Lactic acidosis

The most serious potential side effect of metformin is lactic acidosis; this complication is very rare, and seems limited to those with impaired liver or kidney function.

Phenformin, another biguanide, was withdrawn because of an increased risk of lactic acidosis (up to 60 cases per million patient-years). However, metformin is safer than phenformin, and the risk of developing lactic acidosis is not increased by the medication so long as it is not prescribed to known high-risk groups.

Gastrointestinal

The most common adverse effect of metformin is gastrointestinal upset, including diarrhea, cramps, nausea and vomiting; metformin is more commonly associated with gastrointestinal side effects than most other anti-diabetic drugs. In a clinical trial of 286 subjects, 53.2% of the 141 who were 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.

Gastrointestinal upset can cause severe discomfort for patients; 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 to 1.7 grams per day) and increasing the dose gradually. Gastrointestinal upset after prolonged, steady use is less common.

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

Hormonal

There is an initial report, involving four patients with impaired thyroid function, that metformin can suppress the TSH level with no accompanying symptoms of hyperthyroidism or changes in measured thyroid hormone levels. The mechanism is currently unknown.