The effect of dapagliflozin on renal function in patients with type 2 diabetes
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Dapagliflozin’s antihyperglycemic effects are mediated by inhibition of renal sodium-glucose cotransporter-2; therefore, renal safety of dapagliflozin was assessed.
Twelve double-blind, placebo-controlled, randomized clinical trials were analyzed up to 24 weeks (N = 4545). Six of the 12 studies included long-term data for up to 102 weeks (N = 3036). Patients with type 2 diabetes with normal or mildly impaired renal function [estimated glomerular filtration rate (eGFR) 60 to <90 mL/min/1.73 m2] were treated with dapagliflozin (2.5, 5, or 10 mg/day) or placebo. Renal adverse events (AEs) were assessed.
Mean eGFR showed small transient reductions with dapagliflozin at week 1, but returned to near baseline values by week 24 and remained stable to week 102. Mean eGFR changes were not very different for dapagliflozin 2.5, 5 and 10 mg versus placebo at 102 weeks: −0.74, 2.52 and 1.38 versus 1.31 mL/min/1.73 m2, respectively. Renal AEs were similar in frequency to placebo through 24 weeks (1.4, 1.3, 0.9, and 0.9 %, respectively) and 102 weeks (2.4, 1.8, 1.9 and 1.7 %, respectively). Few were serious (0.2, 0.1, 0 and 0.3 %, respectively, over 102 weeks). The most common renal event was serum creatinine increase. In sub-group analyses in patients ≥65 years of age or those with moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m2), renal AEs occurred more frequently with dapagliflozin than placebo. No events of acute tubular necrosis were reported.
In patients with normal or mildly impaired renal function, dapagliflozin is not associated with increased risk of acute renal toxicity or deterioration of renal function. All trials included in this analysis are registered at ClinicalTrials.gov: NCT00263276, NCT00972244, NCT00528372, NCT00736879, NCT00528879, NCT00855166, NCT00357370, NCT00680745, NCT00683878, NCT00673231, NCT00643851, NCT00859898.
KeywordsDapagliflozin Renal Safety SGLT2
The study team would like to acknowledge the patients for their participation and commitment during the studies. We also thank the investigators and contributors from each study site. The authors thank Dr. Bruce Leslie for his involvement with this analysis, Dr James List for his contribution to the analysis and initial manuscript development, and Jennifer Sugg for her contribution to statistical analysis. Professional medical writing and editorial assistance was provided by Carolyn Carroll, PhD, an employee of Bristol-Myers Squibb at the time of the development of this manuscript and Shelley Narula, MBBS, of inScience Communications, Springer Healthcare.
The conduct and analyses of these trials were supported by Bristol-Myers Squibb and AstraZeneca.
Compliance with ethical standards
Conflict of interest
DEK is a consultant for Bristol-Myers Squibb and AstraZeneca. PF is a consultant for Bristol-Myers Squibb and AstraZeneca, and participant in boards for Boehringer Ingelheim. KJ and SP are employees and shareholders of AstraZeneca. AP and LY are employees and shareholders of Bristol-Myers Squibb.
The analysis in this article is based on previously conducted studies, and does not involve any new studies of human or animal subjects performed by any of the authors.
Informed consent was obtained from all participants.
- 12.Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S (2011) Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 13:928–938CrossRefPubMedGoogle Scholar
- 13.Nauck MA, Del Prato S, Meier JJ et al (2011) Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 34:2015–2022CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Wilding JP, Norwood P, T’Joen C, Bastien A, List JF, Fiedorek FT (2009) A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: applicability of a novel insulin-independent treatment. Diabetes Care 32:1656–1662CrossRefPubMedPubMedCentralGoogle Scholar
- 18.Committee for Medicinal Products for Human Use European Public Assessment Report (EPAR) Canagliflozin European Medicines Agency 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002649/WC500156457.pdf
- 20.Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ et al (2014) Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 2:369–384CrossRefPubMedGoogle Scholar
- 21.Kaku K, Inoue S, Matsuoka O, Kiyosue A, Azuma H, Hayashi N et al (2013) Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 15:432–440CrossRefPubMedGoogle Scholar
- 23.Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM et al (2012) Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab 97:1020–1031CrossRefPubMedGoogle Scholar
- 30.Kohan DE, Fioretto P, List J, et al (2011) Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment. Presented at the American society of nephrology kidney week 2011 annual meeting; Philadelphia, PA, November 8–13, 2011; abstract #TH-PO524Google Scholar
- 36.Wanner C, Lachin JM, Fitchett DH, et al. (2015) Empagliflozin and clinical outcomes in patients with type 2 diabetes and chronic kidney disease. In: American Society of Nephrology, San Diego, CA, pp abstract# HI-OR01Google Scholar