Enemies or weapons in hands: investigational anti-diabetic drug glibenclamide and cancer risk

Introduction: Epidemiological evidence suggests that diabetes is associated with elevated cancer risk through the actions of hyperglycemia, hyperinsulinemia and chronic inflammation. Metformin, a first-line medication for type 2 diabetes mellitus, arouses growing concerns on its anti-cancer effect. However, data regarding the effect of glibenclamide on tumor growth and cancer risk are less consistent, which may be a potential anti-cancer drug.Areas covered: In this review, we clarified probable underlying mechanisms in preclinical studies and reviewed epidemiological evidence on glibenclamide's cancer risk in clinical studies. Glibenclamide inhibited carcinogenesis through ATP-binding cassette protein super-family and ATP-sensitive potassium channels, while majority of clinical researches reported an increased or non-significant elevated cancer risk of glibenclamide users compared with metformin users. Other sulfonylureas and diarylsulfonylureas were also briefly introduced.Expert opinion: The inconsistency between the results of studies was probably ascribed to undiscovered mechanisms, confounding factors, inconsistent comparators and publication bias. Existing clinical trials were prone to be afflicted by time-related bias including immortal time bias, time-window bias, and time-lag bias. Glibenclimiade could be a promising and well-tolerated anti-neoplastic drug targeting ATP-binding cassette protein super-family and KATP channels, but its efficacy still needs to be proven in well-designed long-term randomized controlled clinical trials.