Type 2 diabetes: the cardiovascular benefits of GLP-1 RAs, even in combination

It is well known that GLP-1 receptor agonists have a cardioprotective effect in type 2 diabetes. But little is known about their cardiovascular safety in combination.

GLP-1 RAs and thiazolidinediones in diabetes:

GLP-1 RAs are indicated for diabetics with clinically relevant cardiovascular disease or a high risk thereof.
They improve endothelial function, reduce oxidative stress and have anti-inflammatory effects.
Thiazolidinediones, also known as glitazones or insulin sensitizers, are no longer listed in the 2023 National Care Guideline for Type 2 Diabetes.
Rosiglitazone was withdrawn from the market in 2010, and since 2011 pioglitazone may only be prescribed in justified individual cases.

Can GLP-1 RAs offset the risks of thiazolidinediones?

So why conduct a study on combination therapy with GLP-1 RAs and thiazolidinediones? Firstly, the recommendations in Taiwan are different, and secondly, such a study is also highly informative in this country. This is because thiazolidinediones can increase the risk of myocardial infarction and cardiovascular mortality and also cause increased fluid retention, which is associated with the risk of heart failure. The interesting question is therefore whether GLP-1 RAs can also offset these disadvantages.

In their retrospective cohort study, the researchers included approximately 110,000 patients with type 2 diabetes who received either monotherapy with GLP-1 RA (exenatide, lixisenatide, dulaglutide or liraglutide) or thiazolidinedione, or a combination of both. A propensity score-matched group of patients who did not take either of the two drugs served as a control. The endpoints included all-cause and cardiovascular mortality, major cardiovascular events, and complications such as hypoglycaemia.

Mortality lowest with combination therapy

Patients receiving dual therapy with GLP-1 RA and thiazolidinedione had a significantly lower risk of all-cause mortality (adjusted hazard ratio [AHR] 0.20; 95% CI, 0.19–0.21; P < 0.001), major cardiovascular events (AHR 0.85; 95% CI, 0.82–0.89; P < 0.001) and cardiovascular mortality (AHR 0.20; 95% CI, 0.18–0.23; P < 0.001) than patients who did not receive GLP-1 RA or thiazolidinedione. When comparing the two substances, monotherapy with thiazolidinediones was associated with a significantly higher risk of all-cause mortality (AHR 1.29; 95% CI, 1.24–1.34; P < 0.001) and cardiovascular mortality (AHR 1.28; 95% CI, 1.13–1.45; P < 0.001) compared with GLP-1 RA monotherapy.

Another finding was that while GLP-1 RAs alone were associated with significantly lower overall and cardiovascular mortality, combination with a thiazolidinedione showed an even more pronounced reduction in risk.

However, the risk of hypoglycaemia was higher with both combination therapy and thiazolidinedione monotherapy compared to no treatment. However, it decreased with the duration of use.

From the authors' perspective, the study shows the following:

The cardiovascular benefits of GLP-1 RAs have been confirmed once again. The results suggest that they may even mitigate the adverse effects of thiazolidinediones.
The risk of mortality was reduced even more under dual therapy than with GLP-1 RA alone. This could indicate a possible synergistic effect and confirms the principle of combination therapies for diabetics with cardiovascular disease.

Sources

Li J et al. Combination of Glucagon-Like Peptide 1 Receptor Agonist and Thiazolidinedione for Mortality and Cardiovascular Outcomes in Patients With Type 2 Diabetes. JAMA Netw Open 2025; 8(3): e252577.