Monotherapy with Metformin versus Sulfonylureas and Risk of Cancer in Type 2 Diabetic Patients: A Systematic Review and Meta-Analysis

BACKGROUND: Accumulating evidence suggests that patients with type 2 diabetes mellitus and hyperinsulinemia are at an increased risk of developing malignancies. It remains to be fully elucidated whether the use of metformin, an insulin sensitizer, and/or sulfonylureas, insulin secretagogues, affects cancer incidence in subjects with type 2 diabetes mellitus. OBJECTIVE: A systematic review and meta-analysis was performed to compare the risk of cancer incidence associated with monotherapy with metformin compared with monotherapy with sulfonylureas in type 2 diabetes mellitus patients. METHODS: Search was performed throughout MEDLINE/PubMed, EMBASE, Google Scholar, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov up until December 2018. In this meta-analysis, each raw data (unadjusted) and study-specific (adjusted) relative risks (RRs) was combined and the pooled unadjusted and adjusted RRs with the 95% CI were calculated using the random-effects model with inverse-variance weighting. Heterogeneity among the studies was evaluated using I(2) statistics. Publication bias was evaluated using the funnel plot asymmetry test. The Newcastle-Ottawa scale (NOS) was used to assess the study quality. RESULTS: A total of 8 cohort studies were included in the meta-analysis. Obvious heterogeneity was noted, and monotherapy with metformin was associated with a lower risk of cancer incidence (unadjusted RR = 0.74, 95% CI: 0.55-0.99, I(2) = 97.89%, p < 0.00001; adjusted RR = 0.76, 95% CI: 0.54–1.07, I(2) = 98.12%, p < 0.00001) compared with monotherapy with sulfonylurea, using the random-effects model with inverse-variance weighting. CONCLUSIONS: According to this review, the monotherapy with metformin appears to be associated with a lower risk of cancer incidence than monotherapy with sulfonylurea in patients with type 2 diabetes. This analysis is mainly based on cohort studies, and our findings underscore the need for large-scale randomized controlled trials to establish the effect of metformin monotherapy, relative to sulfonylureas monotherapy on cancer.