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.

1. DR.K.SAMPATHKUMAR,
MD DM FRCP FASN FISN
Meenakshi Mission Hospital
Madurai , India
New Horizons in
CKD management

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

12. A dedicated renal outcome study was
sorely needed

13. CREDENCE
The first dedicated renal outcome study carried out with any antihyperglycaemic agent

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

15. Primary Outcome:
ESKD, Doubling of Serum Creatinine, or Renal or CV Death
0
5
10
15
20
25
0 26 52 78 104 130 156 182
Participantswithanevent
(%)
Months since randomization
Hazard ratio, 0.70 (95% CI, 0.59–0.82)
P = 0.00001
6 12 18 24 30 36 42
340 participants
245 participants
Placebo
Canagliflozin
No. at risk
Placebo 2199 2178 2132 2047 1725 1129 621 170
Canagliflozin 2202 2181 2145 2081 1786 1211 646 196
Participantswithanevent(%)
30%
risk
reduction vs
placebo

16. 3P MACE: Composite of CV death, Myocardial infarction or
Stroke
No. at risk
Placebo 2199 2152 2100 2022 1717 1143 635 168
Canagliflozin 2202 2163 2106 2047 1756 1196 642 198
0
5
10
15
20
25
0 26 52 78 104 130 156 182
Months since randomization
Hazard ratio, 0.80 (95% CI, 0.67–0.95)
P = 0.01
269 participants
217 participants
6 12 18 24 30 36 42
Participantswithanevent(%)
Placebo
Canagliflozin
20%
risk
reduction vs
placebo

17. Canagliflozin: Effects on eGFR
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
0 26 52 78 104 130 156 182
LSMeanChange(±SE)
ineGFR(mL/min/1.73
m2)
Months since randomization
No. of Participants
Placebo 2178 2084 1985 1882 1720 1536 1006 583 210
Canagliflozin 2179 2074 2005 1919 1782 1648 1116 652 241
56.4 56.0
Canagliflozin Placebo
Chronic eGFR slope
Difference: 2.74/year (95% CI, 2.37–3.11)
–4.59/year
6 12 18 24 30 36 42
LSmeanchange(SE)in
eGFR(mL/min/1.73m2)
Baseline
–3.72
Acute eGFR slope (3 weeks)
Difference: –3.17 (95% CI, –3.87, –2.47)
On treatment
–0.55
–1.85/year

18. CREDENCE Primary Outcome:
Benefits in eGFR 30 to <45 Subgroup
Hazard ratio
(95% CI)
Interaction
P value
Screening eGFR 0.11
30 to <45 mL/min/1.73 m2 0.75 (0.59–0.95)
45 to <60 mL/min/1.73 m2 0.52 (0.38–0.72)
60 to <90 mL/min/1.73 m2 0.82 (0.60–1.12)
Favors Canagliflozin Favors Placebo
0.25 0.5 1.0 2.0 4.0
16
NNT in patients with eGFR 30 to <45 mL/min/1.73 m2

19. DAPA-CKD: Dapagliflozin And Prevention of
Adverse outcomes in Chronic Kidney Disease Trial

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.

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

23. 22

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

36. Exploratory Composite Outcome:
Chronic Dialysis, Kidney Transplantation, or Renal Death1,2
DAPA = dapagliflozin; 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 2035 2021 2004 1977 1887 1481 985 373
2152 2031 2006 1971 1936 1849 1444 955 356
DAPA 10 mg
Placebo
DAPA 10 mg
71 events
Placebo
103 events
0
2
4
6
8
10
0 4 8 12 16 20 24 28 32
Months from Randomization
CumulativeIncidence%
N at Risk
HR (95% CI) p-value
0.66 (0.49-0.90) 0.0072
34%
RRR

37. Secondary Composite Outcome:
CV Death or Hospitalization for Heart Failure
CV = cardiovascular; DAPA = dapagliflozin; HR = hazard ratio; RRR = relative risk reduction.
Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.
DAPA 10 mg
100 events
Placebo
138 events
2152 2035 2021 2003 1975 1895 1502 1003 384
2152 2023 1989 1957 1927 1853 1451 976 360
DAPA 10 mg
Placebo
0
2
4
6
8
10
0 4 8 12 16 20 24 28 32
Months from Randomization
CumulativeIncidence%
N at Risk
HR (95% CI) p-value
0.71 (0.55-0.92) 0.0089
29%
RRR

38. Secondary Outcome:
All-cause Mortality
DAPA = dapagliflozin; HR = hazard ratio; RRR = relative risk reduction.
Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.
2152 2039 2029 2017 1998 1925 1531 1028 398
2152 2035 2018 1993 1972 1902 1502 1009 379
DAPA 10 mg
Placebo
DAPA 10 mg
101 events
Placebo
146 events
0
2
4
6
8
10
12
0 4 8 12 16 20 24 28 32
Months from Randomization
CumulativeIncidence%
N at Risk
HR (95% CI) p-value
0.69 (0.53-0.88) 0.0035
31%
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

43. Renal handling of glucose in non-
diabetic individuals
Glomerulus
Distal
tubule
Collecting
duct
Loop
of Henle
Proximal
tubule
~10% glucose reabsorbed
• Facilitated by SGLT1
~90% glucose reabsorbed
• Facilitated by SGLT2
Glucose
reabsorption
~10%
~90%Glucose
filtration
(180 L/day)
(1000 mg/L)
=180 g/day
No/minimal
glucose
excretion
SGLT = Sodium-dependent glucose transporter.
1. Bailey, Trends in Pharmacol Sci 2011;32:63-71.
2. Chao, Core Evidence 2012;7:21-28.

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 .

47. 46

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.

49. BODY WIEGHT, BP,INSULIN LEVELS CAME DOWN. HCT AND EPO
LEVELS WENT UP ON SGLT2i
48

50. Adenosine induced PGI2 release may be the reason why Glomerular
hypertension is reduced
49

51. 50

52. 51

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