ABSTRACT
The urotensin system has been hypothesized to play an important role in the pathophysiology of diabetic nephropathy. In this multicenter, randomized, double-blind, placebo-controlled, 2-period crossover study, the effects of the urotensin receptor antagonist palosuran on urinary albumin excretion and blood pressure in hypertensive patients with type 2 diabetic nephropathy treated with a single blocker of the renin-angiotensin-aldosterone system were assessed. Patients with 24-hour albuminuria >0.5 and <3.0 g, systolic blood pressure >135 and <170 mm Hg, and/or diastolic blood pressure >85 and <110 mm Hg received both palosuran 125 mg BID and placebo for 4 weeks each. Fifty-four patients (20% women; mean age: 61.6 years, blood pressure: 155/84 mm Hg, and albuminuria: 1016 mg per 24 hours) were included in the per-protocol analysis. Palosuran did not affect albuminuria, blood pressure, glomerular filtration rate, or renal plasma flow significantly. These results question whether urotensin receptor antagonism represents a new treatment strategy in this high-risk patient population.
Subject(s)
Antihypertensive Agents/therapeutic use , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/complications , Hypertension/complications , Hypertension/drug therapy , Quinolines/therapeutic use , Urea/analogs & derivatives , Adult , Aged , Albuminuria/prevention & control , Blood Pressure/drug effects , Blood Pressure/physiology , Creatinine/urine , Cross-Over Studies , Female , Humans , Hypertension/urine , Male , Middle Aged , Placebos , Receptors, G-Protein-Coupled/antagonists & inhibitors , Renin-Angiotensin System/drug effects , Urea/therapeutic use , Urotensins/drug effects , Urotensins/metabolismABSTRACT
Microalbuminuria is a risk factor for renal and cardiovascular disease. A role for insulin resistance in the pathogenesis of microalbuminuria has been suggested but is still unproven. In this case-control, cross-sectional study, we compared glucose disposal rate (GDR), measured by hyperinsulinemic-euglycemic clamp, in 50 pairs of matched type 2 diabetic patients with micro- or normoalbuminuria (main study) and in 29 matched pairs of diabetic patients with macro- or microalbuminuria (substudy). In the main study, GDR was approximately 25% lower in micro- than in normoalbuminuric patients (5.20 +/- 1.91 vs. 6.86 +/- 2.88 mg . kg(-1) . min(-1), P < 0.05) and was independently associated with microalbuminuria (P = 0.002), with each 1 mg . kg(-1) . min(-1) decrease predicting approximately 40% increased prevalence (odds ratio 1.37 [95% CI 1.14-1.70]). Microalbuminuria was threefold more frequent in patients with GDR < or =7.50 +/- 2.56 mg . kg(-1) . min(-1) than in those with higher GDR (60% vs. 20%, P < 0.005). In the substudy, GDR in macro- and microalbuminuric patients was comparable (5.52 +/- 2.56 vs. 5.16 +/- 1.61 mg . kg(-1) . min(-1)) and independent of macroalbuminuria. GDR was significantly correlated with urinary albumin excretion rate in the main study (P = 0.004) but not in the substudy (P = 0.60). In type 2 diabetes, more severe insulin resistance is independently associated with microalbuminuria. Longitudinal studies are needed to clarify the role of insulin resistance in the pathogenesis of microalbuminuria and related complications.
