numerically lower on semaglutide. | 0.5% (9/1,648) | 0.7% (12/1,649) |
| Malignant neoplasms No imbalance in overall cancer incidence between arms over the trial period. | 5.0% (82/1,648) | 4.9% (81/1,649) |
| Diabetic retinopathy complications (composite) Statistically significant excess on semaglutide (HR 1.76; P=0.02). Concentrated in participants with pre-existing retinopathy plus rapid HbA1c lowering — the FDA label now flags this and recommends monitoring. | 3.0% (50/1,648) | 1.8% (29/1,649) |
| Severe or blood-glucose-confirmed symptomatic hypoglycemia Semaglutide does not itself cause hypoglycemia, but background sulfonylurea and insulin use was high in this cohort. | Lower than placebo (per protocol-defined definitions); rate ratios not significant overall | Baseline rate from background sulfonylureas and insulin |
Subgroup analyses
- Established cardiovascular disease at baseline (~83% of cohort): MACE hazard ratio consistent with the overall result (~0.74)
Pre-specified subgroup; benefit observed across the secondary-prevention majority of the trial. This is the population that ultimately matched the FDA's cardiovascular-risk-reduction label.
- Lower-risk participants (≥60 years with CV risk factors only, no established disease; ~17% of cohort): Smaller numerical signal; the trial was not powered for this subgroup
The FDA's resulting Ozempic cardiovascular indication is narrower than the trial enrollment criteria for this reason.
- Semaglutide 0.5 mg vs 1.0 mg dose: MACE hazard ratios were similar between doses (0.5 mg HR ≈ 0.74; 1.0 mg HR ≈ 0.74)
The cardiovascular benefit did not appear dose-dependent, even though HbA1c and weight effects were. This is part of the argument that GLP-1 cardiovascular benefit is not driven by glucose lowering alone.
- Baseline retinopathy status: Excess retinopathy complications on semaglutide were concentrated in participants with retinopathy at baseline
Aligns with the 'early worsening' phenomenon documented in the DCCT when glycemia falls rapidly. The semaglutide label recommends ophthalmologic monitoring in patients with a history of retinopathy.
Clinical significance
SUSTAIN-6 is the trial that moved semaglutide from a glucose-lowering drug into a cardioprotective one and supplied the regulatory evidence for Ozempic's cardiovascular-risk-reduction indication. The 26% MACE reduction over roughly two years cleared the FDA's post-2008 standard for diabetes-drug cardiovascular safety and went further by demonstrating superiority. The dissection of the composite tells two clinical stories: cardiovascular benefit drove the win (stroke first, MI directionally), but cardiovascular and all-cause mortality were unchanged at this duration. The nephropathy result foreshadowed the FLOW kidney-outcomes trial. The retinopathy signal — modest in absolute terms but statistically real — is the durable safety caveat: clinicians should look at the eye exam before titrating rapidly in patients with established retinopathy. Together, SUSTAIN-6 plus LEADER (liraglutide) established that GLP-1 receptor agonism in T2D reduces cardiovascular events; the SELECT trial later extended the principle to obesity without diabetes.
Frequently asked questions
Does SUSTAIN-6 apply to weight-loss patients without diabetes?
No, not directly. SUSTAIN-6 enrolled only adults with type 2 diabetes at high cardiovascular risk, used the T2D doses (semaglutide 0.5 mg and 1.0 mg, not the 2.4 mg obesity dose), and supports the Ozempic cardiovascular indication, not the Wegovy one. The trial that extends GLP-1 cardiovascular benefit to obesity without diabetes is SELECT (Lincoff 2023, NEJM, PMID 37952131), which enrolled 17,604 adults with BMI ≥27 and established cardiovascular disease but no diabetes, used semaglutide 2.4 mg, and reported a 20% reduction in three-point MACE. SUSTAIN-6 is the diabetes piece of that story; SELECT is the obesity piece.
How worried should I be about the retinopathy signal?
Worth knowing, not a reason to refuse therapy for most people. SUSTAIN-6 reported 3.0% retinopathy complications on semaglutide versus 1.8% on placebo — a hazard ratio of 1.76 (95% CI 1.11–2.78). The excess was concentrated in participants who already had retinopathy at baseline and whose HbA1c fell sharply, consistent with the long-recognized 'early worsening' phenomenon that the DCCT documented decades ago with intensive insulin. The FDA semaglutide label and ADA standards recommend a baseline ophthalmologic exam before starting therapy in patients with established or risk-factor-laden retinopathy and monitoring during periods of rapid glycemic improvement. Patients without baseline retinopathy in SUSTAIN-6 did not show a meaningful excess.
How does SUSTAIN-6 compare to the SELECT trial?
Both trials answer the same question in different populations. SUSTAIN-6 tested semaglutide 0.5 mg or 1.0 mg weekly versus placebo over a median 104 weeks in 3,297 adults with type 2 diabetes and high cardiovascular risk; MACE hazard ratio was 0.74 (P=0.02 for superiority). SELECT tested semaglutide 2.4 mg weekly versus placebo over a mean 39.8 months in 17,604 adults with obesity, established cardiovascular disease, and no diabetes; MACE hazard ratio was 0.80 (P<0.001). Together they show the cardiovascular benefit holds whether or not the patient has diabetes, supports both the Ozempic and Wegovy cardiovascular indications, and that the effect size is broadly similar across populations and doses. SUSTAIN-6 came first and built the regulatory pathway; SELECT closed the loop for the obesity indication.
How did SUSTAIN-6 lead to the Ozempic cardiovascular indication?
The FDA approved semaglutide for type 2 diabetes (as Ozempic) in December 2017 based on the SUSTAIN program of efficacy trials. SUSTAIN-6 was the dedicated cardiovascular-outcomes trial. After approval, Novo Nordisk submitted SUSTAIN-6 as the pivotal evidence for adding a cardiovascular-risk-reduction claim to the label, and in January 2020 the FDA expanded the Ozempic label to include reducing the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease. The wording of the indication tracks the SUSTAIN-6 inclusion criteria for established cardiovascular disease, which is why the cardiovascular indication is narrower than the broader anti-hyperglycemic indication.
Why is 1.0 mg the higher T2D dose rather than something larger?
SUSTAIN-6 tested 0.5 mg and 1.0 mg head-to-head against placebo and showed dose-dependent gains for HbA1c and body weight without a clear dose-dependent gain for MACE. The FDA approved both doses for type 2 diabetes (Ozempic 0.5 mg and 1.0 mg) based on the SUSTAIN efficacy program, with 1.0 mg as the higher maintenance step. The 2.0 mg dose for type 2 diabetes was added later based on the SUSTAIN FORTE trial, which showed additional HbA1c lowering. The 2.4 mg dose became the obesity dose under the Wegovy label, supported by the STEP program rather than SUSTAIN-6. So 1.0 mg is the historical T2D maintenance dose because it was the highest dose tested in the original SUSTAIN cardiovascular trial — not because larger doses were unsafe.
Did SUSTAIN-6 show a survival benefit?
No. All-cause mortality was 3.8% on pooled semaglutide versus 3.6% on pooled placebo over a median 104 weeks (hazard ratio 1.05; 95% CI 0.74–1.50), and cardiovascular mortality was essentially identical between arms (HR 0.98). The MACE benefit was driven by nonfatal stroke and nonfatal myocardial infarction, not by fewer deaths. This is a different result pattern than LEADER (liraglutide, Marso 2016, PMID 27295427), where cardiovascular death itself was reduced. The difference probably reflects SUSTAIN-6's smaller size and shorter follow-up rather than a real biological gap, but the trial as published does not demonstrate a mortality benefit on its own.
References
- 1.Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, Woo V, Hansen O, Holst AG, Pettersson J, Vilsbøll T; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016. PMID: 27633186.
- 2.Novo Nordisk A/S. Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) — Study Results. ClinicalTrials.gov, NCT01720446. 2018. https://clinicaltrials.gov/study/NCT01720446
- 3.Marso SP, Daniels GH, Brown-Frandsen K, et al.; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016. PMID: 27295427.
- 4.Lincoff AM, Brown-Frandsen K, Colhoun HM, et al.; SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023. PMID: 37952131.
- 5.U.S. Food and Drug Administration. Ozempic (semaglutide) injection — Prescribing Information (cardiovascular-risk-reduction indication added January 2020). FDA Drug Label. 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209637s003lbl.pdf