Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease

Donadon,; Balbi, Massimiliano; Ghersetti, Michela; Grazioli, Silvia; Perciaccante, Antonio; G, Della Valentina; R, Gardenal; M, Dal Mas; Casarin, Pietro; Zanette, Giorgio; Miranda, Cesare

doi:10.3748/wjg.15.2506

Cited by 130 publications

(119 citation statements)

References 26 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…When analysis was done separately by cancer incidence and cancer mortality, we found similar SRRs with a decrease in heterogeneity for mortality and no statistically significant difference (P = 0.90) between the two estimates. When the six studies on incidence of single cancer sites, that is, colon (40), pancreatic (38), HCC (34,45), breast (46), and prostate (39) cancers, were included, similar summary risk estimates were obtained (SRR, 0.55; 95% CI, 0.42-0.70). A trend toward a large risk reduction was noted for colon and pancreatic cancer (60-80% risk reduction) in two independent studies for each cancer site, even when only those cancers diagnosed >2 years after diabetes developed were included (to minimize effects of reverse causation).…”

Section: Discussionmentioning

confidence: 84%

“…Seven studies were conducted in Europe, three in the United States, and one in Canada. Four studies (34,38,39,45) also included a subgroup of nondiabetic patients.…”

Section: Resultsmentioning

confidence: 99%

“…A trend toward a large risk reduction was noted for colon and pancreatic cancer (60-80% risk reduction) in two independent studies for each cancer site, even when only those cancers diagnosed >2 years after diabetes developed were included (to minimize effects of reverse causation). Two studies showed a significant trend for metformin on HCC (34,45), whereas risk estimates were not statistically significant for colon, breast, and prostate cancer. A dose duration-response relationship was noted, although it was not statistically significant probably due to low power and heterogeneity of the end points (only three studies evaluating different cancer sites).…”

Section: Discussionmentioning

confidence: 98%

“…Eight of these articles were not included in the meta-analysis for the following reasons: (a) two referred to the same study cohort: Evans et al (35) presented a subset of patients included in a study published later (36), and Jecht (37) published in a German language journal the results already presented in English by Libby et al (36); (b) six did not report overall cancer incidence but data on a single organ site, that is, pancreatic cancer (38), hepatocellular cancer (HCC; refs. 34,45), breast (46), prostate (39), and colorectal cancer (40). These studies were analyzed separately for descriptive purposes.…”

Section: Methodsmentioning

confidence: 99%

“…Metformin has been associated with cancer risk reduction in recent epidemiologic studies in diabetic patients (34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46). With these premises, we performed a systematic review and meta-analysis of available studies to better define the effect of metformin on cancer incidence and mortality in diabetic patients.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis

DeCensi

Puntoni

Goodwin

et al. 2010

Cancer Prevention Research

820

569

View full text Add to dashboard Cite

Metformin, an insulin-lowering agent, has been associated with decreased cancer risk in epidemiologic studies in diabetic patients. We performed a comprehensive literature search and meta-analysis of epidemiologic studies to assess the effect of metformin on cancer incidence and mortality in diabetic patients, using Pubmed, ISI Web of Science, Embase, and the Cochrane library until May 2009, with no language or time restrictions. Independent reports with sufficient information to allow risk estimation of cancer risk/mortality and a measure of uncertainty were reviewed and cross-checked independently by three investigators. Eleven studies were selected for relevance in terms of intervention, population studied, independence, and reporting of cancer incidence or mortality data, reporting 4,042 cancer events and 529 cancer deaths. A 31% reduction in overall summary relative risk (0.69; 95% confidence interval, 0.61-0.79) was found in subjects taking metformin compared with other antidiabetic drugs. The inverse association was significant for pancreatic and hepatocellular cancer, and nonsignificant for colon, breast, and prostate cancer. A trend to a dose-response relationship was noted. Metformin is associated with a decreased risk of cancer incidence compared with other treatments among diabetic patients. Given the retrospective nature of most studies and the possibility that the control treatments increase risk, phase II trials are needed before large cancer prevention trials are launched. Cancer Prev Res; 3(11); 1451-61. ©2010 AACR.

show abstract

Section: Discussionmentioning

confidence: 84%

“…Seven studies were conducted in Europe, three in the United States, and one in Canada. Four studies (34,38,39,45) also included a subgroup of nondiabetic patients.…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis

DeCensi

Puntoni

Goodwin

et al. 2010

Cancer Prevention Research

820

569

View full text Add to dashboard Cite

show abstract

Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma

Hassan

Curley

et al. 2010

Cancer

285

239

View full text Add to dashboard Cite

Background Despite the observed association between diabetes mellitus and hepatocellular carcinoma (HCC), little is known about the effect of diabetes duration prior to HCC diagnosis and whether some diabetes medications reduced the risk of HCC development. Aim We aimed at determining the association between HCC risk and diabetes duration and type of diabetes treatment. Methods A total of 420 HCC patients and 1104 healthy controls were enrolled in an ongoing hospital-based case-control study. We used multivariate logistic regression models to adjust for HCC risk factors. Results The prevalence of diabetes mellitus was 33.3% in HCC and 10.4% in the control group, yielding an adjusted odds ratio (AOR) and 95% confidence interval (CI) of 4.2 (3.0-5.9). In 87% of cases, diabetes was present prior to HCC diagnosis yielding an AOR of 4.4 (95%CI, 3.0-6.3). Compared to patients with a diabetes duration of 2-5 years, the estimated AORs (95% CI) for those with a diabetes duration of 6-10 years and those with diabetes duration > 10 years were 1.8 (0.8-4.1) and 2.2 (1.2-4.8) respectively. In respect to diabetes treatment, the AORs (95% CI) were 0.3 (0.2-0.6), 0.3 (0.1-0.7), 7.1 (2.9-16.9), 1.9 (0.8-4.6), and 7.8 (1.5-40.0) for those treated with biguanides, thiazolidinediones, sulfonylureas, insulin, and dietary control respectively. Conclusions Diabetes increases HCC risk, and such risk is correlated with long duration of diabetes. Relying on dietary control and treatment with sulfonylureas or insulin conferred the highest magnitude of HCC risk, while biguanides or thiazolidinediones treatment was associated with 70% HCC risk-reduction among diabetics.

show abstract

Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis

DePeralta

Wei

Ghoshal

et al. 2016

Cancer

View full text Add to dashboard Cite

Background Hepatocellular carcinoma (HCC) associated mortality is increasing at an alarming rate and there is a readily identifiable cohort of at risk patients with cirrhosis, viral hepatitis, non-alcoholic fatty liver disease, and diabetes. These patients are candidates for chemoprevention. Metformin is an attractive agent for chemoprevention since it is inexpensive, has a favorable safety profile and is well tolerated over long time periods. Methods We studied the efficacy of metformin as a prevention agent in a clinically relevant rat model of HCC, where tumors develop in the setting of chronic inflammation and cirrhosis. We used repeated injections of diethylnitrosamine to induce sequential cirrhosis and HCC and administered metformin either at the first signs of fibrosis or cirrhosis. Results Prolonged metformin exposure was safe and associated with decreases in fibrotic and inflammatory markers especially when administered early at the first signs of fibrosis. In addition, early metformin treatment led to a 44% decrease in HCC incidence, while tumor burden was unchanged when metformin was administered at the first signs of cirrhosis. Interestingly, activation of the hepatic progenitor/stem cell compartment was first observed at the onset of cirrhosis and therefore only early metformin treatment suppressed receptor for advanced glycation end products and inhibited the activation of hepatic progenitor cells. Conclusions Our results are the first to demonstrate an effect on progenitor/stem cells in the setting of chemoprevention and provide further rationale to explore metformin as an early intervention in clinical trials of patients with chronic liver disease at high risk for HCC.

show abstract

Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease

Cited by 130 publications

References 26 publications

Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis

Metformin and Cancer Risk in Diabetic Patients: A Systematic Review and Meta-analysis

Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma

Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis

Contact Info

Product

Resources

About