UMEM Educational Pearls

Metformin, a biguanide, is the most widely used and recommended first line treatment for type 2 diabetes due to its efficacy and  low hypoglycemic risk.  It's mechanisms of action include inhibition of mitochondrial complex I electron transport  and oxidative phosphorylation (causing inhibition of hepatic gluconeogenesis and increases insulin sensitivity) and decreased intestinal absorption of glucose. It does not stimulate pancreatic insulin secretion so does not cause hypoglycemia even in overdose (except in massive dosages > 60 grams and rare cases). 

Metformin’s most serious toxicity is due to lactic acidosis. Metformin associated lactic acidosis (MALA) is a rare but life-threatening condition with incidence of 1 in 30,0000 and high mortality rate of 30-50%. Lactic acidosis can occur in both acute overdose and chronic therapeutic use in predisposed individuals. MALA is a serious condition with  that requires early recognition and aggressive treatment to increase survival and should be considered in all patients on metformin who present with lactic acidosis.

Additional Information

Metfromin associated lactic acidosis (MALA) occurs due to reduced lactate clearance caused by metformin’s inhibition of the mitochondrial electron transport chain causing a shift to anerobic metabolism (pyruvate -->lactate) and is at highest risk of occurrence when combined with other co-morbid states that cause lactate accumulation due to reduced lactate clearance (hepatic disease) or increased lactate production (hypotension, dehydration, sepsis, decompensated heart failure, hypoxia) and heavy alcohol use. The most significant risk factor for MALA is renal insufficiency, as metformin does not undergo hepatic metabolism but is almost entirely eliminated unchanged by renal excretion. Diminished renal excretion of metformin significantly prolongs its elimination half-life, leading to increased blood and tissue levels. 

Metformin carries a FDA black box warning for lactic acidosis in patients with liver and kidney impairment and should not be prescribed for patient’s with GFR < 30 ml/min.  Remember to discontinue metformin in patients at risk for lactic acidosis and AKI (sepsis, dehydration, administration of radiologic contrast).

In acute overdose, toxicity can be delayed for many hours. Observation for 12 hours is recommended to rule out lactic acidosis.

Diagnostic criteria for MALA include high AGMA with pH < 7.35 (in studies mean 7.02) and lactic acid level out of proportion > 5 (in studies mean >14) in patients using metformin. Lactic acid levels are usually higher than what would be considered survivable for other disease states.

Treatment of MALA:

• STOP Metformin
• Aggressive fluid hydration (consider D5W with sodium bicarb) 
• Vasopressors
• Ventilatory support (consider HFNC O2/ avoid intubation unless medically necessary)
• Treat other causes of lactic acidosis 
• Early nephrology consultation for intermittent hemodialysis (preferred) or continuous renal replacement therapy

Definitive Indications for hemodialysis include: Lactate >20,  pH < 7.0 , comorbid conditions (shock, renal insufficiency, liver failure), decreased level of consciousness, lack of response to supportive measures.

CNS depression is a marker of severe toxicity due to cerebral mitochondrial inhibition and depletion of ATP,  focal cerebral lactate accumulation,  systemic acidosis , and should prompt evaluation for the possibility of rare hypoglycemia.

References

Do Patients Die with or from Metformin-Associated Lactic Acidosis (MALA)? Systematic Review and Meta-analysis of pH and Lactate as Predictors of Mortality in MALA. Blumenberg A, Benabbas R, Sinert R, et al. J Med Toxicol. 2020 Apr;16(2):222-229. doi: 10.1007/s13181-019-00755-6. Epub 2020 Jan 6. PMID: 31907741; PMCID: PMC7099117.

See KC. Metformin-associated lactic acidosis: A mini review of pathophysiology, diagnosis and management in critically ill patients. World J Diabetes. 2024 Jun 15;15(6):1178-1186. doi: 10.4239/wjd.v15.i6.1178. PMID: 38983827; PMCID: PMC11229964.

Metformin-Associated Lactic Acidosis (MALA): When a Common Drug Turns Catastrophic. Kessler LE, Sachdeva D, Singhal R, et al. Cureus. 2025 Aug 3;17(8):e89292. doi: 10.7759/cureus.89292. PMID: 40904982; PMCID: PMC12404583.

Time to development of metformin-associated lactic acidosis. Theobald J, Schneider J, Cheema N, DesLauriers C. Clin Toxicol (Phila). 2020 Jul;58(7):758-762. doi: 10.1080/15563650.2019.1686514. Epub 2019 Nov 6. PMID: 31691608.

https://www.extrip-workgroup.org/metformin

Extracorporeal treatment of metformin associated lactic acidosis in clinical practice: a retrospective cohort study. van Berlo-van de Laar IRF, Vermeij CG, van den Elsen-Hutten M, et al.  Eur J Clin Pharmacol. 2020 Jun;76(6):815-820. doi: 10.1007/s00228-020-02857-5. Epub 2020 Mar 13. PMID: 32170333; PMCID: PMC7239820.