New Users of Metformin Are at Low Risk of Incident Cancer: A cohort study among people with type 2 diabetes

OBJECTIVE

The antidiabetic properties of metformin are mediated through its ability to activate the AMP-activated protein kinase (AMPK). Activation of AMPK can suppress tumor formation and inhibit cell growth in addition to lowering blood glucose levels. We tested the hypothesis that metformin reduces the risk of cancer in people with type 2 diabetes.

RESEARCH DESIGN AND METHODS

In an observational cohort study using record-linkage databases and based in Tayside, Scotland, U.K., we identified people with type 2 diabetes who were new users of metformin in 1994–2003. We also identified a set of diabetic comparators, individually matched to the metformin users by year of diabetes diagnosis, who had never used metformin. In a survival analysis we calculated hazard ratios for diagnosis of cancer, adjusted for baseline characteristics of the two groups using Cox regression.

RESULTS

Cancer was diagnosed among 7.3% of 4,085 metformin users compared with 11.6% of 4,085 comparators, with median times to cancer of 3.5 and 2.6 years, respectively (P < 0.001). The unadjusted hazard ratio (95% CI) for cancer was 0.46 (0.40–0.53). After adjusting for sex, age, BMI, A1C, deprivation, smoking, and other drug use, there was still a significantly reduced risk of cancer associated with metformin: 0.63 (0.53–0.75).

CONCLUSIONS

These results suggest that metformin use may be associated with a reduced risk of cancer. A randomized trial is needed to assess whether metformin is protective in a population at high risk for cancer.Recent research suggests that the antidiabetic drug metformin, which exerts its effects by activating the AMP-activated protein kinase (AMPK), may have potential for the treatment of cancer in humans (1). The hypothesis that metformin may have anticancer effects is supported by laboratory studies showing that metformin is associated with reduced incidence of pancreatic cancer in hamsters (2) and delays onset of mammary (3) and other tumors (4) in tumor-prone mice. Metformin also inhibits growth of human breast cancer cells (5). Although the potential for prevention of cancer in humans using metformin has not been explored, we previously reported the results of a pilot case-control study that identified a reduced risk of cancer among patients with type 2 diabetes who had used metformin (6). However, the outcome was limited to hospital admissions for cancer, and the date of diagnosis was assumed to be date of first hospital admission.Other diabetic drugs may also have cancer-related effects. An independent epidemiological study found that users of sulfonylureas were at higher risk of cancer-related mortality than metformin users (7). Sulfonylureas (and insulin) increase circulating insulin levels, and hyperinsulinemia may promote carcinogenesis (8). Treatments such as metformin and glitazones reduce insulin resistance, with insulin resistance possibly associated with increased risk of cancer (9). The objective of this study was to test the hypothesis that metformin use is associated with a reduced risk of cancer in people with type 2 diabetes using a national cancer registry to ensure valid diagnoses of cancer with precise dates of diagnosis. We also adjusted results for the effects of exposure to other diabetic drugs.