Diabetes mellitus and metformin in hepatocellular carcinoma

Table 1 The influence of diabetes mellitus on the incidence, recurrence, and mortality of hepatocellular carcinoma

Ref.	Year	Study design	Type of diabetes	Results
Maynard[43]	1910	Case-control	Not differentiated	Cancer mortality increased
Greenwood and Wood[44]	1914	Case-control	Not differentiated	Cancer mortality increased in American cities; no significant correlation was observed in European cities
Marble[45]	1934	Case-control	Not differentiated	Pancreatic cancer incidence increased
Kessler[46]	1970	Case-control	Not differentiated	Pancreatic cancer deaths increased
Lawson et al[47]	1986	Case-control	Not differentiated	HCC incidence increased (HR = 3.9)
Levine et al[67]	1990	Cohort	IGT	HCC deaths increased in men; post-load plasma glucose increased
Adami et al[48]	1991	Cohort	Not differentiated	Incidences of primary liver (RR = 1.5), pancreatic (RR = 1.4) and endometrial (RR = 1.5) cancers increased
Smith et al[164]	1992	Cohort	IGT	Pancreatic cancer increased (RR = 2.25); post-load plasma glucose increased in IGT men. HCC was not analyzed in organ-specific statistics
La Vecchia et al[51]	1994	Case-control	Not differentiated	Liver cancer incidence remained elevated 10 yr after the diagnosis of diabetes (RR = 2.6)
Adami et al[49]	1996	Cohort	Not differentiated	Primary liver cancer incidence increased (SIR = 4.7 in men and 3.4 in women)
Wideroff et al[50]	1997	Cohort	Not differentiated	Primary liver cancer incidence increased (SIR = 4.0 in men and 2.1 in women)
La Vecchia et al[165]	1997	Case-control	Not differentiated	Liver cancer incidence increased (OR = 2.2) for at least 10 yr after the diagnosis of diabetes
Ikeda et al[54]	1998	Cohort	Not differentiated	Recurrence-free survival after hepatic resection decreased in diabetic cases
Balkau et al[52]	2001	Cohort	Not differentiated	HCC incidence increased with fasting hyperinsulinemia (HR = 2.72) and 2-h hyperinsulinemia (HR = 3.41)
Huo et al[55]	2003	Cohort	Not differentiated	HCC recurrence increased in HBV-seropositive cases
Coughlin et al[58]	2004	Cohort	Not differentiated	Liver cancer mortality increased in men (RR = 2.19)
Batty et al[68]	2004	Cohort	IGT	HCC (HR = 2.47) and pancreatic cancer (HR = 1.35) increased; post-load plasma glucose increased in IGT men
El-Serag et al[60]	2006	Meta-analysis	Not differentiated	HCC incidence increased in 9 case-control studies (OR = 2.5) and 7 cohort studies (OR = 2.5)
Inoue et al[64]	2006	Cohort	Not differentiated	HCC incidence increased (HR = 2.24 in men and 1.94 in women)
Komura et al[56]	2007	Cohort	Not differentiated	Postoperative recurrence-free survival decreased in diabetic cases
Kawamura et al[57]	2008	Cohort	Not differentiated	HCC recurrence increased (HR = 4.61)
Landman et al[59]	2010	Cohort	Type 2	HCC death increased (SMR = 1.47)
Lee et al[53]	2011	Cohort	Type 2	Incidences of total cancer, HCC and pancreatic cancer increased
Hense et al[166]	2011	Cohort	Type 2	HCC incidence increased (SIR = 1.94)
Johnson et al[70]	2011	Cohort	Type 2	After detection biases were excluded, incidences of HCC (HR = 2.53), pancreatic (HR = 1.65) and endometrial (HR = 1.58) cancers increased
Wang et al[167]	2012	Meta-analysis	Type 1 and type 2	HCC incidence (RR = 2.23) and mortality (RR = 2.43) increased in cohort studies
Wang et al[168]	2012	Meta-analysis	Not differentiated	HCC incidence (RR = 2.01) and mortality (RR = 1.56) increased
Lai et al[101]	2012	Cohort	Not differentiated	HCC incidence increased (HR = 1.73)
Schlesinger et al[62]	2013	Cohort	Not differentiated	HCC incidence increased (RR = 2.17) in HBV/HCV-negative individuals
Koh et al[63]	2013	Cohort	Not differentiated	HCC incidence increased (HR = 2.14), particularly in non-viral cases (HR = 5.15)
Wang et al[169]	2014	Meta-analysis	Not differentiated	HCC in diabetic cases was related to overall survival (RR = 1.46) and disease-free survival (RR = 1.57)
Harding et al[69]	2015	Case-control	Type 1 and type 2	Incidences of total, liver, pancreatic and endometrial cancer increased in cases involving type 2 diabetes mellitus

RR: Relative risk; OR: Odds ratio; HR: Hazard ratio; SIR: Standardized incidence ratio; SMR: Standardized mortality ratio; IGT: Impaired glucose tolerance.

Table 2 Efficacy of metformin on the incidence, recurrence and mortality of hepatocellular carcinoma and other tumors

Ref.	Year	Study design	Type of diabetes	Results
Evans et al[26]	2005	Case-control	Type 2	HCC incidence decreased (OR = 0.79)
Bowker et al[96]	2006	Cohort	Type 2	Mortality was lower among metformin users than among insulin or sulfonylurea users (HR = 0.77)
Libby et al[97]	2009	Cohort	Type 2	Total cancer incidence decreased (HR = 0.63)
Donadon et al[98]	2009	Case-control	Type 2	HCC incidence was lower among metformin users (OR = 0.33) than among insulin users (OR = 2.99)
Donadon et al[99]	2010	Cohort	Type 2	HCC incidence was lower among metformin users (OR = 0.15) than among insulin or sulfonylurea users
Hassan et al[100]	2010	Case-control	Not differentiated	HCC incidence decreased (OR = 0.30)
Home et al[107]	2010	Randomized controlled trial	Type 2	Total cancer incidence did not decrease compared with rosiglitazone users
Landman et al[59]	2010	Cohort	Type 2	HCC deaths decreased (HR = 0.43)
Hosono et al[119]	2010	Randomized controlled trial	Non-diabetic	A surrogate marker of colorectal cancer incidence decreased
Ferrara et al[104]	2011	Cohort	Not differentiated	No decreases in the incidence of any cancer; no data on HCC were available
Lee et al[53]	2011	Cohort	Type 2	Incidences of total cancer (HR = 0.12), HCC (HR = 0.06) and colorectal cancer (HR = 0.36) decreased
Hense et al[166]	2011	Cohort	Type 2	HCC incidence did not decrease
Lai et al[101]	2012	Cohort	Not differentiated	HCC incidence was decreased by metformin (HR = 0.49) and thiazolidinedione (HR = 0.56)
Ruiter et al[170]	2012	Cohort	Not differentiated	Incidences of total cancer (HR = 0.90) and HCC (HR = 0.67) were lower among metformin users than among sulfonylurea users
Stevens et al[108]	2012	Meta-analysis	Type 2 and at-risk for diabetes	The summary RR for cancer outcomes was 1.02 across all trials
Thakkar et al[109]	2013	Meta-analysis	Type 2	Total cancer incidence decreased in case-control studies (RR = 0.90) and cohort studies (RR = 0.70) but did not significantly decrease in randomized controlled trials
Yin et al[110]	2013	Meta-analysis	Type 2	Overall survival (HR = 0.65) and cancer-specific survival (HR = 0.62) for total cancers were better for metformin than for other glucose-lowering medications
Tsilidis et al[105]	2014	Cohort	Type 2	Incidences of total cancer and HCC were not significantly lower among metformin users than among sulfonylurea users
Gandini et al[106]	2014	Meta-analysis	Not differentiated	After adjusting for time-related biases, total cancer incidence decreased (RR = 0.90), but this decrease became insignificant after adjusting for BMI in addition to time-related biases. Total cancer mortality and HCC incidence did not decrease after adjusting for time-related biases
Higurashi et al[120]	2016	Randomized controlled trial	Non-diabetic	Incidences of metachronous colorectal adenomas (HR = 0.60) and total polyps (HR = 0.67) decreased

RR: Relative risk; OR: Odds ratio; HR: Hazard ratio.