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A lion in the room: Has the CAROLINA trial definitely resolved the issue of the cardiovascular safety of sulfonylureas?

T. Koufakis,G. Dimitriadis,K. Kotsa

Published 2020 in Journal of Diabetes

ABSTRACT

Sulfonylureas (SUs) are the second most prescribed antidiabetic therapy, following metformin, around the world. Although inexpensive, they induce serious side effects, such as hypoglycemic reactions and an increase in body weight. Moreover, their glucose-lowering effect is not sustainable over time. The cardiovascular (CV) safety of this class of drugs has been one of the most highly debated issues in the diabetes literature. The association between SUs and CV safety should be primarily seen within the context of the potential of hypoglycemia to deteriorate CV outcomes, albeit glucoseindependent mechanisms have been also suggested. For example, binding of SUs to myocardial adenosine triphosphate-dependent potassium channels has been shown to negatively affect cardiac ischemic preconditioning; this undesired effect seems to be agent specific since it was related to tolbutamide and glyburide, but not to gliclazide, glipizide, or glimepiride. It is important to underline that all SUs are not the same, with differences in their pharmacodynamic and pharmacokinetic profiles probably explaining variations in hypoglycemic risk, extrapancreatic effects, and CV safety. For example, gliclazide blocks SU receptor 1 (SUR1) with greater affinity than SUR2, in contrast to glibenclamide and glimepiride that block both receptors equally. The GUIDE study showed a lower percentage of confirmed hypoglycemia (plasma glucose levels <55 mg/dL/3.0 mmol/L) in subjects with type 2 diabetes (T2D) treated with gliclazide modified release compared to glimepiride (3.7% vs 8.9%, P = .003). Accordingly, a systematic review and network meta-analysis demonstrated that gliclazide and glimepiride were associated with a lower risk of all-cause and CVrelated mortality compared with glibenclamide. Besides, evidence regarding an interclass variability in terms of CV safety is also available with thiazolidinediones; while pioglitazone has been shown to protect against macrovascular complications, rosiglitazone is known to have a potentially harmful effect. Then again, hypoglycemia seems to be an unavoidable side effect of all SUs; this is due to their mechanism of action since they trigger a non-glucose-dependent stimulation of insulin release from the β-cells. Hypoglycemia has been linked to severe electrocardiogram (ECG) abnormalities, including lengthening of the QT interval and cardiac repolarization, which have been documented in adults with type 1 diabetes (T1D) with the simultaneous use of ECG and continuous blood glucose monitoring during sleep at night. Increased QT dynamicity and QTc prolongation have been also demonstrated in wellcontrolled, SU-treated T2D patients during hypoglycemia; of note, the latter was typically nocturnal (67%) and asymptomatic (73%). In 1991, Tattersall and Gil described a series of deaths of individuals with T1D in the United Kingdom, identifying 22 cases that, despite being in apparently good health before going to bed, were found dead in the morning. Although the diagnosis of hypoglycemia post mortem is almost unfeasible, it was concluded that low blood glucose or a hypoglycemia-related event during the Received: 12 January 2020 Revised: 9 February 2020 Accepted: 5 March 2020

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