Effects of valsartan, benazepril and their combination in overt nephropathy of type 2 diabetes: A prospective, randomized, controlled trial

• Published in: Diabetes, obesity & metabolism obesity & metabolism, 2019-05, Vol.21 (5), p.1177-1190
• Main Authors: Ruggenenti, Piero, Trillini, Matias, P. Barlovic, Drazenka, Cortinovis, Monica, Pisani, Antonio, Parvanova, Aneliya, Iliev, Ilian P., Ruggiero, Barbara, Rota, Stefano, Aparicio, Maria C., Perna, Annalisa, Peraro, Francesco, Diadei, Olimpia, Gaspari, Flavio, Carrara, Fabiola, Stucchi, Nadia, Martinetti, Davide, Janez, Andrej, Gregoric, Nadan, Riccio, Eleonora, Bossi, Antonio C., Trevisan, Roberto, Manunta, Paolo, Battaglia, Giovanni, David, Salvatore, Aucella, Filippo, Belviso, Antonio, Satta, Andrea, Remuzzi, Giuseppe
• Format: Article
• Language: English
• Subjects: Adult; Aged; Angiotensin; Angiotensin II; Benzazepines - administration & dosage; Benzazepines - adverse effects; Biomarkers - analysis; Blood pressure; Blood Pressure - drug effects; Creatinine; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetic Nephropathies - drug therapy; Diabetic nephropathy; Drug Therapy, Combination; Evidence-based medicine; Female; Health risk assessment; Humans; Italy; Kidney Function Tests; Male; Middle Aged; Nephropathy; phase III study; Proteinuria; Slovenia; Treatment Outcome; type 2 diabetes; Valsartan - administration & dosage; Valsartan - adverse effects
• ISSN: 1462-8902; 1463-1326
• DOI: 10.1111/dom.13639

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.