Addition of aliskiren to losartan provides additional renal protective effects in hypertensive patients with type 2 diabetic nephropathy

Key Points

A recent multinational, randomized, double-blind, placebo-controlled clinical trial demonstrated that administration of aliskiren provides additional renal protection to patients with hypertension, type 2 diabetes mellitus, and nephropathy who are already receiving optimal antihypertensive therapy and renal protective therapy with the angiotensin receptor blocker (ARB) losartan. These study results were published in the New England Journal of Medicine.

The renal protective benefits of renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting enzyme (ACE) inhibitors and ARBs are well known; however, it is hypothesized that monotherapy with either agent alone may not optimally delay or prevent the progression of diabetic nephropathy. Aliskiren is the first of a new class of drugs that inhibit the enzyme renin, preventing the conversion of angiotensinogen to angiotensin I and ultimately decreasing downstream concentrations of angiotensin II. Thus, when used in conjunction with ACE inhibitors or ARBs, aliskiren may provide the additive benefit of further slowing the progression of diabetic nephropathy and staving off the development of end-stage renal disease (ESRD).

In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) trial, investigators randomized 599 patients with hypertension and type 2 diabetic nephropathy (defined as early morning urinary albumin-to-creatinine ratio of >300 mg/g or >200 mg/g in patients receiving RAAS-targeted therapy) to receive treatment with losartan 100 mg/d plus additional antihypertensive therapy in combination with either aliskiren for 6 months (150 mg/d for 3 mo followed by 300 mg/d for 3 mo) or placebo for 6 months. The primary end point of the trial was the reduction in the ratio of urinary albumin-to-creatinine, which is a surrogate marker for measuring the progression of nephropathy.

Less than half of all patients in the trial achieved their systolic blood pressure goal of 130 mmHg. At the end of the trial, aliskiren-treated patients demonstrated a mean blood pressure that was 2/1 mmHg lower than that of placebo recipients (P=.07/.08), suggesting that the renal protective effects of aliskiren are independent of blood pressure reductions.

Patients treated with aliskiren had qualitatively higher incidences of serum potassium elevations >5.5 (13.7% vs 10.8%) and ≥6.0 mmol/L (4.7% vs 1.7%) compared with patients who received placebo.

The investigators discussed several study limitations, noting the possibility that changes in antihypertensive medications after randomization may have at least partially skewed the study's results. Furthermore, they pointed out that there is currently no evidence that aliskiren's renal protective effect is sustained over longer time periods, emphasizing that "long-term studies (more than two years' duration) must be conducted to elucidate whether the beneficial effect on the kidney that is seen in the short term is sustained."

SOURCE

Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK; for the AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358: 2433–2446.