Impact of Adding GLP-1 Receptor Agonists to Insulin Therapy on Cardiovascular and Microvascular Outcomes in Type 2 Diabetes: A Nationwide Cohort Study from Taiwan

<b>Background/Objectives:</b> Selecting appropriate non-insulin hypoglycemic agents to complement insulin therapy is essential for achieving optimal glycemic control. This study aimed to evaluate the impact of glucagon-like peptide-1 receptor agonist (GLP-1 RA) plus insulin therapy on long-term cardiovascular and microvascular outcomes in patients with type 2 diabetes (T2D), with the goal of optimizing treatment strategies. <b>Methods:</b> Using Taiwan's National Health Insurance Research Database (2008-2021), we conducted a retrospective cohort study and identified 6779 propensity score-matched pairs of insulin-treated patients with T2D who initiated either GLP-1 RAs or dipeptidyl peptidase-4 (DPP-4) inhibitors. Cox proportional hazard models were applied to compare outcome risks between the two groups. <b>Results:</b> The mean follow-up was 3.45 years. Compared with DPP-4 inhibitor use, GLP-1 RA use was significantly associated with a reduced risk of major adverse cardiovascular events (aHR 0.52, 95% CI 0.46-0.58), including hospitalizations for coronary artery disease (aHR 0.64, 95% CI 0.54-0.75), stroke (aHR 0.48, 95% CI 0.40-0.56), and heart failure (aHR 0.33, 95% CI 0.25-0.42). GLP-1 RA use was also linked to lower risks of major microvascular complications (aHR 0.42, 95% CI 0.35-0.50), end-stage kidney disease (aHR 0.08, 95% CI 0.04-0.14), sight-threatening retinopathy (aHR 0.62, 95% CI 0.50-0.76), leg amputation (aHR 0.16, 95% CI 0.05-0.57), and all-cause mortality (aHR 0.38, 95% CI 0.32-0.44). <b>Conclusions:</b> In this nationwide cohort, adding GLP-1 RAs to insulin therapy in patients with T2D was associated with significantly lower risks of cardiovascular events, major microvascular complications, and all-cause mortality compared with adding DPP-4 inhibitors. These findings suggest that incorporating GLP-1 RAs into insulin regimens may optimize treatment, lessen disease burden, and improve survival.