Diabetes mellitus and metformin in hepatocellular carcinoma

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.