Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study

OBJECTIVE

Numerous studies have suggested a decreased risk of cancer in patients with diabetes on metformin. Because different comparison groups were used, the effect magnitude is difficult to estimate. Therefore, the objective of this study was to further analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with users of sulfonylurea derivatives.

RESEARCH DESIGN AND METHODS

Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. The association between the risk of cancer in those using metformin compared with those using sulfonylurea derivatives was analyzed using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant.

RESULTS

Use of metformin was associated with a lower risk of cancer in general (hazard ratio 0.90 95% CI 0.88–0.91]) compared with use of sulfonylurea derivatives. When specific cancers were used as end points, similar estimates were found. Dosage-response relations were identified for users of metformin but not for users of sulfonylurea derivatives.

CONCLUSIONS

In our study, cumulative exposure to metformin was associated with a lower risk of specific cancers and cancer in general, compared with cumulative exposure to sulfonylurea derivatives. However, whether this should indeed be seen as a decreased risk of cancer for the use of metformin or as an increased risk of cancer for the use sulfonylurea derivatives remains to be elucidated.As the drug of first choice in type 2 diabetes, metformin is the most widely prescribed oral glucose-lowering drug (OGLD) (1,2). However, the decision to prescribe metformin also depends on patient characteristics: metformin use is contraindicated in those with renal failure, cardiac, or hepatic failure (2).A statistically nonsignificant relationship between use of metformin and the risk of colon cancer was described in 2004 (3). However, 1 year later, metformin was found to be associated with a decreased risk of cancer in general in a case-control study in a diabetic population (4). Numerous studies followed; among which studies confirming the association between use of metformin and a decreased risk of cancer in general (5–8) or in specific cancers (5,6,9–14). However, for breast cancer (5,6) and prostate cancer (5,14), the decreased risk was not consistently demonstrated; for other cancers, no association with use of metformin was found (6,12). Hence, there is heterogeneity among published studies on cancer in patients with diabetes on metformin (15), partly because different comparison groups were used, such as nonmetformin users, users of other OGLDs, or users of insulin. Higher endogenous insulin levels have been linked to an increased risk of certain cancers (16). Moreover, specifically for insulin glargine, the debate whether this specific insulin increases the risk of cancer is ongoing (17–21).Owing to factors such as different drugs used to attain metabolic control, the duration of diabetes, and the presence of other diseases, the assessment of cancer risk in diabetic patients remains difficult. Therefore, the objective of this study was to analyze whether, and to what extent, use of metformin is associated with a decreased risk of cancer in a cohort of incident users of metformin compared with use of sulfonylurea derivatives.