Case-control study of oral glucose-lowering drugs in combination with long-acting insulin and the risks of incident myocardial infarction and incident stroke

Abstract

Background: The use of oral glucose-lowering therapies with insulin is common, but the cardiovascular effects are largely unknown. Among users of long-acting insulin, we conducted a population-based case-control study to evaluate the incident myocardial infarction (MI) and incident stroke risks associated with the use of sulfonylureas and the use of metformin.

Methods: Cases were Group Health Cooperative enrollees with type 2 diabetes who used long-acting insulin at the time of diagnosis with a first MI (n = 413) or first stroke (n = 247) from 1995 to 2010. Controls (n = 443) with type 2 diabetes who used long-acting insulin were matched to cases on age, sex, and calendar year. Sulfonylurea and metformin use was classified as current, past, or never using electronic pharmacy records. MI and stroke diagnoses were validated by medical record review. Analyses were adjusted for potential confounders.

Results: Current use of sulfonylureas compared with never use was associated with a higher risk of MI (odds ratio [OR] 1.67; 95% confidence interval [CI], 1.10-2.55) but not stroke (OR 1.22; 95%CI, 0.74-2.00). Current use of metformin compared with never use was associated with a lower risk of stroke (OR 0.54; 95%CI, 0.31-0.95) but not MI (OR 0.77; 95%CI, 0.44-1.33). Past use of sulfonylureas and past use of metformin were not associated with either outcome.

Conclusions: Sulfonylureas in combination with long-acting insulin may increase the risk of MI compared with the use of insulin alone. Metformin may be an important cardiovascular disease prevention therapy for patients on insulin therapy. Copyright © 2015 John Wiley & Sons, Ltd.

Keywords: case-control study; insulin; metformin; myocardial infarction; pharmacoepidemiology; stroke; sulfonylureas.

Figure 1

Secular trends in the use of glucose-lowering drugs with long-acting insulin among control subjects on the index date.

Figure 2. Interaction and subgroup analyses of sulfonylurea and metformin associations with myocardial infarction and stroke risks among users of long-acting insulin

CI = confidence interval, DM = diabetes mellitus, OR = odds ratio, P (int) = P value for interaction. Subgroups based on continuous variables were dichotomized at the median. All analyses were adjusted for index year, age, sex, hypertension status, smoking, prior cardiovascular disease, atrial fibrillation, nephrotic syndrome, diastolic blood pressure, body mass index, total cholesterol, serum creatinine, duration of diabetes, and the use of statins, ACE inhibitors, and regular and rapid-acting insulin. Dotted lines indicate the odds ratio for the comparison of current users with never users from primary analyses.