Impact of aliskiren treatment on urinary aldosterone levels in patients with type 2 diabetes and nephropathy: An AVOID substudy

Steno Diabetes Center, Gentofte, Denmark.
Journal of Renin-Angiotensin-Aldosterone System (Impact Factor: 2.4). 08/2011; 13(1):118-21. DOI: 10.1177/1470320311417272
Source: PubMed


Aldosterone blockade reduces albuminuria in diabetic patients with chronic kidney disease (CKD), and improves prognosis in chronic heart failure. This study assessed the effects of direct renin inhibition with aliskiren in combination with losartan and optimal antihypertensive therapy on urinary aldosterone, plasma renin activity (PRA) and plasma renin concentration (PRC).
In the AVOID study, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months aliskiren (150 mg force titrated to 300 mg once daily after 3 months) or placebo added to losartan 100 mg and optimal antihypertensive therapy. Urinary aldosterone excretion, PRA and PRC were measured at baseline and after 24 weeks in a prespecified subset of 133 patients.
Aliskiren added to losartan provided reductions from baseline in urinary aldosterone compared with adding placebo (-24% vs. -4%, p = 0.017) at week 24. There was no significant difference between the aliskiren and placebo groups in the proportion of patients with aldosterone breakthrough (aliskiren 35%, placebo 46%, p = 0.199). Aliskiren treatment reduced PRA by 90% at 24 weeks and increased PRC by 328%.
Adding aliskiren to recommended renoprotective treatment with losartan and optimal antihypertensive therapy provided significant reductions in urinary aldosterone excretion which may attenuate decline in kidney function.

Download full-text


Available from: Frederik Persson, Mar 06, 2014
  • Source

    Full-text · Chapter · Feb 2012
  • [Show abstract] [Hide abstract]
    ABSTRACT: Renin-angiotensin system (RAS) blockade with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) has become a major therapeutic approach in medicine since the end of the 1970's. Although these molecules were the first RAS blockers to be developed, it would have been physiologically and pharmacologically more pertinent to selectively inhibit renin itself. Indeed, the reaction between renin and its unique substrate, angiotensinogen, is the highly regulated and rate-limiting step of the RAS. The development of direct renin inhibitors (DRI) has been a slow and complex process and the synthesis of the first orally active DRI, aliskiren, was only achieved in the 2000's. Its pharmacological profile in patients with hypertension, diabetic nephropathy or heart failure, in addition to experimental evidence, suggests that aliskiren may be of value for the management of cardiovascular and renal diseases. However, the long-term, randomized, placebo-controlled, morbidity/mortality trial, ALTITUDE, which included 8,600 patients with type 2 diabetes, proteinuria and a high cardiovascular risk already treated with ACE inhibitors or ARBs was terminated in December 2011 because of futility and an increased incidence of serious adverse events in the aliskiren 300 mg arm. Other long-term studies are still ongoing to demonstrate the safety and efficacy of aliskiren to reduce cardiovascular morbidity and mortality in patients with heart failure and in elderly individuals (≥65 years) with systolic blood pressure of 130 to 159 mmHg, no overt cardiovascular disease, and a high cardiovascular risk profile. In the meantime, according to the European Medicines Agency recommendations, aliskiren should not be prescribed to diabetic patients in combination with ACE inhibitors or ARBs.
    No preview · Article · Mar 2012 · Cardiovascular Drugs and Therapy
  • [Show abstract] [Hide abstract]
    ABSTRACT: Aldosterone levels increase in 30%-40% of patients on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers over the long term. This "aldosterone breakthrough" may carry important clinical consequences given aldosterone's nonepithelial, pro-fibrotic actions. The renin inhibitor, aliskiren, by suppressing the renin-angiotensin-aldosterone system (RAAS) proximally, may limit breakthrough compared to conventional RAAS blockade. This open-label study (NCT01129557) randomized subjects to aliskiren 300 mg daily (A), valsartan 320 mg daily (V), or aliskiren 150 mg + valsartan 160 mg daily (A+V) for 9 months. Eligible subjects had proteinuria >300 mg/day, estimated glomerular filtration rate (eGFR) >45 mL/min/1.73 m(2), and systolic blood pressure (BP) >130 or diastolic BP >80 mm Hg. Serum and 24-hour urine aldosterone (indexed to 24-hour urine Na) were checked before initiation of therapy and at 3, 6, and 9 months. Aldosterone breakthrough was defined as a sustained increase from baseline aldosterone by study end. The study was intended to enroll 120 subjects but was terminated early by the sponsor. We present here the results of 33 subjects who completed the protocol, of which 12 were randomized to A, 11 were randomized to V, and 10 were randomized to A+V. Mean baseline eGFR was 75.5 (±23.3) mL/min/1.73 m(2); baseline proteinuria was 3104 (±2943) mg/day; and baseline BP was 134.7 (±10.5)/84.8 (±8.4) mm Hg. Three (27%) subjects on V, three (25%) subjects on A, and three (30%) subjects on A+V had aldosterone breakthrough. Mean proteinuria reduction was 31% from baseline in all subjects: 30% in subjects with breakthrough vs. 32% in subjects without breakthrough. Mean BP reduction was 11.0/8.8 mm Hg in all subjects: 8.4/6.1 mm Hg in subjects with breakthrough vs. 12.0/9.8 mm Hg in subjects without breakthrough. Aliskiren, alone or in combination with valsartan, did not reduce the incidence of aldosterone breakthrough in subjects with hypertension and proteinuria compared with conventional RAAS blockade.
    No preview · Article · Sep 2012 · Journal of the American Society of Hypertension (JASH)
Show more