Pharmacotherapy for weight management in HFpEF: Do we have to lose big to win small?

Globally, there are now more obese than underweight people, and the dramatic rise in obesity over the last four decades has been accompanied by a deluge of associated complications[1]. Among these, obesity-related heart failure with preserved ejection fraction (HFpEF) has emerged as a distinct pathological entity, mediated by a combination of direct deleterious effects on cardiac structure and function combined with systemic multi-organ damage.[2] Patients with obesity-related HFpEF have more fluid retention, worse symptom burden and lower exercise capacity than those with normal weight HFpEF.[3] 

Unsurprisingly, there have been numerous calls for treatments aimed specifically at obesity-related HFpEF. Although small trials have shown that lifestyle-mediated weight loss improves exercise capacity in obesity-related HFpEF[4], only modest body weight reductions (~5% to 10%) are achieved even with intensive lifestyle modification, and long-term sustainability is limited.[5] 

Alternatively, bariatric surgery achieves more marked (>15%) and sustained weight loss, with observed reductions in downstream major adverse cardiovascular events (including heart failure hospitalisation) in obese patients with cardiovascular disease.[6] Large-scale availability and fitness for surgery of HFpEF patients with multimorbidity, however, hinders widespread feasibility of bariatric surgery. The emergence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as safe, tolerable and efficacious weight-loss pharmacotherapies brings new hope for the treatment of obesity and related complications, including HFpEF.

The STEP-HFpEF trial (Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity) was a multicentre, international, placebo-controlled, randomised study aiming to determine whether treatment with the GLP-1 RA semaglutide, in addition to weight loss, would improve symptom burden and exercise capacity in obesity-related HFpEF.[7] 529 nondiabetic subjects with symptomatic HFpEF and BMI ≥30 kg/m² were randomised to receive either semaglutide 2.4 mg/week via subcutaneous injection or placebo for 52 weeks. The overall trial cohort was slightly younger (median age 69 years) and with a higher proportion of females (56%) than previous major HFpEF trials[8–10], indicative of the specific obesity-related HFpEF phenogroup targeted (median body weight and BMI were 105 kg and 37 kg/m², respectively). 

Compared with placebo, participants in the semaglutide group experienced an anticipated and marked reduction in body weight (mean change –13.3%, compared with –2.6% for placebo), consistent with previous weight loss trials of semaglutide.[11] Crucially, greater improvements in heart failure symptoms (Kansas City Cardiomyopathy Questionnaire clinical summary score [KCCQ-CSS], the co-primary outcome measure together with percentage weight reduction) and exercise capacity (6-minute walk test, a secondary outcome measure) were observed in the active treatment compared with placebo arm. 

The absolute improvement in heart failure symptoms with semaglutide was especially promising: KCCQ-CSS increased from ~59 to ~76 points overall (median overall change 16 points). This represents a moderate-to-large clinical improvement in symptoms[12], although the estimated difference in KCCQ-CSS at 52 weeks between semaglutide and placebo arms was a more modest 8 points. 

Unpacking whether these improvements in symptoms were attributable primarily to weight loss or, indeed, a true reduction in specific heart failure symptom burden will always be challenging. Nevertheless, these improvements in symptoms were far in excess of the change in KCCQ scores in the DELIVER and EMPEROR-Preserved trials of dapagliflozin and empagliflozin in HFpEF, where only small increases of between ~2 and 5 points, respectively, were observed. 

Less impressive in STEP-HFpEF was the increase in 6-minute walk distance, which increased from 316 to 338 m in the semaglutide arm – a mere 7% improvement in exercise capacity. Safety and tolerability were no different between trial arms. A digest of the study can be read here. 

Where does STEP-HFpEF leave us in the management of obesity-related HFpEF and, indeed, other secondary diseases resulting from obesity? It has always been assumed that obesity is a major, but reversible, driver of heart failure, and treating obesity could hold the key to reducing the burden of symptoms associated with the specific obesity-related HFpEF phenotype. This is certainly supported by the findings of STEP-HFpEF, where marked improvements in heart failure symptoms were seen, with pharmacological weight loss induced by the GLP-1 RA semaglutide. 

Indeed, in a prespecified secondary analysis of the trial, a dose–response relationship is seen between the magnitude of weight loss and the extent of symptom benefit: each 10% reduction in body weight with semaglutide was associated with a 6-point increase in KCCQ-CSS and a 14-m increase in 6-minute walk distance.[13] In other words, every percentage reduction in body weight led to a just over a 1-point increase in KCCQ-CSS and 2 m gained in exercise capacity. 

At first glance this may appear like big losses for small gains, but the reality is that obesity is on the rise, treatment options until recently have been scarce or ineffective, and GLP-1 RA pharmacological weight loss therapies represent a major opportunity for treatment both of the disease itself and the host of associated complications. Indeed, emerging data suggest that GLP-1 RA treatment attenuates progression of renal impairment in people with type 2 diabetes and chronic kidney disease. The recent phase III FLOW trial (once-weekly injectable semaglutide kidney outcomes trial in people with type 2 diabetes) has been stopped early following interim results meeting the pre-specified criteria for efficacy. We eagerly await the full study results, but the manufacturer’s press release is available here.

References

1. NCD Risk Factor Collaboration (2016) Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet 387: 1377–96
2. Borlaug BA, Jensen MD, Kitzman DW et al (2023) Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc Res 118: 3434–50
3. Reddy YNV, Lewis GD, Shah SJ et al (2019) Characterization of the obese phenotype of heart failure with preserved ejection fraction: A RELAX trial ancillary study. Mayo Clin Proc 94: 1199–209
4. Kitzman DW, Brubaker P, Morgan T et al (2016) Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: A randomized clinical trial. JAMA 315: 36–46
5. Papamargaritis D, le Roux CW, Holst JJ, Davies MJ (2022) New therapies for obesity. Cardiovasc Res 30 Nov [Epub ahead of print]
6. Doumouras AG, Wong JA, Paterson JM et al (2021) Bariatric surgery and cardiovascular outcomes in patients with obesity and cardiovascular disease: A population-based retrospective cohort study. Circulation 143: 1468–80
7. Kosiborod MN, Abildstrom SZ, Borlaug BA et al; the STEP-HFpEF Trial Committees and Investigators (2023) Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med 389: 1069–84
8. Anker SD, Butler J, Filippatos G et al (2021) Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 385: 1451–61
9. Solomon SD, McMurray JJV, Claggett B et al (2022) Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 387: 1089–98
10. Solomon SD, McMurray JJV, Anand IS et al (2019) Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med 381: 1609–20
11. Wilding JPH, Batterham RL, Calanna S et al (2021) Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 384: 989–1002
12. Stogios N, Fezza G, Wong JV et al (2021) Current challenges for using the Kansas City Cardiomyopathy Questionnaire to obtain a standardized patient-reported health status outcome. Eur J Heart Fail 23: 205–7
13. Borlaug BA, Kitzman DW, Davies MJ et al (2023) Semaglutide in HFpEF across obesity class and by body weight reduction: a prespecified analysis of the STEP-HFpEF trial. Nat Med 29: 2358–65