Do weight loss interventions challenge the obesity paradox in heart failure?

Abstract

Cardiovascular disease (CVD) remains a significant global health concern, with obesity recognized as a prominent risk factor. The ‘obesity paradox’ (OP) suggests that obesity does not always lead to adverse outcomes, particularly in heart failure (HF). In this forum, we discuss the relevance of the OP in the current therapeutic landscape for cardiometabolic diseases.

Obesity: statistics and impact in heart failure

In 2023, obesity rates exceeded 20% in every US state and territory, affecting over one in five adults. Among patients with HF, 29–40% are classified as overweight, and 30–49% are diagnosed with obesity. Notably, patients with HF with preserved ejection fraction (HFpEF) (see Glossary) have a higher prevalence of overweight and obesity (>80%) compared with those with HF with reduced ejection fraction (HFrEF) [1]. Obesity and HF share intricate links, including chronic inflammation, adipose dysfunction, insulin resistance, and altered adipokine secretion. These factors contribute to adverse cardiac remodeling and metabolic disturbances central to HF. Recent research questions the reliability of the concept of ‘metabolically healthy obese’ in predicting future CVD risk, emphasizing the importance of weight loss and lifestyle management for all individuals with obesity. Recent cardiology guidelines emphasize the importance of addressing obesity-related risks through screening and intervention [1]. Both American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology (ESC) guidelines stress comprehensive lifestyle interventions to address obesity and overweight for CVD prevention. ACC/AHA emphasize counseling, caloric restriction, physical activity, and weight management, while ESC includes dietary modifications, increased activity, and behavioral support. ESC also provides specific recommendations for weight-loss medications and bariatric surgery for patients at high risk of obesity, which the ACC/AHA guidelines do not [1].

Despite the acknowledged benefits of weight loss, guidelines for HF management vary in their recommendations. The 2022 AHA/ACC/HFSA guideline omits recommendation for glucagon-like peptide 1 receptor agonists (GLP-1RAs) and bariatric surgery. By contrast, the 2021 ESC guideline advises against using GLP-1RAs due to safety concerns and a lack of evidence for HF prevention; neither does it provide recommendations for bariatric surgery [1]. Of note, implementing weight-loss strategies in HF management is complex due to uncertainties regarding efficacy and risks, such as loss of lean muscle mass from both treatments and potential cardiovascular (CV) safety concerns associated with the positive chronotropic effects of GLP-1RAs. Sarcopenic obesity, frequently observed in HF, accelerates functional decline and worsens survival rates. The condition further limits cardiopulmonary fitness, diminishes quality of life, and reduces both exercise tolerance and functional capacity, which likely contribute to poorer clinical outcomes [2]. Although muscle loss is a common consequence of aging, the potential for additional muscle loss associated with GLP-1RAs or bariatric surgery could further exacerbate these challenges.

Advances in GLP-1RAs and bariatric surgery are reshaping the management of HF in patients with obesity, providing compelling evidence that challenges the concept of the OP. Often cited as a survival advantage associated with higher body mass index (BMI), the OP is increasingly called into question because these therapies demonstrate significant CV benefits beyond weight loss, reinforcing the potential of weight-loss interventions as a cornerstone in HF management. With more data emerging from clinical studies, here we present a compelling and balanced discussion suggesting that the OP is not a true phenomenon. By critically analyzing recent findings, we provide a comprehensive understanding of this paradox and its implications for clinical practice in the management of patients with HF.

Is the obesity paradox in HF still relevant in the era of GLP-1RAs and bariatric surgery?

The OP refers to the observation that individuals with overweight or mild obesity often have better short-term prognosis or survival rates compared with leaner individuals with conditions such as CVD, some types of cancer, end-stage renal disease, as well as HF. The underlying mechanisms driving this paradox remain incompletely understood; moreover, as the treatment landscape for obesity and HF evolves with the introduction of GLP-1RAs and the growing use of bariatric surgery, conflicting observations surrounding the OP have once again brought its validity into question. With GLP-1RAs and bariatric surgery improving HF outcomes beyond weight loss [3], the survival advantage of a higher BMI is no longer evident, suggesting that the paradox does not exist after all.

In both the STEP-HFpEF and STEP-HFpEF DM trials, patients with HFpEF and obesity with and without type 2 diabetes mellitus showed notable improvements in body weight, HF-related symptoms, physical limitations, and exercise capacity with the GLP-1RA semaglutide over placebo [4,5]. In the SELECT trial, semaglutide outperformed placebo in reducing HF hospitalizations, with no HF subtype interaction, in nondiabetic patients with pre-existing CVD and overweight or obesity [6]. Unlike GLP-1RAs, most evidence for bariatric surgery comes from observational studies. While limited, these studies still provide valuable insights into its impact on CV and metabolic outcomes. In individuals with type 2 diabetes mellitus with obesity and CVD, bariatric surgery notably decreased HF hospitalizations rates [7], and was associated with lower mortality in those with pre-existing HF, indicating its potential as an alternative treatment [8]. Bariatric surgery has also been reported as a safe and effective intervention for patients with severe HF and obesity, demonstrating improvements in both cardiac function and symptoms [9].

Interestingly, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor co-agonist tirzepatide demonstrated efficacy comparable to that of bariatric surgery [10], raising questions about whether weight loss alone determines CV benefits in people with obesity and CVD. Emerging data, such as from the SELECT trial, also suggest that CV benefits do not necessarily correlate with the degree of weight loss achieved [6]: indeed, in patients with obesity-related HFpEF, semaglutide significantly reduced body weight, with a stronger effect in women, yet it provided similar improvements in HF outcomes for both men and women, suggesting that the drug offers CV benefits beyond only weight loss [11]. These observations are crucial when comparing different weight-loss modalities in high-risk populations, highlighting the need to consider weight-dependent and independent CV effects in future trials.

Concluding remarks and future perspectives

With the advent of effective anti-obesity interventions, the validity of the OP has been fundamentally challenged, and we believe that it is becoming increasingly irrelevant. While some studies continue to report paradoxical outcomes, suggesting that the OP still exists in the current therapeutic landscape, these findings can often be attributed to several limitations inherent in observational studies, including selection bias and inadequate adjustments for confounding factors, such as fat distribution and body composition.

For instance, in the FIGHT trial, liraglutide did not improve posthospitalization clinical stability in patients with HFrEF, suggesting limited efficacy in this setting [12]. Similarly, in the LIVE trial involving patients with stable chronic HFrEF, liraglutide showed no improvement in left ventricular function over 24 weeks compared with placebo, but raised concerns about increased heart rate and serious cardiac events [13]. Furthermore, one study reported that 44% of patients who underwent bariatric surgery still had abnormal cardiac function 1 year post surgery [14]. This variability underscores the complexity of obesity, HF, and weight-loss interventions, and highlights the need for further research. While increasingly popular and theoretically beneficial for HF, bariatric surgery suffers from a lack of robust clinical trial data. Similarly, despite their metabolic advantages, GLP-1RAs may have differing effects depending on the specific formulation or the subtype of HF.

A critical issue is the reliance on BMI as a measure of obesity, because it fails to differentiate between lean muscle and visceral fat. This crude metric often misclassifies metabolically healthy individuals as ‘obese’ and creates the illusion of a protective effect, especially concerning muscle mass and racial backgrounds. When the waist-to-height ratio is used instead of BMI, the observed survival benefit in patients with obesity and HF disappears. Furthermore, reverse causality, where unintentional weight loss due to disease severity correlates with poorer outcomes, can falsely make higher BMI appear protective. Factors such as cachexia, altered neurohormonal pathways, and inflammatory mediators may further contribute to OP [15].

To address the OP practically, several straightforward strategies can be implemented in clinical practice while waiting for a ‘true’ clinical trial assessing the paradox. First, incorporating body composition analysis, such as waist circumference and waist-to-hip ratio [1], into routine evaluations provides more relevant information compared with BMI alone and helps clinicians better assess CV risk in patients with obesity. In addition, shifting the focus from BMI to metabolic health markers allows for better identification of at-risk patients regardless of their BMI category, enabling more personalized treatment approaches. Implementing standardized evaluation protocols that integrate both CV assessments and obesity-related metrics can further enhance patient care while minimizing the influence of confounding factors that contribute to the perceived paradox. Lastly, increasing education and awareness among healthcare providers about the limitations of the OP and the importance of considering body composition and metabolic health can be achieved through simple educational modules and updated guidelines integrated into existing training programs. By adopting these practical and applicable strategies while awaiting more definitive clinical trials, we can move beyond the outdated concept of the OP and focus on interventions that more accurately reflect patient health and treatment outcomes.

Taken together, we suggest that the OP is more likely an artifact of biased observational data rather than a real physiological phenomenon. With the introduction of therapies such as GLP-1RAs and bariatric surgery, which effectively target obesity, and with the hope of future definitive clinical trials, the clinical relevance of the OP will likely be further diminished.

Glossary

FIGHT trial

double-blind, placebo-controlled, randomized clinical trial designed to test the efficacy, safety, and tolerability of liraglutide at a dosage of 1.8 mg/day during the first 30 days (as tolerated) and continued for 180 days in patients with HFrEF (LVEF ≤40% within the 3 months before the study) and recent hospitalization with HF (within the previous 2 weeks), compared with placebo

Heart failure with preserved ejection fraction (HFpEF)

signs and symptoms of HF with left ventricular EF (LVEF) ≥50%

Heart failure with reduced ejection fraction (HFrEF)

signs and symptoms of HF with LVEF ≤40%

LIVE trial

investigator-initiated, randomized, double-blinded, placebo-controlled, multicenter trial investigating the effect of liraglutide (1.8 mg once daily) versus matching placebo over 24 weeks on LV function in patients with stable chronic HF

SELECT trial

multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial involving patients aged 45 years or older with pre-existing CVD and a body mass index of ≥27 kg/m² or greater, but no history of diabetes. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2 ± 13.7 months, and the mean duration of follow-up was 39.8 ± 9.4 months

STEP-HFpEF DM trial

international multicenter, double-blind, placebo-controlled trials that randomized adults with HFpEF, diabetes mellitus, and a body mass index ≥30 kg/m² to receive once-weekly semaglutide at a dose of 2.4 mg or placebo for 52 weeks as an add-on to standard care, with a follow-up period of 5 weeks after the end of treatment

STEP-HFpEF trial

international multicenter, double-blind, placebo-controlled trial that randomized adults with HFpEF and a body mass index ≥30 kg/m² to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks as an add-on to standard care, with a follow-up period of 5 weeks after the end of treatment