An Approach to the Management of Diabetes Mellitus in Cirrhosis: A Primer for the Hepatologist
2021; Elsevier BV; Volume: 12; Issue: 2 Linguagem: Inglês
10.1016/j.jceh.2021.09.010
ISSN2213-3453
Autores Tópico(s)Pancreatic function and diabetes
ResumoThe management of diabetes in cirrhosis and liver transplantation can be challenging. There is difficulty in diagnosis and monitoring of diabetes as fasting blood sugar values are low and glycosylated hemoglobin may not be a reliable marker. The challenges in the management of diabetes in cirrhosis include the likelihood of cognitive impairment, risk of hypoglycemia, altered drug metabolism, frequent renal dysfunction, risk of lactic acidosis, and associated malnutrition and sarcopenia. Moreover, calorie restriction and an attempt to lose weight in obese diabetics may be associated with a worsening of sarcopenia. Many commonly used antidiabetic drugs may be unsafe or be associated with a high risk of hypoglycemia in cirrhotics. Post-transplant diabetes is common and may be contributed by immunosuppressive medication. There is inadequate clinical data on the use of antidiabetic drugs in cirrhosis, and the management of diabetes in cirrhosis is hampered by the lack of guidelines focusing on this issue. The current review aims at addressing the practical management of diabetes by a hepatologist. The management of diabetes in cirrhosis and liver transplantation can be challenging. There is difficulty in diagnosis and monitoring of diabetes as fasting blood sugar values are low and glycosylated hemoglobin may not be a reliable marker. The challenges in the management of diabetes in cirrhosis include the likelihood of cognitive impairment, risk of hypoglycemia, altered drug metabolism, frequent renal dysfunction, risk of lactic acidosis, and associated malnutrition and sarcopenia. Moreover, calorie restriction and an attempt to lose weight in obese diabetics may be associated with a worsening of sarcopenia. Many commonly used antidiabetic drugs may be unsafe or be associated with a high risk of hypoglycemia in cirrhotics. Post-transplant diabetes is common and may be contributed by immunosuppressive medication. There is inadequate clinical data on the use of antidiabetic drugs in cirrhosis, and the management of diabetes in cirrhosis is hampered by the lack of guidelines focusing on this issue. The current review aims at addressing the practical management of diabetes by a hepatologist. Diabetes Mellitus is common in patients with chronic liver disease (CLD) and is associated with an increased risk of hepatic complications and mortality in patients with cirrhosis.1Harrison S.A. Liver disease in patients with diabetes mellitus.J Clin Gastroenterol. 2006; 40: 68-76Google Scholar, 2de Marco R. Locatelli F. Zoppini G. Verlato G. Bonora E. Muggeo M. Cause-specific mortality in type 2 diabetes. The verona diabetes study.Diabetes Care. 1999; 22: 756-761Google Scholar, 3Bianchi G. Marchesini G. Zoli M. Bugianesi E. Fabbri A. Pisi E. Prognostic significance of diabetes in patients with cirrhosis.Hepatology. 1994; 20: 119-125Google Scholar Management of diabetes mellitus in CLD can be challenging for the clinician due to the risk of hypoglycemia, frequent renal dysfunction, and altered drug metabolism. Many hypoglycemic drugs are either contraindicated or should be used with caution. While there is an emphasis on personalized patient care in patients with diabetes, the management of diabetes in patients with chronic liver disease has not been adequately addressed. The recently published 2021 update to the American Diabetes Association (ADA) Standards of Medical Care in Diabetes4American Diabetes AssociationStandards of medical care in diabetes—2021.Diabetes Care. 2021; 44: S1-S232Google Scholar has sections in the guidelines giving individualized recommendations in patients with cardiovascular disease, diabetic kidney disease, etc. However, there are no recommendations for patients with liver disease. This review focuses on the management of diabetes mellitus in a patient with cirrhosis of the liver. Diabetes is common in patients with CLD, and approximately 30%–60% of cirrhotic patients will have diabetes mellitus.5García Compean D. Jaquez-Quintana J.O. Maldonado-Garza H. Hepatogenous diabetes. Current views of an ancient problem.Ann Hepatol. 2009; 8: 13-20Google Scholar A systemic review and metanalysis of the prevalence of diabetes in cirrhosis found that the overall prevalence of diabetes was 31%, and the prevalence of diabetes was highest in patients with nonalcoholic fatty liver disease (56%), cryptogenic (51%), hepatitis C virus (HCV) (32%), or alcoholic cirrhosis.6Lee W.G. Wells C.I. McCall J.L. Murphy R. Plank L.D. Prevalence of diabetes in liver cirrhosis: a systematic review and meta-analysis.Diabetes Metab Res Rev. 2019; 35: e3157Google Scholar The prevalence of diabetes is higher in patients with nonalcoholic steatohepatitis (NASH), HCV infection, hereditary hemochromatosis, hepatocellular carcinoma (HCC), and alcoholism.7Tolman K.G. Fonseca V. Dalpiaz A. Tan M.H. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease.Diabetes Care. 2007; 30: 734-743Google Scholar, 8Mehta S.H. Strathdee S.A. Thomas D.L. Association between hepatitis C virus infection and diabetes mellitus.Epidemiol Rev. 2001; 23: 302-312Google Scholar, 9Singh B.M. Grunewald R.A. Press M. Muller B.R. Wise P.H. Prevalence of haemochromatosis amongst patients with diabetes mellitus.Diabet Med. 1992; 9: 730-731Google Scholar, 10Lai M.S. Hsieh M.S. Chiu Y.H. Chen T.H. Type 2 diabetes and hepatocellular carcinoma: a cohort study in high prevalence area of hepatitis virus infection.Hepatology. 2006; 43: 1295-1302Google Scholar, 11Hsieh P.S. Hsieh Y.J. Impact of liver diseases on the development of type 2 diabetes mellitus.World J Gastroenterol. 2011; 17: 5240-5245Google Scholar The high prevalence of cirrhosis in patients with NASH is attributable to the fact that insulin resistance is common in the pathogenesis of both the disorders.12Chitturi S. Abeygunasekera S. Farrell G.C. et al.NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome.Hepatology. 2002; 35: 373-379Google Scholar,13Schattenberg J.M. Schuppan D. Nonalcoholic steatohepatitis: the therapeutic challenge of a global epidemic.Curr Opin Lipidol. 2011; 22: 479-488Google Scholar The association of HCV with liver disease is also explained by higher insulin resistance due to higher steatosis, inflammation, and fibrosis, as well as beta-cell dysfunction.14Grancini V. Trombetta M. Lunati M.E. et al.Contribution of β-cell dysfunction and insulin resistance to cirrhosis-associated diabetes: role of severity of liver disease.J Hepatol. 2015; 63: 1484-1490Google Scholar The pathogenesis of diabetes in hemochromatosis, is due to loss of insulin-secreting capacity, and insulin resistance secondary to liver damage.15Pelusi C. Gasparini D.I. Bianchi N. Pasquali R. Endocrine dysfunction in hereditary hemochromatosis.J Endocrinol Invest. 2016; 39: 837-847Google Scholar Independent of cirrhosis, the risk of HCC has been shown to be increased in diabetes, and metabolic syndrome.16Kasmari A.J. Welch A. Liu G. Leslie D. McGarrity T. Riley T. Independent of cirrhosis, hepatocellular carcinoma risk is increased with diabetes and metabolic syndrome.Am J Med. 2017; 130: 746.e1-746.e7Google Scholar Hyperglycemia, hyperinsulinemia, insulin resistance, and activation of insulin-like growth factor (IGF) signaling pathway may play a role in initiation and progression of HCC. The hyperglycemia initiates modification in cell vasculature and results in defects in endothelial cells. Insulin, IGF-1, and vascular endothelial growth factor (VEGF) can stimulate the proliferation of hepatocytes.17Singh M.K. Das B.K. Choudhary S. Gupta D. Patil U.K. Diabetes and hepatocellular carcinoma: a pathophysiological link and pharmacological management.Biomed Pharmacother. 2018; 106: 991-1002Google Scholar Insulin therapy has been related to a higher risk of HCC18Chang C.H. Lin J.W. Wu L.C. Lai M.S. Chuang L.M. Oral insulin secretagogues, insulin, and cancer risk in type 2 diabetes mellitus.J Clin Endocrinol Metab. 2012; 97: E1170-E1175Google Scholar, while metformin19Zhang H. Gao C. Fang L. Zhao H.C. Yao S.K. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis.Scand J Gastroenterol. 2013; 48: 78-87Google Scholar and statins20Kim G. Jang S.Y. Nam C.M. Kang E.S. Statin use and the risk of hepatocellular carcinoma in patients at high risk: a nationwide nested case-control study.J Hepatol. 2018; 68: 476-484Google Scholar are associated with a lower risk. Management of diabetes in patients with cirrhosis has challenges not only in diagnosis but also in management.21Hamed A.E. Elsahar M. Elwan N.M. et al.Managing diabetes and liver disease association.Arab J Gastroenterol. 2018; 19: 166-179Google Scholar,22Gangopadhyay K.K. Singh P. Consensus statement on dose modifications of antidiabetic agents in patients with hepatic impairment.Indian J Endocrinol Metab. 2017; 21: 341-354Google Scholar Diagnosis of diabetes mellitus in cirrhosis is confounded by inappropriately low fasting blood sugar and glycosylated hemoglobin A1c (HbA1c). The lower fasting blood sugar may be due to impaired gluconeogenesis and decreased glycogen storage in the liver. HbA1c reflects the previous 2–3 months of glycemic status and is commonly used to diagnose and monitor patients with diabetes. However, HbA1c may be falsely low because of shortened erythrocyte life span resulting from hemolysis due to hypersplenism or blood loss due to gastrointestinal bleeding.23Krishnan S.M. Dixit N.M. Estimation of red blood cell lifespan from alveolar carbon monoxide measurements.Transl Res. 2009; 154: 15-17Google Scholar The utility of HbA1c has been compared against the oral glucose tolerance test (OGTT). Considering OGTT as the gold standard, the sensitivity of HbA1c for diagnosing diabetes was good when evaluated in outpatients with cirrhosis. However, the sensitivity of HbA1c for diagnosing diabetes decreased when it was used for hospitalized patients with cirrhosis. The sensitivity of HbA1c for diagnosing diabetes was also low in patients with moderate to severe anemia.24Sehrawat T. Jindal A. Kohli P. et al.Utility and limitations of glycated hemoglobin (HbA1c) in patients with liver cirrhosis as compared with oral glucose tolerance test for diagnosis of diabetes.Diabetes Ther. 2018; 9: 243-251Google Scholar These fallacies of fasting blood sugar and HbA1c have implications in diagnosing and monitoring patients with cirrhosis. The management of diabetes in patients with cirrhosis may be affected by cognitive impairment due to overt hepatic encephalopathy and unrecognized minimal hepatic encephalopathy. Cognitive impairment may impact their self-management of diabetes due to forgetting to take drugs, errors in calculating insulin dose, or missing meals. They may also have difficulty in prevention, recognition, or treatment of hypoglycemia.25American Diabetes Association12. Older adults: standards of medical care in diabetes-2021.Diabetes Care. 2021; 44: S168-S179Google Scholar Insulin resistance is common in patients with cirrhosis.26Kawaguchi T. Taniguchi E. Itou M. Sakata M. Sumie S. Sata M. Insulin resistance and chronic liver disease.World J Hepatol. 2011; 3: 99-107Google Scholar Also, there is reduced insulin clearance due to loss of hepatic mass and portosystemic shunting, putting cirrhotic patients at risk of hypoglycemia. Cirrhotic patients have low glycogen storage and inadequate gluconeogenesis, hampering their ability to combat hypoglycemia. Glycemic targets and the therapeutic regimen should, therefore, be tailored to avoid hypoglycemic events. Fasting is a common practice of many religions and cultures, which may affect the management of diabetes.27Saboo B. Joshi S. Shah S.N. et al.Management of diabetes during fasting and feasting in India.J Assoc Phys India. 2019; 67: 70-77Google Scholar Fasting may make cirrhotic patients prone to develop hypoglycemia, and they may require appropriate dose adjustment. Decreased portal blood flow, increased hepatic arterial resistance, and portosystemic shunting contribute to the hepatic first-pass drug extraction. Capillarization of sinusoids may also interfere with the transfer of drugs to the hepatocytes. These may lead to higher serum concentrations of the drugs.28Edginton A.N. Willmann S. Physiology-based simulations of a pathological condition: prediction of pharmacokinetics in patients with liver cirrhosis.Clin Pharmacokinet. 2008; 47: 743-752Google Scholar,29Le Couteur D.G. Fraser R. Hilmer S. Rivory L.P. McLean A.J. The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance.Clin Pharmacokinet. 2005; 44: 187-200Google Scholar Metabolism and excretion of the oral hypoglycemic drugs may be affected by hepatic dysfunction.30Hamed A.E. Abas B. Shaltout I. Esmt G. Gomez R. Managing diabetes and liver disease association, guidelines (consensus) development.J Endocrinol Diabetes Obes. 2015; 3: 1-19Google Scholar Patients with cirrhosis have reduced hepatic metabolism, altered intestinal mucosal permeability, and intestinal microbiota changes. Cytochrome P-450 (CYP-450) metabolic activity is also decreased in patients with cirrhosis.31Dietrich C.G. Götze O. Geier A. Molecular changes in hepatic metabolism and transport in cirrhosis and their functional importance.World J Gastroenterol. 2016; 22: 72-88Google Scholar Hypoalbuminemia and dilution from fluid retention results in increased free plasma concentration of protein-bound drugs.32Garcia-Martinez R. Caraceni P. Bernardi M. Gines P. Arroyo V. Jalan R. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications.Hepatology. 2013; 58: 1836-1846Google Scholar Cholestasis can also impact drug clearance.33Delcò F. Tchambaz L. Schlienger R. Drewe J. Krähenbühl S. Dose adjustment in patients with liver disease.Drug Saf. 2005; 28: 529-545Google Scholar These factors can affect absorption, distribution, bioavailability, metabolism, and elimination of drugs.34Kumar R. Hepatogenous diabetes: an underestimated problem of liver cirrhosis.Indian J Endocr Metab. 2018; 22: 552-559Google Scholar, 35Lewis J.H. Stine J.G. Review article: prescribing medications in patients with cirrhosis – a practical guide.Aliment Pharmacol Ther. 2013; 37: 1132-1156Google Scholar, 36Papazafiropoulou A. Melidonis A. Antidiabetic agents in patients with hepatic impairment.World J Meta-Anal. 2019; 7: 380-388Google Scholar Renal dysfunction is frequent in patients with cirrhosis due to multiple factors that may result in the accumulation of the oral hypoglycemic drug or its metabolite. Patients with cirrhosis may be prone to lactic acid accumulation with metformin, especially in the presence of sepsis and renal failure.37Ahya S.N. José Soler M. Levitsky J. Batlle D. Acid-base and potassium disorders in liver disease.Semin Nephrol. 2006; 26: 466-470Google Scholar,38DeFronzo R. Fleming G.A. Chen K. Bicsak T.A. Metformin-associated lactic acidosis: current perspectives on causes and risk.Metabolism. 2016; 65: 20-29Google Scholar Malnutrition and sarcopenia are common in patients with liver disease. Increased dietary requirements for malnutrition and sarcopenia may affect glycemic control in diabetic patients with cirrhosis. Dietary restrictions to manage obesity may also result in the worsening of sarcopenia. Some oral hypoglycemic drugs have a risk of hepatotoxicity and need to be avoided or require modifications in their doses in patients with cirrhosis. Patients with cirrhosis already have marginal liver functions at baseline, and even mild hepatocellular injury may tilt the balance. The specific issues in the management of diabetes in cirrhosis are enumerated in Table 1.Table 1Issues in the Management of Diabetic Patients with Cirrhosis.•Difficulty in diagnosis and monitoring of diabetic patients with cirrhosis:-Lower fasting blood sugar-HbA1C levels are poor indicators of glycemic control•Hepatic encephalopathy and cognitive impairment may affect self-management•Altered drug metabolism distribution and excretion:-Reduced hepatic first-pass extraction of drugs due to portosystemic shunting-Lower hepatic mass-Reduced cytochrome P450 metabolic activity-Alterations in plasma proteins and altered protein binding of drugs-Altered intestinal mucosal permeability-Cholestasis may affect hepatic excretion•High risk of hypoglycemia•Malnutrition and sarcopenia with resultant increased nutritional requirements•Renal dysfunction is common, resulting in a risk of lactic acidosis•Hepatotoxicity of some oral hypoglycemic drugs Open table in a new tab As has been enumerated above, diagnosis of diabetes mellitus using fasting blood sugar and HbA1c may not be accurate. Since fasting blood sugar may be lower in cirrhotics, fasting blood glucose alone may miss diabetes. Postprandial blood glucose measurement should also be done, and OGTT should be considered. Glycated albumin and fructosamine may reflect the glycemic status more accurately than HbA1c. However, due to their shorter half-life, they would reflect glycemic control over 2–3 weeks. However, their efficacy needs further validation.39Trenti T. Cristani A. Cioni G. Pentore R. Mussini C. Ventura E. Fructosamine and glycated hemoglobin as indices of glycemic control in patients with liver cirrhosis.Ric Clin Lab. 1990; 20: 261-267Google Scholar Frequent self-monitoring of blood glucose (SMBG) may be necessary for managing diabetes in patients with cirrhosis and should be done preprandial and 2 h postprandially. However, SMBG does not provide trend information on glucose or glycemic variations, and SMBG can never pick up nocturnal hypoglycemia. On the other hand, continuous glucose monitoring systems can provide complete information on fluctuations in glucose and may be considered in those on insulin or those with recurrent hypoglycemic episodes and to assess glycemic variability.40Honda F. Hiramatsu A. Hyogo H. et al.Evaluation of glycemic variability in chronic liver disease patients with type 2 diabetes mellitus using continuous glucose monitoring.PLoS One. 2018; 13e0195028Google Scholar The issues in diagnosis and monitoring diabetic patients with cirrhosis are depicted in Table 2.Table 2Diagnosis and Monitoring of Diabetic Patients with Cirrhosis.•Fasting blood sugar may be lower in cirrhotics•Glycosylated hemoglobin (HbA1c) may be unreliable in cirrhosis, especially in patients with shortened red blood cell half-life•Glycated albumin and fructosamine may reflect glycemic status more accurately than HbA1C in cirrhosis•Frequent self-monitoring of blood glucose and continuous glucose monitoring may be considered Open table in a new tab Assessment of nutritional status for malnutrition and sarcopenia should be done before planning diet and pharmacotherapy for patients with diabetes and cirrhosis. While anthropometric measurements can be used in patients with compensated cirrhosis without fluid retention, body mass index (BMI) may not be an accurate tool in patients with ascites and edema. Computerized tomography or magnetic resonance imaging can be used to assess sarcopenia by calculating skeletal muscle index in patients with decompensated cirrhosis who undergo these tests for other indications. Patients with NASH or alcohol-related cirrhosis are often obese. Despite having increased adiposity, these patients may have reduced muscle mass, referred to as sarcopenic obesity.41Periyalwar P. Dasarathy S. Malnutrition in cirrhosis: contribution and consequences of sarcopenia on metabolic and clinical responses.Clin Liver Dis. 2012; 16: 95-131Google Scholar,42Hong H.C. Hwang S.Y. Choi H.Y. et al.Relationship between sarcopenia and nonalcoholic fatty liver disease: the Korean Sarcopenic Obesity Study.Hepatology. 2014; 59: 1772-1778Google Scholar Diet and physical activity are the first steps in the management of diabetes mellitus in patients with cirrhosis. Exercise improves sarcopenia and favors weight loss in obese cirrhotic patients. Exercise improves insulin sensitivity and liver steatosis, which is unrelated to weight loss.43Sullivan S. Kirk E.P. Mittendorfer B. Patterson B.W. Klein S. Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease.Hepatology. 2012; 55: 1738-1745Google Scholar Patients should be advised 150–300 min of moderately intense physical activity per week in 3–5 sessions.44European association for the study of the liver (EASL), European association for the study of diabetes (EASD) and European association for the study of obesity (EASO). EASL–EASD–EASO clinical practice guidelines for the management of nonalcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Google Scholar,45Lassailly G. Caiazzo R. Pattou F. Mathurin P. Perspectives on treatment for nonalcoholic steatohepatitis.Gastroenterology. 2016; 150: 1835-1848Google Scholar Besides aerobic training, resistance training (repetitive weight-based exercises to improve muscle strength) also improves nonalcoholic fatty liver disease (NAFLD).46Zelber-Sagi S. Buch A. Yeshua H. et al.Effect of resistance training on nonalcoholic fatty-liver disease a randomized-clinical trial.World J Gastroenterol. 2014; 20: 4382-4392Google Scholar,47Hallsworth K. Fattakhova G. Hollingsworth K.G. et al.Resistance exercise reduces liver fat and its mediators in nonalcoholic fatty liver disease independent of weight loss.Gut. 2011; 60: 1278-1283Google Scholar Dietary recommendations need to not only achieve glycemic control but also avoid the worsening of sarcopenia and malnutrition. The nutritional requirements of cirrhotics are calorie intake of 35–40 kcal/kg/day and daily protein requirement of 1.2 gm/kg48Swart G.R. van den Berg J.W. van Vuure J.K. Rietveld T. Wattimena D.L. Frenkel M. Minimum protein requirements in liver cirrhosis determined by nitrogen balance measurements at three levels of protein intake.Clin Nutr. 1989; 8: 329-336Google Scholar in the absence of malnutrition or 1.5 gm/kg in the presence of malnutrition.44European association for the study of the liver (EASL), European association for the study of diabetes (EASD) and European association for the study of obesity (EASO). EASL–EASD–EASO clinical practice guidelines for the management of nonalcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Google Scholar Multiple, small, frequent meals are recommended to prevent prolonged periods of fasting. A higher protein breakfast and an energy-dense late evening snack of complex carbohydrates are recommended.49Vaisman N. Katzman H. Carmiel-Haggai M. Lusthaus M. Niv E. Breakfast improves cognitive function in cirrhotic patients with cognitive impairment.Am J Clin Nutr. 2010; 92: 137-140Google Scholar,50Plank L.D. Gane E.J. Peng S. et al.Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial.Hepatology. 2008; 48: 557-566Google Scholar Processed foods and foods and beverages high in added fructose should not be included in the diet.51Puri P. Dhiman R.K. Taneja S. et al.Nutrition in chronic liver disease: consensus statement of the Indian national association for study of the liver.J Clin Exp Hepatol. 2021; 11: 97-143Google Scholar Management of obesity may be complex in obese patients with cirrhosis and diabetics as dietary restrictions worsen sarcopenia. Only moderate calorie restriction (500–800 kcal/day) should be done.44European association for the study of the liver (EASL), European association for the study of diabetes (EASD) and European association for the study of obesity (EASO). EASL–EASD–EASO clinical practice guidelines for the management of nonalcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Google Scholar Protein intake needs to be maintained or even increased to achieve weight loss without inducing muscle catabolism.52Dasarathy S. Merli M. Sarcopenia from mechanism to diagnosis and treatment in liver disease.J Hepatol. 2016; 65: 1232-1244Google Scholar A weight reduction of 5–10% should be targeted.44European association for the study of the liver (EASL), European association for the study of diabetes (EASD) and European association for the study of obesity (EASO). EASL–EASD–EASO clinical practice guidelines for the management of nonalcoholic fatty liver disease.J Hepatol. 2016; 64: 1388-1402Google Scholar There is no evidence of the safety of antiobesity drugs in patients with cirrhosis. There are few reports of bariatric surgery53Shimizu H. Phuong V. Maia M. et al.Bariatric surgery in patients with liver cirrhosis.Surg Obes Relat Dis. 2013; 9: 1-6Google Scholar and intragastric balloon54Choudhary N.S. Puri R. Saraf N. et al.Intragastric balloon as a novel modality for weight loss in patients with cirrhosis and morbid obesity awaiting liver transplantation.Indian J Gastroenterol. 2016; 35: 113-116Google Scholar in cirrhotic patients with obesity. There are few therapeutic studies of the safety and efficacy of antidiabetic drugs in patients with cirrhosis.55García-Compeán D. González-González J.A. Lavalle-González F.J. González-Moreno E.I. Maldonado-Garza H.J. Villarreal-Pérez J.Z. The treatment of diabetes mellitus of patients with chronic liver disease.Ann Hepatol. 2015; 14: 780-788Google Scholar Cirrhotic patients are predisposed to hypoglycemia, and therefore, drugs associated with a low risk of hypoglycemia are preferred. Besides insulin, the other antidiabetic drugs are the insulin sensitizers (metformin and thiazolidinediones), secretagogues (sulfonylureas and meglitinides), incretin-based therapies [dipeptidyl-peptidase 4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists] and drugs that interfere with glucose absorption or reabsorption [inhibitors of α-glucosidase and sodium-glucose cotransporter 2 (SGLT2)].(a)Metformin Metformin improves insulin resistance, promotes weight loss, and has a low risk of hypoglycemia. It is recommended as the first-line agent in the management of patients with type 2 diabetes mellitus. However, there have been concerns about the safety of metformin in patients with cirrhosis. While there has been concern about the risk of lactic acidosis in patients with advanced liver disease, this risk is rare in patients without renal dysfunction.56Edwards C.M.B. Barton M.A. Snook J. David M. Mak V.H. Chowdhury T.A. Metformin associated lactic acidosis in a patient with liver disease.QJM. 2003; 96: 315-316Google Scholar,57Misbin R.I. Green L. Stadel B.V. Gueriguian J.L. Gubbi A. Fleming G.A. Lactic acidosis in patients with diabetes treated with metformin.N Engl J Med. 1998; 338: 265-266Google Scholar Metformin is avoided by many clinicians in patients with cirrhosis due to exaggerated concern for metformin-associated lactic acidosis (MALA). However, MALA is extremely rare and estimated to be < 10 per 100,000 patient-years of exposure in patients without significant renal impairment. MALA is more likely in patients who develop acute renal dysfunction due to dehydration, vomiting, diarrhea, etc., especially in elderly patients with low glomerular filtration rates.38DeFronzo R. Fleming G.A. Chen K. Bicsak T.A. Metformin-associated lactic acidosis: current perspectives on causes and risk.Metabolism. 2016; 65: 20-29Google Scholar Even in patients with renal impairment with estimated glomerular filtration rates (eGFR) of 10–30 ml/min/1.73 m2, it has been suggested that using a lower dose (500–1,500 mg/day) may be safe.58Adam W.R. O'Brien R.C. A justification for less restrictive guidelines on the use of metformin in stable chronic renal failure.Diabet Med. 2014; 31: 1032-1038Google Scholar Some studies have shown that metformin use in the management of diabetes in patients with liver disease may be safe and be associated with better survival, lower risk of HCC, and lower hepatic encephalopathy. The pharmacokinetics of metformin is not altered sufficiently in CLD patients, and unsafe plasma lactate concentrations have not been observed in CLD patients receiving metformin to raise concerns regarding its safety.59Smith F.C. Stocker S.L. Danta M. et al.The safety and pharmacokinetics of metformin in patients with chronic liver disease.Aliment Pharmacol Ther. 2020; 51: 565-575Google Scholar Long-term metformin use may improve clinical outcomes in diabetic patients with cirrhosis.60Vilar-Gomez E. Vuppalanchi R. Desai A.P. et al.Long-term metformin use may improve clinical outcomes in diabetic patients with nonalcoholic steatohepatitis and bridging fibrosis or compensated cirrhosis.Aliment Pharmacol Ther. 2019; 50: 317-328Google Scholar Zhang et al61Zhang X. Harmsen W.S. Mettler T.A. et al.Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes.Hepatology. 2014; 60: 2008-2016Google Scholar have shown that continuation of metformin use after diagnosis of cirrhosis significantly improved survival of patients with diabetes (overall survival 11.8 vs. 5.6 years; P < 0.0001). In patients with type 2 diabetes and HCV cirrhosis, the use of metformin was independently associated with reduced incidence of HCC and liver-related death/transplantation.62Nkontchou G. Cosson E. Aout M. et al.Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients.J Clin Endocrinol Metab. 2011; 96: 2601-2608Google Scholar A meta-analysis of 19 studies involving 550,882 diabetic subjects found that, relative to nonuse, metformin reduced liver cancer ratio by 48%.63Ma S. Zheng Y. Xiao Y. Zhou P. Tan H. Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients.Medicine (Baltimore). 2017; 96: e6888Google Scholar It has been shown that metformin reduces the risk of hepa
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