Sergei Petrykiv1, C David Sjöström2, Peter J Greasley2, John Xu3, Frederik Persson4, Hiddo J L Heerspink5. 1. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 2. AstraZeneca Gothenburg, Mölndal, Sweden. 3. AstraZeneca, Gaithersburg, Maryland; and. 4. Steno Diabetes Center, Gentofte, Denmark. 5. Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; h.j.lambers.heerspink@umcg.nl.
Abstract
BACKGROUND AND OBJECTIVE: Sodium glucose cotransporter 2 inhibition with dapagliflozin decreases hemoglobinA1c (HbA1c), body weight, BP, and albuminuria (urinary albumin-to-creatinine ratio). Dapagliflozin also modestly increases hematocrit, likely related to osmotic diuresis/natriuresis. Prior studies suggest that the HbA1c-lowering effects of dapagliflozin attenuate at lower eGFR. However, effects on other cardiovascular risk factors at different eGFR levels are incompletely understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This pooled analysis of 11 phase 3 clinical trials assessed changes in HbA1c, body weight, BP, hematocrit, and urinary albumin-to-creatinine ratio with placebo (n=2178) or dapagliflozin 10 mg (n=2226) over 24 weeks in patients with type 2 diabetes according to baseline eGFR (eGFR≥45 to <60 ml/min per 1.73 m2, eGFR≥60 to <90 ml/min per 1.73 m2, and eGFR≥90 ml/min per 1.73 m2). RESULTS: Compared with placebo, reductions in HbA1c with dapagliflozin were 0.6%, 0.5%, and 0.3%, respectively, for each consecutive lower eGFR subgroup (P value interaction <0.001). Effects of dapagliflozin on hematocrit, body weight, and BP were similar regardless of baseline eGFR, suggesting that effects potentially related to volume and natriuresis are eGFR independent. Moreover, among individuals with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, placebo-adjusted reductions in urinary albumin-to-creatinine ratio were larger in the lowest eGFR subgroup (P value interaction <0.001). Adverse events occurred more frequently in the lowest eGFR subgroup; this was true for both dapagliflozin- and placebo-treated patients. CONCLUSIONS: The HbA1c-lowering effects of dapagliflozin decrease as renal function declines. However, dapagliflozin consistently decreases body weight, BP, and urinary albumin-to-creatinine ratio regardless of eGFR. These effects in conjunction with the finding of similar effects on hematocrit, a proxy for volume contraction, suggest that the effects of dapagliflozin are partly mediated via nonglucosuric-dependent mechanisms.
RCT Entities:
BACKGROUND AND OBJECTIVE: Sodium glucose cotransporter 2 inhibition with dapagliflozin decreases hemoglobin A1c (HbA1c), body weight, BP, and albuminuria (urinary albumin-to-creatinine ratio). Dapagliflozin also modestly increases hematocrit, likely related to osmotic diuresis/natriuresis. Prior studies suggest that the HbA1c-lowering effects of dapagliflozin attenuate at lower eGFR. However, effects on other cardiovascular risk factors at different eGFR levels are incompletely understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This pooled analysis of 11 phase 3 clinical trials assessed changes in HbA1c, body weight, BP, hematocrit, and urinary albumin-to-creatinine ratio with placebo (n=2178) or dapagliflozin 10 mg (n=2226) over 24 weeks in patients with type 2 diabetes according to baseline eGFR (eGFR≥45 to <60 ml/min per 1.73 m2, eGFR≥60 to <90 ml/min per 1.73 m2, and eGFR≥90 ml/min per 1.73 m2). RESULTS: Compared with placebo, reductions in HbA1c with dapagliflozin were 0.6%, 0.5%, and 0.3%, respectively, for each consecutive lower eGFR subgroup (P value interaction <0.001). Effects of dapagliflozin on hematocrit, body weight, and BP were similar regardless of baseline eGFR, suggesting that effects potentially related to volume and natriuresis are eGFR independent. Moreover, among individuals with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, placebo-adjusted reductions in urinary albumin-to-creatinine ratio were larger in the lowest eGFR subgroup (P value interaction <0.001). Adverse events occurred more frequently in the lowest eGFR subgroup; this was true for both dapagliflozin- and placebo-treated patients. CONCLUSIONS: The HbA1c-lowering effects of dapagliflozin decrease as renal function declines. However, dapagliflozin consistently decreases body weight, BP, and urinary albumin-to-creatinine ratio regardless of eGFR. These effects in conjunction with the finding of similar effects on hematocrit, a proxy for volume contraction, suggest that the effects of dapagliflozin are partly mediated via nonglucosuric-dependent mechanisms.
Authors: H J L Heerspink; T Ninomiya; F Persson; B M Brenner; P Brunel; N Chaturvedi; A S Desai; S M Haffner; J J V Mcmurray; S D Solomon; M A Pfeffer; H-H Parving; D de Zeeuw Journal: Diabetes Obes Metab Date: 2016-01-13 Impact factor: 6.577
Authors: J Bolinder; Ö Ljunggren; L Johansson; J Wilding; A M Langkilde; C D Sjöström; J Sugg; S Parikh Journal: Diabetes Obes Metab Date: 2013-08-29 Impact factor: 6.577
Authors: Lawrence A Leiter; William T Cefalu; Tjerk W A de Bruin; Ingrid Gause-Nilsson; Jennifer Sugg; Shamik J Parikh Journal: J Am Geriatr Soc Date: 2014-06-02 Impact factor: 5.562
Authors: Rosalie A Scholtes; Michaël J B van Baar; Yuliya Lytvyn; Petter Bjornstad; Max Nieuwdorp; David Z I Cherney; Daniël H van Raalte Journal: Diabetes Obes Metab Date: 2019-04 Impact factor: 6.577
Authors: Yuliya Lytvyn; Petter Bjornstad; Jacob A Udell; Julie A Lovshin; David Z I Cherney Journal: Circulation Date: 2017-10-24 Impact factor: 29.690
Authors: Tamara Y Milder; Sophie L Stocker; Dorit Samocha-Bonet; Richard O Day; Jerry R Greenfield Journal: Eur J Clin Pharmacol Date: 2019-08-03 Impact factor: 2.953