The most common adverse effect of<unk>  is gastrointestinal irritation, including diarrhea, cramps, nausea, vomiting, and increased flatulence;<unk>  is more commonly associated with gastrointestinal adverse effects than most other antidiabetic medications. The most serious potential adverse effect of<unk>  is lactic acidosis; this complication is rare, and the vast majority of these cases seem to be related to conditions such as impaired liver or kidney function, rather than to the<unk>  itself.<unk>  is not approved for use in those with severe kidney disease, but may still be used at lower doses in those with kidney problems. Gastrointestinal Gastrointestinal upset can cause severe discomfort; it is most common when<unk>  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 g/day) and increasing the dose gradually, but even with low doses, 5% of people may be unable to tolerate<unk> . Use of slow or extended-release preparations may improve tolerability. Long-term use of<unk>  has been associated with increased homocysteine levels and malabsorption of vitamin B12. Higher doses and prolonged use are associated with increased incidence of vitamin B12 deficiency, and some researchers recommend screening or prevention strategies. Lactic acidosis Lactic acidosis almost never occurs with<unk>  exposure during routine medical care. Rates of<unk> -associated lactic acidosis are about nine per 100,000 persons/year, which is similar to the background rate of lactic acidosis in the general population. A systematic review concluded no data exists to definitively link<unk>  to lactic acidosis.<unk>  is generally safe in people with mild to moderate chronic kidney disease, with proportional reduction of<unk>  dose according to severity of estimated glomerular filtration rate (eGFR) and with periodic assessment of kidney function, (e.g., periodic plasma creatinine measurement). The FDA recommends avoiding the use of<unk>  in more severe chronic kidney disease, below the eGFR cutoff of 30 ml/minute/1.73 m2. Lactate uptake by the liver is diminished with<unk>  use because lactate is a substrate for hepatic gluconeogenesis, a process that<unk>  inhibits. In healthy individuals, this slight excess is cleared by other mechanisms (including uptake by unimpaired kidneys), and no significant elevation in blood levels of lactate occurs. Given severely impaired kidney function, clearance of<unk>  and lactate is reduced, increasing levels of both, and possibly causing lactic acid buildup. Because<unk>  decreases liver uptake of lactate, any condition that may precipitate lactic acidosis is a contraindication. Common causes include alcoholism (due to depletion of NAD+ stores), heart failure, and respiratory disease (due to inadequate tissue oxygenation); the most common cause is kidney disease.<unk> -associated lactate production may also take place in the large intestine, which could potentially contribute to lactic acidosis in those with risk factors. The clinical significance of this is unknown, though, and the risk of<unk> -associated lactic acidosis is most commonly attributed to decreased hepatic uptake rather than increased intestinal production. The risk of<unk> -associated lactic acidosis is also increased by a massive overdose of<unk> , although even quite large doses are often not fatal. Overdose The most common symptoms following an overdose include vomiting, diarrhea, abdominal pain, tachycardia, drowsiness, and rarely, hypoglycemia or hyperglycemia. Treatment of<unk>  overdose is generally supportive, as no specific antidote is known. Extracorporeal treatments are recommended in severe overdoses. Due to<unk> 's low molecular weight and lack of plasma protein binding, these techniques have the benefit of removing<unk>  from the blood plasma, preventing further lactate overproduction.<unk>  may be quantified in blood, plasma, or serum to monitor therapy, confirm a diagnosis of poisoning, or to assist in a forensic death investigation. Blood or plasma<unk>  concentrations are usually in a range of 1–4 mg/l in persons receiving therapeutic doses, 40–120 mg/l in victims of acute overdosage, and 80–200 mg/l in fatalities. Chromatographic techniques are commonly employed. Interactions The H2-receptor antagonist cimetidine causes an increase in the plasma concentration of<unk>  by reducing clearance of<unk>  by the kidneys; both<unk>  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. A small double-blind, randomized study found the antibiotic cephalexin to also increase<unk>  concentrations by a similar mechanism; theoretically, other cationic medications may produce the same effect.<unk>  also interacts with anticholinergic medications, due to their effect on gastric motility. Anticholinergic drugs reduce gastric motility, prolonging the time drugs spend in the gastrointestinal tract. This impairment may lead to more<unk>  being absorbed than without the presence of an anticholinergic drug, thereby increasing the concentration of<unk>  in the plasma and increasing the risk for adverse effects.
Metformin
Rosiglitazone
Pioglitazone
Glibenclamide
Liraglutide
Miglitol
Exenatide
Glipizide