Comparative Heart Outcomes of GLP-1 Receptor Agonists in Diabetes Treatment

In recent years, the emergence of anti-obesity drugs has prompted an increase in research focusing on their side effects and benefits. Endocrine News examines two studies aimed at understanding how these medications, often referred to as ‘miracle drugs,’ could influence cardiac health.

Key Findings Among individuals with type 2 diabetes and atherosclerotic cardiovascular disease (CVD), tirzepatide, a dual agonist, demonstrated noninferiority to dulaglutide regarding a composite of cardiovascular-related deaths, myocardial infarction (MI), or stroke. Additionally, a prespecified secondary analysis indicated a potential lower rate of overall and non-cardiovascular deaths with tirzepatide. It is important to note that GLP-1 receptor agonists (GLP-1RAs) can be safely administered to patients with moderate cardiovascular risk associated with type 2 diabetes.

Two studies published towards the end of 2025 analyzed cardiovascular outcomes in patients receiving different GLP-1RAs, yielding valuable insights into the disparities in effectiveness within this drug class. As federal policies aim to enhance the accessibility of GLP-1RAs, targeting more patients who could benefit from these therapies, evaluating their safety and efficacy profiles is timely.

Tirzepatide Versus Dulaglutide The first study, titled “Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes,” published in the New England Journal of Medicine in December, led by Stephen J. Nicholls from Monash University in Australia, was designed to address key questions related to glucagon-like peptide-1 receptor agonists. The goal was to assess whether combination therapies could produce improved clinical or metabolic outcomes. A total of 6,586 patients with type 2 diabetes were randomly assigned to receive either tirzepatide, which acts on both GIP and GLP-1 receptors, or dulaglutide, a selective GLP-1RA, in an active comparator-controlled and double-blind trial lasting four years.

The primary outcome was the time until the first major adverse cardiovascular event (MACE), which includes cardiovascular-related deaths, myocardial infarctions, or strokes. Secondary outcomes encompassed cardiovascular mortality, all-cause mortality, composite cardiovascular metrics, kidney functionality changes after 36 months, and variations in A1c levels, weight, blood pressure, and lipid profiles within specified time frames.

Results showed that tirzepatide was as safe and effective as dulaglutide concerning major cardiovascular events (noninferior, but not superior), with noted gastrointestinal (GI) side effects but superior A1c reductions and weight loss. Moreover, tirzepatide showed a lower occurrence of the broader composite outcomes, including revascularization and reduced all-cause mortality.

Nicholls expressed no surprise at tirzepatide's noninferiority but highlighted the importance of the findings concerning reduced all-cause mortality. He noted that while the anticipated metabolic benefits of tirzepatide were expected, the extent of its effects on clinical outcomes, particularly concerning broader MACE like coronary revascularization, was significant. This indicates that individuals suffering from CVD and type 2 diabetes may face multiple health complications but could benefit from tirzepatide.

Further investigating the reasons behind the lower mortality rates associated with tirzepatide may prove worthwhile, as Nicholls pointed to a potential decrease in non-cardiovascular deaths, a hypothesis already subject to prior investigations. He explained that understanding the mechanisms behind these incretin therapies remains an ongoing effort that is likely multifaceted. It may involve various factors, not solely limited to weight loss or improved glycaemic control.

Dulaglutide, Exenatide, Liraglutide, and Semaglutide The second major study titled “Comparative Effectiveness of GLP-1 Receptor Agonists on Cardiovascular Outcomes Among Adults with Type 2 Diabetes and Moderate Cardiovascular Risk” aimed to analyze the cardiovascular effects of several GLP-1RAs among adults identified as having moderate cardiovascular risk. Conducted by Stacey M. Sklepinski and Rozalina G. McCoy, the study sought to fill a research gap concerning the comparative outcomes following the initiation of GLP-1RAs.

This research focused on adults with type 2 diabetes presumed to be at moderate CVD risk—those predicted to have a MACE rate of 1% to 5% within the following year. The study encapsulated data of over 81,000 adults who began treatment with dulaglutide, exenatide, liraglutide, or semaglutide between 2019 and 2021. The results revealed that semaglutide and liraglutide had the most favorable cardiovascular outcomes.

Semaglutide was linked to a significantly reduced risk of MACE, increased MACE, both types of mortality, acute strokes, and arterial revascularization compared with dulaglutide. Similarly, liraglutide exhibited a lower risk of MACE and all-cause mortality relative to dulaglutide.

The researchers noted the significance of understanding GLP-1RAs in combination with SGLT2 inhibitors, as both classes effectively lower cardiovascular risks in type 2 diabetes patients and may yield additive benefits when used together. However, direct evidence supporting this notion remains absent.

In conclusion, these findings underscore the need for further research to clarify the advantages of various GLP-1RAs, especially given the projected increase in their utilization and demand in clinical practice. Increased understanding will not only guide therapeutic choices but also enhance patient care by aligning treatment options based on individual needs.