TY - JOUR
T1 - Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes
T2 - a prespecified analysis from the DAPA-CKD trial
AU - DAPA-CKD Trial Committees and Investigators
AU - Jongs, Niels
AU - Greene, Tom
AU - Chertow, Glenn M.
AU - McMurray, John J.V.
AU - Langkilde, Anna Maria
AU - Correa-Rotter, Ricardo
AU - Rossing, Peter
AU - Sjöström, C. David
AU - Stefansson, Bergur V.
AU - Toto, Robert D.
AU - Wheeler, David C.
AU - Heerspink, Hiddo J.L.
N1 - Funding Information:
We thank all investigators, trial teams, and patients for their participation. We thank David Smeijer and Sjoukje Hoek for their assistance recording the precipitating factors for acute kidney injury. We also acknowledge Nicola Truss (inScience Communications; London, UK), for assistance in editing and preparation of figures; this support was funded by AstraZeneca.
Funding Information:
TG has received grants for statistical consulting from AstraZeneca, CSL Pharma, and Boehringer-Ingelheim, and has received personal fees from Janssen Pharmaceuticals, DURECT Corporation and Pfizer for statistical consulting. GMC has received fees from AstraZeneca for the DAPA-CKD trial steering committee, research grants from the US National Institute of Diabetes and Digestive and Kidney Diseases, and Amgen, is on the board of directors for Satellite Healthcare, has received fees for advisory boards from Baxter, Cricket, DiaMedica, and Reata, holds stock options for Ardelyx, CloudCath, Durect, DxNow, and Outset, has received fees from Akebia, Sanifit and Vertex for trial steering committees, and has received fees for data safety and monitoring board service from Angion, Bayer, and ReCor. JJVM's employer, Glasgow University, has received payments for his work on clinical trials, consulting, and is on the advisory board of Alnylam, Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cardurion, Cytokinetics, DAICor, GSK, Ionis Pharmaceuticals, KBP Biosciences, Novartis, and Theracos; and had received personal lecture fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus. AML, CDS, and BVS are employees and stockholders of AstraZeneca. RC-R has received consulting fees from Boehringer Ingelheim and Chinook; lecture fees from Amgen, Boehringer Ingelheim, and Janssen; honoraria for advisory boards from Boehringer Ingelheim and Novo Nordisk; and research support from GSK, Novo Nordisk, and AstraZeneca. PR has received honoraria to Steno Diabetes Center Copenhagen for lecture fees, steering group participation, and advisory board participation from AstraZeneca, Bayer, Boehringer Ingelheim,Gilead, Novo Nordisk, Sanofi,and Eli Lilly, and research support from AstraZeneca. RDT is a consultant for AstraZeneca, Amgen, Bayer, Boehringer-Ingelheim, Medscape, Otsuka, Reata, and Relypsa. DCW provides ongoing consultancy services to AstraZeneca and has received honoraria or consultancy fees from Amgen, AstraZeneca, Astellas, Boehringer Ingelheim, Bayer, GlaxoSmithKline, Janssen, Napp, Mundipharma, Tricida, and Vifor Fresenius. HJLH is consultant for AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Gilead, Janssen, Merck, Mundi Pharma, Mitsubishi Tanabe, Novo Nordisk, and Travere, and has received research support from Abbvie, AstraZeneca, Boehringer Ingelheim, and Janssen. NJ declares no competing interests.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/11
Y1 - 2021/11
N2 - Background: Reductions in albuminuria are associated with a subsequent lower risk of kidney failure in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney function. Whether this effect persists in patients with chronic kidney disease with and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on albuminuria in patients with chronic kidney disease with and without type 2 diabetes in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial. Methods: DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) between 25 mL/min per 1·73 m2 and 75 mL/min per 1·73 m2 and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6 to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca; Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered, fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio. Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from less than 3000 mg/g to 3000 mg/g or greater, were additional discrete endpoints. The trial is registered with ClinicalTrials.gov, NCT03036150. Findings: Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949 mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric mean UACR by 29·3% (95% CI –33·1 to –25·2; p<0·0001); relative to placebo, treatment with dapagliflozin resulted in a geometric mean percentage change of −35·1% (95% CI −39·4 to −30·6; p<0·0001) in patients with type 2 diabetes and −14·8% (−22·9 to −5·9; p=0·0016) in patients without type 2 diabetes over the follow-up visits (pinteraction<0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60 to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions in UACR at day 14 during dapagliflozin treatment were significantly associated with attenuated eGFR decline during subsequent follow-up (β per log unit UACR change –3·06, 95% CI –5·20 to –0·90; p=0·0056). Interpretation: In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR, suggest that part of the protective effect of dapagliflozin in patients with chronic kidney disease might be mediated through pathways unrelated to reduction in albuminuria. Funding: AstraZeneca.
AB - Background: Reductions in albuminuria are associated with a subsequent lower risk of kidney failure in patients with chronic kidney disease. The SGLT2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes and normal or near-normal kidney function. Whether this effect persists in patients with chronic kidney disease with and without type 2 diabetes is unknown. We assessed the effects of dapagliflozin on albuminuria in patients with chronic kidney disease with and without type 2 diabetes in the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial. Methods: DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 sites in 21 countries. Patients were eligible for the trial if they had chronic kidney disease, defined as an estimated glomerular filtration rate (eGFR) between 25 mL/min per 1·73 m2 and 75 mL/min per 1·73 m2 and a urinary albumin-to-creatinine ratio (UACR) between 200 mg/g and 5000 mg/g (22·6 to 565·6 mg/mmol). Participants were randomly assigned to dapagliflozin 10 mg (AstraZeneca; Gothenburg, Sweden) once daily or matching placebo, in accordance with the sequestered, fixed randomisation schedule, using balanced blocks to ensure an approximate 1:1 ratio. Change in albuminuria was a pre-specified exploratory outcome of DAPA-CKD. Regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to microalbuminuria or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from less than 3000 mg/g to 3000 mg/g or greater, were additional discrete endpoints. The trial is registered with ClinicalTrials.gov, NCT03036150. Findings: Between Feb 2, 2017, and April 3, 2020, 4304 patients were recruited and randomly assigned to either dapagliflozin (n=2152) or placebo (n=2152). Median UACR was 949 mg/g (IQR 477 to 1885). Overall, compared with placebo, dapagliflozin reduced geometric mean UACR by 29·3% (95% CI –33·1 to –25·2; p<0·0001); relative to placebo, treatment with dapagliflozin resulted in a geometric mean percentage change of −35·1% (95% CI −39·4 to −30·6; p<0·0001) in patients with type 2 diabetes and −14·8% (−22·9 to −5·9; p=0·0016) in patients without type 2 diabetes over the follow-up visits (pinteraction<0·0001) Among 3860 patients with UACR of 300 mg/g or greater at baseline, dapagliflozin increased the likelihood of regression in UACR stage (hazard ratio 1·81, 95% CI 1·60 to 2·05). Among 3820 patients with UACR less than 3000 mg/g at baseline, dapagliflozin decreased the risk of progression in UACR stage (0·41, 0·32 to 0·52). Larger reductions in UACR at day 14 during dapagliflozin treatment were significantly associated with attenuated eGFR decline during subsequent follow-up (β per log unit UACR change –3·06, 95% CI –5·20 to –0·90; p=0·0056). Interpretation: In patients with chronic kidney disease with and without type 2 diabetes, dapagliflozin significantly reduced albuminuria, with a larger relative reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR, suggest that part of the protective effect of dapagliflozin in patients with chronic kidney disease might be mediated through pathways unrelated to reduction in albuminuria. Funding: AstraZeneca.
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U2 - 10.1016/S2213-8587(21)00243-6
DO - 10.1016/S2213-8587(21)00243-6
M3 - Article
C2 - 34619106
AN - SCOPUS:85117279560
SN - 2213-8587
VL - 9
SP - 755
EP - 766
JO - The Lancet Diabetes and Endocrinology
JF - The Lancet Diabetes and Endocrinology
IS - 11
ER -