Long-Term Weight Loss Effects of Semaglutide in Obesity Without Diabetes in the SELECT Trial

The SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial was the first cardiovascular outcomes trial of a GLP-1 receptor agonist in people with established CVD and obesity but without diabetes. This prespecified analysis reported weight loss data from 17,604 participants over 208 weeks.

Semaglutide 2.4 mg weekly produced a mean weight loss of 10.2% versus 1.5% in the placebo group at 4 years, with sustained reduction without plateau after an initial plateau at approximately week 65. Among those on treatment at 104 weeks, 67.8% achieved ≥5% weight loss, 44.2% achieved ≥10%, and 22.9% achieved ≥15% — proportions far exceeding any prior pharmacotherapy. Weight loss was consistent across sex, race, BMI category, and geographic region. Serious adverse events were actually fewer in the semaglutide group.

The SELECT trial’s main cardiovascular outcome result (a 20% reduction in MACE) was reported separately. This weight loss analysis establishes that the degree of weight loss achieved is unprecedented for a pharmacological agent — approaching what was previously achievable only with bariatric surgery. For cardiovascular prevention, sustained 10% weight loss produces meaningful reductions in blood pressure, glucose, triglycerides, and inflammatory markers.

The SELECT data define a new standard for obesity pharmacotherapy in patients with established CVD, changing the expectation of what is achievable without surgery.

We rate the evidence strong. A well-powered prespecified analysis establishing semaglutide as a transformative weight loss agent in CVD patients with obesity — redefining the pharmacological ceiling for weight management.