Semaglutide in patients with obesity and heart failure with preserved ejection fraction: A systematic review and meta-analysis

Abstract

BACKGROUND

Obesity-related heart failure in patients is often associated with a high symptom burden. However, no treatments have been proven to specifically target obesity-related heart failure with preserved ejection fraction (HFpEF).

AIM

To evaluate the efficacy of semaglutide in patients with obesity and HFpEF.

METHODS

Per the PRISMA guidelines, studies reporting clinical outcomes of semaglutide in patients with obesity and HFpEF were included. The outcomes included percentage weight change and adjudicated heart failure events. Both random and common effects models were used for the data analysis. The random intercept logistic regression model was used to compute the proportions, and the Peto method was used to compute the odds ratios (OR). A P ≤ 0.05 was considered significant.

RESULTS

In total, three studies with 1463 patients with obesity and HFpEF were included in the study. The mean age of the patients was 68.8 ± 3.47 years. 50.7% of the patients were females. Patients who received semaglutide had statistically higher odds of achieving 10% (OR = 6.35; 95%CI: 1.54-26.21; P < 0.00001) and 15% (OR = 9.44; 95%CI: 2.91-30.60; P < 0.0001) weight reductions compared to those who received placebo. Additionally, patients who received semaglutide had lower odds of adjudicated heart failure event (OR = 0.29; 95%CI: 0.14-0.58; P = 0.0005) when compared to patients on placebo.

CONCLUSION

Our study demonstrates that semaglutide is significantly effective in reducing weight and potentially lowering the risk of heart failure events. This suggests that semaglutide could be a promising therapeutic option for managing obesity-related HFpEF.

Key Words: Semaglutide; Heart failure with preserved ejection fraction; Obesity; Weight-loss; Glucagon-like peptide-1 receptor agonists; Meta-analysis

Core Tip: This meta-analysis demonstrates that semaglutide is effective in reducing weight and potentially lowering the risk of heart failure events in patients with obesity and heart failure with preserved ejection fraction (HFpEF). This suggests semaglutide as a promising therapeutic option for managing obesity-related HFpEF, a condition with limited current treatment options. The findings showed statistically higher odds of 10% and 15% weight reduction, as well as lower odds of adjudicated heart failure events, in patients receiving semaglutide compared to those receiving placebo. Further large-scale trials are needed to confirm these benefits and explore long-term outcomes.

INTRODUCTION

Heart failure with preserved ejection fraction (HFpEF) represents a significant and growing clinical challenge, characterized by its substantial prevalence and complex diagnostic criteria, leading to delayed identification and notable difficulties in effective management[1-3]. Unlike heart failure with reduced ejection fraction (HFrEF), management strategies for HFpEF remain limited, underlining the pressing need for novel interventions[2,3]. Obesity, a critical comorbidity frequently observed in patients with HFpEF, is associated with a significant clinical burden, manifesting as more severe symptoms, greater functional limitations, and an elevated risk of hospitalization and mortality[3,4]. Compelling data demonstrates a strong association between increased body mass index (BMI) and the development of HFpEF. Studies have estimated that the majority (80%) of HFpEF patients are either overweight or obese[4]. This link is further supported by intricate pathophysiological mechanisms through which excess adiposity exerts detrimental effects on the cardiac structure and functioning[5-7].

Obesity enables and fosters chronic systemic inflammation and, in turn, dysregulates the secretion of adipokines, ultimately contributing to cardiovascular dysfunction[8,9]. Epicardial adipose tissue releases paracrine factors that can directly impact cardiac cells[10]. Obesity is also implicated in the development of left ventricular diastolic dysfunction and adverse cardiac remodeling, increases both preload and afterload on the heart, and promotes endothelial dysfunction and microvascular disease[7,8,11]. Furthermore, obesity significantly increases the risk of obstructive sleep apnea, chronic kidney disease, metabolic syndrome, hypertension, diabetes, and dyslipidemia[12-17], all of which are known risk factors for the development of coronary artery disease, which in turn is a predisposing factor for heart failure[8]. Studies have reported obesity-related HFpEF as a clinically relevant phenotype, a genuine form of cardiac failure[18,19].

However, despite the interplay between obesity and HFpEF, there exists a significant gap in management, with a lack of evidence-based therapies specifically designed to target this complex interplay and improve outcomes in this vulnerable population. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a promising therapeutic class in cardiometabolic medicine. Semaglutide, a potent GLP1-RA, has multifaceted actions. It stimulates glucose-dependent insulin secretion from the pancreas[20,21], suppresses glucagon release[21], delays gastric emptying[22,23], and modulates appetite, significantly leading to weight reduction[24]. Studies reported that the benefits of GLP-1 RAs extend beyond weight loss and glycemic control[25]. GLP-1 RAs improve metabolic parameters[26,27], lower blood pressures[28-30], and improve endothelial functioning[31-33]. Furthermore, multiple preclinical and clinical studies suggested more direct cardiac effects, including anti-inflammatory and anti-fibrotic effects[25]. Notably, large-scale clinical trials focusing on cardiovascular outcomes in patients with diabetes and obesity have reported favorable cardiovascular outcomes with GLP-1RAs[34-37]. While previous meta-analyses have examined GLP-1RAs in heart failure generally, to our knowledge, no prior systematic review and meta-analysis has specifically evaluated the efficacy of semaglutide in the distinct phenotype of obesity-related HFpEF. The primary objective of this systematic review and meta-analysis is to evaluate the efficacy of semaglutide in patients with obesity and HFpEF. Preliminary findings of this analysis have been presented at the American Heart Association (AHA) Scientific Sessions, 2024[38].

MATERIALS AND METHODS

Per the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines[39], a comprehensive literature search was conducted in several prominent, reliable databases, including PubMed/MEDLINE, Cochrane Central Register of Controlled Trials, EMBASE, Google Scholar, and ClinicalTrials.gov. Subject headings and keywords for “semaglutide”, “obesity”, “heart failure”, and “heart failure with preserved ejection fraction” were used along with appropriate Boolean operators. The references of the selected studies were also examined to verify the comprehensiveness of the search. The search strategy utilized for the study is outlined in Supplementary Table 1. Studies reporting clinical outcomes of semaglutide in patients with obesity and HFpEF were included. A detailed list of inclusion and exclusion criteria was outlined in Supplementary Table 2. Screening of the title and abstract was done independently by two reviewers, Vazquez SC and Obi O, and conflicts were resolved by a third reviewer, heart failure. Full-text screening was done independently by two reviewers, Huda NU and Lysak Y, and conflicts were resolved by a third reviewer, Mylavarapu M. Figure 1 depicts the PRISMA flow chart outlining the study selection process[40].

Figure 1  PRISMA flowchart.

The risk of bias assessment was conducted using the Cochrane Risk of Bias tool[41] for randomized control trials and the adaptation of the New Castle Ottawa Scale[42] for observational study. Primary endpoints include weight reduction and adjudicated heart failure events (suspected clinical outcome due or because of heart failure). Secondary endpoints include adverse events, namely all-cause mortality (ACM), cardiac arrhythmias, and infections. Both random and common effects models were used for the data analysis. A random-effects model (DerSimonian-Laird) was applied for outcomes with anticipated significant heterogeneity, such as weight reduction. The Peto method, a fixed-effect model, was utilized for analyzing rare dichotomous outcomes, specifically adjudicated heart failure events, as it minimizes bias when event rates are low. Heterogeneity was assessed using the χ² test and I² statistics. The I² statistic was interpreted as follows: 25% (low heterogeneity), 50% (moderate heterogeneity), and 75% (high heterogeneity). Visualization interpretation of funnel plots was utilized to evaluate for publication bias. All the statistical analyses were performed using the Review Manager (RevMan) version 5.4.1[43]. A P value < 0.05 was considered to be statistically significant. The protocol of the study was registered in the open science framework registry (Id: OSF.IO/K6HZV).

RESULTS

A total of three studies with 1463 patients with obesity and HFpEF[44-46]. Table 1 outlines the key characteristics of the included studies. The mean age of the patients was 68.8 ± 3.47 years, with 50.7% being female. Table 2 outlines the baseline characteristics of the included population. Regarding primary endpoints, patients who received semaglutide had significantly higher odds of weight reduction [odds ratio (OR) = 7.71; 95%CI: 3.30-17.99; P < 0.00001] compared to those who received placebo (Figure 2A). When sub-grouped, patients who received semaglutide had significantly higher odds in both 10% weight reduction (OR = 6.35; 95%CI: 1.54-26.21; P = 0.01) and 15% weight reduction (OR = 9.44; 95%CI: 2.91-30.60; P = 0.0002). Furthermore, patients who received semaglutide had significantly lower odds of adjudicated heart failure events (OR = 0.29; 95%CI: 0.14-0.58; P = 0.0005) (Figure 2B).

Figure 2 Primary endpoints. A: Weight reduction; B: Adjudicated heart failure event.

Table 1 Key characteristics of the included studies.

Ref.	Study design	Population characteristics	Type of HF	Intervention	Control
Kosiborod et al[44], 2024	RCT (STEP-HFpEF DM)	O with HF and DM-II	HFpEF	Semaglutide (2.4 mg)	Placebo
Butler et al[45], 2023	RCT (STEP-HFpEF)	O with HF	HFpEF	Semaglutide (2.4 mg)	Placebo
Rehman et al[46], 2024	Retrospective	O with HF	HFpEF	Semaglutide (2.4 mg)	Placebo

O: Obesity; HF: Heart failure; RCT: Randomized control trial; DM-II: Type 2 diabetes; HFpEF: Heart failure with preserved ejection fraction.

Table 2 Baseline characteristics, n (%)/median (25^th-75^th percentiles).

Ref.	mean ± SD	Total patients	Number of females	BMI		LVEF		Hypertension		CAD
				Semaglutide	Placebo	Semaglutide	Placebo	Semaglutide	Placebo	Semaglutide	Placebo
Kosiborod et al[44]	69.0 ± 3.49	616	273	36.9 (33.6-41.5)	36.9 (33.5-41.1)	57.0 (50.0-61.0)	55.0 (50.0-60.0)	255 (82.3)	271 (88.6)	79 (25.5)	69 (22.5)
Butler et al[45]	68.5 ± 3.45	529	297	37.2 (33.9-41.1)	36.9 (33.3-41.6)	57.0 (50.0-60.0)	57.0 (50.0-60.0)	216 (82.1)	217 (81.6)	53 (20.2)	45 (16.9)
Rehman et al[46]	69.0 ± 3.47	318	172	37.2 (33.9-41.1)	36.9 (33.3-41.6)	57.0 (50.0-60.0)	57.0 (50.0-60.0)	82 (78.8)	163 (76.2)	23 (22.1)	47 (22.0)

BMI: Body mass index; LVEF: Left ventricular ejection fraction; CAD: Coronary artery disease.

Regarding adverse events, the semaglutide group had significantly lower odds of infections (OR = 0.36; 95%CI: 0.20-0.63; P = 0.0004). Although ACM (OR = 0.75; 95%CI: 0.36-1.56; P = 0.45) and cardiac arrhythmias (OR = 0.69; 95%CI: 0.26-1.84; P = 0.46) were also lower, they weren’t significant (Figure 3). Additionally, patients who received semaglutide had a higher frequency of other clinical and laboratory outcomes, including change in systolic blood pressure, change in 6-minute walking distance, and change in C-reactive protein (CRP) (Figure 4).

Figure 3 Adverse events. Forest plots reporting adverse events in the semaglutide group compared to placebo.

Figure 4 Other clinical and laboratory outcomes. CRP: C-reactive protein; NT-proBNP: N-terminal pro-B-type natriuretic peptide.

Overall, the risk of bias assessment indicates that while one randomised controlled trial (RCT) was of high quality, the other RCT and the observational study had some methodological limitations (Supplementary Table 3). Regarding heterogeneity, the primary endpoints showed significant heterogeneity (Supplementary Table 4). Leave-one-out sensitivity analysis, performed to investigate high heterogeneity in weight reduction, revealed that removing the Rehman et al[46] study reduced I² from 96% to 70% for the 10% weight reduction outcome, while removing the Butler et al[45] study reduced I² from 90% to 52% for the 15% weight reduction outcome (Supplementary Table 5). Publication bias is insignificant (Supplementary Figure 1).

DISCUSSION

This systematic review and meta-analysis, the first-ever meta-analysis to evaluate the efficacy of semaglutide in patients with obesity and HFpEF, demonstrates that semaglutide is associated with a significant increase in the odds of weight reduction, including both 10% and 15% weight reduction thresholds, when compared to placebo. The observed weight reduction with semaglutide is consistent with findings from previous studies that have established its efficacy in promoting weight loss in obese individuals with[47,48] and without diabetes, both type 1[49] and type 2[50]. The magnitude of weight reduction observed in our analysis suggests that semaglutide may offer a clinically meaningful benefit for patients with obesity-related HFpEF, a population for whom weight management is a critical therapeutic target. Our analysis also reports a favorable safety profile of semaglutide in patients with obesity and HFpEF. Although not statistically significant, the odds of cardiac arrhythmias and ACM were numerically lower in the semaglutide group.

The finding that semaglutide is associated with reducing adjudicated heart failure events is particularly noteworthy. HFpEF is a complex and challenging condition with limited effective treatment options[51]. As shown by previous research, while medications like angiotensin-converting enzyme inhibitors[52], ARBs[53,54], and beta-blockers have shown significant benefits in treating HFrEF, their impact on HFpEF has been limited[55]. The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial demonstrated that spironolactone reduced hospitalizations in HFpEF patients but did not significantly improve mortality or morbidity[55,56], highlighting the need for effective interventions to reduce heart failure events in this population. The reduction in adjudicated heart failure events is clinically significant, as these events often lead to hospitalization, reduced functional capacity, and a decline in overall quality of life, which could potentially lead to increased mortality[57-60].

The impact of GLP-1RA on heart failure has always been debated. Ferreira et al[61], in their meta-analysis of RCTs, reported that although GLP-1RAs did not reduce the mortality due to heart failure and heart failure-based hospitalizations in patients with a history of heart failure, they significantly prevented new-onset heart failure in patients with type 2 diabetes without heart failure. Notably, the meta-analysis did not discuss HFpEF and HFrEF separately, nor did it assess the effects in obese patients. However, new clinical trials report evidence supporting the use of GLP-1RAs in patients with heart failure, especially HFpEF. The functional impact of GLP-1 RA for Heart Failure Treatment trial[62] reports that patients with HFpEF have improved exercise capabilities and quality of life in the liraglutide group compared to placebo. Furthermore, a recent meta-analysis by Sobral et al[63] reported clinical and laboratory benefits in patients with HFpEF, including an increase in 6-minute walk distance, reduction in systolic blood pressure, and lower CRP levels. Direct inotropic and lusitropic effects on the heart, improving contractility, glucose-lowering, and anti-inflammatory events, and improvement in endothelial functioning by GLP-1RAs could potentially explain our study’s findings[25,62]. Figure 5 outlines the cardio-protective actions of GLP-1RAs. The mechanisms for these cardioprotective actions are likely multifactorial, extending beyond weight loss alone. Our analysis noted significant improvements in CRP (Figure 4), a key inflammatory marker. This clinical finding aligns with the known anti-inflammatory properties of GLP-1RAs (Figure 5). Similarly, the observed increase in the 6-minute walk distance may be mediated not only by reduced body mass but also by direct GLP-1RA effects on endothelial function and skeletal muscle metabolism, which are key cardioprotective pathways. However, it is crucial to note that the observed benefits may not be solely attributable to weight reduction. The primary STEP-HFpEF trial (45) reported that improvements in heart failure outcomes and symptoms persisted even after statistical adjustment for the change in body weight, suggesting semaglutide imparts direct cardioprotective effects, potentially via the anti-fibrotic or microvascular pathways (Figure 5).

Figure 5 Cardioprotective actions of glucagon-like peptide-1 receptor agonists. Actions of glucagon-like peptide-1 receptor agonists on various organs and organ systems, potentially explaining the cardioprotective effect of glucagon-like peptide-1 receptor agonists. GLP-1RA: Glucagon-like peptide-1 receptor agonist.

Several limitations of our meta-analysis should be acknowledged. First, the number of included studies was small (n = 3), limiting the statistical power of our analysis and the generalizability of the findings. Second, while one RCT was of high quality, another RCT and the observational study had some methodological limitations, which may introduce bias. Third, significant heterogeneity was observed for the primary endpoints related to weight reduction. This variability, particularly in terms of study populations, intervention protocols, and outcome definitions, resulting in wider confidence intervals, restricts our ability to synthesize the data more conclusively and limits the generalizability of the findings. Fourth, the included trials did not provide stratified data regarding background therapies, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors, which prevented a subgroup analysis to assess for potential confounding or additive effects.

While these findings are promising, it is important to situate them within current clinical practice. SGLT2 inhibitors remain the first-line, guideline-directed therapy for HFpEF, regardless of diabetes or obesity status. Semaglutide is not yet guideline-approved specifically for HFpEF management, and its use in this context (outside of type 2 diabetes or weight loss indications) would be considered off-label.

Current guidelines[64] recommend SGLT2 inhibitors as the first line of management in patients with HFpEF due to a significant reduction in cardiovascular death or hospitalizations in patients with heart failure[65]. However, this meta-analysis provides preliminary evidence suggesting that semaglutide may be a promising therapeutic option for managing obesity-related HFpEF. The observed benefits of weight reduction and heart failure events warrant further investigation in larger, well-designed clinical trials. Future research should also explore the long-term effects of semaglutide on cardiovascular outcomes, quality of life, and mortality in this patient population. Furthermore, research is needed to elucidate the precise mechanisms by which semaglutide affects the heart in patients with HFpEF. Studies should investigate the potential role of inflammation, endothelial function, and cardiac remodeling in mediating the beneficial effects of semaglutide. Additionally, studies should also assess the cost-effectiveness of semaglutide in managing obesity-related HFpEF, considering both the direct costs of the medication and the potential cost savings associated with reduced hospitalizations and improved long-term outcomes.

CONCLUSION

This meta-analysis provides evidence that semaglutide is effective in promoting significant weight reduction and potentially reducing the risk of heart failure events in patients with obesity and HFpEF, suggesting a promising therapeutic option for managing obesity-related HFpEF. However, future research with large-scale clinical trials and adequate sample sizes is warranted further to assess the observed benefits and long-term cardiovascular outcomes.