- Jason Chu, MD
Jason Chu, MD
- Assistant Professor of Medicine
- Icahn School of Medicine at Mount Sinai
- Andrew Stolbach, MD
Andrew Stolbach, MD
- Assistant Professor, Department of Emergency Medicine
- Johns Hopkins University
In normal individuals, fasting plasma glucose levels range from about 60 to 100 mg/dL (3.3 to 5.6 mmol/L) . In patients with diabetes mellitus, insulin deficiency or insulin resistance leads to a state of hyperglycemia. Galega officinalis (goat's rue or French lilac) was used to treat diabetes in medieval Europe. The active ingredient, guanidine, was used to synthesize other antidiabetic agents in the 1920s , and the biguanide hypoglycemic agents phenformin and metformin became available for clinical use in the 1950s.
Biguanides are antihyperglycemic agents, not hypoglycemic agents; they promote euglycemia but alone are unlikely to cause hypoglycemia. Biguanides are used both as monotherapy and in combination with other oral hypoglycemic agents. They can exacerbate hypoglycemia caused by other types of antidiabetic medicines [3,4].
The major toxicity from acute or chronic biguanide use is lactic acidosis. The high rate of severe lactic acidosis from phenformin led to the withdrawal of this drug from the US market in 1976, although it remains available in several countries. Metformin is the principal biguanide in clinical use.
The management of metformin toxicity is reviewed here. A summary table to facilitate emergent management is provided (table 1). General issues relating to hypoglycemia, the therapeutic use of biguanides, and the general clinical management of drug intoxication are presented separately. (See "Physiologic response to hypoglycemia in normal subjects and patients with diabetes mellitus" and "Hypoglycemia in adults without diabetes mellitus: Diagnostic approach" and "Metformin in the treatment of adults with type 2 diabetes mellitus" and "General approach to drug poisoning in adults".)
Metformin decreases insulin resistance, decreases hepatic glucose output, and enhances peripheral glucose uptake . Proposed mechanisms of action include enhanced suppression of gluconeogenesis by insulin, reduced glucagon-stimulated gluconeogenesis, and increased uptake of glucose by muscle and adipose cells . The net effects of these changes in diabetic patients are to decrease fasting and post-prandial blood glucose by 20 to 40 percent, decrease hemoglobin A1C, decrease body weight slightly, decrease low density lipoprotein (LDL), and increase high density lipoprotein (HDL) . (See "Metformin in the treatment of adults with type 2 diabetes mellitus".)
- Service FJ. Hypoglycemic disorders. N Engl J Med 1995; 332:1144.
- Bailey CJ, Day C. Traditional plant medicines as treatments for diabetes. Diabetes Care 1989; 12:553.
- Harrigan RA, Nathan MS, Beattie P. Oral agents for the treatment of type 2 diabetes mellitus: pharmacology, toxicity, and treatment. Ann Emerg Med 2001; 38:68.
- Dunn CJ, Peters DH. Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs 1995; 49:721.
- Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334:574.
- Howlett HC, Bailey CJ. A risk-benefit assessment of metformin in type 2 diabetes mellitus. Drug Saf 1999; 20:489.
- Graham GG, Punt J, Arora M, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011; 50:81.
- Calello DP, Liu KD, Wiegand TJ, et al. Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations From the Extracorporeal Treatments in Poisoning Workgroup. Crit Care Med 2015; 43:1716.
- Duong JK, Furlong TJ, Roberts DM, et al. The Role of Metformin in Metformin-Associated Lactic Acidosis (MALA): Case Series and Formulation of a Model of Pathogenesis. Drug Saf 2013; 36:733.
- Bailey CJ, Wilcock C, Day C. Effect of metformin on glucose metabolism in the splanchnic bed. Br J Pharmacol 1992; 105:1009.
- Vecchio S, Giampreti A, Petrolini VM, et al. Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy. Clin Toxicol (Phila) 2014; 52:129.
- Sirtori CR, Pasik C. Re-evaluation of a biguanide, metformin: mechanism of action and tolerability. Pharmacol Res 1994; 30:187.
- Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2006; :CD002967.
- Lalau JD, Race JM. Lactic acidosis in metformin-treated patients. Prognostic value of arterial lactate levels and plasma metformin concentrations. Drug Saf 1999; 20:377.
- Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin-associated lactic acidosis: a prognostic and therapeutic study. Crit Care Med 2009; 37:2191.
- Chang CT, Chen YC, Fang JT, Huang CC. Metformin-associated lactic acidosis: case reports and literature review. J Nephrol 2002; 15:398.
- Gan SC, Barr J, Arieff AI, Pearl RG. Biguanide-associated lactic acidosis. Case report and review of the literature. Arch Intern Med 1992; 152:2333.
- Khan IH, Catto GR, MacLeod AM. Severe lactic acidosis in patient receiving continuous ambulatory peritoneal dialysis. BMJ 1993; 307:1056.
- Chang CT, Chen YC, Fang JT, Huang CC. High anion gap metabolic acidosis in suicide: don't forget metformin intoxication--two patients' experiences. Ren Fail 2002; 24:671.
- Pearlman BL, Fenves AZ, Emmett M. Metformin-associated lactic acidosis. Am J Med 1996; 101:109.
- Heaney D, Majid A, Junor B. Bicarbonate haemodialysis as a treatment of metformin overdose. Nephrol Dial Transplant 1997; 12:1046.
- Lalau JD, Mourlhon C, Bergeret A, Lacroix C. Consequences of metformin intoxication. Diabetes Care 1998; 21:2036.
- Dell'Aglio DM, Perino LJ, Kazzi Z, et al. Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature. Ann Emerg Med 2009; 54:818.
- Teale KF, Devine A, Stewart H, Harper NJ. The management of metformin overdose. Anaesthesia 1998; 53:698.
- Lalau JD, Lacroix C, Compagnon P, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care 1995; 18:779.
- Lalau JD, Andrejak M, Morinière P, et al. Hemodialysis in the treatment of lactic acidosis in diabetics treated by metformin: a study of metformin elimination. Int J Clin Pharmacol Ther Toxicol 1989; 27:285.
- Barrueto F, Meggs WJ, Barchman MJ. Clearance of metformin by hemofiltration in overdose. J Toxicol Clin Toxicol 2002; 40:177.
- Rifkin SI, McFarren C, Juvvadi R, Weinstein SS. Prolonged hemodialysis for severe metformin intoxication. Ren Fail 2011; 33:459.
- Guo PY, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin. Semin Dial 2006; 19:80.
- Harvey B, Hickman C, Hinson G, et al. Severe lactic acidosis complicating metformin overdose successfully treated with high-volume venovenous hemofiltration and aggressive alkalinization. Pediatr Crit Care Med 2005; 6:598.
- Lacher M, Hermanns-Clausen M, Haeffner K, et al. Severe metformin intoxication with lactic acidosis in an adolescent. Eur J Pediatr 2005; 164:362.
- Lactic acidosis
- HISTORY AND PHYSICAL EXAMINATION
- LABORATORY EVALUATION
- Studies to obtain
- Metformin concentration
- MANAGEMENT OF OVERDOSE
- Airway, breathing, circulation
- Gastrointestinal decontamination
- Sodium bicarbonate
- Extracorporeal removal
- PEDIATRIC CONSIDERATIONS
- ADDITIONAL RESOURCES
- SUMMARY AND RECOMMENDATIONS