Diabetes, metformin use, and colorectal cancer survival in postmenopausal women

Abstract

Background Observational studies have associated metformin use with lower colorectal cancer (CRC) incidence but few studies have examined metformin’s influence on CRC survival. We examined the relationships among metformin use, diabetes, and survival in postmenopausal women with CRC in the Women’s Health Initiative (WHI) Clinical Trials and Observational Study. Methods 2,066 postmenopausal women with CRC were followed for a median of 4.1 years, with 589 deaths after CRC diagnosis from all causes and 414 deaths directly attributed to CRC. CRC-specific survival was compared among women with diabetes with metformin use (n=84); women with diabetes with no metformin use (n=128); and women without diabetes (n=1854). Cox proportional hazard models were used to estimate associations among metformin use, diabetes and survival after CRC. Strategies to adjust for potential confounders included: multivariate adjustment with known predictors of colorectal cancer survival and construction of a propensity score for the likelihood of receiving metformin, with model stratification by propensity score quintile. Results After adjusting for age and stage, CRC specific survival in women with diabetes with metformin use was not significantly different compared to that in women with diabetes with no metformin use (HR 0.75; 95% CI 0.40 –1.38, p=0.67) and to women without diabetes (HR 1.00; 95% CI 0.61 – 1.66, p=0.99). Following propensity score adjustment, the HR for CRC-specific survival in women with diabetes with metformin use compared to non-users was 0.78 (95% CI 0.38 – 1.55, p=0.47) and for overall survival was 0.86 (95% CI 0.49 – 1.52; p=0.60). Conclusions In postmenopausal women with CRC and DM, no statistically significant difference was seen in CRC specific survival in those who used metformin compared to non-users. Analyses in larger populations of colorectal cancer patients are warranted.

A Retrospective Study on the Role of Diabetes and Metformin in Colorectal Cancer Disease Survival

“…Previous studies have attempted to identify the effect of diabetes and metformin on both cancer-specific and overall mortality in crc patients, but with varying results 17,[29][30][31][32] . One focused on postmenopausal women only, another did not examine specific diabetes treatments, and the remaining studies did not provide a comparison to a nondiabetic control group [17][18][19]33,34 . Other studies, including a recent meta-analysis looking at the role of metformin with respect to cancer risk and mortality, suggested that metformin could reduce the risks, but did not assess the effect of tumour stage 35,36 .…”

“…Although strong evidence supports the association of diabetes with crc, and recent work has examined metformin as a prognostic factor in crc, results are contradictory and tend to be related to specific patient populations [15][16][17][18][19] . In the present retrospective study, we set out to investigate whether metformin use in diabetic patients diagnosed with crc was associated with survival.…”

Metformin use and survival after colorectal cancer: A population‐based cohort study

“…In a separate analysis of 212 postmenopausal women with colorectal cancer and type 2 diabetes, no statistically significant difference in colorectal cancer-specific survival was observed among users of metformin compared to non-users (HR 0.75, 95% CI 0.40-1.38) although unfortunately, the authors of this study were unable to obtain data on the timing of metformin use in relation to colorectal cancer diagnosis. 28 Other epidemiological studies investigating metformin use after colorectal cancer diagnosis and all-cause mortality and have indicated a beneficial effect with metformin use, 11,12 however these investigations are limited by small sample size and the use of only one exposure timepoint. Moreover, findings from studies which only examine the impact of metformin on all-cause mortality may be reflective of non-cancer mortality.…”

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

“…30-35 ) associated with metformin exposure must be balanced against others that do not show such associations (e.g., refs. [36][37][38][39]. Some studies suggest unexpected variables that might modify the effects of metformin, including pharmacoepidemiologic evidence that exposure to both a statin drug and metformin is necessary for an important antineoplastic effect to be observed ( 40 ) and laboratory evidence that administration of proton pump inhibitors limits cellular uptake of metformin ( 41 ).…”