Thiazolidinedione add-ons associated with less CV risk, study finds

The U.K.-based retrospective cohort study used a database that linked national hospitalization and mortality data for people who were prescribed second-line regimens after metformin.


Thiazolidinedione add-on treatments to metformin were associated with lower risks of major cardiovascular (CV) disease or CV death compared with sulfonylurea, a study found.

To examine the risk of major CV events associated with second-line diabetes therapies in type 2 diabetes, researchers in the United Kingdom conducted a retrospective cohort study using data from a database that linked national hospitalization and mortality data for people who were prescribed second-line regimens after metformin.

The study cohort included those with at least 1 diagnostic medical code for type 2 diabetes who were age 40 or older at diagnosis and who were prescribed at least 90 days of first-line metformin monotherapy. Patients were eligible for inclusion if they had been prescribed a second-line treatment between 1998 and 2011. Patients with a history of type 1 diabetes or nonspecific diabetes were excluded.

Eligible cases were followed from the start date of the second-line therapy until a major CV event, including CV death, myocardial infarction, stroke, acute coronary syndrome, unstable angina, or coronary revascularization (coronary artery bypass graft or percutaneous transluminal coronary angioplasty), associated with second-line therapies, or until censoring. Patients were censored if there was a change in prescribed second-line diabetes therapy, if they transferred out of the practice, if they died, or when the study ended. Analyses were adjusted for patient demographic characteristics, comorbidities, glycated hemoglobin, socioeconomic status, ethnicity, smoking status, and concurrent medications.

Results of the study were published online on June 30 by Diabetes, Obesity and Metabolism.

A total of 10,118 patients began second-line treatment with either a sulfonylurea (n=6,740), a dipeptidyl peptidase-4 (DPP-4) inhibitor (n=1,030), or a thiazolidinedione (n=2,348). After a mean of 2.4 years of follow-up, 386, 36, and 95 major CV events occurred in the sulfonylurea, DPP-4 inhibitor, and thiazolidinedione groups, respectively. In comparison with the metformin-sulfonylurea regimen, adjusted hazard ratios were 0.78 (95% CI, 0.55 to 1.11) for the metformin-DPP-4 inhibitor regimen and 0.68 (95% CI, 0.54 to 0.85) for the metformin-thiazolidinedione regimen. Crude event rates for CV events per 1,000 person-years were 24.4 (95% CI, 22.04 to 26.91) in patients prescribed metformin and sulfonylurea, 18.4 (95% CI, 13.26 to 25.48) in patients treated with metformin and DPP-4 inhibitors, and 15.9 (95% CI, 12.99 to 19.42) in patients prescribed metformin and thiazolidinedione.

In an additional analysis that restricted the cohort to patients who initiated second-line therapies during or after 2007, the risk estimates remained the same as in the main analysis. In another sensitivity analysis that examined thiazolidinedione regimens separately, the adjusted hazard ratio was 0.58 (95% CI, 0.41 to 0.80) for pioglitazone users and 0.79 (95% CI, 0.58 to 1.06) for rosiglitazone users compared with sulfonylurea users.

“The high cardiovascular risk in patients with type 2 diabetes calls for further randomized controlled trials and larger observational studies with longer follow-up so that further data on the cardiovascular safety and efficacy of different glucose-lowering regimens can be obtained,” the authors concluded.