Metformin does not improve survival in patients with hepatocellular carcinoma.
OBJECTIVE
To assess whether metformin, which has a chemopreventive effect in chronic liver disease, has any chemotherapeutic effect in hepatocellular carcinoma.


METHODS
This was a retrospective study of 701 patients with newly diagnosed hepatocellular carcinoma (HCC) seen between January 2005 and June 2011 at Mayo Clinic, Rochester, Minnesota. This patient cohort was a part of the global HCC BRIDGE study, which is a large longitudinal study of HCC determining the real-world experience of HCC characteristics, management and patient outcomes. We defined significant metformin exposure as continuation of this agent at least 90 d beyond diagnosis of HCC, and compared survival of diabetic patients on metformin to diabetic patients not on metformin and non-diabetics.


RESULTS
Our cohort was 72.9% male, with a mean ± SD age of 62.6 ± 12.3 years. The most common etiologies of liver disease were hepatitis C (34%), alcoholic liver disease (29%), fatty liver disease (15%) and hepatitis B (9%). By univariate analysis, using diabetics not on metformin as the reference group, diabetic patients with HCC on metformin had no survival advantage, with a HR (95%CI) of 1.0 (0.8-1.3). Non-diabetic HCC patients also did not appear to have a survival advantage as compared to diabetic HCC patients not on metformin, as demonstrated by a HR (95%CI) of 1.1 (0.7-1.7). Diabetics on metformin beyond 90 d after HCC diagnosis had a longer median survival at 34.2 mo, as compared to 25.5 mo among diabetic patients who were not on metformin or had discontinued metformin within 90 d after HCC diagnosis. This finding was likely due to potential survival bias among those who lived long enough to receive metformin.


CONCLUSIONS
Although the literature suggests a chemotherapeutic effect in other malignancies, our study demonstrates no survival benefit to the use of metformin in diabetic patients with HCC.
Mamatha Bhat, Roongruedee Chaiteerakij, Ju Dong Yang, Nasra H Giama, Gregory J Gores, Lewis R Roberts, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55902, United States.
Mamatha
M
Bhat
Mamatha Bhat, Roongruedee Chaiteerakij, Ju Dong Yang, Nasra H Giama, Gregory J Gores, Lewis R Roberts, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55902, United States.
Roongruedee
R
Chaiteerakij
Mamatha Bhat, Roongruedee Chaiteerakij, Ju Dong Yang, Nasra H Giama, Gregory J Gores, Lewis R Roberts, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55902, United States.
William S
WS
Harmsen
Mamatha Bhat, Roongruedee Chaiteerakij, Ju Dong Yang, Nasra H Giama, Gregory J Gores, Lewis R Roberts, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55902, United States.
Cathy D
CD
Schleck
Mamatha Bhat, Roongruedee Chaiteerakij, Ju Dong Yang, Nasra H Giama, Gregory J Gores, Lewis R Roberts, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55902, United States.
Ju Dong
JD
Yang
Mamatha Bhat, Roongruedee Chaiteerakij, Ju Dong Yang, Nasra H Giama, Gregory J Gores, Lewis R Roberts, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55902, United States.
Nasra H
NH
Giama
Mamatha Bhat, Roongruedee Chaiteerakij, Ju Dong Yang, Nasra H Giama, Gregory J Gores, Lewis R Roberts, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55902, United States.
Terry M
TM
Therneau
Mamatha Bhat, Roongruedee Chaiteerakij, Ju Dong Yang, Nasra H Giama, Gregory J Gores, Lewis R Roberts, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55902, United States.
Gregory J
GJ
Gores
Mamatha Bhat, Roongruedee Chaiteerakij, Ju Dong Yang, Nasra H Giama, Gregory J Gores, Lewis R Roberts, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55902, United States.
Lewis R
LR
Roberts
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000401:mortality* / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000175:diagnosis / Q000401:mortality* / Q000517:prevention & control; D008297:Male; D008687:Metformin / Q000627:therapeutic use*; D008875:Middle Aged; D008910:Minnesota / Q000453:epidemiology; D016017:Odds Ratio; D011379:Prognosis; D016016:Proportional Hazards Models; D065840:Protective Factors; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult
D007004:Hypoglycemic Agents; D008687:Metformin
Diabetes; Hepatocellular carcinoma; Lactic acidosis; Liver disease; Metformin; Survival