What were the results of the SELECT trial of semaglutide (glucagon-like peptide-1 receptor agonist)?

SELECT Trial of Semaglutide: Key Findings

Primary Results

The SELECT trial demonstrated that semaglutide 2.4 mg weekly reduced major adverse cardiovascular events by 20% in adults with preexisting cardiovascular disease and obesity/overweight without diabetes, with sustained weight loss of 10.2% maintained over 4 years. 1

Trial Design and Population

• 17,604 patients were enrolled and randomized 1:1 to receive once-weekly subcutaneous semaglutide 2.4 mg or placebo 1
• Inclusion criteria: age ≥45 years, preexisting cardiovascular disease, BMI ≥27, and no history of diabetes 1
• Mean duration of exposure was 34.2 months, with mean follow-up of 39.8 months 1

Cardiovascular Outcomes

• Primary endpoint (composite of cardiovascular death, nonfatal MI, or nonfatal stroke) occurred in:
  • 6.5% of semaglutide group (569/8803 patients)
  • 8.0% of placebo group (701/8801 patients)
  • Hazard ratio: 0.80 (95% CI 0.72-0.90; P<0.001) 1

This represents a 20% relative risk reduction in major adverse cardiovascular events, establishing superiority over placebo in this non-diabetic population with established cardiovascular disease 1

Weight Loss and Anthropometric Changes

• Weight loss was progressive through 65 weeks and sustained for up to 4 years 2

• At 208 weeks (4 years), semaglutide produced:

  • Mean weight reduction: -10.2% vs -1.5% with placebo (P<0.0001) 2
  • Waist circumference reduction: -7.7 cm vs -1.3 cm with placebo (P<0.0001) 2
  • Waist-to-height ratio reduction: -6.9% vs -1.0% with placebo (P<0.0001) 2

• Clinically meaningful weight loss occurred across all subgroups: both sexes, all races, all body sizes, and all geographic regions 2

Safety Profile

• Serious adverse events were LOWER with semaglutide across all BMI categories 2:

  • BMI <30: 43.23 vs 50.48 events per 100 patient-years
  • BMI 30-<35: 43.54 vs 49.66 events per 100 patient-years
  • BMI 35-<40: 51.07 vs 52.73 events per 100 patient-years
  • BMI ≥40: 47.06 vs 60.85 events per 100 patient-years

• Treatment discontinuation was higher with semaglutide: 16.6% vs 8.2% with placebo (P<0.001), primarily due to gastrointestinal adverse effects 1

• Discontinuation rates increased as BMI class decreased 2

Clinical Significance

This trial is groundbreaking because it extends cardiovascular benefits of semaglutide beyond the diabetic population, demonstrating that GLP-1 receptor agonists can reduce cardiovascular events in patients with obesity and established cardiovascular disease even without diabetes 1. This contrasts with earlier trials (SUSTAIN-6, PIONEER-6) which only included patients with type 2 diabetes 3.

Key Distinctions from Prior Semaglutide Trials:

• SUSTAIN-6: 3,297 patients with type 2 diabetes, 26% MACE reduction (HR 0.74), but only 2-year duration 3
• PIONEER-6: 3,183 patients with type 2 diabetes, demonstrated cardiovascular safety (noninferiority) but not superiority for oral formulation 3
• SELECT: 17,604 patients WITHOUT diabetes, 20% MACE reduction, with 4-year sustained outcomes 1

Important Caveats

• The higher discontinuation rate (16.6%) requires careful patient counseling about gastrointestinal side effects and the importance of adherence 1
• Weight loss benefits require continued treatment; long-term sustainability beyond 4 years remains to be established 2
• This trial used the 2.4 mg dose (approved for obesity), which is higher than diabetes treatment doses (0.5-1.0 mg) 1