By Michael H. Crawford, MD
Synopsis: A recent randomized, placebo-controlled trial of the long-acting glucagon-like peptide-1 receptor agonist tirzepatide in patients with heart failure with preserved left ventricular ejection fraction who have obesity, diabetes, and one other weight-related comorbidity has shown that tirzepatide reduces both the symptoms of heart failure as well as the incidence of worsening heart failure events.
Source: Packer M, Zile MR, Kramer CM, et al. Tirzepatide for heart failure with preserved ejection fraction and obesity. N Eng J Med. 2024; Nov 16. doi: 10.1056/NEJMoa2410027. [Online ahead of print].
Agonists of glucagon-like peptide-1 receptors (GLP-1) and other weight loss interventions have been shown to reduce the risk of incident heart failure (HF) and reduce symptoms in those with established HF associated with preserved left ventricular ejection fraction (HFpEF). However, data on their effects on cardiovascular (CV) outcomes are lacking. Thus, Packer et al conducted the SUMMIT trial of tirzepatide (TZ) a long-acting GLP-1 agonist, in 731 patients (mean age 65 years, 54% women) with HFpEF and obesity in 129 centers in nine countries recruited from 2021-2023.
Enrollment criteria included age ≥ 40 years, HF symptoms (New York Heart Association class II-IV), an ejection fraction ≥ 50%, a body mass index (BMI) of ≥ 30 k/m (mean, 38), and one or more of the following: N-terminal pro-B-type natriuretic peptide (NT-proBNP) > 200 pg/mL in sinus rhythm or > 600 pg/mL in atrial fibrillation, left atrial enlargement, increased LV filling pressures, decompensated HF in the last 12 months, or an estimated glomerular filtration rate of < 70 mL/min/1.73 m².
The patients were randomized to placebo or TZ 2.5 mg/week subcutaneously plus usual care. Every four weeks, if there were no intolerable adverse effects, the dose was progressively increased up to 20 mg/week. More than 90% of the patients were followed for at least 52 weeks, with a mean follow-up of 104 weeks. The primary endpoints were a composite of cardiovascular (CV) death or a worsening HF event and the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ).
Secondary endpoints included the six-minute walk distance, change in weight, and change in high sensitivity C-reactive protein (hs-CRP). The primary composite endpoint occurred in 10% of the TZ group and 15% in the placebo group (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.41-0.95; P = 0.026), which was driven by HF, since mortality was not significantly different (19% vs. 15%, respectively).
The KCCQ increased by 20 points in the TZ group vs. 13 points in the placebo group (HR, 6.9; 95% CI, 3.3-10.6; P < 0.001). Weight decreased more in the TZ group (-14 kg vs. -2 kg; P < 0.001) as did hs-CRP (-39% vs. -6%; P < 0.001). Six-minute walking distance increased by 26 m in the TZ group and 10 m in the placebo group (P < 0.001). Trial drug discontinuation rate because of adverse events (mainly gastrointestinal) occurred in 6% vs. 1%, respectively.
The authors concluded that in patients with obesity and HFpEF, TZ reduced the risk of the combined endpoint of CV mortality and HF exacerbation and improved overall health status.
Commentary
Obesity is present in the majority of patients with HFpEF. Visceral adiposity is believed to be a driver of the evolution and progression of HF. Previous studies of the GLP-1 agonist semaglutide in obese patients with HFpEF showed reductions in weight (average 9 kg) and symptoms but fell short of demonstrating a reduction in HF events. TZ is a long-acting GLP-1 agonist, which reduces weight more effectively than semaglutide in the reported trials. Thus, TZ’s effectiveness for preventing HF events is of interest.
SUMMIT showed a robust average weight loss of 14 kg and a reduction in worsening HF events. However, CV mortality was numerically higher with TZ, but not significantly so. The likely explanation is that SUMMIT was underpowered to detect a mortality difference at one year. Also, four of the 15 deaths in SUMMIT were associated with progression in HF.
It is interesting that long-term trials of GLP-1 agonists in patients with obesity and diabetes have shown reductions in CV and all-cause mortality. In addition to the improvement in the KCCQ measure of health status and the increase in the six-minute walking distance, TZ significantly reduced hsCRP, reflecting a reduction in inflammation, which may be an important pathophysiologic mechanism in HFpEF. Finally, a small decrease in systolic blood pressure was observed on TZ (-5 mmHg vs. 0.1 mmHg), which, in blood pressure treatment outcomes studies, has been sufficient to demonstrate a reduction in CV events.
There are limitations to SUMMIT. A BMI of at least 30 was required to enroll, but many patients with HFpEF have lower BMIs but may have abnormal waist to height ratios, which also has been shown to indicate excess visceral adiposity.
Also, in addition to obesity, at least one other adverse CV comorbidity was required to enroll in SUMMIT. This probably was to increase the chances of having an HF event in the study population. Those at a lower risk of events may not receive the same magnitude of benefits from TZ seen in this trial.
TZ (Mounjaro or Zepbound) is U.S Food and Drug Administration-approved for use in overweight or obese patients with a weight-related comorbidity (e.g., diabetes), with the maximum recommended dose of 15 mg/week subcutaneously.
Michael H. Crawford, MD, is Professor of Medicine and Consulting Cardiologist, University of California Health, San Francisco.
A recent randomized, placebo-controlled trial of the long-acting glucagon-like peptide-1 receptor agonist tirzepatide in patients with heart failure with preserved left ventricular ejection fraction who have obesity, diabetes, and one other weight-related comorbidity has shown that tirzepatide reduces both the symptoms of heart failure as well as the incidence of worsening heart failure events.
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