This article was created with Dr. Michelle Kittleson, Director of Heart Failure Research at the Smidt Heart Institute at Cedars-Sinai.This article was edited by Elizabeth Hyska.
Obesity and heart failure with preserved ejection fraction (HFpEF) are converging epidemics with profound public health implications. Obesity is not merely a comorbidity in HFpEF; it is a key pathophysiologic driver that shapes disease development, diagnostic accuracy, clinical presentation, and therapeutic response. As the prevalence of both conditions rises, practical strategies to diagnose and manage obesity in HFpEF have become central to contemporary heart failure care.
Epidemiology and Risk: A Growing Public Health Crisis
In the United States, the prevalence of obesity—defined as a body mass index (BMI) greater than or equal to 30 kg/m²—currently affects approximately 42% of adults and, in most states, is forecasted to exceed 60% adult obesity by 2050. In parallel, the prevalence of heart failure is expected to increase from 6.7 million individuals to more than 11 million by 2050. These trends are tightly linked.
Obesity is highly prevalent among patients with heart failure, particularly those with HFpEF, and is strongly associated with adverse cardiovascular remodeling, metabolic dysfunction, and systemic inflammation. Excess adiposity contributes to hypertension, insulin resistance, dyslipidemia, obstructive sleep apnea, and chronic kidney disease, all of which promote the development of HFpEF. Epidemiologic data demonstrate a graded relationship between body size and heart failure risk: each 4 kg/m² increase in BMI is associated with an approximately 1.2-fold higher risk of incident heart failure. This association is especially pronounced for HFpEF, underscoring obesity as a dominant upstream risk factor.
Diagnosing Obesity: Beyond Body Mass Index
Although BMI remains the most widely used metric to define obesity, it has significant limitations. BMI does not distinguish between fat mass and lean mass, nor does it capture the distribution of adipose tissue, which is critical to cardiometabolic risk. Visceral and ectopic fat depots—particularly abdominal and epicardial fat—are more strongly associated with inflammation, insulin resistance, and adverse cardiac mechanics than total body weight alone.
The waist-to-height ratio has emerged as a complementary anthropometric measure that better reflects central adiposity and cardiometabolic risk and may improve obesity classification in patients with heart failure. In addition, obesity should be conceptualized as a chronic disease, defined not solely by anthropometric thresholds but also by clinical impairment. Obesity-related complications such as obstructive sleep apnea, exertional dyspnea, exercise intolerance, osteoarthritis, and metabolic dysfunction provide essential context for disease severity and therapeutic decision-making.
Challenges in Diagnosing HFpEF in Obesity
The evaluation of heart failure in patients with obesity presents unique diagnostic challenges. Among the most important is the interpretation of natriuretic peptides, particularly N-terminal pro–B-type natriuretic peptide (NT-proBNP). NT-proBNP is a cornerstone biomarker for diagnosing, prognosticating, and risk-stratifying heart failure. However, circulating natriuretic peptide levels are systematically lower in individuals with higher BMI, even when cardiac filling pressures are elevated—potentially reducing diagnostic sensitivity at standard thresholds.
This paradoxical suppression of NT-proBNP in obesity likely reflects increased clearance, altered peptide processing, and reduced myocardial secretion relative to wall stress. The resulting discordance limits accurate risk assessment, contributes to underdiagnosis of obesity-related HFpEF, and creates barriers to enrollment of representative patients in HFpEF clinical trials that rely on natriuretic peptide thresholds. Consequently, obesity-related HFpEF may be underrecognized, undertreated, and underrepresented in evidence-generating studies.
Management Strategies for Obesity in HFpEF
Lifestyle and Behavioral Interventions
Lifestyle modification remains the foundation of obesity management. In individuals without heart failure, behavioral interventions—including caloric restriction, structured dietary patterns, and increased physical activity—are associated with 5–10% weight loss at 1 year, though results vary widely across trials. Long-term durability, however, is limited.
The Look AHEAD (Action for Health in Diabetes) trial provides essential insights. Participants randomized to an intensive lifestyle intervention achieved significantly greater weight loss at 1 year than those in usual care (8.6% vs 0.7%). Over time, these differences attenuated, with a mean weight loss of approximately 6% versus 3.5% at almost 10 years. While lifestyle interventions improve metabolic health and physical function, their modest and often transient effects highlight the need for adjunctive therapies, particularly in patients with symptomatic HFpEF.
Pharmacologic Therapy: Incretin-Based Agents
Recent advances in anti-obesity pharmacotherapy have transformed the treatment landscape. Third-generation weight-loss medications, particularly glucagon-like peptide-1 (GLP-1) receptor agonists and dual incretin agonists, have demonstrated substantial and sustained weight loss with favorable cardiometabolic effects.
Two pivotal trials have specifically evaluated these agents in patients with symptomatic HFpEF and obesity (BMI ≥30 kg/m²):
- STEP-HFpEF Program: This program randomized 1,145 patients across two trials with LVEF ≥45% to semaglutide or placebo, titrated to 2.4 mg once weekly for 1 year.
- SUMMIT Trial: This trial enrolled 731 patients with EF >50%, randomized to tirzepatide or placebo, titrated to 15 mg once weekly, with a median follow-up of 104 weeks.
In both trials, semaglutide and tirzepatide were associated with marked weight loss, significant improvements in quality of life, functional capacity, and NYHA functional class, as well as reductions in blood pressure, NT-proBNP, and high-sensitivity C-reactive protein, reflecting improved hemodynamics and reduced systemic inflammation and notably, in the SUMMIT trial, cardiovascular death or worsening heart failure event occurred in 9.9% in the tirzepatide group and in 15.3% in the placebo group (hazard ratio,0.62; P=0.026). Worsening heart failure events occurred in 8% in the tirzepatide group and in 14.2% in the placebo group, providing evidence that pharmacologic weight loss can favorably modify clinical outcomes in HFpEF.
MARITIME-HF is currently underway with a new, first-in-class, peptide-antibody with GLP1-R agonist and GIP antagonist, and testing the hypothesis that this new antibody, administered sc, once a month, is superior to placebo when given as an adjunct to standard of care on the composite endpoint of heart failure hospitalization, CV death in patients with HFpEF or HFmrEF, and BMI >30 kg/m2.
Invasive Interventions: Bariatric Surgery
Metabolic and bariatric surgery, including Roux-en-Y gastric bypass and sleeve gastrectomy, represents the most effective weight-loss intervention currently available. These procedures achieve around 25-35% weight loss at 1 year, with approximately 70% of patients maintaining >20% weight reduction at 10 years.
Although there are no randomized controlled trials of bariatric surgery in patients with established heart failure, data from populations without heart failure are compelling. Bariatric surgery has been associated with improvements in cardiac structure, including reduced LV mass, and a 50% reduction in the risk of subsequent heart failure, along with significant reductions in cardiovascular death, myocardial infarction, and stroke. Additional benefits include sustained improvements in systolic blood pressure, lipid profiles, and glycemic control. The role of bariatric surgery in HFpEF remains an essential but untested area of investigation.
Despite significant advances, substantial knowledge gaps remain. Key unanswered questions include:
- Which weight-loss therapy offers the most significant benefit in HFpEF?
- What are the dominant mechanisms of benefit? Potential contributors include attenuation of systemic inflammation and improved renal function.
- Does greater weight loss translate into greater heart failure benefit?
- Can weight-loss interventions improve hard outcomes, including heart failure hospitalization and mortality, across the broader HFpEF population?
Addressing these questions will require long-term, adequately powered trials that integrate mechanistic endpoints with clinical outcomes.
Conclusion
Obesity is a central driver of HFpEF pathophysiology, diagnostic complexity, and therapeutic opportunity. Emerging evidence demonstrates that targeted weight-loss therapies—particularly incretin-based pharmacologic agents—can meaningfully improve symptoms, functional capacity, and heart failure–related outcomes in patients with HFpEF and obesity. As the twin epidemics of obesity and heart failure continue to expand, integrating obesity management into the core treatment paradigm for HFpEF represents a critical step toward improving patient-centered and population-level outcomes.
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