Cardiovascular risk of oral antidiabetic drugs: current evidence and regulatory requirements for new drugs.

Background: Better control of diabetes mellitus reduces microvascular complications, but has limited effect on macrovascular complications including cardiovascular mortality. A spate of controversial reports has shown that some new oral antidiabetic drugs may paradoxically increase cardiovascular events and mortality. We review here published data on cardiac safety of currently available oral antidiabetic drugs.

Methods: Literature search was performed for "cardiovascular risk" and "antidiabetic drugs" or individual oral antidiabetic drugs.

Results: Some sulfonylureas increase cardiovascular risk presumably by preventing protective ischemic cardiac preconditioning. Rosiglitazone increases risk of myocardial infarction and death possibly by increasing serum triglycerides and LDL-cholesterol levels. Muraglitazar increased risk of cardiovascular death, myocardial infarction, or stroke due to as yet unidentified reasons. Only insulin sensitizing drugs like metformin and pioglitazone have been consistently shown to reduce cardiovascular risk. Beneficial effects of tight glucose control with insulin or insulin secretagogues on macrovascular complications are inconsistent; their benefits may be negated by increased risk of hypoglycemia which in turn increases adverse cardiovascular events. Increased cardiovascular risk of some antidiabetic drugs was missed during drug development and detected only on meta-analysis of clinical trial data. Regulatory agencies in North America and Europe have therefore proposed stringent guidelines for study design, data analysis and quantification of cardiovascular risk of new antidiabetic drugs.

Conclusions: Physicians should weigh the cardiovascular risk against potential benefits when prescribing antidiabetic medications. The proposed regulatory measures will ensure approval of safer drugs, but may also lengthen the drug development cycle or even deter development of potentially useful drugs.