Although tirzepatide showed no heterogeneity in primary cardiovascular outcomes for differing baseline BMI or central adiposity, individuals with heart failure (HF) with preserved ejection fraction (HFpEF) with higher BMI at baseline showed greater improvement in six-minute walking distance (6MWD) during tirzepatide treatment and those with greater weight loss during treatment saw greater improvement in both exercise capacity and symptomology, according to a secondary analysis of the SUMMIT trial, published July 21 in JACC.

In the SUMMIT trial, investigators randomized 731 participants to either weekly subcutaneous tirzepatide (n=364) or placebo (n=367). Participants had baseline NYHA functional class II-IV HFpEF, BMI ≥30 kg/m2, 6MWD=100-425 m, and a KCCQ-CSS ≤80. Of the total participants, 728 (99.6%) had an elevated waist-height ratio of ≥0.5 – a measurement for central adiposity.

Among participants, greater baseline BMI was associated with younger age, female sex, more volume overload and inflammation, and more severe HF in patients with obesity-related HFpEF. Greater waist-height ratio was also associated with greater impairment in kidney function and exercise capacity.

Results at 52 weeks showed that tirzepatide consistently reduced risk of HF or cardiovascular death regardless of BMI. 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 body weight (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. There was also a trend toward greater improvement in KCCQ-CSS (p=0.097).

Barry A. Borlaug, MD, FACC, et al., note that their analysis provides "further evidence supporting the importance of excess body fat, particularly visceral fat, as driving HF severity in patients with the obesity phenotype of HFpEF."

In an accompanying editorial comment, Klara R. Klein, MD, PhD, et al., note that "while these findings reinforce the role of incretin therapies in HFpEF management, these data, perhaps more importantly, highlight the urgent need for precision strategies to define obesity and direct therapy to those who will benefit most."