Pioglitazone Combined with Insulin Linked to Higher Ischemic Heart Disease Risk in Type 2 Diabetes Patients: Study Reveals

Type 2 diabetes mellitus, a leading global chronic illness, is linked to insulin resistance and pancreatic cell failure. Cardiovascular disease is the primary cause of death in T2DM patients, with IHD being the most common cause. Metformin failure may prompt the addition or replacement of other anti-diabetic drugs. The ADA/EASD recommends SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors over pioglitazone, given concerns about cardiovascular risks.

Studies on the cardiovascular safety of pioglitazone have shown inconsistent results, and the risk of ischemic heart disease linked to various anti-diabetic drugs added to metformin in uncontrolled type 2 diabetes remains unexplored. Therefore, Hsin-An Lin, Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan, and colleagues aimed to assess the IHD risk associated with the addition of pioglitazone and/or insulin in patients with metformin-uncontrolled T2DM.

For this purpose, the researchers extracted data from the National Health Insurance Research Database of Taiwan. The study included a total of 19,952 patients with T2DM who were uncontrolled on metformin and received either pioglitazone and/or insulin as an additional treatment.

The study led to the following findings:

• Patients receiving both insulin and pioglitazone had a higher cumulative risk of ischemic heart disease (IHD) compared to those who never received pioglitazone and/or insulin (adjusted HR = 1.911).
• Pioglitazone alone was associated with a higher risk of IHD (adjusted HR = 1.446).
• Insulin alone was also linked to an increased risk of IHD (adjusted HR = 1.351).
• The combination of both pioglitazone and insulin showed a higher cumulative risk of IHD than either drug alone.
• Similar results were observed in the cumulative defined daily dose (cDDD) of the drugs.

The authors concluded that adding pioglitazone to the treatment regimen of T2DM patients uncontrolled on metformin showed a significant difference in the risk of IHD. Compared to the use of insulin or pioglitazone alone, combining pioglitazone with insulin was associated with an increased risk of IHD.

"The findings suggest that, in clinical practice, managing the choice of alternative second-line anti-diabetic medications may help reduce the likelihood of developing IHD in T2DM patients who are uncontrolled on metformin," the researchers wrote.

Reference:

Tsai, M., Chien, W., Lin, H., Chung, C., Chen, L., Huang, K., & Lin, H. (2024). Pioglitazone increases risk of ischemic heart disease in patients with type 2 diabetes receiving insulin. Journal of Diabetes and its Complications, 38(12), 108898. https://doi.org/10.1016/j.jdiacomp.2024.108898