Diabetic Lactic Acidosis in relation to Metformin
Diabetic Lactic Acidosis
Medics for Humanity
Anaerobic glycolysis results in the production of lactate and hydrogen ions, which are extracted by the liver, kidneys, and heart under normal aerobic conditions, and either oxidised completely to carbon dioxide and water, or entered the gluconeogenic pathway. Lactic acidosis may be classified according to the presence or absence of hypoxia
Causes of lactic acidosis
Type A lactic acidosis (anaerobic/hypoxic) occurs in states of profound tissue hypoxia such as myocardial infarction, cardiogenic shock, or profound sepsis. In this situation, anaerobic metabolism produces excess lactate that swamps the body’s capability to clear it and clearance of lactate may also be decreased. This situation is not peculiar to diabetes but people with diabetes (particularly type 2 diabetes) are at increased risk of hypoxic cardiovascular complications.
Type B lactic acidosis (aerobic) is rarer and is associated with several systemic diseases (including diabetes), drugs, toxins, and inborn errors of metabolism. The biguanides metformin and phenformin, used in the treatment of type 2 diabetes, have both been associated with the development of type B lactic acidosis. Phenformin was withdrawn from the market because of this complication; the incidence of lactic acidosis is much lower with metformin, with an estimated incidence of 0.03 episodes per 1000 patient years.
Metformin associated lactic acidosis may be either type A lactic acidosis, where the acidosis is the result of concurrent complicating illness without the accumulation of metformin; type B arising from marked metformin accumulation without concurrent hypoxic factors; or mixed, resulting from a combination of the above factors. Ninety percent of absorbed metformin is excreted unchanged by the kidneys and so it is renal function that determines metformin clearance. The principal contraindication to using metformin is renal impairment: the American Diabetes Association recommends avoiding metformin use if serum creatinine concentration exceeds 125 μmol/l.
Because of the accumulation of lactate in hypoxia, metformin is also contraindicated in conditions such as uncontrolled heart failure that predispose to lactic acidosis.
Clinical presentations of lactic acidosis are non-specific, and include hyperpnoea (Kussmaul respiration), nausea, vomiting, diarrhoea, epigastric pain, anorexia, lethargy, thirst, and decreased level of consciousness. Hypotension, hypothermia, cardiac dysrhythmias, and respiratory failure may also occur in severe metformin-associated lactic acidosis. Blood glucose levels may be low, normal, or high in diabetic subjects and lactic acidosis may also accompany ketoacidosis.
Treatment of lactic acidosis includes appropriate supportive care (usually on an intensive care unit), treatment of any concomitant condition and elimination of any offending drug by renal excretion or dialysis. Bicarbonate therapy is still one of the principal management modalities for lactic acidosis despite conflicting reports as to its efficacy and even reports of potential adverse consequences including the lowering of mixed venous pH and intracellular pH when it is used to treat metabolic acidosis associated with concurrent tissue hypoxia. Metformin is a dialysable drug and the use of bicarbonate in combination with haemodialysis has been successful in the management of metformin associated lactic acidosis. Other experimental approaches include the use of dichloroacetate, which activates pyruvate dehydrogenase, reducing intracellular lactate formation and increasing lactate disposal. Unfortunately, despite initially promising results, controlled trials have shown no improvements in haemodynamic or survival in acidotic patients treated with this drug. The use of Carbicarb (sodium bicarbonate and sodium carbonate in equimolar mixture) and THAM (an amino alcohol) is similarly experimental. Despite these management measures the prognosis in lactic acidosis of all causes is poor with only between 12%–17% of patients surviving to discharge in one well conducted study.
In summary, general management of the underlying condition, appropriate supportive care, bicarbonate therapy and haemodialysis are the key approaches to the management of severe lactic acidosis, but further trials are needed before we can be clear as to what represents optimum care.