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Breast cancer risk elevated with glibenclamide / glyburide over other sulfonylureas

Glyburide is associated with an increased risk for cancer compared with other diabetes drugs of the sulfonylurea class, new research suggests. Previous observational studies have linked the use of sulfonylureas in general to an increased risk of cancer, but only a few studies have examined the association by type of sulfonylurea, the authors explain.

Findings from the population-based cohort study were published online September 4, 2015 in Diabetes Care by Marco Tuccori, PhD, of the Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, and colleagues.

Glyburide (also known as glibenclamide) seems to trigger the production of reactive oxygen species, a well-known pro-oncogenic factor, and this activity appears specific to glyburide and not to other sulfonylureas, the authors note.

Among the 52,600 patients in their large UK primary-care database who had been newly prescribed a sulfonylurea for type 2 diabetes over a 25-year period, the overall use of glyburide among 3413 patients was associated with a nonsignificant 9% increased risk of any cancer.

However, secondary analyses revealed significant duration- and dose-response increased risks.

According to principal investigator Laurent Azoulay, PhD, assistant professor, department of oncology, McGill University, Montreal, Quebec, the take-home message is that glyburide may be associated with an increased risk of cancer when compared with other second-generation sulfonylureas. These findings should help physicians better assess the risks and benefits of this drug.

“We believe that physicians should be vigilant with the use of glyburide,” he added. “[In addition to] cancer, this drug has also been associated with important cardiovascular events. While our findings need to be replicated, there are fortunately several other sulfonylureas that, thus far, seem to have a better safety profile than glyburide.”

Risk increased with duration, dose of glyburide use

The investigators analyzed data from the UK Clinical Practice Research Datalink, a comprehensive primary-care repository of medical records for more than 13 million people in over 680 general practices. All study subjects were at least 40 years of age and had been newly prescribed a second-generation sulfonylurea (glyburide, glicazide, gliquidone, glimepiride, or gliplizide) between January 1, 1988 and July 31, 2013.

During a mean follow-up of 5.3 years, a total of 4105 patients were newly diagnosed with cancer, for a crude incidence rate of 14.6 per 1000 person-years.

After adjustment for several potential confounders, including year of study entry, age, sex, body mass index, HbA1c, and use of other glucose-lowering medications, the use of glyburide was associated with an overall nonsignificantly increased risk for any cancer compared with the use of other second-generation sulfonylureas (15.1 vs 14.6 per 1,000 person-years, respectively; hazard ratio, 1.09).

However, a significant duration-response was seen in secondary analyses, with the risk gradually increasing with longer cumulative durations of use.

After at least 36 months of use, the risk for cancer among those who had used glyburide was 21% greater than for other sulfonylureas.

There was also a dose-response relationship, with a cumulative defined daily dose (a validated measure from the World Health Organization) of at least 1096 associated with a 27% increased risk of cancer.

When the primary analysis was repeated separately for each of four major cancers — prostate, lung, breast, and colorectal — no single cancer type was statistically associated with an increased risk, although the hazard ratio for breast cancer was 1.19. And a significantly lower risk was actually seen for lung cancer, with a hazard ratio of 0.93.

“Our findings seem to suggest that certain cancer types may be more affected than others — for example, breast cancer. However, the analysis of individual cancers was part of a secondary analysis and should therefore be interpreted with caution. According to Dr Azoulay, along those lines, the decreased risk observed with lung cancer may be due to the play of chance.

The use of glyburide declined in the United Kingdom during the course of this study, but it remains widely used in some other countries. “Thus, given the growing prevalence of type 2 diabetes worldwide and the relatively high prevalence of patients exposed to glyburide, the current findings raise concerns that need to be corroborated in other well-designed studies,” the authors conclude.

Source: Diabetes Care. Published online September 4, 2015. Abstract

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