Metformin Improves Survival in Patients with Pancreatic Ductal Adenocarcinoma and Pre-Existing Diabetes: A Propensity Score Analysis

Abstract

OBJECTIVES Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease. Diabetes mellitus (DM) is both a risk factor for and a sequela of PDAC. Metformin is a commonly prescribed biguanide oral hypoglycemic used for the treatment of type II DM. We investigated whether metformin use before PDAC diagnosis affected survival of patients with DM, controlling confounders such as diabetic severity. METHODS We used the Surveillance, Epidemiology, and End Results registry (SEER)-Medicare linked database to identify patients with PDAC diagnosed between 2007 and 2011. The diabetic comorbidity severity index (DCSI) controlled for DM severity. Inverse propensity weighted Cox Proportional-Hazard Models assessed the association between metformin use and overall survival adjusting for relevant confounders. RESULTS We identified 1,916 patients with PDAC and pre-existing DM on hypoglycemic medications at least 1 year before cancer diagnosis. Of these, 1,098 (57.3%) were treated with metformin and 818 (42.7%) with other DM medications. Mean survival for those on metformin was 5.5 months compared with 4.2 months for those not on metformin (P<0.01). After adjusting for confounders including DCSI, Charlson score, and chronic kidney disease (CKD), patients on metformin had a 12% decreased risk of mortality compared with patients on other medications (hazard ratio (HR): 0.88, 95% confidence interval (CI): 0.81–0.96, P<0.01). In stratified analysis, differences persisted regardless of the Charlson score, the DCSI score, the presence of kidney disease, or the use of insulin/other hypoglycemic medications (P<0.01 for all). CONCLUSIONS Metformin is associated with increased survival among diabetics with PDAC. If confirmed in a prospective study, then these results suggest a possible role for metformin as an adjunct to chemotherapy among diabetics with PDAC.

Effects of metformin on survival outcomes of pancreatic cancer patients with diabetes: A meta-analysis

“…After reading the full text, 20 were excluded because article overlapping, no survival information, not diabetic patients and no sufficient data. At last, 8 full articles (16,17,(29)(30)(31)(32)(33)(34) matched our inclusion criteria and included in this meta-analysis. The process of study selection is shown in a flow diagram (Fig.…”

“…These studies were all published in recent years (2012 to 2017), and six studies were published in 2016. Five studies were conducted in the United States (29,(31)(32)(33)(34), two in Korea (16,30), one in UK (17). These eight eligible papers are all retrospective cohort studies.…”

“…In a total of 8 studies, 4 studies reported a statistically decreased risk of death from all causes in pancreatic cancer patients with diabetes by multivariate analysis (16,30,32,33). However, no statistically significant differences were observed in the other 4 studies (17,29,31,34). Considering the presence of significant heterogeneity among all the included studies (P=0.01; I 2 =64%), we used the random-effects models to conduct the pooled analysis.…”

Survival Benefit of Metformin Adjuvant Treatment For Pancreatic Cancer Patients: a Systematic Review and Meta-Analysis

“…Moreover, the pooling analysis by Zhang et al indicated that metformin may improve the survival for cancer patients with concurrent diabetes, particularly for breast, colorectal, ovarian, and endometrial cancer, but they failed to show such survival benefit in pancreatic cancer with only 3 studies included (HR=0.80, 95% CI= 0.62-1.03) [14]. Additionally, a recent meta-analysis combining 27 studies comprising 24178 participants was conducted to qualify the adjuvant effect of metformin in cancers, suggesting a better survival, particularly in colorectal and prostate cancer, however without special attention to pancreatic cancer Reni,2016 [26] Italy ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ 8 Lee,2016 [27] Korea ▲ ▲ ▲ ▲ ▲ ▲ ▲ 7 Ambe,2016 [21] USA ▲ ▲ ▲ ▲ ▲ ▲ 6 Cheon,2014 [28] Korea ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ 8 Hwang,2013 [29] USA ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ 9 Amin,2016 [30] USA ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ 8 Kordes,2015 [31] Netherlands ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ 9 Chaiteerakij,2016 [32] USA ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ 8 Sadeghi,2012 [33] USA ▲ ▲ ▲ ▲ ▲ ▲ 6 Cerullo,2016 [34] USA ▲ ▲ ▲ ▲ ▲ ▲ ▲ 7 Kozak,2016 [35] USA ▲ ▲ ▲ ▲ ▲ ▲ ▲ 7 Toomey,2015 [36] USA ▲ ▲ ▲ ▲ ▲ 5 Choi,2015 [37] Korea ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ 8 Beg,2017 [38] USA ▲ ▲ ▲ ▲ ▲ ▲ ▲ 7 Jang,2017 [39] Korea ▲ ▲ ▲ ▲ ▲ ▲ ▲ ▲ 8 Frouws,2017 [40] Netherlands ▲ ▲ ▲ ▲ ▲ ▲ ▲ 7 E,2017 [41] USA ▲ ▲ ▲ ▲ ▲ ▲ ▲ 7 [46] and by E et al (6 studies with 12,057 participants) have represented similar findings with demonstrating a survival benefit of metformin therapy for pancreatic cancer patients [47]. Furthermore, the subgroup analyses based on ethnicity in the current study revealed a more favorable prognosis for metformin therapy in Asian population (HR=0.74, P=0.01) but not evident in Caucasian population (HR= 0.92, P=0.10) which was in line with the findings by Zhou et al, indicating that ethnicity variation may contribute to the metformin action, however, the underlying mechanism for the discrepancy remains undefined.…”

Metformin: od mehanizmov delovanja do napredne klinične uporabe

“…Za zdravljenje z metforminom so v številnih raziskavah pokazali vpliv na zmanjšanje pojavnosti določenih vrst raka (76)(77)(78)(79)(80). Zdravljenje z metforminom je pri bolnikih s sladkorno boleznijo tipa 2 vplivalo na zmanjšanje pojavnosti in umrljivosti zaradi raka debelega črevesa (79,81).…”