NPC Archive Item: Is aliskiren plus losartan renoprotective in patients with type 2 diabetes and nephropathy?

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Parving H-H, Persson F, Lewis JB et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. NEJM 2008;358:2433-46

Aliskiren reduces the mean urinary albumin-to-creatinine ratio when added to losartan and optimal antihypertensive medication in patients with type 2 diabetes (T2DM), nephropathy and hypertension. It is not known whether this translates into patients living longer or better.

Use of aliskiren in the prevention of progression of diabetic nephropathy should be reserved for patients whose renal function continues to deteriorate despite usual anti-hypertensive therapy. This relatively short-term trial measuring biochemical markers of renal disease is encouraging but data on long-term safety plus renal and cardiovascular (CV) morbidity/mortality are required before we should consider using this agent on a more widespread basis. In addition, we cannot extrapolate these findings to those who had severe renal impairment as this study excluded those with estimated glomerular filtration rate (eGFR) less than 30ml/minute.

What is the background to this?
Diabetic nephropathy is the main cause of end-stage renal disease in the western world [1]. The renin-angiotensin-aldosterone system (RAAS) plays a major role in the pathogenesis of diabetic nephropathy. Aliskiren, a direct inhibitor of renin, is currently licensed for the treatment of essential hypertension [2].

What does this study claim?
The AVOID study, sponsored by Novartis, was a randomised, double-blind, trial compared aliskiren plus losartan (n=301) with losartan and placebo (n=298) in adult patients with T2DM, proteinuria and hypertension [1]. Exclusion criteria included eGFR less than 30ml/minute/1.73m2, serum potassium more than 5.1mmol/litre and a urinary albumin-to-creatinine ratio of more than 3500mg/g. 805 patients initially entered a 3-month open-label phase during which all drugs which block the RAAS were stopped, except for beta-blockers. Losartan 100mg per day was started with additional antihypertensive therapy aimed at reaching a blood pressure (BP) of less than 130/80mm Hg. 206 patients were then excluded, leaving 599 patients to be randomly assigned to placebo or aliskiren 150mg daily for 3 months then 300mg daily for a further 3 months.

The primary end-point was percentage reduction in the early morning urinary albumin-to-creatinine ratio from baseline to the end of the trial (24 weeks), a surrogate end-point for renoprotection. By the end of the trial, aliskiren plus losartan had reduced the mean morning urinary albumin-to-creatinine ratio by 20% (95% confidence interval 9-30, P<0.001) with no reduction seen in the group taking losartan plus placebo. A reduction of 50% or more in albuminuria was seen in 24.7% of those in the aliskiren group compared with 12.5% on placebo (P<0.001). No analysis was made on the proportion of patients who responded nor on the relative change from baseline of the aliskiren group compared to the placebo group. There was no statistically significant difference in BP readings between the two groups.

No difference was seen in the groups in terms of adverse effects – 66.8% of the aliskiren group and 67.1% of those on placebo had adverse events (such as headache, nasopharyngitis, dizziness and peripheral oedema). Hyperkalaemia was seen in 5.0% of the aliskiren patients and 5.7% of those on placebo.

So what?
Studies have shown that renal disease progresses in many of these patients despite taking an ACE inhibitor or angiotensin II receptor antagonist [1]. Despite this study suggesting some beneficial effects of aliskiren on biochemical markers of renal disease, it is still not known if adding aliskiren to an ACE inhibitor or angiotensin II receptor antagonist will reduce actual kidney disease or indeed morbidity or mortality over the long-term.

The authors note that changes in antihypertensive treatment after randomisation could have comfounded the results. A longer-term trial of more than 8,000 patients is currently recruiting (ALTITUDE), which may give us a better understanding of this complex area. The trial aims to determine whether, in patients with T2DM and pre-existing CV disease and/or kidney disease, aliskiren, on top of conventional treatment, could reduce CV death and CV or renal morbidity.

It should be noted that the summary of product characteristics for aliskiren states that the risk of hyperkalaemia is increased when aliskiren is combined with other drugs which inhibit the RAAS or in patients with impaired kidney function and/or diabetes [2]. Caution is needed when treating hypertensive patients with severe renal impairment, as safety information is limited.

1. Parving H H, Persson F, Lewis JB et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. NEJM 2008;358:2433-46

2. Rasilez. Summary of Product Characteristics. Novartis. Dated 7 September 2007. Accessed from URL: on 23 June 2008