Abstract
2586 Background: Metformin has anticancer effect by inhibiting mTOR pathway in CRC via TSC2 activation and by reducing circulating insulin and adiponectin. Thiazolidinediones (TZD) suppress intestinal polyp formation in APC-min mice through PPAR γ pathway. Sulfonylureas activate MAP kinase, promote cellular growth through mTOR inactivation of GSK3, and increase circulating insulin and adiponectin. The effect of antidiabetic agents on the survival of subjects with colorectal cancer was evaluated. Methods: A retrospective cohort study of male diabetics aged ≥40 was conducted from the patient data base VISN 16 comprising 10 VA hospitals. Subjects with CRC between 10/01/96 and 12/31/05 were identified using ICD 9 codes, and followed from diagnosis to death or last recorded visit. Data were analyzed for effects of diabetes treatment on OS using multivariate Cox regression with drug exposures as time-dependent covariates, and with stratification on race and age quartiles. Results: 845 deaths were observed among CRC subjects during a total follow-up of 8870.4 years. Median age (quartiles) at CRC diagnosis was 70 yrs (62–75). 19% were African-American, 65% were Caucasian, and 16% were other /unknown. The Table shows the influence of antidiabetic agents on the survival of subjects with colorectal cancer. Conclusions: Metformin and TZDs appear to have beneficial effects on OS in subjects with CRC. Insulin and sulfonylureas appear to have detrimental effect on OS. The effects of these agents on the stage and the influence of coexisting treatments of colorectal cancer need further analysis. Exposure summary and multivariate Cox-regression results Diabetes treatment >Exposure summary Adjusted HR3 (95% confidence limits) P value N (%1) Years (%2) Deaths Diet only 526 (21%) 2826.9 (32%) 198 1.00 (reference) — Insulin 730 (29%) 1983.4 (22%) 282 1.91 (1.65–2.21) <.0001 Metformin 573 (23%) 1610.0 (18%) 116 0.80 (0.66–0.98) 0.0323 Sulfonylureas 1304 (52%) 4130.7 (47%) 448 1.34 (1.17–1.54) <.0001 TZDs 401 (16%) 899.3 (10%) 63 0.63 (0.48–0.82) 0.0005 1 % of total number of 2,496 subjects on study. 2 % of total follow-up of 8870.4 years. 3 Hazard ratio of each treatment adjusting for the presence of the other treatments. No significant financial relationships to disclose.
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