Toxicology of Oral Antidiabetic Medications

Henry A. Spiller; Tama S. Sawyer

Disclosures

Am J Health Syst Pharm. 2006;63(10):929-938. 

In This Article

Antihyperglycemics: Biguanides

In 1996, the Food and Drug Administration approved the labeling for metformin (dimethylbiguanide), the only biguanide currently available in the United States. Phenformin, the other previously available biguanide, was withdrawn from the market in 1977 because of an association with lactic acidosis. Buformin, another biguanide, is not available in the United States.

The complex of mechanisms of action of metformin is multifaceted but appears to include delayed glucose absorption, increased intestinal glucose utilization, increased intestinal lactate production, inhibition of hepatic gluconeogenesis, decreased lipid oxidation, decreased free fatty acid concentration, and increased peripheral insulin-related glucose uptake.[70]

Metformin absorption is incomplete, with 20-30% found in the feces. Oral bioavailability is 40-60%, depending on the dose ingested, with greater doses producing lower bioavailability.[71] The reduced bioavailability may result from the drug binding by the intestinal wall.[72] The rate of absorption is slower than the rate of elimination, which makes absorption a rate-limiting step in the elimination half-life.[73,74] Absorption, in therapeutic doses, is expected to be complete in 6 hours. In an overdose situation involving massive doses, absorption may be prolonged. About 90% of the absorbed metformin is eliminated through the kidneys within the first 24 hours in patients with normal renal function.[72] Metformin has no metabolites.

Metformin is the second most commonly prescribed oral antidiabetic medication in both monotherapy and combination therapy.[11] In 2004, metformin had the highest number of reports to U.S. poison control centers and the highest number of severe outcomes and fatalities compared with any other oral antidiabetic drug.[7] The major risk associated with metformin is that of metformin-associated lactic acidosis (MALA). The incidence of MALA is not clear. Reported estimates of MALA range from three to nine cases per 100,000 patient-years.[75,78] Hypoglycemia is not expected to be a major concern after metformin exposure.[28,29,79,81]

The pathogenesis of MALA in metformin overdose is complex and not completely understood.[75,82] Metformin, which accumulates in much higher concentrations in the intestines than in other tissues, doubles the production of lactate in the intestines.[82] This causes increases in portal lactate concentrations and subsequently decreases the pH of the liver, causing a decrease in lactate metabolism due to suppression of pyruvate carboxylase.[83] In addition, high concentrations of metformin, such as those seen in overdose or from significant drug accumulation due to renal failure, decrease glucose utilization and increase lactate production by hepatocytes.[82] Cumulatively, these actions result in an accumulation of lactate in the blood. Peripherally, metformin increases glucose uptake by muscles and in overdose conditions may promote increased nonoxidative metabolism.[72,82] Furthermore, diabetes itself may increase the risk of lactic acidosis in these patients, secondary to the abnormal lactate metabolism that is part of the disease.[75]

During chronic therapy there is a small but significant risk of MALA. The primary risk factor for MALA is renal impairment or a concomitant illness leading to hypoxemia or renal failure (i.e., septicemia, acute hepatic decompensation, alcohol abuse, acute myocardial infarction, and shock).[76] However, MALA in patients with no history of risk factors has been reported.[84,85] Recent evidence suggests that during periods of reduced clearance secondary to renal impairment or renal failure, metformin accumulates in the erythrocytes.[86] Due to rapid clearance from plasma and accumulation in tissues and erythrocytes, use of plasma metformin versus whole-blood metformin levels may produce plasma levels after chronic accumulation that appear normal.[84,86,88]

Clinical Findings. Toxicity from acute metformin overdose may present as abdominal pain, vomiting, and diarrhea.[81,89,90] The remaining clinical effects appear to be secondary to the resultant profound lactic acidosis. Altered mental status, including agitation, confusion, lethargy, and coma, may occur. Tachypnea, hypotension, hypothermia, ventricular dysrhythmia, decreased cardiac output, shock, and death may occur as acidosis progresses.[79,81,89,93] Decreased peripheral circulation, secondary to hypotension, may lead to type A lactic acidosis in addition to the metformin-induced lactic acidosis.[89] Hypotension results from decreased systemic vascular resistance and may be resistant to standard pressor therapy until the acidosis is resolved.[89,91] Also, as the patient becomes hypotensive, decreased renal perfusion, increased risk of renal failure, and decreased metformin clearance may occur, prolonging and potentially worsening the overdose. While rare, mild hypoglycemia has been reported.[79,89] Hyperglycemia has also been reported.[79,87,94,95] The hyperglycemia may be related to the patient's preexisting disease or to metformin-induced acute pancreatitis.[94,95] Profound lactic acidosis may take 4-8 hours to become prominent but may persist for 24-48 hours postingestion.[81,89,90]

Treatment. The management of metformin overdose is primarily supportive, with efforts to restore normal acid-base status, removal of the absorbed metformin, and support of cardiovascular function. There is no specific antidote.

Activated charcoal is expected to absorb metformin and prevent absorption and is recommended. Also, because a large portion of metformin remains in the gut, activated charcoal, even late in the overdose, may play an important decontamination role. The vomiting that accompanies metformin overdose may complicate administration of charcoal. In the obtunded patient with a known risk of vomiting, it may be prudent to protect the airway before administration of charcoal to reduce risk of aspiration.

Prompt efforts at correction of metabolic acidosis are central to treatment. Initial correction of acidosis with infusions of sodium bicarbonate has been recommended.[81] A reasonable initial dose is 1-2 meq/kg of sodium bicarbonate. However, large infusions of sodium bicarbonate present a large sodium load and may worsen intracellular acidosis.[89,96,97] In addition, in a number of cases, sodium bicarbonate alone has not stopped the acidosis.[83,91,98] Hemodialysis with a bicarbonate-buffered solution is recommended in severe cases of MALA.[83,88,90,93,98,100] Hemodialysis will help correct the acid-base balance; help normalize the potassium, sodium, and fluid balance; and efficiently remove metformin and lactate from plasma. In patients considered too unstable to handle hemodialysis, hemofiltration using continuous venous-venous renal replacement therapy has been recommended.[89,101] Alternative therapies of diuresis and dextrose with insulin infusion have been used with equivocal results and are not recommended.[81,91]

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