Journal of Human Hypertension (2011) 25, 186–195 & 2011 Macmillan Publishers Limited All rights reserved 0950-9240/11 www.nature.com/jhh ORIGINAL ARTICLE Comparative efficacy and safety of aliskiren and irbesartan in patients with hypertension and metabolic syndrome W Krone1, M Hanefeld2, H-F Meyer3, T Jung4, M Bartlett5, C-M Yeh6, I Rajman5, MF Prescott6 and WP Dole7 1Klinik II und Poliklinik fu¨r Innere Medizin, Zentrum fu¨r Molekulare Medizin der Universita¨tzuKo¨ln, Cologne, Germany; 2Centre for Clinical Studies, GWT-TUD GmbH, Dresden, Germany; 3Facharzt fu¨r Allgemeinmedizin, Marl, Germany; 4Facharzt fu¨r Allgemeinmedizin, Deggingen, Germany; 5Novartis Institutes for Biomedical Research, Basel, Switzerland; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA and 7Novartis Institutes for Biomedical Research Inc., Cambridge, MA, USA Metabolic syndrome, a cluster of risk factors that than the 5.8/2.8 mm Hg reduction observed in patients increase the risk of cardiovascular morbidity and mor- treated with irbesartan 300 mg. A significantly greater tality, is common in patients with hypertension. Chronic proportion of patients treated with aliskiren achieved BP renin–angiotensin–aldosterone system (RAAS) activa- control to o135/85 mm Hg (29.2 vs 16.7% with irbesartan; tion, shown by elevated plasma renin activity (PRA), is P ¼ 0.019). Aliskiren treatment led to a 60% decrease in implicated in many of the features of metabolic syn- PRA from baseline, whereas irbesartan increased PRA drome. The direct renin inhibitor aliskiren may be of by 99% (both Po0.001). Aliskiren and irbesartan had benefit in this patient group as aliskiren targets the similar effects on glucose and lipid profiles and on a RAAS at the rate-limiting step. In this double-blind panel of biomarkers of inflammation and cardiovascular study, 141 patients with hypertension (mean baseline risk. Both aliskiren and irbesartan were well tolerated. BP 155/93 mm Hg) and metabolic syndrome (modified Collectively, these results suggest that aliskiren 300 mg National Cholesterol Education Program ATP III criteria) may offer treatment benefits compared with irbesartan were randomized to aliskiren 300 mg or irbesartan 300 mg 300 mg for BP reduction in patients with hypertension once daily. Patients treated with aliskiren 300 mg had and metabolic syndrome. their mean sitting blood pressure (BP) lowered by 13.8/ Journal of Human Hypertension (2011) 25, 186–195; 7.1 mm Hg after 12 weeks, significantly greater (Pp0.001) doi:10.1038/jhh.2010.38; published online 8 April 2010 Keywords: aliskiren; direct renin inhibitor; irbesartan; metabolic syndrome; plasma renin activity Introduction converting enzyme and angiotensin receptors.7 The local generation and release of angiotensin II (Ang II) Approximately one-third of patients with hyperten- 1,2 by adipose tissue may therefore contribute to sion have metabolic syndrome, a cluster of risk hypertension and can also influence adipocytokine factors including high blood pressure (BP), central secretion, thereby having a potential role in the adiposity, dyslipidaemia and impaired fasting development of features of the metabolic syndrome.5 glucose that result in increased cardiovascular 3 Guidelines from the European Society of Hyper- morbidity and mortality. Chronic activation of the tension recommend that RAAS inhibition with renin–angiotensin–aldosterone system (RAAS) is angiotensin-converting enzyme inhibitors should implicated in many of the key features of metabolic be preferred over calcium channel blockers, syndrome, including hypertension, insulin resis- 4–6 b-blockers and thiazide diuretics for anti-hypertensive tance and abdominal obesity. Human adipocytes therapy in patients with metabolic syndrome.8 How- express mRNA and protein of many components of ever, despite current anti-hypertensive treatment the RAAS, including angiotensinogen, angiotensin- approaches, patients with obesity and metabolic syndrome still have greater difficulty achieving BP Correspondence: Professor W Krone, Klinik II und Poliklinik fu¨r control compared with patients with hypertension Innere Medizin, Zentrum fu¨ r Molekulare Medizin der Universita¨t who do not have these additional risk factors.9 This zu Ko¨ln, Kerpener Str. 62, 50937 Cologne, Germany. reflects the more complex pathophysiology, in E-mail: [email protected] Received 14 November 2009; revised 10 February 2010; accepted particular the involvement of insulin resistance and 13 February 2010; published online 8 April 2010 low-grade inflammation. Aliskiren in patients with metabolic syndrome W Krone et al 187 Aliskiren is the first direct renin inhibitor msSBPX180 mm Hg and/or msDBPX110 mm Hg were approved for the treatment of hypertension.10 It is excluded, as were those with secondary hypertension, the only RAAS agent that directly inhibits the angina pectoris requiring pharmacological therapy, activity of renin and thereby lowers plasma renin heart failure, valvular heart disease or diabetes (type I activity (PRA), in contrast to angiotensin-converting or type II), and those with a history of hypertensive enzyme inhibitors or angiotensin-receptor blockers encephalopathy, myocardial infarction or stroke. (ARBs), which increase PRA.11 Several studies have Each patient provided written informed consent shown an association of elevated PRA with an before study entry. The study design was approved increased risk of cardiovascular events.12–14 Given by the independent ethics committee or institutional the importance of RAAS overactivation in metabolic review board at each centre, and was conducted in disorders, direct renin inhibition may be of parti- accordance with Good Clinical Practice and in compli- cular benefit for patients with metabolic syndrome. ance with the Declaration of Helsinki Principles. Previous studies have shown that aliskiren-based Following screening, patients entered a 21-day treatment is superior to thiazide diuretic treatment washout period before randomization to once-daily for BP control in patients with hypertension and treatment with aliskiren 150 mg or irbesartan 150 mg. obesity.15,16 Indeed, aliskiren added to hydrochloro- Randomization was performed by Novartis Drug thiazide provided significant additional BP reduc- Supply Management using a validated system to tions over hydrochlorothiazide monotherapy in randomly assign treatment groups to randomization patients with grade 3 obesity (body mass index numbers. Aliskiren and irbesartan were identical in (BMI)X40 kg mÀ2).17 Moreover, a pooled analysis of packaging and labelling, and all patients received 7219 patients from 10 randomized trials showed that one tablet and one capsule to maintain the double- aliskiren monotherapy (150 or 300 mg once daily) blind protocol. After 2 weeks of treatment, doses in lowered BP effectively and with similar good both groups were increased to 300 mg (Figure 1). tolerability in patients with or without metabolic syndrome.18 We report the results of a 12-week, double-blind, Study objectives randomized, multi-centre trial conducted to com- The objective of this study was to assess changes pare the effects of direct renin inhibition with from baseline in a panel of biomarkers of inflamma- aliskiren and ARB monotherapy with irbesartan on tion and other markers associated with cardio- BP, RAAS activity, and a panel of biomarkers of vascular risk and/or metabolic syndrome. These inflammation and cardiovascular risk in patients included BP and markers of RAAS activity, inflam- with hypertension and metabolic syndrome. mation, fibrosis, coagulation/thrombosis, immuno- modulation, oxidative stress and metabolism, neurohormones, adipocytokines and lipoproteins. Materials and methods Changes from baseline in msSBP and msDBP at each time point, the proportion of subjects attaining This was a randomized, double-blind, parallel- BP control (o135/85 mm Hg) at day 85, changes group trial of 141 men and women aged 40–75 years from baseline in biomarkers at day 85 and safety and with hypertension and metabolic syndrome. It was tolerability of study treatments in patients were conducted in 27 centres in Germany. All patients assessed for each treatment group and compared entered into the study had metabolic syndrome between treatment groups. according to the modified National Cholesterol Education Program ATP III criteria:3 elevated BP (mean sitting systolic BP (msSBP)X130 mm Hg and/ BP measurements or mean sitting diastolic BP (msDBP)X85 mm Hg), Sitting and standing BP measurements were central obesity (waist circumference X102 cm for taken according to American Heart Association men, X88 cm for women), and elevated triglyce- guidelines19 using an automatic BP device (OMRON ride levels (X1.7 mmol lÀ1), and/or fasting plasma 705IT (HEM-759-E); Omron Medizintechnik, Mann- glucose (X5.6 and o7.0 mmol lÀ1). Patients with heim, Germany) and an appropriately sized arm Randomization Aliskiren 150 mg Aliskiren 300 mg Screening Washout Irbesartan 150 mg Irbesartan 300 mg Blood sample BP BP BP Blood sample BP BP –28 –22 –21 –1 1 14 1529 57 85 Day Figure 1 Study design. BP, blood pressure. Journal of Human Hypertension Aliskiren in patients with metabolic syndrome W Krone et al 188 cuff at screening, baseline and on days 14, 29, 57 biotinylated reporter antibodies for each multiplex and 85 (Figure 1). were then added robotically and after thorough mixing were incubated for an additional hour at room temper- ature. Multiplexes were developed using an excess Biomarker assessments of streptavidin–phycoerythrin