SUSTAIN-6: The First Semaglutide Outcomes Signal
Last verified November 2026 · Phase 3 · Finished; published November 2016 · NCT01720446 ↗
After 2008, FDA required new diabetes drugs to demonstrate they did not increase cardiovascular risk, which is why this generation of trials exists at all. SUSTAIN-6 was built to rule out harm and instead found a 26% relative reduction in events, a result large enough to change practice from a trial not powered to prove superiority. That distinction matters when reading it. A pre-specified non-inferiority design that lands on superiority is a strong signal, but it is weaker evidence than a trial designed from the start to test it, which is part of why SELECT was run.
- Enrollment
- 3,297
- Duration
- A median 2.1 years under observation, with 104 weeks of planned treatment and 5 weeks of follow-up after
- Drug
- Semaglutide 0.5 mg and 1.0 mg (subcutaneous)
- Population
- Adults with type 2 diabetes and an HbA1c of 7.0% or higher, entering either at 50 and over with established cardiovascular disease, reduced kidney function or chronic heart failure, or at 60 and over with risk factors alone. Of those enrolled, 83% arrived already carrying one of those conditions. Average age 64.6, 39.3% women, average BMI 32.8, average HbA1c 8.7%, and nearly 14 years since diagnosis. Most were on other diabetes drugs (metformin in 73%, insulin in 58%, sulfonylureas in 43%), which matters for the low-blood-sugar rows below.
The Semaglutide drug page covers the drug itself: its dosing, cost and side effects.
Primary endpoint
Cardiac death, a nonfatal heart attack, or a nonfatal stroke — whichever came first
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
A 26% reduction, or about 45 people treated for two years to prevent one event. Note what the trial set out to do: it was designed to prove the drug did not cause harm, and its published conclusion confirmed only that. The 26% reduction also points to benefit, but a trial built to rule out harm is weaker ground for a benefit claim than one built to test it, which is why SELECT was run later.
Secondary endpoints
| Endpoint | Treatment | Comparator | Difference |
|---|---|---|---|
| Heart attacks that were not fatal Down about a quarter, though the confidence interval crossed 1. The direction agrees with the headline; the certainty does not. | 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 |
| Strokes that were not fatal Down 39%, the largest relative reduction of the three components and the only one that was statistically significant on its own. This differs from the liraglutide trial, where cardiac deaths drove the benefit and neither heart attacks nor strokes fell significantly. Two drugs in one class, two different patterns. | 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 |
| Death from a cardiac cause No reduction at all. The whole headline came from non-fatal events, which is a materially different claim from what most summaries of this trial imply. | 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 at all Flat, and slightly numerically worse on the drug. This trial does not show people living longer, and it was never large enough or long enough to. | 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 |
| Kidney decline: new protein in the urine, kidney function halving, dialysis, or death from kidney causes A 36% reduction, but driven mainly by fewer new cases of protein in the urine, the softest component. It is the observation that eventually justified the dedicated kidney trial, which is where the real kidney evidence now lives. | 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 eye disease getting worse — bleeding into the eye, blindness, or needing injections or laser treatment The most important safety row on this page: a 76% relative increase, and the only clear harm signal in the trial. Read the FAQ below before drawing a conclusion. The excess was concentrated in people who already had eye disease and whose blood sugar fell fast. | 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 |
| Three-month average blood sugar at two years A clear dose response, starting from an average of 8.7%. It is why 1.0 mg became the standard higher strength in diabetes. | −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 |
| Weight change at two years Under 5 kg even at the higher dose, a fraction of what the same molecule produces at the weight-management dose. This trial is not evidence about semaglutide as a weight drug. | −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 |
| A wider count adding stent and bypass procedures and admissions for unstable chest pain or heart failure A 26% reduction across the broader definition too, which makes the headline harder to dismiss as an artifact of how events were counted. Figures are per the trial's ClinicalTrials.gov results. | 12.1% of 1,648 | 16.0% of 1,649 | Hazard ratio 0.74 (95% CI 0.62–0.89); P=0.002 |
Adverse events
| Event | Treatment rate | Comparator rate |
|---|---|---|
| Stopped the drug over a side effect 13.0% on semaglutide, rising with dose and higher than on placebo, and driven by stomach and bowel effects during the weeks the dose was climbing. | 13.0% (0.5 mg: 11.5%; 1.0 mg: 14.5%) | Lower on placebo |
| Nausea The most common complaint, roughly two to three times the placebo rate, mostly mild to moderate and concentrated in the early weeks. This row and the two below are the nonserious events in the trial's ClinicalTrials.gov results. | 17.3% (0.5 mg); 21.8% (1.0 mg) | 7.8% (pooled placebo) |
| Diarrhea About 1.6 times the placebo rate at either dose. | 17.9% (0.5 mg); 18.0% (1.0 mg) | 11.2% (pooled placebo) |
| Vomiting Two to more than three times the placebo rate. | 10.5% (0.5 mg); 14.8% (1.0 mg) | 4.5% (pooled placebo) |
| Pancreatitis, confirmed by independent review No increase; numerically there were fewer cases on the drug than on placebo. | 0.5% (9/1,648) | 0.7% (12/1,649) |
| Cancers of any kind, confirmed by independent review No overall difference (hazard ratio 0.94, 95% CI 0.67 to 1.32, per the FDA and EMA reviews); the 1.0 mg arm ran slightly above placebo (4.9%) and the 0.5 mg arm below it (3.1%). | 4.0% (66/1,648; 0.5 mg: 26, 1.0 mg: 40) | 4.2% (70/1,649) |
| Diabetic eye disease getting worse A statistically significant excess, and the reason the label now carries an eye warning. If you have any existing retinopathy, this row is the reason to get your eyes checked before you start rather than after. | 3.0% (50/1,648) | 1.8% (29/1,649) |
| Confirmed low blood sugar Lower than placebo. Semaglutide does not cause lows by itself, but 58% of this trial was on insulin and 43% on a sulfonylurea, and those are what cause them. If you take either, the doses need reviewing when you start. | Lower than placebo (per protocol-defined definitions); rate ratios not significant overall | Baseline rate from background sulfonylureas and insulin |
Subgroup analyses
- People who already had cardiovascular disease, kidney disease or both — about 83% of the trial: Benefit in line with the trial overall
This is the group the FDA indication was ultimately written around, which is why the approved use is narrower than the trial's entry criteria.
- People 60 and over with risk factors but no established disease — about 17%: A smaller signal, in a subgroup the trial was never sized to assess
Not evidence of benefit and not evidence of its absence. It is the reason the label does not cover this group.
- The lower dose against the higher one: Essentially identical reductions in cardiac events at both doses
One of the more revealing findings in this literature. Blood sugar and weight both improved more at the higher dose; cardiac events did not. That is a strong argument that the heart benefit is not simply a consequence of lowering glucose.
- Whether someone already had diabetic eye disease: The excess eye complications were concentrated almost entirely in those who did
This is what turns an alarming headline into an instruction you can act on: it is a warning about who needs monitoring, not a reason for everyone to avoid the drug.
Clinical significance
This is the origin of the claim that semaglutide protects the heart, and it applies to a specific population: type 2 diabetes with established cardiovascular disease or high risk. SELECT later extended the finding to people without diabetes, which is the version most readers of this site are in. The doses here were 0.5 and 1.0 mg, the diabetes range, not the 2.4 mg used for weight management, so this is not a trial about the drug as sold for obesity.
Who sells semaglutide, and for how much
This trial tested Semaglutide 0.5 mg and 1.0 mg (subcutaneous). Across the 734 sellers on this register, 463 publish a standing monthly cash price for compounded semaglutide, from $47 a month, with a median of $174.
⛔ None of those sellers was in this trial. A compounded preparation is not the product studied here: no agency has reviewed that specific preparation for safety, effectiveness or manufacturing quality, and its concentration is set by whichever pharmacy filled it. The result above is the strongest evidence available for semaglutide and it was generated on something else. Every seller, with its price record.
Frequently Asked Questions
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
- 6.US Food and Drug Administration Ozempic (semaglutide) NDA 209637 medical review FDA. 2017. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209637Orig1s000MedR.pdf
- 7.European Medicines Agency Ozempic: EPAR public assessment report EMA. 2018. https://www.ema.europa.eu/en/documents/assessment-report/ozempic-epar-public-assessment-report_en.pdf