Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation

Background and Aim: Type 2 diabetes increases the risk of cancer development and mortality. However, antidiabetic treatment with metformin can reduce the risk of cancer. We studied whether metformin users among diabetic patients with early hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA) would have a favorable survival compared with those without metformin treatment. Methods: A total of 135 patients with early stage HCC having 162 tumors underwent RFA. Among them, 53 patients were diabetic, including 21 metformin users and 32 patients without metformin treatment. Results: Diabetic patients had an inferior survival rate compared with nondiabetic patients (1 year, 82.8% vs 93.9%; 3 years, 55.1% vs 80.2%; 5 years, 41.3% vs 64.7%; P = 0.004). With regards to antidiabetic treatments, metformin users had better survival outcome (adjusted hazard ratio [HR] 0.24; 95% confidence interval [CI], 0.07–0.80; P = 0.020) compared to patients without metformin treatment after adjustments for potential confounders. Sulfonylureas and insulin exposures did not achieve significant conclusions. For the whole studied population including nondiabetic and diabetic patients, the multivariate analysis revealed that maximum tumor size more than 2.5 cm (HR, 3.49; 95% CI, 1.74–6.99; P < 0.001) and diabetic patients without metformin treatment (HR, 3.34; 95% CI, 1.67–6.71, P = 0.001) were independent explanatory variables associated with unfavorable survival. Conclusions: Metformin users among diabetic patients with HCC undergoing RFA had a favorable overall survival compared with patients without metformin treatment.     

Epidemiology and prevalence of lean nonalcoholic fatty liver disease and associated cirrhosis,hepatocellular carcinoma,and cardiovascular outcomes in the United States: a population-based study and review of literature

Backgrounds

Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and metabolic syndrome conditions. However, a subset of NAFLD patients express a normal or low body mass index (lean NAFLD [L-NAFLD]). Our aim is to compare the prevalence of L-NAFLD to the obesity-associated NAFLD in the United States by assessing prevalence, potential risk factors, liver-related complications, and coronary artery disease outcomes.

Methodology

A multicenter database (Explorys Inc.) of >70 million patients across the United States was screened. A cohort of patients with “nonalcoholic fatty liver” between 1999 and 2021 was identified. Two sub-cohorts of NAFLD patients were identified: those with a body mass index (BMI) < 25 kg/m² (L-NAFLD) and those with a BMI > 30 kg/m² (obesity-associated NAFLD). We excluded patients with age <18 and those who have viral hepatitis, hemochromatosis, Wilson's disease, biliary cirrhosis, alcoholic liver disease, cystic fibrosis, alpha-1-antitrypsin deficiency, and autoimmune hepatitis. Multivariate analysis was performed to adjust for confounders.

Results

68 892 260 individuals were screened. NAFLD prevalence was four per 100 000, and L-NAFLD prevalence was 0.6 per 100 000. Compared with those without, patients with L-NAFLD tended to be older (OR 2.16), females (OR 1.28), and smokers (OR 4.67) and of Asian race (OR 2.12). L-NAFLD patients were more likely to have acute coronary syndromes (OR 30.00) and metabolic syndrome (OR 2.31) despite the normal/low BMI. Esophageal varices and hepatocellular carcinoma risks were high in both cirrhosis patients.

Conclusion

This is the largest study to assess L-NAFLD prevalence in the United States. L-NAFLD are at a significantly higher risk for acute coronary syndromes, esophageal varices, and hepatocellular carcinoma.     

Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease

1. Download : Download high-res image (312KB)
2. Download : Download full-size image

     

Pharmacokinetics of metformin in patients with gastrointestinal intolerance

Aims

To assess potential causes of metformin intolerance, including altered metformin uptake from the intestine, increased anaerobic glucose utilization and subsequent lactate production, altered serotonin uptake, and altered bile acid pool.

Methods

For this pharmacokinetic study, we recruited 10 severely intolerant and 10 tolerant individuals, matched for age, sex and body mass index. A single 500‐mg dose of metformin was administered, with blood sampling at 12 time points over 24 hours. Blood samples were analysed for metformin, lactate, serotonin and bile acid concentrations, and compared across the phenotypes.

Results

The intolerant individuals were severely intolerant to 500 mg metformin. No significant difference was identified between tolerant and intolerant cohorts in metformin pharmacokinetics: median (interquartile range [IQR]) peak concentration 2.1 (1.7‐2.3) mg/L and 2.0 (1.8‐2.2) mg/L, respectively (P = .76); time to peak concentration 2.5 hours; median (IQR) area under the curve (AUC)_0–24 16.9 (13.9‐18.6) and 13.9 (12.9‐16.8) mg/L*h, respectively (P = .72). Lactate concentration peaked at 3.5 hours, with mean peak concentration of 2.4 mmol/L in both cohorts (95% CI 2.0‐2.8 and 1.8‐3.0 mmol/L, respectively), and similar incremental AUC_0–24 in each cohort: tolerant cohort 6.98 (95% CI 3.03‐10.93) and intolerant cohort 4.47 (95% CI –3.12‐12.06) mmol/L*h (P = .55). Neither serotonin nor bile acid concentrations were significantly different.

Conclusions

Despite evidence of severe intolerance in our cohort, there was no significant difference in metformin pharmacokinetics or systemic measures of lactate, serotonin or bile acids. This suggests that metformin intolerance may be attributable to local factors within the lumen or enterocyte.     

二甲双胍对乳腺癌合并2型糖尿病患者癌组织Caspase-3、Caspase-9表达的影响

目的 观察二甲双胍对乳腺癌合并2型糖尿病患者癌组织中半胱天冬氨酸蛋白酶-3（Caspase-3）及Caspase-9表达的影响.方法 选择乳腺癌合并2型糖尿病112例,其中应用二甲双胍治疗者43例（二甲双胍组）、未用二甲双胍治疗者69例（糖癌组）,单纯乳腺癌112例（单纯癌症组）,采用免疫组化SP法检测癌组织中的Caspase-3、Caspase-9.结果 二甲双胍组癌组织中Caspase-3、Caspase-9表达量分别为138.24±8.68、140.21±6.34,糖癌组分别为153.43±5.59、156.17±8.25,单纯癌症组分别为112.70±4.28、121.43±6.67;三组两两比较,P均＜0.05.结论 二甲双胍可降低乳腺癌合并2型糖尿病患者癌组织中Caspase-3及Caspase-9表达,这可能是其抑制乳腺癌发展的作用机制.     

Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease

Background: Previous studies have reported the association between type 2 diabetes mellitus (DM2) and hepatocellular carcinoma (HCC). Aims: To explore the relationships among DM2, antidiabetic therapy and HCC risk. Methods: We recruited 610 HCC patients compared with 618 matched cirrhotic patients and 1696 Controls. The odds ratio (OR) for HCC in diabetic subjects treated with insulin, sulphonylureas and metformin was calculated. Results: DM2 prevalence was 31.2% in HCC, 23.3% in cirrhotic patients and 12.7% in Controls (P<0.0001). The OR for HCC in diabetic HCC patients vs Controls was 3.12 [confidence interval (CI) 2.40–3.90; P<0.001] in univariate analysis and 2.50 (CI 1.70–3.69; P<0.0001) in multivariate analysis. Comparing diabetic HCC patients vs liver cirrhosis (LC) cases, univariate analysis showed an OR for HCC of 2.09 (CI 1.50–2.90; P<0.001), whereas on multivariate analysis we found an OR of 1.46 (CI 1.07–1.98; P=0.02). In 84% of the cases, type 2 diabetes mellitus has been present before the HCC diagnosis. Multivariate analysis showed that metformin treatment was associated with a strong and statistically significant reduction of the risk of HCC, as compared with the use of sulphonylureas or insulin, in diabetic HCC patients vs Controls and vs LC cases (OR of 0.15; CI 0.04–0.50; P=0.005 and OR=0.16; CI 0.06–0.46; P=0.0006 respectively). Conclusions: Our study shows that DM2 is an independent risk factor for HCC and pre‐exists to HCC occurrence. In DM2 patients with HCC, metformin therapy is associated with a reduced HCC risk and seems to have a protective effect on HCC development.     

Influence of diabetes mellitus and effectiveness of metformin on hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers, and it is important to elucidate the carcinogenic factors and improve the recurrence and prognosis of HCC patients. Diabetes mellitus (DM) has been reported to be a risk factor for the carcinogenesis of many cancers including HCC, and the mechanism of DM for carcinogenesis is gradually being elucidated. Metformin, a drug for DM, has been reported to have anticancer effects on many cancers, including HCC. Metformin not only suppresses carcinogenesis but also improves the prognosis of recurrence after treatment, and there are many reports on the mechanism of these effects. In this review, we describe the mechanism of action of hyperglycemia and hyperinsulinemia on carcinogenesis by DM against HCC. The carcinogenic effects of DM on hepatitis B, hepatitis C, and nonalcoholic fatty liver disease by etiology are also described. In addition, the carcinogenic effect of metformin on HCC and its mechanism of action are reviewed. We also discuss the effects of metformin on recurrence after hepatectomy and radiofrequency therapy and the effects of metformin in combination with anticancer medicine, focusing on the inhibition of HCC development.     

Sustained viral response prolonged survival of patients with C-viral hepatocellular carcinoma.

BACKGROUND: We conducted this retrospective study to evaluate the position of interferon therapy in the curative treatment of hepatitis C virus-associated hepatocellular carcinoma (HCC). METHODS: We compared overall and recurrence-free survival rates between 191 patients who received interferon therapy before HCC development (15 with sustained virologic response (SVR)), 53 who received interferon therapy after HCC ablation (17 with SVR), and 399 HCC patients with Child-Pugh class A liver function who did not receive interferon (controls). RESULTS: The overall survival rate in the controls was 82.4%, 53.2%, and 28.3% at 3, 6, and 9 years, respectively, whereas that in patients who developed HCC after achieving SVR was 93.3%, 93.3%, and 93.3%; those with HCC after non-SVR, 87.8%, 56.5%, and 35.8%; SVR after HCC, 100%, 87.5%, and 59.7%; and non-SVR after HCC, 94.3%, 70.9%, and 53.2%. Cox proportional hazard regression analysis revealed that the risk of death was significantly reduced in patients with HCC after SVR and those with SVR after HCC, with a risk ratio of 0.124 (95% confidence interval (95% CI): 0.017-0.890, P = 0.0378) and 0.388 (95% CI: 0.169-0.887, P = 0.0250), respectively, compared with the controls. Improved survival was attributable mainly to sustained liver function among patients with SVR, and recurrence-free survival did not differ significantly. CONCLUSION: Interferon therapies before and after HCC development were both significantly associated with prolonged survival when SVR was achieved.     

Metabolic dysfunction outperforms ultrasonographic steatosis to stratify hepatocellular carcinoma risk in patients with advanced hepatitis C cured with direct-acting antivirals

Background and Aims

Metabolic dysfunction (MD)-associated fatty liver disease has been proposed to identify individuals at risk of liver events irrespectively of the contemporary presence of other liver diseases. The aim of this study was to examine the impact of MD in patients cured of chronic hepatis C (CHC).

Patients and Methods

We analysed data from a real-life cohort of 2611 Italian patients cured of CHC with direct antiviral agents and advanced liver fibrosis, without HBV/HIV, transplantation and negative for hepatocellular carcinoma (HCC) history (age 61.4 ± 11.8 years, 63.9% males, median follow-up 34, 24–40 months). Information about ultrasonographic steatosis (US) after sustained virological response was available in 1978.

Results

MD affected 58% of patients, diagnosed due to the presence of diabetes (MD-diabetes, 19%), overweight without diabetes (MD-overweight, 37%) or multiple metabolic abnormalities without overweight and diabetes (MD-metabolic, 2%). MD was more frequent than and not coincident with US (32% MD-only, 23% MD-US and 13% US-only). MD was associated with higher liver stiffness (p < 0.05), particularly in patients with MD-diabetes and MD-only subgroups, comprising older individuals with more advanced metabolic and liver disease (p < 0.05). At Cox proportional hazard multivariable analysis, MD was associated with increased risk of HCC (HR 1.97, 95% CI 1.27–3.04; p = 0.0023). Further classification according to diagnostic criteria improved risk stratification (p < 0.0001), with the highest risk observed in patients with MD-diabetes. Patients with MD-only appeared at highest risk since the sustained virological response achievement (p = 0.008), with a later catch-up of those with combined MD-US, whereas US-only was not associated with HCC.

Conclusions

MD is more prevalent than US in patients cured of CHC with advanced fibrosis and identifies more accurately individuals at risk of developing HCC.     

Circulating DNA level is negatively associated with the long-term survival of hepatocellular carcinoma patients

AIM: To quantify the circulating DNA in plasma from patients with hepatocellular carcinoma (HCC) and to evaluate its prognostic value. METHODS: Blood samples were collected from 79 patients with HCC before operation, 20 patients with liver cirrhosis, and 20 healthy volunteers. Circulating DNA was extracted from plasma and quantified. The association between circulating DNA level and prognosis of HCC patients was evaluated. RESULTS: Compared with the healthy volunteers (17.6±9.5 ng/mL), a significant higher circulating DNA level was found in the patients with HCC (47.1±43.7 ng/ mL, P = 0.000) or with liver cirrhosis (30.0±13.3 ng/ mL, P - 0.002). The circulating DNA level was closely associated with tumor size (P = 0.008) and TNM stage (P = 0.040), negatively associated with the 3-year disease-free survival (DFS) (P - 0.017) and overall survival (OS) (P = 0.001). CONCLUSION: Large or invasive tumor may release more circulating DNA, and higher level of circulating DNA may be associated with poor prognosis of HCC patients.     

Circulating DNG level is negatively associated with the long-term survival of hepatocellular carcinoma patients

AIM: To quantify the circulating DNA in plasma from patients with hepatocellular carcinoma (HCC) and to evaluate its prognostic value.METHODS: Blood samples were collected from 79patients with HCC before operation, 20 patients with liver cirrhosis, and 20 healthy volunteers. Circulating DNA was extracted from plasma and quantified. The association between circulating DNA level and prognosis of HCC patients was evaluated.RESULTS: Compared with the healthy volunteers (17.6± 9.5 ng/mL), a significant higher circulating DNA level was found in the patients with HCC (47.1±43.7 ng/mL, P = 0.000) or with liver cirrhosis (30.0 ± 13.3 ng/mL, P = 0.002). The circulating DNA level was closely associated with tumor size (P = 0.008) and TNM stage (P = 0.040), negatively associated with the 3-year diseasefree survival (DFS) (P = 0.017) and overall survival (OS) (P = 0.001).CONCLUSION: Large or invasive tumor may release more circulating DNA, and higher level of circulating DNA may be associated with poor prognosis of HCC patients.     

The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus

Aims: This study was conducted to compare the glycaemic efficacy and safety of initial combination therapy with the fixed‐dose combination of sitagliptin and metformin versus metformin monotherapy in drug‐naive patients with type 2 diabetes. Methods: This double‐blind study (18‐week Phase A and 26‐week Phase B) randomized 1250 drug‐naÏve patients with type 2 diabetes [mean baseline haemoglobin A1c (HbA1c) 9.9%] to sitagliptin/metformin 50/500 mg bid or metformin 500 mg bid (uptitrated over 4 weeks to achieve maximum doses of sitagliptin/metformin 50/1000 mg bid or metformin 1000 bid). Results of the primary efficacy endpoint (mean HbA1c reductions from baseline at the end of Phase A) are reported herein. Results: At week 18, mean change from baseline HbA1c was ?2.4% for sitagliptin/metformin FDC and ?1.8% for metformin monotherapy (p < 0.001); more patients treated with sitagliptin/metformin FDC had an HbA1c value <7% (p < 0.001) versus metformin monotherapy. Changes in fasting plasma glucose were significantly greater with sitagliptin/metformin FDC (?3.8 mmol/l) versus metformin monotherapy (?3.0 mmol/l; p < 0.001). Homeostasis model assessment of β‐cell function (HOMA‐β) and fasting proinsulin/insulin ratio were significantly improved with sitagliptin/metformin FDC versus metformin monotherapy. Baseline body weight was reduced by 1.6 kg in each group. Both treatments were generally well tolerated with a low and similar incidence of hypoglycaemia. Abdominal pain (1.1 and 3.9%; p = 0.002) and diarrhoea (12.0 and 16.6%; p = 0.021) occurred significantly less with sitagliptin/metformin FDC versus metformin monotherapy; the incidence of nausea and vomiting was similar in both groups. Conclusion: Compared with metformin monotherapy, initial treatment with sitagliptin/metformin FDC provided superior glycaemic improvement with a similar degree of weight loss and lower incidences of abdominal pain and diarrhoea.