Ondansetron and metformin-induced gastrointestinal side effects

Treatment with metformin is associated with a high incidence of gastrointestinal side effects of unknown mechanism. Metformin is a biguanide derivative, which resembles 5-HT3-receptor agonists in its structure. Activation of 5-HT3 receptors is known to induce nausea, vomiting, and diarrhea. In this study, we investigated if the gastrointestinal side effects produced by metformin were antagonized by ondansetron, a selective antagonist of 5-HT3 receptors. Patients experiencing gastrointestinal side effects were randomized to ondansetron (4 mg bid p.o.) or placebo while maintained on metformin (double-blind, parallel-group design). If side effects persisted or worsened, metformin was discontinued and the patient considered a therapeutic failure. Of the 98 subjects treated with metformin, 22 developed side effects to match the study entry criteria. Diarrhea was the most frequent side effect. Subjects were randomized to ondansetron (10/2 F/M, 42.8 +/- 2.3 years, 28.6 +/- 1.1 kg/m2, 2585 +/- 35 mg/d metformin) or placebo (9/1 F/M, 43 +/- 4.3 years, 29.7 +/- 1.8 kg/m2, 2715 +/- 71 mg/d metformin). Ondansetron showed no efficacy against metformin-induced side effects. A comparable number of therapeutic failures were observed in ondansetron (8/12; 66%) and placebo-treated subjects (5/10; 50%) (P<0.1). Mean nausea scores (numeric analog scale) before and during treatment with ondansetron were 6.3 +/- 1 and 6.9 +/- 1 cm, respectively. Nausea scores averaged 7.3 +/- 1.5 and 5.9 +/- 1.5 cm, before and during treatment with placebo (P>0.1). In conclusion, 5-HT3 receptors do not seem to play a role in metformin-induced gastrointestinal side effects.