Effect of pioglitazone in acute ischemic stroke patients with diabetes mellitus: a nested case-control study

Abstract

Background: Pioglitazone is an oral antidiabetic drug with multiple pleiotropic actions. Recent clinical trials have demonstrated that treatment with pioglitazone reduces cardiovascular risk in patients who have had an ischemic stroke. We examined the secondary preventive effects of pioglitazone in acute ischemic stroke patients with diabetes mellitus (DM) based on nationwide real-world data.

Methods: A nested case-control study was conducted with data from the National Health Insurance Service-National Sample Cohort in Korea. Study subjects were diabetic patients admitted for acute ischemic stroke (ICD-10 code; I63) between 2002 and 2013. Cases were defined as patients who suffered from composites of recurrent stroke (I60-63), myocardial infarction (I21), or all-cause mortality after ischemic stroke. Controls were selected by incidence density sampling. Three controls were matched to each case for sex, age, treatment with insulin, and oral antidiabetic medications, with the exception of pioglitazone. Medication history after ischemic stroke was obtained by accessing the prescription records. In the matched dataset, conditional logistic regression analysis was performed with adjustments for hypertension, atrial fibrillation, prior myocardial infarction, and treatment with oral antithrombotics and statins.

Results: From the patients with acute ischemic stroke and DM, 1150 cases with primary outcomes were matched to 3450 controls. In the matched analysis, treatment with pioglitazone was significantly associated with a lower cardiovascular risk (adjusted OR [95% CI], 0.43 [0.23-0.83]).

Conclusions: In this nested case-control study using real-world data, treatment with pioglitazone exhibited significant cardiovascular preventive effect in diabetic patients with acute ischemic stroke.

Keywords: Diabetes mellitus; Ischemic stroke; Pioglitazone; Secondary prevention.

Fig. 1

Flow diagram for the selection of cases and controls in a nested case–control study design. NHIS-NSC the National Health Insurance Service-National Sample Cohort in Korea

Fig. 2

Risk factors for primary outcomes in the patients with acute ischemic stroke and diabetes mellitus. Primary outcome is defined as composites of recurrent stroke, myocardial infarction, or all-cause death after acute ischemic stroke. Cases and controls are matched for same sex, age, and treatment with sulfonylurea, biguanide, dipeptidyl peptidase 4 inhibitor, alpha-glucosidase inhibitor, and insulin. Adjusted OR (odds ratio), 95% CI (confidence interval) and p value are derived from conditional logistic regression analyses, which included the listed variables

Fig. 3

Event-free survival plot according to treatment with pioglitazone. The plot illustrates an estimated event-free survival curve according to treatment with pioglitazone (defined as exposure within the past 30 days) during the followed-up period after acute ischemic stroke. p value is obtained from the Mantel–Byar test which compares survival curves by treatment with pioglitazone