Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy

Objective: Hypertension and insulin resistance might be associated through peripheral vascular hypertrophy/ rarefaction which compromises skeletal muscle blood flow and decreases glucose uptake, inducing insulin resistance. We hypothesized that treatment with losartan as compared to atenolol would improve insulin sensitivity through regression of peripheral vascular hypertrophy/rarefaction. Methods: In 70 hypertensive patients with electrocardiographic left ventricular hypertrophy, we measured minimal forearm vascular resistance (MFVR) by plethysmography and insulin sensitivity (M/IG) by a 2-h isoglycemic hyperinsulinemic clamp at baseline and after 1, 2 and 3 years of blinded treatment with atenolol- or losartan-based regimens. Results: Blood pressures were reduced similarly in the two treatment groups. After 3 years, MFVR was increased (3.7 versus 3.2 mm Hg × min × 100, P < 0.05) and M/IG decreased (8.6 versus 12.1 I²/kg × mmol × min, P < 0.05) in patients treated with atenolol, whereas MFVR and M/IG were unchanged (3.5 versus 3.5 mmHg × min × 100 and 12.6 versus 11.1 I²/kg × mmol × min, both P = NS) in patients treated with losartan. As compared to atenolol, losartan treatment was associated with less increase in MFVR (4.3 versus 27%, P < 0.05) and less decrease in M/IG (24 versus -14%, P < 0.01). The relative change in M/IG was inversely associated with the relative change in MFVR (r = -0.16, P < 0.05) independently of the relative change in body mass index (r = -0.29, P < 0.001). Conclusions: As compared to atenolol, losartan treatment was associated with less peripheral vascular hypertrophy/ rarefaction and higher insulin sensitivity. The relative change in MFVR and M/IG were inversely related, supporting the hypothesis that peripheral vascular changes in hypertension may induce insulin resistance. The ability of losartan to preserve insulin sensitivity may explain the lower incidence of new onset diabetes in patients treated with losartan in the LIFE study.