Sergei I Petrykiv1, Gozewijn D Laverman2, Dick de Zeeuw1, Hiddo J L Heerspink1. 1. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. 2. Department of Nephrology, Ziekenhuisgroep Twente, Almelo and Hengelo, the Netherlands.
Abstract
AIMS: Albuminuria reduction is essential for renal and cardiovascular protection. We characterized the efficacy of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, on albuminuria. Secondly, we assessed whether the albuminuria-lowering effect varies among patients, and whether this variability in response is reproducible. MATERIAL AND METHODS: A double-blind, randomized, placebo controlled crossover trial was conducted. Patients with type 2 diabetes and albumin:creatinine ratio > 100 mg/g on a stable dose of anangiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) were enrolled. Patients were assigned to 6-week treatment periods with dapagliflozin 10 mg/d or placebo in random order, separated by 6-weeks wash-out periods. After the 2 treatment periods, half of the patients were re-exposed for 6 weeks to dapagliflozin 10 mg/d. Primary outcome was change in 24-hour urinary albumin excretion rate (24 h UAE). To assess reproducibility in individual albuminuria response, responses from the first and second exposure to dapagliflozin were correlated. RESULTS: A total of 33 patients (age, 61 years; female gender, 24.2%; median 24 h UAE, 470 mg/24 h) completed the study. Dapagliflozin, as compared to placebo, reduced 24 h UAE by 36.2% (95% CI, 22.9-47.2; P < .001). Systolic blood pressure fell by 5.2 mm Hg (95% CI, 0.5-10.0) and eGFR by 5.3 (95% CI, 2.7-8.0). All effects were reversible directly after treatment discontinuation. In a subgroup of 15 patients who were exposed twice to dapagliflozin, 24 h UAE responses showed a large variation among individuals: first exposure (range, -76% to +52%) and second exposure (-90% to +95%) and first and second individual response were significantly correlated (r = 0.69 [95% CI, 0.27-0.89]; P < .004). CONCLUSION:Dapagliflozin significantly reduces albuminuria when given as adjunct to ACEi or ARB. The albuminuria response to dapagliflozin markedly varies among patients. This variation is not a random phenomenon, but is reproducible upon re-exposure. These data support personalized therapy approaches to optimize diabetic kidney disease.
RCT Entities:
AIMS: Albuminuria reduction is essential for renal and cardiovascular protection. We characterized the efficacy of dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, on albuminuria. Secondly, we assessed whether the albuminuria-lowering effect varies among patients, and whether this variability in response is reproducible. MATERIAL AND METHODS: A double-blind, randomized, placebo controlled crossover trial was conducted. Patients with type 2 diabetes and albumin:creatinine ratio > 100 mg/g on a stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) were enrolled. Patients were assigned to 6-week treatment periods with dapagliflozin 10 mg/d or placebo in random order, separated by 6-weeks wash-out periods. After the 2 treatment periods, half of the patients were re-exposed for 6 weeks to dapagliflozin 10 mg/d. Primary outcome was change in 24-hour urinary albumin excretion rate (24 h UAE). To assess reproducibility in individual albuminuria response, responses from the first and second exposure to dapagliflozin were correlated. RESULTS: A total of 33 patients (age, 61 years; female gender, 24.2%; median 24 h UAE, 470 mg/24 h) completed the study. Dapagliflozin, as compared to placebo, reduced 24 h UAE by 36.2% (95% CI, 22.9-47.2; P < .001). Systolic blood pressure fell by 5.2 mm Hg (95% CI, 0.5-10.0) and eGFR by 5.3 (95% CI, 2.7-8.0). All effects were reversible directly after treatment discontinuation. In a subgroup of 15 patients who were exposed twice to dapagliflozin, 24 h UAE responses showed a large variation among individuals: first exposure (range, -76% to +52%) and second exposure (-90% to +95%) and first and second individual response were significantly correlated (r = 0.69 [95% CI, 0.27-0.89]; P < .004). CONCLUSION:Dapagliflozin significantly reduces albuminuria when given as adjunct to ACEi or ARB. The albuminuria response to dapagliflozin markedly varies among patients. This variation is not a random phenomenon, but is reproducible upon re-exposure. These data support personalized therapy approaches to optimize diabetic kidney disease.
Authors: Maarten A de Jong; Sergei I Petrykiv; Gozewijn D Laverman; Antonius E van Herwaarden; Dick de Zeeuw; Stephan J L Bakker; Hiddo J L Heerspink; Martin H de Borst Journal: Clin J Am Soc Nephrol Date: 2018-12-17 Impact factor: 8.237
Authors: Marjolein Y A M Kroonen; Jeroen V Koomen; Sergei I Petrykiv; Gozewijn D Laverman; Hiddo J L Heerspink; Jasper Stevens Journal: Diabetes Obes Metab Date: 2020-02-17 Impact factor: 6.577
Authors: Claire C J Dekkers; Sergei Petrykiv; Gozewijn D Laverman; David Z Cherney; Ron T Gansevoort; Hiddo J L Heerspink Journal: Diabetes Obes Metab Date: 2018-04-23 Impact factor: 6.577