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

Abstract

Aims/hypothesis 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. Methods 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. Results 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 ≥12 insulin dispensations/year, respectively, compared with patients not on insulin. We observed a similar risk gradient among the sub-cohort of new insulin users. Conclusions/interpretation 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.

Insulin, glucose and the increased risk of cancer in patients with type 2 diabetes

“…Recent observational studies have linked increasing insulin exposure with an increased risk of cancer incidence or increased cancer mortality rates [2,4,6,7]. As observational studies, they have a number of limitations and by themselves do not allow inference of causation.…”

“…This has been highlighted by observational studies suggesting a protective effect on cancer outcomes for metformin [1][2][3][4] and glitazones [5], but on the other hand a potential increased cancer risk associated with exogenous insulin [2,4,6,7], insulin analogues [8,9] and sulfonylurea therapies [2,4,7].…”

Diabetes and cancer (2): evaluating the impact of diabetes on mortality in patients with cancer

“…In addition, studies report that glucoselowering treatments may modulate cancer risk but many of these pharmaco-epidemiological studies have methodological limitations. For this paper, we note that some studies on the relationship between treatments for diabetes and cancer risk report cancer incidence as the primary endpoint [2][3][4][5][6][7][8], while others report cancer mortality [9][10][11][12][13][14]-but are these two endpoints interchangeable? Here, we develop a conceptual framework within which to evaluate this question.…”

Metformin: A candidate for the treatment of gynecological tumors based on drug repositioning

“…In a population-based study including 11,876 patients with type 2 diabetes, Evans et al (26) reported a reduced incidence of cancer in patients treated with metformin, compared with patients not treated with metformin [odds ratio (OR), 0.79; 95% confidence interval (CI), 0.67-0.93]. Bowker et al (27) compared patients with type 2 diabetes in the metformin (monotherapy or combined) group and sulfonylurea monotherapy group, and reported that the cancer mortality rate was significantly decreased in the metformin group [hazard ratio (HR), 0.80; 95% CI, 0.65-0.98; P= 0.03), compared with the sulfonylurea group. In a study of 4,085 patients exhibiting type 2 diabetes, Libby et al (28) identified that the incidence of cancer in patients treated with metformin (7.3%) was significantly lower than that observed in patients treated with alternative drugs (11.6%).…”