Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy

Study Questions:

What is the safety and efficacy of combination therapy with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II-receptor blocker (ARB), as compared with ARB monotherapy, in slowing the progression of proteinuric diabetic nephropathy?


The VA NEPHRON-D (Veterans Affairs Nephropathy in Diabetes) study was a multicenter, double-blind, randomized, controlled study. Eligible veterans had type 2 diabetes, an estimated glomerular filtration rate (GFR) of 30.0-89.9 ml/min/1.73 m2 of body surface area, and a urinary albumin-to-creatinine ratio of at least 300. Patients who were taking 100 mg of losartan daily were randomized to receive lisinopril (dosing of 10-40 mg daily) or placebo. The primary endpoint was the first occurrence of a decline in the estimated GFR, end-stage renal disease, or death. Safety outcomes were all-cause mortality, serious adverse events, hyperkalemia, and acute kidney injury.


A total of 1,448 patients were randomized. The study was stopped early because of safety concerns; median patient follow-up was 2.2 years at study closure. There were 152 primary endpoint events in the monotherapy group, compared to 132 in the combination therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70-1.12; p = 0.30). Serious adverse events occurred in more patients in the combination-therapy group. The hazard ratio for acute kidney injury, the main reason for the higher rate of serious adverse events with combination therapy, was 1.7 (95% CI, 1.3-2.2; p < 0.001). The hazard ratio for hyperkalemia with combination therapy was 2.8 (95% CI, 1.8-4.3; p < 0.001).


Among type 2 diabetics with nephropathy, combination therapy with an ACE inhibitor and ARB is associated with an increased risk of acute kidney injury and hyperkalemia.


The VA NEPHRON-D trial was stopped early because of safety concerns. Although the study was stopped early with only a fraction of the planned events, the clinical benefit of combination therapy seems unlikely. Juxtaposed to the increase in adverse events and along with generally corroborative findings from the ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) and the ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints) trials, the findings from the present multicenter trial offer convincing evidence that there is no overall clinical benefit to be gained from combination therapy with ACE inhibitor and ARB.

Clinical Topics: Novel Agents

Keywords: Lisinopril, Losartan, Body Surface Area, Veterans, Benzimidazoles, Acute Kidney Injury, Diabetes Mellitus, Type 2, Hyperkalemia, Glomerular Filtration Rate, Diabetic Nephropathies, Benzoates

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