In patients with heart failure with preserved ejection fraction (HFpEF) and obesity, tirzepatide significantly reduced the composite risk of cardiovascular death or worsening heart failure and improved health status compared to placebo, though it was associated with higher gastrointestinal side effects.
PICO Summary
Population:
- Adults (N=731) aged ≥40 years with HFpEF (LVEF ≥50%), obesity (BMI ≥30), and functional impairment, with or without type 2 diabetes.
Intervention:
- Tirzepatide, titrated subcutaneously up to 15 mg weekly over 20 weeks, with a median follow-up of 104 weeks.
Comparison:
- Placebo, administered with usual therapy.
Outcome:
- Efficacy: Composite primary endpoint: Cardiovascular death or worsening heart failure (hazard ratio [HR] 0.62; P=0.026).
- Health status: Mean increase in KCCQ-CSS score at 52 weeks was 19.5 points in the tirzepatide group versus 12.7 in placebo (difference: 6.9 points; P<0.001).
- Secondary outcomes: Significant weight reduction (−13.9% vs −2.2%; P<0.001), improved 6-minute walk distance (difference: +18.3 m; P<0.001), and reduced CRP levels (−38.8% vs −5.9%; P<0.001).
- Safety and Tolerability: Adverse events: Higher discontinuation due to side effects in tirzepatide (6.3% vs 1.4%), primarily gastrointestinal symptoms.
Clinical Summary
Main Finding:
Tirzepatide significantly reduced the risk of cardiovascular death or worsening HFpEF events and enhanced health status in obese patients, with a favourable impact on weight and inflammatory markers.
Clinical Relevance:
These findings support tirzepatide as a dual-benefit therapy for obesity-associated HFpEF, targeting both metabolic and cardiac dysfunction. Its efficacy in reducing heart failure events and improving quality of life underscores its potential role in managing a challenging patient population, though gastrointestinal tolerability remains a consideration.
Study Overview:
Type of Study:
- International, double-blind, randomised, placebo-controlled trial (SUMMIT Trial).
Sample Size & Population:
- 731 patients (mean age 65 years; 53.8% female; mean BMI 38.3).
Intervention Duration & Doses:
- Weekly subcutaneous tirzepatide titrated up to 15 mg over 20 weeks, followed by a maintenance phase for a median of 104 weeks.
Comparison:
- Placebo plus usual care.
Outcomes:
- Primary Measure: Reduction in cardiovascular death or worsening heart failure events (HR 0.62, P=0.026).
- Secondary Measures: Improved health status (KCCQ-CSS), functional capacity, body weight reduction (mean −11.6 percentage points), and reduced systemic inflammation.
- Safety Profile: Gastrointestinal side effects leading to discontinuation were higher in the tirzepatide group.
Expanded Outcomes
Primary Outcomes:
Cardiovascular Death or Worsening Heart Failure:
Tirzepatide significantly reduced the composite risk of cardiovascular death or worsening heart failure events compared to placebo. This outcome was driven by a reduction in hospitalisations or urgent care visits for heart failure (HR 0.54; 95% CI, 0.34–0.85). Death from cardiovascular causes was similar between the groups (2.2% vs 1.4%, HR 1.58, 95% CI, 0.52–4.83), but the event rate was low, making it difficult to draw definitive conclusions.
Health Status and Quality of Life:
Measured using the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), tirzepatide improved health status more than placebo, with a mean increase of 19.5 points versus 12.7 points at 52 weeks (difference of +6.9 points; P<0.001). This improvement suggests meaningful enhancement in symptoms, physical limitations, and social functioning.
Secondary Outcomes:
1. Weight Reduction:
Patients in the tirzepatide group experienced significant weight loss (mean −13.9% vs −2.2%; between-group difference −11.6 percentage points; P<0.001). This degree of weight reduction is clinically meaningful and aligns with the metabolic benefits of the intervention.
2. Functional Capacity (6-Minute Walk Distance):
The tirzepatide group showed an improved walking distance of +26.0 metres at 52 weeks, compared to +10.1 metres in the placebo group (difference +18.3 metres; P<0.001). This improvement in functional capacity is a key benefit in this population with compromised exercise tolerance.
3. Systemic Inflammation (CRP Levels):
High-sensitivity C-reactive protein (CRP), a marker of systemic inflammation, decreased by 38.8% in the tirzepatide group compared to 5.9% in placebo (difference −34.9 percentage points; P<0.001). This suggests a potential role in mitigating obesity-related inflammatory pathways linked to HFpEF.
4. Safety Profile:
Tirzepatide was generally well-tolerated, but adverse events, primarily gastrointestinal, led to higher discontinuation rates (6.3% vs 1.4%). Serious adverse events occurred at similar rates between the two groups. Gastrointestinal side effects were dose-dependent but tended to dissipate over time.
Considerations
- Gastrointestinal tolerability challenges its widespread adoption.
- Further exploration in patients with BMI <30 or elevated waist-to-height ratios may enhance applicability.
- Long-term cardiovascular mortality effects warrant additional studies.
Reference:
Packer M, Zile MR, Kramer CM, et al. (2024). “Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity.” New England Journal of Medicine. DOI: 10.1056/NEJMoa2410027 .
Disclosure:
This article on Hormone Insight was created with both human and AI assistance. The human expert editor reviewed the article before publication to ensure accuracy, quality, and clarity.
