Metformin, Diabetes, and Survival among U.S. Veterans with Colorectal Cancer

Abstract

Background Metformin has been associated with improved CRC survival, but investigations are limited by small numbers of patients and confounding by diabetic severity. We examined the association between metformin use and overall survival (OS) in patients with diabetes and CRC in a large population of U.S. veterans, while adjusting for measures of diabetic severity. Methods Patients diagnosed with CRC from 1/2001-12/2008 were identified from the Veterans Affairs Central Cancer Registry. Multivariable models were used to examine the adjusted association of OS with diabetes and use of anti-diabetic medications. Results 21352 patients diagnosed with CRC were identified (n=16355 non-diabetic patients, n=2038 diabetic patients on metformin, n=2136 diabetic patients on medications other than metformin, n=823 diabetic patients not on anti-diabetic medication). Diabetic patients had a significantly worse OS than non-diabetic patients, but metformin users had only a 10% increase in death (HRadj 1.10; 95% CI 1.03-1.17, p=0.004), as compared to 22% for users of other anti-diabetic medications (HRadj 1.22; 95% CI 1.15-1.29, p<0.0001). Among CRC patients with diabetes, metformin users had a 13% improved OS versus patients taking other anti-diabetic medications (HRadj 0.87; 95% CI 0.79-0.95, p=0.003), while diabetic patients not on any anti-diabetic medications did not differ with respect to OS (HRadj 1.02; 95% CI 0.90-1.15, p=0.76). Conclusion Among diabetics with CRC, metformin use is associated with improved survival, despite adjustments for diabetes severity and other risk factors. Impact These data lend further support to the conduct of randomized studies of possible anti-cancer effects of metformin among patients with CRC.

The relationship between diabetes and colorectal cancer prognosis: A meta-analysis based on the cohort studies

“…In our meta-analysis, year of publication ranged from 2003 to 2016, and the regions included 2 American countries[7, 13–15, 18, 19, 27, 30, 33, 37, 41, 42, 45, 46], 6 European countries[6, 11, 17, 28, 32, 39, 40, 44], 2 Asian countries[8, 9, 12, 16, 20, 29, 34–36, 38, 43, 47] and 1 Oceania country[31]; the included studies contained 15 retrospective[9, 10, 14, 16–20, 27, 33, 36, 37, 39, 41, 47] and 21 prospective[6–8, 11–13, 15, 28–32, 34, 35, 38, 40, 42–46] cohort studies; the sample size ranged from 391 to 1056243, and the mean age of study ranged from 46.4 to 72.07. In DM ascertainment, 25 studies[6, 8, 9, 11–15, 18, 19, …”

“…In DM ascertainment, 25 studies[6, 8, 9, 11–15, 18, 19, 28, 29, 31, 33–37, 39–42, 44–46] used the method of medical records, 5 studies[16, 20, 38, 43, 47] used the method of blood sugar test, and 6 studies[7, 10, 17, 27, 30, 32] used the method of self-reported. To avoid the effects of confounders, we preferred to extract the adjusted outcome effect estimates, but we still found that the outcome effect estimates of 4 studies were not adjusted.…”

The association between metformin use and colorectal cancer survival among patients with diabetes mellitus: An updated meta‐analysis

“…The literature search yielded 81 studies, and 8 observational studies 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 were included in this meta-analysis ( Fig. 1 ).…”

“…The selected studies were all published in the past 4 years (2012–2016). Seven studies 19 , 20 , 21 , 22 , 24 , 25 , 26 reported the HR s for OS among CRC patients with T2DM, and four studies 19 , 21 , 23 , 25 reported the HR s for CS among CRC patients with T2DM. Of the included studies, four 19 , 20 , 22 , 23 were performed in Europe (Ireland, Netherlands, Denmark, UK), and three 21 , 24 , 26 in the United States.…”

Metformin, Diabetes, and Survival among U.S. Veterans with Colorectal Cancer—Response

“…We appreciate the letter of Alam and colleagues, who underscore the point we made in our discussion section when we noted that time-related biases, such as immortal time bias, can threaten pharmacoepidemiologic studies of metformin as a potential chemotherapeutic agent (1). Vivid illustrations of this bias are available among prior metformin studies that defined exposure based on receipt of multiple prescriptions, with the interval of time between prescriptions being immortal, and discordant time zero definitions between comparison groups (2).…”