Dual‐Agent Blockade of the Renin‐Angiotensin System by Adding a Direct Renin Inhibitor to an Angiotensin Receptor Blocker Reduces Clinical Proteinuria in Type 2 Diabetics With Hypertension: The AVOID Study
Diabetic nephropathy is the leading cause of end‐stage renal disease (ESRD) in the developed world. The degree of proteinuria in patients with diabetes is directly associated with the rates of renal and cardiovascular (CV) events. In the Effects of Losartan on Renal and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Nephropathy (RENAAL) study, reduction in proteinuria with the angiotensin receptor blocker (ARB) losartan, dosed at 100 mg/d, improved CV and renal outcomes in patients with type 2 diabetes mellitus (T2DM), hypertension, and nephropathy. Most clinical studies, however, show that renal disease continues to progress despite the use of the maximum recommended dose of ARB or angiotensin‐converting enzyme (ACE) inhibitor therapy. Accordingly, the optimal way to antagonize the renin‐angiotensin system (RAS) continues to be explored. The Aliskiren Combined With Losartan in Type 2 Diabetes and Nephropathy (AVOID) study evaluated the renal protective effects of dual blockade of the RAS by adding the direct renin inhibitor (DRI) aliskiren to treatment with the maximum recommended dose of losartan in patients with hypertension, T2DM, and nephropathy.
AVOID was an international, double‐blind, prospective, randomized, placebo‐controlled trial sponsored by the makers of aliskiren, who were involved with the study design as well as the collection and analysis of the data. Conducted in 15 countries and 150 centers, the study included patients with a known history of hypertension, T2DM, and nephropathy (defined as an early morning urinary albumin‐to‐creatinine ratio [UACR] of >300 mg albumin/g creatinine or >200 mg albumin/g creatinine) in those receiving antihypertensive agents that block the RAS. Exclusion criteria included known nondiabetic kidney disease, a UACR of >3500 mg albumin/g creatinine, an estimated glomerular filtration rate (GFR) of <30 mL/min/1.73 m2 of body surface area, chronic urinary tract infection, a serum potassium level >5.1 mmol/L at the time of randomization, severe hypertension, or major CV disease within the previous 6 months. Eligible patients who met these criteria were enrolled in a 3‐month open‐label run‐in period during which all antihypertensive agents that block the RAS (except β‐blockers) were discontinued and treatment with losartan 100 mg/d was initiated. Additional antihypertensive medications, except those that block the RAS, were added during the run‐in period to reach a target blood pressure (BP) of <130/80 mm Hg. Patients who tolerated losartan and remained eligible after the open‐label run‐in period were subsequently randomized to either aliskiren (150 mg/d for 3 months followed by 300 mg/d for an additional 3 months) or matching placebo. Both investigators and patients were blinded to treatment allocation. Open‐label losartan 100 mg/d was continued in all patients throughout the entire study. After randomization, patients were evaluated at 1, 4, 8, 11, 12, 16, and 24 weeks. At each visit, BP, pulse, adverse events, concomitant medications, and adherence to study medications were assessed. Investigators were encouraged to add additional antihypertensive medications if BP was not <130/80 mm Hg at each visit. Early morning urine samples were obtained 2 weeks before randomization and at 4, 8, 12, 16, and 24 weeks after randomization. Three overnight urine samples were also obtained on 3 sequential nights 2 weeks before randomization and at 12 and 24 weeks after randomization. The primary outcome was a reduction of the UACR, as measured in an early morning sample, at 6 months.
A total of 1892 patients aged 18 to 85 years (mean age, 60 years) were screened, with 805 entering the open label run‐in period with losartan. During this 3‐month period, 206 patients were excluded, allowing 599 patients to be randomized. Baseline characteristics at the time of randomization were similar in the aliskiren and placebo groups except that those in the aliskiren group were slightly younger (59.8 vs 61.8 years) and had fewer years of known diabetes (13.2 vs 14.9). Baseline BP was similar (134–135/77–78 mm Hg) as was estimated GFR (67 mL/min/1.73 m2) and glycosylated hemoglobin (7.9%–8%). Mean baseline UACR was 513 mg albumin/g creatinine in the aliskiren group and 553 mg albumin/g creatinine in the placebo group.
During the 6‐month double‐blind period, in addition to losartan, 60.4% of placebo and 52.2% of aliskiren patients received a calcium channel blocker, 40.6% of placebo and 36.2% of aliskiren patients received a β‐blocker, and 34.2% of placebo and 32.9% of aliskiren patients received a thiazide‐type diuretic. Use of other classes of antihypertensive agents, including loop diuretics (33.2% vs 30.9%) and α‐adrenergic blockers (3.4% vs 3.0%), were also modestly more common in the placebo than in the aliskiren group, respectively. At the conclusion of the study, mean BP was 2/1 mm Hg lower in the aliskiren than in the placebo group.
At the end of the study, the early morning UACR (primary end point) was 20% lower in the aliskiren group than the placebo group (95% confidence interval [CI], 9%–30%; P<.001). After adjustment for the greater reduction in systolic BP in the aliskiren group (2 mm Hg), the reduction in UACR was 18% (95% CI, 7%–28%; P<.001). The overnight urinary albumin excretion demonstrated a similar finding, with a decrease of 18% in the aliskiren group compared with the placebo group (95% CI, 5%–30%; P=.009). Subgroup analysis demonstrated similar findings in favor of aliskiren for all major subgroups investigated, including those based on sex, race, age, UACR, estimated GFR, systolic and diastolic BP, and glycosylated hemoglobin. A reduction in the UACR of at least 50% was seen in 24.7% of patients receiving aliskiren and 12.5% of patients receiving placebo. Although the mean decline in GFR was less in the aliskiren group than in the placebo group, the difference was not statistically significant. There was no difference in the incidence of all adverse events, major adverse events, or adverse events leading to discontinuation between randomized groups. The incidence of significant hyperkalemia was actually lower in the aliskiren (5.0%) than in the placebo group (5.7%).
In patients with hypertension, T2DM, and nephropathy (clinical proteinuria), addition of the DRI aliskiren to the renoprotective dose of the ARB losartan leads to a significant reduction in the UACR independent of BP reduction, without an increase in the risk of adverse events, including hyperkalemia.—Parving HH, Persson F, Lewis JB, et al; AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358:2433–2446.
Comment
Multiple clinical trials confirm the benefits of RAS blockade with ACE inhibitor or ARB therapy in patients with T2DM and hypertension who are at risk for ESRD. In the landmark RENAAL study, the ARB losartan (100 mg/d) significantly reduced the incidence of the composite end point of doubling of serum creatinine, ESRD, or death in patients with T2DM, hypertension, and nephropathy—an effect that was independent of BP reduction. In the Renoprotective Effect of the Angiotensin Receptor Antagonist Irbesartan in Patients With Nephropathy due to Type 2 Diabetes Trial (IDNT), the ARB irbesartan, when also given at its maximum approved dosage of 300 mg/d, also significantly reduced the incidence of composite of renal end points. These trials led the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) to place T2DM with clinical nephropathy as a compelling indication for the use of ACE inhibitor or ARB therapy in those with hypertension.
In the absence of compelling head‐to‐head data comparing the effect of ACE inhibitor and ARB therapy in hypertensive patients with T2DM and clinical nephropathy, the choice between these classes often depends on tolerability, cost, and physician and formulary preference. It is also important to recall that neither ACE inhibitors nor ARBs completely block the RAS. While ACE inhibitor therapy specifically blocks the conversion of angiotensin I to angiotensin II, the conversion of angiotensin I to angiotensin II can also be catalyzed by enzymes such as trypsin, cathepsin, and chymase, with up to 40% of angiotensin II being formed by enzymes other than ACE. The increased levels of angiotensin II produced by this RAS “escape” promotes the trophic effects of angiotensin II and increased aldosterone secretion in the setting of ACE inhibitor therapy. Similarly, ARBs incompletely block the RAS, as their long‐term use results in increased levels of angiotensin I and angiotensin II. This leads to inhibition of the negative feedback loop by which angiotensin II suppresses renin release, resulting in increased plasma renin activity. As animal data suggests, the DRI aliskiren may have unique renoprotective effects, perhaps through its effects on down‐regulation of the (pro)renin receptor in the kidney; it has been suggested that newer renoprotective strategies involving treatment with 2 RAS‐blocking drugs, one of which is a DRI, through their differing mechanisms of action might confer a particular advantage in those with diabetic nephropathy. The present study was therefore undertaken to address whether combining a DRI with an ARB is beneficial in patients with T2DM, hypertension, and clinical nephropathy.
The AVOID study was well designed and implemented. All patients received the exact agent and dosage (losartan 100 mg/d) as background therapy shown to be beneficial in the RENAAL study and approved for the treatment of hypertension in those with diabetic nephropathy. The sample size in AVOID was adequate to detect a clinically meaningful result, as the number of patients randomized was actually greater than initially required in the power calculations. In addition, the AVOID investigators achieved similar BP control in both groups by using non–RAS‐blocking antihypertensive agents. Since the 2/1‐mm Hg difference in BP between the aliskiren and placebo groups was unlikely to account for the majority of the benefit seen, it seems reasonable to conclude that the use of dual RAS blockade led to reductions in the UACR independent of its effect on BP.
AVOID does have some weaknesses. Foremost is probably the choice of the primary end point, the UACR. Although previous studies, including the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, suggested that a reduction in proteinuria correlates directly with the risk of subsequent CV and renal events, one most still consider UACR a surrogate end point for clinical events. This is in sharp contrast to the RENAAL and IDNT studies, in which hard clinical events were the primary end points, including the development of ESRD and death. This is not to imply that a reduction in the UACR is not clinically important, just that it is not the same level of evidence evaluated in these other trials. Second, the trial was only 6 months in duration, leaving unanswered important questions about the risks and benefits of using this combination over the long term, especially since improvement in urinary protein excretion and improvement in renal function do not always directly correlate. While the mean decline in GFR was less in the aliskiren group than in the placebo group, the difference was not statistically significant. Third, while adverse events were not different, participating patients were chosen carefully, as patients with a GFR <30 mL/min or a serum potassium level >5.1 mg/dL were excluded; as such, these results cannot be extrapolated to those with severe renal dysfunction or hyperkalemia at baseline. Finally, although the BP differences between the 2 arms of the study was small, the fact that BP was not effectively controlled in either group allows the reader to wonder whether the differences found would have been as great had a BP <130/80 mm Hg, the currently recommended BP goal in these individuals, been reached in both groups.
Based on the results of previous landmark clinical trials in patients with hypertension and diabetic nephropathy, initial antihypertensive therapy with either an ACE inhibitor or an ARB at their maximum recommended dosage in combination with other antihypertensive agents to reach a BP goal <130/80 mm Hg remains essential. AVOID suggests that in patients with GFRs >30 mL/min/1.73 m2, with no evidence of hyperkalemia, and who continue to have evidence of clinical proteinuria despite reasonably good BP control when receiving evidence‐based ARB therapy for renal protection, the addition of aliskiren 300 mg/d allows further reduction in albuminuria, at least in the short term. Future studies, including the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Disease Endpoints (ALTITUDE), will evaluate the long‐term benefits on hard clinical end points in hypertensive patients with type 2 diabetic nephropathy. Results are not expected until 2012.
Disclosure: Both Dr Bloch and Dr Basile wish to disclose that they receive research support, honoraria, and speaker’s bureau fees from Novartis Pharmaceuticals, the sponsor of the AVOID study.