Introduction

Heart failure with preserved ejection fraction (HFpEF) affects an estimated 3 million people in the United States and up to 32 million worldwide, with an estimated lifetime risk of heart failure (HF) exceeding 10% at 45 years of age in both men and women.¹ Obesity is a common clinical phenotype, with ≤80% of patients with HFpEF classified as having overweight or obesity, and adiposity contributing to the hemodynamic, inflammatory, and myocardial substrate of the disease.² GLP-1 receptor agonists (GLP1RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP1RAs therefore target an important pathophysiologic component of obesity-related HFpEF, and both semaglutide and tirzepatide have been shown to improve symptoms and physical limitations. However, a potential concern with these agents is loss of lean mass and physical reserve, which is particularly relevant in older adults.³

This expert analysis addresses: 1) how sarcopenia and sarcopenic obesity relate to outcomes in HFpEF; 2) whether incretin-based therapy measurably worsens muscle mass, muscle function, or frailty in this population; and 3) which mitigation and monitoring strategies are supported by current evidence, with particular attention paid to older adults.

Sarcopenia and Frailty in HFpEF

Sarcopenia (defined by low muscle strength and either low muscle quantity and quality) and sarcopenic obesity (defined by the coexistence of excess adiposity with reduced skeletal muscle mass and impaired muscle function) are both prevalent in patients with HFpEF.³ In a deep learning analysis of 55,768 cardiovascular MRI examinations from the UK Biobank, a sarcopenic obesity index combining body weight with pectoralis major muscle mass was associated with incident HF (hazard ratio [HR], 1.31; 95% CI, 1.16-1.49), cardiovascular death (HR, 1.51; 95% CI, 1.25-1.81), and all-cause death (HR, 1.37).⁴ This analysis showed more consistent associations with adverse remodeling and outcomes than did BMI, waist-to-hip ratio, or waist-to-height ratio.⁴ The important question that follows is whether incretin-based therapy can cause or accelerate sarcopenia. In animal models, low-dose GLP1RA exposure has been associated with greater muscle cross-sectional area and grip strength. In pooled trial data, however, approximately 25% of weight lost during GLP1RA therapy has been attributed to fat-free mass.^5,6 In a prespecified, pooled, participant-level frailty analysis of data from 1,145 patients enrolled in the STEP-HFpEF (Semaglutide Treatment Effect in People With Obesity and HFpEF) and STEP-HFpEF DM (Semaglutide Treatment Effect in People With Obesity and Heart Failure With Preserved Ejection Fraction and Diabetes Mellitus) trials, semaglutide 2.4 mg reduced body weight similarly across frailty strata, produced greater improvements in symptoms and physical limitations among the participants with the greatest degree of frailty, and reduced frailty burden at 52 weeks (odds ratio for not having frailty at week 52, 3.16; 95% CI, 2.44-4.09).⁷

Several caveats are important when interpreting these findings. Changes in muscle mass during GLP1RA-associated weight loss should be considered in the context of other weight-loss interventions, including bariatric surgery and caloric restriction, as well as the overall clinical benefits of treatment. The frailty index used in the STEP-HFpEF and STEP-HFpEF DM trials incorporated multiple HF-related variables; therefore, improvement in HF status may not fully reflect changes in overall frailty. None of the large GLP1RA trials in HFpEF included prespecified measures of muscle strength or physical performance, limiting direct assessment of clinically meaningful sarcopenia. In addition, follow-up remains relatively short, and objective assessments of skeletal muscle quantity and quality have been limited. Other considerations in older adults include gastrointestinal tract adverse effects, which may contribute to reduced oral intake, dehydration, and orthostatic hypotension, as well as the challenges of polypharmacy and medication adherence. Dedicated trials in older adults with frailty and HFpEF that incorporate measures of body composition, muscle strength, and physical function are needed to guide treatment in this expanding population.

Mitigation Strategies (Exercise, Protein, Emerging Drugs)

A joint advisory from the American College of Lifestyle Medicine (ACLM), American Society for Nutrition (ASN), Obesity Medicine Association (OMA), and The Obesity Society (TOS) recommends that GLP1RA-based therapies be accompanied by structured physical activity, including resistance training and ≥150 min per week of moderate-intensity aerobic activity.⁸ In addition, adequate protein intake should be prioritized during active weight reduction. Proposed targets include approximately 1.2-1.6 g/kg/day, or an absolute target of 80-120 g/day when appropriate; in individuals with obesity, protein requirements may be more appropriately estimated using fat-free or adjusted body weight rather than actual body weight.⁸

Agents targeting activin-myostatin signaling are being evaluated as adjuncts to preserve lean mass during incretin-associated weight loss. In the phase 2 EMBRAZE (Efficacy and Safety of Apitegromab for the Treatment of Adults Who Are Overweight or Obese) trial in adults with overweight or obesity, tirzepatide plus apitegromab produced similar total body weight loss compared with tirzepatide plus placebo, but lean mass loss accounted for 14.6% of total weight loss with apitegromab versus 30.2% with placebo, whereas fat mass accounted for 85.3% of total weight loss with apitegromab versus 69.5% with placebo.⁹ In the phase 2b BELIEVE (Safety and Efficacy of Bimagrumab and Semaglutide in Adults Who Are Overweight or Obese) trial, 507 adults with obesity received bimagrumab (Eli Lilly and Company), semaglutide, or combination therapy. At week 48, total lean mass changed by approximately +1-1.1% with bimagrumab, -4.7% to -6.9% with semaglutide, and -0.8% to -2.3% with combination therapy.¹⁰ These studies were conducted in populations with obesity rather than HFpEF and did not specifically focus on older adults with multimorbidity or functional impairment. Whether these therapies can provide clinically meaningful preservation of muscle mass or function in HFpEF remains unknown.

Conclusion

GLP1RA and dual GIP/GLP1RAs are emerging as promising therapies for patients with obesity-related HFpEF. However, the associated loss of lean mass warrants particular consideration in older adults at risk of frailty and sarcopenia. A multimodal approach combining structured resistance exercise, adequate protein intake, and, when clinically appropriate, assessment of body composition and physical function may help mitigate this concern. Dedicated trials in older adults with HFpEF and obesity receiving incretin-based therapy are needed and should incorporate detailed assessments of body composition, muscle strength, and physical function.

References

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