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N Engl J Med. 2013 Nov 14;369(20):1892-903. doi: 10.1056/NEJMoa1303154. Epub 2013 Nov 9.

Combined angiotensin inhibition for the treatment of diabetic nephropathy.

Collaborators (248)

Brophy M, Duckworth W, Davis S, Emanuele N, Fried L, Hostetter T, McCullough P, O'Connor T, Palevsky P, Peduzzi P, Pfeffer M, Seliger S, Sinnott P, Star R, Toto R, Warren S, Zhang J, Fried L, Emanuele N, Duckworth W, Brophy M, Conner T, Guarino P, McCullough P, O'Connor T, Peduzzi P, Seliger S, Warren S, Zhang J, Berl T, Himmelfarb J, Tuttle K, Verter J, Woolson R, Servilla K, Thomas G, McQuade C, Bernauer M, Seliger S, Fink J, Luck J, Parsa A, Fink W, Scism B, Brown J, Purohit N, Jones T, Reddy C, Natarajan L, Lopez R, Durr J, Kaufman J, Cxypoliski R, Hamburger T, Lohr J, Cloen D, Arora P, Ranjan R, Lopes-Virella M, Pittman C, Caulder S, Soule J, Miller R, Julius M, Zhao J, Kern E, Watts J, Drawz P, Othersen J, Rosansky S, Reynolds J, Peterson A, Smith B, Neumann T, Duffy C, Talmor L, Warner R, Reilly R, Jain N, Wadsworth M, Mehta P, Penfield J, Elsayed E, Muzina R, Kourany W, Gitter K, Patel U, Cooney S, Zimering M, DeMarco C, Shin J, Rosenberg F, Sama A, Quinn S, Martinez E, Tantravahi J, Leehey D, Emanuele N, Linnerud P, Agrawal L, Lteif A, Moore K, Walsh J, Dixon B, Moss L, Franzwa B, Wallace W, Goel A, Hurst A, Wiegmann T, Somers D, Michaels R, Price V, Krause M, Satter E, McMillan J, Peterson M, Jaipaul N, Firek A, Sadjadi S, Fernando R, Simpson V, Ding G, Wadie M, Hawley A, Kato J, Gunneman T, Christiansen H, Blakely P, Wall B, Madison J, Cooke C, Naseer A, Huch K, Mangold T, Perumareddi P, Ma K, Kollman L, Rust J, Slinin Y, Ikizler A, Egbert P, Booker C, Davis D, Hung A, Davis S, Harper P, Venkatarman A, Blumenthal S, Yug B, Hussain S, Anderson R, Gerety M, Dunning D, Vogel M, Wagstaff S, Chadwell T, DeSouza C, Ludwig S, Lit Y, Gorodetskaya I, Meyer T, Baker P, Orozco L, Plummer E, Collier S, Herb C, Reaven P, Ramkumar M, Hartwig K, Homer M, Rao R, Sonel E, Dailey A, Lea D, Watnick S, Walczyk J, Johnston T, Zieve F, Kimmel M, Frederickson S, Levy J, Tarkington P, Larrick L, Weiler L, Clark S, Grimsdale A, Gopalakrishnan R, Conwill L, Clark E, Rauchman M, Giddings S, Felton S, Benabe J, Serrano-Rodriguez J, Mercado Z, Vidal-Cardona A, Arroyo L, Melendez A, Santiago L, Padilla B, Lamarche J, Peguero A, Reinhard R, Courville C, Hozo A, Thomas C, Crowley S, Zelas C, Murphy M, Peixoto A, Federman D, Churak J, Joncas C, Perez I, Fried L, Overberger P, Emanuele N, Milks L, Duckworth W, Christenson R, Rebuck H, Guarino P, Antonelli M, Chiu S, Dellert K, Hunter B, Joncas C, McBride V, O'Connor T, Peduzzi P, Sayers D, Smith J, Zhang J, Sather M, Conner T, Day J, Warren S, Haakenson C, Krueger D, Brophy M, Humphries D, Govan D, Cockroft J, Bobra S, Baylosis A, Nuckles L, O'Leary T.

Author information

From the Veterans Affairs (VA) Pittsburgh Healthcare System and University of Pittsburgh School of Medicine, Pittsburgh (L.F.F., P.M.P.); Hines VA Hospital, Hines, and Loyola University Medical Center, Maywood - both in Illinois (N.E., D.J.L.); Cooperative Studies Program Coordinating Center, VA Connecticut Healthcare System, West Haven (J.H.Z., T.O., P.P., P.G.), and Yale School of Public Health, New Haven (P.P.) - both in Connecticut; VA Boston Healthcare System and Boston University School of Medicine, Boston (M.B.); VA Cooperative Studies Program Research Pharmacy and University of New Mexico College of Pharmacy, Albuquerque (T.A.C., S.R.W.); Carl T. Hayden VA Medical Center, Arizona State University, Tempe, and University of Arizona, Phoenix (W.D.); St. John Providence Health System, Warren, St. John Hospital and Medical Center, Detroit, St. John Oakland Macomb Center, Warren and Madison Heights, and Providence Hospitals and Medical Centers, Southfield and Novi - all in Michigan (P.A.M.); VA North Texas Healthcare System and University of Texas Southwestern Medical Center, Dallas (R.F.R.); VA Maryland Healthcare System and University of Maryland School of Medicine, Baltimore (S.L.S.); and Portland VA Medical Center and Oregon Health and Sciences University, Portland (S.W.).

Erratum in

  • N Engl J Med. 2014;158:A7255.


Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D number, NCT00555217.).

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