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Tirzepatide reduced the risk for worsening heart failure (HF) compared with placebo in patients with HF with preserved ejection fraction (HFpEF) and obesity, while delivering an acceptable safety profile. The phase 3 SUMMIT trial is the first study to demonstrate a drug effect on major HF outcomes as the primary outcome in patients with HFpEF and obesity.
“We know that obesity is a major contributor to HFpEF,” said Prof. Milton Packer, MD, from Baylor University Medical Center, in Texas1. The long-action gastric inhibitory polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide has been associated with profound weight loss in people with obesity2. Thus, the current SUMMIT trial (NCT04847557) investigated tirzepatide among patients with HFpEF and obesity at high risk for events, as estimated with the enrichment criteria of the trial: 6-minute walk distance less than 426 meters, Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) less than 81, and HF decompensation within 12 months or an eGFR <70 ml/min/1.73m2 1,3. The 731 participants were randomly assigned 1:1 to up to 15 mg once a week of tirzepatide or placebo for at least 52 weeks. The first primary outcome was cardiovascular death or worsening HF events, defined as the need for hospitalization, urgent intravenous drug therapy, or oral diuretic intensification with worsening HF. The second primary endpoint was the KCCQ-CSS at week 52.
Cardiovascular death or worsening HF was observed in 15.3% of the patients in the placebo arm and 9.9% of the patients in the tirzepatide arm (HR 0.62; 95% CI 0.41–0.95; P=0.026). “The result was still significant when we omitted the primary events that were treated with oral diuretic intensification from the analysis,” said Prof. Packer (HR 0.57; 95% CI 0.34–0.95)1. The change from baseline to week 52 in KCCQ-CSS was +19.5 in the tirzepatide arm and +12.7 in the placebo arm, a significant difference in favor of the experimental arm (P<0.001). Prof. Packer noted that gastrointestinal reports, such as diarrhea, nausea, or constipation, led 4% discontinuation in the tirzepatide arm.
“Compared with placebo, tirzepatide reduced the composite of cardiovascular death and worsening HF by 38%, an effect that was driven by a decreased risk for worsening HF,” concluded Prof. Packer. “Next to this, improvements were seen in the KCCQ-CSS, 6-minute walk distance, and inflammatory markers.”
Medical writing support was provided by Robert van den Heuvel.
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