By Sophia Ramirez

What Multiple NEJM Trials Show on Semaglutide and Cardiovascular Risk

Three trials published in the New England Journal of Medicine tested semaglutide and liraglutide for effects on heart health. The largest one, called SELECT, looked at adults with overweight or obesity who did not have diabetes. It found that semaglutide cut the rate of major adverse cardiovascular events by 20 percent compared with placebo.

The results add to earlier data from patients with type 2 diabetes. Together the studies show a pattern of lower cardiovascular risk, weight loss, and shifts in related markers such as blood pressure and lipids. These findings have drawn attention from clinicians tracking treatment options for high-risk groups.

SELECT Trial in Obesity Without Diabetes

The SELECT trial enrolled 17,604 participants. Semaglutide 2.4 mg given weekly reduced major adverse cardiovascular events by 20 percent versus placebo, with a hazard ratio of 0.80 (95 percent CI 0.72-0.90, p<0.001). [1] Average weight dropped 9.4 percent in the semaglutide group at 104 weeks, compared with 0.9 percent for those on placebo. [1]

SUSTAIN-6 Results in Type 2 Diabetes

The SUSTAIN-6 trial tested subcutaneous semaglutide in patients with type 2 diabetes. It reported a 26 percent lower rate of major adverse cardiovascular events, with a hazard ratio of 0.74 (95 percent CI 0.58-0.95, p=0.02). [3] Improvements in glycemic control, blood pressure, and lipid levels appeared alongside the cardiovascular findings.

LEADER Trial With Liraglutide

Researchers examined liraglutide in the LEADER trial, which included 9,340 adults with type 2 diabetes. The drug was associated with a 13 percent reduction in major adverse cardiovascular events (hazard ratio 0.87, 95 percent CI 0.78-0.97, p=0.01). [2] This study helped establish the broader class effect for GLP-1 receptor agonists.

Observed Cardiometabolic Patterns

Across the trials, participants on active treatment showed weight reductions between 9 and 15 percent at higher doses of semaglutide. Blood pressure and lipid profiles also moved in favorable directions. The cardiovascular benefit showed up even after researchers accounted for glucose changes, which points to effects that go beyond sugar control alone.

What this means

The body of evidence links GLP-1 receptor agonists to fewer composite cardiovascular events in adults who have established heart disease or elevated risk. Benefits appeared in groups both with and without type 2 diabetes. Weight loss and other metabolic shifts occurred at the same time, yet the studies do not clarify how these changes drive the heart outcomes.

Key takeaways

• The SELECT trial found semaglutide reduced major adverse cardiovascular events by 20 percent in adults with overweight or obesity but without diabetes (HR 0.80, 95 percent CI 0.72-0.90). [1]
• Semaglutide lowered MACE by 26 percent in the SUSTAIN-6 trial among patients with type 2 diabetes (HR 0.74). [3]
• Liraglutide showed a 13 percent reduction in MACE in the LEADER trial (HR 0.87). [2]
• Mean weight loss reached 9.4 percent with semaglutide versus 0.9 percent with placebo at 104 weeks in SELECT. [1]
• Gastrointestinal side effects were the most common reason for stopping treatment across the studies.

Limitations

The trials mainly recruited people who already had atherosclerotic cardiovascular disease or high risk for it. Information on primary prevention in lower-risk adults stays limited. Long-term data beyond four years on safety, muscle loss, and bone health remain sparse. High discontinuation rates tied to gastrointestinal tolerability, cost, and access issues reduce how well the results translate to everyday settings. Most evidence comes from injectable forms, while comparisons with oral versions continue to develop.

FAQ

What was the primary cardiovascular outcome and result in the SELECT trial for semaglutide?
The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke. Semaglutide reduced this outcome by 20 percent compared with placebo (HR 0.80). [1]

Do GLP-1 receptor agonists demonstrate cardiometabolic benefits in adults without type 2 diabetes?
The SELECT trial reported cardiovascular event reduction and 9.4 percent average weight loss in participants without diabetes. Improvements in blood pressure and lipids were also observed. [1]

What are the key safety findings and limitations across GLP-1 cardiovascular outcome trials?
Gastrointestinal events were the most frequent side effects and the leading cause of discontinuation. The studies enrolled mostly high-risk patients, so data on broader populations and very long-term use are limited. [1][2][3]

Sources / References

1. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa2307563

2. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa1603827

3. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. The New England Journal of Medicine. https://www.nejm.org/doi/full/10.1056/NEJMoa1607141