What were the results of the HOPE study with semaglutide (Glucagon-like peptide-1 receptor agonist) in patients with established cardiovascular disease?

Summary of the SELECT Trial with Semaglutide

The SELECT trial demonstrated that semaglutide 2.4 mg weekly reduces major adverse cardiovascular events by 20% in patients with established cardiovascular disease and overweight/obesity but without diabetes, establishing it as the first weight-loss medication proven to prevent heart attacks, strokes, and cardiovascular death in this population. 1

Study Design and Population

The SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity) trial was a randomized, double-blind, placebo-controlled, event-driven superiority trial conducted across 41 countries between October 2018 and March 2021. 1

Key enrollment criteria included: 1

• Adults ≥45 years of age
• BMI ≥27 kg/m²
• Established atherosclerotic cardiovascular disease
• No history of diabetes

Study population characteristics: 1

• 17,604 total participants randomized 1:1 to semaglutide 2.4 mg weekly or placebo
• Mean age: 61.6 years
• Mean BMI: 33.4 kg/m²
• 72.3% male
• Mean exposure duration: 34.2 months
• Mean follow-up: 39.8 months

Primary Cardiovascular Outcomes

The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE). 1

Primary results showed: 1

• MACE occurred in 6.5% of semaglutide patients vs. 8.0% of placebo patients
• Hazard ratio: 0.80 (95% CI 0.72-0.90; P<0.001)
• This represents a 20% relative risk reduction in major cardiovascular events

Individual Component Outcomes

Cardiovascular death: 2

• 17% reduction with semaglutide (HR 0.83,95% CI 0.71-0.98)

All-cause mortality: 2

• 21% reduction with semaglutide (HR 0.79,95% CI 0.70-0.89)

Non-fatal myocardial infarction: 2

• 24% reduction with semaglutide (HR 0.76,95% CI 0.66-0.88)

Coronary revascularization: 2

• 24% reduction with semaglutide (HR 0.76,95% CI 0.69-0.85)

Heart Failure Outcomes

In a prespecified analysis of patients with prevalent heart failure at baseline (24.3% of participants), semaglutide demonstrated consistent benefits: 3

• MACE reduction: HR 0.72 (95% CI 0.60-0.87)
• Heart failure composite endpoint (cardiovascular death or heart failure hospitalization/urgent visit): HR 0.79 (95% CI 0.64-0.98)
• Cardiovascular death: HR 0.76 (95% CI 0.59-0.97)

Benefits were observed across heart failure subtypes: 3

• Heart failure with reduced ejection fraction: HR 0.65 (95% CI 0.49-0.87) for MACE
• Heart failure with preserved ejection fraction: HR 0.69 (95% CI 0.51-0.91) for MACE
• Hospitalization for heart failure was reduced by 76% overall (HR 0.24,95% CI 0.12-0.57) 2

Glycemic Status and Outcomes

A critical finding was that cardiovascular benefits occurred independent of baseline HbA1c or changes in HbA1c. 4

Baseline HbA1c distribution: 4

• <5.7%: 33.5% of participants
• 5.7% to <6.0%: 34.6%
• 6.0% to <6.5%: 31.9%

Cardiovascular risk reduction was consistent across all baseline HbA1c subgroups and across categories of HbA1c change, indicating that the cardiovascular benefits are not mediated primarily through glycemic effects. 4

Safety Profile

Adverse events leading to permanent discontinuation: 1

• 16.6% in semaglutide group vs. 8.2% in placebo group (P<0.001)
• Predominantly gastrointestinal side effects (nausea, vomiting, diarrhea) 5

Serious adverse events were actually less frequent with semaglutide versus placebo, regardless of heart failure subtype. 3

Mechanisms of Cardiovascular Benefit

The cardiovascular protection appears mediated through multiple pathways beyond weight loss and glycemic control: 5, 6

• Improved myocardial substrate utilization
• Anti-inflammatory and anti-atherosclerotic effects
• Reduced myocardial ischemia injury
• Lower systemic and pulmonary vascular resistance
• Improved lipid profiles
• Blood pressure reduction (mean 5.1 mmHg systolic reduction) 6
• Reduced myocardial work and filling pressures
• Upregulated nitric oxide and suppressed NF-κB activation 6

Clinical Implications and Regulatory Status

The FDA has approved semaglutide (Ozempic) for: 7

• Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
• To reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease

Based on SELECT, the American College of Cardiology recommends semaglutide for patients with established cardiovascular disease, particularly when comorbid with obesity, even in the absence of diabetes. 6

The 2025 Diabetes Care Standards recommend GLP-1 receptor agonists with demonstrated cardiovascular benefit (including semaglutide) for individuals with type 2 diabetes, obesity, and symptomatic heart failure with preserved ejection fraction to reduce heart failure-related symptoms, physical limitations, and improve exercise function. 5

Important Caveats

Semaglutide has not been studied in patients with a history of pancreatitis, and the American Association of Clinical Endocrinologists recommends using it with caution in this population. 5

Long-term use is necessary, as weight regain occurs after discontinuation (mean weight regain of 11.6% of lost weight at 52 weeks post-cessation). 5

Slow dose titration over 16 weeks to the target 2.4 mg dose is essential to minimize gastrointestinal side effects. 6