SGLT2 Inhibitor therapy has opened up an exciting avenue for the Physicians to manage the patients with CKD . The slide set highlights the major trials on the drug showing remarkable benefits.
5. 10 YEAR HOROSCOPE OF PATIENTS WITH CKD
100 with
CKD
65 CV
events/death
15 HD
/PD/TX
6. • CKD is an important
Exclusion criterion for most
of the drug trials in Medicine
Evidence Desert in Nephrology
7. Brenner B, et al. N Engl J Med. 2001;345(12):861-869.
Risk reduction, 16%
P = 0.02
RENAAL
Risk reduction, 20%
P = 0.02
Lewis EJ, et al. N Eng J Med. 2001;345(12):851-860.
IDNT
Doubling of serum creatinine, ESKD, or death
Trials in 1990s were the only saving grace
8. An apple a day keeps the Doc
away
•1980s Research
•Phlorizin from
Apple tree Bark
•Blocks the
SGLT2
•Glycosuria
9. Effect on Renal outcomes
Data from cardiovascular outcome trials of SGLT2 inhibitors
EMPA-REG Outcome
N Engl J Med 2016; 375:323-334;
46% risk reduction in
composite renal outcome
vs placebo
10. Effect on Renal outcomes
Data from cardiovascular outcome trials of SGLT2 inhibitors
CANVAS Program
Lancet Diabetes Endocrinol.2018 ;6:691-704; N Engl J Med 2016; 375:323-
334; Lancet Diabetes Endocrinol 2019; 7: 606–17
DECLARE-TIMI 58
47% risk reduction in
composite renal outcome
vs placebo
47% risk reduction in
composite renal outcome
vs placebo
composite renal outcome (doubling of serum creatinine, end-stage kidney disease, renal death); for DECLARE-TIMI 58-composite of
≥40% decrease in eGFR to <60 ml/min/1.73 m2, ESRD, or death from renal cause.
11. However….
• These studies were all CVOTs designed to evaluate the CV safety of SGLT2 inhibitors
• Renal outcomes were secondary outcomes
• Patients included in these CVOTs were low renal risk populations
Low
Moderately
increased
High Very high
<30
30-44
45-59
60-90
≥90
GFRcategories
(mL/min/1.73m2)
Albuminuria categories (mg/g)
A1: <30 A2: 30-300 A3: >300
D
C E
DECLARE
CANVAS Program
EMPA-REG OUTCOME
MedianU
ACR
(mg/g)
13
12
18
Mean eGFR
(mL/min/1.73 m2)
85
76
74
Total of 29 sustained RRT events reported across
trials
Sustained RRT Events
DECLARE Not reported
CANVAS Program 18
EMPA-REG OUTCOME 11
D
C
E
14. Higher Renal Risk Population in CREDENCE
Low
Moderately
increased
High Very high
<30
30-44
45-59
60-90
≥90
GFRcategories
(mL/min/1.73m2)
Albuminuria categories (mg/g)
A1: <30 A2: 30-300 A3: >300
D
C E
DECLARE
CANVAS Program
EMPA-REG OUTCOME
CREDENCE
Median
UACR
(mg/g)
13
12
18
927
Mean eGFR
(mL/min/1.73 m2)
85
76
74
56
Sustained RRT Events
DECLARE Not reported
CANVAS Program 18
EMPA-REG OUTCOME 11
CREDENCE 176
D
C
E
20. Rationale for DAPA-CKD
• CKD represents a global healthcare burden and is a significant contributor to CV morbidity,
all-cause mortality and diminished quality of life1
• Until recently, the only classes of medication specifically proven to slow progression of CKD
were ACEis or ARBs2-5
• The DECLARE trial demonstrated the beneficial effects of dapagliflozin on HF and renal
outcomes in patients with T2D with predominantly preserved renal function with or without
established CV disease.6
• The DAPA-HF trial demonstrated that dapagliflozin reduced the risk of worsening HF or death
from CV causes, as well as a trend towards improved renal outcomes, in patients with HFrEF,
with or without T2D7
• The DAPA-CKD trial was designed to evaluate the effect of dapagliflozin on renal and CV
outcomes and mortality in people with CKD, with or without T2D8
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; CKD = chronic kidney disease; CV = cardiovascular; HF = heart failure; HFrEF = heart failure with reduced
ejection fraction; SGLT-2 = sodium glucose co-transporter 2; T2D = type 2 diabetes.
1. GBD Chronic Kidney Disease Collaboration. Lancet. 2020;395:709-733. 2. Ruggenenti P et al. Lancet. 1999;354:359-364. 3. Hou FF et al. N Engl J Med. 2006;354:131-140. 4. Brenner BM et al.
N Engl J Med. 2001;345:861-869. 5. Lewis EJ et al. N Engl J Med. 2001;345:851-860. 6. Wiviott SD et al. N Engl J Med. 2019;380:347-357. 7. McMurray JJV et al. N Engl J Med. 2019; 381:1995-2008.
8. Heerspink HJL et al. Nephrol Dial Transplant. 2020;35:274–282.
21.
22. DAPA-CKD:
Dapagliflozin in Patients With Chronic Kidney Disease1,2
aESKD defined as the need for maintenance dialysis (peritoneal or hemodialysis) for at least 28 days and renal transplantation or sustained eGFR <15mL/min/1.73m2 for at least 28 days.
ACEi = angiotensin-converting enzyme inhibitor; ANCA = anti-neutrophil cytoplasmic antibody; ARB = angiotensin-receptor blocker; CKD = chronic kidney disease; CV = cardiovascular; eGFR = estimated glomerular
filtration rate; ESKD = end-stage kidney disease; hHF = hospitalization for heart failure; T1D = type 1 diabetes; T2D = type 2 diabetes; UACR = urinary albumin-to-creatinine ratio.
1. Heerspink HJL et al. Nephrol Dial Transplant. 2020;35:274–282; 2. Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.
• Composite of sustained
≥50% eGFR decline, ESKD, or renal death
• Composite of CV death or hHF
• All-cause mortality
Secondary Outcomes
Dapagliflozin 10 mg
+ standard of care
Placebo
+ standard of care
1:1
Double-blind
EndPoints
Composite of sustained ≥50% eGFR decline,
ESKDa, renal or CV death
Primary Outcome
4304 Randomized
Median follow-up 2.4 years
To assess whether treatment with dapagliflozin, compared with placebo, reduced the risk of renal and CV events in patients with
CKD with or without T2D, and who were receiving standard of care including a maximum tolerated dose of an ACEi or ARB
Objective
Key Inclusion Criteria
• ≥18 years of age
• eGFR ≥25 to ≤75 mL/min/1.73m2
• UACR ≥200 to ≤5000 mg/g
• Stable max tolerated dose of
ACEi/ARB for ≥4 weeks
• With and without T2D
Key Exclusion Criteria
• T1D
• Polycystic kidney disease,
lupus nephritis, ANCA-
associated vasculitis
• Immunosuppressive therapy
≤6 months prior to enrollment
24. Latin America
Argentina (n=235)
Brazil (n=302)
Mexico (n=154)
Peru (n=221)
North America
Canada (n=280)
United States (n=533)
Countries Participating in DAPA-CKD1,2
1. Heerspink HJL et al. Nephrol Dial Transplant. 2020;35:274–282; 2. Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.
Western Europe
Denmark (n=45)
Germany (n=138)
Spain (n=260)
Sweden (n=40)
UK (n=60)
Eastern Europe
Hungary (n=140)
Poland (n=103)
Russia (n=255)
Ukraine (n=192) Asia
China (n=210)
India (n=201)
Japan (n=244)
Philippines (n=115)
South Korea (n=294)
Vietnam (n=282)
21
Countries
386
Sites
4304
Participants
25. Etiology of CKD
HTN = hypertensive; IgA = immunoglobulin A; T2D = type 2 diabetes.
Wheeler DC et al. Online ahead of print. Nephrol Dial Transplant. 2020.
58.3%
86.4%
16.0%
6.9%
34.8%
16.1%
3.3%
42.8%
0%
20%
40%
60%
80%
100%
Overall Population (N = 4304) T2D (N = 2906) No Diabetes (N = 1398)
Investigator-ReportedEtiologyofCKD(%)
Diabetic Nephropathy Ischemic/HTN Nephropathy Chronic Glomerulonephritis
Chronic Pyleonephritis Chronic Interstital Nephritis Obstructive Nephropathy
Renal Artery Stenosis Unknown Other
Chronic glomerulonephritis
IgA nephropathy (6.3%)
Focal segmental glomerulosclerosis (2.7%)
Membranous nephropathy (1.0%)
Minimal change disease (0.3%)
Other (5.9%)
Chronic glomerulonephritis
IgA nephropathy (1.3%)
Focal segmental glomerulosclerosis (0.8%)
Membranous nephropathy (0.3%)
Minimal change disease (0.1%)
Other (0.9%)
Chronic glomerulonephritis
IgA nephropathy (16.6%)
Focal segmental glomerulosclerosis (6.7%)
Membranous nephropathy (2.4%)
Minimal change disease (0.6%)
Other (16.5%)
Ischemic/HTN nephropathy
Ischemic/HTN nephropathy
Diabetic
nephropathy
Diabetic nephropathy
Ischemic/HTN nephropathy
26. Baseline Characteristics by Diabetes Status
Overall Population
(N=4304)
T2D
(N=2906)
No Diabetes
(N=1398)
Demographics and Baseline Clinical Chemistry
Mean age, years 61.8 64.4 56.4
Gender, female % 33.1 33.2 32.9
SBP >130 mmHg, % 64.2 70.0 52.1
BMI, kg/m2, mean 29.5 30.3 27.9
HbA1c, %, mean 7.1 7.8 5.6
Medical History and Comorbidities, %
Obese (BMI ≥30 kg/m2) 44.5 49.4 34.3
Hypertension 95.7 98.3 90.5
Any history of CV disease 37.4 44.1 23.5
Heart failure 10.9 12.4 7.7
Myocardial infarction 9.1 11.0 5.1
Stroke 6.9 7.9 4.9
Baseline Medication, %
RAS blockade 97.0 96.9 97.1
ACEi 31.5 30.8 32.9
ARB 66.7 67.4 65.2
Direct renin inhibitor 0.1 0 0.2
ARNI 0.1 0.1 0
Diuretic 43.7 50.4 29.8
MRA 5.3 5.9 4.1
Beta-blocker 39.0 43.6 29.5
Calcium channel blocker 50.7 53.3 45.4
Statin 64.9 71.6 50.9
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; BMI = body mass index; CV = cardiovascular; HbA1c =
glycated haemoglobin; MRA = mineralocorticoid-receptor antagonist; RAS = renin–angiotensin system; SBP = systolic blood pressure; T2D = type 2 diabetes.
Wheeler DC et al. Online ahead of print. Nephrol Dial Transplant. 2020.
27. Renal Characteristics by Diabetes Status
eGFR = estimated glomerular filtration rate; T2D = type 2 diabetes; UACR = urinary albumin-to-creatinine ratio
Wheeler DC et al. Online ahead of print. Nephrol Dial Transplant. 2020.
Overall Population
(N=4304)
T2D
(N=2906)
No Diabetes
(N=1398)
Serum creatinine, mg/dL, mean 1.7 1.6 1.8
eGFR, mL/min/1.73m2, mean 43.1 43.8 41.7
eGFR categories, %
≥60 mL/min/1.73m2 10.5 12.0 7.6
45-59 mL/min/1.73m2 30.9 31.6 29.3
30-44 mL/min/1.73m2 44.1 42.6 47.1
<30 mL/min/1.73m2 14.5 13.8 16.0
UACR, mg/g, median 949.3 1016.5 861.0
Median UACR categories, %
30-300 mg/g (Stage A2) 10.3 10.6 9.7
>300 mg/g (Stage A3) 89.7 89.4 90.3
The normal range for creatinine in the blood may be 0.84 to 1.21 milligrams per deciliter (74.3 to 107 micromoles per liter). According to the National Kidney
Foundation, normal results range from 90 to 120 mL/min/1.73 m2. Older people will have lower than normal GFR levels, because GFR decreases with age
28. Baseline Characteristics: Balanced Between Treatment Groups
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; BL = baseline; CKD = chronic kidney disease;
eGFR = estimated glomerular filtration rate; UACR = urinary albumin-to-creatinine ratio.
Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.
Dapagliflozin 10 mg
(N=2152)
Placebo
(N=2152)
Age, years, mean 62 62
Gender, female, % 33 33
Race, %
White
Black or African-American
Asian
Other
52
5
35
8
54
4
33
8
Type 2 diabetes, % 68 67
Systolic blood pressure, mmHg, mean 137 137
eGFR, mL/min/1.73m2, mean 43 43
UACR, mg/g, median 965 934
ACEi or ARB, % 97 97
29. Baseline Characteristics by Diabetes Status
Overall Population
(N=4304)
T2D
(N=2906)
No Diabetes
(N=1398)
Demographics and Baseline Clinical Chemistry
Mean age, years 61.8 64.4 56.4
Gender, female % 33.1 33.2 32.9
SBP >130 mmHg, % 64.2 70.0 52.1
BMI, kg/m2, mean 29.5 30.3 27.9
HbA1c, %, mean 7.1 7.8 5.6
Medical History and Comorbidities, %
Obese (BMI ≥30 kg/m2) 44.5 49.4 34.3
Hypertension 95.7 98.3 90.5
Any history of CV disease 37.4 44.1 23.5
Heart failure 10.9 12.4 7.7
Myocardial infarction 9.1 11.0 5.1
Stroke 6.9 7.9 4.9
Baseline Medication, %
RAS blockade 97.0 96.9 97.1
ACEi 31.5 30.8 32.9
ARB 66.7 67.4 65.2
Direct renin inhibitor 0.1 0 0.2
ARNI 0.1 0.1 0
Diuretic 43.7 50.4 29.8
MRA 5.3 5.9 4.1
Beta-blocker 39.0 43.6 29.5
Calcium channel blocker 50.7 53.3 45.4
Statin 64.9 71.6 50.9
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; ARNI = angiotensin receptor-neprilysin inhibitor; BMI = body mass index; CV = cardiovascular; HbA1c =
glycated haemoglobin; MRA = mineralocorticoid-receptor antagonist; RAS = renin–angiotensin system; SBP = systolic blood pressure; T2D = type 2 diabetes.
Wheeler DC et al. Online ahead of print. Nephrol Dial Transplant. 2020.
30. Renal Characteristics by Diabetes Status
eGFR = estimated glomerular filtration rate; T2D = type 2 diabetes; UACR = urinary albumin-to-creatinine ratio
Wheeler DC et al. Online ahead of print. Nephrol Dial Transplant. 2020.
Overall Population
(N=4304)
T2D
(N=2906)
No Diabetes
(N=1398)
Serum creatinine, mg/dL, mean 1.7 1.6 1.8
eGFR, mL/min/1.73m2, mean 43.1 43.8 41.7
eGFR categories, %
≥60 mL/min/1.73m2 10.5 12.0 7.6
45-59 mL/min/1.73m2 30.9 31.6 29.3
30-44 mL/min/1.73m2 44.1 42.6 47.1
<30 mL/min/1.73m2 14.5 13.8 16.0
UACR, mg/g, median 949.3 1016.5 861.0
Median UACR categories, %
30-300 mg/g (Stage A2) 10.3 10.6 9.7
>300 mg/g (Stage A3) 89.7 89.4 90.3
31. Primary Composite Outcome:
Sustained ≥50% eGFR Decline, ESKD, Renal or CV Deatha
aESKD defined as the need for maintenance dialysis (peritoneal or hemodialysis) for at least 28 days and renal transplantation or sustained eGFR <15mL/min/1.73m2 for at least 28 days. Renal death was defined as
death due to ESKD when dialysis treatment was deliberately withheld for any reason.2 CV = cardiovascular; DAPA = dapagliflozin; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease;
HR = hazard ratio; ; NNT = number needed to treat; RRR = relative risk reduction.
1. Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020. 2. Heerspink HJL et al. Nephrol Dial Transplant. 2020;35:274–282.
2152 2001 1955 1898 1841 1701 1288 831 309
2152 1993 1936 1858 1791 1664 1232 774 270
DAPA 10 mg
Placebo
DAPA 10 mg
197 events
Placebo
312 events
0
4
8
12
16
20
24
0 4 8 12 16 20 24 28 32
Months from Randomization
CumulativeIncidence%
N at Risk
NNT=19
HR (95% CI) p-value
0.61 (0.51-0.72) 0.000000028
39%
RRR
32. Primary Composite Outcome:
All Components Contributed to the Observed Treatment Effect
CV = cardiovascular; DAPA = dapagliflozin; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HR = hazard ratio; NC = not calculable
Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.
Number of Events
HR (95% CI)
DAPA 10 mg
(N=2152)
Placebo
(N=2152) HR 95% CI p-value
Primary Composite Outcome
Composite of ≥50% eGFR Decline,
ESKD, or Renal or CV Death
197 312 0.61 (0.51, 0.72) 0.000000028
Components of the Primary Composite Outcome
≥50% eGFR Decline 112 201 0.53 (0.42, 0.67) <0.0001
ESKD 109 161 0.64 (0.50, 0.82) 0.0004
eGFR <15mL/min/1.73m2 84 120 0.67 (0.51, 0.88) 0.0045
Chronic Dialysis 68 99 0.66 (0.48, 0.90) 0.0080
Transplantation 3 8 NC
Renal Death 2 6 NC
CV Death 65 80 0.81 (0.58, 1.12) 0.2029
0.30 0.60 1.00 1.25
DAPA 10 mg Better Placebo Better
33. Number of Events
HR (95% CI)
DAPA 10 mg
(N=2152)
Placebo
(N=2152) HR 95% CI
p-value
Interaction
Composite of ≥50% eGFR Decline, ESKD, or Renal or CV Death
All Patients 197 312 0.61 (0.51, 0.72)
T2D at Baseline 0.24
Yes 152 229 0.64 (0.52, 0.79)
No 45 83 0.50 (0.35, 0.72)
UACR (mg/g) at Baseline 0.52
≤1000 44 84 0.54 (0.37, 0.77)
>1000 153 228 0.62 (0.50, 0.76)
eGFR (mL/min/1.73m2) at Baseline 0.22
<45 152 217 0.63 (0.51, 0.78)
≥45 45 95 0.49 (0.34, 0.69)
Primary Composite Outcome:
Treatment Benefit Consistent Across Prespecified Subgroups
CV = cardiovascular; DAPA = dapagliflozin; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HR = hazard ratio; T2D = type 2 diabetes; UACR = urinary albumin-to-
creatinine ratio.
Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.
0.13 0.50 1.00 1.25
DAPA 10 mg Better Placebo Better
34. Primary Composite Outcome:
Treatment Benefit Consistent Across Prespecified Subgroups
CV = cardiovascular; DAPA = dapagliflozin; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HR = hazard ratio.
Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.
Number of Events
HR (95% CI)
DAPA 10 mg
(N=2152)
Placebo
(N=2152) HR 95% CI
p-value
Interaction
Composite of ≥50% eGFR Decline, ESKD, or Renal or CV Death
All Patients 197 312 0.61 (0.51, 0.72)
Age (years) 0. 53
≤65 122 191 0.64 (0.51, 0.80)
>65 75 121 0.58 (0.43, 0.77)
Gender 0.50
Male 126 209 0.57 (0.46, 0.72)
Female 71 103 0.65 (0.48, 0.88)
Race 0.68
White 110 174 0.62 (0.49, 0.79)
Black 7 14 0.33 (0.13, 0.81)
Asian 53 77 0.66 (0.46, 0.93)
Other 27 47 0.54 (0.33, 0.86)
Geographic Region 0.77
Asia 50 69 0.70 (0.48, 1.00)
Europe 57 89 0.60 (0.43, 0.85)
North America 35 69 0.51 (0.34, 0.76)
Latin America 55 85 0.61 (0.43, 0.86)
Systolic Blood Pressure (mmHg) at Baseline 0.04
≤130 46 96 0.44 (0.31, 0.63)
>130 151 216 0.68 (0.56, 0.84)
0.13 0.50 1.00 1.25
DAPA 10 mg Better Placebo Better
35. Secondary Composite Outcome:
Sustained ≥50% eGFR Decline, ESKD, or Renal Deatha
aESKD defined as the need for maintenance dialysis (peritoneal or hemodialysis) for at least 28 days and renal transplantation or sustained eGFR <15mL/min/1.73m2 for at least 28 days. Renal death
was defined as death due to ESKD when dialysis treatment was deliberately withheld for any reason.2 DAPA = dapagliflozin; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney
disease; HR = hazard ratio; RRR = relative risk reduction.
1. Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020. 2. Heerspink HJL et al. Nephrol Dial Transplant. 2020;35:274–282.
2152 2001 1955 1898 1841 1701 1288 831 309
2152 1993 1936 1858 1791 1664 1232 774 270
DAPA 10 mg
Placebo
DAPA 10 mg
142 events
Placebo
243 events
0
4
8
12
16
20
0 4 8 12 16 20 24 28 32
Months from Randomization
CumulativeIncidence%
N at Risk
HR (95% CI) p-value
0.56 (0.45-0.68) 0.000000018
44%
RRR
39. Statistical Significance Achieved for the Primary and All Secondary Outcomes
CV = cardiovascular; DAPA = dapagliflozin; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HF = heart failure.
Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.
Number of Events
HR (95% CI)
DAPA 10 mg
(N=2152)
Placebo
(N=2152)
Hazard
Ratio 95% CI p-value
Primary Composite Outcome
Composite of ≥50% eGFR Decline,
ESKD, and Renal or CV Death
197 312 0.61 (0.51, 0.72) <0.0001
Secondary Outcomes
Composite of ≥50% eGFR Decline,
ESKD, or Renal Death
142 243 0.56 (0.45, 0.68) <0.0001
Composite of CV Death or
Hospitalization for HF
100 138 0.71 (0.55, 0.92) 0.0089
All-cause mortality 101 146 0.69 (0.53, 0.88) 0.0035
0.4 0.6 0.8 1.0 1.2
DAPA 10 mg Better Placebo Better
40. Safety Outcomes
aSafety outcomes reported in participants on and off treatment; bSurgical or spontaneous/non-surgical amputation, excluding amputation due to trauma;
cBased on pre-defined list of preferred terms; dAdverse events with the following criteria confirmed by the investigator: i) symptoms of severe impairment in consciousness or behavior,
ii) need of external assistance, iii) intervention to treat hypoglycemia, iv) prompt recovery of acute symptoms following the intervention
Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.
Safety Outcomesa, n (%)
Dapagliflozin 10 mg
(N=2149)
Placebo
(N=2149)
Discontinuation of study drug 274 (12.8) 309 (14.4)
Discontinuation due to adverse event 118 (5.5) 123 (5.7)
Any serious adverse event 633 (29.5) 729 (33.9)
Adverse events of interest
Amputationb
Any definite or probable diabetic ketoacidosis
Fracturec
Renal-related adverse eventc
Major hypoglycemiad
Volume depletionc
Serious adverse events of volume depletion
35 (1.6)
0
85 (4.0)
155 (7.2)
14 (0.7)
127 (5.9)
22 (1.0)
39 (1.8)
2 (0.1)
69 (3.2)
188 (8.7)
28 (1.3)
90 (4.2)
18 (0.8)
41. Summary
• DAPA-CKD1, the first dedicated renal outcomes trial to assess the efficacy and safety of an SGLT-
2 inhibitor in patients with CKD with and without T2D, demonstrated:
• Consistent treatment effect in patients with CKD across major subgroups including in patients with
and without T2D, and by baseline eGFR and UACR categories
• Dapagliflozin was well-tolerated for the treatment of CKD (in patients with and without T2D)
and data confirm the known safety profile
• DAPA-CKD builds upon the evidence for dapagliflozin in the prevention of hHF and worsening of
renal disease in DECLARE2 and reduction in the risk of worsening HF and CV death in DAPA-HF3
CKD = chronic kidney disease; CV = cardiovascular; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HF = heart failure; hHF = hospitalization for heart failure;
RRR = relative risk reduction; SGLT-2 = sodium glucose co-transporter 2; T2D = type 2 diabetes; UACR = urinary albumin-to-creatinine ratio.
1. Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020. 2. Wiviott SD. et al. N Engl J Med. 2019;380:347-357. 3. McMurray JJV et al. N Engl J
Med. 2019;381:1995-2008.
39% RRR
for the primary composite
endpoint (≥50% sustained
decline in eGFR, ESKD,
renal or CV death)
44% RRR
for the renal composite
(≥50% sustained decline
in eGFR, ESKD, or
renal death)
29% RRR
for the composite
of CV death or
hospitalization
for heart failure
31% RRR
all-cause
mortality
44. Renal handling of glucose In T2DM:
Increased glucose reabsorption
Glomerulus
Distal
tubule
Collecting
duct
Loop
of Henle
Proximal
tubule
Glucose
reabsorption
~10%
~90%Glucose
filtration
Excess glucose
(≥240 g)
Increased expression of
SGLT2 and SGLT1
= more glucose filtered,
more glucose absorbed
Urinary Glucose
Excretion
80-100 g / day
(300-400 cal / day)
SGLT = Sodium-dependent glucose transporter.
1. Bailey, Trends in Pharmacol Sci 2011;32:63-71.
2. Chao, Core Evidence 2012;7:21-28.
45. Easy way of caloric restriction without
straining !
46. Prevailing Dogma
Pre glom. Vasoconstr. Leads to renal benefits
45
SGLT2i-induced proximal natriuresis activates
tubuloglomerular feedback (TGF), leading to
preglomerular vasoconstriction, via macula densa–derived
adenosine. This induces preglomerular vasoconstriction,
increases renal vascular resistance (RVR), and reduces
hyperfiltration, which could preserve long-term renal
function
But these were borne out of studies done on T1DM with
Hyperfiltation .
48. 47
The mGFR and effective renal plasma flow were
assessed using inulin and para-aminohippurate
clearances in the fasted state, during clamped euglycemia
(5 mmol/L) and during clamped hyperglycemia (15
mmol/L). Filtration fraction and renal vascular resistance
were calculated. Additionally, factors known to modulate
renal hemodynamics were measured.
54. Key take home messages
• 1. SGLT2 inhibitors should be form the std of care in most of
patients with CKD stage 2-4
• 2.Since Nephrologists rarely get referrals for CKD 2-4 , the
onus is on Primary care Physicians to initiate these drugs
• 3. Patient selection and followup are important
• 4.These drugs should be stopped during acute illnesses
53
Hinweis der Redaktion
Present slide
References:
GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395:709-733.
Ruggenenti P, Perna A, Gherardi G, et al. Renoprotective properties of ACE inhibition in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet. 1999;354:359-364.
Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med. 2006;354:131-140.
Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869.
Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860.
Wiviott SD, Raz I, Bonaca MP, et al, for the DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;347-357.
McMurray JJV, Solomon SD, Inzucchi SE, et al, for the DAPA-HF Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019; 381:1995-2008.
Heerspink HJL, Steffansson BV, Chertow GM, et al for the DAPA-CKD Investigators. Rationale and protocol of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant. 2020;35:274–282.
Speaker Notes:
The DAPA-CKD trial was designed to evaluate the effect of dapagliflozin on renal and cardiovascular events in a broad range of patients with CKD stages 2-4, with and without T2D.1
DAPA-CKD was a multinational, multicenter, event-driven, randomized, double-blind, parallel-group, placebo-controlled study.1
Patients (N = 4304) with CKD (eGFR ≥25 but ≤75 mL/min/1.73m2 and a UACR ≥200 mg/g but ≤5000 mg/g) with or without T2D were randomized to dapagliflozin 10 mg once daily or placebo in addition to stable maximum tolerated doses of ACEis or ARBs.1,2
The primary outcome was the composite of sustained ≥50% eGFR decline, ESKD, renal or CV death. ESKD was defined as the need for maintenance dialysis (peritoneal or hemodialysis) for at least 28 days and renal transplantation or sustained eGFR <15mL/min/1.73m2 for at least 28 days. Renal death was defined as death due to ESKD when dialysis treatment was deliberately withheld for any reason.1
Secondary outcomes (in hierarchical order) included the composite outcome of sustained ≥50% eGFR decline, ESKD, or renal death; composite of CV death or hHF; or all-cause mortality.1
Exploratory outcomes included the composite of chronic dialysis, kidney transplantation or renal death.1
Safety outcomes included serious adverse events and adverse events of interest or leading to premature study drug discontinuation, study drug interruption or dose reduction.
Adverse events of interest included volume depletion, renal events, major hypoglycemia, fractures, potential diabetic ketoacidosis (DKA), and amputations.1
The trial was planned to conclude when 681 primary renal events had occurred, with a total study duration of ~45 months. The trial stopped early based on the data monitoring committee (DMC) recommendation due to overwhelming efficacy based on 408 primary endpoint events (60% of planned events). The median follow-up was 2.4 years.2
References:
Heerspink HJL, Stefansson BV, Chertow GM, et al, for the DAPA-CKD Investigators. Rationale and protocol of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant. 2020;35:274–282.
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Present slide
References:
Heerspink HJL, Stefansson BV, Chertow GM, et al, for the DAPA-CKD Investigators. Rationale and protocol of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant. 2020;35:274–282.
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Note to Speaker: Click on the “Arrow” icon to return to the Demographic Characteristics slide.
Speaker Notes:
In the overall population (n=4304), the most common investigator-reported causes of CKD were diabetic nephropathy (58.3%), followed by ischemic/hypertensive nephropathy (16.0%) and chronic glomerulonephritis (16.1%).
In the group with T2D (n=2906), the most common cause of CKD was diabetic nephropathy (86.4%). The most common causes of CKD after diabetic nephropathy were ischemic/hypertensive nephropathy (6.9%) and chronic glomerulonephritis (3.3%), of which IgA nephropathy was most common (1.3%).
In participants without T2D (n=1398), the most common causes of CKD were chronic glomerulonephritis (42.8%), of which IgA nephropathy was most common (16.6%), and ischemic/hypertensive nephropathy (34.8%). The cause of CKD was considered “unknown” in 11.9% of patients without T2D.
Reference:
Wheeler DC, Stefansson BV, Batiushin M, et.al. The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics [published online ahead of print August 30, 2020]. Nephrol Dial Transplant. 2020. https://doi.org/10.1093/ndt/gfaa234. Accessed August 30, 2020.
Note to Speaker: Click on the “Arrow” icon to return to the Demographic Characteristics slide.
Speaker Notes:
Patients with T2D tended to be older than those without diabetes (mean age, 64.4 vs. 56.4 years) and the proportion ≥65 years was greater (48% vs. 30%).
Patients with T2D diabetes had a higher BMI than those without diabetes (mean BMI, 30.3 vs. 27.9 kg/m2), and were more likely to be hypertensive (98.3% vs. 90.5%),
Participants with T2D were more likely to have had a prior MI (11.0% vs. 5.1%) or history of HF (12.4% vs. 7.7%).
The majority of the study population (97%) was receiving an ACEi or ARB; 5.3% were receiving an MRA.
After ACE inhibitors and ARBs, calcium channel blockers were the most commonly prescribed blood pressure medication (50.7%), followed by diuretics (43.7%) and beta-blockers (39.0%). Statins were prescribed for 64.9% in the overall population, with a higher proportion of participants with T2D (71.6%) receiving this class of medication than those without diabetes (50.9%).
Reference:
Wheeler DC, Stefansson BV, Batiushin M, et.al. The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics [published online ahead of print August 30, 2020]. Nephrol Dial Transplant. 2020. https://doi.org/10.1093/ndt/gfaa234. Accessed August 30, 2020.
Note to Speaker: Click on the “Arrow” icon to return to the Demographic Characteristics slide.
Speaker Notes:
In the overall population, mean eGFR was 43.1 mL/min/1.73m2, and the median UACR was 949.3 mg/g.
Those with T2D had a slightly higher mean eGFR compared to those without diabetes (43.8 vs. 41.7 mL/min/1.73m2) and higher median UACR (1016.5 mg/g vs. 861.0 mg/g).
Reference:
Wheeler DC, Stefansson BV, Batiushin M, et.al. The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics [published online ahead of print August 30, 2020]. Nephrol Dial Transplant. 2020. https://doi.org/10.1093/ndt/gfaa234. Accessed August 30, 2020.
Note to Speaker: Click on the icons for more information about CKD etiologies, and baseline and renal characteristics by diabetes status.
Speaker Notes:
Demographic characteristics were balanced between treatment groups.1
The mean age of the participants in DAPA-CKD was 62 years and 33% were female.1
There was a mix of races in the participants, with ~53% white, ~34% Asian and ~4% black.2
Overall, 2906 participants (68%) had a diagnosis of T2D.2
Mean eGFR was 43.1 mL/min/1.73m2 and median UACR was 949.3 mg/g. 2
Mean systolic BP was 137.1 mmHg. 2
Baseline medications included ACEi or ARB in 97% of patients.1
References:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Wheeler DC, Stefansson BV, Batiushin M, et.al. The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics [published online ahead of print August 30, 2020]. Nephrol Dial Transplant. 2020. https://doi.org/10.1093/ndt/gfaa234. Accessed August 30, 2020.
Note to Speaker: Click on the “Arrow” icon to return to the Demographic Characteristics slide.
Speaker Notes:
Patients with T2D tended to be older than those without diabetes (mean age, 64.4 vs. 56.4 years) and the proportion ≥65 years was greater (48% vs. 30%).
Patients with T2D diabetes had a higher BMI than those without diabetes (mean BMI, 30.3 vs. 27.9 kg/m2), and were more likely to be hypertensive (98.3% vs. 90.5%),
Participants with T2D were more likely to have had a prior MI (11.0% vs. 5.1%) or history of HF (12.4% vs. 7.7%).
The majority of the study population (97%) was receiving an ACEi or ARB; 5.3% were receiving an MRA.
After ACE inhibitors and ARBs, calcium channel blockers were the most commonly prescribed blood pressure medication (50.7%), followed by diuretics (43.7%) and beta-blockers (39.0%). Statins were prescribed for 64.9% in the overall population, with a higher proportion of participants with T2D (71.6%) receiving this class of medication than those without diabetes (50.9%).
Reference:
Wheeler DC, Stefansson BV, Batiushin M, et.al. The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics [published online ahead of print August 30, 2020]. Nephrol Dial Transplant. 2020. https://doi.org/10.1093/ndt/gfaa234. Accessed August 30, 2020.
Note to Speaker: Click on the “Arrow” icon to return to the Demographic Characteristics slide.
Speaker Notes:
In the overall population, mean eGFR was 43.1 mL/min/1.73m2, and the median UACR was 949.3 mg/g.
Those with T2D had a slightly higher mean eGFR compared to those without diabetes (43.8 vs. 41.7 mL/min/1.73m2) and higher median UACR (1016.5 mg/g vs. 861.0 mg/g).
Reference:
Wheeler DC, Stefansson BV, Batiushin M, et.al. The dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial: baseline characteristics [published online ahead of print August 30, 2020]. Nephrol Dial Transplant. 2020. https://doi.org/10.1093/ndt/gfaa234. Accessed August 30, 2020.
Speaker Notes:
A significant reduction in the risk of the primary composite outcome (sustained ≥50% eGFR decline, ESKD, renal or CV death) was observed with dapagliflozin compared to placebo (197 vs. 312 events; HR 0.61; 95% CI 0.51-0.72; p=0.000000028).1
Additional Information2
ESKD was defined as the need for maintenance dialysis (peritoneal or hemodialysis) for at least 28 days and renal transplantation or sustained eGFR <15mL/min/1.73m2 for at least 28 days.
Renal death was defined as death due to ESKD when dialysis treatment was deliberately withheld for any reason.
References:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Heerspink HJL, Stefansson BV, Chertow GM, et al for the DAPA-CKD Investigators. Rationale and protocol of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant. 2020;35:274–282.
Speaker Notes:
Each of the components of the primary composite outcome (sustained ≥50% eGFR decline, ESKD, renal or CV death) occurred less frequently in the dapagliflozin group compared to the placebo group, with all components contributing to the observed treatment effect.1
Additional Information2
ESKD was defined as the need for maintenance dialysis (peritoneal or hemodialysis) for at least 28 days and renal transplantation or sustained eGFR <15mL/min/1.73m2 for at least 28 days.
Renal death was defined as death due to ESKD when dialysis treatment was deliberately withheld for any reason.
References:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Heerspink HJL, Stefansson BV, Chertow GM, et al for the DAPA-CKD Investigators. Rationale and protocol of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant. 2020;35:274–282.
Speaker Notes:
The effect of dapagliflozin on the primary outcome was generally consistent across prespecified subgroups, including patients with or without T2D, those with eGFR <45 or ≥45 mL/min/1.73m2, and those with UACR ≤1000 or >1000 mg/g at baseline.
Reference:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Speaker Notes:
The effect of dapagliflozin on the primary outcome was generally consistent across prespecified baseline subgroups including age, gender, race and geographic region.
A significant interaction p-value was observed for SBP. In patients with SBP ≤130 mmHg at baseline the hazard ratio for the comparison of dapagliflozin and placebo for the primary outcome was 0.44 (95% CI, 0.31 to 0.63) as compared with 0.68 (95%CI, 0.56 to 0.84) for patients with SBP >130 mmHg at baseline. However, the effect of dapagliflozin on the primary outcome was consistent in both SBP subgroups.
Reference:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Speaker Notes:
A significant reduction in the risk of the secondary renal composite outcome (sustained ≥50% eGFR decline, ESKD, or renal death) was observed with dapagliflozin compared to placebo (142 vs. 243 events; HR 0.56; 95% CI 0.45-0.68; p=0.000000018).
Reference:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Speaker Notes:
A significant reduction in the risk of the exploratory composite outcome of chronic dialysis, kidney transplantation, or renal death was observed with dapagliflozin compared to placebo (71 vs. 103 events; HR 0.66; 95% CI 0.49-0.90; p=0.0072).
Reference:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Speaker Notes:
A significant reduction in the risk of the composite of CV death or hospitalization for heart failure was observed with dapagliflozin compared to placebo (100 vs. 138 events; HR 0.71; 95% CI 0.55-0.92; p=0.0089).
Reference:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Speaker Notes:
A significant reduction in the risk of all-cause mortality was observed with dapagliflozin compared to placebo (101 vs. 146 events; HR 0.69; 95% CI 0.53-0.88; p=0.0035).
Reference:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Speaker Notes:
A statistically significant reduction in the risk of the primary composite outcome was observed with dapagliflozin compared to placebo.
Dapagliflozin significantly reduced the risk of all secondary outcomes including the renal-only composite outcome, composite of CV death or hHF, and all-cause mortality.
Reference:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Speaker Notes:
Dapagliflozin was well-tolerated, consistent with its established safety profile.
There were fewer serious adverse events, discontinuations of study drug, and discontinuations due to adverse events in the dapagliflozin group compared to the placebo group.
Amputations were similar between the dapagliflozin and placebo groups (1.6 vs. 1.8%).
DKA events were very rare. All definite or probable DKA events occurred in the placebo group (0.1%).
Fractures occurred in 4.0% of patients in the dapagliflozin group and 3.2% in the placebo group.
There were fewer renal adverse events in the dapagliflozin group compared to the placebo group (7.2% vs. 8.7%).
Major hypoglycemic events were two-fold higher in the placebo group compared with the dapagliflozin group (0.7% vs. 1.3%).
Volume depletion adverse events occurred in 5.9% of patients in the dapagliflozin group and 4.2% in the placebo group. Serious adverse events of volume depletion were balanced between the dapagliflozin and placebo groups (1.0 vs 0.8%)
Reference:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Present slide
References:
Heerspink HJL. Dapagliflozin in patients with chronic kidney disease [presentation]. Presented at: European Society of Cardiology Congress – The Digital Experience; August 29 - September 1, 2020.
Wiviott SD, Raz I, Bonaca MP, et al, for the DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;347-357.
McMurray JJV, Solomon SD, Inzucchi SE, et al, for the DAPA-HF Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019; 381:1995-2008.
SPEAKER NOTES:
This slide provides a closer look at the functional unit of the kidney - the nephron.
In normal glucose-tolerant subjects, virtually all filtered glucose is reabsorbed back into the bloodstream in the proximal tubule, and a minimal amount of glucose is excreted in the urine.
The majority of renal glucose reabsorption takes place in the convoluted segment (S1) of the proximal tubule where the high-capacity, low-affinity sodium-glucose transporter (SGLT) 2 and facilitative glucose transporter (GLUT) 2 are located.
The remaining 10% is reabsorbed in the distal straight segment (S3) of the proximal tubule where the high-affinity, low-capacity SGLT1 transporter, and GLUT1, are located.
This variation is thought to allow the majority of glucose to be reabsorbed in the S1 segment of the proximal tubule, whereas any glucose that is left in the ultrafiltrate by the time it reaches S3 is avidly reabsorbed.
Reference:
Adapted from:
Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends in Pharamcol Sci 2011;32:63-71.
Chao EC. Dapagliflozin: an evidence-based review of its potential in the treatment of type-2 diabetes. Core Evidence 2012;7:21-28.
#tagRenal#
SPEAKER NOTES:
This slide provides a closer look at the functional unit of the kidney - the nephron.
In normal glucose-tolerant subjects, virtually all filtered glucose is reabsorbed back into the bloodstream in the proximal tubule, and a minimal amount of glucose is excreted in the urine.
The majority of renal glucose reabsorption takes place in the convoluted segment (S1) of the proximal tubule where the high-capacity, low-affinity sodium-glucose transporter (SGLT) 2 and facilitative glucose transporter (GLUT) 2 are located.
The remaining 10% is reabsorbed in the distal straight segment (S3) of the proximal tubule where the high-affinity, low-capacity SGLT1 transporter, and GLUT1, are located.
This variation is thought to allow the majority of glucose to be reabsorbed in the S1 segment of the proximal tubule, whereas any glucose that is left in the ultrafiltrate by the time it reaches S3 is avidly reabsorbed.
Reference:
Adapted from:
Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends in Pharamcol Sci 2011;32:63-71.
Chao EC. Dapagliflozin: an evidence-based review of its potential in the treatment of type-2 diabetes. Core Evidence 2012;7:21-28.
#tagRenal#