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.

Role of salt sensitivity, blood pressure, and hyperinsulinemia in determining high upper normal levels of urinary albumin excretion in a healthy adult population.

BACKGROUND: The objective of this study was to investigate the role of blood pressure (BP), salt sensitivity (SS), and the cardiovascular metabolic syndrome in determining the urinary albumin excretion (UAE) in glucose-tolerant, normoalbuminuric (<20 mg/day) healthy adults. METHODS AND RESULTS: We evaluated 177 healthy subjects (age, 38.3 +/- 0.9 years; weight, 75.2 +/- 1.1 kg; body mass index, 28.8 +/- 0.4 kg/m(2); systolic BP, 117 +/- 1 mm Hg; diastolic BP, 77.5 +/- 0.8 mm Hg; UAE, 8.2 +/- 0.3 mg/24 h). Subjects with UAE levels of 15 to 20 mg/day had higher systolic BP, diastolic BP, and pulse pressures than those with UAE levels less than 15 mg/day (P <.0001). Hypertension (HT) and SS were more prevalent in the high normal UAE group (15 to 20 mg/day) than in groups with lower UAE (47% v 8% for HT and 67% v 24% for SS). In normotensives (n = 156), no differences in BP were observed among the different UAE strata; yet, the prevalence of SS was greater in the high (57%) compared to the low normal (17% to 21%) UAE groups. Similar levels of UAE, BP, and similar prevalence of SS were found in men with and without abdominal obesity, despite the fact that obesity was associated with hypertriglyceridemia and hyperinsulinemia. CONCLUSIONS: In healthy normoalbuminuric adults, high normal UAE is associated with SS in normotensives and with SS and higher BP in a mixed population (88% normotensive and 12% hypertensive). Abdominal obesity, hypertriglyceridemia, and hyperinsulinemia were not related to UAE. Therefore, UAE levels of 15 to 20 mg/day should be accepted as microalbuminuria, and these subjects may benefit from early intervention (ie, salt restriction and BP lowering).