Key Points
- SUMMIT, a randomized control trial of tirzepatide versus placebo in patients with HFpEF and obesity, found that tirzepatide significantly reduced the risk of worsening heart failure events and improved physical functioning.
- This sub-analysis found that tirzepatide also led to a significant decrease in systolic blood pressure, estimated plasma blood volume, CRP, and troponin-T in this population, as well as an increase in eGFR, providing insights into the mechanisms by which tirzepatide exerts is positive clinical effects
Tirzepatide is currently approved by the US Food and Drug Administration to treat obesity. The SUMMIT trial demonstrated a positive effect of tirzepatide versus placebo on a composite of worsening heart failure events and cardiovascular mortality among patients with HFpEF and obesity, but its impact on biometric outcomes in this population is uncertain.
On November 17th 2024, the results of “Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial” were presented at AHA Scientific Sessions 2024 with simultaneous publication in the Nature. The purpose of this mechanist secondary analysis was to determine the impact of tirzepatide on biometric measures of cardiometabolic health. .
The SUMMIT trial randomized 731 adults aged 40 or older with HFpEF (congestive heart failure with an EF ≥ 50%) and obesity (BMI ≥ 30 kgm2) to weekly injections of tirzepatide or placebo in a 1:1 fashion, and found that at a a median of 2 years of follow up, tirzepatide was associated with a significantly lower risk of cardiovascular death or a worsening heart failure events — driven primarily by a decrease in worsening heart failure — as well as a significant improvement in KCCQ scores compared to placebo. This secondary analysis found that tirzepatide, when compared to placebo, was also associated with a reduction in systolic blood pressure (estimated treatment difference [ETD] – 5 mmHg [95% CI -7 to -3]; p<0.001), estimated blood volume (ETD -0.58 L [-0.63 to -0.52]; p < 0.001), C-reactive protein (CRP) (ETD -37.2% [-45.7 to -27.3]; p < 0.001), and troponin T (-10.4% [-16.7 to -3.6]; p = 0.003). In addition, tirzepatide was also associated with a significant increase in eGFR (+1.85 ml/min/1.73 m2 [0.19–3.51]; p = 0.029) and borderline significant reductions in N-terminal prohormone B-type natriuretic peptide levels and urine albumin–creatinine ratio. In a post-hoc exploratory analysis, a decrease in estimated blood volume was significantly correlated with a decrease in systolic blood pressure, microalbuminuria, and improved functional status as measured by the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and 6-min walk distance. Similarly, a decrease in CRP was associated with a decrease in troponin-T levels. Overall, the hemodynamic effects were observed early in treatment, whereas the anti-inflammatory effects occurred later in the treatment course.
Dr. Barry A. Borlaug, MD, of the Mayo Clinic in Rochester, Minnesota concluded: “Tirzepatide reduced circulatory pressure-volume overload and mitigated end organ damage in the kidney and heart in patients with HFpEF and obesity, providing new insight into the mechanisms of benefit from tirzepatide in patients with obesity-related HFpEF.”
- Borlaug, B.A., Zile, M.R., Kramer, C.M. et al.Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: a secondary analysis of the SUMMIT trial. Nat Med (2024). https://doi.org/10.1038/s41591-024-03374-z