Blockade of the RAA system in diabetic patients: ACE inhibition, ARBs, and the potential role of direct renin inhibition

Modulation of the renin-angiotensin-aldosterone (RAA) system using angiotensin-converting enzyme (ACE) inhibitors or an­giotensin receptor blockers (ARBs) has been shown to have beneficial effects on blood pressure, diabetic nephropathy, coronary heart disease, and heart failure. Recently, upstream modulation using the renin blocker aliskiren (Tekturna) has become available.^1-18 Several large stud­ies of ACE inhibitors and ARBs have been performed in diabetic patients to assess the effects of these agents on diabetic nephropathy and cardio­vascular disease (CVD) risk reduction.^18-33 The current question facing clinicians is whether renin blockade, alone or in combination with ACE inhibitors or ARBs, will achieve comparable or greater blood pressure reduction and less nephropathy or CVD.

This article provides a brief overview of RAA system modulation, summarizes the ACE inhibitor and ARB studies on diabetic nephropathy and CVD, and discusses the reported effects of aliskiren on hypertension, both when used alone and in combination with ACE inhibitors or ARBs. It also examines the limited data on diabetic nephropathy. Because there are no CVD outcome studies in diabetic patients, what such studies might show and what the concerns of combination therapy might be can only be speculated.

RAA system and sites for modulation

Although ACE inhibitors, ARBs, and renin blockers all work on the RAA system, their mechanisms of action are quite different (Figure 1).¹⁷ ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, while ARBs block the action of angiotensin II at the angiotensin I receptor. ACE inhibitors and ARBs are associated with increased plasma renin ac­tivity. ACE inhibitors also result in an accumulation of bradykinin, which is the likely source of ACE inhibitor—induced cough. Furthermore, angio­tensin I may be converted to angiotensin II via ACE inhibitor–independent pathways, possibly contributing to an “ACE inhibitor escape” effect (ie, a loss of ACE inhibitor efficacy over time). Direct renin inhibition reduces angiotensin II by decreas­ing the production of angiotensin I, thereby avoiding any risk of this escape effect. Complete blockade at any step is essentially impos­sible mechanistically, so combina­tion blockade (ie, ACE inhibition plus ARB, direct renin inhibition plus ACE inhibition, direct renin inhibition plus ARB) has been the subject of much speculation, and several preliminary studies on the effects on blood pressure and diabetic nephropathy have been conducted.

Cardiorenal protection: ACE inhibitor and ARB studies

Diabetic nephropathy

The first large study demonstrating the ability of an ACE inhibitor to slow the progression of nephropa­thy was performed by the Collab­orative Study Group and evaluated captopril (Capoten).¹⁸ The efficacy of enalapril (Vasotec) in managing type 2 diabetes mellitus was re­ported by Ravid and colleagues.³⁰ Reduction in albuminuria, as a measure of renal protection, using the ACE inhibitor ramipril (Altace) was confirmed by much larger tri­als, including HOPE (Heart Out­comes Protection Study).²⁴ When ARBs became available, 3 large tri­als showed a reduction in albumin­uria.^20,27,29 Small studies examin­ing combination therapy with ACE inhibitors and ARBs had mixed results regarding efficacy, raising questions about whether benefits accrued beyond blood pressure control.

^21,34

CVD outcomes

Many of the nephropathy tri­als were underpowered to address the related questions of CVD, and there were no large head-to-head trials until 2008. In a comprehen­sive review of the topic in 2004, Strippoli and colleagues concluded: “Although the survival benefits of ACE inhibitors for patients with di­abetic nephropathy are known, the relative effects of ACE inhibitors and angiotensin II receptor antago­nist on survival are unknown ow­ing to the lack of adequate head-to-head trials.”³² HOPE and EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in stable Coronary Artery Disease) demonstrated a reduction in CVD events beyond the effects of blood pressure reduction in the diabetic cohorts.^19,31,35-37

Most recently, ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Glob­al Endpoint Trial), which included more than 25,000 participants (~38% with diabetes mellitus), re­ported no difference in CVD outcomes in participants randomized to ramipril compared with telmisartan (Micardis) and the combina­tion of ramipril and telmisartan.³⁸ The combination arm, however, was associated with some increased risk for hyperkalemia. Renal out­comes from this study have not yet been reported, but the distilled in­terpretation of these studies is that both ACE inhibitors and ARBs reduce the risk for diabetic neph­ropathy and poor CVD outcomes. Combination therapy does not ap­pear to benefit CVD outcomes and only limited data suggest a benefit on diabetic nephropathy.

Direct renin inhibition: Effects on blood pressure and diabetic nephropathy

Although aliskiren enters the RAA—system inhibition arena with a great deal of anticipation, there is a paucity of data; thus, interpre­tation of these data is akin to the speculation that accompanied the introduction of ARBs into clinical usage. Conclusions about the future role of aliskiren that are drawn in this article stem from the currently available data, and the role of aliskiren will no doubt change as more studies become available.

Blood pressure

Several blood pressure trials, largely in nondia­betic subjects, have demonstrated that aliskiren used as monotherapy has a modest dose re­sponse on systolic blood pressure (Figure 2).^6,17,39-42 In addition, the blood pressure effects appear to be comparable with those of several other antihypertensive agents, in­cluding ACE inhibitors, ARBs, and calcium channel blockers.^13,41,43-46 The addition of an ACE inhibitor or an ARB to aliskiren is associ­ated with a small further reduction in blood pressure, between 1.1 to 4.6 mm Hg systolic and 1.1 to 2.6 mm Hg diastolic.^{4,6,42,44,46,47} There is a small but tangible increase in the risks for hyperkalemia. These blood pressure effects are similar in diabetic patients.

Diabetic nephropathy

P

Stud&shy;ies of the effects of aliskiren on diabetic nephropathy are limited to 1 adequately powered study by Parving and colleagues.⁴⁸ This study was a randomized, double-blind, placebo-controlled trial that included 509 subjects with type 2 diabetes mellitus and elevated uri&shy;nary albumin and creatinine ratios (>300 mg/gm off treatment and >200 mg/gm with ARB therapy), who were receiving stable doses of losartan (100 mg daily) for 3 months.⁴⁸ Subjects were random&shy;ized to placebo or aliskiren 150 mg daily for 3 months, which was followed by 300 mg daily for an&shy;other 3 months. The authors found a mean 20% reduction in urine albumin and creatinine ratios with aliskiren (<.001), and nearly 25% of subjects had a 50% reduction. Aliskiren subjects had a slightly lower blood pressure (approxi&shy;mately 2.0 mm Hg less systolic and 1.0 mm Hg less diastolic), which did not explain the difference in albumin excretion. A confirmatory abstract on data from a small trial (n = 24) in type 2 diabetes mellitus subjects with hypertension and al&shy;buminuria randomized to placebo, aliskiren (300 mg daily), losartan (300 mg daily), and an aliskiren/losartan combination was present&shy;ed at the of the American Diabetes Association Scientific Sessions in June 2008.⁴⁹ In the trial, reduction in urinary albumin excretion was comparable in the aliskiren and losartan groups, with greater ef&shy;fects observed in the combination therapy group.

Cardiovascular disease

There are no published studies to assess the effects of aliskiren on CVD outcomes in diabetic subjects. No&shy;vartis has recently announced de&shy;tails of several large clinical trials as part of the company’s ASPIRE HIGHER clinical trials programs. One of these trials is designed to assess the effects of renin inhi&shy;bition on cardiorenal outcomes in patients with type 2 diabetes mellitus.

Conclusions

Large-scale clinical trials have demonstrated favorable cardiorenal outcomes in diabetic patients with blockade of the RAA system using ACE inhibitors and ARBs. The fa&shy;vorable effects of these agents are related to both blood pressure re&shy;duction and direct effects of RAA system blockade. Combination therapy may improve renal out&shy;comes; however, the largest trial on CVD outcomes (ONTARGET) has not shown improved CVD out&shy;comes with combination therapy using ACE inhibitors and ARBs.

The renin inhibitor, aliskiren, has favorable effects on blood pres&shy;sure reduction when used with ACE inhibitors and ARBs. Limited data suggest that renin inhibition in combination with ARB therapy has a favorable effect on diabetic nephropathy, as measured by uri&shy;nary albumin excretion. This may translate into a reduced need for renal replacement therapy, includ&shy;ing dialysis or renal transplanta&shy;tion, but it is clearly premature to speculate on the outcomes of CVD trials in which CVD outcomes (in non—heart failure patients) are not reduced with ACE inhibitors plus ARB therapy.