Piero Ruggenenti1,2, Matias Trillini1, Drazenka P Barlovic3, Monica Cortinovis1, Antonio Pisani4, Aneliya Parvanova1, Ilian P Iliev1, Barbara Ruggiero1, Stefano Rota2, Maria C Aparicio1, Annalisa Perna1, Francesco Peraro1, Olimpia Diadei1, Flavio Gaspari1, Fabiola Carrara1, Nadia Stucchi1, Davide Martinetti1, Andrej Janez3, Nadan Gregoric3, Eleonora Riccio4, Antonio C Bossi5, Roberto Trevisan6, Paolo Manunta7, Giovanni Battaglia8, Salvatore David9, Filippo Aucella10, Antonio Belviso11, Andrea Satta12, Giuseppe Remuzzi1,13. 1. Department of Renal Medicine, Clinical Research Centre for Rare Diseases "Aldo e Cele Daccò": Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica (Bergamo), Italy. 2. Unit of Nephrology and Dialysis, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy. 3. Clinical Department of Endocrinology, Diabetes and Metabolic Diseases University Medical Centre Ljubljana, Ljubljana, Slovenia. 4. Chair of Nephrology, Department of Public Health, Federico II University of Naples, Naples, Italy. 5. Unit of Diabetology and Metabolic Diseases, Azienda Socio-Sanitaria Territoriale Bergamo Ovest, Treviglio-Caravaggio-Romano (Bergamo), Italy. 6. Unit of Diabetology and Endocrinology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy. 7. Chair of Nephrology, Genomics of Renal Diseases and Hypertension Unit, IRCCS San Raffaele Scientific Institute-Chair of Nephrology, Università Vita Salute San Raffaele, Milan, Italy. 8. Department of Nephrology and Dialysis, Hospital "S. Marta e S. Venera", Acireale (Catania), Italy. 9. Department of Nephrology and Dialysis, Hospital "Azienda Ospedaliera di Parma", Parma, Italy. 10. Department of Nephrology and Dialysis, Research Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo (Foggia), Italy. 11. Poliambulatorio Extra-ospedaliero, ASST Bergamo Ovest, Brembate di Sopra (Bergamo), Italy. 12. Institute of Medical Pathology, University AUSL 1, Sassari, Italy. 13. L. Sacco, Department of Biomedical and Clinical Science, University of Milan, Milan, Italy.
Abstract
AIMS: To evaluate whether angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) combination therapy is more nephroprotective than ACE inhibitor or ARB monotherapy in people with type 2 diabetes and overt nephropathy. MATERIALS AND METHODS: In this prospective, randomized, open, blind-endpoint phase III trial sponsored by the Italian Drug Agency, 103 consenting patients with type 2 diabetes, aged >40 years, with serum creatinine levels 159 to 309 μmol/L, spot morning urinary albumin-creatinine ratio > 1000 mg/g (or >; 500 mg/g in those on ACE inhibitor or ARB therapy at inclusion) were stratified by centre and randomized to 4.5-year treatment with valsartan 320 mg/d (n = 36), benazepril 20 mg/d (n = 34) or halved doses of both medications (n = 33). The primary endpoint was end-stage renal disease (ESRD). Modified intention-to-treat analyses were performed. RESULTS:Recruitment took place between June 2007 and February 2013 at 10 centres in Italy and one in Slovenia. A total of 77 participants completed the study and 26 were prematurely withdrawn. During a median (interquartile range) of 41 (18-54) months, 12 participants on benazepril (35.3%) and nine on combination therapy (27.3%) progressed to ESRD, versus five on valsartan (13.9%). Differences between benazepril (hazard ratio [HR] 3.59, 95% confidence interval [CI] 1.25-10.30; P = 0.018) or combination therapy (HR 3.28, 95% CI 1.07-10.0; P = 0.038) and valsartan were significant, even after adjustment for age, gender and baseline serum creatinine, systolic blood pressure and 24-hour proteinuria (HR 5.16, 95% CI 1.50-17.75, P = 0.009 and HR 4.75, 95% CI 1.01-22.39, P = 0.049, respectively). Adverse events were distributed similarly among the groups. CONCLUSIONS: In people with type 2 diabetes with nephropathy, valsartan (320 mg/d) safely postponed ESRD more effectively than benazepril (20 mg/d) or than halved doses of both medications.
RCT Entities:
AIMS: To evaluate whether angiotensin-converting enzyme (ACE) inhibitor and angiotensin II receptor blocker (ARB) combination therapy is more nephroprotective than ACE inhibitor or ARB monotherapy in people with type 2 diabetes and overt nephropathy. MATERIALS AND METHODS: In this prospective, randomized, open, blind-endpoint phase III trial sponsored by the Italian Drug Agency, 103 consenting patients with type 2 diabetes, aged >40 years, with serum creatinine levels 159 to 309 μmol/L, spot morning urinary albumin-creatinine ratio > 1000 mg/g (or > 500 mg/g in those on ACE inhibitor or ARB therapy at inclusion) were stratified by centre and randomized to 4.5-year treatment with valsartan 320 mg/d (n = 36), benazepril 20 mg/d (n = 34) or halved doses of both medications (n = 33). The primary endpoint was end-stage renal disease (ESRD). Modified intention-to-treat analyses were performed. RESULTS: Recruitment took place between June 2007 and February 2013 at 10 centres in Italy and one in Slovenia. A total of 77 participants completed the study and 26 were prematurely withdrawn. During a median (interquartile range) of 41 (18-54) months, 12 participants on benazepril (35.3%) and nine on combination therapy (27.3%) progressed to ESRD, versus five on valsartan (13.9%). Differences between benazepril (hazard ratio [HR] 3.59, 95% confidence interval [CI] 1.25-10.30; P = 0.018) or combination therapy (HR 3.28, 95% CI 1.07-10.0; P = 0.038) and valsartan were significant, even after adjustment for age, gender and baseline serum creatinine, systolic blood pressure and 24-hour proteinuria (HR 5.16, 95% CI 1.50-17.75, P = 0.009 and HR 4.75, 95% CI 1.01-22.39, P = 0.049, respectively). Adverse events were distributed similarly among the groups. CONCLUSIONS: In people with type 2 diabetes with nephropathy, valsartan (320 mg/d) safely postponed ESRD more effectively than benazepril (20 mg/d) or than halved doses of both medications.
Authors: Oleg Palygin; Denisha Spires; Vladislav Levchenko; Ruslan Bohovyk; Mykhailo Fedoriuk; Christine A Klemens; Olga Sykes; John D Bukowy; Allen W Cowley; Jozef Lazar; Daria V Ilatovskaya; Alexander Staruschenko Journal: Am J Physiol Renal Physiol Date: 2019-09-30