https://orcid.org/0000-0002-1604-2593
In contrast to heart failure with reduced ejection fraction, heart failure with preserved ejection fraction (HFpEF) has proven a challenging condition to treat. The first class of drugs to significantly improve outcomes were the sodium-glucose co-transporter-2 (SGLT2) inhibitors. SGLT2 inhibitor trials have demonstrated an 18–21% reduction in the rate of HF hospitalization or cardiovascular death.1,2 The EMPEROR and DELIVER trials have shown statistically significant, but on average modest improvements in quality-of-life scores measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ): 1.50 (95% CI, 0.64–2.36) points increase with empagliflozin and 2.3 (95% CI, 1.5–3.2) points with dapagliflozin. While SGLT2 inhibitors lower the risk of ‘hard’ HFpEF outcomes, the debilitating symptoms of the condition—dyspnoea, fatigue and swelling, as well as physical limitations in the activities of daily living3—appear only modestly improved by their use as captured by KCCQ changes.
Obesity has been increasingly proposed to be a key driver of HFpEF, with some referring to HFpEF as the cardiac manifestation of the metabolic syndrome, marked by hypertension, dyslipidaemia and type 2 diabetes mellitus,3 conditions to varying extents exacerbated or promoted by excess adipose tissue. Other risk factors for incident HFpEF include older age, and coronary artery disease.4 Considering these circumstances, incretin therapies now licenced for obesity, present a promising choice for management of HFpEF.
Glucagon-like peptide 1 [GLP-1] is an incretin hormone derived from the proglucagon gene that influences several metabolic pathways.5 Receptors are found in various tissues, including pancreatic beta cells, heart, blood vessels, kidneys, immune system, brain and liver.5 Pharmacological activation of GLP-1 receptors through agents such as semaglutide stimulates pancreatic insulin secretion, slows down gastric emptying and suppresses appetite, with the effects of improved blood glucose control and weight loss, the latter more so at higher doses. Besides their antidiabetic properties, GLP-1 receptor agonists reduce the incidence of major adverse cardiovascular events (MACE), likely predominantly via direct tissue effects.6 Additionally, the incretin-induced weight loss decreases blood pressure, with greater weight loss corresponding to greater blood pressure reductions, and adds metabolic benefits.6
Recent seminal trials have demonstrated the efficacy of incretin-based anti-obesity medicines (AOMs) therapies in HFpEF, particularly in improving the quality of life in a clinically meaningful way. Specifically, the STEP-HFpEF and STEP-HFpEF DM trials demonstrated impressive improvements in KCCQ Clinical Summary Score of 7.5 points (95% CI, 5.3–9.8) with once-weekly subcutaneous semaglutide (up to 2.4 mg) in patients with HF and obesity with or without type 2 diabetes, respectively.7 The trials also demonstrated improvements in 6-minute walk distance (6MWD) and CRP levels, as well as suggestive improvements in harder outcomes, in particular HF events.7 These findings have recently been strongly supported by the results of the SUMMIT trial, which tested the impact of the dual GLP-1 receptor and glucose-dependent insulinotropic polypeptide agonist, tirzepatide in patients with HFpEF.8 In the latter trial, the two primary outcomes—a composite of death from cardiovascular causes or worsening heart failure and change in health status in patients with HFpEF and obesity—were both significantly improved.8
Further relevant HF data come from secondary analyses of the FLOW (patients with T2D and CKD) and SELECT (patients post ASCVD or Peripheral arterial disease) trials as part of a meta-analysis combined with the STEP heart failure trials.9 Across the three combined trials, semaglutide reduced the risk of the combined endpoint of cardiovascular death or heart failure by 31%, hazard ratio of 0.69 (95% CI, 0.53–0.89) relative to placebo.
The totality of these remarkable and perhaps largely ‘unexpected’ findings confirms semaglutide to be an important treatment option for people with HFpEF, particularly in improving health status, with tirzepatide a robust alternative. At this stage, it is important to ask whether the benefits of these AOMs in HFpEF stem largely from their direct tissue effects or more from their associated weight loss. In support of the latter, a trial by Kitzman and colleagues (2016)10 investigating 20 weeks of aerobic exercise or caloric restriction in patients with HFpEF found a 7-unit (95% CI, 2.6–12.3) improvement in KCCQ in the caloric restriction group. Caloric restriction also resulted in a 7% loss of body weight and a decrease in left ventricular mass of 4 g (95% CI, −7 to 0) measured by echocardiography. For comparison, pooled analysis of STEP-HFpEF and STEP-HFpEF DM trials found a −8.4% (95% CI, −9.2–−7.5) change in bodyweight, and a 7.5-point (95% CI, 5.3–9.8) improvement in KCCQ-CSS, suggestive of similar improvements in reported outcomes with both semaglutide and caloric restriction. CRP reductions were also similar. An echocardiography substudy of STEP-HFpEF,11 however, did not find significant changes in the left ventricular dimensions, mass, or systolic function. By contrast, the SUMMIT substudy using more powerful cardiac MRI noted a –13.9% (95% CI, −14.3 to −13.5) change in bodyweight8 and a placebo-corrected decline in LV mass of −11 g (95% CI, −19 to −4).
Our reading of these data, together with considerable prior evidence linking obesity to incident HFpEF,12 is that the improvements in KCCQ and cardiac remodelling could be largely attributed to incretin-induced weight loss, more so than any direct effects of these AOMs on cardiac tissue. Proposed beneficial mechanisms could include weight loss-induced reductions in plasma volume, epicardial fat, blood pressure and inflammation, but many other pathways are likely relevant and need investigation (Figure 1). As many of the highlighted pathways in the figure will change with intentional weight loss, it will be difficult to work out which pathways are most relevant to noted symptomatic and outcome benefits in HFpEF.
The range of potential mechanisms by which weight loss or anti-obesity medicines could improve symptomatic or hard outcomes in patients with HFpEF and excess adiposity. This figure illustrates the range of pathways that may link obesity to HFpEF. Some of the pathways may also be influenced directly by incretin molecules independent of any weight loss. Head-to-head trials of lifestyle vs. AOM-induced weight loss would be useful in this space.
Of interest, Withaar and colleagues (2023)13 compared the effects of semaglutide with weight loss by pair feeding in a mouse model of HFpEF and noted semaglutide exhibited superior cardio-protective effects compared to pair feeding. As preclinical studies do not always translate to humans, this hot topic would greatly benefit from future head-to-head clinical trials of sufficient power comparing the impacts of incretin-based weight loss with dietary-induced weight loss in HFpEF on KCCQ and, ideally, on harder outcomes. Such trials should also place close attention to mechanistic comparisons of these two modes of intervention across a range of potential pathways (Figure 1). The results of such head-to-head trials are important since if weight loss proves to be largely responsible for symptomatic and/or outcome benefits, this would mean cardiologists will be more motivated to target excess weight earlier in the course of the disease in people living with obesity (as well as considering weight loss in the prevention of HFpEF). In addition, the much lower cost of lifestyle dietary interventions could be important in low- and middle-income countries to treat HFpEF before AOMs come substantially down in price.
On a final point, intentional weight loss as an intervention (by dietary means or AOMs) has not received the recognition it deserves in cardiovascular medicine, in part because the tools to lose weight sustainably were not considered robust until recently. Yet, the exciting AOM-associated trials results in HFpEF suggest that the community may have underestimated the impact of excess adiposity on several non-atherosclerotic cardiovascular conditions, many of which are now rising in incidence, in contrast to atherosclerotic outcomes which have declined over time.14 Biological and clinical scientists would do well to collaborate to fill important gaps in understanding the links between obesity and cardiovascular disease. Only by doing so might we better understand the documented and future potential impacts of newer AOMs on a range of interlinked cardiovascular-kidney and metabolic conditions.
Acknowledgements
The authors thank Liz Coyle, University of Glasgow, for assistance with the preparation of this article.
Funding
None.
Data availability
No new data were generated or analysed in support of this research.
References
Authors
Katarzyna Stefanska, BMedSci, is an undergraduate MBChB (Hons) student at the University of Edinburgh, currently in her clinical years. She is interested in cardiometabolic health and the mechanisms behind promoting health and preventing chronic diseases. Katarzyna has a keen interest in integrating evidence-based strategies into patient care and aspires to pursue a career where she can combine clinical research and practice with public health advocacy.
Naveed Sattar is a professor of Cardiometabolic Medicine, with ongoing clinical activities in Cardiovascular prevention. He works across cardiometabolic disease and obesity-related studies, with epidemiology, mechanistic and trial expertise. He has contributed to several randomised lifestyle trials (e.g. DIRECT, STANDBY, UPBEAT, EUROFIT, RE-DIRECT) and multiple drug trials (e.g. REMOVAL, TRUST, AMPLITUDE-O, EMPEROR- HF TRIALS) and has ongoing activity in several large cardiovascular outcome trials, with an increasing focus on weight lowering interventions. He has been on several national and international guideline committees, including the European Society of Cardiology 2023 Guidelines on Diabetes and cardiovascular diseases; Joint British Societies 3 CVD prevention recommendations; SIGN obesity and CVD prevention guidelines (as Chair); and European CVD prevention guidelines. He has contributed to over 1300 published papers, with more than 170 K citations, working collaboratively with many hundreds of colleagues nationally and internationally. He has been amongst the top 1% of cited academics in Clinical Medicine for the last decade. Naveed has received several national and international awards for his research, including the prestigious Camillo Golgi and Minkowski Prizes from the European Association for the Study of Diabetes, and the Banting Memorial and Rank Nutrition Lectures from Diabetes UK. He is an Associate Editor for Diabetes Care, and past Associate Editor for Circulation and Diabetologia. He contributes to new health initiatives in the Scottish Health Service and in late 2023 was appointed as the UK Government’s Obesity Mission Chair, now renamed the Obesity Health Care Goals Programme.
Author notes
Conflict of interest: N.S. reports consulting/speaker honoraria from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, GlaxoSmithKline, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Metsera, Novartis, Novo Nordisk, Pfizer, Roche Diagnostics, and Sanofi; grants from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics outside the submitted work. K.S. has no conflicts to declare.
