aliskiren and Diabetic-Angiopathies

Aliskiren is an orally active direct renin inhibitor which inhibits the synthesis of angiotensin I by linking to active renin on a deep cleft of its molecular structure, the site of hydrolysis of the Leu10-Val11 bond of angiotensinogen. At variance with angiotensin-converting enzyme (ACE) inhibitors, aliskiren eliminates the main substrate for the 'escape' phenomenon (synthesis of angiotensin II from angiotensin I through alternative enzymatic pathways). The possibility that the antihypertensive effect of aliskiren differs from that of ACE inhibitors needs to be proved in specifically designed clinical trials. Over the past 2 years, three studies have been published which directly compared aliskiren with ramipril, in patients with hypertension. We made a pooled analysis of these studies. In order to avoid interference with additional drugs, analysis was restricted to trial periods when the two drugs were given as monotherapy. In each individual study, systolic blood pressure (BP) was slightly lower with aliskiren. Overall, systolic BP was lower with aliskiren than with ramipril (weighted mean difference between the treatments 1.84 mmHg; fixed effect model; p < 0.0001; and 1.87 mmHg; random effect model; p = 0.0055). The standardized mean difference between the treatments was 2.58 (fixed effect model; p < 0.0001) and 2.92 (random effect model; p = 0.0017) in favor of aliskiren. Compared with ramipril, aliskiren may have induced a more complete 'upstream' inhibition of the renin-angiotensin-aldosterone system, with consequent greater suppression of angiotensin II. Another potential explanation may be the longer terminal elimination halflife of aliskiren (about 40 hours) compared with ramiprilat (13-17 hours). These data provide further evidence that aliskiren monotherapy provides a sustained BP reduction over the 24 hours.

Topics: Aging; Amides; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetic Angiopathies; Fumarates; Half-Life; Humans; Hypertension; Ramipril; Renin-Angiotensin System

Aliskiren previously was found to have potentially harmful effects in diabetic individuals prescribed concomitant angiotensin converting enzyme inhibitors (ACEI) or angiotenisn receptor antagonists (ARB). We explored potential effects of aliskiren on coronary atheroma progression and major adverse cardiovascular events (MACE: death/non-fatal MI/non-fatal stroke/hospitalization for heart failure/hospitalization for ACS/arterial revascularization) in patients with and without diabetes mellitus (DM).. AQUARIUS employed serial intravascular ultrasound measures of coronary atheroma volume in coronary artery disease patients randomized to receive daily aliskiren 300 mg or placebo for 104 weeks. This post hoc analysis compared changes in plaque volume [percent atheroma volume (PAV) and total atheroma volume (TAV)] and MACE in patients with (n = 115) and without (n = 343) DM stratified by treatment allocation.. In multivariable propensity-weighted analyses, which included controlling for baseline and concomitant ACEI/ARB therapy and duration of aliskiren therapy, aliskiren-treated non-DM patients demonstrated the greatest PAV and TAV regression, whereas aliskiren-treated DM patients demonstrated the greatest TAV progression and greater PAV. Aliskiren-treated non-DM patients appeared at significantly lower risk of MACE compared with their aliskiren-treated DM counterparts [HR 95% CI 0.28 (0.10, 0.80)]. Statistical interactions were noted between DM status and treatment allocation for both changes in PAV (p < 0.001), TAV (p = 0.010) and MACE (p = 0.057).. Aliskiren appears to be relatively anti-atherosclerotic in non-diabetic patients. Due to the limited number MACE and low numbers of diabetic patients in AQUARIUS, the pro-atherosclerotic effects of aliskiren in this population are inconclusive, and these results should be thus considered hypothesis generating. Further outcome studies are required in non-diabetic patients to confirm the possible favorable effects of aliskiren.

Topics: Aged; Amides; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Chi-Square Distribution; Coronary Artery Disease; Coronary Vessels; Diabetic Angiopathies; Disease Progression; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Fumarates; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Plaque, Atherosclerotic; Prehypertension; Propensity Score; Proportional Hazards Models; Risk Assessment; Risk Factors; Stroke; Time Factors; Treatment Outcome; Ultrasonography, Interventional

To evaluate the effect of aliskiren compared to amlodipine on QT duration and dispersion in hypertensive patients with type 2 diabetes.. A total of 170 outpatients aged 50-75 years with mild to moderate hypertension (SBP >130 and <180 mmHg and DBP >80 and <100 mmHg) and type 2 diabetes were randomly treated with aliskiren 300 mg or amlodipine 10 mg, both given once daily for 24 weeks, according to a prospective, open label, blinded-end point, parallel group design. At the end of the placebo run-in, and after 12, and 24 weeks of treatment blood pressure (BP) measurements (by mercury sphygmomanometer, Korotkoff I and V), plasma biochemistry and a standard 12-lead surface ECG were evaluated.. Both aliskiren and amlodipine significantly reduced systolic blood pressure (SBP)/diastolic blood pressure (DBP) values (-27.2/-14.3 mmHg, p < 0.001 vs. placebo and -27.8/-14.2 mmHg, p < 0.001 vs. placebo, respectively), with no statistical difference between the two drugs. Aliskiren, but not amlodipine, significantly reduced maximum QT interval (QTmax) (-14 ms at 12 weeks and -17 ms at 24 weeks, both p < 0.05 vs. placebo) and corrected QT max (QTc max) (-26 ms and -31 ms, p < 0.01) as well as the dispersion of both QT (-11 ms and -13 ms, p < 0.01) and QTc (-18 ms and -19 ms, p < 0.01).. Despite similar BP lowering effect, aliskiren, but not amlodipine, reduced QT duration and dispersion, which might be related to the ability of aliskiren to interfere with mechanisms underlying myocardial electrical instability in the heart of diabetic hypertensive patients.

Topics: Aged; Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Electrocardiography; Female; Fumarates; Heart Conduction System; Humans; Hypertension; Long QT Syndrome; Male; Middle Aged; Prospective Studies

Aliskiren, a direct renin inhibitor (DRI), has therapeutic effects in patients with hypertension and associated complications, but its potential mechanism in diabetic nephropathy is lacking. The effects of aliskiren in Streptozotocin (STZ)-induced renal complication in diabetic rats were investigated. Aliskiren treatment for eight weeks at the dose of 10 mg/kg/day, via osmotic mini-pump, induced improvement in blood glucose levels, systolic blood pressure (BP) and serum creatinine. Improvement of insulin resistance by aliskiren was confirmed by increased glucose translocation in liver and muscle and hence insulin levels. The treated group also showed improvement in glomerulosclerosis and tubulointerstitial injury. Aliskiren treatment also improved albumin levels in plasma, suppressed profibrotic and proinflammatory cytokine synthesis viz TNF-α and TGF-β and angiogenesis by a decrease in VEGF. In addition, the level of total proteins and GFR via cystatin c and beta-2microglobulin along with adiponectin and erythropoietin were also improved. These results suggest that the beneficial organ protective effect of aliskiren is mediated by improvement in insulin resistance as well as a direct anti-fibrotic effect in the target organ in STZ-induced diabetic rats with a slight effect on blood pressure. Aliskiren may be a useful therapeutic agent in the treatment of type 2 diabetes and diabetic nephropathy.

Topics: Amides; Animals; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Nephropathies; DNA Fragmentation; Extracellular Matrix; Fumarates; Glomerular Filtration Rate; Glucose Transporter Type 2; Glucose Transporter Type 4; Hemodynamics; Humans; Inflammation; Insulin; Insulin Resistance; Liver; Mice; Muscles; Rats; Rats, Wistar; ROC Curve

Aliskiren is a direct renin inhibitor (DRI) and provides an organ-protective effect in human and animal experiments. However, there is no current evidence of the effect of DRI on insulin resistance and metabolic abnormalities in type 2 diabetic animals. Methods. We investigated the effects and molecular mechanism of aliskiren in db/db mice and cultured mesangial cells (MCs).. Aliskiren treatment for 3 months at a dose of 25 mg/kg/day via an osmotic mini-pump did not induce significant changes in blood glucose levels, systolic blood pressure, serum creatinine and electrolyte levels. However, aliskiren treatment improved insulin resistance confirmed by insulin tolerance test and various biomarkers including homeostasis model assessment index levels and lipid abnormalities. The treated group also exhibited significant improvement in cardiac functional and morphological abnormalities including left ventricular hypertrophy, and induced phenotypic changes in adipose tissue. Aliskiren treatment also markedly decreased urinary albumin excretion, glomerulosclerosis and suppressed profibrotic and proinflammatory cytokine synthesis and improved renal lipid metabolism. In cultured MCs, high glucose stimulation increased MC renin concentration. Furthermore, renin treatment directly up-regulates synthesis of proinflammatory and profibrotic cytokines, which were abolished by prior treatment with aliskiren and angiotensin receptor (AT1) antagonist. These results suggest that the beneficial effect of aliskiren is mediated by an angiotensin-dependent mechanism.. Together, these results imply that aliskiren provides an organ-protective effect through improvement in insulin resistance and lipid abnormality, as well as direct anti-fibrotic effect in target organ in db/db mice. Aliskiren may be a useful new therapeutic agent in the treatment of type 2 diabetes mellitus and diabetic nephropathy.

Topics: Amides; Animals; Biomarkers, Tumor; Blood Glucose; Blood Pressure; Blotting, Western; Body Weight; Cells, Cultured; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Fumarates; Gene Expression Profiling; Humans; Immunoenzyme Techniques; Insulin; Insulin Resistance; Male; Mesangial Cells; Mice; Mice, Mutant Strains; Oligonucleotide Array Sequence Analysis; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

The effect of renin inhibition on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of aliskiren, a direct renin inhibitor, on cardiovascular injuries, glucose intolerance and pancreatic injury in a mouse model of type 2 diabetes.. Groups of db/db mice, with obesity and type 2 diabetes, were treated with aliskiren (3, 6, 12 and 25 mg kg(-1) day(-1)) or hydralazine (80 mg kg(-1) day(-1)) for 6 weeks, and the protective effects were extensively compared among groups.. All sub-pressor and hypotensive doses of aliskiren significantly attenuated cardiac fibrosis, macrophage infiltration and coronary remodelling, and improved vascular endothelial function in db/db mice. These protective effects of aliskiren were attributed to the attenuation of cardiac p22(phox)-related NADPH oxidase-induced superoxide and the restoration of vascular endothelial nitric oxide synthase (eNOS) production. Aliskiren at the highest dose (25 mg kg(-1) day(-1)), but not at lower doses, partially reduced glucose intolerance in db/db mice. Furthermore, the highest dose of aliskiren significantly attenuated the decreases in pancreatic islet insulin content and beta cell mass, and prevented pancreatic islet fibrosis in db/db mice, being associated with the reduction of 8-hydroxy-2'-deoxyguanosine-positive cells and Nox2 (also known as Cybb) expression in pancreatic islets by aliskiren.. Our work provides the first evidence that direct renin inhibition with aliskiren protects against cardiovascular complications and pancreatic injury, through the attenuation of oxidative stress. Thus, we propose that aliskiren may be a promising therapeutic agent for type 2 diabetes.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Fumarates; Glucose Intolerance; Hydralazine; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Obesity; Organ Size; Pancreas; Renin