- Email: [email protected]
Metformin-Associated Lactic Acidosis
Special Feature CASE REPORT/FOCUSED REVIEW
Metformin-Associated Lactic Acidosis
Authors Francisco J. Pasquel, MD, Robin Klein, MD, Adaeze Adigweme, MD, Ziad Hinedi, MD, Richard Coralli, MD, Juan L. Pimentel, MD and Guillermo E. Umpierrez, MD Editor Fred A. Lopez, MD Abstract: Metformin is the most commonly prescribed oral antidiabetic agent. Despite a good safety profile in most patients with diabetes, the risk of metformin-associated lactic acidosis is real if safety guidelines are ignored. Experience with 3 cases of metformin-associated lactic acidosis is reported. Two cases were caused by inappropriate use of metformin in the presence of renal, cardiac and hepatic failure and 1 case followed an intentional overdose. The literature was reviewed on the clinical presentation, prevalence, pathogenesis, prognosis and management of metformin-associated lactic acidosis. This report highlights the importance of proper patient selection, clinical and laboratory monitoring and recommendation on when to stop the drug in ambulatory and hospitalized patients to prevent this unusual but potentially lethal complication. Key Indexing Terms: Diabetes; Acidosis; Lactate; Metformin; Inpatient diabetes. [Am J Med Sci 2015;349(3):263–267.]
M
etformin is the most commonly prescribed oral antidiabetic agent for the management of type 2 diabetes (T2D).1 The mechanism of action is not completely understood, but experimental and human data have shown that metformin reduces hepatic glucose production by inhibiting key enzymes in the gluconeogenesis pathway and by mitochondrial depletion of the energy necessary for gluconeogenesis.2 In addition, it improves islet cell responsiveness to a glucose load through the correction of glucose toxicity and improves peripheral glucose utilization by enhancing muscle uptake of glucose.3 Metformin also seems to modulate components of the incretin axis, increasing glucagon-like peptide 1 levels and the expression of From the Divisions of Endocrinology (FJP, ZH, GEU) and General Medicine (RK, AA), Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Atlanta Heart Group (RC), Atlanta, Georgia; and Northwest Nephrology Clinic (JLP), Decatur, Georgia. Submitted January 29, 2013; accepted in revised form May 15, 2013. The authors have no financial or other conflicts of interest to disclose. Correspondence: Guillermo E. Umpierrez, MD, Division of Endocrinology, Department of Medicine, Emory University School of Medicine, 49 Jesse Hill Jr Dr, Atlanta, GA 30303 (E-mail: [email protected]).
The American Journal of the Medical Sciences
genes encoding receptors for both glucagon-like peptide 1 and glucose-dependent insulinotropic peptide.4,5 Despite its introduction in Europe and Canada in 1957, metformin was not licensed in the United States until 1995 because of fear of lactic acidosis, a rare but fatal complication associated with phenformin.6 The risk of lactic acidosis during metformin therapy has been the matter of continuous debate.7–12 Data from comparative trials, cohort studies and meta-analyses have reported a frequency of lactic acidosis in 2 to 5 cases per 100,000 patients receiving metformin, a similar risk observed in patients with diabetes not receiving the drug.8,13–15 Impaired kidney function is the most important risk factor for metforminassociated lactic acidosis. In the United States, the use of metformin is contraindicated in men and women with serum creatinine concentrations $1.5 mg/dL and $1.4 mg/dL ($132 and $123 mmol/L), respectively. The National Institute for Health and Clinical Excellence in the United Kingdom recommends that metformin may be continued (or initiated) with estimated glomerular filtration rates (eGFR) ,60 mL/min per 1.73 m2; to reduced dose when the eGFR falls below 45 mL/min per 1.73 m2 and stopping when the eGFR is less than 30 mL/min per 1.73 m2.7 Similarly, the Canadian Diabetes Association and the Australian Diabetes Society recommend as contraindication to metformin use when the eGFR is ,30 mL/min per 1.73 m2.7,16 A history of heart failure was also considered a contraindication to the use of metformin; however, the Food and Drug Administration removed heart failure as contraindication from the packaging label in 200617 after several observational studies reported lower morbidity and mortality in stable patients with a history of heart failure compared with other antidiabetic medications.18–21 There is lack of randomized studies on the safety and efficacy of metformin in the hospital setting. Metformin is commonly used for the management of inpatients with hyperglycemia,7,8 and it is estimated that up to 1/4 of hospitalized patients with T2D are treated with metformin, even in the presence of contraindications.22 The inpatient use of metformin seems to be well tolerated, in particular in those who were receiving the drug before admission, with few patients experiencing serious adverse effects or pH changes
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during the hospital stay.22 These reports have raised questions about restrictions to prescribe metformin.7,8 The excellent efficacy and safety profile of metformin use in patients with diabetes have resulted in poor patient selection and ignoring safety guidelines, with recent reports suggesting increasing numbers of cases of metformin-associated lactic acidosis around the world.23–30 To highlight the need of caution, we report our experience of 3 patients presenting with metforminassociated lactic acidosis and review the clinical presentation, prognosis and recommended approaches for managing metformin-associated lactic acidosis.
CASE PRESENTATIONS Case 1 A 70-year-old patient with T2D treated with metformin (500 mg twice daily), dilated cardiomyopathy (ejection fraction of 10%) and stage III chronic kidney disease (serum creatinine: 1.5 mg/dL, eGFR: 59.4 mL/min per 1.73 m2) presented with chest pain and progressive shortness of breath. On admission, his blood pressure was 149/77 mm Hg and heart rate was 60 beats per minute with Kussmaul respiratory pattern. Examination revealed bilateral lung crackles in the bases and the presence of S3 and S4 gallops, but no peripheral edema. Admission laboratory tests showed acute kidney injury with creatinine of 2.8 mg/dL, a lactic acid level of 11.1 mmol/L (normal , 2.2 mmol/L), an arterial pH of 7.03, a serum bicarbonate of 3.8 mmol/L, an anion gap of 26 mEq/L, blood glucose of 206 mg/ dL and negative serum ketones. Chest x-ray showed no evidence of pulmonary edema. The patient underwent emergent hemodialysis. The patient’s high gap metabolic acidosis promptly resolved after dialysis. Predialysis metformin level was 25 mg/mL (therapeutic range: 1–2 mg/mL), and postdialysis metformin was 1.5 mg/mL (Table 1). Case 2 A 56-year-old male patient with T2D, cirrhosis, hepatitis C and hepatocellular carcinoma presented after a syncopal spell. One-day before admission, he underwent liver biopsy and paracentesis with removal of 4 L of ascitic fluid. On admission, his blood pressure was 86/64 mm Hg (mean arterial pressure 71 mm Hg), heart rate was 95 beats per minute and saturation was 100%. Examination revealed the presence of jaundice, ascites and pretibial pitting edema. Lungs were clear to auscultation, and no jugular venous distention was noted. Laboratory results
revealed acute kidney injury with a creatinine of 2.1 mg/dL (baseline 1.1 mg/dL), bicarbonate of 18 mEq/L and anion gap of 12 mEq/L. Diuretics and lisinopril were held but metformin (500 mg twice daily) was continued. On day 3, the patient developed altered mental status and respiratory failure. Laboratory results revealed worsening renal function with a serum creatinine of 3.2 mg/dL, a lactic acid level of 10.6 mmol/L, an arterial pH of 7.0, PCO2 of 21 mm Hg, bicarbonate of 4 mEq/L, anion gap of 47 mEq/L, aspartate aminotransferase of 3598 U/L, alanine aminotransferase of 898 U/L and international normalized ratio of 7.0. He underwent emergency hemodialysis with correction of the high anion gap metabolic acidosis. Predialysis metformin level was 31 mg/mL (therapeutic range: 1–2 mg/mL), and postdialysis metformin level was 5.4 mg/mL. Case 3 A 60-year-old man with T2D treated with a combination of metformin and neutral protamine Hagedorn and regular insulin presented after an intentional metformin overdose. The patient reported ingesting more than 10 metformin tablets (500 mg) in the setting of alcohol use. On arrival, he was in mild distress with stable vital signs. He was treated with activated charcoal and intravenous hydration. Laboratory studies showed a serum creatinine of 0.8 mg/dL, pH of 7.35, anion gap of 22 mEq/L and a lactic level of 7.4 mmol/L. The patient was admitted to the medical intensive care unit with a plan for hemodialysis; however, his clinical status improved with conservative measures with resolution of metabolic acidosis during the next 24 hours.
DISCUSSION Metformin is the most commonly prescribed oral antidiabetic agent for the management of patients with T2D. Metformin is safe when used correctly, and in properly selected patients, there is no increased risk of lactic acidosis compared with non-metformin–treated patients.13,31 The risk of metformin-associated lactic acidosis is remarkably low with a frequency similar to that reported in patients with diabetes not receiving metformin treatment.8,13 The COSMIC trial evaluated the risk of serious adverse events including lactic acidosis with metformin therapy among 7,227 patients with T2D treated with metformin for more than 1 year.31 This trial reported no significant differences in the frequency of serious adverse events compared with patients not receiving metformin therapy. A 2010 Cochrane systematic review reported no increase in the
TABLE 1. Characteristics of patients with metformin-associated lactic acidosis Case 1 Case 2
Case 3
Age, yr 70 56 60 Risk factor for lactic acidosis CKD stage III, AKI, heart failure Cirrhosis, AKI Alcohol abuse, metformin overdose Diabetes treatment Metformin monotherapy Metformin monotherapy Metformin, NPH/R insulin Serum creatinine before admission, mg/dL 1.5 1.1 0.8 Admission serum creatinine, mg/dL 2.8 2.1 0.8 Admission eGFR 30.3 40 .60 Serum bicarbonate, mEq/L 3.8 4 9 Anion gap 26 47 22 Arterial pH 7.03 7.0 7.35 Lactic acid level, mmol/L 11.1 10.6 .10 Serum metformin level, U/L 25 31 N/A Therapy Hemodialysis Hemodialysis Activated charcoal, hydration CKD, chronic kidney disease; AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; N/A, data not available; NPH, neutral protamine Hagedorn insulin; R, regular insulin.
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number of cases of lactic acidosis across 347 clinical trials, with 70,490 patient-years of metformin use.8 Patients with diabetes, however, as indicated in this report, are at increased risk of developing lactic acidosis if safety guidelines are ignored and the drug is continued in the presence of contraindications. Impaired kidney function is the most important risk factor for metformin-associated lactic acidosis. Other risk factors include the presence of decompensated heart failure, hypoxemia, alcoholism, cirrhosis, contrast exposure, sepsis and shock8,16 (Figure 1). Recent observational studies have reported a higher than expected number of cases of metformin-associated lactic acidosis.26–30 The reported cases of inquiries to the Swedish Poison Information Centre for metformin intoxication and lactic acidosis increased 10 times during the past decade, with 25 cases of severe lactic acidosis in 2007 and 2008.30 In 2 recent studies,27,29 the estimated incidence of metforminassociated lactic acidosis was 30 to 47 cases per 100,000 patient-years, which represents a 5 to 16 times higher incidence than previously reported.31 The American Association of Poison Control Centers reported that metformin contributed to 21 fatalities in the United States in 2008,23 and 49 cases of lactic acidosis and accidental metformin accumulation resulting in 11 deaths were also reported by the Poison Control Centre of Pavia, Italy, between January 2005 and August 2010.32 Lactic acid, the product of anaerobic glycolysis, is primarily produced and is fully dissociated into lactate and protons in both extracellular and intracellular fluids. Several studies have reported a small but significant increase in lactic acid levels with metformin use, in particular after meals.6,32–39 Metformin raises lactic acid levels by affecting the redox potential and promoting anaerobic metabolism.40 It interferes with complex I of the respiratory chain, leading to an inhibition of mitochondrial respiration.41 In the presence of hypoxia or tissue hypoperfusion, it can block mitochondrial oxidative phosphorylation inhibiting adenosine triphosphate (ATP) synthesis, leading to a decrease in the ATP:ADP ratio and an increase in the NADH:NAD ratio. This can result in an accumulation of pyruvate (by inhibition of pyruvate dehydrogenase) that is later converted into lactate. This conversion allows for the regeneration of NAD+, enabling the production of ATP by
anaerobic glycolysis, a much less efficient pathway.42,43 Increasing evidence indicates genetic differences that may explain interindividual variation in clinical response as well as renal clearance and bioavailability of the drug.44,45 Drug transporters, including plasma membrane monoamine transporter (PMAT), organic cation transporters (OCT-1, -2 and -3) and multidrug and toxin extrusion transporter 1 (MATE-1), have been recognized to play a major role in the absorption, distribution and elimination of metformin.46,47 In animal models, it was recently reported that MATE-1 dysfunction can lead to lactic acidosis after metformin treatment.48 Measurement of metformin plasma concentration is important in confirming the involvement of the drug in patients with suspected metformin-associated lactic acidosis. The mean plasma concentrations of metformin in healthy subjects fluctuate between about 0.5 and 1 mg/L while fasting and 1 to 2 mg/L after a meal.6,46 Metformin concentrations in erythrocytes may be more useful than plasma levels because it better represents tissue accumulation.40,49 After confirmation of the diagnosis, treatment should rapidly involve forced diuresis or hemodialysis, both of which favor rapid elimination of the drug.40 The estimated mortality rate of metformin-associated lactic acidosis has been reported between 30% and 60%,14,26,50–52 but more favorable outcomes have been reported with the use of intermittent hemodialysis or with continuous renal replacement therapy.32,40,52 In general, the prognosis depends on the severity of underlying pathologic conditions (ie, renal and liver failure, sepsis, heart failure).52,53 In summary, extensive data from clinical studies and meta-analyses have shown that metformin is an effective and safe drug when used in properly selected patients. Despite a mild increase in serum concentration of lactic acid, metformin rarely results in metabolic acidosis unless it is inappropriately used in patients with disorders associated with increased generation of lactate acid or in impaired clearance of metformin. For most ambulatory patients, metformin-associated lactic acidosis should be considered as a preventable complication if we avoid or stop its use in the presence of impaired renal function (eGFR ,45 mL/min per 1.73 m2), liver failure, severe hypoxia, heart failure, surgery and alcohol use. The safety and efficacy of metformin in
FIGURE 1. Pathogenesis of metforminassociated lactic acidosis.
Copyright © 2013 by the Southern Society for Clinical Investigation.
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the hospital setting has not been established. Proper patient selection and stopping the drug in ambulatory patients with impaired kidney function and significant comorbidities, as well as in hospitalized patients with acute illnesses are needed to prevent most cases of metformin-associated metabolic acidosis.
21. Aguilar D, Chan W, Bozkurt B, et al. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ Heart Fail 2011;4:53–8.
REFERENCES
23. Calabrese AT, Coley KC, DaPos SV, et al. Evaluation of prescribing practices: risk of lactic acidosis with metformin therapy. Arch Intern Med 2002;162:434–7.
1. Diamant M. Choosing a blood-glucose-lowering agent after metformin. Lancet 2012;379:2220–1. 2. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167–74. 3. Nyenwe EA, Jerkins TW, Umpierrez GE, et al. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism 2011;60:1–23. 4. Maida A, Lamont BJ, Cao X, et al. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. Diabetologia 2011;54:339–49. 5. Cho YM, Kieffer TJ. New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser. Diabetologia 2011;54:219–22. 6. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574–9. 7. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011;34:1431–7. 8. Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010;CD002967.
22. Kosmalski M, Drozdowska A, Sliwinska A, et al. Inappropriate metformin prescribing in elderly type 2 diabetes mellitus (T2DM) patients. Adv Med Sci 2012;57:65–70.
24. Holstein A, Nahrwold D, Hinze S, et al. Contra-indications to metformin therapy are largely disregarded. Diabet Med 1999;16:692–6. 25. Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 1997;20:925–8. 26. Peters N, Jay N, Barraud D, et al. Metformin-associated lactic acidosis in an intensive care unit. Crit Care 2008;12:R149. 27. van Berlo-van de Laar IR, Vermeij CG, Doorenbos CJ. Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements. J Clin Pharm Ther 2011;36: 376–82. 28. Biradar V, Moran JL, Peake SL, et al. Metformin-associated lactic acidosis (MALA): clinical profile and outcomes in patients admitted to the intensive care unit. Crit Care Resusc 2010;12:191–5. 29. Nyirenda MJ, Sandeep T, Grant I, et al. Severe acidosis in patients taking metformin—rapid reversal and survival despite high APACHE score. Diabet Med 2006;23:432–5.
9. Misbin RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care 2004;27:1791–3.
30. Personne M. Alarming increase of the number of metformin intoxications. Ten times doubled number of inquiries to the Swedish Poison Information Center since 2000 [in Swedish]. Lakartidningen 2009;106: 994.
10. Stades AM, Heikens JT, Erkelens DW, et al. Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Intern Med 2004;255:179–87.
31. Cryer DR, Nicholas SP, Henry DH, et al. Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study. Diabetes Care 2005;28:539–43.
11. Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Arch Intern Med 2003;163:2594–602.
32. Vecchio S, Protti A. Metformin-induced lactic acidosis: no one left behind. Crit Care 2011;15:107.
12. Holstein A, Stumvoll M. Contraindications can damage your health— is metformin a case in point? Diabetologia 2005;48:2454–9. 13. Brown JB, Pedula K, Barzilay J, et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care 1998;21:1659–63. 14. Misbin RI, Green L, Stadel BV, et al. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med 1998;338:265–6. 15. Wiholm BE, Myrhed M. Metformin-associated lactic acidosis in Sweden 1977-1991. Eur J Clin Pharmacol 1993;44:589–91. 16. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55:1577–96. 17. Eurich DT, Tsuyuki RT, Majumdar SR, et al. Metformin treatment in diabetes and heart failure: when academic equipoise meets clinical reality. Trials 2009;10:12.
33. Waters AK, Morgan DB, Wales JK. Blood lactate and pyruvate levels in diabetic patients treated with biguanides with and without sulphonylureas. Diabetologia 1978;14:95–8. 34. Czyzyk A, Lao B, Bartosiewicz W, et al. The effect of short-term administration of antidiabetic biguanide derivatives on the blood lactate levels in healthy subjects. Diabetologia 1978;14:89–94. 35. Schaffalitzky de Muckadell OB, Mortensen H, Lyngsoe J. Metabolic effects of glucocorticoid and ethanol administration in phenformin- and metformin-treated obese diabetics. Acta Med Scand 1979;206:269–73. 36. Irsigler K, Kritz H, Regal H, et al. The risk of lacticate acidosis: a comparison of the 3 biguanides in treatment of diabetics (authors’ transl) [in German]. Wien Klin Wochenschr 1978;90:332–7. 37. Abbasi AA, Kasmikha R, Sotingeanu DG. Metformin-induced lacticacidemia in patients with type 2 diabetes mellitus. Endocr Pract 2000; 6:442–6. 38. Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia 2008;51:1552–3.
18. Eurich DT, Majumdar SR, McAlister FA, et al. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 2005;28:2345–51.
39. Hong Y, Rohatagi S, Habtemariam B, et al. Population exposureresponse modeling of metformin in patients with type 2 diabetes mellitus. J Clin Pharmacol 2008;48:696–707.
19. Masoudi FA, Inzucchi SE, Wang Y, et al. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 2005;111:583–90.
40. Keller G, Cour M, Hernu R, et al. Management of metformin-associated lactic acidosis by continuous renal replacement therapy. PLoS One 2011; 6:e23200.
20. Evans JM, Doney AS, AlZadjali MA, et al. Effect of metformin on mortality in patients with heart failure and type 2 diabetes mellitus. Am J Cardiol 2010;106:1006–10.
41. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000;348:607–14.
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42. Levy B, Perez P, Perny J. Where does the lactate come from? A rare cause of reversible inhibition of mitochondrial respiration. Crit Care 2010;14:136. 43. Leverve XM. Mitochondrial function and substrate availability. Crit Care Med 2007;35(suppl 9):S454–60. 44. Leabman MK, Giacomini KM. Estimating the contribution of genes and environment to variation in renal drug clearance. Pharmacogenetics 2003;13:581–4. 45. Tzvetkov MV, Vormfelde SV, Balen D, et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther 2009;86:299–306. 46. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011;50:81–98. 47. Ali S, Fonseca V. Overview of metformin: special focus on metformin extended release. Expert Opin Pharmacother 2012;13:1797–805.
Copyright © 2013 by the Southern Society for Clinical Investigation.
48. Kusuhara H, Ito S, Kumagai Y, et al. Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects. Clin Pharmacol Ther 2011;89:837–44. 49. Lalau JD, Lacroix C. Measurement of metformin concentration in erythrocytes: clinical implications. Diabetes Obes Metab 2003;5:93–8. 50. Luft D, Schmulling RM, Eggstein M. Lactic acidosis in biguanidetreated diabetics: a review of 330 cases. Diabetologia 1978;14:75–87. 51. Scale T, Harvey JN. Diabetes, metformin and lactic acidosis. Clin Endocrinol (Oxf) 2011;74:191–6. 52. Friesecke S, Abel P, Roser M, et al. Outcome of severe lactic acidosis associated with metformin accumulation. Crit Care 2010;14:R226. 53. Lalau JD, Lacroix C, Compagnon P, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care 1995; 18:779–84.
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Authors Francisco J. Pasquel, MD, Robin Klein, MD, Adaeze Adigweme, MD, Ziad Hinedi, MD, Richard Coralli, MD, Juan L. Pimentel, MD and Guillermo E. Umpierrez, MD Editor Fred A. Lopez, MD Abstract: Metformin is the most commonly prescribed oral antidiabetic agent. Despite a good safety profile in most patients with diabetes, the risk of metformin-associated lactic acidosis is real if safety guidelines are ignored. Experience with 3 cases of metformin-associated lactic acidosis is reported. Two cases were caused by inappropriate use of metformin in the presence of renal, cardiac and hepatic failure and 1 case followed an intentional overdose. The literature was reviewed on the clinical presentation, prevalence, pathogenesis, prognosis and management of metformin-associated lactic acidosis. This report highlights the importance of proper patient selection, clinical and laboratory monitoring and recommendation on when to stop the drug in ambulatory and hospitalized patients to prevent this unusual but potentially lethal complication. Key Indexing Terms: Diabetes; Acidosis; Lactate; Metformin; Inpatient diabetes. [Am J Med Sci 2015;349(3):263–267.]
M
etformin is the most commonly prescribed oral antidiabetic agent for the management of type 2 diabetes (T2D).1 The mechanism of action is not completely understood, but experimental and human data have shown that metformin reduces hepatic glucose production by inhibiting key enzymes in the gluconeogenesis pathway and by mitochondrial depletion of the energy necessary for gluconeogenesis.2 In addition, it improves islet cell responsiveness to a glucose load through the correction of glucose toxicity and improves peripheral glucose utilization by enhancing muscle uptake of glucose.3 Metformin also seems to modulate components of the incretin axis, increasing glucagon-like peptide 1 levels and the expression of From the Divisions of Endocrinology (FJP, ZH, GEU) and General Medicine (RK, AA), Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; Atlanta Heart Group (RC), Atlanta, Georgia; and Northwest Nephrology Clinic (JLP), Decatur, Georgia. Submitted January 29, 2013; accepted in revised form May 15, 2013. The authors have no financial or other conflicts of interest to disclose. Correspondence: Guillermo E. Umpierrez, MD, Division of Endocrinology, Department of Medicine, Emory University School of Medicine, 49 Jesse Hill Jr Dr, Atlanta, GA 30303 (E-mail: [email protected]).
The American Journal of the Medical Sciences
genes encoding receptors for both glucagon-like peptide 1 and glucose-dependent insulinotropic peptide.4,5 Despite its introduction in Europe and Canada in 1957, metformin was not licensed in the United States until 1995 because of fear of lactic acidosis, a rare but fatal complication associated with phenformin.6 The risk of lactic acidosis during metformin therapy has been the matter of continuous debate.7–12 Data from comparative trials, cohort studies and meta-analyses have reported a frequency of lactic acidosis in 2 to 5 cases per 100,000 patients receiving metformin, a similar risk observed in patients with diabetes not receiving the drug.8,13–15 Impaired kidney function is the most important risk factor for metforminassociated lactic acidosis. In the United States, the use of metformin is contraindicated in men and women with serum creatinine concentrations $1.5 mg/dL and $1.4 mg/dL ($132 and $123 mmol/L), respectively. The National Institute for Health and Clinical Excellence in the United Kingdom recommends that metformin may be continued (or initiated) with estimated glomerular filtration rates (eGFR) ,60 mL/min per 1.73 m2; to reduced dose when the eGFR falls below 45 mL/min per 1.73 m2 and stopping when the eGFR is less than 30 mL/min per 1.73 m2.7 Similarly, the Canadian Diabetes Association and the Australian Diabetes Society recommend as contraindication to metformin use when the eGFR is ,30 mL/min per 1.73 m2.7,16 A history of heart failure was also considered a contraindication to the use of metformin; however, the Food and Drug Administration removed heart failure as contraindication from the packaging label in 200617 after several observational studies reported lower morbidity and mortality in stable patients with a history of heart failure compared with other antidiabetic medications.18–21 There is lack of randomized studies on the safety and efficacy of metformin in the hospital setting. Metformin is commonly used for the management of inpatients with hyperglycemia,7,8 and it is estimated that up to 1/4 of hospitalized patients with T2D are treated with metformin, even in the presence of contraindications.22 The inpatient use of metformin seems to be well tolerated, in particular in those who were receiving the drug before admission, with few patients experiencing serious adverse effects or pH changes
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during the hospital stay.22 These reports have raised questions about restrictions to prescribe metformin.7,8 The excellent efficacy and safety profile of metformin use in patients with diabetes have resulted in poor patient selection and ignoring safety guidelines, with recent reports suggesting increasing numbers of cases of metformin-associated lactic acidosis around the world.23–30 To highlight the need of caution, we report our experience of 3 patients presenting with metforminassociated lactic acidosis and review the clinical presentation, prognosis and recommended approaches for managing metformin-associated lactic acidosis.
CASE PRESENTATIONS Case 1 A 70-year-old patient with T2D treated with metformin (500 mg twice daily), dilated cardiomyopathy (ejection fraction of 10%) and stage III chronic kidney disease (serum creatinine: 1.5 mg/dL, eGFR: 59.4 mL/min per 1.73 m2) presented with chest pain and progressive shortness of breath. On admission, his blood pressure was 149/77 mm Hg and heart rate was 60 beats per minute with Kussmaul respiratory pattern. Examination revealed bilateral lung crackles in the bases and the presence of S3 and S4 gallops, but no peripheral edema. Admission laboratory tests showed acute kidney injury with creatinine of 2.8 mg/dL, a lactic acid level of 11.1 mmol/L (normal , 2.2 mmol/L), an arterial pH of 7.03, a serum bicarbonate of 3.8 mmol/L, an anion gap of 26 mEq/L, blood glucose of 206 mg/ dL and negative serum ketones. Chest x-ray showed no evidence of pulmonary edema. The patient underwent emergent hemodialysis. The patient’s high gap metabolic acidosis promptly resolved after dialysis. Predialysis metformin level was 25 mg/mL (therapeutic range: 1–2 mg/mL), and postdialysis metformin was 1.5 mg/mL (Table 1). Case 2 A 56-year-old male patient with T2D, cirrhosis, hepatitis C and hepatocellular carcinoma presented after a syncopal spell. One-day before admission, he underwent liver biopsy and paracentesis with removal of 4 L of ascitic fluid. On admission, his blood pressure was 86/64 mm Hg (mean arterial pressure 71 mm Hg), heart rate was 95 beats per minute and saturation was 100%. Examination revealed the presence of jaundice, ascites and pretibial pitting edema. Lungs were clear to auscultation, and no jugular venous distention was noted. Laboratory results
revealed acute kidney injury with a creatinine of 2.1 mg/dL (baseline 1.1 mg/dL), bicarbonate of 18 mEq/L and anion gap of 12 mEq/L. Diuretics and lisinopril were held but metformin (500 mg twice daily) was continued. On day 3, the patient developed altered mental status and respiratory failure. Laboratory results revealed worsening renal function with a serum creatinine of 3.2 mg/dL, a lactic acid level of 10.6 mmol/L, an arterial pH of 7.0, PCO2 of 21 mm Hg, bicarbonate of 4 mEq/L, anion gap of 47 mEq/L, aspartate aminotransferase of 3598 U/L, alanine aminotransferase of 898 U/L and international normalized ratio of 7.0. He underwent emergency hemodialysis with correction of the high anion gap metabolic acidosis. Predialysis metformin level was 31 mg/mL (therapeutic range: 1–2 mg/mL), and postdialysis metformin level was 5.4 mg/mL. Case 3 A 60-year-old man with T2D treated with a combination of metformin and neutral protamine Hagedorn and regular insulin presented after an intentional metformin overdose. The patient reported ingesting more than 10 metformin tablets (500 mg) in the setting of alcohol use. On arrival, he was in mild distress with stable vital signs. He was treated with activated charcoal and intravenous hydration. Laboratory studies showed a serum creatinine of 0.8 mg/dL, pH of 7.35, anion gap of 22 mEq/L and a lactic level of 7.4 mmol/L. The patient was admitted to the medical intensive care unit with a plan for hemodialysis; however, his clinical status improved with conservative measures with resolution of metabolic acidosis during the next 24 hours.
DISCUSSION Metformin is the most commonly prescribed oral antidiabetic agent for the management of patients with T2D. Metformin is safe when used correctly, and in properly selected patients, there is no increased risk of lactic acidosis compared with non-metformin–treated patients.13,31 The risk of metformin-associated lactic acidosis is remarkably low with a frequency similar to that reported in patients with diabetes not receiving metformin treatment.8,13 The COSMIC trial evaluated the risk of serious adverse events including lactic acidosis with metformin therapy among 7,227 patients with T2D treated with metformin for more than 1 year.31 This trial reported no significant differences in the frequency of serious adverse events compared with patients not receiving metformin therapy. A 2010 Cochrane systematic review reported no increase in the
TABLE 1. Characteristics of patients with metformin-associated lactic acidosis Case 1 Case 2
Case 3
Age, yr 70 56 60 Risk factor for lactic acidosis CKD stage III, AKI, heart failure Cirrhosis, AKI Alcohol abuse, metformin overdose Diabetes treatment Metformin monotherapy Metformin monotherapy Metformin, NPH/R insulin Serum creatinine before admission, mg/dL 1.5 1.1 0.8 Admission serum creatinine, mg/dL 2.8 2.1 0.8 Admission eGFR 30.3 40 .60 Serum bicarbonate, mEq/L 3.8 4 9 Anion gap 26 47 22 Arterial pH 7.03 7.0 7.35 Lactic acid level, mmol/L 11.1 10.6 .10 Serum metformin level, U/L 25 31 N/A Therapy Hemodialysis Hemodialysis Activated charcoal, hydration CKD, chronic kidney disease; AKI, acute kidney injury; eGFR, estimated glomerular filtration rate; N/A, data not available; NPH, neutral protamine Hagedorn insulin; R, regular insulin.
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number of cases of lactic acidosis across 347 clinical trials, with 70,490 patient-years of metformin use.8 Patients with diabetes, however, as indicated in this report, are at increased risk of developing lactic acidosis if safety guidelines are ignored and the drug is continued in the presence of contraindications. Impaired kidney function is the most important risk factor for metformin-associated lactic acidosis. Other risk factors include the presence of decompensated heart failure, hypoxemia, alcoholism, cirrhosis, contrast exposure, sepsis and shock8,16 (Figure 1). Recent observational studies have reported a higher than expected number of cases of metformin-associated lactic acidosis.26–30 The reported cases of inquiries to the Swedish Poison Information Centre for metformin intoxication and lactic acidosis increased 10 times during the past decade, with 25 cases of severe lactic acidosis in 2007 and 2008.30 In 2 recent studies,27,29 the estimated incidence of metforminassociated lactic acidosis was 30 to 47 cases per 100,000 patient-years, which represents a 5 to 16 times higher incidence than previously reported.31 The American Association of Poison Control Centers reported that metformin contributed to 21 fatalities in the United States in 2008,23 and 49 cases of lactic acidosis and accidental metformin accumulation resulting in 11 deaths were also reported by the Poison Control Centre of Pavia, Italy, between January 2005 and August 2010.32 Lactic acid, the product of anaerobic glycolysis, is primarily produced and is fully dissociated into lactate and protons in both extracellular and intracellular fluids. Several studies have reported a small but significant increase in lactic acid levels with metformin use, in particular after meals.6,32–39 Metformin raises lactic acid levels by affecting the redox potential and promoting anaerobic metabolism.40 It interferes with complex I of the respiratory chain, leading to an inhibition of mitochondrial respiration.41 In the presence of hypoxia or tissue hypoperfusion, it can block mitochondrial oxidative phosphorylation inhibiting adenosine triphosphate (ATP) synthesis, leading to a decrease in the ATP:ADP ratio and an increase in the NADH:NAD ratio. This can result in an accumulation of pyruvate (by inhibition of pyruvate dehydrogenase) that is later converted into lactate. This conversion allows for the regeneration of NAD+, enabling the production of ATP by
anaerobic glycolysis, a much less efficient pathway.42,43 Increasing evidence indicates genetic differences that may explain interindividual variation in clinical response as well as renal clearance and bioavailability of the drug.44,45 Drug transporters, including plasma membrane monoamine transporter (PMAT), organic cation transporters (OCT-1, -2 and -3) and multidrug and toxin extrusion transporter 1 (MATE-1), have been recognized to play a major role in the absorption, distribution and elimination of metformin.46,47 In animal models, it was recently reported that MATE-1 dysfunction can lead to lactic acidosis after metformin treatment.48 Measurement of metformin plasma concentration is important in confirming the involvement of the drug in patients with suspected metformin-associated lactic acidosis. The mean plasma concentrations of metformin in healthy subjects fluctuate between about 0.5 and 1 mg/L while fasting and 1 to 2 mg/L after a meal.6,46 Metformin concentrations in erythrocytes may be more useful than plasma levels because it better represents tissue accumulation.40,49 After confirmation of the diagnosis, treatment should rapidly involve forced diuresis or hemodialysis, both of which favor rapid elimination of the drug.40 The estimated mortality rate of metformin-associated lactic acidosis has been reported between 30% and 60%,14,26,50–52 but more favorable outcomes have been reported with the use of intermittent hemodialysis or with continuous renal replacement therapy.32,40,52 In general, the prognosis depends on the severity of underlying pathologic conditions (ie, renal and liver failure, sepsis, heart failure).52,53 In summary, extensive data from clinical studies and meta-analyses have shown that metformin is an effective and safe drug when used in properly selected patients. Despite a mild increase in serum concentration of lactic acid, metformin rarely results in metabolic acidosis unless it is inappropriately used in patients with disorders associated with increased generation of lactate acid or in impaired clearance of metformin. For most ambulatory patients, metformin-associated lactic acidosis should be considered as a preventable complication if we avoid or stop its use in the presence of impaired renal function (eGFR ,45 mL/min per 1.73 m2), liver failure, severe hypoxia, heart failure, surgery and alcohol use. The safety and efficacy of metformin in
FIGURE 1. Pathogenesis of metforminassociated lactic acidosis.
Copyright © 2013 by the Southern Society for Clinical Investigation.
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the hospital setting has not been established. Proper patient selection and stopping the drug in ambulatory patients with impaired kidney function and significant comorbidities, as well as in hospitalized patients with acute illnesses are needed to prevent most cases of metformin-associated metabolic acidosis.
21. Aguilar D, Chan W, Bozkurt B, et al. Metformin use and mortality in ambulatory patients with diabetes and heart failure. Circ Heart Fail 2011;4:53–8.
REFERENCES
23. Calabrese AT, Coley KC, DaPos SV, et al. Evaluation of prescribing practices: risk of lactic acidosis with metformin therapy. Arch Intern Med 2002;162:434–7.
1. Diamant M. Choosing a blood-glucose-lowering agent after metformin. Lancet 2012;379:2220–1. 2. Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001;108:1167–74. 3. Nyenwe EA, Jerkins TW, Umpierrez GE, et al. Management of type 2 diabetes: evolving strategies for the treatment of patients with type 2 diabetes. Metabolism 2011;60:1–23. 4. Maida A, Lamont BJ, Cao X, et al. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. Diabetologia 2011;54:339–49. 5. Cho YM, Kieffer TJ. New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser. Diabetologia 2011;54:219–22. 6. Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574–9. 7. Lipska KJ, Bailey CJ, Inzucchi SE. Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care 2011;34:1431–7. 8. Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2010;CD002967.
22. Kosmalski M, Drozdowska A, Sliwinska A, et al. Inappropriate metformin prescribing in elderly type 2 diabetes mellitus (T2DM) patients. Adv Med Sci 2012;57:65–70.
24. Holstein A, Nahrwold D, Hinze S, et al. Contra-indications to metformin therapy are largely disregarded. Diabet Med 1999;16:692–6. 25. Sulkin TV, Bosman D, Krentz AJ. Contraindications to metformin therapy in patients with NIDDM. Diabetes Care 1997;20:925–8. 26. Peters N, Jay N, Barraud D, et al. Metformin-associated lactic acidosis in an intensive care unit. Crit Care 2008;12:R149. 27. van Berlo-van de Laar IR, Vermeij CG, Doorenbos CJ. Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements. J Clin Pharm Ther 2011;36: 376–82. 28. Biradar V, Moran JL, Peake SL, et al. Metformin-associated lactic acidosis (MALA): clinical profile and outcomes in patients admitted to the intensive care unit. Crit Care Resusc 2010;12:191–5. 29. Nyirenda MJ, Sandeep T, Grant I, et al. Severe acidosis in patients taking metformin—rapid reversal and survival despite high APACHE score. Diabet Med 2006;23:432–5.
9. Misbin RI. The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care 2004;27:1791–3.
30. Personne M. Alarming increase of the number of metformin intoxications. Ten times doubled number of inquiries to the Swedish Poison Information Center since 2000 [in Swedish]. Lakartidningen 2009;106: 994.
10. Stades AM, Heikens JT, Erkelens DW, et al. Metformin and lactic acidosis: cause or coincidence? A review of case reports. J Intern Med 2004;255:179–87.
31. Cryer DR, Nicholas SP, Henry DH, et al. Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study. Diabetes Care 2005;28:539–43.
11. Salpeter SR, Greyber E, Pasternak GA, et al. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Arch Intern Med 2003;163:2594–602.
32. Vecchio S, Protti A. Metformin-induced lactic acidosis: no one left behind. Crit Care 2011;15:107.
12. Holstein A, Stumvoll M. Contraindications can damage your health— is metformin a case in point? Diabetologia 2005;48:2454–9. 13. Brown JB, Pedula K, Barzilay J, et al. Lactic acidosis rates in type 2 diabetes. Diabetes Care 1998;21:1659–63. 14. Misbin RI, Green L, Stadel BV, et al. Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med 1998;338:265–6. 15. Wiholm BE, Myrhed M. Metformin-associated lactic acidosis in Sweden 1977-1991. Eur J Clin Pharmacol 1993;44:589–91. 16. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55:1577–96. 17. Eurich DT, Tsuyuki RT, Majumdar SR, et al. Metformin treatment in diabetes and heart failure: when academic equipoise meets clinical reality. Trials 2009;10:12.
33. Waters AK, Morgan DB, Wales JK. Blood lactate and pyruvate levels in diabetic patients treated with biguanides with and without sulphonylureas. Diabetologia 1978;14:95–8. 34. Czyzyk A, Lao B, Bartosiewicz W, et al. The effect of short-term administration of antidiabetic biguanide derivatives on the blood lactate levels in healthy subjects. Diabetologia 1978;14:89–94. 35. Schaffalitzky de Muckadell OB, Mortensen H, Lyngsoe J. Metabolic effects of glucocorticoid and ethanol administration in phenformin- and metformin-treated obese diabetics. Acta Med Scand 1979;206:269–73. 36. Irsigler K, Kritz H, Regal H, et al. The risk of lacticate acidosis: a comparison of the 3 biguanides in treatment of diabetics (authors’ transl) [in German]. Wien Klin Wochenschr 1978;90:332–7. 37. Abbasi AA, Kasmikha R, Sotingeanu DG. Metformin-induced lacticacidemia in patients with type 2 diabetes mellitus. Endocr Pract 2000; 6:442–6. 38. Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia 2008;51:1552–3.
18. Eurich DT, Majumdar SR, McAlister FA, et al. Improved clinical outcomes associated with metformin in patients with diabetes and heart failure. Diabetes Care 2005;28:2345–51.
39. Hong Y, Rohatagi S, Habtemariam B, et al. Population exposureresponse modeling of metformin in patients with type 2 diabetes mellitus. J Clin Pharmacol 2008;48:696–707.
19. Masoudi FA, Inzucchi SE, Wang Y, et al. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 2005;111:583–90.
40. Keller G, Cour M, Hernu R, et al. Management of metformin-associated lactic acidosis by continuous renal replacement therapy. PLoS One 2011; 6:e23200.
20. Evans JM, Doney AS, AlZadjali MA, et al. Effect of metformin on mortality in patients with heart failure and type 2 diabetes mellitus. Am J Cardiol 2010;106:1006–10.
41. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 2000;348:607–14.
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42. Levy B, Perez P, Perny J. Where does the lactate come from? A rare cause of reversible inhibition of mitochondrial respiration. Crit Care 2010;14:136. 43. Leverve XM. Mitochondrial function and substrate availability. Crit Care Med 2007;35(suppl 9):S454–60. 44. Leabman MK, Giacomini KM. Estimating the contribution of genes and environment to variation in renal drug clearance. Pharmacogenetics 2003;13:581–4. 45. Tzvetkov MV, Vormfelde SV, Balen D, et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin. Clin Pharmacol Ther 2009;86:299–306. 46. Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011;50:81–98. 47. Ali S, Fonseca V. Overview of metformin: special focus on metformin extended release. Expert Opin Pharmacother 2012;13:1797–805.
Copyright © 2013 by the Southern Society for Clinical Investigation.
48. Kusuhara H, Ito S, Kumagai Y, et al. Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects. Clin Pharmacol Ther 2011;89:837–44. 49. Lalau JD, Lacroix C. Measurement of metformin concentration in erythrocytes: clinical implications. Diabetes Obes Metab 2003;5:93–8. 50. Luft D, Schmulling RM, Eggstein M. Lactic acidosis in biguanidetreated diabetics: a review of 330 cases. Diabetologia 1978;14:75–87. 51. Scale T, Harvey JN. Diabetes, metformin and lactic acidosis. Clin Endocrinol (Oxf) 2011;74:191–6. 52. Friesecke S, Abel P, Roser M, et al. Outcome of severe lactic acidosis associated with metformin accumulation. Crit Care 2010;14:R226. 53. Lalau JD, Lacroix C, Compagnon P, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care 1995; 18:779–84.
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