Heart failure with preserved ejection fraction (HFpEF) accounts for over half of all heart failure (HF) cases, many of whom are either overweight or obese.¹ Despite the growing prevalence of patients with both conditions, treatment options remain scarce.¹ Tirzepatide, a once-weekly, dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA), has emerged as a potential treatment.^1-3 The phase 3 SUMMIT trial evaluated the safety and efficacy of tirzepatide in adults with HFpEF and obesity, regardless of diabetes status.^2,4 Recently, topline results from the trial have been announced which found that tirzepatide significantly reduced the risk of HF-related events and improved symptoms and physical limitations compared to placebo, successfully meeting both primary endpoints.² 

HF and obesity are closely intertwined, with obesity significantly contributing to the development and progression of HF, particularly in HFpEF.1 HFpEF, characterized by left ventricular hypertrophic remodeling, increased chamber stiffness, delayed myocardial relaxation, and altered metabolic state with reduced myocardial adenosine triphosphate (ATP) levels, imposes a high symptom burden, including fatigue, shortness of breath and swelling.^1,2,5 In obese HFpEF patients, treatment options are often limited due to impaired exercise tolerance and altered drug pharmacokinetics, complicating the standard management of HF.^1,6 

Tirzepatide, a novel dual GIP and GLP-1 RA, has emerged as a promising therapeutic option for obese patients with HFpEF.^1-3 Its mechanism of action provides obesity-related benefits by reducing body weight, appetite, food cravings, and energy intake while enhancing satiety and eating control.³ Additionally, emerging evidence also indicates that GLP-1 RAs may reduce cardiovascular disease (CVD) risk in individuals with overweight or obesity through weight loss and improvements in key CV risk factors.³ 

The SUMMIT trial was a multi-center, randomized, double-blind, placebo-controlled phase 3 study designed to assess the safety and efficacy of tirzepatide in reducing all-cause mortality, HF events, and improving performance on the 6-Minute Walk Distance test (6MWD) in individuals with HF.^2,4,7 The trial involved 731 participants from 11 countries, who received tirzepatide at a maximum tolerated dose (MTD) of 5mg, 10mg, or 15mg, or a placebo.² The primary endpoints were a reduction in the composite risk of HF events and improvement in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) from baseline to week 52.² 

Earlier in August, topline results from the phase 3 SUMMIT trial have been announced.² Tirzepatide at MTD showed statistically significant improvements in both reduction in the risk of composite HF outcomes (i.e., HF urgent visit or hospitalization, oral diuretic intensification or CV death) and improvements in HF symptoms and physical limitations, as measured by the KCCQ-CSS, compared to placebo.² Over a median follow-up of 104 weeks, tirzepatide reduced the risk of HF events by 38% (HR=0.62, 95% CI: 0.41-0.95; p=0.026).2 Improvements in symptoms and physical limitations, as per KCCQ-CSS, were 24.8 points for tirzepatide vs. 15.0 points for placebo (efficacy estimand), and 19.5 points for tirzepatide vs. 12.7 points for placebo (treatment-regimen estimand).² 

The trial also met all key secondary endpoints, including improved exercise capacity measured by the 6MWD, reduced level of high-sensitivity C-reactive protein, and significant weight loss.² Tirzepatide achieved a reduction in body weight of 15.7% vs. 2.2% for placebo (efficacy estimand), and a reduction of 13.9% vs. 2.2% (treatment-regimen estimand).² 

The safety profile of tirzepatide in the SUMMIT trial was consistent with previous studies, with gastrointestinal side effects such as diarrhea, nausea, and constipation being the most common, but generally graded as mild to moderate.^2-3 

In summary, topline results from the SUMMIT trial support the potential role of tirzepatide in filling a crucial gap in the treatment landscape of obese HFpEF patients, offering a dual-target approach to reduce both CV risk and the burden of obesity.^1-3