Glucose-lowering agents and cancer mortality rates in type 2 diabetes: assessing effects of time-varying exposure

We explored the relationship between glucose-lowering agents and cancer mortality rates in type 2 diabetes patients, hypothesising a decreased risk of cancer mortality with metformin use and a dose-risk gradient for insulin therapy. This was a population-based cohort study using administrative data from Saskatchewan Health, Canada. We identified new users of metformin or sulfonylureas from 1 January 1991 to 31 December 1996, with follow-up until death, departure from the province or 31 December 1999. Cox regression analyses were used to estimate the HR of death from cancer, accounting for time-varying exposure to metformin, sulfonylurea, and exogenous insulin therapy. We identified 10,309 new users of metformin or sulfonylurea. The average follow-up was 5.4 (1.9) years, during which 407 (4.0%) cancer deaths occurred. Adjusting for age, sex and chronic disease score, the adjusted HR for metformin use was 0.80 (95% CI 0.65-0.98) compared with sulfonylurea monotherapy users. Adjusted HRs for subsequent insulin use were 2.22 (0.99-5.00), 3.33 (2.26-4.89) and 6.40 (4.69-8.73) for < 3, 3 to 11 and a parts per thousand yen12 insulin dispensations/year, respectively, compared with patients not on insulin. We observed a similar risk gradient among the sub-cohort of new insulin users. Our results support previous reports of a decreased risk of cancer outcomes associated with metformin use relative to sulfonylurea monotherapy. We also provide new evidence of a gradient of cumulative insulin dispensations and cancer mortality rates.