What are the considerations for using tirzepatide (a dual GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1) receptor agonist) in patients with congestive heart failure (CHF)?

Tirzepatide in Congestive Heart Failure: Clinical Considerations

Tirzepatide should be used with caution in patients with heart failure with reduced ejection fraction (HFrEF), but may provide benefits in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. Recent evidence shows significant clinical benefits for tirzepatide in HFpEF with obesity, while data for HFrEF remains limited with potential safety concerns.

Benefits in HFpEF with Obesity

• Tirzepatide has demonstrated significant benefits in patients with HFpEF and obesity, reducing the combined risk of cardiovascular death or worsening heart failure events by 38% compared to placebo (hazard ratio 0.62; 95% CI, 0.41 to 0.95) 1
• Treatment with tirzepatide in HFpEF patients with obesity significantly improves health status as measured by the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), with a between-group difference of 6.9 points compared to placebo 1
• Tirzepatide improves functional capacity in HFpEF patients, with increases in 6-minute walk distance by 18.3 meters compared to placebo 2
• Patients with HFpEF and obesity treated with tirzepatide experience improved quality of life, reduced symptoms, and decreased heart failure medication burden 2

Concerns in HFrEF

• Limited data exists regarding tirzepatide use in HFrEF, but caution is warranted based on experience with other GLP-1 receptor agonists 3
• Small randomized trials of GLP-1 receptor agonists in HFrEF have shown no benefit and potential safety concerns, including a trend toward worse outcomes in patients with recent decompensation 3
• The LIVE and FIGHT trials of liraglutide in HFrEF showed no improvement in left ventricular ejection fraction and a trend toward increased risk of heart failure readmission 3

Potential Drug Interactions

• Tirzepatide may interact with guideline-directed medical therapy (GDMT) for heart failure, potentially causing symptomatic hypotension and acute kidney injury due to vasodilation, natriuresis, and reduction in extracellular volume 4
• Close monitoring of vital signs and volume status is necessary after initiating tirzepatide in heart failure patients, with potential need to modify heart failure medications 4

Mechanism of Action and Cardiovascular Effects

• Tirzepatide is a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors 5
• GLP-1 receptor agonists have shown modest benefits in preventing heart failure hospitalizations in patients without established heart failure 3
• Tirzepatide and other GLP-1 receptor agonists can cause weight loss, blood pressure reduction, and improved endothelium-dependent vasodilation, which may be beneficial in certain heart failure populations 3
• GLP-1 receptor agonists increase heart rate by 3-10 beats/minute while lowering systolic blood pressure by 2-3 mmHg 3

Safety Profile and Adverse Effects

• The most common adverse effects of tirzepatide are gastrointestinal, including nausea, vomiting, and diarrhea 6
• Higher doses of tirzepatide (10mg or 15mg) are associated with more frequent nausea, discontinuation, and injection-site reactions compared to lower doses 6
• Hypoglycemia risk is increased with tirzepatide 15mg (pooled RR=3.83,95% CI [1.19-12.30]) 6
• Discontinuation rates due to adverse events are higher with tirzepatide (6.3%) compared to placebo (1.4%) in heart failure patients 1

Clinical Recommendations

• For patients with HFpEF and obesity, tirzepatide can be considered as it has demonstrated significant benefits in reducing heart failure events and improving quality of life 1
• For patients with HFrEF, tirzepatide should be used with caution until more data is available, especially in those with recent decompensation 3
• When initiating tirzepatide in heart failure patients:
  • Start with the lowest dose and titrate slowly 6
  • Monitor blood pressure, heart rate, and volume status closely 4
  • Be prepared to adjust doses of other heart failure medications, particularly diuretics and vasodilators 4
  • Watch for signs of hypotension or acute kidney injury 4

Special Considerations

• The American Heart Association and Heart Failure Society of America recommend caution when using GLP-1 receptor agonists in patients with recent heart failure decompensation 3
• European Society of Cardiology guidelines note that GLP-1 receptor agonists have a neutral effect on heart failure risk and may be considered in appropriate patients 3
• Tirzepatide may be particularly beneficial in patients with comorbid diabetes, obesity, and HFpEF 2, 1