03-23-17 How does Metformin differ from other oral hypoglycemic drugs?

Toxicology Question of the Week

March 23, 2017

How does Metformin differ from other oral hypoglycemic drugs?

Metformin is a biguanide agent and the drug-of-choice for the treatment of newly diagnosed type-2 diabetes mellitus, making it one of the most widely prescribed medications in the world. With over half a century of clinical experience, metformin is generally recognized as safe with the most frequent adverse effects being gastrointestinal (i.e. nausea, indigestion, abdominal cramps/bloating, diarrhea). Metformin acts to reduce hepatic glucose production, reduce intestinal glucose absorption, and increase skeletal muscle glucose uptake and utilization. Because it does not affect the release of insulin or other pancreatic hormones, metformin is rarely associated with hypoglycemia.

Metformin impairs mitochondrial respiration and inhibits the conversion of lactate to pyruvate. This results in both an increased production and decreased elimination of lactate with a subsequent acidosis known as metformin-associated lactic acidosis (MALA). MALA is a serious but rare complication of metformin therapy (less than 10 events per 100,000 patient-years of exposure) with a mortality rate that approaches 50%. MALA as a result of therapeutic use is typically due to an acute event that affects the patient’s ability to excrete metformin (i.e. acute kidney injury) coupled with risk factors that increase lactate production and/or retention (see table below). Small changes in hydration, renal function, plasma metformin concentrations, and tissue oxygenation often lead into a positive feedback loop that worsens the lactic acidosis. Acute metformin overdose is the most frequent cause of MALA.

Table 1-1: Risk Factors that Increase

Lactate Production/Retention

Renal Insufficiency

Alcoholism (NAD+ depletion)

Liver Dysfunction

Sepsis

Surgery

Congestive Heart Failure

Hypoxemia

Advanced Age

Symptoms of MALA are nonspecific and include nausea, vomiting, abdominal pain, malaise, myalgia, and dizziness. More severe manifestations of the lactic acidosis include mental status depression, confusion, hypotension, hypothermia, and respiratory insufficiency. Serum metformin levels can be obtained as a diagnostic aid, but concentrations are not directly proportional to the severity of the lactic acidosis.

Patients with an acute overdose of immediate-release tablets require a 6-hour observation period and extended-release tablets a 12-hour observation period. Serum electrolytes and lactate should be checked every 2 hours to monitor for the development of metabolic acidosis or hyperlactatemia. Those who develop symptoms or laboratory abnormalities should be admitted for possible treatment.

The cornerstone of therapy for MALA is resuscitation and supportive care as there is no specific antidote available to reverse the toxic effects of metformin. Hemodialysis is indicated for severe toxicity in order to remove lactate, correct electrolyte abnormalities, and support impaired renal function. Sodium bicarbonate may need required to temporarily correct acidemia until hemodialysis is available, while intravenous fluids and inotropic agents should be used to improve cardiovascular function.

References

  1. Al-Abri SA, Hayashi S, Thoren KL, et al. Metformin overdose-induced hypoglycemia in the absence of other antidiabetic drugs. Clin Tox. 2013; 51(5):444-47.
  2. 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; 43:1716-30.
  3. DeFronzo R, Fleming GA, Chen K, et al. Metformin-associated lactic acidosis: current perspectives on causes and risk. Metabolism. 2016 Feb; 65(2):20-9.
  4. 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 Sep; 36(9):733-46.
  5. Lalau JD. Lactic acidosis induced by metformin: incidence, management, and prevention. Drug Saf. 2010 Sep; 33(9):727-40.

This question prepared by: Justin Loden, PharmD, CSPI (Certified Specialist in Poison Information)