What are the criteria for prescribing Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists (GLP-1 RAs) for patients with type 2 diabetes at high risk for cardiovascular events?

GLP-1 Receptor Agonists and Cardiovascular Benefits: Prescribing Criteria

GLP-1 receptor agonists (GLP-1 RAs) should be prescribed for patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD) or multiple cardiovascular risk factors, regardless of baseline HbA1c or individualized HbA1c target, to reduce the risk of major adverse cardiovascular events (MACE). 1

Cardiovascular Outcome Studies with GLP-1 RAs

Several large cardiovascular outcome trials (CVOTs) have demonstrated significant cardiovascular benefits with GLP-1 RAs:

Key Trials and Findings:

• LEADER trial (Liraglutide): Reduced primary composite outcome (MI, stroke, or CV death) by 13% (HR 0.87) and CV deaths by 22% (HR 0.78) in patients with established CVD 1

• SUSTAIN-6 (Semaglutide): Demonstrated CV benefit in patients with established CVD 1

• REWIND (Dulaglutide): Unique for including a higher proportion (68.5%) of patients without established CVD but with CV risk factors. Showed 12% reduction in MACE (HR 0.88) 1

• HARMONY (Albiglutide): Showed CV benefit (though this agent was later removed from market) 1

• Meta-analyses: GLP-1 RAs reduce MACE by 14%, all-cause mortality by 12%, and hospitalization for heart failure by 11% 2

Prescribing Criteria for GLP-1 RAs

Primary Indications (High Priority Patients):

1. Established ASCVD: Patients with prior myocardial infarction, ischemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging/stress test, or revascularization of coronary, carotid, or peripheral arteries 1

2. Multiple CV Risk Factors without established ASCVD: 1

   • Age ≥55 years with:
     • Coronary, carotid, or lower extremity artery stenosis >50%
     • Left ventricular hypertrophy
     • eGFR <60 mL/min/1.73m²
     • Albuminuria

FDA-Approved Indications:

• Semaglutide (Ozempic): "To reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease" 3

• Dulaglutide (Trulicity): "To reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors" 4

Algorithm for GLP-1 RA Selection in CV Risk Management

1. For patients with established ASCVD where MACE is the primary concern:

   • GLP-1 RAs have the strongest evidence for benefit 1
   • Consider as add-on therapy regardless of current glycemic control 1

2. For patients with heart failure or CKD:

   • SGLT2 inhibitors are preferred first-line agents 1
   • GLP-1 RAs can be considered if SGLT2 inhibitors are contraindicated or not tolerated 1

3. For patients with both ASCVD and heart failure/CKD:

   • Consider combination therapy with both SGLT2 inhibitor and GLP-1 RA for additive CV and renal benefits 1

Important Clinical Considerations

• Baseline HbA1c: CV benefits occur independently of baseline HbA1c or glycemic targets 1

• Contraindications:

  • Personal or family history of medullary thyroid carcinoma
  • Multiple Endocrine Neoplasia syndrome type 2
  • History of pancreatitis (consider alternative therapy)
  • Severe gastrointestinal disease 3, 4

• Common Side Effects: Nausea, vomiting, diarrhea, abdominal pain, and constipation 3

• Monitoring: Patients with history of diabetic retinopathy should be closely monitored 3

Clinical Pearls and Pitfalls

• Not all GLP-1 RAs have demonstrated CV benefit: Lixisenatide and extended-release exenatide did not show superiority for CV outcomes 1

• Differences between short and long-acting GLP-1 RAs: Long-acting agents (liraglutide, once-weekly exenatide, dulaglutide, semaglutide) have more profound effects on fasting glucose and HbA1c 5

• Heart failure considerations: While GLP-1 RAs reduce MACE, they have less robust evidence for heart failure prevention compared to SGLT2 inhibitors 1

• Shared decision-making: Engage patients in discussions about benefits, side effects, and administration preferences 1

• Preferred first injectable: GLP-1 RAs are now recommended as preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment 5

By following these evidence-based recommendations, clinicians can appropriately prescribe GLP-1 RAs to reduce cardiovascular risk in patients with type 2 diabetes, potentially improving morbidity, mortality, and quality of life.