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Original ArticlesDiabetes and the Kidney
Open Access

Empagliflozin and Cardiovascular and Kidney Outcomes across KDIGO Risk Categories

Post Hoc Analysis of a Randomized, Double-Blind, Placebo-Controlled, Multinational Trial

Adeera Levin, Vlado Perkovic, David C. Wheeler, Stefan Hantel, Jyothis T. George, Maximilian von Eynatten, Audrey Koitka-Weber, Christoph Wanner and on behalf of the EMPA-REG OUTCOME Investigators
CJASN October 2020, 15 (10) 1433-1444; DOI: https://doi.org/10.2215/CJN.14901219
Adeera Levin
1Division of Nephrology, University of British Columbia, Vancouver, Canada
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Vlado Perkovic
2The George Institute for Global Health, University of New South Wales, Sydney, Australia
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David C. Wheeler
2The George Institute for Global Health, University of New South Wales, Sydney, Australia
3Centre for Nephrology, University College London, London, United Kingdom
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Stefan Hantel
4Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
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Jyothis T. George
5Boehringer Ingelheim International GmbH, Ingelheim, Germany
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Maximilian von Eynatten
5Boehringer Ingelheim International GmbH, Ingelheim, Germany
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Audrey Koitka-Weber
5Boehringer Ingelheim International GmbH, Ingelheim, Germany
6Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
7Department of Medicine, Würzburg University Clinic, Würzburg, Germany
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Christoph Wanner
7Department of Medicine, Würzburg University Clinic, Würzburg, Germany
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    Figure 1.

    Proportions of patients by Kidney Disease Improving Global Outcomes (KDIGO) risk category in the overall trial population, showing that almost half of patients (47%) were in the low-risk category. The KDIGO “heat map” showing prognosis of CKD by GFR and albuminuria category is shown for reference (3). Of all treated patients, baseline eGFR and urine albumin-creatinine ratio measurements were available for 4635 patients on empagliflozin (98.9%) and 2317 patients on placebo (99.3%). Reprinted from ref. 3, with permission.

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    Figure 2.

    Forest plot showing that the risk reduction of cardiovascular outcomes with empagliflozin versus placebo is consistent across KDIGO risk categories. *Sixty-eight patients were excluded as the subgroup variable was missing. 95% CI, 95% confidence interval; MACE, major adverse cardiovascular event; MI, myocardial infarction.

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    Figure 3.

    Forest plot showing that the risk reduction of kidney outcomes with empagliflozin versus placebo is consistent across KDIGO risk categories. Cox regression analysis in patients treated with one or more doses of study drug. *Sixty-eight patients were excluded as the subgroup variable was missing. †Accompanied by eGFR≤45 ml/min per 1.73 m2. Macroalbuminuria: urine albumin-creatinine ratio >300 mg/g.

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    Figure 4.

    Empagliflozin consistently slowed the long-term annual decline in eGFR across all patient subgroups regardless of KDIGO risk category, as assessed by mean eGFR (Modification of Diet in Renal Disease [MDRD]) slopes on the basis of random intercept/random coefficient models. Adjusted mean eGFR across subgroups of KDIGO risk category. Empa, empagliflozin.

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    Figure 5.

    Adverse event (AE) incidence rate ratios were similar or lower with empagliflozin compared with placebo except for genital infections. Data are from patients treated with one or more doses of study drug, including all events that occurred within 7 days after the last receipt of the study drug. Medical Dictionary for Drug Regulatory Activities version used for reporting: 18.0.

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    Table 1.

    Baseline characteristics and concomitant medications of participants were similar between treatment groups across Kidney Disease Improving Global Outcomes risk categories

    ParameterKidney Disease Improving Global Outcomes Risk Categorya
    LowModerately IncreasedHighVery High
    Placebo, n=1099Empagliflozin,bn=2223Placebo, n=675Empagliflozin,bn=1343Placebo, n=357Empagliflozin,bn=710Placebo, n=186Empagliflozin,bn=359
    Men787 (72)1571 (71)490 (73)970 (72)254 (71)500 (70)136 (73)255 (71)
    Age, yr62±961±864±964±966±966±866±867±8
    BMI, kg/m230.5±5.230.5±5.231.0±5.230.7±5.330.7±5.430.6±5.330.2±5.330.6±5.7
    HbA1c, %8.0±0.88.0±0.88.1±0.98.1±0.98.2±0.98.2±0.98.2±0.98.1±0.8
    Systolic BP, mm Hg133±16132±15138±17137±17139±20139±19140±19141±18
    Diastolic BP, mm Hg77±1077±977±1177±1076±1176±1076±1075±10
    LDL cholesterol, mg/dl83±3485±3585±3485±3689±3988±3789±3990±40
    eGFR (MDRD), ml/min per 1.73 m283±1684±1774±2074±2060±1961±2044±843±9
     ≥601099 (100)2223 (100)470 (70)926 (69)145 (41)286 (40)00
     <6000205 (30)417 (31)212 (59)424 (60)186 (100)359 (100)
    UACR, mg/g
     <301099 (100)2223 (100)205 (30)417 (31)76 (21)139 (20)2 (1)10 (3)
     30–30000470 (70)926 (69)136 (38)285 (40)69 (37)126 (35)
     >3000000145 (41)286 (40)115 (62)223 (62)
    UACR, median (IQR), mg/g7.1 (4.4−14.1)8.0 (5.3−14.1)43.3 (16.8−94.6)43.3 (17.7−89.3)141.4 (37.1−630.3)134.4 (39.8−484.4)406.2 (110.5−908.8)422.6 (114.0−1067.0)
    Background medications
     ACE inhibitors/ARBs846 (77)1754 (79)556 (82)1119 (83)305 (85)585 (82)147 (79)299 (83)
     Diuretics405 (37)841 (38)295 (44)605 (45)172 (48)360 (51)110 (59)216 (60)
    History of heart failure95 (9)181 (8)77 (11)146 (11)48 (13)84 (12)23 (12)50 (14)
    Smoking status
     Never smoked464 (42)902 (41)260 (39)556 (41)144 (40)288 (41)80 (43)164 (46)
     Ex-smoker489 (45)967 (44)326 (48)623 (46)169 (47)353 (50)85 (46)164 (46)
     Currently smokes146 (13)354 (16)89 (13)164 (12)44 (12)69 (10)21 (11)31 (9)
    Duration of diabetes, yr
     ≤135 (3)78 (4)11 (2)31 (2)2 (1)14 (2)4 (2)5 (1)
     >1–5216 (20)424 (19)103 (15)189 (14)41 (12)65 (9)10 (5)25 (7)
     >5–10301 (27)597 (27)159 (24)344 (26)69 (19)156 (22)35 (19)64 (18)
     >10547 (50)1124 (51)402 (60)779 (58)245 (69)475 (67)137 (74)265 (74)
    Metformin use885 (81)1752 (79)514 (76)1022 (76)219 (61)476 (67)104 (56)172 (48)
    Insulin use447 (41)933 (42)338 (50)648 (48)211 (59)412 (58)130 (70)232 (65)
    • BMI, body mass index; HbA1c, glycated hemoglobin; MDRD, Modification of Diet in Renal Disease; UACR, urinary albumin-creatinine ratio; IQR, interquartile range; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

    • ↵a Sixty-eight patients were excluded as the subgroup variable was missing.

    • ↵b Pooled. Data are n (%) or mean ± SD unless otherwise indicated.

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Clinical Journal of the American Society of Nephrology: 15 (10)
Clinical Journal of the American Society of Nephrology
Vol. 15, Issue 10
October 07, 2020
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Empagliflozin and Cardiovascular and Kidney Outcomes across KDIGO Risk Categories
Adeera Levin, Vlado Perkovic, David C. Wheeler, Stefan Hantel, Jyothis T. George, Maximilian von Eynatten, Audrey Koitka-Weber, Christoph Wanner, on behalf of the EMPA-REG OUTCOME Investigators
CJASN Oct 2020, 15 (10) 1433-1444; DOI: 10.2215/CJN.14901219

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Empagliflozin and Cardiovascular and Kidney Outcomes across KDIGO Risk Categories
Adeera Levin, Vlado Perkovic, David C. Wheeler, Stefan Hantel, Jyothis T. George, Maximilian von Eynatten, Audrey Koitka-Weber, Christoph Wanner, on behalf of the EMPA-REG OUTCOME Investigators
CJASN Oct 2020, 15 (10) 1433-1444; DOI: 10.2215/CJN.14901219
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Keywords

  • diabetic nephropathy
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  • glomerular filtration rate
  • KDIGO
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