Cardioprotective effects of glucagon-like peptide 1 receptor agonists in heart failure: Myth or truth?

Abstract

Therapy with glucagon-like peptide 1 (GLP1) receptor agonists has raised great interest for its beneficial cardiovascular effects in preventing atherosclerosis and heart failure-related outcomes. However, while evidence about atherosclerosis consistently suggests a cardioprotective potential with class effect, controversies remain on its impact on heart failure. GLP1 receptor agonists appear to prevent hospitalization for new-onset heart failure and reduce symptoms in heart failure with preserved ejection fraction (as demonstrated by the recent STEP-HFpEF Trial). Still, GLP1 agonism has resulted in neutral or even harmful effects in patients with established heart failure with reduced ejection fraction (the LIVE trial). GLP1 receptor agonists benefit the cardiovascular system indirectly through their marked metabolic effects (improved weight management, glycemic control, blood pressure, systemic and tissue inflammation), while direct effects on the heart have been questioned. Nonetheless, weight loss alone achieved through GLP1 receptor agonists has failed in improving left ventricular functions. Tirzepatide is a dual agonist of GLP1 and glucose-dependent insulinotropic polypeptide, representing an innovative treatment option in diabetes with a major impact on weight loss and promising cardiovascular benefits. Whether this class of therapies is going to change the history of heart failure is an ongoing debate.

Key Words: Atherosclerosis, Cardiovascular system, Glucagon-like peptide-1, Heart failure, Tirzepatide, Type 2 diabetes, Ventricular function, Left

Core Tip: A growing body of evidence supports the potential cardioprotective properties of glucagon-like peptide 1 receptor agonists (GLP1-RAs) beyond glycemic control, especially in the context of cardiovascular disease. Although the effects of these drugs are consistent in reducing atherosclerosis-related diseases, there is an ongoing debate about the validity of the claim that GLP1-RAs have cardioprotective benefits in heart failure (HF)–a topic that sparks both enthusiasm and skepticism in the scientific and medical communities. Herein we provide a narrative review of the available evidence on the cardioprotective actions of GLP1-RAs in patients with HF, summarizing clinical findings and proposed mechanisms.

INTRODUCTION

Heart failure (HF) remains a significant global health challenge with increasing prevalence and elevated mortality, requiring innovative therapeutic approaches. Glucagon-like peptide-1 receptor agonists (GLP1-RAs), originally designed for the management of hyperglycemia in diabetes, have emerged as among the most promising candidates in cardiovascular medicine. Over recent years, a growing body of evidence has demonstrated the potential cardioprotective properties of glucagon-like peptide-1 (GLP1) receptor agonism beyond glycemic control, especially in the context of cardiovascular disease. Nonetheless, while the effects of these drugs are consistent in reducing atherosclerosis-related diseases, there is an ongoing debate about the validity of the claim that GLP1-RAs also have cardioprotective benefits in HF–a topic that sparks both enthusiasm and skepticism in the scientific and medical communities.

CLINICAL EVIDENCE

Therapy with GLP1-RAs is associated with an 18% reduction in hospitalizations for new-onset HF incidence[1-3] regardless of the presence of diabetes[4]. On the contrary, neutral, or even unfavorable outcomes have been reported in overt HF with reduced ejection fraction[5,6]. Recent meta-analyses confirmed this data, reporting that GLP1-RAs reduce hospitalization for new-onset HF but do not reduce HF outcomes in established HF at baseline[7] and might be harmful in those with left ventricular ejection fraction < 40%[8]. It is possible to speculate that this class of drugs may only act on atherosclerotic vascular disease with a secondary effect on HF incidence, while being neutral on established HF - possibly through hypotension and increased heart rate[8]. However, while the cardioprotective benefits of GLP1-RAs become evident after six months of therapy, this time is not enough to reduce HF events due to coronary artery disease. Moreover, most HF cases are of non-ischemic etiology, especially among patients with type 2 diabetes. The available clinical trials reporting HF outcomes were either too short or not powered enough for robust considerations on HF related outcomes alone, especially if considering the different HF phenotypes, as reduced ejection fraction was only present in a minority of patients[8]. Therefore, it remains difficult to extract precise information about efficacy and safety in patients with HF. Even more problematic is the analysis of their effects across subgroups of HF phenotypes. Consequently, this has led to a lack of specific recommendations in the current guidelines about the use of GLP1-RAs in HF. Nonetheless, despite all the limitations, clinical trials and mechanistic studies on GLP1-RAs show potential benefit in HF, which should not be overlooked.

POTENTIAL MECHANISMS AND FUTURE PERSPECTIVES

One of the main effects of these drugs is a significant weight loss due to a combination of digestive, endocrine, metabolic, and cognitive/neurological effects that promote early satiety and reduced hunger. Beyond that, a mild (6 mmHg) but consistent reduction in systolic blood pressure is achieved after therapy with GLP1-RAs in patients with hypertension[9]. Furthermore, increased natriuresis, vasodilation, secretion of natriuretic peptides, as well as anti-inflammatory and anti-oxidative potential have been observed, together with protection against lipotoxicity and albuminuria[10-11]. These mechanisms are expected to provide substantial benefit in HF patients, especially in those with congestion, which is a key trigger to inflammation and progressive organ damage. The potential to address the hemodynamic burden of excess adiposity and hypertension, the natriuretic properties, and the amelioration of metabolic derangements associated with HF might explain their beneficial effects in these patients and underscore the holistic impact of these agents on cardiovascular health. In fact, a reduction in cardiovascular and HF endpoints with GLP1-RAs has been demonstrated in the absence of weight loss in the Harmony outcomes trial[12], reinforcing the hypothesis that GLP1 agonism can exert direct cardiovascular effects. The biological plausibility arises from the observation that GLP1 receptors are expressed both in cardiomyocytes and in the vasculature[13]. Moreover, GLP1 is known to modulate endothelial function[14,15], nitric oxide release and platelet inhibition[16], as well as epicardial adipose tissue[17,18], which has a key role in both diabetes and HF[19]. In pre-clinical and clinical reports it was positively associated with myocardial metabolism[20], as well as systolic[21] and diastolic function[22]. However, most of these proposed mechanisms remain to be fully confirmed in more rigorous human clinical trials[20,23-26].

The pleiotropic effects of GLP1-RAs can be harnessed for maximizing cardioprotection in HF beyond the questioned direct cardioprotective potential. Obesity and metabolic derangements frequently coexist in HF patients, contributing to a complex interplay of factors that exacerbate the disease process. As both diabetes and obesity have an independent negative impact on effort tolerance[27], by promoting weight loss and improving multiple metabolic parameters GLP1-RAs present an intriguing avenue for intervention and amelioration of effort tolerance in HF patients. The dual GLP1/gastric inhibitory peptide (GIP) agonist tirzepatide is expected to have even more pronounced effects, since it has greater metabolic effects compared with “classic” GLP1-RAs[28-31]. However, while weight loss induced by these drugs is generally well-tolerated, concerns regarding potential adverse effects - mainly gastrointestinal symptoms - need to be considered. Beyond exacerbating nausea and dyspepsia, which are frequent in HF patients with splanchnic congestion, the impact of sustained weight loss on nutritional status and muscle mass warrants careful monitoring, particularly in the context of advanced HF wherein cachexia is a concern[13]. Long-term studies evaluating the safety and sustainability of weight loss induced by GLP1-RAs in individuals with severe and advanced HF are essential.

CONCLUSION

GLP1-RAs are expected to become a strategic treatment in HF, even though several unanswered questions remain regarding their efficacy and tolerability in advanced HF and their mechanism of action. The pursuit of these avenues will necessitate collaborative efforts among researchers, clinicians, policymakers, and patients. A commitment to addressing these challenges and uncertainties will not only refine the role of GLP1 receptor agonism in HF, but also contribute to the broader goal of advancing tailored cardiovascular care in the pursuit of better outcomes and improved quality of life.