Validating drug repurposing signals using electronic health records: a case study of metformin associated with reduced cancer mortality

Abstract

Objectives Drug repurposing, which finds new indications for existing drugs, has received great attention recently. The goal of our work is to assess the feasibility of using electronic health records (EHRs) and automated informatics methods to efficiently validate a recent drug repurposing association of metformin with reduced cancer mortality.Methods By linking two large EHRs from Vanderbilt University Medical Center and Mayo Clinic to their tumor registries, we constructed a cohort including 32 415 adults with a cancer diagnosis at Vanderbilt and 79 258 cancer patients at Mayo from 1995 to 2010. Using automated informatics methods, we further identified type 2 diabetes patients within the cancer cohort and determined their drug exposure information, as well as other covariates such as smoking status. We then estimated HRs for all-cause mortality and their associated 95% CIs using stratified Cox proportional hazard models. HRs were estimated according to metformin exposure, adjusted for age at diagnosis, sex, race, body mass index, tobacco use, insulin use, cancer type, and non-cancer Charlson comorbidity index.Results Among all Vanderbilt cancer patients, metformin was associated with a 22% decrease in overall mortality compared to other oral hypoglycemic medications (HR 0.78; 95% CI 0.69 to 0.88) and with a 39% decrease compared to type 2 diabetes patients on insulin only (HR 0.61; 95% CI 0.50 to 0.73). Diabetic patients on metformin also had a 23% improved survival compared with non-diabetic patients (HR 0.77; 95% CI 0.71 to 0.85). These associations were replicated using the Mayo Clinic EHR data. Many site-specific cancers including breast, colorectal, lung, and prostate demonstrated reduced mortality with metformin use in at least one EHR.Conclusions EHR data suggested that the use of metformin was associated with decreased mortality after a cancer diagnosis compared with diabetic and non-diabetic cancer patients not on metformin, indicating its potential as a chemotherapeutic regimen. This study serves as a model for robust and inexpensive validation studies for drug repurposing signals using EHR data.

Reduced colorectal cancer incidence in type 2 diabetic patients treated with metformin: a meta-analysis

“…association between metformin and colon cancer (RR¼0.80, 95% CI: 0.64-1.00) by including 12 included studies without three new studies in 2014 (Cardel et al 2014;Tsilidis et al 2014;Xu et al 2014), which were included in our study. These results imply the potential effects of metformin against the occurrence of colon cancer in T2DM patients.…”

“…Table 1 shows that eight cohort studies (Oliveria et al 2008;Currie et al 2009;Libby et al 2009;Lee et al 2011;Hsieh et al 2012;Ruiter et al 2012;Tsilidis et al 2014;Xu et al 2014) including 175,432 cases and 126,967 controls, and three case-control studies (Yang et al 2004;Bodmer et al 2012;Cardel et al 2014) including 3133 cases and 15,774 controls were retrieved in the meta-analysis. Two studies were based on American (Oliveria et al 2008;Xu et al 2014), seven studies were based on European (Yang et al 2004;Currie et al 2009;Libby et al 2009;Bodmer et al 2012;Ruiter et al 2012;Cardel et al 2014;Tsilidis et al 2014), and two studies were based on Chinese (Taiwan) (Lee et al 2011;Hsieh et al 2012). All the studies were published from 2004 to 2014.…”

“…The remaining 21 articles were all full-reviewed. Bodmer et al 2012;Hsieh et al 2012;Ruiter et al 2012;Cardel et al 2014;Tsilidis et al 2014;Xu et al 2014) were enrolled in the meta-analysis. No study was included after hand-checking.…”

“…Several epidemiological studies reported significantly decreased CRC incidence among T2DM treated with metformin (Oliveria et al 2008;Currie et al 2009;Libby et al 2009;Lee et al 2011;Hsieh et al 2012;Ruiter et al 2012). However, other studies did not detect the relationship between metformin treatment and CRC risk among diabetes (Yang et al 2004;Bodmer et al 2012;Cardel et al 2014;Tsilidis et al 2014;Xu et al 2014). Several meta-analyses were conducted to evaluate the relationship, while the tissue still remains controversial (Decensi et al 2010;Zhang et al 2011;Noto et al 2012;Soranna et al 2012;Gandini et al 2014).…”

“…Gandini et al (2014) performed a new meta-analysis, which shows that metformin may reduce cancer incidence and mortality in patients with diabetes, including the colon cancer. Thereafter, several further studies were conducted to explore the relationship between metformin therapy and CRC risk among T2DM (Tsilidis et al 2014;Xu et al 2014). Accordingly, we performed the meta-analysis through enrolling the studies focusing on the tissue associated with the relationship exposition.…”