Why does metformin cause lactic acidosis
Pro Research Analysisby 
Searched over 200M research papers
Understanding Why Metformin Causes Lactic Acidosis
Introduction to Metformin and Lactic Acidosis
Metformin is a widely used oral anti-hyperglycemic agent for managing type 2 diabetes mellitus. Despite its benefits, there is a concern about its association with lactic acidosis, a rare but serious metabolic condition characterized by the buildup of lactate in the body, leading to a low pH in the bloodstream1 2 3.
Mechanism of Metformin-Induced Lactic Acidosis
Inhibition of Mitochondrial Respiration
Metformin can cause lactic acidosis primarily by inhibiting mitochondrial respiration. This inhibition occurs predominantly in the liver, leading to an increase in anaerobic metabolism and subsequent lactate production3 4. Elevated plasma metformin concentrations, especially in individuals with renal impairment, can exacerbate this effect, as the drug is primarily excreted through the kidneys3 9.
Risk Factors and Secondary Conditions
The development of metformin-associated lactic acidosis (MALA) typically requires the presence of secondary conditions that further disrupt lactate production or clearance. These conditions include renal impairment, cardiovascular diseases, hepatic dysfunction, sepsis, and hypoperfusion3 4 6. Almost all cases of MALA present with at least one independent risk factor, suggesting that metformin alone is rarely the sole cause1 6.
Incidence and Mortality Rates
Low Incidence in Clinical Practice
Despite the theoretical risks, the actual incidence of lactic acidosis in patients taking metformin is very low. Studies have shown that the incidence is less than 10 cases per 100,000 patient-years, which is comparable to or even lower than the incidence in patients not taking metformin2 5. This low incidence is partly due to the conservative prescribing guidelines that limit metformin use in patients with significant renal impairment or other contraindications3 4.
Mortality and Prognostic Factors
While the incidence is low, the mortality rate for MALA can be high, approaching 50% in some studies3 6. Factors predicting poor outcomes include low arterial blood pH and the absence of acute renal failure at the time of hospital admission6. Interestingly, some data suggest that high plasma concentrations of metformin may be associated with better outcomes, possibly due to the drug's vasomotility effects7.
Prevention and Management
Adherence to Dosing Guidelines
Preventing MALA involves strict adherence to dosing guidelines, especially in patients with renal impairment. Over 60% of MALA cases involved doses exceeding recommended guidelines, highlighting the importance of proper dosing1. Patients should be educated about the need to discontinue metformin temporarily during acute illnesses that can affect renal function, such as sepsis or dehydration9.
Treatment Strategies
In cases of severe lactic acidosis, hemodialysis is the treatment of choice as it helps eliminate both lactate and metformin from the bloodstream, thereby correcting acidosis and improving patient outcomes4 8. Continuous renal replacement therapy (CRRT) is particularly beneficial in patients with concurrent acute kidney injury9.
Conclusion
Metformin-associated lactic acidosis is a rare but serious condition that arises primarily due to the inhibition of mitochondrial respiration and the presence of secondary risk factors. While the incidence is low, the condition carries a high mortality rate, underscoring the importance of adherence to dosing guidelines and prompt management of risk factors. Understanding these mechanisms and preventive measures can help mitigate the risks associated with metformin therapy.
Sources and full results
Most relevant research papers on this topic
The Association between Metformin Therapy and Lactic Acidosis
Metformin-associated lactic acidosis is associated with pre-existing risk factors and prescription doses that exceed guidelines in patients with renal impairment, but pre-admission plasma concentrations do not exceed the therapeutic range.
Systematic ReviewRisk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.
Metformin use in type 2 diabetes patients does not increase the risk of lactic acidosis or blood lactate levels compared to other anti-hyperglycemic treatments.
Meta-Analysis
Very Rigorous Journal
Highly CitedMetformin-associated lactic acidosis: Current perspectives on causes and risk.
Metformin-associated lactic acidosis (MALA) is a rare but potentially fatal condition in type 2 diabetes patients, with current renal function cutoffs potentially being too conservative.
Literature ReviewHighly CitedLactic Acidosis Induced by Metformin
Metformin-associated lactic acidosis is rare and may even be protective in severe cases, but addressing liver disease severity and contraindications is crucial for effective patient management and prevention.
Literature ReviewHighly CitedRisk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.
Metformin use in type 2 diabetes patients shows no cases of fatal or nonfatal lactic acidosis compared to placebo or other glucose-lowering treatments.
Meta-AnalysisHighly CitedMetformin-associated lactic acidosis requiring hospitalization. A national 10 year survey and a systematic literature review.
Metformin-associated lactic acidosis is a rare but often fatal complication, with death predicted when patients arrive in the hospital with low pH and no acute kidney injury.
Systematic ReviewHighly CitedMetformin-associated lactic acidosis: case reports and literature review.
Metformin-associated lactic acidosis (MALA) is a serious reaction that requires urgent hemodialysis treatment to prevent complications, even in non-diabetic patients with wide anion gap metabolic acidosis and high blood lactate levels.
Case ReportMetformin, chronic nephropathy and lactic acidosis: a multi-faceted issue for the nephrologist
Metformin has a low risk of lactic acidosis and offers significant benefits for type 2 diabetic patients, with continuous renal replacement therapy (CRRT) playing a crucial role in treating lactic acidosis.
Metformin and other antidiabetic agents in renal failure patients.
Metformin is rarely the sole cause of lactic acidosis in chronic kidney disease patients, and its prognosis for severe lactic acidosis is even better in metformin-treated patients than non-metformin users.
Literature Review
Rigorous JournalHighly Cited