Aliskiren Combined with Losartan in Type 2 Diabetes and Nephropathy

Image via WikipediaThe pathogenesis of diabetic nephropathy is multifactorial, and the renin–angiotensin–aldosterone system plays an important role.1,2 Persistent proteinuria is the hallmark of diabetic nephropathy, a condition that is characterized by a progressive rise in blood pressure, a declining glomerular filtration rate, and a high risk of fatal or nonfatal cardiovascular events. The degree of proteinuria is closely associated with the rates of renal and cardiovascular events.3,4 Furthermore, a reduction in proteinuria is associated with a slowing of both the decline in the glomerular filtration rate5 and the progression to end-stage renal disease.6 In addition, decreasing proteinuria is associated with improved cardiovascular outcomes in patients with diabetic nephropathy7 and arterial hypertension.8 As a result, a reduction in proteinuria has been widely used as a surrogate end point for renoprotection.

During the past two decades, the outlook for patients with diabetes who have microalbuminuria or macroalbuminuria has improved, probably owing to early aggressive lowering of blood pressure and blocking of the renin–angiotensin–aldosterone system.3,4,9,10,11,12 However, there is still a large, unmet need to develop strategies for the prevention of diabetic nephropathy and its progression to end-stage renal disease. Diabetic nephropathy remains the leading cause of end-stage renal disease in the developed world.

The aim of this trial was to evaluate the potential renoprotective capacity of direct renin inhibition with aliskiren in patients with hypertension, type 2 diabetes, and proteinuria who were already receiving the maximal recommended renoprotective treatment with losartan (100 mg daily) and optimal treatment for hypertension. In addition, the safety of dual blockade of the renin–angiotensin–aldosterone system was monitored and recorded.

Characteristics of the Patients

Baseline demographic, clinical, and biochemical characteristics and the number of patients who were receiving glucose-lowering and lipid-lowering therapies and aspirin (≤325 mg daily) were balanced between the two groups, except that the patients in the placebo group were slightly older (P=0.009) (Table 1). The mean glycated hemoglobin values remained unchanged, at 8.0%, in the aliskiren group and rose to 8.1% in the placebo group, and the numbers of severe hypoglycemic episodes were zero and one, respectively. Additional blood-pressure–lowering drugs that were taken by patients in the two groups are shown in Table 2.
Discussion

The present trial shows that treatment with 300 mg of aliskiren daily reduces albuminuria in patients with hypertension, type 2 diabetes, and proteinuria who are receiving the recommended maximal renoprotective treatment with losartan and optimal antihypertensive therapy. Furthermore, a 50% reduction in albuminuria was seen twice as often in the group that received 300 mg of aliskiren daily as in the group that received placebo. The benefits of aliskiren appear to be independent of the systemic blood pressure; average trough systolic and diastolic blood pressures during the study were only marginally lower in the aliskiren group than in the placebo group, and an analysis that adjusted for these small differences confirmed the renoprotective effect of aliskiren. In addition, the decline in kidney function tended to be smaller among the patients who received aliskiren than among those who received placebo.

The benefit of blocking the renin–angiotensin–aldosterone system in patients with diabetes who are at risk for end-stage renal disease is now well established.3,4,10,11,12 However, most studies to date also show that renal disease progresses in many patients despite treatment with angiotensin-converting–enzyme (ACE) inhibitors or angiotensin II–receptor blockers.3,4,10,11,12 Consequently, alternatives that optimize the blockade of the renin–angiotensin–aldosterone system are being explored in the hope that a more complete blockade will lead to a better therapeutic outcome.17 New renoprotective strategies include dual blockade of the renin–angiotensin–aldosterone system with the use of ACE inhibitors and angiotensin II–receptor blockers, very high doses of angiotensin II–receptor blockers,18,19,20 aldosterone blockade,21,22 and, as in the present study, direct renin inhibition.

Aliskiren, the renin inhibitor used in our study, has a 40-hour half-life and reduces both blood pressure and plasma renin activity. It is well established that a dose of 300 mg of aliskiren is optimal for the reduction of blood pressure.23 Further information concerning the development of oral renin inhibitors and their pharmacokinetic and pharmacodynamic properties, with a focus on aliskiren, is available in a recent review.24

In a study reported in 2000 that involved patients with type 2 diabetes, hypertension, and microalbuminuria, Mogensen et al.25 showed that treatment with a combination of submaximal doses of candesartan and lisinopril was more effective in reducing blood pressure (reductions in systolic pressure of approximately 10 mm Hg and in diastolic pressure of approximately 6 mm Hg) than therapy with only one agent; however, the effectiveness of the combined therapy in reducing albuminuria was not firmly established. Since then, numerous small studies, often using submaximal doses of ACE inhibitors in patients with diabetic nephropathy, have shown a significant reduction in blood pressure and albuminuria with this treatment strategy.26 In contrast, a large, randomized, controlled trial involving patients with type 2 diabetes, hypertension, and albuminuria who received the maximal recommended doses of ramipril and irbesartan failed to show a significant effect of combination therapy, as compared with monotherapy, on albuminuria,27 despite a significant reduction in systemic blood pressure. However, this study may have been underpowered, owing to a more marked variability in the urinary albumin excretion rate than anticipated. Our study was larger and adequately powered, and the results clearly support a specific renoprotective effect of aliskiren — namely, a beneficial effect on kidney function beyond the effect on hypertension. However, we cannot completely rule out the possibility that changes in antihypertensive medications after randomization might have confounded the results of our study.

Glomerular proteinuria is determined by four factors: the mean transcapillary hydraulic-pressure difference, the glomerular surface area, and the size selectivity and charge selectivity of the glomerular filter. In diabetic nephropathy several of these variables are abnormal, and blockade of the renin–angiotensin–aldosterone system has been shown to normalize directly measured or estimated glomerular hydraulic pressure,28,29,30 to reduce the shunt-like defects in the membrane, at least in part,31,32 and to restore the charge-selectivity properties of the glomerular membrane.33

In our study, the estimated glomerular filtration rate was nearly identical in the two groups at baseline, whereas the decline in the glomerular filtration rate tended to be smaller among the patients who were treated with aliskiren for 6 months than among the patients who were given placebo. Long-term studies (more than 2 years' duration) must be conducted to elucidate whether the beneficial effect on the kidney that is seen in the short term is sustained.

Previous studies with antihypertensive drugs have usually shown an initial drop in the glomerular filtration rate that is steeper than the sustained decline.11,34 Recently, a study of healthy people on a low-sodium diet has shown that renal vasodilatation with aliskiren far exceeds that seen with ACE inhibitors and angiotensin II–receptor blockers.35 These results indicate that aliskiren may provide greater and thus more effective blockade of the renin system in the kidney. Since the renin system is enhanced in patients with diabetes, as compared with controls,36 a more pronounced difference in renal vasodilatation may be expected during aliskiren therapy.

During the course of the trial, the average difference in blood pressure was only 2 mm Hg systolic and 1 mm Hg diastolic in favor of the dual blockade of the renin–angiotensin–aldosterone system. Studies of the same treatment approach (300 mg of aliskiren combined with 320 mg of valsartan37 or 10 mg of ramipril38) in patients with essential hypertension have shown at least a doubling of the difference in blood pressure in the combination-therapy groups as compared with the monotherapy groups. A likely explanation for this finding is that the patients in these two trials had a much higher average baseline blood pressure than the patients in our study, whose baseline blood pressure was well controlled. Even though many of the patients in both of our study groups received three or more antihypertensive agents, our systolic blood-pressure goal of 130 mm Hg was reached in less than half the patients, whereas our diastolic blood-pressure goal of 80 mm Hg was reached in the majority of patients in both groups. Previous studies among patients with diabetic nephropathy have also shown that ideal control of systolic blood pressure is very difficult to attain in patients with diabetes, probably owing to the presence of diabetic macroangiopathy.2,3,4,11

It is possible that aliskiren also differs from ACE inhibitors or angiotensin II–receptor blockers in other ways that might explain these results. In 2002, Nguyen et al.39 discovered a (pro)renin receptor that was detected in the brain, heart, liver, and kidney. Prorenin, when bound to the (pro)renin receptor, displayed enzymatic activity and activation of intracellular signaling pathways without proteolytic removal of the prosegment. Recent studies in animals with diabetes40,41 and in in vitro conditions with high glucose42 have shown that aliskiren reduces the number of (pro)renin receptors in the kidney, mitigates profibrotic activity in the kidney, and nearly abolishes the apoptotic effects on cultured podocytes. Furthermore, data from transgenic (mRen-2)27 rats with diabetes suggest that aliskiren has a greater renoprotective capacity than ACE inhibitors.43 These findings are consistent with the observation that an elevated plasma prorenin level is associated with the development of diabetic nephropathy.1

The combination therapy consisting of the maximal recommended doses of aliskiren and losartan had similar tolerability to therapy with placebo and losartan, consistent with findings in an earlier study of the combination of aliskiren and valsartan.37 Hyperkalemia was reported in 5.0% of the patients in the aliskiren group and in 5.7% of the patients in the placebo group. The number of patients with a serum potassium level of 6.0 mmol per liter or more was higher with the combined drugs than with placebo, although the occurrence of such cases, after adjustment for the nine patients who were mistakenly enrolled in the trial, was low.

In conclusion, aliskiren appears to have a renoprotective effect that is independent of its blood-pressure–lowering effect in patients with type 2 diabetes who are receiving the maximal recommended renoprotective treatment and optimal antihypertensive therapy.

Supported by Novartis Pharma
References