FINEARTS-HF Analysis Supports Finerenone’s Value in HFpEF With Obesity

Patients who have heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) and high body mass index (BMI) may see more of a benefit from taking nonsteroidal mineralocorticoid receptor antagonists (MRA) than those who are at normal weight or underweight, a prespecified analysis of the FINEARTS-HF trial shows.

When the investigators stratified patients by BMI, finerenone (Kerendia; Bayer AG) was associated with a reduction in cardiovascular death and total worsening HF events across all weight categories compared with placebo, with no interaction by BMI. However, an analysis examining BMI as a continuous variable showed that the beneficial effect of the MRA was more substantial in those with a BMI of 35 or higher.

The study builds on evidence from trials like RALES and EMPHASIS-HF, both of which suggested that the benefit of MRAs may be greater in patients with versus without obesity. The reasoning behind this is that excessive adipocyte-derived aldosterone secretion combined with mineralocorticoid receptor overactivation conveys deleterious effects on top of the risks these patients have from their HF.

The FINEARTS-HF investigators say their findings are of particular importance in patients with HFpEF, who typically have a greater prevalence of obesity than those with HFrEF.

To TCTMD, lead author Jawad H. Butt, MD (University of Glasgow, Scotland), said the data refute the existence of an obesity paradox in this context.

“We have previously debunked this paradox in patients with HFrEF enrolled in the PARADIGM-HF and DANISH trials, and in the present study, we demonstrate that the paradox does not exist in patients with HFpEF either. This finding really underlines the importance of weight loss in obese patients with HF,” he said.

The analysis was published this week in the Journal of the American College of Cardiology in conjunction with its presentation at the Global Cardiovascular Clinical Trialists Forum in Washington, DC.

“This really tells us that we should be using finerenone across the board, but we can be even more confident that it's going to lead to more meaningful improvements for people with more severe obesity,” said Barry A. Borlaug, MD (Mayo Clinic, Rochester, MN), who commented on the study for TCTMD.

He said while the mechanism behind obesity and worsening HFpEF remains unknown, the authors’ suggestion that those in the higher obesity categories are at greater risk for volume overload secondary to high aldosterone levels is a plausible theory.

With two-thirds of HFpEF patients in the United States living with obesity, often alongside diabetes and insulin resistance, Borlaug said this analysis gives credence to the possibility of combining an MRA with glucagon-like peptide-1 (GLP-1) receptor agonists to optimize weight loss and reduce the risk of HF events.

Butt said in the FINEARTS-HF trial approximately 160 patients were treated with a GLP-1 receptor agonist, so the investigators are in the process of looking into the additive effects of both versus either drug. “I personally do think that the effect of finerenone is evident in both patients treated with and without GLP-1 receptor agonists,” Butt noted.

We should be using finerenone across the board, but we can be even more confident that it's going to lead to more meaningful improvements for people with more severe obesity. Barry A. Borlaug

The main FINEARTS-HF study randomized 6,001 patients with symptomatic HF and LVEF 40% or greater (mean LVEF 53%). Patients also had elevated natriuretic peptide levels and evidence of structural heart disease, with the majority having NYHA functional class II symptoms. Those randomized to finerenone received either a 20- or 40-mg dose once daily in addition to usual therapy. Compared with placebo, treatment with finerenone resulted in a lower rate of the composite of total worsening HF events and CV death (primary outcome), driven by the reduction in total worsening HF events, with no significant differences in rates of CV death.

For the prespecified analysis, the investigators grouped the trial population into BMI categories: underweight/normal weight (< 25.0 kg/m²; n = 1,306); overweight (25.0-29.9 kg/m²; n = 1,990); obesity class I (30.0-34.9 kg/m²; n = 1,546); obesity class II (35.0-39.9 kg/m²; n = 751); and obesity class III (≥ 40 kg/m²; n = 395).

The median BMI was 29.2 kg/m². Patients in the higher BMI categories were more likely than those who were categorized as underweight/normal weight to be younger, female, and white; and they were sicker overall, with higher systolic blood pressure, higher hemoglobin A1c levels, poorer quality of life scores, more physical limitations, and worse symptom severity scores. Despite this, those with the highest levels of obesity had lower NT-proBNP levels than those without obesity.

By baseline BMI, there were no differences in the impact of finerenone of the primary outcome  P for interaction = 0.32). But, as a continuous variable with patients stratified for geographic region and LVEF, the beneficial effect of finerenone on preventing CV death and total worsening HF events was greater in those with a higher BMI (P for interaction = 0.005).

Obesity and HFpEF Phenotypes

Management of HFpEF has come a long way in a short time, note Amanda R. Vest, MBBS, MPH (Cleveland Clinic, OH) and Andrew J. Sauer, MD (Saint Luke's Mid America Heart Institute, Kansas City, MO), in an editorial accompanying the study.

They say the next challenge will be to define obesity in ways that help to identify those in need of targeted metabolic HF strategies.

“Growing consensus acknowledges that BMI is a deeply flawed metric for the diagnosis and categorization of obesity given its insensitivity to fat versus lean masses or the distribution of adiposity, and because the relationship between fat mass and BMI is highly influenced by sex and race,” the editorialists explain.

Vest and Sauer suggest that a revised obesity definition should move beyond the simplicity of BMI and include “the metabolic consequences of visceral adipose accumulation.” The Lancet Commission on Obesity, they add, is working on such a definition and revised framework, which is anticipated by early 2025.

To TCTMD, Butt said he has been advocating for using waist-to-height ratio because he believes it is a much better measure of adiposity and it’s part of the NICE guideline recommendations. The FINEARTS-HF investigators in fact gathered a variety of anthropometric measures including waist circumference, waist-to-hip ratio, body shape index, and body roundness index.

According to Borlaug, growing interest in refining identification of patients with the obesity phenotype of HFpEF is a promising avenue for enhancing patient care and honing precision medicine efforts in this area. “It justifies thinking about these people a little bit differently and [referring to] them as having obesity-related HFpEF because it keeps us focused on treating the root cause, which we think is the obesity and the cardiometabolic stress,” he added.