Combined angiotensin inhibition for the treatment of diabetic nephropathy

Linda F. Fried, Nicholas Emanuele, Jane H. Zhang, Mary Brophy, Todd A. Conner, William Duckworth, David J. Leehey, Peter A. McCullough, Theresa O'Connor, Paul M. Palevsky, Robert F. Reilly, Stephen L. Seliger, Stuart R. Warren, Suzanne Watnick, Peter Peduzzi, Peter Guarino

Research output: Contribution to journalArticle

557 Citations (Scopus)

Abstract

BACKGROUND: 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 m2 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 m2 if the initial estimated GFR was ?60 ml per minute per 1.73 m2 or a decline of ≥50% if the initial estimated GFR was <60 ml per minute per 1.73 m2), 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 endpoint 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 ClinicalTrials.gov number, NCT00555217.)

Original languageEnglish (US)
Pages (from-to)1892-1903
Number of pages12
JournalNew England Journal of Medicine
Volume369
Issue number20
DOIs
StatePublished - 2013

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Angiotensins
Diabetic Nephropathies
Glomerular Filtration Rate
Hyperkalemia
Angiotensin Receptor Antagonists
Confidence Intervals
Safety
Angiotensin-Converting Enzyme Inhibitors
Acute Kidney Injury
Chronic Kidney Failure
Albumins
Creatinine
Lisinopril
Therapeutics
Losartan
Mortality
Body Surface Area
Kidney Diseases
Veterans
Group Psychotherapy

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Fried, L. F., Emanuele, N., Zhang, J. H., Brophy, M., Conner, T. A., Duckworth, W., ... Guarino, P. (2013). Combined angiotensin inhibition for the treatment of diabetic nephropathy. New England Journal of Medicine, 369(20), 1892-1903. https://doi.org/10.1056/NEJMoa1303154

Combined angiotensin inhibition for the treatment of diabetic nephropathy. / Fried, Linda F.; Emanuele, Nicholas; Zhang, Jane H.; Brophy, Mary; Conner, Todd A.; Duckworth, William; Leehey, David J.; McCullough, Peter A.; O'Connor, Theresa; Palevsky, Paul M.; Reilly, Robert F.; Seliger, Stephen L.; Warren, Stuart R.; Watnick, Suzanne; Peduzzi, Peter; Guarino, Peter.

In: New England Journal of Medicine, Vol. 369, No. 20, 2013, p. 1892-1903.

Research output: Contribution to journalArticle

Fried, LF, Emanuele, N, Zhang, JH, Brophy, M, Conner, TA, Duckworth, W, Leehey, DJ, McCullough, PA, O'Connor, T, Palevsky, PM, Reilly, RF, Seliger, SL, Warren, SR, Watnick, S, Peduzzi, P & Guarino, P 2013, 'Combined angiotensin inhibition for the treatment of diabetic nephropathy', New England Journal of Medicine, vol. 369, no. 20, pp. 1892-1903. https://doi.org/10.1056/NEJMoa1303154
Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. New England Journal of Medicine. 2013;369(20):1892-1903. https://doi.org/10.1056/NEJMoa1303154
Fried, Linda F. ; Emanuele, Nicholas ; Zhang, Jane H. ; Brophy, Mary ; Conner, Todd A. ; Duckworth, William ; Leehey, David J. ; McCullough, Peter A. ; O'Connor, Theresa ; Palevsky, Paul M. ; Reilly, Robert F. ; Seliger, Stephen L. ; Warren, Stuart R. ; Watnick, Suzanne ; Peduzzi, Peter ; Guarino, Peter. / Combined angiotensin inhibition for the treatment of diabetic nephropathy. In: New England Journal of Medicine. 2013 ; Vol. 369, No. 20. pp. 1892-1903.
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abstract = "BACKGROUND: 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 m2 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 m2 if the initial estimated GFR was ?60 ml per minute per 1.73 m2 or a decline of ≥50{\%} if the initial estimated GFR was <60 ml per minute per 1.73 m2), 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 endpoint 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 ClinicalTrials.gov number, NCT00555217.)",
author = "Fried, {Linda F.} and Nicholas Emanuele and Zhang, {Jane H.} and Mary Brophy and Conner, {Todd A.} and William Duckworth and Leehey, {David J.} and McCullough, {Peter A.} and Theresa O'Connor and Palevsky, {Paul M.} and Reilly, {Robert F.} and Seliger, {Stephen L.} and Warren, {Stuart R.} and Suzanne Watnick and Peter Peduzzi and Peter Guarino",
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T1 - Combined angiotensin inhibition for the treatment of diabetic nephropathy

AU - Fried, Linda F.

AU - Emanuele, Nicholas

AU - Zhang, Jane H.

AU - Brophy, Mary

AU - Conner, Todd A.

AU - Duckworth, William

AU - Leehey, David J.

AU - McCullough, Peter A.

AU - O'Connor, Theresa

AU - Palevsky, Paul M.

AU - Reilly, Robert F.

AU - Seliger, Stephen L.

AU - Warren, Stuart R.

AU - Watnick, Suzanne

AU - Peduzzi, Peter

AU - Guarino, Peter

PY - 2013

Y1 - 2013

N2 - BACKGROUND: 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 m2 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 m2 if the initial estimated GFR was ?60 ml per minute per 1.73 m2 or a decline of ≥50% if the initial estimated GFR was <60 ml per minute per 1.73 m2), 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 endpoint 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 ClinicalTrials.gov number, NCT00555217.)

AB - BACKGROUND: 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 m2 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 m2 if the initial estimated GFR was ?60 ml per minute per 1.73 m2 or a decline of ≥50% if the initial estimated GFR was <60 ml per minute per 1.73 m2), 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 endpoint 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 ClinicalTrials.gov number, NCT00555217.)

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