Losartan, the first specific and orally available angiotensin II receptor antagonist, is a potent antihypertensive drug with a low incidence of side effects in humans. However, the effects of losartan on insulin sensitivity and glucose metabolism have not been investigated in detail. Therefore, we carried out a randomized, double-blind study to compare the effects of losartan (50 mg QD) and metoprolol (95 mg QD) on insulin sensitivity, insulin secretion, glucose tolerance, and lipids and lipoproteins in 20 hyperinsulinemic subjects with essential hypertension. The fall in blood pressure was greater with losartan than with metoprolol. Insulin sensitivity evaluated by the euglycemic clamp technique did not change in either group after 12 weeks of treatment. Similarly, glucose oxidation (losartan: 17.0 +/- 0.9 versus 16.9 +/- 1.0 mumol/kg per minute [before versus after, P = NS]; metoprolol: 17.9 +/- 1.3 versus 16.8 +/- 1.6 [P = NS]) and nonoxidation (losartan: 22.3 +/- 4.0 versus 23.5 +/- 3.4 mumol/kg per minute [P = NS]; metoprolol: 23.3 +/- 3.2 versus 25.6 +/- 4.7 [P = NS]) remained unchanged during the last 30 minutes of the 3-hour euglycemic clamp. Losartan and metoprolol did not have any significant adverse effects on insulin secretion, glucose tolerance, or lipids and lipoproteins. In conclusion, losartan is metabolically neutral, without any significant adverse effect on glucose and lipid metabolism.