Impact of Body Mass Index, Central Adiposity, and Weight Loss on the Benefits of Tirzepatide in HFpEF: The SUMMIT Trial

Funding and conflicts

Funding

not reported in abstract

Industry funded

Unclear

Manufacturer

Novo Nordisk, Eli Lilly, Lilly, AstraZeneca, Boehringer Ingelheim, Amgen, Roche, Innovent

Sponsor role

not reported in abstract

Author conflicts

Funding Support and Author Disclosures The SUMMIT trial was funded by Eli Lilly and Company. Dr Borlaug is supported by R01 HL128526, R01 HL162828, and U01 HL160226 from the National Heart, Lung, and Blood Institute and W81XWH2210245 from the United States Department of Defense; has received research grant funding from AstraZeneca, Axon, Corvia, Novo Nordisk, and Tenax Therapeutics; has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations; and is named inventor (U.S. Patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure. Dr Zile has received research support from the Department of Veterans Affairs; and has served as a consultant for Abbott, Adona Medical, Aria CV, Avery Therapeutics, Boehringer Ingelheim, Boston Scientific, Cardiovascular Research Foundation Clinical Trials Center, CVRx, Diastol Therapeutics, EBR, Edwards, Lilly, GenKardia, Innoventric, KestraMedical, Medtronic, Merck, Morphic Therapeutics, Novartis, Pulnova, Salubris Biotherapeutics, Sonata, Srnalytics, V-Wave, and Vectorious. Dr Kramer has served as a consultant for Eli Lilly. Drs Ye, Ou, Hurt, and Murakami are employees of Eli Lilly and Company. Dr Packer has served as a consultant for 89bio, Abbvie, Actavis, Altimmune, Alnylam, Amarin, Amgen, Ardelyx, Armgo, AstraZeneca, Attralus, Bio

Independent replication

unknown

Notes

Authors declare relationships with the drug's manufacturer: Eli Lilly

Funding is shown on every study and never used to score it.

The source, as retrieved

Abstract

[BACKGROUND] The SUMMIT trial showed that the long-acting glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide 1 receptor agonist tirzepatide decreased the risk of cardiovascular death or worsening heart failure (HF) in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Effects may differ by baseline obesity severity, distribution, or magnitude of weight loss. [OBJECTIVES] In this analysis, the authors compared baseline characteristics and effects of tirzepatide on primary and other endpoints according to baseline obesity severity and distribution, and we explored relationships between degree of weight loss achieved and outcomes. [METHODS] In the SUMMIT trial, 731 patients with NYHA functional class II-IV HFpEF and body mass index (BMI) ≥30 kg/m2 were randomly assigned to tirzepatide (n = 364) or placebo (n = 367). The primary outcomes were time to cardiovascular death or worsening HF and change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 52 weeks. Key secondary outcomes included changes in 6-minute walk distance (6MWD), C-reactive protein (CRP), and body weight (BW) at 52 weeks. In this secondary analysis, primary and secondary endpoints were analyzed based on obesity severity (BMI) and distribution (waist-height ratio [WHR]). Time-to-event endpoints were analyzed with the use of a Cox regression model, and continuous endpoints were assessed with the use of a mixed-effects model for repeated measures. Relationships between changes in BW and waist circumference (WC) on treatment with tirzepatide and changes in key endpoints also were evaluated. [RESULTS] Patients with obesity-related HFpEF and higher BMI were younger and more likely to be female, with more severe HF symptoms and physical limitations, greater volume expansion despite higher diuretic use and lower natriuretic peptide levels, and more severe systemic inflammation compared with patients with lower BMI. These findings were largely similar when contrasting patients by baseline WHR, but those with higher WHR also had poorer exercise capacity and more severe kidney disease. There was no evidence of heterogeneity in the effect of tirzepatide on the risk of worsening HF or cardiovascular death by BMI or WHR tertile. However, with increasing tertiles of baseline BMI, there were greater improvements in 6MWD (estimated treatment difference [ETD]: 9.9 vs 26.3 vs 37.5 m; P = 0.025), and greater decreases in BW (ETD: -10.7% vs -11.8% vs -14.4%; P = 0.006) and systolic blood pressure (ETD: -1.00 vs -6.65 vs -6.62 mm Hg; P = 0.035) with tirzepatide compared with placebo, with a trend for greater improvement in KCCQ-CSS (P = 0.097). Among those randomized to tirzepatide, greater weight loss at 52 weeks was associated with larger improvements in 6MWD, KCCQ-CSS, CRP, and blood pressure, and a greater decrease in WC was associated with larger increases in 6MWD and KCCQ-CSS. Patients with elevated WHR but lower BMI had higher NYHA functional class and N-terminal pro-B-type natriuretic peptide, poorer kidney function, and lower 6MWD compared with those with lower WHR but higher BMI. [CONCLUSIONS] Among patients with obesity-related HFpEF, greater BMI is associated with younger age, female sex, more volume overload and inflammation, and more severe HF, and those with greater WHR also showed greater impairment in kidney function and exercise capacity. Tirzepatide consistently reduced the risk of HF or cardiovascular death regardless of baseline BMI, but there was evidence suggesting greater improvement in 6MWD in those with higher BMI at baseline. Greater weight loss on treatment with tirzepatide was associated with greater improvements in 6MWD and KCCQ. (A Study of Tirzepatide [LY3298176] in Participants With Heart Failure With Preserved Ejection Fraction [HfpEF] and Obesity [SUMMIT]; NCT04847557).

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