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OBJECTIVE: Reduced awareness of hypoglycemic symptoms and compromised hormonal counterregulation increase the risk of severe hypoglycemia in people with diabetes mellitus. Up to the present, angiotensin 1 receptor blockers, which play an important role in controlling diabetic complications, have not been known to increase the risk of hypoglycemia. Nevertheless, we observed 3 cases of diabetic patients complaining of reduced awareness of hypoglycemic symptoms while they were under treatment with losartan in our outpatients clinic. We therefore investigated the effects of losartan on symptomatic and hormonal responses to hypoglycemia in humans. RESEARCH DESIGN AND METHODS: We carried out a randomized, double-blind, crossover study including 16 healthy men. The subjects received losartan 50 mg/d versus placebo. Treatment periods lasted for 7 days and were followed by a stepwise hypoglycemic clamp session (4.5 to 3.8 to 3.1 to 2.4 mmol/L) with measurement of counterregulatory hormones (epinephrine, norepinephrine, adrenocorticotropin, cortisol, glucagon), symptoms, and hemodynamic parameters (blood pressure, heart rate). RESULTS: Losartan attenuated the hypoglycemia-induced rise in plasma epinephrine (6480 +/- 490 pmol/L versus placebo 8970 +/- 790 pmol/L; P <.001) and the rise in plasma adrenocorticotropin (21 +/- 2 pmol/L versus 26 +/- 3 pmol/L; P <.01). Losartan also reduced symptom scores during hypoglycemia (P <.05). CONCLUSION: We conclude that short-term treatment with losartan slightly attenuates symptomatic and hormonal responses to hypoglycemia. At present, for patients who are unaware of hypoglycemia and who require antihypertensive or nephroprotective treatment, we would recommend caution concerning treatment with losartan.