Dose-response relation between sulfonylurea drugs and mortality in type 2 diabetes mellitus: a population-based cohort study

Abstract

Background: Over the past 30 years, the relation between use of sulfonylureas to treat type 2 diabetes and the risk of cardiovascular events has been vigorously debated. The purpose of this study was to determine if the risk of death changes with level of exposure to sulfonylurea drugs.

Methods: This was a retrospective, inception cohort study using administrative data from Saskatchewan Health (1991-1999). The 5795 subjects, identified by their first-ever dispensation for an oral antidiabetic agent, were grouped according to their use of such agents during follow-up. Potential subjects using insulin or combination therapy were excluded. Exposure level was defined by daily dose and degree of adherence. Separate multivariate Cox proportional-hazard models were constructed for each monotherapy group and used to calculate the risk of death associated with higher versus lower exposure category. Disease severity indicators were identified among the administrative data and entered as covariates in each model. The main outcomes were all-cause mortality and death from an acute ischemic event.

Results: The mean age of the cohort members was 66.3 (standard deviation [SD] 13.4) years; 43.4% were female; and their mean duration of follow-up was 4.6 (SD 2.1) years. First-generation sulfonylureas were used exclusively by 120 subjects; glyburide, by 4138; and metformin, by 1537. A greater risk of death was associated with higher daily doses of the first-generation sulfonylureas (adjusted hazard ratio [HR] 2.1, 95% confidence interval [CI] 1.0-4.7) and glyburide (HR 1.3, 95% CI 1.2-1.4), but not metformin (HR 0.8, 95% CI 0.7-1.1). Similar associations were observed for death caused by an acute ischemic event.

Interpretation: Higher exposure to sulfonylureas was associated with increased mortality among patients newly treated for type 2 diabetes. The same relation was not observed with metformin. This implies that the manner in which blood glucose concentration is lowered may be as important as achieving recommended glucose targets.

Fig. 1: Hazard ratios among patients with type 2 diabetes mellitus, comparing 2 subgroups within each drug-monotherapy group: 1A, hazard ratios for deaths from all causes, according to median split for drug exposure (i.e., whether their individual daily dose was more than the group median [higher subgroup] or less [lower subgroup — used as the reference]); 1B, for deaths attributable to an acute ischemic event, also according to median split for drug exposure; and 1C, for all-cause mortality, according to drug-treatment adherence (patients were assigned to the poor-adherence [reference] subgroup if their adherence rate was < 0.8 or if they stopped therapy > 6 months before end of follow-up). Error bars indicate 95% confidence intervals. *Either chlorpropamide or tolbutamide.