Sulfonylurea (SU) drugs were one of the first drug treatments made available to T2D patients in the 1950s with the first of these being tolbutamide. Advancements have led to second and even third-generation SU medications that have improved the glucose-lowering efficacy of this drug class. Even though an array of newer medications now exists such as sensitizers, incretin mimetics and DPP4 inhibitors, SUs continue to be commonly prescribed. Despite their prolonged and widespread use, SUs have a long standing association with cardiovascular safety that has been based on unconvincing data and methods. While recent clinical trials (eg TOSCA.IT, CAROLINA trials) may provide more clarity about this issue, results of these studies are years away and still have study design weaknesses. Alberta Diabetes Institute member Dr Scot Simpson, along with PhD student Ahmed Abdelmoneim and the Institute’s co-members Drs. Peter Senior, Peter Light and Dean Eurich recognized that researchers needed clearer direction when it came to designing future safety studies of SUs. They undertook a comprehensive overview of existing data, focusing on evidence for biological probability and past conclusions made from meta-analyses. Their research strongly suggested a number of important things, one of which was a reasonable conclusion for a plausible, biological mechanism for heart effects based on previous animal and human studies. However, conclusions drawn from meta-analyses are unreliable because observational studies have suffered from bias while randomized clinical trials (RCTs) were not specifically designed to look at cardiovascular safety and lacked the statistical power necessary to make credible inferences regarding risk. The authors suggested that a future RCT should be placebo-controlled and aimed at comparing risk differences between SUs by randomizing patients with T2D to different SU medications.
One exposure group should include either gliclazide or glimerpiride to take advantage of available data from previous observational studies. Participants in the other groups should receive glyburide as the comparison SU in order to test the theoretical, elevated risk of this SU due to its non-selectivity of KATP channel blockage in the pancreas and heart. The complete review article was published in Diabetes, Obesity and Metabolism (17:523-532, 2015).