aliskiren and Obesity

Aliskiren is a novel renin-angiotensin aldosterone system (RAAS) inhibitor, the combination therapy of aliskiren and amlodipine for blood pressure control have been reported recently. The primary objective of this analysis is to review recently reported randomized controlled trials (RCTs) to compare antihypertensive effects and adverse events between mono (amlodipine or aliskiren alone) and combination therapy of both medicines.. Databases for the search included Pubmed, Embase and the Cochrane Central Register of Controlled Trials. Revman v5.0 statistical program was used to analyze the data. Weighted mean differences (WMD) with a 95% confidence interval (CI) were used for the calculation of continuous data, and relative risk (RR) with a 95% CI was used for dichotomous data.. We analyzed the data from 7 RCTs for a total of 6074 participants in this meta-analysis. We found that the aliskiren/amlodipine combination therapy had a stronger effect in lowering blood pressure as compared with the monotherapy using aliskiren (SBP: WMD = -10.42, 95% CI -13.03∼-7.82, P<0.00001; DBP: WMD = -6.60, 95% CI -7.22∼-5.97, P<0.00001) or amlodipine (SBP: WMD = -4.85, 95% CI -6.88∼-2.81, P<0.00001; DBP: WMD = -2.91, 95% CI -3.85∼-1.97, P<0.00001). No differences were found in terms of adverse events between combination therapy and monotherapy, except for the rates of peripheral edema and hypokalaemia which were significantly lower in the combination therapy than in the amlodipine monotherapy (RR = 0.78, 0.66∼0.92, P = 0.004; RR = 0.51, 0.27∼0.97, P = 0.04). Similar antihypertensive effects were found in both obese (body mass index > = 30 kg/m(2)) hypertensive and non-obese (body mass index <30 kg/m(2)) hypertensive patients. Moreover, there was no difference with the blood pressure lowering or adverse effects with regards to the combination therapy in both subgroups.. We found that aliskiren/amlodipine combination therapy provided a more effective blood pressure reduction than monotherapy with either drug without increase in the occurrence of adverse events.

Topics: Amides; Amlodipine; Antihypertensive Agents; Blood Pressure; Fumarates; Humans; Hypertension; Obesity; Publication Bias; Randomized Controlled Trials as Topic

Hypertension is the most prevalent and important risk factor for cardiovascular and renal disease worldwide. Despite the large armamentarium of available blood pressure-lowering agents, the need remains for safer and more effective antihypertensive treatment. Based on current target levels of < 140/90 mm Hg, only one-third of hypertensive Americans have achieved goal blood pressure. Several strategies can help address these challenges, including increasing public awareness, and improving physician awareness of evidence-based therapeutic guidelines. There also remains a need for new therapeutic options. This review examines new developments among those agents having inhibitory activity on the renin-angiotensin-aldosterone system (RAAS). All currently available RAAS blockers cause a reactive increase in plasma renin concentration. However, the direct renin inhibitors are the only class that diminishes plasma renin activity, an effect that may provide additional cardiovascular and/or renoprotective benefit. Aliskiren is the first clinically available direct renin inhibitor that has been shown to be effective and well tolerated both as monotherapy and in combination with other established agents in hypertensive patients. Randomized clinical trials are underway to explore the extent to which direct renin inhibition provides additive protection against cardiovascular and renal disease events.

Topics: Aged; Amides; Antihypertensive Agents; Diabetes Complications; Drug Therapy, Combination; Fumarates; Healthy People Programs; Heart Failure; Humans; Hypertension; Middle Aged; Obesity; Renin; Renin-Angiotensin System

Aliskiren penetrates adipose and skeletal muscle in hypertensive patients with abdominal obesity and reduces renin-angiotensin-aldosterone system activity. After discontinuation, blood pressure-lowering effects are observed possibly through drug-tissue binding. We performed microdialysis evaluation of adipose tissue and skeletal muscle before and during an insulin-modified frequently sampled intravenous glucose tolerance test (IM-FSIGT). Aliskiren 300 mg (n = 8) or amlodipine 5 mg (n = 8) once daily were administered during a 12-week randomized treatment period. Aliskiren elicited variable changes in median interstitial angiotensin II (Ang II) in adipose (2.60-1.30 fmol/mL) and skeletal muscle (2.23-0.68 fmol/mL); amlodipine tended to increase adipose and skeletal muscle Ang II (P = .066 for skeletal muscle treatment difference). Glucose/insulin increased median plasma Ang II 1 hour after glucose injection (1.04-2.50 fmol/mL; P = .001), which was markedly attenuated by aliskiren but not amlodipine. Aliskiren increased glucose disposition index (P = .012) and tended to increase acute insulin response to glucose (P = .067). Fasting adipose glycerol (-17%; P = .064) and fasting muscle glucose dialysate (-17%; P = .025) were decreased by aliskiren but not amlodipine. In summary, aliskiren decreased Ang II production in response to glucose/insulin stimulus and elicited metabolic effects in adipose and skeletal muscle suggestive of increased whole-body glucose utilization.

Topics: Adipose Tissue; Adult; Amides; Amlodipine; Angiotensin II; Antihypertensive Agents; Blood Glucose; Double-Blind Method; Female; Fumarates; Glucose; Humans; Hypertension; Insulin; Lipolysis; Male; Microdialysis; Middle Aged; Muscle, Skeletal; Obesity; Renin; Renin-Angiotensin System

We attempted to test the hypothesis that the direct renin inhibitor aliskiren can improve diastolic dysfunction, glucose, and insulin metabolism (GIM) in overweight and obese hypertensive patients.. Seventy-eight hypertensive patients were divided into two groups: 38 treated with aliskiren for six months, and 40 treated without aliskiren but with only traditional anti-hypertensive therapy, as controls. Doppler mitral flow velocity patterns were assessed before and after aliskiren during a six-month period. GIM (three-hour intravenous glucose tolerance test) was measured after four to six weeks of washout and six months of treatment. The mitral E/A ratio increased from 0.65 ± 0.11 to 0.75 ± 0.19. None of the indexes changed in the control group. In the control group, GIM parameters, fasting glucose levels (5.3 ± 0.9 to 6.0 ± 1.5 mmol/l; p = 0.003), fasting insulin levels (121 ± 121 to 189 ± 228 pmol/l; p = 0.03), and most other relevant metabolic measures (p < 0.05 for all) significantly worsened. Aliskiren did not affect GIM. In the control group LVM/height was not affected (119 ± 12 to 120 ± 17 g/m; p = 0.8), whereas aliskiren significantly reduced LVM/height (120 ± 13 to 111 ± 19 g/m; p = 0.04).. Optimal target BP was achieved in the group as a whole and in both obese patient groups, while benefits to cardiac structure were of a smaller magnitude. In high-risk, overweight/obese patients with hypertension, traditional therapy provides significantly greater BP- versus aliskiren-lowering throughout the 24-hour dosing interval. Therefore in obese, hypertensive individuals, adequate and similar blood pressure control was achieved with aliskiren; however, the aliskiren group and not the control group was associated with a more favorable GIM profile and led to a significant regression of LVM; overall aliskiren-based treatment offers sustained control of PRA.

Topics: Aged; Amides; Antihypertensive Agents; Biomarkers; Blood Glucose; Female; Fumarates; Humans; Hypertension; Insulin; Male; Middle Aged; Obesity; Overweight; Renin; Renin-Angiotensin System; Ultrasonography; Ventricular Function, Left

In animals, the direct renin inhibitor aliskiren showed extensive tissue binding in the kidney and long-lasting renal effects. Aliskiren provides prolonged blood pressure-lowering effects following treatment discontinuation in patients. Therefore, we investigated whether aliskiren attains tissue concentrations sufficient to inhibit local renin-angiotensin system (RAS) activity in patients.. We included 10 hypertensive patients with abdominal adiposity in an open-label study. Following 1-2 weeks washout, patients received 2 weeks placebo, then 4 weeks aliskiren 300 mg once daily, followed by 4 weeks washout, and then 4 weeks amlodipine 5 mg once daily. Drug concentrations and RAS biomarkers were measured in interstitial fluid using microdialysis and in biopsies from abdominal subcutaneous adipose and skeletal muscle.. We detected aliskiren in all compartments. After 4 weeks of treatment, microdialysate aliskiren concentrations (ng/ml) were 2.4 ± 2.1 (adipose) and 7.1 ± 4.2 (skeletal muscle), similar to plasma concentrations (8.4 ± 4.4); tissue concentrations (ng/g) were 29.0 ± 16.7 (adipose) and 107.3 ± 68.6 (skeletal muscle). Eight weeks after discontinuation, aliskiren was measurable in tissue biopsies but not in plasma or in interstitial fluid. Pooled microdialysate samples from two sets of four patients suggested reduction in tissue angiotensin II with aliskiren but not with amlodipine.. In obese hypertensive patients, aliskiren penetrates adipose and skeletal muscle tissue at levels that are apparently sufficient to reduce tissue RAS activity. Furthermore, tissue binding may contribute to aliskiren's prolonged blood pressure-lowering effect following discontinuation.

Topics: Adipose Tissue; Adult; Amides; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Extracellular Fluid; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Muscle, Skeletal; Obesity; Pilot Projects; Renin-Angiotensin System

To compare the long-term efficacy, safety and tolerability of the direct renin inhibitor aliskiren against the diuretic hydrochlorothiazide (HCTZ) in obese patients with hypertension.. A post hoc analysis of 396 obese patients (body mass index > or = 30 kg/m2) in a 52-week study in 1124 patients with hypertension was performed. Patients were randomized to receive aliskiren 150 mg or HCTZ 12.5 mg for 3 weeks, or placebo for 6 weeks. At week 3, active treatment doses were doubled. Patients receiving placebo were randomized to aliskiren 300 mg or HCTZ 25 mg at week 6. Add-on amlodipine 5-10 mg was permitted from week 12 to achieve blood pressure (BP) control (<140/90 mmHg).. In the subgroup of obese patients, aliskiren monotherapy provided significantly greater BP reductions than HCTZ at week 12 endpoint (-16.7/-12.3 vs. -12.2/-9.1 mmHg, P < or = 0.001). Reductions were also greater with aliskiren-based therapy than HCTZ-based therapy at week 52 endpoint (-19.9/-15.5 vs. -17.5/-13.3 mmHg; P = 0.138 for systolic BP and P = 0.007 for diastolic BP). Mean BP reductions from baseline with aliskiren-based therapy were similar in obese and nonobese patients. By contrast, HCTZ-based therapy provided significantly smaller mean reductions in BP from baseline in obese patients vs. nonobese patients (P < 0.05). Aliskiren-based therapy was generally well tolerated in obese patients, and was associated with a significantly lower incidence of hypokalemia (1.0 vs. 14.0%, P < 0.0001) than HCTZ-based therapy.. Aliskiren-based therapy provided superior BP reductions to HCTZ-based therapy with good tolerability in obese patients with hypertension.

Topics: Amides; Antihypertensive Agents; Double-Blind Method; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Obesity; Placebos

Current guidelines from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommend first-line treatment with a thiazide diuretic but do not provide specific guidance for obese patients. The renin system is activated in obesity-associated arterial hypertension. Therefore, we tested the hypothesis that the oral direct renin inhibitor aliskiren could provide additive blood pressure lowering in obese patients with hypertension (body mass index >or=30 kg/m(2); mean sitting diastolic blood pressure: 95 to 109 mm Hg) who had not responded to 4 weeks of treatment with hydrochlorothiazide (HCTZ) 25 mg. After a 2- to 4-week washout, 560 patients received single-blind HCTZ (25 mg) for 4 weeks; 489 nonresponders were randomly assigned to double-blind aliskiren (150 mg), irbesartan (150 mg), amlodipine (5 mg), or placebo for 4 weeks added to HCTZ (25 mg), followed by 8 weeks on double the initial doses of aliskiren, irbesartan, or amlodipine. After 8 weeks of double-blind treatment (4 weeks on the higher dose), aliskiren/HCTZ lowered blood pressure by 15.8/11.9 mm Hg, significantly more (P<0.0001) than placebo/HCTZ (8.6/7.9 mm Hg). Aliskiren/HCTZ provided blood pressure reductions similar to those with irbesartan/HCTZ and amlodipine/HCTZ (15.4/11.3 and 13.6/10.3 mm Hg, respectively), with similar tolerability to placebo/HCTZ. Adverse event rates were highest with amlodipine/HCTZ because of a higher incidence of peripheral edema (11.1% versus 0.8% to 1.6% in other groups). In conclusion, combination treatment with aliskiren is a highly effective and well-tolerated therapeutic option for obese patients with hypertension who fail to achieve blood pressure control with first-line thiazide diuretic treatment.

Topics: Administration, Oral; Adult; Aged; Amides; Amlodipine; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Diastole; Double-Blind Method; Female; Fumarates; Humans; Hydrochlorothiazide; Hypertension; Irbesartan; Male; Middle Aged; Obesity; Renin; Systole; Tetrazoles; Treatment Outcome

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker (fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser(473) phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

Topics: Amides; Animals; Biological Transport; Blood Pressure; Body Weight; Disease Models, Animal; Fatty Acids, Nonesterified; Female; Fumarates; Glucose; Insulin; Insulin Resistance; Muscle, Skeletal; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; Renin; Signal Transduction

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

Renin initiates angiotensin II formation and has no other known functions. We observed that transgenic rats (TGR) overexpressing the human renin gene (hREN) developed moderate obesity with increased body fat mass and glucose intolerance compared with nontransgenic Sprague-Dawley (SD) rats. The metabolic changes were not reversed by an angiotensin-converting enzyme inhibitor, a direct renin inhibitor, or by (pro)renin receptor blocker treatment. The obese phenotype in TGR(hREN) originated from higher food intake, which was partly compensated by increases in resting energy expenditure, total thermogenesis (postprandial and exercise activity), and lipid oxidation during the first 8 weeks of life. Once established, the difference in body weight between TGR(hREN) and SD rats remained constant over time. When restricted to the caloric intake of SD, TGR(hREN) developed an even lower body weight than nontransgenic controls. We did not observe significant changes in the cocaine and amphetamine-regulated transcript, pro-opiomelanocortin, both anorexigenic, or neuropeptide Y, orexigenic, mRNA levels in TGR(hREN) versus SD controls. However, the mRNA level of the agouti-related peptide, orexigenic, was significantly reduced in TGR(hREN) versus SD controls at the end of the study, which indicates a compensatory mechanism. We suggest that the human renin transgene initiates a process leading to increased and early appetite, obesity, and metabolic changes not related to angiotensin II. The mechanisms are independent of any currently known renin-related effects.

Topics: Adipocytes; Amides; Angiotensin II; Animals; Cells, Cultured; Disease Models, Animal; Energy Metabolism; Fumarates; Humans; Leptin; Lipid Metabolism; Male; Obesity; Phenotype; Rats; Rats, Sprague-Dawley; Rats, Transgenic; Renin; Thermogenesis

Overfeeding increases adipose tissue mass and leptin production and up-regulates the renin-angiotensin system in adipose tissue in rodents. Here, we determined the effect of chronic treatment with the renin inhibitor, aliskiren, in a model of diet-induced obesity in mice, on: (i) body weight, adipose tissue weight and plasma leptin; (ii) food intake and caloric efficiency; and (iii) angiotensin II (Ang II) in adipose tissue.. Four-week-old C57BL/6J mice (n= 40) received aliskiren (50 mg.kg(-1).day(-1); 6 weeks) by means of a subcutaneous osmotic Alzet minipump. Animals were given either a low-fat (10% kcal from fat) or a high-fat diet (45% kcal from fat) during this period. Food-intake and body-weight variation were monitored during treatment.. In addition to a decrease of plasma renin activity, aliskiren reduced body-weight gain, adipose pads and plasma leptin concentration, independent of the diet. In adipose tissue, local concentrations of Ang II were also reduced by aliskiren.. Aliskiren limited the gain of adiposity in young mice. This effect was not due to changes in food intake or caloric efficiency and might be related to a down-regulation of the local renin-angiotensin system in adipose tissue. These effects were accompanied by reduced plasma leptin levels. As Ang II favours differentiation of adipocytes, it is possible that the decreased adipose tissue was linked to changes in adipocyte size and number.

Topics: Adipose Tissue; Adiposity; Amides; Animals; Dietary Fats; Eating; Energy Intake; Fumarates; Leptin; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Renin; Renin-Angiotensin System; Weight Gain