Adverse effects

The most common adverse effect of metformin is gastrointestinal irritation, including diarrhea, cramps, nausea, vomiting, and increased flatulence; metformin is more commonly associated with gastrointestinal side effects than most other antidiabetic drugs.^[27] The most serious potential side effect of metformin use is lactic acidosis; this complication is very rare, and the vast majority of these cases seem to be related to comorbid conditions, such as impaired liver or kidney function, rather than to the metformin itself.^[56]

Metformin has also been reported to decrease the blood levels of thyroid-stimulating hormone in people with hypothyroidism,^[57] The clinical significance of this is still unknown.

Gastrointestinal

In a clinical trial of 286 subjects, 53.2% of the 141 given immediate-release metformin (as opposed to placebo) reported diarrhea, versus 11.7% for placebo, and 25.5% reported nausea/vomiting, versus 8.3% for those on placebo.^[58]

Gastrointestinal upset can cause severe discomfort; it is most common when metformin is first administered, or when the dose is increased. The discomfort can often be avoided by beginning at a low dose (1.0 to 1.7 grams per day) and increasing the dose gradually.

Long-term use of metformin has been associated with increased homocysteine levels^[59] and malabsorption of vitamin B₁₂.^[60][61] Higher doses and prolonged use are associated with increased incidence of vitamin B₁₂ deficiency,^[62] and some researchers recommend screening or prevention strategies.^[63]

Lactic acidosis

The most serious potential adverse effect of biguanide use is lactic acidosis (“metformin-associated lactic acidosis” or MALA). Though the incidence for MALA has been measured at about nine per 100,000 person-years,^[64] this is not different from the background incidence of lactic acidosis in the general population. A systematic review concluded no data exists to definitively link metformin to lactic acidosis.^[65] Lactic acidosis can be fatal in some cases.

Phenformin, another biguanide, was withdrawn from the market because of an increased risk of lactic acidosis (rate of 40-64 per 100,000 patient-years).^[64] However, metformin is safer than phenformin, and the risk of developing lactic acidosis is not increased by the medication as long as it is not prescribed to known high-risk groups.^[65]

Lactate uptake by the liver is diminished with metformin administration because lactate is a substrate for hepatic gluconeogenesis, a process which metformin inhibits. In healthy individuals, this slight excess is simply cleared by other mechanisms (including uptake by the kidneys, when their function is unimpaired), and no significant elevation in blood levels of lactate occurs.^[26]When impaired kidney function is present, however, clearance of metformin and lactate is reduced, leading to increased levels of both, and possibly causing a buildup of lactic acid. Because metformin decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication to its use. Common causes of increased lactic acid production include alcoholism (due to depletion of NAD+ stores), heart failure, and respiratory disease (due to inadequate oxygenation of tissues); the most common cause of impaired lactic acid excretion is kidney disease.^[66]

Metformin has also been suggested to increase production of lactate in the large intestine; this could potentially contribute to lactic acidosis in those with risk factors.^[67] However, the clinical significance of this is unknown, and the risk of metformin-associated lactic acidosis is most commonly attributed to decreased hepatic uptake rather than increased intestinal production.^[26][66][68]

Overdose

A review of intentional and accidental metformin overdoses reported to poison control centers over a five-year period found serious adverse events were rare, though the elderly appeared to be at greater risk.^[69] A similar study where cases were reported to Texas poison control centers between 2000 and 2006 found ingested doses of more than 5,000 mg were more likely to involve serious medical outcomes in adults.^[70] Survival following intentional overdoses with up to 63,000 mg (63 g) of metformin have been reported in the medical literature.^[71] Fatalities following overdose are rare, but do occur.^[72][73][74] In healthy children, unintentional doses of less than 1,700 mg are unlikely to cause any significant toxic effects.^[75]

The most common symptoms following overdose appear to include vomiting, diarrhea, abdominal pain, tachycardia, drowsiness, and, rarely, hypoglycemia or hyperglycemia.^[70][73] The major potentially life-threatening complication of metformin overdose is lactic acidosis, which is due to lactate accumulation.^[76][77] Treatment of metformin overdose is generally supportive, as no specific antidote is known. Lactic acidosis is initially treated with sodium bicarbonate, although high doses are not recommended, as this may increase intracellular acidosis.^[74]Acidosis that does not respond to administration of sodium bicarbonate may require further management with standard hemodialysis or continuous venovenous hemofiltration. These treatments are recommended in severe overdoses.^[78] In addition, due to metformin’s low molecular weight and lack of plasma protein binding, these techniques also have the benefit of removing metformin from blood plasma, preventing further lactate overproduction.^[78]

Metformin may be quantified in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Blood or plasma metformin concentrations are usually in a range of 1–4 mg/l in persons receiving the drug therapeutically, 40–120 mg/l in victims of acute overdosage, and 80–200 mg/l in fatalities. Chromatographic techniques are commonly employed.^[79][80]

Interactions

The H₂-receptor antagonist cimetidine causes an increase in the plasma concentration of metformin, by reducing clearance of metformin by the kidneys;^[81] both metformin and cimetidine are cleared from the body by tubular secretion, and both, particularly the cationic (positively charged) form of cimetidine, may compete for the same transport mechanism.^[82] A small double-blind, randomized study found the antibiotic cephalexin to also increase metformin concentrations by a similar mechanism;^[83] theoretically, other cationic medications may produce the same effect.