The IGF-I system and the renal and haemodynamic effects of losartan in normotensive patients with type 2 diabetes mellitus: a randomized clinical trial.

OBJECTIVE: Losartan has been shown to protect the diabetic kidney, at least partly independent of changes in blood pressure. Imbalances in the IGF-I system are associated with the development of diabetic nephropathy. We investigated whether renal as well as haemodynamic effects of losartan are associated with changes in the IGF-I system in normotensive patients with type 2 diabetes mellitus (T2DM). DESIGN AND PATIENTS: This randomized, double-blind placebo-controlled clinical trial involved 74 normotensive patients with T2DM and microalbuminuria. Thirty-eight patients were assigned to receive losartan and 36 patients were assigned to receive placebo for 10 weeks. MEASUREMENTS: Serum levels of total and free IGF-I, IGFBP-3, creatinine and haemoglobin A(1c) (HbA(1c)), as well as urinary albumin excretion rate, creatinine clearance and blood pressure, were measured prior to the start of treatment and after 10 weeks of treatment. RESULTS: At baseline, serum levels of IGFBP-3 were elevated and serum levels of free IGF-I were reduced. Losartan tended to reduce IGFBP-3 levels and to increase free IGF-I levels, although neither effect was statistically significant. These effects were more pronounced in a subanalysis of 18 losartan-treated patients with stable metabolic parameters, with a decrease in IGFBP-3 from 133.2 to 122.6 nmol/l (P=0.006) and an increase in free IGF-I levels by 8% (ns). Serum levels of total IGF-I were unaffected. The change in IGFBP-3 was inversely correlated to the change in creatinine clearance (r=-0.4; P=0.02). Total and free IGF-I inversely correlated to systolic blood pressure (r= -0.46; P=0.007 and r=0.26; P=0.14 respectively). Furthermore, changes in total IGF-I and IGFBP-3 correlated to changes in serum creatinine levels in the metabolically stable patients (r=0.58, P=0.02 and r=0.6, P=0.01, respectively). Changes in the IGF-I system were unrelated to a reduction in microalbuminuria associated with losartan. CONCLUSIONS: Losartan lowered the elevated levels of IGFBP-3, although only significantly in the metabolically stable patients. A tendency towards an increase in free IGF-I levels was also observed, but this change was small and not statistically significant. These changes were not related to reduction in microalbuminuria, but might contribute to effects of losartan on creatinine clearance and blood pressure of losartan in normotensive patients with T2DM.

Effect of losartan on microalbuminuria in normotensive patients with type 2 diabetes mellitus. A randomized clinical trial.

BACKGROUND: Angiotensin-converting enzyme inhibitors have shown antiproteinuric effects in normotensive and hypertensive diabetic patients. Angiotensin-receptor antagonists reduce urinary albumin excretion and the risk for renal and cardiovascular complications in hypertensive patients with type 2 diabetes mellitus. The effect of angiotensin-receptor antagonists in normotensive diabetic patients with microalbuminuria has not yet been reported. OBJECTIVE: To assess the antiproteinuric effects of losartan in normotensive patients with type 2 diabetes and microalbuminuria. DESIGN: Multicenter randomized, double-blind, placebo-controlled clinical trial. SETTING: 19 outpatient clinics in the Netherlands. PATIENTS: 147 normotensive patients with type 2 diabetes mellitus and microalbuminuria. INTERVENTION: 74 patients were randomly assigned to receive losartan and 73 patients were assigned to receive placebo for 10 weeks; 71 patients in each group completed the study. The losartan dose was 50 mg during the first 5 weeks and 100 mg during the subsequent 5 weeks. MEASUREMENTS: Change in urinary albumin excretion rate after 5 and 10 weeks, change in creatinine clearance and blood pressure, and safety and tolerability of losartan. RESULTS: A significant 25% relative reduction in the albumin excretion rate occurred after 5 weeks of the 50-mg losartan dose, with further improvement over the subsequent 5 weeks with the 100-mg dose (relative reduction, 34%). In the losartan group, creatinine clearance did not improve and blood pressure decreased slightly. Side effects did not differ between treatment groups. CONCLUSIONS: The angiotensin-receptor antagonist losartan reduces urinary albumin excretion in normotensive patients with type 2 diabetes and microalbuminuria. In multivariate analysis, the antiproteinuric effect of losartan was independent of the associated reduction in blood pressure. Losartan was safe and well tolerated in these normotensive patients.