BEOORDELINGSRAPPORT METFORMINE

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1 BEOORDELINGSRAPPORT METFORMINE Veiligheids- en doseeradvies Veiligheid: Child-Pugh A+B: Veilig Child-Pugh C: Nadelige effecten bekend Dosering: Child-Pugh A+B: Aanpassing van de dosering is niet nodig Child-Pugh C: Gebruik 50% van de normale dosering Toelichting: Bij Child-Pugh A en B cirrose is er veel bewijs dat metformine veilig gebruikt kan worden en verandert de farmacokinetiek niet. Metformine kan gebruikt worden bij deze patiënten als er geen risicofactoren voor lactaatacidose zijn (nierfunctiestoornissen en actief alcoholgebruik). Bij patiënten met Child-Pugh C cirrose lieten voorspellingen zien dat de blootstelling aan metformine meer dan verdubbeld in vergelijking met controles. Bovendien blijkt uit meerdere case-reports van lactaatacidose dat deze patiënten erg fragiel zijn. Daarom moet indien mogelijk bij deze patiënten een veiliger alternatief worden gekozen en anders 50% van de normale dosering worden gebruikt. Samenvatting van de literatuur Overwegingen Vier studies (bewijsniveau 3) met in totaal 679 patiënten met cirrose (n=26 CTP A/B, n=3 CTP C; rest ernst onbekend) lieten zien dat metformine veilig gebruikt werd. Gebaseerd op de farmacokinetiek van merformine en een modelleringsstudie (niveau ) blijkt dat de blootstelling aan metformine bij Child- Pugh A en B cirrose niet klinisch relevant verandert. Daarom is het geclassificeerd als veilig en wordt er geen dosisaanpassing geadviseerd. Bij Child-Pugh C werd er echter een meer dan verdubbelde blootstelling aan metformine voorspeld. In vijf case-reports (niveau ) trad er lactaatacidose op in patiënten met cirrose, in sommige van deze waren risicofactoren aanwezig. Enkele laten zien dat de patiënt met gevorderde cirrose erg fragiel is en dat shock of een infectie wellicht makkelijker lactaatacidose kan uitlokken. Tevens hebben we weinig bewijs gevonden dat metformine veilig gebruikt kan worden bij patiënten met Child-Pugh C en zijn er veiligere alternatieven. Vanwege deze risico s, is het geclassificeerd als nadelige effecten bekend. Gebaseerd op de resultaten van de modelleringsstudie wordt aangeraden om 50% van de normale dosering te gebruiken, indien toch toegepast. Farmacokinetische gegevens De biologische beschikbaarheid van metformine is ongeveer 50-60% en de plasma-eiwitbinding is te verwaarlozen. Metformine is een hydrofiele base die bij fysiologische ph gekatoniseerd is. Metformine wordt onveranderd uitgescheiden in de urine. Een farmacokinetische modelleringsstudie voorspelde dat de blootstelling bijna verdubbelde in Child-Pugh B en meer dan verdubbelde in Child-Pugh C cirrose. De auteurs leggen uit dat deze verhogingen waarschijnlijk komen door: een verminderde nierfunctie, en verminderde uptake van metformine in de lever en een verminderde biliaire uitscheiding van metformine door OCT1. Veiligheid Het belangrijkste risico bij metformine is het optreden van lactaatacidose. Door cirrose kan de klaring van lactaat verminderd zijn, met als risico stapeling van lactaat en lactaatacidose. Vele studies bewijzen dat metformine, ook bij patiënten met Child-Pugh A en B cirrose, veilig gebruikt kan worden zonder dat deze bijwerking optreedt. Een grote retrospective studie bepaalde het risico bij diabetes type 2 patiënten en 3 patiënten met leverdysfunctie (meeste cirrose) werden geincludeerd. Geen van deze patiënten ontwikkelde lactaatacidose en leverdysfunctie verhoogde niet het risico op lactaatacidose. Er zijn vijf case-reports bekend van een lactaatacidose bij metformine-gebruik. Twee patiënten (Child- Pugh B) werden opgenomen met misselijkheid, braken en zuurstofgebrek met hoge lactaat-spiegels. Een had een verleden van alcoholmisbruik en gebruikte 500 mg dagelijks, hij ontwikkelde vervolgens nierfunctiestoornissen in het ziekenhuis. Hij herstelde na hemofiltratie. De andere patiënt gebruikte 1 gram per dag en was tijdens opname gediagnosticeerd met bacteriële peritonitis en hoge lactaatspiegels. In het ziekenhuis traden er nierfunctiestoornissen op en werd aan een septische shock gedacht. De patiënt overleefde het niet. In de drie andere case-reports was er echter ook sprake van andere risicofactoren. Twee patiënten waren bekend met alcoholmisbruik en een patiënt had acute nierfunctiestoornissen. In het laatste case-report dachten ze aan een overdosis metformine, maar de patiënt had ook eindstadium nierfalen. Om het risico op lactaatacidose te minimaliseren is het daarom van belang dat metformine niet wordt toegepast bij patiënten met andere risicofactoren voor een lactaatacidose; een verminderde nierfunctie of alcoholgebruik. Veranderingen: classificatie van metformine bij Child-Pugh C cirrose is veranderd van veilig in nadelige effecten bekend gebaseerd op nieuwe literatuur. 1

2 Product informatie Metformine BEOORDELINGSRAPPORT METFORMINE Rubriek Metfocell 500 mg tabletten Dutch SPC 5.2 Absorptie Biologische beschikbaarheid is ongeveer 50-60%. De absorptie is verzadigbaar en onvolledig. t max= 2,5 uur Farmacokinetiek van metformine-absorptie is niet-lineair % van de niet-geabsorbeerde fractie wordt teruggevonden in de feces Distributie Metformine verdeelt zich in de erytrocyten, deze lijken een secundair distributiecompartiment. Het verdelingsvolume ligt tussen de liter. De plasma-eiwitbinding is te verwaarlozen. Steady state plasmaconcentraties worden binnen 2-28 uur bereikt. Metabolisme Wordt onveranderd uitgescheiden in de urine. Bij de mens is geen enkele metaboliet geïdentificeerd. Eliminatie Renale klaring is >00 ml/min, dit geeft aan dat metformine wordt geëlimineerd door glomerulaire filtratie en tubulaire secretie. Halfwaardetijd is ong. 6,5 uur..3 Contraindicaties Leverfunctiestoornis, acute alcoholvergiftiging en alcoholisme.. Bijzondere waarschuwingen Leverinsufficiëntie is een risicofactor voor het optreden van lactaatacidose.5 Interacties Gebruik van alcohol bij een leverinsufficiëntie wordt niet aangeraden in verband met een toegenomen risico op lactaatacidose 2

3 1. Literature review Search strategy Pubmed ("Liver cirrhosis"[mesh] OR cirrho*[tiab] OR "hepatic impairment"[tiab] OR "liver impairment"[tiab] OR "hepatic dysfunction"[tiab] OR "liver dysfunction"[tiab] OR "hepatic insufficiency"[tiab] OR "liver insufficiency"[tiab]) AND ("Metformin"[Mesh] OR "metformin"[tiab]) NOT ("animals"[mesh Terms] NOT "humans"[mesh Terms]) Embase ('liver cirrhosis'/exp OR cirrho*:ti OR 'hepatic impairment':ti OR 'liver impairment':ti OR 'hepatic dysfunction':ti OR 'liver dysfunction':ti OR 'hepatic insufficiency':ti OR 'liver insufficiency':ti) AND ('metformin'/exp OR 'metformin':ab,ti) AND [humans]/lim Flowchart (2019 Update) Records found in databases Pubmed: n=66 Embase: n=136 Title and abstract screened (n=202) Removal of duplicate studies (n=29) Excluded records (n=173) - No cirrhosis (n=87) o NAFLD (n=5) o Viral hepatitis (n=8) o Transplantation (n=3) o Cholestatic liver disease (n=) o Other (n=18) - No metformin (n=6) - Drug-induced liver injury (n=2) - Animal study (n=6) - Molecular level (n=16) - Other (n=18) Complete studies screened (n=22) Excluded records (n=12) - Unsure if cirrhosis (n=6) - No metformin (n=2) - Other outcome (n=) Additional records found n=0 Included studies (n=10) 3

4 Search strategy Pubmed ("Liver Diseases"[Mesh] OR "Liver cirrhosis"[tiab] OR "Liver failure"[tiab]) AND ("Metformin"[Mesh] OR "metformin"[tiab]) AND "humans"[mesh Terms] Embase 'liver cirrhosis'/exp OR 'liver cirrhosis' AND ('metformin'/exp OR 'metformin') AND [humans]/lim Cochrane reviews ("liver disease" or "liver cirrhosis" or "liver impairment" or "liver dysfunction" or "liver failure") and ("metformin") Flowchart Records found in databases Pubmed: n=329 Embase: n=503 Cochrane: n=8 Title and abstract screened (n= 916) Excluded records (n=828) - No cirrhosis (n=605) o NAFLD (n=5) o Hepatitis (n=51) o Other (n=100) - No metformin (n=58) - Risk HCC (n=5) - Drug-induced liver injury (n=36) - Molecular level (n=) - Other (n=0) Removal of duplicate studies (n=20) Complete studies screened (n=68) Additional records found References: n=1 Citation tracking via Web of Science: n=1 Excluded records (n=9) - No cirrhosis (n=6) - Drug-induced-liver injury: (n=1) - No metformin (n= ) - Animal study (n=1) - Other outcome (n=2) - Other (n= 13) Included studies (n=21)

5 2. Summary tables of literature 2019 Update: pharmacokinetic studies Level of evidence Rhee; 2017 Design PBPK modelling study Reference Intervention Simulation of multiple administration of metformin 500 mg/12 h Healthy Cirrhotic patients Remarks Results controls CTP A CTP B CTP C Young adults n= X n= X n= X First-order absorption/pbpk model was built in Simcyp. A Cmax, SS (mg/l) mechanistic kidney model (Mech Ratio KiM) and a permeability-limited liver model (PerL) were used for AUCτ, SS (mg.h/l) renal and hepatic disposition Ratio It is presumed that the effect of hepatic impairment on tmax SS (h; range) metformin PK primarily comes from the correlation between Clpo SS (l/h) renal function and the severity Elderly of cirrhosis Decreasing renal and hepatic Cmax, SS (mg/l) clearance contributed to Ratio increased metformin exposure Simulated values of increased AUCτ, SS (mg.h/l) exposure larger for hepatic Ratio impairment than for renal impairment tmax SS (h; range) Simulation, no real PK study (-) Clpo SS (l/h) Results are expressed as simulated median value. ratio= ratio [cirrhotic patients/healthy controls]. 5

6 2019 Update: safety studies Level of evidence 3 Reference Trinkley; 2018 Jacobs; 2018 Nakaruna; 2017 Brönniman n; 2017 Design Patients Intervention -Metformin only group (n=2,936) Retrospective cohort ICD codes mainly used for cirrhosis or complications Casereport 58-yr-old man with cirrhosis due to hepatitis C and end-stage renal disease on hemodialysis Casereport Casereport Diagnosis of type 2 diabetes 71-yr-old man with alcoholic cirrhosis (CTP B) 72-yr-old man with cirrhosis (CTP B) due to NASH -other antihyperglycemic agent group (n=15,059) Admitted for nausea and vomiting caused by lactic acidosis Admitted for loss of appetite and vomiting Admitted for nausea, vomiting and breathlessness Control Results Remarks No medication group (n= 92,785) Hepatic dysfunction defined by ICD-9 code: 571.2, , Among the included patients with hepatic dysfunction (n=3), only 2 patients in the no medication group suffered from acidosis. In this study, hepatic dysfunction was the only potential risk factor for acidosis that did not significantly increase the risk of acidosis (unadjusted RR=3., 95% CI= ). His medications included glimepiride 0.5 mg daily, lactulose, rifaximin, sevelamer, pantoprazole and ergocalciferol. The lactic acidosis resolved with intermittent hemodialysis and the patient was discharged in stable condition after days. However he was admitted again after 36 h for lactic acidosis The patient s pill bottles were opened and it turned out metformin 1 g tablets were mixed in the sevelamer bottle. He had probably been taking 6 g of metformin per day. A plasma metformin level sent from the blood specimen obtained during the second admission, later returned elevated at 33 μg/ml (therapeutic range: 1 2 μg/ml). He was using 500 mg metformin per day Approximately 18 hours before presentation, he developed increasing abdominal pain associated with vomiting and shortness of breath. Marked leucocytosis and renal insufficiency (egfr: 36.1 ml/min/1.73 m2) emerged, other values showed almost no interval change compared with his baseline. Owing to haemodynamic instability with metabolic acidosis, urgent continuous haemodiafiltration was given: it was immediately effective in reducing lactate levels; ph values completely normalized within 18 hours, and he was stabilized and improved. Suffered from type 2 diabetes, treated with metformin 1 g/d. Also: irbesartan, aspirin, torasemide and spironolactone. Paracentesis performed at admission and spontaneous bacterial peritonitis diagnosed, treated with ceftriaxone. Worsened overnight and admitted to ICU with suspicion of septic shock, also decreasing renal function (6 22 ml/min). Lactate stayed high and metformin-associated lactate acidosis was suspected (metformin 6.02 mg/l) in addition to the shock Liver function declined as noted through coagulation function. There were no further treatment options and therapy was ended. The patient died at day 8. Overdose of metformin. Concurrent end-stage renal disease. No information on recent alcohol intake Authors pay no attention to risk of cirrhosis on MALA in discussion? Lactate acidosis possibly induced by shock, acute renal failure and cirrhosis 6

7 Safety data Level of evidence Reference Vyas; 2016 Zhang; 201 Nkontchou 2011 Design Patients Intervention RCT Cirrhosis + Metformin NASH (n=98; (n=50) all CTP A/B) Retrospective cohort study Observational prospective cohort study Continued metformin use after diagnosis of cirrhosis (n=172; 133 CTP-A; 33 CTP-B; 3 CTP-C) 100 diabetic patients with ongoing HCV compensated cirrhosis HCV= hepatitis C virus, NASH= non-alcoholic steatohepatitis Comparison of survival between the groups Metformin therapy (n=26) Control Results Remarks Conventional therapy (n=8) Discontinuation of metformin use within 3 months of cirrhosisdiagnosis (n=78; 8 CTP-A; 28 CTP-B; 2 CTP-C) - Metformin was safe and was not associated with hypoglycaemia or lactic acidosis Main reason for discontinuation of metformin was the diagnosis of cirrhosis (n=61; 78% of patients who discontinued metformin) The median time of metformin use in the continued metformin group was 26.8 months (range, ). The median survival of patients who continued metformin was significantly greater than that of patients who discontinued metformin after cirrhosis diagnosis (11.8 vs. 5.6 years; P<0.0001). Metformin use was significantly associated with a 57% reduction in risk of all-cause mortality in diabetic patients with all stages of cirrhosis (HR, 0.3; 95% CI: ; P=0.0001) Our data suggest that metformin is safe in diabetic patients with cirrhosis because no patients developed lactic acidosis while receiving metformin in our cohort. Liver-related death or transplantation was less frequent in metformin-treated patients than in those not treated with metformin (P 0.01 either considering log-rank or Gray test) No severe complications were observed with metformin treatment. This could partly be explained by the fact that patients with HCV cirrhosis stopped or strongly limited alcohol consumption after the diagnosis. Furthermore, the patients with severe lifethreatening disease, especially cardiac and renal failures, were not included in this cohort. Abstract (-) No details on dosage of metformin No details on severity of cirrhosis 7

8 Level of evidence Referenc e Edwards; 2003 Houwerzijl 2000 Design Patients Intervention Casereport Casereport 0-year-old man 52-jarige vrouw, bekend met overmatig alcoholgebruik (20 jr), DM2 (5jr) en leverfunctiestoornissen Admitted to hospital with shortage of breath at rest, Opgenomen met klachten van haemetemesis, buikpijn en kortademigheid Control Results Remarks - - Arterial blood gas analysis on 60% oxygen revealed severe metabolic acidosis: ph 6.62, pco2 8.3 kpa, po2 7.8 kpa, base excess -31.2, bicarbonate 6. mmol/l, anion gap 37 mmol/l. Serum lactate was extremely high at >20 mmol/l. He had a normal creatinine of 63 mmol/l and hypoglycaemia was confirmed by a venous plasma glucose of 1.9 mmol/l He had been diagnosed with type 2 diabetes 3 years prior to admission. He had not been seen at diabetic clinic for over 2 years, when his diabetes was well controlled with metformin 850 mg twice daily. Eighteen months previously, he was admitted with alcoholic hepatitis, his metformin was not stopped, and he subsequently failed to attend the gastroenterology clinic. The patient developed multi-organ failure and died. Postmortem examination revealed alcoholic cirrhosis. Gebruikte voor DM: tolbutamide 500 mg 2 dd en metformine 850 mg 3 dd. Laatst gemeten serumcreatinine-concentratie, 1 jaar vóór opname, was 71 mmol/l. Bij opname ong. liter sherry gedronken, medicatie wel gebruikt. Lactaatacidose (lactaat> 30mmol/L), met daarnaast o.a. albumine verlaagd, stollingstijden verlengd, hoog ammoniak en creatinine 119 µmol/l. Lever- en nierfunctie verslechterden progressief; 23 dagen na opname overleden. Obductie toonde beeld van macronodulaire cirrose. No renal dysfunction Concomitant Alcohol use Acute renal dysfunction Concomitant severe alcohol use Dutch publication 8

9 Reviews (level 5 evidence) Data of the main reviews are provided in the table, the other retrieved reviews did not provide additional information and are only included as reference. Reference Outcome Expert opinion García- Compeán; Ann of Hepatol; 2015 Scheen; Exp Op Drug Metabol & Toxicol; 201 Loomba; Hepatol; 201 PK Safety PK Safety Safety Metformin is not metabolized in the liver and is excreted almost unchanged by the kidney. Metformin is not recommended in patients with liver cirrhosis by fear of inducing lactic acidosis. However, this complication was reported only in anecdotal cases, particularly with concomitant alcohol intake. Two recent studies have shown that this drug reduced incidence of liver complications and increased survival of patients with liver cirrhosis. In one study, a significant reduction in the incidence of hepatocellular carcinoma and liver complications was observed in patients with DM and HCV cirrhosis after treatment of an average period of 5.7 years. In another study, the long-term survival of diabetic patients with liver cirrhosis who continued taking metformin was longer than the ones who stopped it. Reduction in mortality was also significant in patients with stages B and C of Child Pugh. No patient developed lactic acidosis during a follow up period of 26.8 months. Although these studies did not report the glycemic effects, it is likely that better glycemic control was a contributor to reduced morbidity and mortality. The low incidence of lactic acidosis reported in these studies is encouraging, though caution should still be taken when considering its use in patients with advanced liver failure. Metformin, a biguanide compound, is considered as the first-line drug for the treatment of T2DM. Chemically, it is a hydrophilic base that exists at physiological ph as the cationic species. Consequently, its passive diffusion through hepatocyte membranes is very limited as well as liver metabolism. No metabolites or conjugates of metformin have been identified. Metformin undergoes renal excretion. The elimination is prolonged in patients with renal impairment and correlates with creatinine clearance, even in patients with HI. In contrast, liver impairment stricto sensu should not interfere with the PK of metformin. However, no PK studies are available in patients with chronic liver disease (CLD). Recent experimental data in animals showed that metformin sinusoidal efflux from the liver is consistent with negligible biliary excretion and absence of enterohepatic cycling. The use of metformin has been limited in many diabetic patients considered as at risk of complications, especially lactic acidosis. Manufacturer prescribing information and some current literature caution against metformin use in patients with CLD. This recommendation is interpreted variably by different prescribers, with some believing that the caution implies metformin can cause or worsen liver injury and others rather believing that liver disease predisposes patients to developing lactic acidosis. Metformin does not appear to cause or exacerbate liver injury and, indeed, may be beneficial in patients with NAFLD. The liver appears to be a key organ not only for the antidiabetic effect of metformin but also for the development of lactic acidosis. Literature evidence of liver disease being implicated with metformin-associated metabolic acidosis is largely represented by case reports. Most such patients had cirrhosis, with some degree of renal impairment. For this reason, it seems reasonable to use metformin with caution in patients with moderate CLD and to avoid its use in patients with severe CLD. Furthermore, identifying patients with cirrhosis and controlling renal function before initiating metformin seem prudent. Any circumstance favoring dehydration should promote the interruption of metformin, especially in such fragile patients. Metformin is generally considered safe and well-tolerated. The most common adverse effects include nausea, vomiting, abdominal discomfort, diarrhea, and weight loss. Lactic acidosis is the most severe adverse effect but fortunately it is extremely rare. Furthermore, metformin should not be used in patients with elevated serum creatinine ( 1.7 mg/dl) due to increased risks of precipitating lactic acidosis. Therefore, monitoring of serum creatinine while on metformin would be needed to ensure patient safety, especially in a group of patients with cirrhosis who have diabetes, as they are at increased risk of developing both acute and chronic kidney disease. In addition, physicians are cautioned about the need to temporarily discontinue metformin at least 8 hours prior to any radiographic study that involves intravenous iodinated contrast administration (such as a contrast-enhanced computed tomography for HCC surveillance) due to the risks of contrast nephropathy resulting in lactic acidosis related to concurrent use of metformin. Despite these caveats, metformin is among the safest medications for the treatment of diabetes and would be an acceptable choice to most patients. 9

10 3. References 1. Zhang, et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology (6) 2. Nkontchou, et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. Journal of Clinical Endocrinology and Metabolism (8) 3. Edwards CM, et al. Metformin-associated lactic acidosis in a patient with liver disease. QJM Apr;96(): Houwerzijl EJ, et al. Severe lactic acidosis due to metformin therapy in a patient with contra-indications for metformin. Nederlands tijdschrift voor geneeskunde 1.0 (2000): García-Compeán D, et al. The treatment of diabetes mellitus of patients with chronic liver disease. Ann of Hepatol : Scheen AJ. Pharmacokinetic and toxicological considerations for the treatment of diabetes in patients with liver disease. Expert Opin Drug Metab Toxicol. 201 Jun;10(6): Loomba R. Rationale for conducting a randomized trial to examine the efficacy of metformin in improving survival in cirrhosis: Pleiotropic effects hypothesis. Hepatology 60.6 (201): Reviews with no additional information beyond included review 8. Khan, et al. Managing diabetes in patients with chronic liver disease. Postgraduate medicine 12. (2012): Traussnigg S. Challenges and Management of Liver Cirrhosis: Practical Issues in the Therapy of Patients with Cirrhosis due to NAFLD and NASH. Digestive Diseases (): M Kishimoto. Verification of glycemic profiles using continuous glucose monitoring. J of Medical Invest (1-2): Ahmadieh, H et al. Liver disease and diabetes: Association, pathophysi-ology, and management. Diabet Rese and Clin Pract 201(1): H Schatz, et al. Main safety concern of bloodglucose lowering substances - Metformin.Diabetes Aktuell (6): Tschöpe D. The role of co-morbidity in the selection of antidiabetic pharmacotherapy in type-2 diabetes. Cardiovascular Diabetology Harris K, et al. Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis Annals of Pharmacother 7 (10) Lewis JH, et al. Review article: prescribing medications in patients with cirrhosis a practical guide. Alimentary pharmacology & therapeutics (2013): Scheen A, et al. Metformin revisited: A critical review of the benefit risk balance in at-risk patients with type 2 diabetes. Diabetes & metabolism 39.3 (2013): Gundling F. Metabolic disturbances in liver cirrhosis (part 2), hepatoge-nous diabetes: Diagnostic aspects and treatment Deut Mediz Wochensch :1-2 (22-) 18. Garcia-Compean D. Liver cirrhosis and diabetes: Risk factors, pathophysiology, clinical implications and management. World J of Gastroenterol (3): Gundling F. Hepatogenous diabetes - Diagnostics and treatment.zeitschr fur Gastroenterol (5): Tolman, et al. Spectrum of liver disease in type 2 diabetes and management of patients with diabetes and liver disease. Diabetes care 30.3 (2007): Tolman, et al. Narrative Review: Hepatobiliary Disease in Type 2 Diabetes Mellitus. Ann Intern Med. 200;11: References of 2019 update 1. Rhee SJ, Chung H, Yi S, Yu KS, Chung JY. Physiologically Based Pharmacokinetic Modelling and Prediction of Metformin Pharmacokinetics in Renal/Hepatic-Impaired Young Adults and Elderly Populations. Eur J Drug Metab Pharmacokinet (6): Trinkley KE, Anderson HD, Nair KV, Malone DC, Saseen JJ.Assessing the incidence of acidosis in patients receiving metformin with and without risk factors for lactic acidosis. Ther Adv Chronic Dis (9): Jacob T, Garrick R, Goldberg MD. Recurrent lactic acidosis and hypoglycemia with inadvertent metformin use: a case of look-alike pills. Endocrinol Diabetes Metab Case Rep pii: doi: /EDM Nakamura A, Suzuki K, Imai H, Katayama N. Metformin-associated lactic acidosis treated with continuous renal replacement therapy. BMJ Case Rep doi: /bcr Brönnimann A, Rudofsky G, Paganoni R, Studhalter M. Wenn die Therapie den Patienten bedroht. Praxis (Bern) (25):

11 Reviews with no additional information beyond included review 6. Tacelli M, Celsa C, Magro B, Giannetti A, Pennisi G, Spatola F, Petta S. Antidiabetic Drugs in NAFLD: The Accomplishment of Two Goals at Once? Pharmaceuticals (Basel) (). pii: E121. doi: /ph Gangopadhyay KK, Singh P. Consensus Statement on Dose Modifications of Antidiabetic Agents in Patients with Hepatic Impairment.,"/pubmed/ "," Indian J Endocrinol Metab (2): doi: /ijem.IJEM_512_16 8. Elkrief L, Rautou PE, Sarin S, Valla D, Paradis V, Moreau R. Diabetes mellitus in patients with cirrhosis: clinical implications and management. Liver Int (7): Pfeiffer A.F.H. Hepatogenous diabetes. Diabetologe (2016) 12:7 (68-72). 10. Grancini V, Resi V, Palmieri E, Pugliese G, Orsi E. Management of diabetes mellitus in patients undergoing liver transplantation. Pharmacological Research (2019) 11 ( ). 11