Effects of Tirzepatide on the Clinical Trajectory of Patients With Heart Failure, Preserved Ejection Fraction, and Obesity

Abstract

Background: Patients with heart failure with preserved ejection fraction and obesity have significant disability and frequent exacerbations of heart failure. We hypothesized that tirzepatide, a long-acting agonist of glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, would improve a comprehensive suite of clinical end points, including measures of health status, functional capacity, quality of life, exercise tolerance, patient well-being, and medication burden, in these patients.

Methods: We randomized (double-blind) 731 patients with class II to IV heart failure, ejection fraction ≥50%, and body mass index ≥30 kg/m² to tirzepatide (titrated up to 15 mg SC weekly; n=364) or placebo (n=367) added to background therapy for a median of 104 weeks (quartile 1, 66; quartile 3, 126 weeks). The primary end points were whether tirzepatide reduced the combined risk of cardiovascular death or worsening heart failure and improved Kansas City Cardiomyopathy Questionnaire Clinical Summary Score. The current expanded analysis included sensitivity analyses of the primary end points, 6-minute walk distance, EQ-5D-5L health state index, Patient Global Impression of Severity Overall Health score, New York Heart Association class, use of heart failure medications, and a hierarchical composite based on all-cause death, worsening heart failure, and 52-week changes in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score and 6-minute walk distance.

Results: Patients were 65.2±10.7 years of age; 53.8% (n=393) were female; body mass index was 38.2±6.7 kg/m²; Kansas City Cardiomyopathy Questionnaire Clinical Summary Score was 53.5±18.5; 6-minute walk distance was 302.8±81.7 m; and 53% (n=388) had a worsening heart failure event in the previous 12 months. Compared with placebo, tirzepatide produced a consistent beneficial effect across all composites of death and worsening heart failure events, analyzed as time to first event (hazard ratios, 0.41-0.67). At 52 weeks, tirzepatide increased the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score by 6.9 points (95% CI, 3.3-10.6; P<0.001), 6-minute walk distance 18.3 meters (95% CI, 9.9-26.7; P<0.001), and EQ-5D-5L 0.06 (95% CI, 0.03-0.09; P<0.001). The tirzepatide group shifted to a more favorable Patient Global Impression of Severity Overall Health score (proportional odds ratio, 1.99 [95% CI, 1.44-2.76]) and New York Heart Association class (proportional odds ratio, 2.26 [95% CI, 1.54-3.31]; both P<0.001) and required fewer heart failure medications (P=0.015). The broad spectrum of effects was reflected in benefits on the hierarchical composite (win ratio, 1.63 [95% CI, 1.17-2.28]; P=0.004).

Conclusions: Tirzepatide produced a comprehensive, meaningful improvement in heart failure across multiple complementary domains; enhanced health status, quality of life, functional capacity, exercise tolerance, and well-being; and reduced symptoms and medication burden in patients with heart failure with preserved ejection fraction and obesity.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04847557.

Keywords: heart failure, preserved ejection fraction; obesity; tirzepatide.

Figure 1.

Effects of tirzepatide on fatal and HF events. A, Effect of tirzepatide on time to first all-cause death or worsening heart failure (HF) event. In an intention-to-treat analysis, tirzepatide significantly reduced this end point by 33% compared with placebo (hazard ratio [HR], 0.67 [95% CI, 0.45–0.99]; P=0.045). Worsening HF event was defined as worsening symptoms of HF requiring hospitalization, intravenous therapy in an urgent care setting, or oral diuretic intensification. B, Effect of tirzepatide on time to first HF event (excluding oral diuretic intensification). In an intention-to-treat analysis, tirzepatide significantly reduced this end point by 59% compared with placebo (HR, 0.41 [95% CI, 0.22–0.75]; P=0.004).

Figure 2.

Forest plot examining effects of tirzepatide vs placebo on end-point event rates. In intention-to-treat analysis, 9 composite and individual event combinations were examined; compared with placebo, tirzepatide produced a consistent beneficial effect across all composite and individual event combinations (hazard ratios, 0.41–0.67).

Figure 3.

Effects of tirzepatide on Kansas City Cardiomyopathy Questionnaire. A, Effect of tirzepatide on change from baseline in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) at 24 and 52 weeks of treatment. In an intention-to-treat analysis, compared with placebo, tirzepatide increased KCCQ-CSS with a between-group difference of 6.9 points (95% CI, 3.3–10.6; P<0.001). B, Effect of tirzepatide on the proportion of participants achieving KCCQ-CSS thresholds of ≥5, 10, 15, and 20 points. In intention-to-treat analysis and with prespecified imputation procedures for missing data, tirzepatide increased the proportion of subjects reaching each threshold compared with placebo, with odds ratios ranging from 1.8 to 2.0. *P<0.01, tirzepatide vs placebo.

Figure 4.

Effect of tirzepatide on exercise tolerance and health status. A, Effect of tirzepatide on change from baseline in 6-minute walk distance (6MWD). In an intention-to-treat analysis, compared with placebo, tirzepatide increased 6MWD with a between-group difference of 18.3 m (95% CI, 9.9, 26.7; P<0.001) at 52 weeks. B, Effect of tirzepatide on the proportion of subjects who reached threshold changes of ≥10-, ≥20-, and ≥30-m increase in 6MWD. In intention-to-treat analysis and with prespecified imputation procedures for missing data, tirzepatide increased the proportion of subjects reaching each threshold compared with placebo, with odds ratios ranging from 2.2 to 2.0. *P<0.001, tirzepatide vs placebo.

Figure 5.

Effect of tirzepatide on change from baseline in EQ-5D-5L health state index and PGIS Overall Health. A, Effect of tirzepatide on change from baseline in EQ-5D-5L health state index. At 52 weeks, in an intention-to-treat analysis, tirzepatide increased EQ-5D-5L health state index with a between-group difference of 0.06 (95% CI, 0.033–0.087; P<0.001). B, Effect of tirzepatide on change in Patient Global Impression of Severity (PGIS) Overall Health. At 24 weeks, the tirzepatide group by intention to treat was more likely to show improvement in PGIS Overall Health (55.2% vs 40.4%) and less likely to report worsening in PGIS Overall Health (9.1% vs 11.5%). Proportional odds ratio (OR) for improvement in PGIS Overall Health with tirzepatide vs placebo was 1.68 (95% CI, 1.22–2.29; P=0.001). At 52 weeks, tirzepatide group by intention to treat was more likely to show improvement in PGIS Overall Health (55.2% vs 38.5%) and less likely to report worsening in PGIS Overall Health (7.4% vs 11.3%). Proportional OR for improvement in PGIS Overall Health with tirzepatide vs placebo was 1.99 (95% CI, 1.44–2.76; P<0.001). *P<0.001, tirzepatide vs placebo.

Figure 6.

Effect of tirzepatide on change in NYHA class and medication use. A, Effect of tirzepatide on change in New York Heart Association (NYHA) class. Tirzepatide improved NYHA class at 52 weeks with a proportional odds ratio for improvement in ≥1 NYHA classes of 2.26 (95% CI, 1.54–3.31). B, Effect of tirzepatide on change in medications from baseline to end of follow-up by intention-to-treat analysis. Intensification of heart failure (HF) medications (inclusive of the use of inhibitors of the renin-angiotensin system and neprilysin, beta-blockers, mineralocorticoid receptor antagonists, and diuretics) occurred less frequently in the tirzepatide group; use of these HF medications was reduced more frequently in the tirzepatide group (P=0.015; left). Similar results occurred in changes in diuretics (P<0.001; right).