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.
- Placebo Controlled
- 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
- Decrease in eGFR, ESRD, or death
- Acute kidney injury
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).
Blood pressure medications at randomization: diuretic 71%, calcium channel blocker 59%, beta-blocker 70%, and alpha-blocker 21%
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.
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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