Highlights
- Albiglutide significantly reduces major adverse cardiovascular events (MACE) in patients with Type 2 diabetes and established cardiovascular disease, regardless of a history of atrial fibrillation or flutter (AF).
- Patients with a baseline history of AF face a significantly higher risk of MACE, with event rates nearly double those of patients without AF (12.7 vs. 6.3 events per 100 person-years).
- The treatment effect of albiglutide was consistent across subgroups, showing an 17% to 23% reduction in MACE risk irrespective of AF status.
- While GLP-1 receptor agonists are known to slightly increase heart rate, albiglutide did not increase AF events and showed a trend toward a 18% reduction in new-onset AF during follow-up.
Introduction: The Intersection of Diabetes and Atrial Fibrillation
Type 2 diabetes (T2D) and atrial fibrillation (AF) are two escalating global epidemics that frequently coexist. The presence of T2D is a well-established independent risk factor for the development of AF, likely mediated through complex pathways involving structural, electrical, and autonomic remodeling of the atria. Conversely, when AF occurs in patients with diabetes, it acts as a potent multiplier of cardiovascular risk, leading to increased rates of stroke, heart failure, and mortality.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have revolutionized the management of T2D by demonstrating significant cardiovascular benefits. However, because GLP-1 RAs are known to increase the resting heart rate by approximately 2 to 3 beats per minute, questions have been raised regarding their safety and potential impact on atrial arrhythmias. The Harmony Outcomes trial provided a robust platform to investigate these concerns, specifically looking at albiglutide, a once-weekly GLP-1 RA.
Study Design: The Harmony Outcomes Framework
The Harmony Outcomes trial was a multi-centre, event-driven, double-blind, placebo-controlled study that randomized 9,463 patients aged 40 years or older. All participants had T2D and established cardiovascular disease (coronary, cerebrovascular, or peripheral arterial disease). Patients were randomized to receive either subcutaneous albiglutide (30–50 mg once weekly) or a matching placebo, in addition to standard care.
The primary endpoint was a composite of major adverse cardiac events (MACE), including non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death. In this specific sub-analysis, researchers evaluated the efficacy of albiglutide in patients with and without a history of AF at baseline and monitored the incidence of new or recurrent AF events during a median follow-up of 1.6 years.
Key Findings: MACE Reduction Across Subgroups
At baseline, 8.9% (n=844) of the study population had a documented history of AF. These patients represented a higher-risk cohort, being generally older and having a higher prevalence of heart failure and renal impairment compared to those without AF.
Baseline AF and Cardiovascular Risk
During the follow-up period, the study confirmed that a history of AF is a strong independent predictor of adverse outcomes. Patients with AF at baseline exhibited a MACE rate of 12.7 events per 100 person-years, compared to 6.3 events per 100 person-years in those without a history of AF. After adjustment, the hazard ratio (aHR) for MACE in patients with AF was 1.41 (95% CI 1.14–1.74, P = 0.001).
Efficacy of Albiglutide
Albiglutide demonstrated a consistent reduction in the primary MACE endpoint regardless of whether patients had AF at the start of the trial.
- For patients with a history of AF, the aHR was 0.83 (95% CI 0.58–1.19).
- For patients without a history of AF, the aHR was 0.77 (95% CI 0.66–0.90).
The P-interaction value of 0.71 indicates that the cardiovascular benefit of albiglutide is uniform and not modified by the presence of atrial fibrillation.
The Impact on Atrial Fibrillation and Flutter Incidence
A secondary but clinically vital objective was to determine if albiglutide influenced the development of AF. During the trial, 239 patients (2.5%) experienced an AF event.
Interestingly, despite the known heart-rate-increasing effects of GLP-1 RAs, albiglutide was associated with numerically fewer AF events compared to placebo (108 vs. 131 events). This translated to a hazard ratio of 0.82 (95% CI 0.63–1.06, P = 0.12). While this did not reach the threshold for statistical significance, it provides strong evidence of safety, suggesting that albiglutide does not promote arrhythmias. This trend toward a reduction was consistent whether or not the patients had a prior history of AF (P-interaction = 0.92).
Expert Commentary: Mechanistic Insights and Clinical Implications
The findings from the Harmony Outcomes trial contribute significantly to the safety profile of GLP-1 RAs. The slight increase in heart rate observed with this class of drugs is likely driven by direct stimulation of the GLP-1 receptors in the sinoatrial node or through modulation of the autonomic nervous system. However, the data suggest that this physiological increase does not translate into clinical arrhythmogenesis.
Several mechanisms might explain the trend toward a lower rate of AF events in the albiglutide group:
1. Reduction in Epicardial Fat
GLP-1 RAs have been shown to reduce epicardial adipose tissue, which is a known source of pro-inflammatory cytokines that can infiltrate the atrial myocardium and promote fibrosis, a key substrate for AF.
2. Improved Hemodynamics and Weight Loss
The weight loss and blood pressure improvements associated with albiglutide may reduce left atrial stretch and pressure, thereby decreasing the mechanical triggers for AF.
3. Anti-inflammatory Effects
Systemic and local anti-inflammatory effects of GLP-1 RAs may mitigate the oxidative stress and inflammation that drive atrial remodeling in diabetic patients.
Conclusion
In patients with Type 2 diabetes and established cardiovascular disease, albiglutide effectively reduces the risk of major adverse cardiovascular events, and this benefit is preserved in those with a history of atrial fibrillation. Furthermore, the trial provides reassuring evidence that albiglutide does not increase the risk of AF events. The observed trend toward a reduction in AF incidence warrants further investigation in larger, longer-term trials specifically designed to assess rhythmic outcomes. For clinicians, these data reinforce the use of GLP-1 RAs as a safe and effective strategy for cardiovascular risk reduction in high-risk diabetic populations, including those with pre-existing arrhythmias.
Funding and ClinicalTrials.gov
The Harmony Outcomes trial was funded by GlaxoSmithKline. ClinicalTrials.gov Identifier: NCT02465515.
References
1. Krychtiuk KA, Marquis-Gravel G, Murphy S, et al. Albiglutide and atrial fibrillation in patients with Type 2 diabetes and established cardiovascular disease: insights from the Harmony Outcomes trial. Eur J Prev Cardiol. 2026;33(1):30-41.
2. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised, placebo-controlled trial. Lancet. 2018;392(10157):1519-1529.
3. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7(10):776-785.
