aliskiren and Hyperglycemia

Acute clamped hyperglycaemia activates the renin-angiotensin-aldosterone system (RAAS) and increases the urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Our objective was to determine whether blockade of the RAAS would blunt the effect of acute hyperglycaemia on urinary cytokine/chemokine excretion, thereby giving insights into potentially protective effects of these agents prior to the onset of clinical nephropathy.. Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances) and urinary cytokines/chemokines were measured after 6 h of clamped euglycaemia (4-6 mmol/l) and hyperglycaemia (9-11 mmol/l) on two consecutive days in patients with type 1 diabetes mellitus (n = 27) without overt nephropathy. Measurements were repeated after treatment with aliskiren (300 mg daily) for 30 days.. Before aliskiren, clamped hyperglycaemia increased filtration fraction (from 0.188 ± 0.007 to 0.206 ± 0.007, p = 0.003) and urinary fibroblast growth factor-2 (FGF2), IFN-α2 and macrophage-derived chemokine (MDC) (p < 0.005). After aliskiren, the filtration fraction response to hyperglycaemia was abolished, resulting in a lower filtration fraction after aliskiren under clamped hyperglycaemic conditions (p = 0.004), and none of the biomarkers increased in response to hyperglycaemia. Aliskiren therapy also reduced levels of urinary eotaxin, FGF2, IFN-α2, IL-2 and MDC during clamped hyperglycaemia (p < 0.005).. The increased urinary excretion of inflammatory cytokines/chemokines in response to acute hyperglycaemia is blunted by RAAS blockade in humans with uncomplicated type 1 diabetes mellitus.

Topics: Adult; Amides; Chemokines; Cytokines; Diabetes Mellitus, Type 1; Female; Fumarates; Humans; Hyperglycemia; Insulin; Male; p-Aminohippuric Acid; Proteomics; Young Adult

Hyperglycaemia induces development and progression of microvascular complications in diabetes. A direct link between high glucose levels and intrarenal renin-angiotensin activation has been demonstrated. This post-hoc analysis assessed the influence of baseline glycaemic control on the reduction of albuminuria with aliskiren or placebo added to losartan in the Aliskiren in the EValuation of PrOteinuria In Diabetes (AVOID) study.. In AVOID, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months' aliskiren or placebo added to losartan 100 mg and optimal antihypertensive therapy. Changes in urinary albumin creatinine ratio at end of study were assessed by tertiles of baseline HbA(1c) levels.. Patients were divided into tertiles of HbA(1c) (<7.1%, 7.1 to <8.4% and ≥8.4%). There were no differences between tertiles, except patients in the highest tertile group more frequently used insulin. The antiproteinuric effect of aliskiren was consistent across tertiles, with the largest effect in the highest tertile (HbA(1c) ≥8.4%).. This post-hoc analysis of the AVOID study suggests that renin inhibition with aliskiren 300 mg once daily added to losartan 100 mg once daily plus optimal antihypertensive therapy provides reductions in urinary albumin creatinine ratio that are efficacious in all, but particularly in poorly controlled, diabetic patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amides; Body Mass Index; Diabetes Complications; Female; Fumarates; Glycated Hemoglobin; Health Surveys; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Middle Aged; Placebos; Proteinuria; Renin; Young Adult