“Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy”
by the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) Investigators
N Engl J Med. 2013 Nov 14;369(20):1892-903. [free full text]
Inhibition of the renin-angiotensin-aldosterone system (RAAS) decreases the progression of proteinuric kidney disease, such as diabetic nephropathy. Prior studies have demonstrated that the greater the proteinuria is reduced by RAAS inhibition, the slower the further loss of GFR. Therefore, it had been hypothesized that combination RAAS inhibition with both an ACEi and an ARB in diabetic kidney disease would reduce the rate of renal decline and incidence of ESRD. The investigators of the VA NEPHRON-D trial hypothesized that “the benefit in slowing the progression of kidney disease would outweigh the risks of hyperkalemia and AKI associated with more intensive blockade of the RAAS.”
Population: US veterans with T2DM, eGFR 30.0-89.9 ml/min, and urinary albumin/Cr ratio ≥ 300
Notable exclusion criteria: nondiabetic kidney disease, K > 5.5, current treatment with sodium polystyrene sulfonate (Kayexalate)
Intervention: losartan 100mg PO daily and lisinopril 10mg, uptitrated q2 weeks to 20mg and then 40mg, respectively, as tolerated (meaning no hyperkalemia or Cr rise > 30%)
Comparison: losartan 100mg PO daily and placebo, uptitrated q2 weeks as tolerated
(Note: prior to randomization, there was a run-in period with uptitration to target dose of losartan to ensure hyperkalemia did not develop prior to initiating the study drug.)
Primary – time to first occurrence of composite endpoint of decline in eGFR (≥ 30 ml/min if baseline eGFR ≥60 ml/min, or relative decrease of ≥ 50% if baseline eGFR < 60 ml/min), ESRD, or death
- first occurrence of decline in eGFR or ESRD
- cardiovascular events (MI, stroke, or hospitalization for CHF)
- all-cause mortality
- hyperkalemia (> 6, or requiring ED visit/hospitalization/dialysis)
724 patients were randomized to each treatment arm. Baseline characteristics were similar among the two groups. The trial was stopped early after the data and safety monitoring committee found increased rates of serious adverse events, hyperkalemia, and AKI in the combination-therapy group. Median follow-up at time of study closure was 2.2 years.
132 patients in the combination-therapy group (18.2%) and 152 patients in the monotherapy group (21.0%) met the primary composite endpoint of decline in eGFR, ESRD, or death (p = 0.30).
Decline in eGFR or progression to ESRD occurred in 77 (10.6%) of the combination-therapy group and 101 (14.0%) of the monotherapy group (p = 0.10). There were also no significant group differences in the individual rates of ESRD, all-cause mortality, or MI/stroke/CHF.
AKI events occurred 190 times in 130 patients in the combination-therapy group (12.2 events per 100 person-years). In comparison, there were only 105 AKI events in 80 patients in the monotherapy group (6.7 events per 100 person-years) [HR 1.7, 95% CI 1.3-2.2, p < 0.001]. Hyperkalemia occurred in 72 (9.9%) of the combination-therapy patients versus 32 (4.4%) of the monotherapy patients (p < 0.001).
Among patients with T2DM, CKD, and proteinuria, combination therapy with an ARB and ACEi did not reduce the progression of kidney disease or mortality relative to an ARB alone; in fact, combination therapy increased the risks of AKI and hyperkalemia.
This was a well-designed, double-blind, randomized, controlled trial with definitive results. Its results align with those of its contemporary studies ONTARGET (2008, combination ARB and ACEi vs. monotherapy) and ALTITUDE (2012, ARB or ACEi plus the direct renin inhibitor aliskiren vs. ARB or ACEi monotherapy), which demonstrated no benefit and increased adverse event rates with combination therapy.
Although dual RAAS blockade reduces proteinuria in diabetic nephropathy greater than monotherapy, it is not recommended currently due to a lack of benefit and increased adverse events.
Summary by Duncan F. Moore, MD