Combination of Glucagon-Like Peptide 1 Receptor Agonist and Thiazolidinedione for Mortality and Cardiovascular Outcomes in Patients With Type 2 Diabetes
Authors: Jing-Xing Li, Tzu-Ju Hsu, Heng-Jun Lin, Shu-Bai Hsu, Chiung-Ray Lu, Wei-Hsin Chung, Shinn-Jye Liang, Fuu-Jen Tsai, Kuan-Cheng Chang
Journal: JAMA Network Open (2025)

Importance Combination therapy has emerged as a critical area of interest in managing diabetes; however, the association of combination therapy with a glucagon-like peptide 1 receptor agonist (GLP-1RA) and thiazolidinedione and the risk of diabetes-related complications remains incompletely understood. Objective To compare the hazards of cardiovascular-related morbidities and mortality among patients with type 2 diabetes receiving combination therapy with a GLP-1RA plus thiazolidinedione, those receiving monotherapy with a GLP-1RA or thiazolidinedione, and nonusers. Design, Setting, and Participants This retrospective cohort study used nationwide data obtained from Taiwan’s National Health Insurance Research Database. Patients older than 20 years with type 2 diabetes who received a GLP-1RA or thiazolidinedione between January 1, 2011, and December 31, 2020, were enrolled. The data analysis was performed from May 1 to May 22, 2024. Main Outcomes and Measures This study investigated the hazards of all-cause mortality, major adverse cardiovascular events, cardiovascular mortality, cardiovascular complications, and hypoglycemia in GLP-1RA and thiazolidinedione combination or monotherapy users compared with nonusers. Results A total of 110 411 patients were enrolled (mean [SD] age, 58.3 [11.9] years; 45.5% female; 47 526 GLP-1RA users, 32 203 thiazolidinedione users, and 30 682 GLP-1RA plus thiazolidinedione users), along with a propensity score–matched group of patients who did not use a GLP-1RA or thiazolidinedione, for a total cohort size of 220 822. Patients receiving GLP-1RA and thiazolidinedione dual therapy had significantly lower risk of all-cause mortality (adjusted hazard ratio [AHR], 0.20; 95% CI, 0.19-0.21; P &amp;amp;lt; .001), major adverse cardiovascular events (AHR, 0.85; 95% CI, 0.82-0.89; P &amp;amp;lt; .001), and cardiovascular mortality (AHR, 0.20; 95% CI, 0.18-0.23; P &amp;amp;lt; .001) than those who did not receive a GLP-1RA or thiazolidinedione. However, a higher risk of hypoglycemia was seen in those receiving combination therapy (AHR, 1.61; 95% CI, 1.43-1.82; P &amp;amp;lt; .001) and those receiving thiazolidinedione monotherapy (AHR, 1.69; 95% CI, 1.51-1.90; P &amp;amp;lt; .001) compared with nonuse. This risk was mitigated with prolonged use. Thiazolidinedione monotherapy users had a significantly higher risk of all-cause mortality (AHR, 1.29; 95% CI, 1.24-1.34; P &amp;amp;lt; .001) and cardiovascular mortality (AHR, 1.28; 95% CI, 1.13-1.45; P &amp;amp;lt; .001) than GLP-1RA monotherapy users. Several sensitivity analyses further supported the robustness of these findings. Conclusions and Relevance In this cohort study of patients with type 2 diabetes, combination therapy with a GLP-1RA plus thiazolidinedione was associated with significantly lower hazards of mortality and cardiovascular complications compared with nonuse. The findings suggest that GLP-1RAs may mitigate the adverse cardiovascular effects of thiazolidinedione.