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

Institute of Health Economics, Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta.
Canadian Medical Association Journal (Impact Factor: 5.96). 02/2006; 174(2):169-74. DOI: 10.1503/cmaj.050748
Source: PubMed


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.
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.
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.
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.

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    • "Sulfonylureas may increase the risk of cardiovascular events in patients with type 2 diabetes [14]. However, glimepiride seems to have fewer unfavorable cardiovascular effects compared to other sulfonylureas. "
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    • "However, after a median follow-up of 16.8 years, significant reductions in myocardial infarction (by 15%), diabetes-related death (by 17%) and all-cause mortality (by 13%) were observed in patients randomized to receive SU/insulin compared with dietary advice alone during the intervention part of the study [23]. In the ADVANCE study, intensive glucose control provided by gliclazide did not reduce the risk of major macrovascular events in high-risk patients over a median follow-up of 5 years compared with standard glucose control [22], while in a retrospective cohort study in 5795 patients with T2DM, all-cause mortality was higher in patients receiving monotherapy with higher daily doses of first-generation SUs (adjusted hazard ratio [HR] 2.1) or glibenclamide (adjusted HR 1.3) than in patients receiving lower doses, as was mortality due to acute ischemic events (adjusted HR 1.2 and 1.4, respectively) [25]. A recent review of randomized controlled trials that evaluated the impact of SUs on CV outcomes found no increase in the incidence of CV events with SUs, but noted that the available data are limited and there have been no adequately powered trials addressing the CV safety of SUs [26]. "
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    • "Ever since tolbutamide was implicated with increased mortality secondary to cardiovascular events in the University Group Diabetes Program (UGDP) study, debate on SU cardiovascular safety continues [14]. Recent population studies [15, 16] reported increased coronary heart event and mortality with increased dose of SU exposure, and plausible mechanisms have been related to blockage of SUR-2 receptor in myocardium and impaired the preischemic precondition of myocardium [17]. While the cardiovascular adverse effects associated with SUs remain controversial, it would be rational to dose SUs at the lowest therapeutically effective dose, thus avoiding the loss of selectivity of these agents for pancreatic KATP channels. "
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