Correspondence
Lactic Acidosis in Patients with Diabetes Treated with Metformin
N Engl J Med 1998; 338:265-266January 22, 1998
- Article
To the Editor:
From May 1995, when metformin was introduced in the United States, through June 30, 1996, the Food and Drug Administration (FDA) received reports of lactic acidosis in 66 patients treated with metformin. In 47 patients, the diagnosis was confirmed on the basis of circulating lactate values (>5 mmol per liter), in accordance with established criteria for the diagnosis of lactic acidosis (Table 1Table 1
Characteristics of 47 Patients with Diabetes and Metformin-Associated Lactic Acidosis.).1,2 Of the 47 patients with confirmed diagnoses, 43 had one or more risk factors for lactic acidosis. Thirty (64 percent) had preexisting cardiac disease, of whom 18 had histories of congestive heart failure. Thirteen patients (28 percent) had preexisting renal insufficiency, including two patients undergoing dialysis. Three patients (6 percent) had chronic pulmonary disease with hypoxia. Eight patients (17 percent) were over the age of 80 years. Only four patients had no apparent risk factors when treatment with metformin was initiated, and all four recovered.
There were 19 patients in whom the criteria for the diagnosis of metformin-associated lactic acidosis were not met. Two patients were found not to have been taking metformin. For three patients, no circulating lactate values were reported. Seven patients had circulating lactate values of less than 2.7 mmol per liter, the upper limit for patients with stable diabetes who are taking metformin,3 and seven had values between 2.7 and 4.9 mmol per liter.
On the basis of the estimate that 1 million Americans are taking metformin, the reported rate of confirmed lactic acidosis is about 5 cases per 100,000. However, the actual rate of occurrence may be higher. In an analysis of prescription and hospitalization data in Saskatchewan, Canada, Stang et al. reported 9 cases per 100,000.4
On the basis of the reports received by the FDA, congestive heart failure has recently been included as a contraindication to metformin therapy. The revised label also states that metformin therapy should be withheld in patients with sepsis and should not be initiated in patients who are 80 years of age or older unless their creatinine clearance is normal.5 Limiting metformin therapy to otherwise healthy patients with diabetes who are under the age of 80 years should decrease the incidence of lactic acidosis and associated mortality. (The views expressed are those of the authors and do not necessarily represent the official position of the FDA.)
5 ReferencesRobert I. Misbin, M.D.
Lanh Green, R.Ph., M.P.H.
Bruce V. Stadel, M.D.
John L. Gueriguian, M.D.
Ananda Gubbi, Ph.D.
G. Alexander Fleming, M.D.
Food and Drug Administration, Rockville, MD 208571
Misbin RI . Phenformin-associated lactic acidosis: pathogenesis and treatment. Ann Intern Med 1977;87:591-595
Web of Science | Medline2
Stacpoole PW ,Harman EM ,Curry SH ,Baumgartner TG ,Misbin RI . Treatment of lactic acidosis with dichloroacetate. N Engl J Med 1983;309:390-396
Full Text | Web of Science | Medline3
DeFronzo RA, Goodman AM, Multicenter Metformin Study Group
Full Text | Web of Science | Medline4
Stang MR, Lueck L, Wysowski DK, Downey W, Butler-Jones D. Metformin and lactic acidosis. Canadian Pharmacoepidemiology Forum. April 1997.
5
Prescribing information for Glucophage. Princeton, N.J.: Bristol-Myers Squibb, November 14, 1997.
- Citing Articles (84)
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1
Annette Maznyczka, Aung Myat, Anthony Gershlick. (2012) Discontinuation of metformin in the setting of coronary angiography: clinical uncertainty amongst physicians reflecting a poor evidence base. EuroIntervention 7:9, 1103-1110
CrossRef2
Stephen H. Caldwell, Curtis K. Argo, Abdullah M. S. Al-Osaimi. 2011. Nonalcoholic Fatty Liver Disease. , 868-907.
CrossRef3
S. Dichtwald, A. A. Weinbroum, P. Sorkine, M. P. Ekstein, E. Dahan. (2011) Metformin-associated lactic acidosis following acute kidney injury. Efficacious treatment with continuous renal replacement therapy. Diabetic Medicineno-no
CrossRef4
Salim Surani, Marlene Morales, Mauricio Rodriguez, Joseph Varon. (2011) The resilience of the human body. The American Journal of Emergency Medicine 29:7, 835-837
CrossRef5
Jorge Cerdá, Ashita J Tolwani, David G Warnock. (2011) Critical care nephrology: management of acid–base disorders with CRRT. Kidney International
CrossRef6
I. R. F. van Berlo-van de Laar, C. G. Vermeij, C. J. Doorenbos. (2011) Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements. Journal of Clinical Pharmacy and Therapeutics 36:3, 376-382
CrossRef7
Leonard B. Seeff, Robert J. Fontana. 2011. Drug-Induced Liver Injury. , 478-506.
CrossRef8
Oliver Zolk. (2011) Disposition of metformin: Variability due to polymorphisms of organic cation transporters. Annals of Medicine1-11
CrossRef9
Minghan Wang. 2011. Current Antidiabetic Therapies and Mechanisms. , 253-278.
CrossRef10
Minghan Wang. 2011. Drug Development for Metabolic Diseases: Past, Present and Future. , 469-488.
CrossRef11
T. Scale, J. N. Harvey. (2011) Diabetes, metformin and lactic acidosis. Clinical Endocrinology 74:2, 191-196
CrossRef12
Michael P. Lisanti. (2011) Caveolin-Related Diseases. Annual Review of Pathology: Mechanisms of Disease 7:1, 110301101326014
CrossRef13
Ligong Chen, Bradley Pawlikowski, Avner Schlessinger, Swati S. More, Doug Stryke, Susan J. Johns, Michael A. Portman, Eugene Chen, Thomas E. Ferrin, Andrej Sali, Kathleen M. Giacomini. (2010) Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin. Pharmacogenetics and Genomics 20:11, 687-699
CrossRef14
Kiyoko Bando, Shoko Ochiai, Takeshi Kunimatsu, Jiro Deguchi, Juki Kimura, Hitoshi Funabashi, Takaki Seki. (2010) Comparison of potential risks of lactic acidosis induction by biguanides in rats. Regulatory Toxicology and Pharmacology 58:1, 155-160
CrossRef15
Vassilios Devetzis, Ploumis Passadakis, Stelios Panagoutsos, Marios Theodoridis, Elias Thodis, Anastasia Georgoulidou, Vassilis Vargemezis. (2010) Metformin-related lactic acidosis in patients with acute kidney injury. International Urology and Nephrology
CrossRef16
Kevin Niswender. (2010) Diabetes and obesity: therapeutic targeting and risk reduction - a complex interplay. Diabetes, Obesity and Metabolism 12:4, 267-287
CrossRef17
Christopher Vernon, Jennifer L. LeTourneau. (2010) Lactic Acidosis: Recognition, Kinetics, and Associated Prognosis. Critical Care Clinics 26:2, 255-283
CrossRef18
Jeffrey R. Lewis, Smruti R. Mohanty. (2010) Nonalcoholic Fatty Liver Disease: A Review and Update. Digestive Diseases and Sciences 55:3, 560-578
CrossRef19
James B. Reilly, Jeffrey S. Berns. (2010) Selection and Dosing of Medications for Management of Diabetes in Patients with Advanced Kidney Disease. Seminars in Dialysis 23:2, 163-168
CrossRef20
Gregory Giamouzis, Filippos Triposkiadis, Javed Butler. (2010) Metformin Use in Patients With Diabetes Mellitus and Heart Failure: Friend or Foe?. Journal of Cardiac Failure 16:3, 207-210
CrossRef21
Shelley R Salpeter, Elizabeth Greyber, Gary A Pasternak, Edwin E Salpeter (posthumous), Shelley R Salpeter. 2010. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. .
CrossRef22
Yao-Ko Wen. (2009) Impact of acute kidney injury on metformin-associated lactic acidosis. International Urology and Nephrology 41:4, 967-972
CrossRef23
José Miguel Dora, Lívia H. de Souza, Mirela J. de Azevedo, Jorge L. Gross. (2009) Lactic Acidosis Associated With Metformin in a Patient With Type 2 Diabetes With No Contraindication. The Endocrinologist 19:6, 250
CrossRef24
J.F. Zander, A. Risse. (2009) Perioperative Einstellung und Behandlung des Diabetes mellitus. Der Orthopäde 38:9, 818-827
CrossRef25
Rachandeep Singh, Ravi Nistala, Samy I McFarlane, Adam Whaley-Connell. (2009) Glycemic control and cardiovascular disease in a high-risk chronic kidney disease population. Therapy 6:4, 507-513
CrossRef26
David M. Kendall, Robert M. Cuddihy, Richard M. Bergenstal. (2009) Clinical Application of Incretin-Based Therapy: Therapeutic Potential, Patient Selection and Clinical Use. European Journal of Internal Medicine 20, S329-S339
CrossRef27
Alexandre Seidowsky, Saad Nseir, Nicole Houdret, François Fourrier. (2009) Metformin-associated lactic acidosis: A prognostic and therapeutic study*. Critical Care Medicine 37:7, 2191-2196
CrossRef28
Ole-Petter R. Hamnvik, Graham T. McMahon. (2009) Balancing Risk and Benefit with Oral Hypoglycemic Drugs. Mount Sinai Journal of Medicine: A Journal of Translational and Personalized Medicine 76:3, 234-243
CrossRef29
U.-M. Vischer, B. Bauduceau, I. Bourdel-Marchasson, J.-F. Blickle, T. Constans, A. Fagot-Campagna, E. Kaloustian, V. Lassman-Vague, P. Lecomte, D. Simon, D. Tessier, C. Verny, J. Doucet. (2009) A call to incorporate the prevention and treatment of geriatric disorders in the management of diabetes in the elderly. Diabetes & Metabolism 35:3, 168-177
CrossRef30
Antonio Pérez Pérez, Pedro Conthe Gutiérrez, Manuel Aguilar Diosdado, Vicente Bertomeu Martínez, Pedro Galdos Anuncibay, Gonzalo García de Casasola, Ramón Gomis de Bárbara, José Luis Palma Gamiz, Manuel Puig Domingo, Ángel Sánchez Rodríguez. (2009) Tratamiento de la hiperglucemia en el hospital. Medicina Clínica 132:12, 465-475
CrossRef31
Shereen Abdelghaffar, Abdelhamid M Attia, Shereen Abdelghaffar. 2009. Metformin added to insulin therapy for type 1 diabetes mellitus in adolescents. .
CrossRef32
David Aguilar. (2008) Management of type 2 diabetes in patients with heart failure. Current Treatment Options in Cardiovascular Medicine 10:6, 465-475
CrossRef33
M. K. OH, J. WINN, F. POORDAD. (2008) Review article: diagnosis and treatment of non-alcoholic fatty liver disease. Alimentary Pharmacology & Therapeutics 28:5, 503-522
CrossRef34
Mark A Malesker. (2008) Optimizing Antidiabetic Treatment Options for Patients with Type 2 Diabetes Mellitus and Cardiovascular Comorbidities. Pharmacotherapy 28:2, 193-206
CrossRef35
Shelley R. Salpeter, Nicholas S. Buckley, Justin A. Kahn, Edwin E. Salpeter. (2008) Meta-analysis: Metformin Treatment in Persons at Risk for Diabetes Mellitus. The American Journal of Medicine 121:2, 149-157.e2
CrossRef36
Mouen Khashab, Naga Chalasani. (2007) Use of Insulin Sensitizers in NASH. Endocrinology & Metabolism Clinics of North America 36:4, 1067-1087
CrossRef37
Waleed M. Sweileh. (2007) Contraindications to metformin therapy among patients with type 2 diabetes mellitus. Pharmacy World & Science 29:6, 587-592
CrossRef38
S Abdelghaffar, AM Attia, Shereen Abdelghaffar. 2007. Metformin added to insulin therapy for type 1 diabetes mellitus in adolescents. .
CrossRef39
Paul J. Riesenman, Susan S. Braithwaite, Bruce A. Cairns. (2007) Metformin-Associated Lactic Acidosis in a Burn Patient. Journal of Burn Care & Research 28:2, 342-347
CrossRef40
Frederick A. Masoudi, Silvio E. Inzucchi. (2007) Diabetes Mellitus and Heart Failure: Epidemiology, Mechanisms, and Pharmacotherapy. The American Journal of Cardiology 99:4, 113-132
CrossRef41
Jackie L. Boucher, Carrie S. Swift, Marion J. Franz, Karmeen Kulkarni, Rebecca G. Schafer, Ellen Pritchett, Nathaniel G. Clark. (2007) Inpatient Management of Diabetes and Hyperglycemia: Implications for Nutrition Practice and the Food and Nutrition Professional. Journal of the American Dietetic Association 107:1, 105-111
CrossRef42
John E. Gerich. (2006) Glycemic Control in the Metabolic Syndrome and Implications in Preventing Cardiovascular Disease. Metabolic Syndrome and Related Disorders 4:4, 315-327
CrossRef43
Christian Weber, Kurt Neeser. (2006) Using Individualized Predictive Disease Modeling to Identify Patients with the Potential to Benefit from a Disease Management Program for Diabetes Mellitus. Disease Management 9:4, 242-256
CrossRef44
V Gras, B Bouffandeau, Ph Montravers, JD Lalau. (2006) Effect of metformin on survival rate in experimental sepsis. Diabetes & Metabolism 32:2, 147-150
CrossRef45
Shelley R Salpeter, Elizabeth Greyber, Gary A Pasternak, Edwin E Salpeter, Shelley R Salpeter. 2006. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. .
CrossRef46
Chetan Shenoy. (2006) Metformin-Associated Lactic Acidosis Precipitated by Acute Renal Failure. The American Journal of the Medical Sciences 331:1, 55-57
CrossRef47
Peter Y. F. Guo, Leroy J. Storsley, S. Neil Finkle. (2006) Dialysis Rounds
A Dialysis Case Presentation and Discussion
CrossRef48
A. Holstein, M. Stumvoll. (2005) Contraindications can damage your health—is metformin a case in point?. Diabetologia 48:12, 2454-2459
CrossRef49
Suzanne M. Strowig, Philip Raskin. (2005) Combination therapy using metformin or thiazolidinediones and insulin in the treatment of diabetes mellitus. Diabetes, Obesity and Metabolism 7:6, 633-641
CrossRef50
S. Runge, C. Warnke, P. Abel, S. Friesecke, S. Felix. (2005) T
dliche Metformin-assoziierte Laktazidose bei einem Patienten mit akuter Dekompensation einer chronischen Niereninsuffizienz. Intensivmedizin + Notfallmedizin 42:2, 172-176
CrossRef51
Richard W. Snyder, Jeffrey S. Berns. (2004) Reviews: Use of Insulin and Oral Hypoglycemic Medications in Patients with Diabetes Mellitus and Advanced Kidney Disease. Seminars in Dialysis 17:5, 365-370
CrossRef52
David Parra, Anna M. Legreid, Nick P. Beckey, Sonia Reyes. (2004) Metformin Monitoring and Change in Serum Creatinine Levels in Patients Undergoing Radiologic Procedures Involving Administration of Intravenous Contrast Media. Pharmacotherapy 24:8, 987-993
CrossRef53
W.H Wilson Tang, Anjli Maroo, James B Young. (2004) Ischemic heart disease and congestive heart failure in diabetic patients. Medical Clinics of North America 88:4, 1037-1061
CrossRef54
Mandeep Bajaj, Ralph A. DeFronzo. 2004. Combination Therapy in Type 2 Diabetes. .
CrossRef55
Alan J. Garber. 2004. Metformin and Other Biguanides: Pharmacology and Therapeutic Usage. .
CrossRef56
A. Uygun, A. Kadayifci, A. T. Isik, T. Ozgurtas, S. Deveci, A. Tuzun, Z. Yesilova, M. Gulsen, K. Dagalp. (2004) Metformin in the treatment of patients with non-alcoholic steatohepatitis. Alimentary Pharmacology and Therapeutics 19:5, 537-544
CrossRef57
A. M. E. Stades, J. T. Heikens, D. W. Erkelens, F. Holleman, J. B. L. Hoekstra. (2004) Metformin and lactic acidosis: cause or coincidence? A review of case reports. Journal of Internal Medicine 255:2, 179-187
CrossRef58
David S H Bell. (2004) A Comparison of Agents Used to Manage Type 2 Diabetes Mellitus. Treatments in Endocrinology 3:2, 67-76
CrossRef59
Kurt Neeser, Georg L??bben, Uwe Siebert, Wendelin Schramm. (2004) Cost Effectiveness of Combination Therapy with Pioglitazone for Type 2 Diabetes Mellitus from a German Statutory Healthcare Perspective. PharmacoEconomics 22:5, 321-341
CrossRef60
Andrew J. Palmer, Stéphane Roze, William J. Valentine, Michael E. Minshall, Volker Foos, Francesco M. Lurati, Morten Lammert, Giatgen A. Spinas. (2004) The CORE Diabetes Model: Projecting Long-term Clinical Outcomes, Costs and Costeffectiveness of Interventions in Diabetes Mellitus (Types 1 and 2) to Support Clinical and Reimbursement Decision-making. Current Medical Research and Opinion 20:s1, S5-S26
CrossRef61
S Salpeter, E Greyber, G Pasternak, E Salpeter, Shelley Salpeter. 2003. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. .
CrossRef62
Seth Braunstein. (2003) New developments in type 2 diabetes mellitus: Combination therapy with a thiazolidinedione. Clinical Therapeutics 25:7, 1895-1917
CrossRef63
Robert Lee Page, Wendolyn S. Gozansky, J. Mark Ruscin. (2003) Possible Heart Failure Exacerbation Associated with Rosiglitazone: Case Report and Literature Review. Pharmacotherapy 23:7, 945-954
CrossRef64
Ralph Oiknine, Arshag D. Mooradian. (2003) Drug therapy of diabetes in the elderly. Biomedicine & Pharmacotherapy 57:5-6, 231-239
CrossRef65
Massimo Fantoni, Cosmo Del Borgo, Camillo Autore. (2003) Evaluation and management of metabolic and coagulative disorders in HIV-infected patients receiving highly active antiretroviral therapy. AIDS 17, S162-S169
CrossRef66
F. Zangeneh, Y. C. Kudva, A. Basu. (2003) Insulin Sensitizers. Mayo Clinic Proceedings 78:4, 471-479
CrossRef67
Ripudaman S Hundal, Silvio E Inzucchi. (2003) Metformin. Drugs 63:18, 1879-1894
CrossRef68
P. I. Pillans, P. G. Landsberg, A.-M. Fleming, M. Fanning, J. M. Sturtevant. (2003) Evaluation of dosage adjustment in patients with renal impairment. Internal Medicine Journal 33:1-2, 10-13
CrossRef69
Janice C Parker. (2002) Troglitazone: the discovery and development of a novel therapy for the treatment of Type 2 diabetes mellitus. Advanced Drug Delivery Reviews 54:9, 1173-1197
CrossRef70
Simon C. Mears, Pamela A. Lipsett, Myles D. Brager, Lee H. Riley. (2002) Metformin-Associated Lactic Acidosis After Elective Cervical Spine Fusion. Spine 27:22, E482-E484
CrossRef71
R. Chakrabarti, R. K. Vikramadithyan, M. Prem Kumar, S. K. B. Kumar, N. V. S. Mamidi, P. Misra, J. Suresh, J. Hiriyan, C. S. Rao, R. Rajagopalan. (2002) PMT13, a pyrimidone analogue of thiazolidinedione improves insulin resistance-associated disorders in animal models of type 2 diabetes. Diabetes, Obesity and Metabolism 4:5, 319-328
CrossRef72
Timothy M. E. Davis, Denise Jackson, Wendy A. Davis, David G. Bruce, Paul Chubb. (2001) The relationship between metformin therapy and the fasting plasma lactate in type 2 diabetes: The Fremantle Diabetes Study. British Journal of Clinical Pharmacology 52:2, 137-144
CrossRef73
J. D. Lalau, J. M. Race. (2001) Lactic acidosis in metformin therapy: searching for a link with metformin in reports of ‘metformin-associated lactic acidosis’. Diabetes, Obesity and Metabolism 3:3, 195-201
CrossRef74
Enriqe Z. Fisman, Alexander Tenenbaum, Yehuda Adler, Michael Motro, Valentina Boyko, Michal Benderly, Aharon Friedensohn, Mira Kohanovski, Rene Rotzak, Hanan Schneider, Solomon Behar. (2001) Oral antidiabetic treatment in patients with coronary disease: Time-related increased mortality on combined glyburide/metformin therapy over a 7.7-year follow-up. Clinical Cardiology 24:2, 151-158
CrossRef75
Michael P. Dubé. (2000) Disorders of Glucose Metabolism in Patients Infected with Human Immunodeficiency Virus. Clinical Infectious Diseases 31:6, 1467-1475
CrossRef76
Andrew J Palmer, Arno Brandt, Valerio Gozzoli, Christian Weiss, Harald Stock, Helmut Wenzel. (2000) Outline of a diabetes disease management model: principles and applications. Diabetes Research and Clinical Practice 50, S47-S56
CrossRef77
Evan D. Rosen, Bruce M. Spiegelman. (2000) Peroxisome proliferator–activated receptor γ ligands and atherosclerosis: ending the heartache. Journal of Clinical Investigation 106:5, 629-631
CrossRef78
Alan O. Marcus. (2000) Safety of Drugs Commonly Used to Treat Hypertension, Dyslipidemia, and Type 2 Diabetes (The Metabolic Syndrome): Part 2. Diabetes Technology & Therapeutics 2:2, 275-281
CrossRef79
Jean-Daniel Lalau, Jean-Michel Race. (2000) Metformin and lactic acidosis in diabetic humans. Diabetes, Obesity and Metabolism 2:3, 131-137
CrossRef80
Alan O. Marcus. (2000) Safety of Drugs Commonly Used to Treat Hypertension, Dyslipidemia, and Type 2 Diabetes (The Metabolic Syndrome): Part 1. Diabetes Technology & Therapeutics 2:1, 101-110
CrossRef81
A. Holstein, D. Nahrwold, S. Hinze, E. -H. Egberts. (1999) Contra-indications to metformin therapy are largely disregarded. Diabetic Medicine 16:8, 692-696
CrossRef82
N. N. Chan, H. P. S. Brain, M. D. Feher. (1999) Metformin-associated lactic acidosis: a rare or very rare clinical entity?. Diabetic Medicine 16:4, 273-281
CrossRef83
Gérard Emilien, Jean-Marie Maloteaux, Michel Ponchon. (1999) Pharmacological Management of Diabetes. Pharmacology & Therapeutics 81:1, 37-51
CrossRef84
W. S. Yap, G. M. Peterson, J. H. Vial, C. T. C. Randall, T. M. Greenaway. (1998) Review of management of type 2 diabetes mellitus. Journal of Clinical Pharmacy and Therapeutics 23:6, 457-465
CrossRef
