Combined ACE inhibition and angiotensin receptor blockade shows no advantage over single agent RAS inhibition in patients with diabetic nephropathy: VA-Nephron D study

The results of the recently completed VA-Nephron D study were presented at a Late Breaking Abstract Session at the ASN-Kidney Week and simultaneously published in the New England Journal of Medicine.  The study randomized 1448 type 2 diabetic patients half of whom were randomly assigned to losartan (an angiotensin receptor blocker) plus placebo and the other half to receive losartan plus lisinopril (an angiotensin converting enzyme inhibitor).   The mean eGFR was 53.7 ± 16.2 ml/min/1.73 m2 for the ARB + placebo group and 53.6 ± 15.5 ml/min/1.73 m2 for the combined ARB + ACE inhibitor group.   The median urinary albumin to Cr ratio was approximately 500 mg/g for both groups.   At the start of the trial, 2/3rd of the patients were on ACE inhibitor monotherapy, 16-20% on ARB monotherapy, around 6% on combination therapy and 8% on neither ACE nor ARB therapy.   The primary endpoint was the first occurrence of a change in the eGFR, end-stage renal disease, or death.   The study was an event-driven study, and the sample size was expected to be adequate for an expected 5-year cumulative rate of 758 primary end-point events during a minimum of 2 years follow up on treatment [see CJASN design paper].  The safety of the enrolled subjects was monitored every 6 months by a Data and Safety Monitoring Committee (DMC).

In October 2012, the DMC recommended that the treatment be stopped due to safety concerns, namely increased rates of serious adverse events (hyperkalemia and acute kidney injury) in the combination therapy  arm [see NEJM].  There were 152 primary endpoint events in the monotherapy group and 132 in the combination group [HR 0.88, p=0.30].  Further, there was no change in mortality [HR 1.04, p=0.75] or cardiovascular events with combination therapy, while there was an increased risk of hyperkalemia [p<0.001] and AKI [p<0.001] with combination therapy. The authors concluded that [combination therapy with an ACE inhibitor and an ARB is associated with an increased risk of adverse events among patients with diabetic nephropathy].


There is general agreement that both ACE inhibitors and ARBs reduce proteinuria over and above their anti-hypertensive effects, particularly in patients with diabetic nephropathy [see Maschio et al.,  Lewis et al., and Lewis et al; Brenner et al].  It also appears that the anti-proteinuric and renoprotective effects of these drugs are similar [see here and here] and the selection of a particular agent is primarily based on the adverse events profile and convenience.  Similarly, the addition of aliskiren, a direct renin inhibitor to maximal doses of losartan was found to further reduce proteinuria in a study of patients with type 2 diabetes and nephropathy [see here].   In contrast with diabetic patients with macroalbuminuria, a renoprotective effect of RAS blockade in subjects without macroalbuminuria is not certain [see here].  A meta-analysis of 49 studies conducted by Regina Kuntz and colleagues, also suggested that combination of ACEI and ARBs is more effective [see here] than either agent alone.  However, as the authors commented, proteinuria is a surrogate marker and may not be predictive of progression of CKD or end-stage renal disease.  In addition to anti-proteinuric and reno-protective effects, RAS blockade also provides cardio-protection in patients without heart failure and multiple trials have been conducted that confirm this [summarized here].

The encouraging results of these trials led to a large outcome trial of ramipril, an ACE inhibitor, and telmisartan, an ARB called ONTARGET Study, which included 25,620 patients 55 years or older with established atherosclerotic vascular disease or with diabetes and end-organ damage, randomly assigned to ramipril, telmisartan or a combination of both drugs.  Surprisingly, the combination treatment led to worse renal outcomes than monotherapy.   Another trial, (ALITITUDE Trial), used aliskiren, a renin inhibitor, in combination with an ACE inhibitor or an ARB in type 2 diabetic patients with CKD, CVD or both.  As  reported previously in KDDD, this trial was terminated due to increased adverse events.  Now, the VA Nephron D trial has reached a similar outcome, which also includes increased risk of hyperkalemia and acute kidney injury.  HALT-PKD is another trial of combination ACE inhibitors and ARBs in patients with autosomal dominant polycystic kidney disease (ADPKD) that aims to determine whether this regimen will slow the progression of renal disease.  There is in vitro and in vivo animal evidence of overactivity of the intrarenal RAS in ADPKD (see here and here), which may drive the early development of hypertension and also independently contribute to the progression of kidney damage.  The results of HALT-PKD trial are anxiously awaited.

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