Cardiovascular safety of sulphonylureas: over 40 years of continuous controversy without an answer

Abstract

More than 40 years after publication of the University Group Diabetes Program trial, the cardiovascular safety of sulphonylureas is still contentious. Although several hypotheses linking sulphonylureas to adverse cardiovascular effects exist, none provide conclusive evidence. Adding to the controversy, current clinical trials and observational studies provide inconsistent, and sometimes conflicting, evidence for the cardiovascular effects of sulphonylureas. Overall, observational evidence suggests that an increased risk of adverse cardiovascular outcomes is associated with sulphonylureas; however, these data may be subject to residual confounding and bias. Although evidence from randomized controlled trials has suggested a neutral effect, the majority of these studies were not specifically designed to assess the effect of sulphonylureas on adverse cardiovascular event risk. Current ongoing large clinical trials may provide some clarity on the cardiovascular safety of sulphonylureas, but the results are not expected for several years. With the continued uncertainties concerning the cardiovascular safety of all antidiabetic drugs, a clear answer with regard to sulphonylureas is warranted. The objectives of the present article were to provide an overview of the controversy surrounding sulphonylurea-related cardiovascular effects, to discuss the limitations of the current literature, and to provide recommendations for future studies aiming to elucidate the true relationship between sulphonylureas and adverse cardiovascular effects in people with type 2 diabetes.

Pharmacological management of type 2 diabetes: what’s new in 2017?

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“…Indeed, observational studies have associated adverse cardiovascular outcomes and increased mortality with both sulphonyureas and insulin, albeit the data from clinical trials are less conclusive. 48,49 This is not to say that metformin does not have its own problems: in addition to the association with lactic acidosis, gastrointestinal side-effects limit its tolerability in some patients and it has been associated with vitamin B12 deficiency. 9,50 But when tolerated and appropriately monitored, metformin is cheap, simple to administer and safe.…”

Diabetes-Old Therapies Revisited

“…There are several studies that assess the association between SU and cardiovascular events, but with limitations. Eight meta-analyses were carried out and published recently [50]. Observational studies suggest a high risk, but randomized trials suggest that there is no difference in risk.…”