The document summarizes emerging concepts around SGLT2 inhibitors and renal outcomes. It discusses the mechanism of action of SGLT2 inhibitors including reducing glucose reabsorption and increasing sodium delivery to the macula densa. A key trial on the SGLT2 inhibitor dapagliflozin showed it reduced the composite of sustained ≥50% eGFR decline, end-stage kidney disease, or renal or cardiovascular death by 39% compared to placebo in patients with chronic kidney disease. Updated guidelines now recommend SGLT2 inhibitors to reduce renal and cardiovascular risk in patients with chronic kidney disease based on these renal protection benefits shown in clinical trials.

1. EMERGING CONCEPTS OF SGLT2
INHIBITORS IN RENAL OUTCOMES
Peerapat Thanapongsatorn, MD
Critical Care Nephrologist
Central Chest Institute of Thailand
27th Oct 2022

2. DISCLOSURE
 This presentation is supported by AstraZeneca.
 I have no conflicts of interest relative to this presentation.

3. OUTLINE
 Mechanism of SGLT2 inhibitor with renal protection
 Landmark trial of Dapagliflozin on renal outcomes
 Updated guideline on SGLT2 inhibitors for CKD patients
 Clinical practice for SGLT2 inhibitors

4. OUTLINE
 Mechanism of SGLT2 inhibitor with renal protection
 Landmark trial of Dapagliflozin on renal outcomes
 Updated guideline on SGLT2 inhibitors for CKD patients
 Clinical practice for SGLT2 inhibitors

5. DEVELOPMENT OF SGLT2 INHIBITORS
Phlorizin
 “Phlorizin” isolated from apple bark in 1835
 SGLT1 and SGLT2 inhibition but poor oral absorption
 Resurgence of interest in 1990s led to new drugs
 Development of the “Gliflozins”
 Dapagliflozin is the first molecule in SGLT2i class
approved in T2D

6. Cowie, M.R., Fisher, M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol 17, 761–772 (2020).
RENAL GLUCOSE
REABSORPTION
> 90%
< 10%
Glucose
reabsorption
160-180 g/day
Glucose
Filtration
160-180 g/day
No glucose
excretion
Normal

7. Cowie, M.R., Fisher, M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol 17, 761–772 (2020).
RENAL GLUCOSE
REABSORPTION
> 90%
< 10%
Glucose
reabsorption
160-180 g/day
Glucose
Filtration
>180 g/day
Glucosuria
DM

8. MECHANISM
OF SGLT2
INHIBITORS
1
SGLT2i
2
3
Blocks proximal
glucose and sodium
reabsorption
Increased
sodium delivery
to macula densa
TGF leads
to
↓ intraglomerular
pressure and
↓ proteinuria
Heerspink HJL et al. Kidney Int. 2018;94:26-39

9. RENAL HEMODYNAMIC EFFECTS WITH SGLT2 INHIBITOR
Chilton RJ. Effects of sodium-glucose cotransporter-2 inhibitors on the cardiovascular and renal complications of type 2 diabetes. Diabetes Obes Metab. 2020;22(1):16-29.

10. RENAL-PROTECTIVE PATHWAYS WITH SGLT2 INHIBITORS
Reduce inflammation
Restoration of TGF
Enhanced ketogenesis
Weight loss
Decrease BP
Increase Hct
Reduce arterial stiffness
Giorgino et al. Cardiovasc Diabetol (2020) 19:196
Decrease plasma volume

11. DAPAGLIFLOZIN
HbA1c
~ 0.5% to 1% decrease from
baseline
2/3 of the weight loss from
reductions in fat, both abdominal VAT
and SAT volumes
Weight
~1.5 to 3 kg weight loss from
baseline
SBP
Cardiovascular effect
Renoprotective effect
5.1 mm Hg reduction from
baseline at 24 weeks
eGFR
UACR
Remains stable out to 4 years
Improves albuminuria (-33%) on top
of ACEi/ARB at 12 weeks
Yu kurata, et al. Expert Review of Endocrinology & Metabolism, 17:4. 275-291
SGLT-
Inhibitor
Selectivity
(SGLT2 vs
STLT1)
Dosage (mg) Half-life
Dapagliflozin >1400-times 5-10 mg 13 h
Canagliflozin 250-times 100-300 mg 11-13 h
Empagliflozin >2500-times 10-25 mg 13 h
Ertugliflozin 2000-times 5-15 mg 16.6 h Hct Increase 2-3% from baseline

12. PHARMACOKINETICS OF SGLT2 INHIBITORS
Dapagliflozin Empagliflozin Canagliflozin Ertugliflozin
Absorption (T max) 2 h 1.5 h 1-2 h 1 h
Bioavailability 78% 78% 65% 100%
Fraction bound to
protein
91% 86% 99% 93.6%
Volume of distribution 118 L 73.8 L 83.5 L 86 L
Half life 12.9 h 12.4 h 13.1 h 17 h
SGLT2 inhibition IC50 1.2 nM 3.1 nM 2.7 nM 0.9 nM
SGLT1 inhibition IC50 1400 nM 8300 nM 710 nM 1960 nM
Metabolism Glucuronidation Glucuronidation Glucuronidation Glucuronidation
Elimination route 21% feces
75% urine
41% feces
54% urine
52% feces
33% urine
41% feces
50% urine
Adapted from Papakitsou et al. Clinical Pharmacology; Advances and Applications 2019:11

13. OUTLINE
 Mechanism of SGLT2 inhibitor with renal protection
 Landmark trial of Dapagliflozin on renal outcomes
 Updated guideline on SGLT2 inhibitors for CKD patients
 Clinical practice for SGLT2 inhibitors

14. LANDMARK TRIAL OF SGLT2 INHIBITOR
HF Trial
T2D CVOT
CKD/DKD
Trial

15. DECLARE-TIMI 58: Broad CV risk population & 2 clinically
relevant and important CV primary endpoints in type 2 diabetes
Placebo
Dapagliflozin (10 mg per day)
1:1
Double-blind
T2D, ≥40 years plus:
▪ Multiple (≥2) risk factors OR
▪ Established CV disease
N=17,160
Primary
Endpoints
CV death, MI, stroke (MACE)
Hospitalization for heart failure or CV
death
Composite endpoint of
Composite endpoint of
Secondary Endpoints
• Renal composite endpoint
• All-cause mortality
Baseline Characteristics
Dapa
(N=8,582)
Placebo
(N=8,578)
HbA1C, %, mean (SD) 8.3 (1.2) 8.3 (1.2)
eGFR, mean (SD) 85.4 (15.8) 85.1 (16.0)
Multiple risk factors, n (%) 10,186 (59.4%)
Est CV disease, n (%) 6,974 (40.6%)
median follow-up of 4.2 years
Primary outcomes: Dapagliflozin did not result in a lower
rate of MACE but did result in a lower rate of
cardiovascular death or hospitalization for heart failure

16. Time since randomization (years)
5389
7409
7932
8056
8200
8326
8422
8508
8578
Placebo
5472
7534
8009
8136
8248
8347
8436
8533
8582
DAPA 10 mg
No. at Risk
0.06
0.05
0.04
0.03
0.02
0.01
0
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Cumulative
Probability
of
Event
Placebo (5.6%)
DAPA 10 mg (4.3%)
HR 95% CI p-value*
0.76 (0.67, 0.87) <0.0001
Dapagliflozin is shown to reduce
progression to Nephropathy in ALL
T2D patients (with multiple CV risk
factors or established CV disease)
vs placebo
24%
DECLARE-TIMI 58: Secondary Renal Composite Outcome:
Decrease eGFR ≥40%, ESRD or Renal or CV Death

17. Change in eGFR over Time Improvement of Albuminuria
Deterioration of Albuminuria
DECLARE-TIMI 58: Renal outcomes

18. LANDMARK TRIAL OF SGLT2 INHIBITOR
A1 (< 30) A2 (30-300) A3 (> 300)
G1 (≥90)
G2 (60-90)
G3a (45-59)
G3b (30-45)
G4 (30-44)
G5 (<15)
eGFR
categories
(mL/min/1.73m2)
Albuminuria categories (mg/g)
Low
Moderately
increased
High
Very High
EMPA-REG
DECLARE-TIMI 58
CANVAS
CREDENCE
DAPA-CKD
EMPA-KIDNEY

20. DAPAGLIFLOZIN IN PATIENTS WITH CHRONIC KIDNEY DISEASE
4304 patients
• 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
End
Points
Composite of sustained ≥50% eGFR decline,
ESKD, renal or CV death
Primary Outcome
Median follow-up 2.4 years
N Engl J Med 2020; 383:1436-1446

21. DIABETES STATUS AND INVESTIGATOR-REPORTED CAUSE OF
KIDNEY DISEASE AT BASELINE
Diabetes Status
67.5%
32.5%
With type 2 diabetes
Without type 2 diabetes
Diabetic nephropathy
Glomerulonephritis
Ischemic / hypertensive nephropathy
Other / unknown causes
16.0%
16.1%
Investigator-reported Cause of Kidney Disease
58.3%
9.6%
N Engl J Med 2020; 383:1436-1446

22. PRIMARY COMPOSITE OUTCOMES
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
Cumulative
Incidence
%
N at Risk NNT=19
39%
RRR
ESKD 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
DAPA
9.2%
Placebo
14.5%
HR (95% CI)
0.61 (0.51-0.72)
p-value
0.000000018
N Engl J Med 2020; 383:1436-1446

23. 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
All Individual Components Contributed to the Significant
Primary Outcome Treatment Effect
N Engl J Med 2020; 383:1436-1446

24. PRIMARY OUTCOME TREATMENT EFFECT
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)
0.13 0.50 1.00 1.25
DAPA 10 mg Better Placebo Better
Treatment Benefit Was Consistent Across Key Pre-Specified Subgroups
N Engl J Med 2020; 383:1436-1446

25. CV DEATH OR HOSPITALIZATION FOR HEART FAILURE
1. Heerspink HJL et al. N Engl J Med. 2020; 383:1436-1446; 2. 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
Cumulative
Incidence
%
N at Risk
29%
RRR
Secondary outcomes

26. ALL-CAUSE MORTALITY
Secondary outcomes
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 2039 2029 2017 1998 1925 1531 1028 398
DAPA 10 mg
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
Cumulative
Incidence
%
N at Risk
2152 2035 2018 1993 1972 1902 1502 1009 379
Placebo
31%
RRR

27. CHANGE IN ALBUMINURIA IN THE OVERALL POPULATION
Mean reduction in UACR dapagliflozin vs. placebo:
29.3% (95% CI 25.2, 33.1); p<0.001
Dapagliflozin 2152 2085 2047 2048 1943 1884 1843 1778 1631 1172 692 233
Placebo 2152 2090 2054 2033 1909 1854 1818 1748 1581 1135 640 229
Median (IQR) baseline UACR, mg/g
Dapagliflozin: 965 (472–1903)
Placebo: 934 (482–1868)
Dapagliflozin 10 mg
42.9% reduction
Placebo
19.2% reduction
0
-60
-40
-20
0 4 8 12 16 20 24 28 32
Time, months
Adjusted
Mean
Change
in
UACR,
%
(95%
CI)
2 36

28. CHANGE IN ALBUMINURIA BY T2D STATUS
Patients with T2D
35.1% mean reduction in UACR (dapagliflozin vs. placebo)
(95% CI 30.6, 39.4; p<0.001)
Patients without T2D
14.8% mean reduction in UACR (dapagliflozin vs. placebo)
(95% CI 5.9, 22.9; p=0.001)
1455
1451
1411
1415
1387
1383
1398
1368
1339
1297
1288
1258
1262
1237
1206
1182
1127
1088
826
791
482
446
159
158
Dapagliflozin
Placebo
697
701
674
675
660
671
650
665
604
612
596
596
581
581
572
566
504
493
346
344
210
194
74
71
Dapagliflozin
Placebo
Adjusted
Mean
Change
in
UACR,
%
(95%
CI)
0
60
-40
-20
0 4 8 12 16 20 24 28 32
Time, months
2 36
Dapagliflozin
-46.6%
Placebo
-17.7%
Adjusted
Mean
Change
in
UACR,
%
(95%
CI)
0
60
-40
-20
0 4 8 12 16 20 24 28 32
Time, months
2 36
Dapagliflozin
-33.9%
Placebo
-22.5%
Median (IQR) baseline UACR, mg/g
Dapagliflozin: 1025 (473–2111)
Placebo: 1005 (493–2017)
Median (IQR) baseline UACR, mg/g
Dapagliflozin: 870 (472–1554)
Placebo: 842 (459–1555)

29. CHANGE FROM BASELINE IN EGFR
0 4 8 12 16 20 24 28 32 36
-15
-10
-5
0
Months Since Randomization
Least-Squares
Mean
Change
in
eGFR
(mL/1.73m
2
)
DAPA
Mean BL eGFR: 43.2 mL/min/1.73m2
Placebo
Mean BL eGFR: 43.0 mL/min/1.73m2
No. of Patients
Dapagliflozin 2152 2031 2001 1896 1832 1785 1705 1482 978 496 157
Placebo 2152 2029 1981 1866 1795 1753 1672 1443 935 447 157
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.
During first 2 weeks
Greater reduction in eGFR in DAPA
(-3.97±0.15 vs -0.82±0.15 mL/min/1.73m2)
From baseline to 30 months
Small reduction in eGFR in DAPA
(-2.86±0.11 vs -3.79±0.11 mL/min/1.73m2)

31. SAFETY OUTCOMES
Safety Outcomesa, n (%)
Dapagliflozin 10 mg
(N=2149)
Placebo
(N=2149)
p-value
Discontinuation of study drug 274 (12.7) 309 (14.4) NA
Discontinuation due to adverse event 118 (5.5) 123 (5.7) 0.79
Any serious adverse event 633 (29.5) 729 (33.9) 0.002
Adverse events of interest
Amputationb
Any definite or probable diabetic ketoacidosis
Fracturec
Renal-related adverse event
Major hypoglycemiad
Volume depletion
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)
0.73
0.50
0.22
0.07
0.04
0.01
NA
Fournier’s Gangrene 0 1(<0.1) NA
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.
N Engl J Med 2020; 383:1436-1446

32. The Largest SGLT2i Development ProgramWorldwide
The FIRST treatment for patients with CKD, with and without T2D, to
improve cardiorenal outcomes and reduce mortality
39% RRR
in a composite of sustained ≥50% eGFR decline, ESKD, renal, or
CV death
HR, 0.61 (0.51-0.72); p<0.000000028
44% RRR
in composite outcome of sustained
≥50% eGFR decline, ESKD, or renal death
HR, 0.56 (0.45-0.68); p=0.000000018
29% RRR
in CV death or hHF
HR, 0.71 (0.55-0.92); p=0.0089
31% RRR
in all-cause mortality
HR, 0.69 (0.53-0.88); p=0.0035
Safety
Dapagliflozin was well tolerated, keeping with
its established safety profile
Adverse events rarely led to discontinuation of treatment
Very few events of major hypoglycemia or DKA
Trial stopped early due to overwhelming efficacy
• Results consistent in patients with and without T2D
• First renal outcomes study to show robust benefit on all-cause mortality
• HHF/CV benefit in CKD patients that is consistent with DAPA-HF
• With DECLARE demonstrates the ability to prevent and treat cardiorenal complications across the
spectrum of diabetic kidney disease severity
DAPA-CKD Overview
1:1
double-blind
Inclusion Criteria: ≥18 years, eGFR 25 to 75 mL/min/1.73m2
UACR 200–5000 mg/g, stable maximum tolerated dose of ACEi or ARB for
≥4 weeks (if not contraindicated)
DAPA 10 mg
n=2152
Placebo
n=2152
N=4304
32%
No T2D
68%
T2D
Placebo
Dapagliflozin
197 Events
312 Events
NNT=19
36% RRR in
patients with T2D
HR, 0.64 (0.52-0.79)
50% RRR in
patients without T2D
HR, 0.50 (0.35-0.72)

33. RENAL OUTCOMES IN DAPAGLIFLOZIN
a Because the trial met only one of its dual primary composite outcomes for superiority (CV death or hospital admission for heart failure), all other analyses of additional outcomes should
be considered hypothesis generating only.
ASCVD = atherosclerotic cardiovascular disease; CV = cardiovascular; CKD = chronic kidney disease; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HF = heart
failure; HFrEF = heart failure with reduced ejection fraction; hHF = hospitalization for heart failure; T2D = type 2 diabetes.
1. Wiviott SD. et al. N Engl J Med. 2019;380:347-357. 2. McMurray JJV et al. N Engl J Med. 2019;381:1995-2008. 3. Heerspink HJL. Presented at: ESC Congress – The Digital Experience;
August 29 - September 1, 2020; 4. Heerspink HJL et al. Online ahead of print. N Engl J Med. 2020.
Patient
Population
Glycemic Status With T2D With (45%) or Without (55%) T2D With (68%) or Without (32%) T2D
Mean eGFR 85.2 mL/min/1.73m2 66 mL/min/1.73m2 43 mL/min/1.73m2
Primary
Endpoint
• hHF or CV death
0.83 (0.73, 0.95) p=0.005
• CV death or worsening HF (hHF, or urgent
hHF visit)
0.74 (0.65, 0.85) p<0.001
• ≥50% eGFR Decline, ESKD, or Renal or CV
Death
0.61 (0.51-0.72) p=0.000000028
Key
Endpoint
• eGFR decrease ≥40% to <60, ESKD or renal
death
0.53 (0.43, 0.66) p<0.0001a
• ≥50% sustained decline in eGFR,
ESKD or renal death
0.71 (0.44, 1.16) p=0.17
• CV death or hHF
0.71 (0.55, 0.92) p=0.0089
ASCVD (~40%) or MRF (~60%)
eGFR ≥60 mL/min/1.73m2
HFrEF
eGFR ≥30 mL/min/1.73m2
CKD
eGFR ≥25 to ≤75 mL/min/1.73m2
N = 17,1601
N = 47442 N = 43043,4
CV
Renal

34. OUTLINE
 Mechanism of SGLT2 inhibitor with renal protection
 Landmark trial of Dapagliflozin on renal outcomes
 Updated guideline on SGLT2 inhibitors for CKD patients
 Clinical practice for SGLT2 inhibitors

35. Ian H. de Boer, et al. Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Diabetes Care 2022
Published Oct 2022

36. Published Oct 2022

37. KDIGO 2022 GUIDELINES
KDIGO guideline on diabetes in CKD 2022

38. KDIGO guideline on diabetes in CKD 2022
Recommend an eGFR > 20 ml/min
per 1.73 m2 with an SGLT2i

39. KDIGO 2022 GUIDELINES
Recommendation 1.3.1: We recommend treating patients with T2D, CKD, and an eGFR > 20
ml/min per 1.73 m2 with an SGLT2i (1A).
• The recommendation for SGLT2i is for kidney and cardiovascular protection and has been shown to have
safety and benefit in CKD with or without T2D
• Withhold SGLT2i during times of prolonged fasting, surgery, or critical medical illness (when patients may be
at greater risk for ketosis).
• If a patient is at risk for hypovolemia, consider decreasing thiazide or loop diuretic dosages
• Advise patients about symptoms of volume depletion and low blood pressure, and follow up on volume
status after drug initiation.
• A reversible decrease in the eGFR with commencement of SGLT2i treatment may occur and is generally NOT
an indication to discontinue therapy.
• Once an SGLT2i is initiated, it is reasonable to continue an SGLT2i even if the eGFR falls below 20 ml/min per
1.73 m2 , unless it is not tolerated or kidney replacement therapy is initiate.
Practical Points
KDIGO guideline on diabetes in CKD 2022

40. Ian H. de Boer, et al. Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Diabetes Care 2022

41. ADA AND KDIGO 2022 RECOMMENDATION
Ian H. de Boer, et al. Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Diabetes Care 2022

42. OUTLINE
 Mechanism of SGLT2 inhibitor with renal protection
 Landmark trial of Dapagliflozin on renal outcomes
 Updated guideline on SGLT2 inhibitors for CKD patients
 Clinical practice for SGLT2 inhibitors

43. PRACTICAL PROVIDER GUIDE TO INITIATING SGLT2 INHIBITORS
KDIGO guideline on diabetes in CKD 2022

44. PERIPROCEDURAL MANAGEMENT
• Inform patients about risk of DKA associated with procedure.
• Procedure required admission or colonoscopy → Stop SGLT2i at least 3 days pre-
procedure (2 days prior to surgery and the day of surgery)
• Day-stay procedure → Stop SGLT2i at the day of procedure. However, fasting before
and after the procedure should be minimized
• Measure blood glucose and blood ketone levels.
• If patients is clinically well and ketone < 1 mmol/L → Proceed to surgery
• Consider hourly blood glucose and blood ketone testing during procedure and 2
hourly following procedure until eating and drinking normally.
• Restart SGLT2i only when the patient is eating and drinking normally or close to
discharge to hospital
• Patient who have day surgery/procedure should only recommence SGLT2i if on full oral
intake. Consider delaying recommencement for a further 24 h
Pre-procedure
On admission
Post-procedure
Australian Diabetes Society. Periprocedural diabetic ketoacidosis with SGLT2 inhibitors use. Jan 2020

45. TAKE HOME MESSAGE - MY CLINICAL PRACTICE
Stable hemodynamic and
renal function
Pre-initiation eGFR
Pre-initiation albuminuria
Empagliflozin ≥ 200 mg/g
if eGFR 45-90
ml/min/1.73m2
Dapagliflozin 200-5000
mg/g
Canagliflozin 300-5000
mg/g
Patients with T2DM with at
high risk for CV disease,
already on metformin
• Below HbA1C target →
Switch non-metformin to
SGLT2i
• Above HbA1c target →
Start SGLT2i
Patients with both HFrEF and
HFpEF
Patients with CKD (eGFR > 20)
esp. albuminuria
Drugs
Empagliflozin (Jardiance®),
Dapagliflozin (Forxiga®),
Canagliflozin (Invokana®)
Starting dose
Consider combination
therapy to limit non-
adherence and pill burden
Anticipatory guidance
Decrease dose diuretic, anti-
hyperglycemic drugs
Patients counseling
Genital/ perineal hygiene
Orthostatic hypotension
Symptom of DKA
Avoid excessive alcohol
Multidisciplinary care team
Follow-up and Monitoring
• Self-assessment of renal function,
BW, BP, and symptoms
• Dose up-titrate guide by glycemic
control (Not HF and renal)
• Essure adherence to SGLT2
• Multidisciplinary care team
Discontinuation
• Withhold if prolonged fasting,
surgery, or critical medical illness
• Receiving RRT
DAPA 10 mg
DAPA ≥ 25
ml/min/1.73m2
Adapted from Orly Vardeny, et al. JACC, 2019

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