This study used information from administrative health databases to further explore the relation between individual antidiabetic drug classes and the risk of death among people with type 2 diabetes. We found that the risk of death was dose-related for chlorpropamide, tolbutamide and glyburide, even after controlling for demographic variables and comorbidities. In contrast, higher doses of metformin were not associated with an increased risk of death.
Our observation of a dose–response relation for sulfonylureas fulfills another element of the Bradford–Hill conditions to establish causality from observational studies.30
Subjects exposed to higher levels of sulfonylurea monotherapy had a higher mortality. In contrast, the level of exposure to metformin monotherapy had no apparent effect on mortality. The results generated from the UGDP more than 30 years ago suggested that sulfonylurea use may be associated with an increased risk of cardiovascular events and death.4
Since then, investigations in animal and human models and post-hoc analyses of clinical trial data and observational studies have shown a consistent but perhaps underappreciated association between the use of sulfonylurea drugs and poor cardiac outcomes.10,12,18,31
One biological mechanism for this relation, as hypothesized by several authors,10,32,33
may be impairment of ischemic preconditioning. Sulfonylureas promote release of insulin from pancreatic β cells by binding to the sulfonylurea receptor and maintaining closure of the adenosine triphosphate (ATP)-sensitive potassium channel.32
In cardiac myocytes and smooth muscle cells, the closure of ATP-sensitive potassium channels impairs ischemic preconditioning, a phenomenon that enables myocardial cells to survive brief periods of ischemia.10,33
The effect on ischemic preconditioning varies substantially among the sulfonylureas, likely because of the wide range of binding affinities for sulfonylurea receptors on cardiac myocytes.12
For example, glyburide has a high affinity for both pancreatic and cardiac sulfonylurea receptors, whereas gliclazide and nateglinide have high selectivity for pancreatic sulfonylurea receptors.12
Equally plausible explanations for sulfonylurea toxicity include direct arrhythmogenic effects, associated weight gain, hypoglycemia and the toxicity of elevated insulin levels.10,33
This study builds on observations from our previous analyses illustrating a difference in the risks of morbidity and death among classes of oral antidiabetic drugs used by patients.15,16
The reason for this risk difference has been the topic of much recent discussion.12,17,18
The focus appears to be on differences in pharmacologic effects, whereby sulfonylureas may be cardiotoxic and metformin may provide some degree of cardioprotection.17
Although the potential cardiotoxic effects of sulfonylureas have been debated over the last 30 years,4,13
the potential cardioprotective effects of metformin, first shown by the UKPDS,20
have not been well described. In our current study, stratification by monotherapy group eliminated confounding from pharmacologic differences between drug classes. This allowed us to evaluate the effect of different levels of exposure by comparing the risk of death among users of the same antidiabetic agent. Although our study provides additional evidence to support the theory of a cardiotoxic effect of sulfonylureas, it does not resolve the question of whether the risk difference between antidiabetic drug classes is the result of different pharmacologic effects.
There are several limitations to this observational study. First, our observations are based on administrative data. Such databases do not record clinical information such as the subject's height, weight, blood pressure, cholesterol profiles or glucose control. We believe that information on glucose control would not change our observations substantially, given that the largest randomized controlled study involving people with type 2 diabetes did not demonstrate that good glucose control reduced the risk of all-cause mortality.14
Nevertheless, residual confounding, such as differences in underlying cardiovascular risk between exposure groups, may partially explain our observed differences in risk of death. We used available prescription drug data (i.e., nitrate use to identify subjects with cardiovascular disease, and the chronic disease score as a measure of chronic disease burden), demographic information (age and sex) and health resource utilization information (i.e., physician visits and hospital admissions) to control for these underlying risks and to adjust for case mix.
Second, our measures for exposure share the same limitations as other pharmacy claims databases.22
We assumed that drug acquisition is a surrogate marker for consumption and thereby may have overestimated actual exposure.
Third, subjects using higher doses of oral antidiabetic agents may have required this level of drug use to manage higher blood-glucose levels or more advanced diabetes — a form of confounding by indication. If confounding by indication were present, the positive association observed in the unadjusted model could be expected to move toward unity with adjustment for disease severity.28
The addition of physician visits and hospital admissions to the multivariate models, however, did not have a substantial effect on the observations. Furthermore, enrolment criteria for our inception cohort controlled for duration of disease by identifying subjects filling their first prescription for an oral antidiabetic agent. Intriguingly, subjects in the group taking lower daily doses had a longer follow-up than subjects prescribed higher daily doses.
Fourth, the index period for our data set predated the availability of the thiazolidinediones acarbose and repaglanide. If ischemic preconditioning, rather than the other postulated mechanisms, is responsible for the potential toxicity of the older but commonly used sulfonylureas that we studied, then this may become less of an issue as accepted practice shifts to the newer sulfonylureas.12,13
In conclusion, we observed a dose–response relation between sulfonylurea exposure and risk of death. This evidence, taken within the context of observations collected over the last 30 years, suggests that clinicians should carefully assess the need for sulfonylurea therapy in subjects at high risk of cardiovascular events — particularly now, when several other classes of antidiabetic oral medications are available.
@ See related article page 185