Toxicology Brief: Metformin overdose in dogs and cats
Metformin is available in single-ingredient preparations as well as in combination with other antidiabetic agents. Under the trade name Glucophage (Bristol-Myers Squibb) and in several generic formulations, metformin is available as tablets containing 500, 850, or 1,000 mg of metformin hydrochloride. Glucophage XR, the extended-release formulation, contains 500 or 750 mg of metformin hydrochloride. Two other metformin-only products available in the United States are Riomet (Ranbaxy Pharmaceuticals), a liquid oral formulation containing 500 mg/5 ml of metformin hydrochloride, and Fortamet (First Horizon Pharmaceutical) 500- or 1,000-mg extended-release tablets.MECHANISM OF ACTION AND PHARMACOKINETICS
Biguanides are thought to lower postprandial glucose concentrations in diabetic patients by increasing glucose uptake and decreasing glucose production. Although the precise mechanisms by which metformin exerts its antihyperglycemic effects are not entirely certain, they are largely attributed to a reduction in hepatic gluconeogenesis, a decrease in intestinal glucose absorption, and an increase in peripheral tissue sensitivity to insulin.1,4,5 To a lesser degree, metformin may also increase glucose uptake by skeletal muscles.6
Although experience with metformin in animals is limited, studies have shown that the general pharmacokinetics of metformin in cats is similar to that reported in people.2,7 In people, metformin is absorbed slowly from the gastrointestinal (GI) tract, with peak plasma concentrations reached within one to three hours after ingestion. The absolute bioavailability under fasting conditions is about 50% to 60%. Peak plasma concentrations are achieved within four to eight hours after ingestion of a dose of a metformin extended-release product.1,2,8
Metformin is not metabolized in the liver and is eliminated unchanged primarily in urine, with a small percentage of unabsorbed drug excreted in feces. The elimination half-life in people is 6.2 hours. With oral doses, by 24 hours after ingestion, about 90% of the absorbed drug has been eliminated by the kidneys. For that reason, the elimination half-life can be delayed in individuals with significant renal insufficiency and is therefore contraindicated in those patients.8,9
CLINICAL SIGNS AND TOXICITY
In all cases of metformin ingestion reported to the aspca apcc, the patients were symptomatic, and most of the affected animals were dogs. The most common clinical sign reported was vomiting (92%), with about half the patients exhibiting this sign alone. The onset of vomiting ranged from 15 minutes to eight hours after ingestion.
In one diabetic cat being treated with metformin, an oral dose of 250 mg given twice daily was associated with severe vomiting and diarrhea.10
Signs reported to the ASPCA APCC less frequently include lethargy, diarrhea, hypothermia, hypotension, pale mucous membranes, and hindlimb tremors. The duration of signs is not known; however, it is presumably three or four metformin half-lives (18 to 24 hours).