Tirzepatide shown to improve clinical outcomes for patients with heart failure with preserved ejection fraction (HFpEF) and obesity

The last decade has seen the emergence of novel and highly effective therapies to induce weight loss and subsequent improvement in obesity-related co-morbidities. Heart failure has also increasingly been recognized to be highly prevalent and an important adverse outcome in patients with cardio-metabolic diseases such as obesity. Although most patients with heart failure have preserved ejection fraction (HFpEF) rather than reduced ejection fraction (HFrEF), treatment options for HFpEF remain limited. For example, while previous trials using the glucagon-like peptide-1 (GLP-1) agonist, semaglutide—STEP HFpEF¹ and STEP HFpEF Diabetes² which enrolled patients with HFpEF and obesity showed improvements in quality of life, physical limitations, and weight loss, these studies were not powered for a reduction in major clinical outcomes.

The SUMMIT trial was therefore the first trial to investigate the efficacy of tirzepatide, a long-acting dual agonist of GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors on a composite outcomes of death from cardiovascular causes or a worsening heart failure event. The study has shown for the first time that a drug therapy can reduce major heart failure clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF) and obesity. The study is published in the New England Journal of Medicine.³

In this study, 731 patients with heart failure and an ejection fraction of more than 50%, who also had obesity defined as a body mass index of at least 30 kg/m² were randomized to receive tirzepatide up to 15 mg subcutaneously once per week or placebo for at least 52 weeks. The mean duration of follow-up was 104 weeks.

The two co-primary endpoints were a composite of adjudicated death from cardiovascular causes or a worsening heart failure event and change from baseline to 52 weeks in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating better quality of life).

Results showed tirzepatide significantly reduce death from cardiovascular causes or a worsening heart failure event by 38% (hazard ratio [HR], 0.62; 95% CI, 0.41–0.95; p = .026). The significant results were largely driven by a reduction in worsening heart failure events defined as those requiring hospitalization or urgent intravenous drug therapy, which occurred in 8.0% and 14.2% of the tirzepatide and placebo groups, respectively (HR, 0.54; 95% CI, 0.34–0.85). Death rate from cardiovascular causes observed in the study was actually quite small and occurred only in eight patients (2.2%) and five patients (1.4%), for Tirzepatide versus placebo respectively (HR, 1.58; 95% CI, 0.52–4.83).

Tirzepatide also showed improvement in KCCQ-CSS score of 19.5 in the tirzepatide group versus 12.7 with placebo. Reported secondary endpoints included significant improvements in 6-min walk distance of 18 m, a 12% reduction in body weight, and a 34.9% reduction in C-reactive protein (a measure of systemic inflammation) with tirzepatide. The benefit with tirzepatide was consistent across all major subgroups.

Adverse events (mainly gastrointestinal) leading to discontinuation of the trial drug occurred in 6.3% of the tirzepatide group and in 1.4% of the placebo group.

The major limitation to prescribe these therapies however relates to the relatively high cost of these therapies for the large population of people who will potentially benefit from them. These findings in my opinion support further role of these weight loss therapies for patients with specific obesity related co-morbidities.