The Effect of Direct Renin Inhibition Alone and in Combination With ACE Inhibition on Endothelial Function, Arterial Stiffness, and Renal Function in Type 1 Diabetes

Abstract

OBJECTIVEDiabetes is associated with renin-angiotensin system (RAS) activation, leading to renal and systemic vascular dysfunction that contribute to end-organ injury and significant morbidity. RAS blockade with ACE inhibitors reduces, but does not abolish, RAS effects. Accordingly, our aim was to determine if direct renin inhibition alone, and in combination with an ACE inhibitor, corrects early hemodynamic abnormalities associated with type 1 diabetes.RESEARCH DESIGN AND METHODSArterial stiffness (augmentation index), flow-mediated vasodilatation (FMD), and renal hemodynamic function (inulin and paraaminohippurate clearance) were measured at baseline under clamped euglycemic and hyperglycemic conditions (n = 21). Measures were repeated after 4 weeks of aliskiren therapy and again after aliskiren plus ramipril.RESULTSBlood pressure–lowering effects of aliskiren were similar during clamped euglycemia and hyperglycemia. Combination therapy augmented this effect under both glycemic conditions (P = 0.0005). Aliskiren reduced arterial stiffness under clamped euglycemic and hyperglycemic conditions, and the effects were augmented by dual RAS blockade (−3.4 ± 11.2 to −8.0 ± 11.5 to −14.3 ± 8.4%, respectively, during euglycemia, P = 0.0001). During clamped euglycemia, aliskiren increased FMD; dual therapy exaggerated this effect (5.1 ± 3.3 to 7.5 ± 3.0 to 10.8 ± 3.5%, repeated-measures ANOVA, P = 0.0001). Aliskiren monotherapy caused renal vasodilatation during clamped hyperglycemia only. In contrast, dual therapy augmented renal vasodilatory effects during clamped euglycemia and hyperglycemia.CONCLUSIONSIn patients with uncomplicated type 1 diabetes, aliskiren-based dual RAS blockade is associated with greater arterial compliance, FMD, and renal vasodilatation.

The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes

“…Whether the protective effect observed with lowsodium diet and RAAS inhibition in this post hoc analysis was due to greater haemodynamic effects, enhanced antiinflammatory effects or both, is unknown and requires further study. Nevertheless, as previously reported by our group [17][18][19] and by other investigators [46], RAAS inhibitors still exert prominent haemodynamic effects on the intrarenal RAAS in the presence of relative RAAS suppression induced by a high-salt diet in diabetic patients. Our results extend this previous haemodynamic-focused body of work by suggesting that RAAS inhibition during salt repletion also reduces inflammatory urinary cytokines/chemokines.…”

“…Although it is known that RAAS blockade is more effective under conditions of dietary sodium depletion, RAAS inhibitors are still effective in both diabetic and non-diabetic sodium-replete individuals [17][18][19][20]. These observations suggest persistent intrarenal RAAS activation despite high dietary sodium intake.…”

“…These observations suggest persistent intrarenal RAAS activation despite high dietary sodium intake. As a consequence, in sodium-replete individuals RAAS inhibitors exert important renal haemodynamic and blood-pressure effects, and in patients with established diabetic nephropathy these agents suppress urinary levels of inflammatory mediators [17,[21][22][23][24][25]. In patients with uncomplicated type 1 diabetes mellitus who would not otherwise be candidates for RAAS inhibition, the effect of these agents on urinary biomarker excretion or biomarker responses to acute clamped hyperglycaemia remain unknown.…”

Effect of Add‐on Aliskiren to Type 1 Angiotensin Receptor Blocker Therapy on Endothelial Function and Autonomic Nervous System in Hypertensive Patients With Ischemic Heart Disease

“…Direct renin inhibitor monotherapy using aliskiren and combination therapy with ACE inhibitors or calcium blockers improves endothelial function. [15][16][17] Virdis and colleagues reported that aliskiren, compared with ramipril, increased nitric oxide availability in forearm resistance arterioles of patients with essential hypertension. 12 In addition, aliskiren significantly decreased PRA, compared with ramipril, whereas BP, plasma Ang II level, and plasma aldosterone level remained unchanged.…”

Editorial: Do We Have Effective Means to Treat Arterial Stiffness and High Central Aortic Blood Pressure in Patients with and without Hypertension?

“…Increased leisure time physical activity, weight reduction, avoidance of diatery salt and alcohol abuse as well as increased consumption of diatery heavy chain omega fatty acids as recommended [7]. Drug treatment for arterial hypertension [diuretics, angiotensin-converting enzyme inhibitors (ACE-I), angiotensin-receptor blockers (ARBs), and calcium-channel blockers (CCB)] [8][9][10]; lipid-lowering agents, mainly statins [11,12], hypoglecaemic drugs (thiazolidinediones) [13]; and potentially other novel agents, including AGE breakers [14]. There are been data suggesting that the reduction in AS during treatment for arterial hypertension is not only attributed to the reduction in BP per se but to additional BP loweringindependent effects of antihypertensive drugs [15].…”