What is the role of GLP-1 (Glucagon-like peptide-1) analogues in managing cardiovascular disease (CVD)?

Role of GLP-1 Analogues in Cardiovascular Disease Management

GLP-1 receptor agonists significantly reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus and established cardiovascular disease, with semaglutide and liraglutide demonstrating the strongest evidence for cardiovascular benefit. 1

Cardiovascular Benefits of GLP-1 Receptor Agonists

Proven Cardiovascular Outcomes

• GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or stroke) in patients with type 2 diabetes mellitus and established cardiovascular disease 1
• Liraglutide reduced the primary composite outcome of cardiovascular death, non-fatal myocardial infarction, or stroke by 13% (HR 0.87,95% CI 0.78-0.97) in the LEADER trial 1
• Semaglutide reduced the primary composite outcome by 26% (HR 0.74,95% CI 0.58-0.95) in the SUSTAIN-6 trial 1
• In non-diabetic patients with pre-existing cardiovascular disease and BMI >27, semaglutide 2.4 mg weekly reduced cardiovascular endpoints by 20% compared to placebo (6.5% vs 8.2%, p=0.001) 1
• Liraglutide is FDA-approved to reduce the risk of MACE in adults with type 2 diabetes and established cardiovascular disease 1
• Semaglutide is FDA-approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease 2
• Dulaglutide is FDA-approved to reduce the risk of MACE in adults with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors 3

Mechanisms of Cardiovascular Protection

• Cardioprotective effects are mediated through multiple mechanisms 1:
  • Improved myocardial substrate utilization
  • Anti-inflammatory and anti-atherosclerotic effects
  • Reduced myocardial ischemia injury
  • Lower systemic and pulmonary vascular resistance
  • Improved lipid profiles
• GLP-1 receptors are localized primarily to the sinoatrial node and arterial walls, where they influence endothelial function and autonomic nervous system activity 1
• GLP-1 receptor agonists lower systolic blood pressure by 1-6 mmHg and can reduce LDL cholesterol by up to 16% 1
• Recent evidence suggests improvement in left ventricular global longitudinal strain after 6 months of treatment with semaglutide or dulaglutide 4

Clinical Application Guidelines

Patient Selection for GLP-1 Receptor Agonists

• First-line consideration for patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) 1
• Can be considered in patients without established ASCVD but with specific high-risk indicators, including 1:
  • Age ≥55 years with coronary, carotid, or lower extremity artery stenosis >50%
  • Left ventricular hypertrophy
  • eGFR <60 mL/min/1.73m²
  • Albuminuria
• The decision to use GLP-1 receptor agonists for cardiovascular risk reduction should be considered independently of baseline HbA1c or individualized HbA1c targets 1

Comparative Effectiveness with Other Agents

• For patients with heart failure, particularly heart failure with reduced ejection fraction (HFrEF), SGLT2 inhibitors have stronger evidence for benefit than GLP-1 receptor agonists 1
• For patients where atherosclerotic cardiovascular disease is the primary concern, GLP-1 receptor agonists have the strongest evidence for MACE reduction 1
• There is uncertainty about whether GLP-1 receptor agonists prevent heart failure, especially regarding their safety in individuals with manifest heart failure with reduced ejection fraction 1

Safety Considerations and Adverse Effects

Common Adverse Effects

• Gastrointestinal effects are most common 1:
  • Nausea and vomiting (avoid in gastroparesis)
  • Dyspepsia (start at low dose and titrate slowly)
  • Diarrhea (reduce meal size)
  • Gastrointestinal reflux (limit alcohol and carbonated drinks)
  • Constipation (avoid high-fat diet)
• Cardiac arrhythmia/tachycardia may occur (monitor and consider beta-blockers if symptomatic) 1
• Acute pancreatitis is a rare adverse effect; use with caution in patients with history of pancreatitis 1

Perioperative Considerations

• GLP-1 receptor agonists may delay gastric emptying, potentially increasing the risk of regurgitation and pulmonary aspiration 1
• Some studies suggest an association between perioperative GLP-1 receptor agonist use and increased risk of pulmonary aspiration 1
• The effect of tachyphylaxis on gastric emptying with long-term use is unclear 1

Clinical Pearls and Pitfalls

• Pitfall: Not considering GLP-1 receptor agonists for cardiovascular risk reduction independent of glycemic control needs 1
• Pitfall: Using GLP-1 receptor agonists as first-line therapy in patients with heart failure, where SGLT2 inhibitors have stronger evidence 1
• Pearl: The cardiovascular benefits of GLP-1 receptor agonists appear to be specific to agents providing longer-acting agonism at the GLP-1 receptor 5
• Pearl: When initiating therapy, slow titration helps increase gastrointestinal tolerability 1
• Pearl: GLP-1 receptor agonists offer the unique advantage of addressing multiple cardiovascular risk factors simultaneously through weight reduction, blood pressure lowering, and improved lipid profiles 6