The numbers: cardiovascular

The main benefits of semaglutide treatments are reducing weight, improving metabolic factors, and reducing multiple hard clinical endpoints (such as MACE, CV death, and all-cause death). 

Major Cardiovascular Outcomes

• Reduced risk of MACE by 20% (RRR)
• Hazard ratio for MACE was 0.8
• Absolute risk: a primary cardiovascular endpoint occurred in 6.5% in the semaglutide group, compared to 8.0% in the placebo group

Mortality Outcomes

Outcome	Absolute Risk (semaglutide vs placebo)	Hazard ratio
Death of any cause (all-cause death)	4.3% vs 5.2%	0.81
Death from cardiovascular causes (CV death)	2.5% vs 3.0%	0.85

Patients with prevalent heart failure subgroups:

• All-cause death: HR 0.81
• CV death: HR 0.76

• Heart Failure
  • Endpoints:
    • Cardiovascular death
      • HR 0.83
      • Absolute risk: 3.4% vs 4.1% (semaglutide vs placebo)
    • Hospitalization or urgent medical visit for heart failure
      • HR 0.79
• Anthropometric and metabolic benefits (change from baseline)
  • Improvements in physical measures and cardiometabolic markers
    • weight loss sustained up to 4 years

Outcome	SemaglutideAchieved by:	PlaceboAchieved by:
≥10% weight loss	44.2%	6.9%
≥20% weight loss	11.0%	0.6%
Improvement of BMI category	52.4%	15.7%

• Safety profile
  • Serious adverse events: less frequent is semaglutide vs placebo (33.4% vs 36.4%)
  • Cardiac disorders: lower with semaglutide (11.5% vs 13.5%)

Risks

Treatment of semaglutide also has its risk. These risks mainly relate to gastrointestinal disorders and adverse events

• Discontinuation in trials

Outcome	Semaglutide	Placebo
Adverse events	16.6%	8.2%
Gastrointestinal disorders	10.0%	2.0%

The numbers: the STEP trials and a review.

Outside of the benefits, there are also side effects and risks to taking this medication, as well as possible recurrence of weight when stopping.

STEP 1

• Population: Adults with overweight/obesity without diabetes.
• Results:
  • ~15% mean weight loss at 68 weeks with semaglutide 2.4 mg weekly (vs ~2.4% with placebo).
  • 86% achieved ≥5% weight loss, and ~50% achieved ≥15%.
  • Improvements in waist circumference, BP, CRP, quality of life metrics.
• Safety: Mostly GI adverse effects; low hypoglycemia risk (non-diabetic population).

STEP 4

• Design: 20-week run-in with semaglutide; then randomized to continue semaglutide vs switch to placebo.
• Results:
  • Those who continued semaglutide lost an additional ~7.9%, while those switched to placebo regained ~6.9%.
  • Demonstrates weight-maintenance depends strongly on continued drug use.

5. Risks and Benefits Review

Highlights semaglutide as a “double-edged sword” requiring careful clinical selection and monitoring.

Balanced review of benefits and risks of semaglutide.

Benefits:

• Significant weight loss (10–20% depending on protocol).
• Cardiovascular risk reduction (SELECT).
• Improvements in metabolic parameters, BP, inflammatory markers.

Risks & Concerns:

• GI intolerance (nausea, vomiting, diarrhea).
• Gallbladder disease and pancreatitis signal (rare).
• Loss of lean mass proportionally with fat mass.
• Discussion of post-marketing concerns (e.g., potential suicidal ideation signals, still unproven).