A two-year follow-up analysis of the SELECT trial, the landmark cardiovascular outcomes study for semaglutide, shows that the drug's heart-protective effects persist and appear to strengthen over extended treatment. The analysis, published in The Lancet on March 12, found that semaglutide reduced major adverse cardiovascular events (MACE) by 23% compared to placebo over an extended observation period, up from the 20% reduction reported in the original trial results [1].
The SELECT trial, which enrolled 17,604 adults aged 45 and older with established cardiovascular disease and obesity but without diabetes, was the first study to demonstrate that a GLP-1 receptor agonist could reduce heart attacks, strokes, and cardiovascular death independently of its effects on blood sugar [2].
Extended Follow-Up Results
The original SELECT results, published in 2023, covered a median follow-up of 39.8 months. This new analysis extends the observation period to a median of 52 months (approximately 4.3 years) for participants who continued in the open-label extension phase.
Key findings from the extended analysis include a 23% reduction in the composite MACE endpoint (cardiovascular death, nonfatal heart attack, or nonfatal stroke), compared to the original 20% reduction. Heart attack risk dropped by 26%, compared to the original 28% in the primary analysis. Stroke risk decreased by 22%, which was not statistically significant in the original analysis but reached significance with additional follow-up time. Cardiovascular death decreased by 17%, a new finding that was not significant in the shorter follow-up period [1].
Dr. A. Michael Lincoff, the principal investigator and chair of cardiovascular medicine at the Cleveland Clinic, said the extended data strengthens the case for semaglutide as a cardiovascular medication, not just a weight loss drug.
"The durability of benefit is critical," Dr. Lincoff said during a press briefing at the American College of Cardiology meeting. "These results suggest that the cardiovascular protection does not plateau or wane with continued treatment. If anything, it deepens."
How Semaglutide Protects the Heart
The mechanism by which semaglutide reduces cardiovascular events is not fully understood, and the extended follow-up data adds new clues. Weight loss alone cannot fully explain the results, because the cardiovascular benefits appeared before most participants had achieved maximum weight loss and persisted even among the subset of patients who lost relatively little weight.
Researchers identified several pathways that likely contribute. Semaglutide reduces systemic inflammation, as measured by C-reactive protein (CRP), which dropped by 38% in treated patients and remained suppressed throughout the follow-up period. Chronic inflammation is a well-established driver of atherosclerotic plaque formation and rupture [1].
Blood pressure improvements were sustained. Treated patients maintained an average systolic blood pressure reduction of 4.8 mmHg compared to placebo over the full follow-up period. Lipid profiles improved, with LDL cholesterol decreasing by 5% and triglycerides by 18%. Insulin resistance, measured by HOMA-IR, improved by 42% even in this non-diabetic population [1].
Dr. Christie Ballantyne, professor of medicine and chief of cardiology at Baylor College of Medicine, who was not involved in the trial, noted that the multi-pathway effect distinguishes semaglutide from other cardiovascular drugs. "Statins primarily work through LDL reduction. SGLT2 inhibitors primarily affect fluid dynamics and cardiac metabolism. Semaglutide appears to work across multiple risk factors simultaneously, which may explain why the benefit grows over time."
Implications for Prescribing
The SELECT follow-up data is reshaping how cardiologists think about GLP-1 medications. The American Heart Association and the American College of Cardiology have not yet updated their formal guidelines, but several influential physicians in the cardiology community have called for faster incorporation of the evidence.
Dr. Deepak Bhatt, director of Mount Sinai Heart in New York, published an editorial accompanying The Lancet paper arguing that semaglutide should be considered alongside statins and blood pressure medications as a standard cardiovascular preventive therapy for patients with obesity and established heart disease [3].
"We would not hesitate to prescribe a statin to a patient with atherosclerotic cardiovascular disease," Dr. Bhatt wrote. "The evidence for semaglutide in patients with obesity and ASCVD is now comparable in magnitude and robustness."
Not all cardiologists agree. Some point out that the SELECT trial enrolled only patients with established cardiovascular disease, not those at risk but without a prior event. Extending these findings to a broader population requires additional trials, which are currently underway.
Cost-Effectiveness in Cardiovascular Prevention
The extended follow-up also strengthens the cost-effectiveness argument for insurance coverage of semaglutide in cardiovascular patients. A health economics analysis published alongside the main results estimated that semaglutide for secondary cardiovascular prevention has an incremental cost-effectiveness ratio of approximately $38,000 per quality-adjusted life year (QALY) gained, well below the commonly used $50,000-$100,000 per QALY threshold [4].
This analysis accounts for reduced hospitalizations for heart attacks and strokes, decreased need for cardiovascular procedures (stenting, bypass surgery), and lower medication costs for managing cardiovascular risk factors. The extended follow-up data, showing growing benefit over time, would likely make the cost-effectiveness ratio even more favorable.
What This Means for Patients
For patients currently taking semaglutide for weight management, the SELECT follow-up provides additional reassurance that the medication is delivering cardiovascular benefits alongside weight loss. For patients with both obesity and established heart disease, the data argues for continued long-term treatment.
Patients who are considering stopping semaglutide should be aware that the SELECT trial did not study what happens to cardiovascular protection after discontinuation. However, given that many of semaglutide's cardiovascular effects (inflammation reduction, blood pressure improvement) are likely medication-dependent, most experts recommend continued treatment for patients who tolerate it.
Dr. Lincoff emphasized one practical point. "The cardiovascular benefits in SELECT were seen at the 2.4 mg weekly dose, the same dose used in Wegovy for weight management. Patients do not need a different formulation or dose to obtain heart protection."
Sources
- Lincoff AM, et al. "Extended follow-up of semaglutide and cardiovascular outcomes in patients with overweight or obesity (SELECT)." The Lancet. March 2026.
- Lincoff AM, et al. "Semaglutide and cardiovascular outcomes in obesity without diabetes." NEJM. 2023.
- Bhatt DL. "GLP-1 receptor agonists as cardiovascular preventive therapy: time to act." The Lancet Editorial. March 2026.
- Rind DM, et al. "Cost-effectiveness of semaglutide for secondary cardiovascular prevention." JAMA Network Open. February 2026.