Review Article

Understanding the Role of Glucagon-like Peptide-1 Receptor Agonists in the Treatment of Heart Failure

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Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed for glycaemic control in patients with type 2 diabetes, have demonstrated significant cardiometabolic benefits beyond glucose regulation. These agents have multiple effects, including reducing body weight, improving insulin sensitivity, anti-inflammatory properties and enhancing endothelial function. All these mechanisms are potentially beneficial in patients with heart failure (HF), specifically those with HF with preserved left ventricular ejection fraction. Recent trials, including STEP-HFpEF and SUMMIT, underscore the efficacy of GLP-1 RAs in improving quality of life and exercise capacity, as well as possibly reducing major adverse cardiovascular events. Furthermore, these trials demonstrated improvements in other endpoints, such plasma N-terminal pro B-type natriuretic peptide, troponin and C-reactive protein concentrations, consistent with the beneficial effects of GLP-1 RAs on myocardial function and inflammation. Further data are needed regarding the effects of GLP-1 RAs on cardiovascular outcomes, and possibly in a broader range of patients with HF, such as those with HF reduced ejection fraction and/or patients without obesity.

Keywords

Glucagon-like peptide-1 (GLP-1), heart failure, heart failure with preserved ejection fraction (HFpEF), pharmacotherapy,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/cfr.2025.10

Disclosure: AR has received honoraria from AstraZeneca and Boehringer Ingelheim and is on the Cardiac Failure Review editorial board; this did not influence peer review. MM has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Novo Nordisk and Roche Diagnostics; honoraria from Boehringer Ingelheim and Zoll; is the president of the Heart Failure Association of the European Society of Cardiology; and is a senior consulting editor for Journal of the American College of Cardiology and European Journal of Heart Failure. DT has received honoraria from AstraZeneca, Boehringer Ingelheim, Roche Diagnostics, Alnylam Pharmaceuticals and Pfizer; has had expenses paid by Alnylam Pharmaceuticals and Pfizer; and has participated on a board for Bayer. MP has received honoraria from Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Novartis, Novo Nordisk, Roche Diagnostics and Vifor Pharma and has participated on a board for Novo Nordisk. GBB has no conflicts of interest to declare.

Correspondence: Giovanni Battista Bonfioli, Cardiology, ASST Spedali Civili di Brescia, Piazzale Spedali Civili 1, 25123 Brescia, Italy. E: giovob@gmail.com

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Heart failure (HF) is a clinical syndrome characterised by symptoms and signs caused by structural and/or functional cardiac abnormalities associated with elevated natriuretic peptide levels and/or objective evidence of pulmonary or systemic congestion.1 HF is commonly categorised according to left ventricular ejection fraction ranges into HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF), each of which has distinct possible pathophysiological mechanisms.2 HF affects more than 64 million people worldwide and is associated with significant morbidity, mortality and economic burden. In recent years, the prognosis of HF has improved slightly thanks to newer and more effective therapies, but mortality remains high, if not higher, compared with previous years.3–5 Significant advances in pharmacological treatment have primarily focused on HFrEF, the current therapy for which is built on four key pillars: angiotensin receptor–neprilysin inhibitor (ARNI) or, alternatively, ACE inhibitors or angiotensin receptor blockers; β-blockers; mineralocorticoid receptor antagonists (MRAs); and sodium–glucose cotransporter 2 inhibitors (SGLT2i). Notably, SGLT2i have also been shown to be effective for the treatment of patients with HFmrEF and HFpEF, with their efficacy independent of ejection fraction.2,6

SGLT2i represent the first class of HF drugs targeting pathophysiological mechanisms different from neurohormonal activation and providing not only cardioprotective effects but also important metabolic benefits.

Within this framework, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), originally developed for the treatment of type 2 diabetes (T2D), have recently shown cardioprotective effects beyond their role in glycaemic control.7–9 The promising benefits observed in major cardiovascular trials have sparked interest in their potential application for HF, particularly in patients with comorbid T2D or metabolic syndrome.10–17 This review examines the mechanisms, evidence and therapeutic implications of GLP-1 RAs in the context of HF.

Glucagon-like Peptide-1 Receptor Agonists and Their Mechanism of Action in Heart Failure

GLP-1 RAs are synthetic analogues of the incretin hormone GLP-1, which is secreted by intestinal L cells in response to nutrient ingestion. The physiological actions of GLP-1 include stimulation of glucose-dependent insulin secretion, inhibition of glucagon release, slowing of gastric emptying and the promotion of satiety, contributing to both reducing glycaemic levels and weight loss. Unlike endogenous GLP-1, which is rapidly degraded by dipeptidyl peptidase-4, GLP-1 receptor agonists are resistant to degradation and have longer half-lives, particularly for modern long-acting agents, such as liraglutide, dulaglutide, semaglutide and tirzepatide.18–22

GLP-1 receptor agonists exhibit several cardioprotective mechanisms that make them interesting candidates for the treatment of HF.8,9,23

Obesity, Diabetes and Heart Failure

Obesity and insulin resistance are major contributors to HF. In patients with T2D, chronic hyperglycaemia, as evidenced by high HbA1c levels, is strongly related to the risk of cardiovascular disease (CVD) and death by inducing oxidative stress and inflammation and promoting atherosclerosis and endothelial dysfunction.24 GLP-1 RAs are an antidiabetic class of drugs, but their effect on the relative reduction in HbA1c compared with placebo was moderate (0.4–1.2%) in the cardiovascular outcomes trials (CVOTs).10–17 As reported previously, the effect of GLP-1 RAs on major adverse cardiovascular events (MACE) goes beyond glycaemic control.7

Obesity is a strong cardiovascular risk factor and it is strictly related to HF, particularly HFpEF.25 GLP-1 RAs induce significant weight loss through appetite suppression and consequent reduced caloric intake. Weight loss was significant in outcome trials, ranging from a 0.6 kg reduction at 12 weeks in the ELIXA trial to a 4.3 kg reduction at 2 years with injectable semaglutide in the SUSTAIN-6 trial.12,13 However, the results of randomised controlled trials (RCTs) revealed significant heterogeneity among different medications, both in terms of body weight reduction and their effects on clinical outcomes, including HF. A meta-analysis conducted by Yao et al. showed notable differences in weight loss outcomes among various GLP-1 RAs.26 Among the GLP-1 RAs, semaglutide resulted in the most significant weight reduction. In addition, tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide and GLP-1 receptors, resulted in even more pronounced weight loss effects, suggesting a potential advantage over traditional GLP-1 RAs.27 As in the case of tirzepatide, combining GLP-1 RAs with other enteropancreatic hormones holds promise for larger body weight reductions compared with GLP-1 RAs alone.28 Conversely, significant variability in the therapeutic efficacy of GLP1-RAs has been shown. Notably, weight loss did not always correlate with improved clinical outcomes in patients with HF. This was evident in the LIVE and FIGHT trials, in which liraglutide, despite leading to significant weight loss compared with placebo, failed to demonstrate any beneficial effects on clinical outcomes or left ventricular ejection fraction (LVEF) in patients with HFrEF.29,30 Caution has been advocated for the use of these medications in patients with HFrEF.31,32

Patients with obesity have a higher quantity of epicardial adipose tissue. When epicardial adipose tissue is in excess, its potential benefits on thermoregulation and mechanical protection of the heart are countered by proinflammatory activity and with a worse haemodynamic and metabolic profile in patients with HFpEF.33 Interestingly, many clinical studies have demonstrated that the administration of GLP-1 RAs produces a rapid, substantial and dose-dependent reduction in epicardial adipose tissue thickness.34–36

Renal Protection

Cardiovascular–kidney–metabolic (CKM) syndrome has been recently defined as a health disorder attributable to connections among obesity, diabetes, chronic kidney disease (CKD) and cardiovascular disease, including HF.37 CKD is often present in patients with HF, because CKD, T2D, obesity and adiposity frequently coexist in these patients, particularly in those with HFpEF.38,39 The relationship between cardiac and renal dysfunction is critical for disease progression and prognosis. HF may cause kidney dysfunction through multiple mechanisms, including neurohormonal activation, inflammation and oxidative stress, with consequent reductions in renal perfusion and augmentation of renal venous pressure. The reduction in renal function leads to fluid retention and further neurohormonal activation, combined with oxidative stress and anaemia, aggravating cardiac dysfunction.40

Recently, CKM syndrome has become a focus of clinical research: the importance of targeted therapy for CKD in patients with HF has even been underlined in the recent 2023 update of the European Society of Cardiology (ESC) guidelines for HF management, with SGLT2i and finerenone approved for the treatment of diabetic nephropathy to prevent HF events.6

GLP-1 RAs exhibit significant nephroprotective effects, including reducing albuminuria, improving renal haemodynamics and attenuating oxidative stress and inflammation in the kidneys.41 In most CVOTs, the use of GLP-1 RAs was associated with reductions in adverse renal outcomes, analysed either as secondary endpoints or in subsequent subanalyses.10–17

In the LEADER trial, liraglutide resulted in a 22% reduction in adverse renal outcomes (HR 0.78; 95% CI [0.67–0.92]; p=0.003) compared with placebo in 9,340 patients with T2D and a high risk of CVD.42 This benefit was primarily driven by a significant reduction in the incidence of new-onset persistent macroalbuminuria (HR 0.74; 95% CI [0.60–0.91]; p=0.004), a finding corroborated by the SUSTAIN-6 trial.12 In SUSTAIN-6, semaglutide reduced macroalbuminuria by 46% and resulted in a lower rate of new or worsening nephropathy in patients with T2D and risk factors for CVD. The AMPLITUDE-O trial, involving 4,076 patients with T2D and a history of either CVD or kidney disease, participants were randomised to receive efpeglenatide or placebo.16 As a secondary outcome, the trial demonstrated a 32% reduction in renal events with efpeglenatide (HR 0.68; 95% CI [0.57–0.79]; p<0.001).16 More recently, the FLOW trial enrolled 3,533 patients with T2D and CKD (estimated glomerular filtration rate [eGFR] 50–75 ml/min/1.73 m2 with an albumin-to-creatinine ratio of 300–5,000 or eGFR 25–49 ml/min/1.73 m2 with an albumin-to-creatinine ratio of 100–5,000).43 Participants were randomised to receive subcutaneous semaglutide or placebo, and the semaglutide group had a 24% lower risk of the primary renal outcome (HR 0.76; 95% CI [0.66–0.88]; p=0.003), as well as a slower mean annual decline in eGFR.43

The favourable results regarding renal function, combined with the reduction in major cardiovascular events in the CVOTs and the effects on weight loss, may confer GLP-1 RAs a central role in the treatment of CKM syndrome.

Anti-inflammatory and Antifibrotic Effects

Chronic inflammation and myocardial fibrosis are hallmarks of HF progression. The reduction in cardiovascular events observed in the CVOTs is related not only to the antidiabetic properties of GLP-1 RAs but probably also to a reduction in meta-inflammation, defined as a low-grade chronic inflammatory status.8 GLP-1 RAs achieve this by downregulating proinflammatory cytokines and, in particular, by suppressing nuclear factor (NF)-κB signalling.44 In the latest clinical trials, namely the STEP-HFpEF and STEP-HFpEF-DM trials, semaglutide resulted in a significant reduction in C-reactive protein levels versus placebo in a pooled analysis of the two trials (−43% versus −10%, respectively).45–47 Furthermore, in a meta-analysis of 40 RCTs that included patients with T2D, GLP-1 RAs significantly reduced levels of inflammatory markers and oxidative stress.48

In vivo models have also shown that GLP-1 RAs positively modulate cardiac remodelling with less cardiac hypertrophy and fibrosis.49,50

Endothelial Function and Vasodilation

In patients with HF, the nitric oxide pathway is downregulated, producing a vasoconstrictor effect. Nitric oxide has fundamental vasodilator properties, reducing systemic vascular resistance and improving artery compliance, all of which would alleviate the haemodynamic burden in HF.51,52 By increasing nitric oxide availability, GLP-1 RAs improve endothelial function versus lifestyle intervention alone, an effect demonstrated through the measurement of coronary flow velocity reserve by echocardiographic evaluation after the administration of exenatide.53 The benefits of GLP-1 RAs on endothelial function combined with their anti-inflammatory properties may partly explain the positive effects of GLP-1 RAs on atherogenesis, and consequently on MACE.

Glucagon-like Peptide-1 Receptor Agonists and Ischaemic Heart Disease

Ischaemic heart disease is a major risk factor for HF (both HFrEF and HFpEF).3,54 GLP-1 RAs have emerged as a key therapeutic option for cardiovascular risk reduction, particularly in patients with T2D who are at high risk or have a history of atherosclerotic CVD (ASCVD). Large-scale CVOTs have demonstrated that GLP-1 RAs significantly reduce the incidence of MACE, including cardiovascular death, non-fatal MI and non-fatal stroke. Notably, the benefits appear to be more pronounced in patients with established ASCVD, reinforcing the importance of GLP-1 RAs as a cardioprotective intervention.10–17

The ESC guidelines for the management of cardiovascular disease in patients with diabetes recommend GLP1-RAs in patients with T2D and ASCVD to reduce cardiovascular events.55 Furthermore, the reduction in ischemic cardiac events may indirectly help prevent the development of HF. In fact, CVOTs have shown that in patients without a history of HF but with high cardiovascular risk, GLP-1 RAs led to a 15% reduction in the composite outcome of cardiovascular death and hospitalisation for HF.31

Clinical Evidence

The cardiovascular effects of GLP-1 RAs have been extensively studied in major RCTs, primarily focusing on patients with T2D. In the beginning, conflicting results were obtained regarding the reduction in cardiovascular events in patients with HF. The LEADER trial demonstrated a 13% reduction in MACE with liraglutide in high-risk patients with T2D.11 Subgroup analyses suggested a trend towards reduced HF hospitalisations, although this was not the primary endpoint.11 In the SUSTAIN-6 trial, semaglutide showed a 26% reduction in MACE, whereas its effects on HF hospitalisation were neutral.12 The REWIND trial evaluated dulaglutide in a broader population, including those with a lower baseline cardiovascular risk, and demonstrated a significant reduction in composite cardiovascular outcomes, together with a favourable trend in HF-related events.15 EXSCEL explored the effects of exenatide in a mixed population of T2D patients with and without CVD and observed a numerical, albeit non-significant, reduction in HF hospitalisations, suggesting potential benefits in specific subgroups.13

In the CVOTs, GLP-1 RAs were associated with a reduction in new-onset HF among patients with cardiovascular risk factors, but neutral effects were observed on HF events among patients with already diagnosed and stable HF. However, the effect appears to differ according to baseline LVEF, with worse results in patients with reduced ejection fraction.31,32 Accordingly, a meta-analysis including 68,653 patients from 10 trials showed that GLP-1 RAs reduce HF hospitalisations only in patients without history of previously diagnosed HF.56

Apart from CVOTs, the FIGHT and LIVE trials were the first to directly evaluate the effects of the GLP-1 RA liraglutide in patients with HFrEF.29,30 The FIGHT trial was a phase II double-blind placebo-controlled RCT of 300 patients with an established diagnosis of HFrEF and a recent (<14 days) hospitalisation for acute HF despite already receiving evidence-based therapies and a preadmission oral diuretic dose of at least 40 mg furosemide.21 Liraglutide showed no effect on the hierarchical primary endpoint of time to death, time to rehospitalisation for HF and time-averaged change in N-terminal pro B-type natriuretic peptide (NT-proBNP) from baseline to 180 days (p=0.31), with even an increased risk of emergency department visit, HF hospitalisation or all-cause death events (HR 1.36; 95% CI [0.99–1.185]; p=0.05). T2D and obesity were not inclusion criteria, but the median BMI was 31 kg/m2 in the liraglutide group and 33 kg/m2 in the placebo group.29 The LIVE trial enrolled 241 clinically stable patients with LVEF ≤45% on optimal medical treatment for HF.30 Liraglutide did not affect left ventricular function, but increased heart rate (mean difference 7 BPM; p<0.0001). Also in that trial, T2D and obesity were not inclusion criteria and the median BMI at baseline was 28 kg/m2 in the liraglutide group and 29.8 kg/m2 in the placebo group.30 Therefore, to date, GLP-1 RAs have not shown any significant benefit in patients with HFrEF.

Recent evidence supports the use of GLP-1 RAs in patients with obesity-related HFpEF. The SELECT trial recruited 17,604 patients with pre-existing CVD and BMI ≥27 kg/m2, but without a history of diabetes. The primary endpoint was a composite of death from cardiovascular causes, non-fatal MI or non-fatal stroke, with a significant 20% reduction in the semaglutide group versus placebo. SELECT was the first trial to underline the efficacy of the treatment in patients with obesity independent of the concomitant presence of T2D.57 The confirmatory secondary endpoints analysis included a composite HF endpoint of death from cardiovascular causes or hospitalisation/urgent visit for HF. In that study, semaglutide resulted in an 18% reduction in the HF composite outcome (HR 0.82; 95% CI [0.71–0.93]).57 Furthermore, a subsequent prespecified analysis of the trial examined the effects of semaglutide in patients with and without history of HF at enrolment, with a significant reduction in MACE in patients with HFrEF and HFpEF and a 21% and 25% reduction in the HF composite endpoint, respectively.51 HF hospitalisations were significantly reduced in patients with a preserved, but not reduced, ejection fraction.23

The STEP-HFpEF and STEP-HFpEF-DM trials randomised patients with HFpEF and an LVEF ≥45% to oral semaglutide or placebo. Treatment with a GLP-1 RA led to a significant improvement in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CCS) compared with placebo (7.8 and 7.3 points, respectively) and in the 6-minute walk distance (20.3 m and 14.3 m, respectively) at the 52-week follow-up.45,46 These results were confirmed by a pooled analysis that demonstrated that the improvement in quality of life and functional capacity may be primarily related to weight loss, and that there were significant declines in HF hospitalisations or urgent visits (8 [1%] versus 30 [5%] patients in the semaglutide and placebo groups, respectively; HR 0.27; 95% CI [0.12–0.56]), as well as in adjudicated cardiovascular death or HF events.47 However, the number of events in these trials was relatively small compared with other trials in patients with HF.9,58

Tirzepatide has recently been evaluated in the SUMMIT trial.59 In that trial, 731 patients with HFpEF and BMI ≥30 kg/m2 were randomised to receive tirzepatide or placebo for at least 52 weeks. Unlike the STEP-HFpEF trials, cardiovascular outcomes were included as a co-primary endpoint in the SUMMIT trial.59 Tirzepatide showed significant benefits on both co-primary endpoints, namely adjudicated death from cardiovascular causes or worsening HF events (HR 0.62; 95% CI [0.41–0.95]; p=0.026), as well as on mean changes in the KCCQ-CCS scores (6.9 difference versus placebo; p<0.001).58 In particular, worsening HF events occurred in 29 (8.0%) patients in the tirzepatide group and 52 (14.2%) patients in the placebo group (HR 0.54; 95% CI [0.34–0.85]).59 Recently, the SURMOUNT-5 trial demonstrated that tirzepatide was superior to semaglutide in obese patients without diabetes with respect to reductions in body weight and waist circumference at week 72.27

A timeline of different trials regarding GLP-1 RAs is presented in Figure 1. Outcomes regarding HF events are summarised in Table 1.

Figure 1: Timeline of Randomised Clinical Trials of Glucagon-like Peptide-1 Receptor Agonists

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Table 1: Overview of Randomised Clinical Trials Analysing the Effectiveness of Glucagon‑like Peptide-1 Receptor Agonists With Specific Focus on Heart Failure Outcomes

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Future Directions

Identifying HF subgroups most likely to benefit from GLP-1 RAs will optimise patient selection and clinical outcomes. Patients with obesity, particularly when affected by cardiovascular and renal comorbidities in the context of CKM, may represent an ideal target population.

As previously noted, the strict relationship between CKM syndrome and HF has led to the development of different therapeutic strategies targeting multifaceted pathophysiological aspects. GLP-1 RAs and SGLT2i have different and synergistic effects in CKM syndrome. Beyond body weight reduction, GLP-1 RAs have anti-inflammatory and antioxidative effects, with plaque stabilisation associated with a specific reduction in cardiovascular events and, in particular, ischaemic events, stroke and acute MI.7,9–17,43,58 Conversely, the slight but significant increase in heart rate and possibly other effects have been associated with a neutral, if not untoward in some cases, effects of GLP-1 RAs in patients with HFrEF. In contrast, SGLT2i have metabolic effects on the myocardial and renal cells that mimic energy starvation, simulating autophagy and other changes that counteract the progression of HF.9,43,60 Therefore, the combination of these therapies may become fundamental, offering a comprehensive therapeutic approach to HFpEF.

In a retrospective cohort study including 7,044 patients with T2D, obesity (BMI ≥27 kg/m2) and HFpEF, combination therapy with an SGLT2i and GLP-1 RA showed a lower risk of HF exacerbation, all-cause emergency department visits and new-onset kidney injury compared with patients only receiving SGLT2i.61 Moreover, in an actuarial analysis, combination therapy with an GLP-1 RA, SGLT2i and finerenone was associated with a reduction in MACE (HR 0.65; 95% CI [0.55–0.76]), with a corresponding estimated absolute RR over 3 years of 4.4% and a number needed to treat of 23.62 There were also projected gains in survival free from hospitalisation for HF and CKD progression.62 Practical considerations for combination therapy have been recently reviewed.63

In addition to their benefits on quality of life in HFpEF, further randomised trials are needed to effectively assess the effects of GLP-1 RA on harder clinical outcomes. To date, GLP-1 RAs have demonstrated efficacy in obese patients with HFpEF, but data in HFrEF remain scarce. Furthermore, the administration of GLP-1 RAs in the acute setting still needs to be tested.

Adverse Events, Safety and Adherence

GLP-1 RAs have shown a favourable setting profile both in clinical trials and real-world studies. Major adverse events are rare. However, adherence may be low due to mild to moderate gastrointestinal symptoms, mainly nausea and constipation.64 Real-world data show relatively high rates of discontinuation.65

Conclusion

GLP-1 RAs have become an important therapeutic option for patients with HFpEF, particularly those with comorbid T2D or obesity. The pleiotropic effects of GLP-1 RAs, encompassing metabolic, vascular and anti-inflammatory benefits, address multiple facets of HF pathophysiology. Although the existing evidence in HFpEF is compelling, further trials seem warranted, particularly with respect to the effects of GLP-1 RAs on clinical outcomes and, possibly, in broader patient populations, such as patients with HFrEF or those without obesity.

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