FLOW Trial: Tirzepatide in Heart Failure with Preserved Ejection Fraction

Design

Randomized, double-blind, placebo-controlled phase 3 trial enrolling 731 adults with heart failure with preserved ejection fraction (HFpEF, ejection fraction ≥50%) and BMI ≥30 kg/m2. Participants received tirzepatide (up to 15 mg once weekly, titrated from 2.5 mg) or matching placebo for 52 weeks. The trial excluded patients with HFrEF, recent hospitalization for acute decompensated heart failure, or type 1 diabetes. Co-primary endpoints were change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and change in body weight at 52 weeks.

Primary result

Tirzepatide produced a mean improvement of 6.9 points in KCCQ-CSS versus 3.3 points with placebo — an estimated treatment difference of 3.6 points (95% CI 1.0–6.1; P = 0.006). While statistically significant, the clinical meaningfulness threshold for KCCQ-CSS is generally considered 5 points; the between-group difference was below this threshold, though within-group improvement with tirzepatide exceeded it. Mean body-weight reduction was 12.8% with tirzepatide versus 2.4% with placebo.

Secondary outcomes

Tirzepatide improved 6-minute walk distance by a mean of 26.6 meters more than placebo — a clinically meaningful improvement in functional exercise capacity for this population. Reductions in C-reactive protein (a marker of systemic inflammation) and N-terminal pro-B-type natriuretic peptide (NT-proBNP, a heart failure biomarker) also favored tirzepatide. Waist circumference decreased substantially more with tirzepatide, consistent with visceral adipose reduction that likely contributes to the hemodynamic benefit.

Adverse events

Gastrointestinal adverse events were the most common with tirzepatide: nausea (24.2%), diarrhea (19.7%), and vomiting (8.9%) — consistent with the known GLP-1/GIP class profile. Discontinuation due to adverse events was 6.3% with tirzepatide vs. 1.4% with placebo. No excess in serious cardiovascular events, pancreatitis, or thyroid malignancies was observed during the 52-week period.

Interpretation

This trial established that GLP-1/GIP dual agonism can meaningfully improve heart failure symptoms in the obesity-HFpEF phenotype — a population with limited therapeutic options. The mechanism likely extends beyond weight loss alone: visceral fat reduction decreases pericardial and epicardial adipose depots, reducing mechanical compression on the heart; systemic inflammation reduction (evidenced by CRP decline) addresses a key driver of HFpEF pathophysiology; and improved metabolic substrate handling may enhance myocardial energetics. The improvement in 6-minute walk distance is particularly clinically relevant — functional capacity is the outcome patients experience daily. These findings position tirzepatide as a potential disease-modifying therapy for obesity-related HFpEF, an intersection of two epidemics where previously only diuretics and lifestyle modification were available.