Impact of glucagon-like peptide-1 receptor agonists on the incidence of atrial fibrillation

Abstract

BACKGROUND

Atrial fibrillation (AF) stands as the most prevalent type of arrhythmia, affecting approximately 60 million individuals world-wide. Although antiarrhythmic drugs (AADs) remain the gold standard for AF treatment, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are arising as potential therapeutic alternatives.

AIM

To evaluate the impact of GLP-1 RAs on the incidence of AF.

METHODS

Inclusion criteria included systematic reviews (SRs) that based their analyses on clinical trials, observational studies, controlled trials and network meta-analyses. A total of 8 SRs were selected for data extraction, focusing on semaglutide, liraglutide and dulaglutide. Additionally, the effects of GLP-1 RAs on AF incidence were compared with those of sodium-glucose co-transporter 2 (SGLT2) inhibitors.

RESULTS

Findings indicate that semaglutide, evaluated in the largest patient cohort across the 8 SRs, consistently reduced AF incidence. However, dulaglutide and liraglutide exhibited inconsistent effects. Notably, as opposed to variable outcomes associated with GLP-1 RAs, SGLT2 inhibitors a class of antidiabetic agents with weight-reducing properties exhibit significant cardiovascular benefits, including reductions in both AF and atrial flutter.

CONCLUSION

GLP-1 RAs emerge as a promising and potential alternative for AADs in reduction of incidence of AF. However, further research is required to fully determine their therapeutic potential and long-term cardiovascular effects.

Key Words: Glucagon-like peptide-1 receptor agonists; Antiobesity medication; Atrial fibrillation; Liraglutide; Semaglutide; Dulaglutide

Core Tip: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are emerging as potential therapeutic agents in atrial fibrillation (AF) management due to their cardiovascular benefits and weight-reducing effects. While semaglutide has shown promise in reducing AF incidence, liraglutide and dulaglutide have yielded inconsistent results. Compared to sodium-glucose co-transporter 2 inhibitors, which demonstrate more consistent AF reduction, GLP-1 RAs require further investigation to establish their role in AF prevention and management.

INTRODUCTION

The global health is increasingly strained by non-communicable diseases (NCDs), with obesity and cardiovascular diseases (CDs) posing major public health challenges. According to estimates from the World Health Organization, NCDs account for 75% of all deaths worldwide, with CDs causing approximately 19 million deaths each year[1]. Atrial fibrillation (AF), the most prevalent type of arrhythmia, impacts approximately 60 million individuals globally[2]. Numerous risk factors contribute to the development and progression of AF, such as advancing age, genetics, high blood pressure, obesity, diabetes and obstructive sleep apnea. Epidemiological research indicates that, after hypertension, obesity is the most significant predictor of AF onset[3].

Structural and electrical remodeling driven by obesity both play a role in AF[3]. Deposits of ectopic cardiac fat, especially epicardial adipose tissue (EAT), are thought to be key contributors, making them a promising focus for new treatments. On the molecular level, adipose tissue releases various pro-inflammatory and pro-fibrotic factors that contribute to the structural and functional remodeling of the left atrium, promoting the development and persistence of electrical conduction abnormalities. Additionally, oxidative stress triggered by adipose tissue and the activation of autonomic nerves in the ganglion plexus also play a role in the onset of AF[4].

Antiarrhythmic drugs (AADs) remain a gold-standard treatment of AF and are used to restore normal cardiac rhythm or to prevent the recurrence of arrhythmias. Most prescribed drugs include amiodarone, sotalol, flecainide, and dofetilide, but their widespread use is limited by moderate efficacy and the risk of proarrhythmic side effects. In response, efforts are being made to repurpose medications initially developed for other conditions, such as colchicine and metformin, or to modify existing AADs to improve their safety and efficacy. Catheter ablation has become a crucial non-pharmacological strategy, effectively isolating arrhythmia triggers such as pulmonary veins, markedly lowering AF recurrence rates, especially in patients who do not respond positively to the pharmacotherapy[5].

Body composition improvements through lifestyle changes effectively reduce the burden of AF[6,7]. However, the potential of weight loss medications hasn’t been fully explored. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide, liraglutide and dulaglutide, are emerging as promising therapeutic agents. These medications have demonstrated the ability to promote significant weight loss while also offering cardiovascular benefits, including anti-inflammatory effects and improvements in atrial structural integrity[7,8]. This suggests they could play a role in lowering the risk of AF incidence. However, while these benefits are encouraging, we don’t yet have enough direct clinical evidence to confirm that GLP-1 RAs improve AF outcomes. This uncertainty highlights the need for further research to clarify the potential benefits of these medications in individuals with AF and obesity, guiding their integration into treatment strategies.

This minireview examines the incidence of AF in patients treated with GLP-1 RAs, identifying gaps in current knowledge and proposing future research directions to better define their role in antiarrhythmic treatment.

MATERIALS AND METHODS

Literature search was conducted for systematic reviews (SRs) focused on the effects of GLP-1 RAs investigating the incidence, frequency, and impact of AF. The search was performed using PubMed and Medline, with keywords such as "GLP-1 RAs", "glucagon-like peptide-1 receptor agonists", "antiobesity medication", "atrial fibrillation", "AF", "liraglutide", "semaglutide" and "dulaglutide" in various combinations. Boolean search operators, such as "AND" and "OR" were utilized to optimize the search and retrieve the most relevant SRs related to this topic of investigation. The initial research identified 16 SRs, which were then further analyzed. Of these 8 were excluded as they either did not mention AF or did not focus on it specifically. Data collected on GLP-1 RAs on the incidence of AF is summarized in 4 paragraphs named: Effect of semaglutide, liraglutide and dulaglutide on AF incidence and GLP-1 RAs vs sodium-glucose co-transporter 2 (SGLT2) inhibitors effect on AF. Paragraphs are presented based on the number of patients that were enrolled in studies investigating each subtype of GLP-1 RA, starting from the highest to lowest. Last section regards the overall comparison of GLP-1 RAs vs SGLT2 inhibitors and AF incidence.

RESULTS

Effect of semaglutide on AF incidence

Data about the effect of semaglutide on the incidence of AF investigated in this minireview has been collected and analyzed from a total of 90299 across 3 SRs. One of them described the effect of semaglutide based on 5 randomized clinical trials (RCTs). Semaglutide showed an inverse trend compared to the increasing trend toward AF incidence observed with dulaglutide. Specifically, semaglutide exhibited a decreasing trend in AF incidence (P = 0.02)[9]. A second SR, that included a post hoc analysis indicated that once-weekly injectable semaglutide, compared to placebo, reduced the risk of new-onset AF by 29%. However, due to incomplete results, these findings could not be considered reliable[10]. The last SR which compiled data from 12751 participants (7825 in the semaglutide group and 5366 in the placebo group) showed that the pharmacological intervention reduced the incidence of AF by 42%[11]. These findings highlight a consistent reduction in the incidence of AF and a better efficacy in comparison with liraglutide.

Effect of liraglutide on AF incidence

Data on liraglutide and its effect on the incidence of AF has been collected and analyzed from 84532 participants and presented in 2 SRs, that contained 48 clinical trials. Authors of the first SR described a neutral or potentially negative impact on arrhythmic events, especially AF in patients treated with liraglutide. The second SR included 10 RCTs that showed that liraglutide, among other GLP-1 RAs, had no significant effect on the risk of incidence of AF[9]. The third SR summarized findings from 5 original studies found a statistically significant risk of increase of adverse outcomes such as AF in patients treated with liraglutide[12]. These findings indicate that liraglutide not only failed to reduce the risk of AF incidence but also significantly increased its occurrence, in contrast to the neutral or beneficial effects of semaglutide on AF incidence.

Effect of dulaglutide on AF incidence

Data regarding dulaglutide and the effects has on incidence of AF has been collected from 83894 patients described in 2 SRs. As previously mentioned, a SR that included 10 studies on dulaglutide described a potential increase the incidence of AF in RCTs. The second SR, which included a post hoc analysis of RCTs with 9543 participants, found that treatment with dulaglutide, compared to placebo, was not associated with a reduced incidence of atrial arrhythmias, including both AF and atrial flutter (AFL)[10]. These findings emphasize the variability and inconsistency in dulaglutide’s impact on AF, indicating the need for further research to clarify its role in AF management.

GLP-1 RAs vs SGLT2 inhibitors effect on AF incidence

The performance of GLP-1 RAs vs SGLT2 on incidence of AF was compared with data collected from 5 SRs. Interestingly, while GLP-1 RAs showed contradicting effects, SGLT2 inhibitors, a class of antidiabetic agents with weight-reducing properties, demonstrated significant cardiovascular benefits, including reductions in AF and AFL incidence[10].

This strongly contrasts with the performance of GLP-1 RAs, which largely failed to reduce AF incidence and frequency across the trials reviewed in this minireview. Clinical trials from 2 different SRs indicated that GLP-1 RAs had no significant association with the risk of incident AF[13,14]. According to another SR, there was no difference in the risk of incidence of AF between GLP-1 RAs and SGLT2 inhibitors with subgroup analysis finding no significant difference in AF consistently in all[15]. Different SR, in which data was analyzed from 34 trials, concluded that GLP-1 RAs did not increase the risk of AF, with no difference between different groups of trials (P = 0.026)[16]. Last SR observed two different effects of GLP-1 RA therapy. First described observational study showed no association with a lower risk of incident of AF, while a second indicated a surprisingly higher risk of new-onset AF[10].

DISCUSSION

The present review originally reports on the impact of GLP-1 RAs on the incidence of AF. While traditional treatments for AF focus on AADs and ablation, GLP-1 RAs are gaining attention for their dual benefits in weight loss and cardiovascular health. GLP-1 RAs, such as semaglutide and liraglutide, have shown mixed results in reducing the risk of AF incidence (Table 1)[9-13,17]. Semaglutide appears promising, with studies reporting up to a 42% reduction in AF incidence, while liraglutide and dulaglutide have been less consistent.

Table 1 Presenting detailed results.

Title	Clinical trials	Observational studies	Controlled trials	Network meta-analyses
Antidiabetic agents and risk of atrial fibrillation/flutter: A comparative critical analysis with a focus on differences between SGLT2 inhibitors and GLP-1 receptor agonists		GLP-1RA therapy was not associated with a lower risk of incident AF in patients with T2DM (HR = 1.01, 95%CI: 0.86-1.1). GLP-1 RAs were associated with a surprising higher risk of new-onset AF (adjusted HR = 2.27, 95%CI: 1.49-3.47)	A total of 31 RCTs with a duration ≥ 12 weeks (enrolling 17966 patients and 15305 patients in GLP-1 RAs and comparator arms, respectively), treatment with GLP-1 RAs had no significant impact on the incidence of AF (OR = 0.87, 95%CI: 0.71-1.05, P = 0.15). In a further meta-analysis by the same research group that comprised 43 RCTs (63134 patients) with a duration ≥ 52 weeks, again GLP-1 RAs did not influence the risk of AF (OR = 0.94, 95%CI: 0.84-1.04) when compared to placebo or any other non-GLP-1 RA drug. Treatment with dula-glutide compared with placebo was not associated with a reduced incidence of atrial arrhythmias (combined AF and AFL: 5.6% vs 5%). GLP-1RA agonist tirzepatide compared with a placebo or active comparator did not have a signifi- cant effect on the risk for AF. Once-weekly injectable semaglutide compared to placebo reduced the risk of stroke (HR = 0.61, 95%CI: 0.38-0.99) while it also diminished the risk of new-onset AF by 29%	GLP-1 RAs were associated with a significant reduction in AF/AFL events compared with metformin (OR = 0.17, 95%CI: 0.04-0.61), SU (OR = 0.23, 95%CI: 0.07-0.73), insulin (OR = 0.20, 95%CI: 0.07-0.86), and non-SU compounds (OR = 0.18, 95%CI: 0.04-0.66). Thus, compared with other glucose-lowering agents, GLP-1 RAs could reduce the risk of AF/AFL in patients with diabetes. Compared with placebo, a significant lower AF/AFL risk was reported with both GLP-1 RAs (RR = 0.86, 95%CI: 0.76-0.97) and SGLT2 is (RR = 0.82, 95%CI: 0.68-0.99)
Association of glucagon-like peptide-1 receptor agonists with cardiac arrhythmias in patients with type 2 diabetes or obesity: A systematic review and meta-analysis of randomized controlled trials	Pooled data from all these trials indicated that GLP-1 RAs therapy had no significant association with the risk of incident AF (RR = 0.97, 95%CI: 0.83–1.12, P = 0.65). Dulaglutide displayed an increasing trend toward incident AF (RR = 1.40, 95%CI: 1.03–1.90, P = 0.03), while oral semaglutide displayed an inverse trend (RR = 0.43, 95%CI: 0.21–0.87, P = 0.02). Other GLP-1 RAs agents including albiglutide, exenatide, liraglutide, lixisenatide, and semaglutide had no significant effect on the risk of AF. GLP-1 RAs use did not significantly increase the incidence of AFL (RR = 0.83, 95%CI: 0.59–1.17, P = 0.96) compared to controls
Glucagon-like peptide-1 receptor agonist semaglutide reduces atrial fibrillation incidence: A systematic review and meta-analysis				Meta-analysis revealed that semaglutide reduces the risk of incident AF episodes by 42% (RR = 0.58, 95%CI: 0.40–0.85), with low heterogeneity across the included studies (I2 = 0%)
GLP-1 receptor agonists and myocardial metabolism in atrial fibrillation	Liraglutide, exenatide, dulaglutide, albiglutide, and semaglutide have all been shown to reduce major adverse cardiovascular events. Accordingly, recent guidelines have recommended the use of GLP-1 RAs for patients with T2DM at high risk of cardiovascular disease, especially heart failure and chronic kidney disease. However, treatment with GLP-1 RAs only has minimal benefit in reducing the risk of AF
Glucagon-like peptide-1 receptor agonists in the context of pathophysiology of diverse heart failure with preserved ejection fraction phenotypes: Potential benefits and mechanisms of action	GLP-1 RA therapy in diabetic mice reduced susceptibility to AF and duration of arrhythmia episodes. Meta-analysis, GLP-1 RAs significantly reduced AF events compared to metformin, sulfonylurea, insulin and non-sulfonylurea inpatients with T2DM and were associated with better outcomes compared toother medications. Two large meta-analyses of RCTs concerning T2DM did not show any significant risk for atrial and ventricular arrhythmias or sudden cardiac death associated with GLP-1 RAs
Role of Liraglutide Use in Patients With Heart Failure	Established a statistically significant risk of adverse outcomes in patients under the liraglutide group against the placebo group with [HR = 1.41, (95%CI: 1.01, 1.97), P = 0.043]

AF: Atrial fibrillation; AFL: Atrial flutter; GLP-1 Ras: Glucagon-like peptide-1 receptor agonists; HR: Hazard ratio; OR: Odds ratio; RCTs: Randomized clinical trials; RR: Relative risk; SGLT2: sodium-glucose co-transporter 2; SU: Sulfonylurea; T2DM: Type 2 diabetes mellitus.

Obesity plays a significant role in the development of cardiovascular conditions such as AF, with inflammation and changes in heart structure increasing the risk. As of today, more than one in three adults lives with obesity and by 2035, the global overweight and obesity prevalence is projected to reach 51%, with South Pacific Islands leading the course of the obesity epidemic. Even more strikingly, by 2030, 78% of the United States adults are projected to be affected by excess weight[18,19].

On the molecular level GLP-1 RAs appear to attenuate systemic and local inflammation via activation of AMP-activated protein kinase and inhibition of the nuclear factor-kappa B[20,21]. These changes, accompanied by lowering of EAT volume, may help prevent AF by reducing cardiac inflammation and fibrosis leading to structural and functional remodeling of the cardiac muscle[21,22].

In contrast SGLT2 inhibitors have been associated with reduced AF incidence via reduction in atrial wall stretch through natriuresis and volume unloading, attenuation of oxidative stress, mitochondrial efficiency improvements and direct effects on ion channels[23].

This investigation was based on thorough research using PubMed and Medline; however, it is important to acknowledge certain limitations. The SRs analyzed were not exclusively focused on AF, which restricted the scope of the data available for this minireview. Additionally, as only open-access sources were included, some relevant studies may have been overlooked, potentially influencing the findings. These factors highlight the need for further research incorporating a broader range of databases to ensure a more comprehensive analysis. In addition, the need for clinical trials investigating the effect of GLP-1 RAs incorporation in patients with obesity and AF is emphasized.

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA, has recently gathered significant attention for its efficacy in improving glycemic control and promoting weight loss. Preliminary evidence suggests that its dual-action mechanism may offer cardiovascular benefits. For instance, one study found that tirzepatide reduced the combined risk of cardiovascular death and worsening heart failure events by 38% compared to placebo in patients with heart failure with preserved ejection fraction and obesity[24]. However, a recently published analysis showed no significant effect on AF in patients treated with GIP versus a placebo group[25].

CONCLUSION

While GLP-1 RAs show potential for reducing the risk of occurrence of AF, their specific role is still unclear. There is a critical need for RCTs to evaluate the effects of GLP-1 RAs on AF incidence, burden, and recurrence after interventions such as cardioversion or catheter ablation. In addition, future research should explore the therapeutic potential of emerging agents such as tirzepatide, which may offer cardiovascular or anti-arrhythmic benefits. Finally, evaluating combination strategies involving GLP-1 RAs and SGLT2 inhibitors, given their complementary mechanisms of action, could provide valuable insights into optimizing AF prevention in high-risk populations, including living with overweight, obesity and diabetes.