Do Glucagon-like peptide-1 (GLP-1) receptor agonists provide cardiac and renal protection?

GLP-1 Receptor Agonists Provide Significant Cardiac and Renal Protection

GLP-1 receptor agonists definitively provide both cardiac and renal protection in patients with type 2 diabetes, with evidence showing reduced risk of major adverse cardiovascular events, slower eGFR decline, and reduced albuminuria. 1

Cardiovascular Benefits

GLP-1 receptor agonists demonstrate significant cardioprotective effects through multiple mechanisms:

• Reduced MACE risk: GLP-1 RAs reduce the risk of major adverse cardiovascular events (MACE) by 12% (HR 0.88,95% CI 0.82-0.94) 2

• Specific cardiovascular outcomes:

  • Cardiovascular death: 12% reduction (HR 0.88,95% CI 0.81-0.96)
  • Fatal or non-fatal stroke: 16% reduction (HR 0.84,95% CI 0.76-0.93)
  • Fatal or non-fatal myocardial infarction: 9% reduction (HR 0.91,95% CI 0.84-1.00)
  • Hospitalization for heart failure: 9% reduction (HR 0.91,95% CI 0.83-0.99) 2

• Mechanism of cardioprotection: These agents exert their cardioprotective effects through improved myocardial substrate utilization, anti-inflammatory and anti-atherosclerotic effects, reduced myocardial ischemia injury, and lower systemic and pulmonary vascular resistance 3

Renal Benefits

GLP-1 receptor agonists provide significant kidney protection:

• Reduced composite kidney outcomes: 17% reduction in broad composite kidney outcomes (HR 0.83,95% CI 0.78-0.89) 2

• Specific renal benefits:

  • Reduced albuminuria
  • Slower eGFR decline
  • Decreased risk of progression to kidney failure 1

• Evidence in CKD: In patients with moderate-to-severe CKD (stages G3 and G4), dulaglutide produced similar glycemic control compared to insulin glargine but resulted in significantly slower GFR decline 1

Preferred GLP-1 RAs with Proven Benefits

The following GLP-1 receptor agonists have demonstrated cardiovascular and renal benefits in large clinical trials:

• Dulaglutide
• Liraglutide
• Injectable semaglutide
• Oral semaglutide 1, 3

These agents are preferred over other GLP-1 RAs without proven cardiovascular benefits.

Clinical Application Algorithm

1. For patients with T2D and established cardiovascular disease:

   • GLP-1 RAs are recommended as they have proven CV benefit (Class I, Level A evidence) 3
   • MACE risk reduction with liraglutide was significantly greater for those with eGFR <60 ml/min/1.73 m² than for those with higher eGFR 1

2. For patients with T2D and CKD:

   • GLP-1 receptor agonist with proven cardiovascular benefit is recommended for patients who do not meet their individualized glycemic target with metformin and/or an SGLT2i or who are unable to use these drugs 1
   • Can be used with eGFR as low as 15 ml/min/1.73 m² and retain glucose-lowering potency across the range of eGFR and among dialysis patients 1

3. For overweight/obese patients without diabetes:

   • Semaglutide should be considered to reduce CV mortality, MI, or stroke (Class IIa, Level B evidence), particularly in those with chronic coronary syndrome and a BMI >27 kg/m² 3

Combination with SGLT2 Inhibitors

Recent evidence supports the use of GLP-1 RAs with SGLT2 inhibitors:

• The cardiovascular and kidney benefits of GLP-1 receptor agonists are consistent regardless of SGLT2 inhibitor use 4
• Effects on MACE (HR 0.77 with SGLT2i vs HR 0.79 without SGLT2i), hospitalization for heart failure, composite kidney outcomes, and eGFR slope were all similar regardless of concurrent SGLT2 inhibitor use 4

Safety Considerations and Adverse Effects

Common adverse effects include:

• Gastrointestinal effects: Nausea, vomiting, diarrhea (15-20% of patients with moderate-to-severe CKD)

  • Usually tolerable with dose titration
  • Typically abate over several weeks to months 1

• Cardiovascular: Heart rate typically increases by ~5 bpm but has not been associated with higher BP or other adverse events 1

• Contraindications:

  • Patients at risk for thyroid C-cell tumors (e.g., multiple endocrine neoplasia)
  • Personal or family history of medullary thyroid carcinoma
  • History of pancreatitis 1, 5

Important Caveats

1. Heart failure consideration: Use GLP-1 RAs with caution in patients with established heart failure with reduced ejection fraction (HFrEF) due to no evidence of benefit and a trend toward worse outcomes in small RCTs 3

2. Hypoglycemia risk: GLP-1 RAs do not cause hypoglycemia by themselves, but when used with insulin or insulin secretagogues, doses of these drugs may need to be reduced 1

3. Perioperative management: The American Society of Anesthesiologists recommends continuing GLP-1 RAs throughout the perioperative period 3

By incorporating GLP-1 receptor agonists into treatment regimens for appropriate patients, clinicians can significantly reduce cardiovascular and renal risks while improving glycemic control.