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

ABSTRACT

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.

KEYWORDS:

• Glibenclamide
• cancer risk
• cancer mortality
• diabetes mellitus
• sulfonylureas

Article highlights

• Glibenclamide, a second-generation agent of sulfonylureas, was proven to be an anti-tumor agent in preclinical studies basically through two categories of mechanisms: a general inhibitor of the ABC protein super-family and an inhibitor of KATP channels.

• Inconsistent results were found among clinical studies, with two researches claiming glibenclamide was related to reduced cancer risks in a dose-response manner and others demonstrating non-significant or increased cancer risks compared with other hypoglycaemic drugs.

• Other sulfonylureas were also proven to have promising anti-cancer effects in preclinical and clinical studies, such as gliclazide diminishing oxidative stress-related DNA damage and glipizide inhibiting tumor angiogenesis.

• The inconsistency between preclinical studies and clinical researches was probably ascribed to time-related bias, confounding factors, inconsistent comparators and publication bias. Further well-design long-term randomized controlled clinical trials are needed to provide new insight of glibenclamide as a promising anti-neoplastic drug.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (81370657), Project of National Key Clinical Specialty, National Science & Technology Pillar Program (2014BAI09B12), and Project funded by Jiangsu Provincial Special Program of Medical Science (BL2014086).