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/m 2 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/m 2 ; 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.
Article Details
Authors (12)
Michael R. Zile
From Baylor University Medical Center, Dallas (M.P.); Imperial College, London (M.P.); RHJ Department of Veterans Affairs, Health System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.); the Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (C.M.K.); Flourish Research, Boca Raton, FL (S.J.B.); the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland (V.M.); the Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (J.G.); Eli Lilly, Indianapolis (G.J.W., Y.O., M.C.B., K.C.H., M.M.); and the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.).
Barry A. Borlaug
From Baylor University Medical Center, Dallas (M.P.); Imperial College, London (M.P.); RHJ Department of Veterans Affairs, Health System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.); the Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (C.M.K.); Flourish Research, Boca Raton, FL (S.J.B.); the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland (V.M.); the Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (J.G.); Eli Lilly, Indianapolis (G.J.W., Y.O., M.C.B., K.C.H., M.M.); and the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.).
Christopher M. Kramer
From Baylor University Medical Center, Dallas (M.P.); Imperial College, London (M.P.); RHJ Department of Veterans Affairs, Health System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.); the Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (C.M.K.); Flourish Research, Boca Raton, FL (S.J.B.); the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland (V.M.); the Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (J.G.); Eli Lilly, Indianapolis (G.J.W., Y.O., M.C.B., K.C.H., M.M.); and the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.).
Seth J. Baum
From Baylor University Medical Center, Dallas (M.P.); Imperial College, London (M.P.); RHJ Department of Veterans Affairs, Health System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.); the Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (C.M.K.); Flourish Research, Boca Raton, FL (S.J.B.); the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland (V.M.); the Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (J.G.); Eli Lilly, Indianapolis (G.J.W., Y.O., M.C.B., K.C.H., M.M.); and the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.).
Sheldon E. Litwin
From Baylor University Medical Center, Dallas (M.P.); Imperial College, London (M.P.); RHJ Department of Veterans Affairs, Health System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.); the Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (C.M.K.); Flourish Research, Boca Raton, FL (S.J.B.); the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland (V.M.); the Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (J.G.); Eli Lilly, Indianapolis (G.J.W., Y.O., M.C.B., K.C.H., M.M.); and the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.).
Venu Menon
Cleveland Clinic Coordinating Center for Clinical Research (C5 Research), Cleveland Clinic, Cleveland
Yang Ou
Center of Electron Microscopy and State Key Laboratory of Silicon and Advanced Semiconductor Materials, School of Materials Science and Engineering
Govinda J. Weerakkody
From Baylor University Medical Center, Dallas (M.P.); Imperial College, London (M.P.); RHJ Department of Veterans Affairs, Health System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.); the Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (C.M.K.); Flourish Research, Boca Raton, FL (S.J.B.); the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland (V.M.); the Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (J.G.); Eli Lilly, Indianapolis (G.J.W., Y.O., M.C.B., K.C.H., M.M.); and the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.).
Karla C. Hurt
From Baylor University Medical Center, Dallas (M.P.); Imperial College, London (M.P.); RHJ Department of Veterans Affairs, Health System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.); the Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (C.M.K.); Flourish Research, Boca Raton, FL (S.J.B.); the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland (V.M.); the Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (J.G.); Eli Lilly, Indianapolis (G.J.W., Y.O., M.C.B., K.C.H., M.M.); and the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.).
Chisom Kanu
Eli Lilly and Company, Indianapolis, IN (Y.O., G.J.W., K.C.H., C.K., M.M.).
Masahiro Murakami
Milton Packer
From Baylor University Medical Center, Dallas (M.P.); Imperial College, London (M.P.); RHJ Department of Veterans Affairs, Health System and Medical University of South Carolina, Charleston (M.R.Z., S.E.L.); the Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville (C.M.K.); Flourish Research, Boca Raton, FL (S.J.B.); the Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland (V.M.); the Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China (J.G.); Eli Lilly, Indianapolis (G.J.W., Y.O., M.C.B., K.C.H., M.M.); and the Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN (B.A.B.).