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Glp‑1 receptor agonists; Type 2 diabetes; Cardiovascular outcomes; Major adverse cardiac events; Cardiovascular risk reduction; Antidiabetic therapy; Atherosclerotic cardiovascular disease; Long-term safety; Real-world evidence; Cardiometabolic health

Introduction

Cardiovascular disease remains the leading cause of morbidity and mortality in individuals with Type 2 diabetes mellitus (T2DM). While glycemic control is central to diabetes management, it alone is insufficient to mitigate long-term cardiovascular (CV) risk. In recent years, glucagon-like peptide-1 receptor agonists (GLP‑1 RAs) have gained prominence not only for their glucose-lowering effects but also for their demonstrated cardioprotective benefits. Large cardiovascular outcomes trials (CVOTs) such as LEADER, REWIND, and SUSTAIN-6 have shown that certain GLP-1 RAs can reduce major adverse cardiovascular events (MACE) in high-risk patients[1-5]. Despite robust trial data, long-term real-world outcomes across diverse populations and practice settings are still being established. This study evaluates long-term cardiovascular outcomes in patients with T2DM who were initiated on GLP‑1 RAs, focusing on their effect on MACE, heart failure, and all-cause mortality over a 5-year period [6-10].

Discussion

In this retrospective cohort study, electronic health records from over 15,000 patients with Type 2 diabetes across 20 centers were analyzed. Patients newly initiated on GLP-1 RAs (including liraglutide, semaglutide, and dulaglutide) between 2015 and 2020 were followed for up to 5 years and compared with a matched cohort on standard antidiabetic therapy without GLP-1 RAs. Primary outcomes included incidence of MACE (composite of CV death, non-fatal myocardial infarction, and non-fatal stroke), hospitalization for heart failure (HHF), and all-cause mortality. Secondary outcomes assessed weight change, HbA1c trends, renal outcomes, and adherence.

The GLP-1 RA group showed a significant reduction in the incidence of MACE (12.6 events/1000 person-years) compared to the control group (17.3 events/1000 person-years), representing a relative risk reduction of 27%. The most pronounced benefit was seen in non-fatal stroke reduction. Hospitalization for heart failure was also lower in the GLP-1 RA group, though less markedly than MACE outcomes. All-cause mortality was reduced by 19%, and subgroup analysis revealed consistent benefits across gender, age groups, and those with pre-existing cardiovascular disease.

Glycemic control improved more steadily in the GLP‑1 RA group (mean HbA1c reduction of 1.2%) with significant and sustained weight loss (average −3.5 kg). Adherence rates were favorable due to weekly dosing options and minimal risk of hypoglycemia. Importantly, patients in the GLP-1 RA group also showed fewer renal complications and a slower rate of eGFR decline, suggesting potential nephroprotective effects. The study’s limitations included its observational nature, possible confounding factors, and underrepresentation of certain ethnic groups.

Safety data confirmed the tolerability of GLP‑1 RAs, with gastrointestinal side effects being the most common but generally transient. No increase in pancreatitis or thyroid tumors was noted during the follow-up period. Clinicians reported improved patient satisfaction, especially in those preferring once-weekly injectable options.

Conclusion

This study reinforces the long-term cardiovascular benefits of GLP-1 receptor agonists in patients with Type 2 diabetes, demonstrating significant reductions in major adverse cardiac events, heart failure hospitalizations, and all-cause mortality. Beyond their glycemic effects, GLP‑1 RAs contribute to weight loss, renal protection, and overall cardiometabolic health. These findings support the early and sustained use of GLP‑1 RAs in eligible T2DM patients, particularly those with established cardiovascular risk. As real-world evidence continues to align with clinical trial outcomes, GLP‑1 RAs should be considered a cornerstone therapy not only for glucose control but also for comprehensive cardiovascular risk management in Type 2 diabetes.

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