Veterans Affairs Nephropathy in Diabetes - VA NEPHRON-D


The goal of the trial was to evaluate treatment with combination angiotensin-converting enzyme inhibitor (ACE-I) and angiotensin-receptor blocker (ARB) compared with ACE-I alone among patients with diabetic nephropathy.


Combination ACE-I and ARB will improve renal outcomes.

Study Design

  • Placebo Controlled
  • Parallel
  • Randomized
  • Stratified

Patient Populations:

  • Patients with diabetes, eGFR (30.0-89.9 ml/min/1.73 m2), and a urinary albumin-to-creatinine ratio >300

    Number of enrollees: 1,448 patients
    Duration of follow-up: 2.2 years
    Mean patient age: 65 years
    Percentage female: 1%


  • Nondiabetic kidney disease
  • Potassium >5.5 mmol/L
  • Current treatment with sodium polystyrene sulfonate
  • Inability to stop medications that increase the risk of hyperkalemia

Primary Endpoints:

  • Decrease in eGFR, ESRD, or death

Secondary Endpoints:

  • Death
  • Hyperkalemia
  • Acute kidney injury

Drug/Procedures Used:

Patients with diabetic nephropathy were randomized to losartan 100 mg daily and lisinopril 10-40 mg daily (n = 724) versus losartan 100 mg daily and placebo (n = 724).

Concomitant Medications:

Blood pressure medications at randomization: diuretic 71%, calcium channel blocker 59%, beta-blocker 70%, and alpha-blocker 21%

Principal Findings:

Overall, 1,448 patients were randomized. The mean age was 65 years, 1% were women, mean body mass index was 35 kg/m2, mean systolic blood pressure was 137 mm Hg, mean low-density lipoprotein cholesterol was 82 mg/dl, and mean estimated glomerular filtration rate (eGFR) was 53.6 ml/min/m2.

The primary outcome of decrease in eGFR, end-stage renal disease (ESRD), or death occurred in 18.2% of the ACE-I/ARB group vs. 21.0% of the ARB group (p = 0.30).

- ESRD: 3.7% vs. 5.9% (p = 0.07), respectively, for ACE-I/ARB vs. ARB alone
- Death: 8.7% vs. 8.3% (p = 0.75), respectively
- Myocardial infarction: 7.2% vs. 5.5% (p = 0.20), respectively
- Congestive heart failure: 12.3% vs. 14.6% (p = 0.17), respectively
- Stroke: 2.5% vs. 2.5% (p = 0.95), respectively

- Serious adverse events: 57.5% vs. 52.5% (p = 0.06), respectively
- Acute kidney injury: 18.0% vs. 11.0% (p < 0.001), respectively
- Hyperkalemia: 9.9% vs. 4.4% (p < 0.001), respectively


Among patients with diabetic nephropathy, combination therapy (ACE-I/ARB) did not improve renal outcomes compared with monotherapy (ARB). The trial was terminated early due to an increased risk of adverse events (hyperkalemia/acute kidney injury) without apparent benefit. Had the trial continued as planned, it is unlikely a beneficial effect on the primary outcome would have occurred. This trial is consistent with other studies documenting no benefit or harm from dual inhibition of the renin-angiotensin system among high-risk patients.


Fried LF, Emanuele N, Zhang JH, et al., on behalf of the VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013;369:1892-903.

Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Lipid Metabolism, Nonstatins, Acute Heart Failure

Keywords: Losartan, Stroke, Myocardial Infarction, Follow-Up Studies, Cholesterol, LDL, Kidney Failure, Chronic, Receptors, Angiotensin, Diuretics, Acute Kidney Injury, Renin-Angiotensin System, Hyperkalemia, Blood Pressure, Creatinine, Diabetic Nephropathies, Systole, Calcium Channel Blockers, Lipoproteins, LDL, Lisinopril, Body Mass Index, Heart Failure, Glomerular Filtration Rate

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