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TOPLINE:

In patients with type 2 diabetes (T2D), combination therapy with glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and thiazolidinediones was associated with a reduced risk for all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACEs) compared with those who used none or one of these therapies.

METHODOLOGY:

• For people with T2D, the potential benefits of combination therapies with GLP-1 RAs are reviving interest in thiazolidinediones, particularly pioglitazone, despite the earlier cardiovascular safety concerns of rosiglitazone that limited their use.
• Researchers conducted a retrospective cohort study using national health insurance data from Taiwan (2011-2020) to examine the effects on diabetes complications of combination therapy with GLP-1 RAs (exenatide, lixisenatide, dulaglutide, or liraglutide) and thiazolidinediones (rosiglitazone or pioglitazone) compared with those who received none or one of the medications.
• The cohort included 110,411 patients with T2D (mean age, 58 years; 45% women) who received one or both medications. They were propensity-score matched to 110,411 patients who did not use either medication.
• Primary outcomes included all-cause mortality, MACEs (a composite of nonfatal myocardial infarction [MI], nonfatal cerebrovascular disease [CVD], and cardiovascular mortality), and cardiovascular mortality (a composite of MI, CVD, ischemic heart disease, heart failure [HF] and peripheral artery disease). Secondary outcomes included the individual outcomes and hypoglycemia.
• Patients were followed from the first day of either medication until death, the occurrence of outcomes, or the end of the study.

TAKEAWAY:

• Compared with patients who did not use either medicine, those on the combination therapy of GLP-1 RAs and thiazolidinediones had a lower risk for all-cause mortality (adjusted hazard ratio [aHR], 0.20), MACEs (aHR, 0.85), and cardiovascular mortality (aHR, 0.20; P < .001 for all). The benefits were more pronounced among those treated for more than 900 days.
• Lower risks for secondary outcomes were also seen with the combination therapy compared with people who used neither medicine — MI (aHR, 0.73; P < .001), CVD (aHR, 0.93; P = .002), and heart failure (aHR, 0.85; P < .001).
• However, the risk for hypoglycemia was higher in patients who used thiazolidinedione monotherapy (aHR, 1.69; P < .001) or combination therapy (aHR, 1.61; P < .001) than in those who did not use either medicine. These risks decreased with use for longer than 900 days.
• Patients who used thiazolidinedione monotherapy had a higher risk for all-cause mortality and cardiovascular mortality than those who used GLP-1 RA monotherapy (P < .001 for both).

IN PRACTICE:

“This finding suggests a potential synergistic effect on mortality,” the study authors wrote. “The benefits of thiazolidinediones are tempered by their associated risks, such as fluid retention and an increased risk of HF. This study showed that GLP-1 RAs could mitigate the risk of HF associated with thiazolidinedione use,” they added.

“[This study], together with other emerging evidence and practice guideline recommendations, may offer a new frontier to consider the value of cost-effective combination therapy of a thiazolidinedione plus a GLP-1 RA in patients with T2D,” the authors of an invited commentary wrote.

SOURCE:

This study was led by Jing-Xing Li, MD, MS, of the China Medical University Hospital, Taichung, Taiwan. It was published online in JAMA Network Open.

LIMITATIONS:

The observational design of this study limited the ability to establish causality, and the outcomes might have been influenced by residual confounding. The elderly study population may limit the generalizability of the results to younger individuals or those having different baseline characteristics. The increased risk for hypoglycemia observed with combination therapy could be a significant concern.

DISCLOSURES:

This study was partly supported by grants from the Taiwan Ministry of Health and Welfare Clinical Trial Center and China Medical University Hospital Clinical Trial Center. The authors reported having no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.