Exploring the Therapeutic Potential of Metformin in Cirrhotic Patients with Diabetes: Safety, Efficacy, and Future Directions
Cirrhosis is a leading cause of mortality, responsible for over 29,000 deaths annually in the United States and one million deaths worldwide. It ranks as the 12th leading cause of mortality in the U.S. and globally 1, 2. Type 2 diabetes mellitus (T2DM) is a chronic disease that poses a significant public health challenge worldwide and can lead to complications in vital organs 3. In patients with chronic liver disease (CLD), the prevalence of diabetes is high, with approximately 30%–60% of cirrhotic patients having diabetes mellitus. Liver cirrhosis significantly impairs glucose homeostasis, primarily through a defect in glucose uptake, resulting in marked and sustained hyperglycemia. Diabetes is not only highly prevalent in patients with cirrhosis but is also an independent risk factor for poor prognosis. It is associated with the occurrence of major complications of cirrhosis, such as ascites, encephalopathy, renal dysfunction, bacterial infection, and hepatocellular carcinoma. Hence, it is crucial to systematically screen patients with cirrhosis for diabetes 4,5.
The management of diabetes in cirrhosis is hindered by the lack of guidelines and insufficient clinical data on the use of antidiabetic drugs. This review seeks to address the practical management of diabetes using metformin in cirrhosis by analyzing the existing literature.
In this context, the use of metformin, a commonly prescribed oral hypoglycemic agent, in cirrhotic patients with diabetes requires careful consideration. Concerns have been raised regarding the safety of metformin in patients with liver impairment, particularly due to the potential risk of lactic acidosis. As a result, metformin is often discontinued once cirrhosis is diagnosed. However, the evidence linking metformin to liver injury is weak. The incidence of lactic acidosis in diabetic patients treated with metformin is low, ranging from approximately 0.03 to 0.5 cases per 1,000 patient-years. Furthermore, the incidence of lactic acidosis among diabetic patients who take metformin does not differ significantly from the incidence in patients not receiving metformin. Most of the reported cases of lactic acidosis in patients with liver disease are limited to cirrhotic patients who were actively drinking alcohol, which may not represent the general population with cirrhosis and diabetes 6–9.
Despite these concerns, some studies have shown potential benefits of metformin use in the management of diabetes in cirrhosis. These benefits include improved survival, lower risk of hepatocellular carcinoma (HCC), and lower incidence of hepatic encephalopathy. The FDA-approved label for metformin includes a warning about lactic acidosis in patients with hepatic insufficiency, but there is limited evidence supporting this risk 10. Studies assessing the safety and pharmacokinetics of metformin in patients with CLD have shown that plasma metformin and lactate concentrations remain below the safety thresholds, indicating no significant risk of lactic acidosis. These findings suggest that concerns regarding unsafe metformin concentrations in patients with cirrhosis are unwarranted 4, 11.
Emerging evidence supports the continuation of metformin usage in diabetic patients with cirrhosis. A retrospective study investigated the potential effects of metformin on liver inflammation and carcinogenesis and proposed that the continuation of metformin usage after the diagnosis of cirrhosis could lead to improved survival outcomes for diabetic patients. The study included a total of 250 patients, of whom 172 continued metformin while 78 discontinued its use. The findings revealed that patients who continued metformin exhibited a significantly longer median survival compared to those who stopped it (11.8 vs. 5.6 years overall, p< 0.0001; 11.8 vs. 6.0 years for Child A patients, p= 0.006; and 7.7 vs. 3.5 years for Child B/C patients, p= 0.04, respectively). Importantly, even after adjusting for other variables, the continuation of metformin remained an independent predictor of better survival, with a hazard ratio (HR) of 0.43 (95% confidence interval [CI] 0.24 to 0.78; p= 0.005). Notably, no patients developed metformin-associated lactic acidosis during the follow-up period 6.
In another retrospective study involving 191 diabetic patients with biopsy-proven non-alcoholic steatohepatitis (NASH) and advanced fibrosis, the impact of metformin use was examined. Among these patients, 100 were long-term metformin users, while 81 were non-users. The findings revealed that metformin use was associated with a lower risk of overall mortality/transplant (HR 0.42; 95% CI 0.24 to 0.74, p= 0.003) as well as a reduced risk of hepatocellular carcinoma (HR 0.25; 95% CI 0.11 to 0.58; p= 0.001). These associations remained significant even after propensity-score and covariate-adjusted analyses. Importantly, no cases of hepatotoxicity or lactic acidosis were observed. The study provides evidence that long-term metformin use is associated with a decreased risk of all-cause mortality/transplantation and hepatocellular carcinoma in diabetic patients with NASH and advanced fibrosis 12.
Metformin has demonstrated a protective effect against the development of cancer and cancer-related mortality in patients with type 2 diabetes. Specifically, metformin use has been associated with a decreased risk of HCC development in diabetic patients with chronic liver disease. Furthermore, metformin has been independently linked to a reduction in liver-related death in patients with T2DM and hepatitis C virus (HCV)-induced cirrhosis 6.
The incidence of HCC is significant, with approximately 850,000 new cases reported annually, making it the fifth most common cancer worldwide 13. Given the elevated risk of liver cancer in diabetic patients, metformin has gained considerable interest as a potential chemopreventive agent. A meta-analysis conducted in 2017 aimed to investigate the impact of metformin use on liver cancer risk in individuals with diabetes. This analysis, incorporating 19 studies involving 550,882 diabetic subjects, revealed a 48% reduction in the incidence of liver cancer among metformin users compared to non-users (odds ratio [OR] 0.52; 95% CI 0.40 to 0.68). These findings suggest that metformin may have a protective effect against liver cancer in diabetic patients 14.
In patients with T2DM and HCV cirrhosis, the use of metformin has been independently associated with a reduced incidence of HCC and liver-related death or transplantation 15. A meta-analysis of ten studies involving a total of 334,307 patients with 2DM, including 22,650 cases of HCC, revealed a significant 50% reduction in HCC incidence associated with metformin use 16. Compared to treatment with sulphonylureas or insulin, metformin was associated with a significantly lower risk of HCC in both the cirrhosis group (OR 0.16; p= 0.0006) and the control group (OR 0.15; p= 0.005) 17. These findings highlight the potential benefit of metformin as an adjunctive therapy for diabetic patients with CLD, particularly in reducing the risk of HCC and improving patient outcomes.
Similarly, in a 2021 study involving 1,061 cirrhotic patients with T2DM, the use of metformin was associated with a lower incidence of HCC. Among the 719 patients who were exposed to metformin, 17.4% developed HCC, while 37.4% of the 342 patients without metformin exposure developed HCC. Furthermore, the study demonstrated that metformin use was independently associated with a reduced risk of HCC, as determined through multivariate analysis (HR 0.48; 95% CI 0.36 to 0.61; p< 0.001). Moreover, survival analysis of 327 HCC patients revealed that metformin exposure was associated with a longer median survival time (6.9 years vs. 3.88 years; p= 0.003) and improved univariate survival (HR 0.63; 95% CI 0.45 to 0.88; p= 0.006). These findings suggest that the use of metformin in cirrhotic patients with T2DM may not only lower the incidence of hepatocellular carcinoma but also potentially extend survival. Therefore, considering the absence of contraindications, the continued use of metformin should be taken into consideration as part of the treatment strategy for these patients 3.
In another cohort study conducted in 2021 involving 857 patients diagnosed with HCC, the impact of metformin on HCC recurrence was investigated. Among these patients, 222 had T2DM. The study followed these patients for an average of 75 months and found that 54.9% of the patients experienced HCC recurrence, while 18.4% died during the follow-up period. Multivariate analysis was performed to identify independent predictors of recurrence-free survival (RFS). Among the patients with diabetes, high HbA1c levels (>9%), hypoalbuminemia, and vascular invasion were identified as independent risk factors for HCC recurrence. However, the use of metformin did not show a significant impact on HCC recurrence in these diabetic patients who had undergone initial liver resection 13.
Hepatic encephalopathy is one of the major complications of liver cirrhosis, affecting one-third of cirrhotic patients. In a 2012 retrospective cohort study, the influence of metformin use on liver dysfunction and hepatic encephalopathy was investigated in diabetic cirrhotic patients. The study included 82 cirrhotic patients with type 2 diabetes, with 41 patients classified as metformin users and 41 as controls (diabetic cirrhotic patients without metformin treatment). It was found that hepatic encephalopathy occurred in 23.2% with metformin vs. 41.5% without metformin (p= 0.002). They also studied the in vitro glutaminase activity inhibition in colonic epithelial mammalian cell line and found that metformin decreased glutaminase activity up to 24% at 72 h post-treatment (p< 0.05). These findings suggest that metformin use may be protective against hepatic encephalopathy in diabetic cirrhotic patients, possibly through its inhibitory effect on glutaminase activity 18.
Additionally, portal hypertension is a major factor contributing to clinical decompensation in patients with liver cirrhosis. A randomized, double-blind study examined the acute effects of metformin on hepatic venous pressure gradient (HVPG) and liver perfusion. The study included 32 patients with cirrhosis who were given either 1000 mg of metformin or a placebo, and HVPG and liver perfusion were assessed before and 90 minutes after ingestion. The results showed that the metformin group had a mean relative decrease in HVPG of 16%, while the placebo group had a mean increase of 4% (p= 0.008). In patients with baseline HVPG ≥12 mm Hg, a clinically significant improvement in HVPG (HVPG <12 mm Hg or >20% reduction) was observed in 46% of metformin-treated patients compared to 8% of placebo-treated patients (p= 0.07). No significant changes were observed in systemic blood pressure, heart rate, liver hemodynamics, or inflammatory markers between the two groups. The study suggests that a single oral dose of metformin acutely reduces HVPG in patients with portal hypertension without affecting systemic or liver hemodynamics or inflammatory biomarkers. This finding presents a promising perspective for a safe and cost-effective treatment option, which should be further investigated in larger clinical studies with long-term outcomes in patients with cirrhosis and portal hypertension 19.
However, a recent population-based study from the Taiwan National Health Insurance Research Database by Yen et al. found that metformin use was associated with higher risks of mortality and decompensation in patients with compensated cirrhosis. In this 2022 study comparing metformin users and non-users with diabetes and cirrhosis, the incidence rates of all-cause mortality and cirrhotic decompensation were evaluated. The study found that metformin users had slightly higher rates of mortality and cirrhotic decompensation compared to non-users, with adjusted hazard ratios (aHR) of 1.13 and 1.15, respectively. There was a significantly higher risk of death in those who received >1,000 mg of metformin per day, while those who took ≤1,000 mg did not have higher risks. The study suggests that metformin use may be associated with higher risks in patients with compensated liver cirrhosis and highlights the need for prospective studies to confirm these findings. This study lacked complete information on factors such as body weight, alcohol consumption, smoking, physical activity, and family history, which could influence the observed outcomes. The use of clinical diagnosis instead of biochemical results to classify the severity of liver cirrhosis is another limitation. Overall, the study suggests that caution should be exercised, especially with higher doses of metformin, and lower doses may be considered for patients with cirrhosis. Prospective randomized studies are necessary to validate these results and address potential confounding factors 20.
In conclusion, the available epidemiological and clinical evidence suggests several positive effects associated with the use of metformin in patients with T2DM and cirrhosis. These benefits include an increased rate of survival, reduced all-cause mortality, and a decreased risk of HCC development. However, caution should be exercised when considering metformin use in patients with moderately or severely impaired liver function to avoid the potential complications of lactic acidosis. Patients with multiple comorbidities, who are at a higher risk of lactic acidosis, should be particularly monitored closely. Based on the available data, it may be reasonable to prescribe metformin in lower doses for patients with cirrhosis, taking into account the potential benefits and the need for caution. Healthcare providers should carefully evaluate decompensated patients with borderline renal function and avoid metformin use in cirrhotic patients with an estimated glomerular filtration rate (eGFR) of less than 30 ml/min/1.73 m2. It is important to note that individual patient factors, including liver function, renal function, and overall comorbidity profile, should be taken into consideration when making decisions regarding metformin use in patients with cirrhosis. Regular monitoring and close medical supervision are crucial to ensure patient safety and optimize treatment outcomes.
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