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Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function

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Petrykiv, Sergei I. ; Sjöström, C David ; Greasley, Peter J ; Xu, John ; Persson, Frederik ; Heerspink, Hiddo J Lambers. / Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function. In: Clinical journal of the American Society of Nephrology : CJASN. 2017 ; Vol. 12, No. 5. pp. 751-759.

Bibtex

@article{b0a0425bdc7c4f4fb9442eb473daed36,
title = "Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function",
abstract = "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 m(2), eGFR≥60 to <90 ml/min per 1.73 m(2), and eGFR≥90 ml/min per 1.73 m(2)).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.",
keywords = "Journal Article",
author = "Petrykiv, {Sergei I.} and Sj{\"o}str{\"o}m, {C David} and Greasley, {Peter J} and John Xu and Frederik Persson and Heerspink, {Hiddo J Lambers}",
note = "Copyright {\circledC} 2017 by the American Society of Nephrology.",
year = "2017",
month = "5",
day = "8",
doi = "10.2215/CJN.10180916",
language = "English",
volume = "12",
pages = "751--759",
journal = "American Society of Nephrology. Clinical Journal",
issn = "1555-9041",
publisher = "American Society of Nephrology",
number = "5",

}

RIS

TY - JOUR

T1 - Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function

AU - Petrykiv, Sergei I.

AU - Sjöström, C David

AU - Greasley, Peter J

AU - Xu, John

AU - Persson, Frederik

AU - Heerspink, Hiddo J Lambers

N1 - Copyright © 2017 by the American Society of Nephrology.

PY - 2017/5/8

Y1 - 2017/5/8

N2 - 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 m(2), eGFR≥60 to <90 ml/min per 1.73 m(2), and eGFR≥90 ml/min per 1.73 m(2)).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.

AB - 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 m(2), eGFR≥60 to <90 ml/min per 1.73 m(2), and eGFR≥90 ml/min per 1.73 m(2)).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.

KW - Journal Article

U2 - 10.2215/CJN.10180916

DO - 10.2215/CJN.10180916

M3 - Journal article

VL - 12

SP - 751

EP - 759

JO - American Society of Nephrology. Clinical Journal

JF - American Society of Nephrology. Clinical Journal

SN - 1555-9041

IS - 5

ER -

ID: 51454659