Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

Background:  Renin inhibition allows for a reduction in proteinuria, thus reducing renal events such as diabetic nephropathy.  There is little information regarding combined blockade of the renin system with a direct renin inhibitor and an angiotensin receptor blocker. 

Objective:  The purpose of this study was to evaluate the renoprotective properties of aliskiren in addition to losartan 100 mg/day and optimal treatment for hypertension, in patients with hypertension, type 2 diabetes, and proteinuria. 

Methods:  The study design was randomized, double-blind, and placebo controlled.  The patients were 18-85 years old, had type 2 diabetes and nephropathy.  The patients were excluded if they had nondiabetic kidney disease, urinary albumin-to-creatinine ratio of > 3500 mg/gram, an estimated GFR of < 30 ml/min per 1.73 m2 BSA, chronic UTI, a serum potassium level > 5.1 mmol/L at time of randomization, severe hypertension, or major cardiovascular disease within the past 6 months.  A total of 805 patients were involved in a 3 month open-label period in which all RAAS drugs were discontinued, except beta blockers, and treatment with losartan 100 mg/day in addition to other antihypertensive therapy aimed to achieve target blood pressures.  206 patients were excluded after the open label phase, leaving 599 patients for randomization to receive 150 mg aliskiren (301 patients) once daily for 3 months, then 300 mg once daily for 3 months, or placebo (298 patients) once daily for 6 months. The primary outcome is to reduce the albumin-to-creatinine ratio in early-morning urine samples at 6 months.  Secondary outcomes include:  change from baseline in systolic/diastolic blood pressure, mean change in urinary excretion rate of albumin, and mean rate of decline in GFR.   The study assessed the data with the intention-to-treat population.  The power of this study was approximately 94%. 

Results:  524 patients (87%) completed the study, the aliskiren group had 259 patients (86%), and the placebo group had 265 (88%).  The mean urinary albumin-to-creatinine ratio was reduced by 20% in the aliskiren group compared to the placebo group (95% CI, 9 to 30, P<0.001).  Mean blood pressure was 2/1 mmHg lower in the aliskiren group compared to placebo.  (P=0.07 for systolic, P=0.08 for diastolic).  The mean rate of decline in GFR at 24 weeks was 2.4 mL/min per 1.73 m2 in aliskiren group (95% CI, 1.1 to 3.7) and 3.8 mL/min per 1.73 m2 in the placebo group (95% CI, 2.5 to 5.1) (P=0.07). The GFR was nearly identical at baseline, and the decline tended to be smaller in the aliskiren group after 6 months, but longer term studies (2 years) must be done to verify the benefits on GFR. 

Strengths:  The study design was parallel, placebo-controlled which is appropriate for determining drug efficacy because the outcomes from each group (aliskiren and placebo) can be compared and analyzed.  The intention-to-treat method sufficiently interprets the results of the study by reflecting the actual clinical usefulness of the drug. 

Weaknesses:  There was a large difference between the albumin-to-creatinine ratio that the study used as inclusion (>300, or >200) and exclusion (>3500) criteria.  Aliskiren’s activity on renin inhibition could not be clearly determined because of the use of losartan.  The patient’s in the study were all on different antihypertensive regimens; therefore it is difficult to determine the actual effectiveness of aliskiren’s dual therapy with losartan.  The study was supported by Novartis the makers of the study drug aliskiren.  Compliance was addressed at each patient evaluation; however, it was not noted what method the investigators used to confirm compliance.    

Conclusion:  The authors concluded that aliskiren appears to have renoprotective activity independent of its blood pressure lowering effects in type 2 diabetes patients receiving losartan 100 mg/day and optimal antihypertensive therapy.  Aliskiren is a direct renin inhibitor and may have a place in therapy were there is difficultly controlling a patient’s proteinuria and/or hypertension; otherwise, further research needs to be completed in order to evaluate the effectiveness of aliskiren as dual therapy with an RAAS drug.  Also, it needs to be considered, for cost-effective purposes, as to whether or not aliskiren plus an RAAS drug is more effective at lowering blood pressure and controlling the albumin-to-creatinine ratio than other dual treatment regimens with ACEI’s and ARB’s. 

Parving HH, Persson F, Lewis JB, et al.  Aliskiren combined with losartan in type 2 diabetes and nephropathy.  N Engl J Med. 2008 Jun 5;358(23):2503-5.

Marce Hoyland, Pharm.D. Candidate, 2009