Tirzepatide Shows Greater Benefits in Higher BMI Patients with Heart Failure and Obesity, SUMMIT Trial Analysis Reveals
Key Insights
A post hoc analysis of the SUMMIT trial found that tirzepatide provides cardiovascular benefits across all obesity levels in patients with heart failure with preserved ejection fraction (HFpEF), but those with higher baseline BMI experience significantly greater improvements in exercise capacity and weight loss.
Patients in the highest BMI tertile showed 37.5-meter improvement in 6-minute walk distance compared to 9.9 meters in the lowest tertile, along with greater weight loss (14.4% vs 10.7%) and blood pressure reduction when treated with tirzepatide.
The findings support broader use of tirzepatide in obesity-related HFpEF patients while suggesting that those with more severe obesity may derive enhanced benefits from treatment.
A new analysis of the landmark SUMMIT trial reveals that while tirzepatide provides cardiovascular benefits across all obesity levels in patients with heart failure with preserved ejection fraction (HFpEF), those with higher baseline body mass index (BMI) experience significantly greater improvements in physical function and weight loss.
The post hoc analysis, published in the Journal of the American College of Cardiology, examined data from 731 adults with HFpEF and obesity who were randomly assigned to receive tirzepatide 15 mg once weekly or placebo for at least 52 weeks. The study population had a mean age of 65 years, with 54% women and 70% white participants.
Differential Benefits Based on Obesity Severity
Barry A. Borlaug, MD, consultant in the department of cardiovascular medicine at Mayo Clinic, explained the rationale for the analysis: "We wanted to learn if the benefits we observed in SUMMIT differ by obesity severity at baseline, including assessment of visceral adiposity or central obesity. One could certainly imagine that those with more severe obesity may derive greater benefit from tirzepatide, a medicine that causes substantial weight loss."
The analysis revealed that patients with higher baseline BMI were typically younger, more likely to be women, and presented with more severe heart failure symptoms, lower Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, and greater volume expansion despite more frequent diuretic use. They also had lower N-terminal pro-B-type natriuretic peptide levels and elevated C-reactive protein compared to those with lower baseline BMI.
Enhanced Physical Function Improvements
While tirzepatide's impact on the coprimary endpoints of cardiovascular death or worsening heart failure remained consistent across BMI levels, individuals in the highest versus lowest tertile of baseline BMI experienced significantly greater estimated treatment differences in key secondary outcomes:
- 6-minute walk distance: 37.5 meters versus 9.9 meters improvement (P = 0.025)
- Body weight reduction: 14.4% versus 10.7% loss (P = 0.006)
- Systolic blood pressure: 6.62 mm Hg versus 1 mm Hg reduction (P = 0.035)
Similar patterns emerged when examining waist-to-height ratio, with higher ratios associated with shorter 6-minute walk distances and poorer renal function as measured by estimated glomerular filtration rate and cystatin C levels.
Weight Loss Magnitude Correlates with Clinical Benefits
Among participants assigned to tirzepatide, those achieving 15% or more reduction in body weight at 52 weeks experienced substantially greater improvements compared to patients with 5% or less weight loss:
- 6-minute walk distance: Significant improvement (P < 0.0001)
- KCCQ score: Enhanced quality of life measures (P < 0.0001)
- C-reactive protein: Reduced inflammation (P = 0.017)
- Systolic blood pressure: Greater reduction (P = 0.0009)
Similarly, a 15% or more reduction in waist circumference was associated with significant increases in 6-minute walk distance (P = 0.0002) and KCCQ score (P < 0.0001) compared to less than 5% reduction.
Clinical Implications and Future Directions
"These data support broader use of tirzepatide in patients with obesity-related HFpEF, and they suggest that those patients with more severe obesity may even derive greater benefit, but the data show that treatment should not be restricted only to those with severe obesity," Borlaug stated.
The findings represent a novel observation distinct from previous studies with semaglutide. "The finding of greater benefit with higher BMI was novel and had not been observed previously with semaglutide in the previous study," Borlaug noted, referencing earlier STEP-HFpEF trial results.
However, limitations remain in understanding the relationship between weight loss and heart failure outcomes. "One thing we cannot examine from these data is how the degree of weight loss relates to reduction in the risk for worsening HF," Borlaug acknowledged. "Future studies will more directly assess the effects of GLP-1 receptor agonists on the hemodynamic abnormalities in HF that lead to hospitalization."
Patient Characteristics by Adiposity Distribution
The analysis also revealed important differences between patients with varying adiposity patterns. SUMMIT participants with elevated waist-to-height ratio and lower BMI were more often NYHA functional class III to IV (35.2% versus 17.3%) with higher mean NT-proBNP levels (265.5 ng/L versus 122 ng/L), lower estimated glomerular filtration rate (54.8 versus 70.9 mL/min/1.73 m²), higher cystatin C (1.5 versus 101 mg/L), and shorter 6-minute walk distance (252.4 versus 334 meters) compared to those with lower waist-to-height ratio and elevated BMI.
The SUMMIT trial was the first major cardiovascular outcomes trial of tirzepatide in adults with HFpEF and obesity, demonstrating a 38% reduction in risk for cardiovascular death or worsening heart failure compared to placebo, with parallel improvements in health status, exercise tolerance, systemic inflammation, and body weight.