1091217-Thinking Twice for Diabetes：Cardio-Renal or Renal-Cardiac Benefits of SGLT2i in Diabetic Patients

1. Thinking Twice for Diabetes: Cardio-Renal
or Renal-Cardiac Benefits of SGLT2i in
Diabetic Patients
台大醫院 雲林分院
心臟血管中心 許智能

2. DM
CVD
HF
CKD

3. TIMI Risk Score for HF in Diabetes (TRS-HFDM)
Circulation. 2019;140:1569–1577
V
V
V

4. Meta-analysis shows modest benefit
of intensive glycemic control on macrovascular risk
Meta-analysis including 27,049 participants and 2370 major vascular events
Trials
Number of events (annual event
rate, %)
ΔHbA1c (%)
Favours more
intensive
Favours less
intensiveMore intensive Less intensive
Major cardiovascular events*
ACCORD 352 (2.11) 371 (2.29) -1.01 0.90 (0.78 – 1.04)
ADVANCE 557 (2.15) 590 (2.28) -0.72 0.94 (0.84 – 1.06)
UKPDS 169 (1.30) 87 (1.60) -0.66 0.80 (0.62 – 1.04)
VADT 116 (2.68) 128 (2.98) -1.16 0.90 (0.70 – 1.16)
Overall 1194 1176 -0.88 0.91 (0.84 – 0.99)
Stroke
Overall 378 370 -0.88 0.96 (0.83 – 1.10)
Myocardial infarction
Overall 730 745 -0.88 0.85 (0.76 – 0.94)
Hospitalised/fatal heart failure
Overall 459 446 -0.88
1.00 (0.86 – 1.16)
1.00.5 2.0
Hazard ratio (95% CI)
†
Q=1.32, p=0.72, I2=0.00%)
Hazard ratio
(95% CI)
Q=0.40, p=0.94, I2=0.00%)
Q=2.25, p=0.52, I2=0.00%)
Q=3.59, p=0.31, I2=16.4%)
*Major CV events = CV death or non-fatal stroke or non-fatal MI.
†Diamonds incorporate point estimate (vertical dashed line) and encompass 95% CI of overall effect for each outcome.
Turnbull et al. Diabetologia 2009;52:2288–98.

5. More intensive glucose control improved kidney
outcome
Lancet Diabetes Endocrinol 2017; 5: 431–37
Δ HbA1c 0.9%

6. Intensive glucose control improved kidney outcome
Lancet Diabetes Endocrinol 2017; 5: 431–37
Primarily driven by reduced risks of development of macroalbuminuria

7. What is the renal benefit of lowering glucose?
Kidney Int 2013;83:517-23 Lancet 2010;376:419-30

8. RENAAL (losartan vs placebo)

9. IDNT (irbesartan vs placebo)

10. Danish registry: T2D and impact of cardiac-renal
disease on prognosis
Circ Cardiovasc Qual Outcomes. 2020;13:e006260.
DOI: 10.1161/CIRCOUTCOMES.119.006260
153,405 patients with a new T2D diagnosis
The 5-year risk of death after one CV or renal diagnosis
stratified according to time since T2D diagnosis. Only
including patients diagnosed and alive in the year
before.

11. Cardiorenal disease is the most common first CV
manifestation in T2D
EASD 2019

12. Primary and co-primary endpoints are in cursive. Statistically significant endpoints are in bold. Due to differences in study design, inclusion criteria and study population direct comparison can
and should not be drawn between trials but are purely illustrative. Refer to slide notes for abbreviations
Zinman B et al. N Engl J Med 2015;373:2117; Neal B et al. N Engl J Med 2017;377:644; Wiviott SD et al. N Engl J Med 2019;380:347; ADA 2020 congress
#Did not include albuminuria
EMPA-REG
OUTCOME
CANVAS DECLARE-TIMI 58 VERTIS-CV
3P-MACE
HR 0.86
[CI: 0.74, 0.99]
HR 0.86
[CI: 0.75, 0.97]
HR 0.93
[CI: 0.84, 1.03]
HR 0.99
[CI: 0.88, 1.12]
CV death or hHF
HR: 0.66 [CI: 0.55,
0.79]
HR 0.72
[CI: 0.55, 0.94]
HR 0.83
[CI: 0.73, 0.95]
HR 0.88
[CI: 0.75, 1.03]
hHF
HR: 0.65
[CI: 0.50, 0.85]
HR 0.67
[CI: 0.52, 0.87]
HR 0.73
[CI: 0.61, 0.88]
HR 0.70
[CI: 0.54, 0.90]
Renal composite
HR: 0.54 [CI: 0.40,
0.75]
HR 0.59
[CI: 0.44, 0.79]
HR 0.53
[CI: 0.43, 0.66]
HR 0.81
[CI: 0.63, 1.04]
SGLT2 inhibitors CVOTs overview

13. HHF with GLP-1 RA
Lancet Diabetes Endocrinol 2019;7:776-85
Hospital admission for heart failure

14. Kidney outcomes with GLP-1 RA
Worsening of kidney function
Lancet Diabetes Endocrinol 2019;7:776-85
NNTs are calculated over an
estimated median follow-up of 3·2
years
Composite kidney outcome including macroalbuminuria

15. CANVAS
Outcome
(per 1000 patient-yr)
Canagliflozin
(n=5795)
Placebo
(n=4347)
Hazard
ratio
95% CI P
Primary outcome (CV
death, nonfatal MI, or
nonfatal stroke)
26.9 31.5 0.86 0.75–0.97
0.02 for
superiority
All-cause death 17.3 19.5 0.87 0.74–1.01
CV death 11.6 12.8 0.87 0.72–1.06
Hospitalization for HF 5.5 8.7 0.67 0.52–0.87
a. P < .001 for noninferiority
b. Primarily at the toe or metatarsal level

16. CVOTs of SGLT2is: Time to first HHF
Benefit occurred early and sustained throughout the trial

17. Meta-analysis of SGLT2i trials on HHF stratified by
history of ASCVD

18. Meta-analysis of SGLT2i trials on HHF stratified by
history of HF
Lancet. 2019;393:31-39.

19. CANVAS
Outcome
(per 1000 patient-yr)
Canagliflozin
(n=5795)
Placebo
(n=4347)
Hazard
ratio
95% CI
Albuminuria progression 89.4 128.7 0.73 0.67–0.79
Renal composite (40% eGFR
reduction, renal replacement
therapy, or death)
5.5 9.0 0.60 0.47–0.77
a. P < .001 for noninferiority
b. Primarily at the toe or metatarsal level

20. CKDPC meta-analysis : Albumin is a continuous predictor starting
at low levels while eGFR is predictive only below a certain threshold
eGFR <60 ml/min/1.73 m2 and UACR >1.1 mg/mmol (10 mg/g)
are independent predictors of mortality risk in the general population
5105 120 10
HR(95%CI)
8
0.5
CV mortality: eGFR
eGFR (ml/min/1.73 m2)
15 30 75
2
4
1
45 60 90
HR(95%CI)
8
0.5
CV mortality: UACR
UACR (mg/g)
2.65 300 1000
2
4
1
30
HR(95%CI)
8
0.5
All-cause mortality: eGFR
2
4
1
HR(95%CI)
8
0.5
All-cause mortality: UACR
2
4
1
Matsushita K, et al. Lancet. 2010;375:2073-81

21. 2021 ADA: Diagnosis of DKD
•Diabetic kidney disease is usually a
clinical diagnosis made based on the
presence of albuminuria and/or reduced
eGFR in the absence of signs or
symptoms of other primary causes of
kidney damage.

23. Clin Kidney J. 2019;12:313-321

24. CREDENCE: Study design
Participants continued treatment if eGFR was <30 mL/min/1.73 m2 until chronic dialysis was
initiated or kidney transplant occurred.
Key inclusion criteria
• ≥30 years of age
• T2DM and HbA1c 6.5% to 12.0%
• eGFR 30 ~ 90 mL/min/1.73 m2
• UACR 300 to 5000 mg/g
• Stable max tolerated labelled dose of
ACEi or ARB for ≥4 weeks
Key exclusion criteria
• Other kidney diseases, dialysis, or kidney transplant
• Dual ACEi and ARB; direct renin inhibitor; MRA
• Serum K+ >5.5 mmol/L
• CV events within 12 weeks of screening
• NYHA class IV heart failure
• Diabetic ketoacidosis or T1DM
2-week placebo run-in
Placebo
Canagliflozin 100 mg
R
Double-blind
randomization
(1:1)
Follow-up at Weeks 3, 13, and 26 (F2F)
then every 13 weeks (alternating phone/F2F)
Jardine MJ, et al. Am J Nephrol. 2017;46(6):462-472.

25. Lower baseline renal function in CREDENCE
participants
20 26
9
60
-8 -11 -7
-88
-100
-80
-60
-40
-20
0
20
40
60
80
100
eGFR
<60
UACR
>300
1. Neal B, et al. N Engl J Med. 2017;377(7):644-657.
2. Zinman B, et al. N Engl J Med. 2015;373(22):2117-2128.
3. Raz I, et al. Diabetes Obes Metab. 2018;20(5):1102-1110.
CREDENCE
CANVAS
Program1
EMPA-REG
OUTCOME2 DECLARE3

26. CREDENCE: CV-related baseline demographics
Canagliflozin
(n = 2202)
Placebo
(n = 2199)
Total
(N = 4401)
Hypertension, % 97 97 97
Heart failure (NYHA I-III), % 15 15 15
CV disease, % 51 50 50
Renal and CV protective agents, %
RAAS inhibitor >99.9 99.8 99.9
Statin 70 68 69
Antithrombotic 61 58 60
Beta blocker 40 40 40
Diuretic 47 47 47
Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.

27. CREDENCE: 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
Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.
NNT over 3 years=19
Median FU 2.6 yr
61.2/1000 patient-year
43.2/1000 patient-year

28. CREDENCE: Across categories of baseline HbA1c, treatment
with canagliflozin resulted in similar risk reductions
Circulation. 2020 Feb 4;141(5):407-410.

29. CREDENCE
Primary outcome by screening eGFR and albuminuria
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)
Baseline UACR 0.49
≤1000 mg/g 0.76 (0.55–1.04)
>1000 mg/g 0.67 (0.55–0.81)
Favors Canagliflozin Favors Placebo
0.25 0.5 1.0 2.0 4.0

30. Anticipated effects of SGLT2 inhibitors on clinical parameters
in patients with T2DM at different CKD stages
J Am Coll Cardiol 2019;74:2511–24

31. 19. N Engl J Med 2017; 377:644-657
21. N Engl J Med 2019; 380:2295-2306
Canagliflozin reduced UACR
Mean eGFR 76 ml/min
Mean ACR 12mg/gCr
Mean eGFR 56 ml/min
Mean ACR 923 mg/gCr
Secondary renal outcomes of CANVAS/CANVAS R CREDENCE

32. Data from the United Kingdom Prospective Diabetes Study (UKPDS). Data presented as annual
transition rates with 95% confidence intervals. Adler A, et al. Kidney Int. 2003;63:225-32.
The UKPDS: Albuminuria – A marker of renal damage –
Is associated with ↑ CV morbidity and mortality
Death
No nephropathy
Microalbuminuria (MAU)
Macroalbuminuria
↑ Plasma creatinine or
renal replacement therapy
2.0%
(1.9-2.2%)
2.8%
(2.5-3.2%)
2.3%
(1.5-3.0%)
1.4%
(1.3-1.5%)
3.0%
(2.6-3.4%)
4.6%
(3.6-5.7%)
19.2%
(14.0-24.4%)
Annual transition rates through stages of albuminuria in patients with T2D

33. CREDENCE: Acute and long-term effects on eGFR
-21.
-17.5
-14.
-10.5
-7.
-3.5
0.
3.5
0 26 52 78 105 131 157
LSMeanChange(±SE)
ineGFR(mL/min/1.73m2)
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
Baseline
60% reduction in the rate of eGFR decline
with canagliflozin
On treatment
–1.85/year
Perkovic V, et al. N Engl J Med.
2019. doi: 10.1056/NEJMoa1811744.
Average age: 63

34. CANVAS: Canagliflozin slowed the loss of kidney
function across all UACR subgroups
JASN 30: 2229–2242, 2019

35. CREDENCE: Acute and long-term effects on eGFR
56.4 56.0
Canagliflozin Placebo
Baseline
60% reduction in the rate of eGFR decline
with canagliflozin
Perkovic V, et al. N Engl J Med.
2019. doi: 10.1056/NEJMoa1811744.
Average age: 63
0
5
10
15
20
25
30
35
40
45
50
55
60
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
eGFR
Years
Canagliflozin
Placebo
15 years
2014 年65歲第 2 型糖尿病人之平均餘命
男性 16.3 ± 0.2 年
女性 19.0 ± 0.7 年

36. CREDENCE: End-stage kidney disease
0.
6.25
12.5
18.75
25.
0. 26. 52. 78. 104. 130. 156. 182.
Months since randomization
Hazard ratio, 0.68 (95% CI, 0.54–0.86)
P = 0.002
165 participants
116 participants
6 12 18 24 30 36 42
Participantswithanevent(%)
No. at risk
Placebo 2199 2182 2141 2063 1752 1152 641 178
Canagliflozin 2202 2182 2146 2091 1798 1217 654 199
Placebo
Canagliflozin
Perkovic V, et al. N Engl J Med. 2019. doi: 10.1056/NEJMoa1811744.

38. CREDENCE: Hospitalization for heart failure
No. at risk
Placebo 2199 2165 2122 2043 1735 1147 638 170
Canagliflozin 2202 2171 2131 2076 1789 1226 668 199
0.
5.
10.
15.
20.
25.
0. 26. 52. 78. 104. 130. 156. 182.
Months since randomization
Hazard ratio, 0.61 (95% CI, 0.47–0.80)
P <0.001
141 participants
89 participants
6 12 18 24 30 36 42
Participantswithanevent(%)
Placebo
Canagliflozin

39. CREDENCE: CV death or hospitalization for HF
ACC 2020

40. CREDENCE
CV outcomes by primary & secondary prevention
Hazard ratio
(95% CI)
Interaction P value
CV death or hospitalization for heart failure
0.74 (0.54–1.03) 0.57
0.66 (0.52–0.83)
0.69 (0.57–0.83)
CV death, MI, or stroke
0.68 (0.49–0.94) 0.25
0.85 (0.69–1.06)
0.80 (0.67–0.95)
CV death
0.75 (0.48–1.16) 0.86
0.79 (0.58–1.07)
0.78 (0.61–1.00)
Favors Canagliflozin Favors Placebo
0.25 0.5 1.0 2.0 4.0
Secondary
prevention
Primary
prevention
Overall
population
Circulation. 2019;140:739–750

41. CREDENCE: NNT for the primary and CV outcomes
Circulation.
2019;140:739–
750

42. No. at risk
Placebo 2197 2169 2131 2065 1766 1177 658 182
Canagliflozin 2200 2163 2118 2071 1788 1228 667 202
CREDENCE: Lower extremity amputation
0.
6.25
12.5
18.75
25.
0. 26. 52. 78. 104. 130. 156. 182.
Months since randomization
63 participants
70 participants
Hazard ratio, 1.11 (95% CI, 0.79–1.56)Participantswithanevent(%)
6 12 18 24 30 36 42
Placebo
Canagliflozin
Includes all treated patients through the end of the trial.

43. 0.
6.25
12.5
18.75
25.
0. 26. 52. 78. 104. 130. 156. 182.
Months since randomization
CREDENCE: Fracture
68 participants
67 participants
No. at risk
Placebo 2197 2166 2128 2061 1769 1178 656 176
Canagliflozin 2200 2171 2121 2074 1785 1225 668 200
Hazard ratio, 0.98 (95% CI, 0.70–1.37)Participantswithanevent(%)
6 12 18 24 30 36 42
Placebo
Canagliflozin
Includes all treated patients through the end of the trial.

44. Primary composite outcome
Sustained ≥50% eGFR decline, ESKD, renal or CV deatha
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
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
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.
T2D 68%
Mean age 62
Mean eGFR 43
Mean UACR ~950

45. Primary composite outcome
Treatment benefit consistent across prespecified subgroups
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
Heerspink HJL. Presented at: ESC Congress – The Digital Experience; August 29 - September 1, 2020.

46. Change from baseline in eGFR
N Engl J Med 2020; 383:1436-1446
–2.86/year
–3.79/year
25% reduction in the rate of eGFR decline
with dapagliflozin

47. Secondary composite outcome
CV death or hospitalization for HF
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
mgPlacebo
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
Heerspink HJL. et.al. Presented at ESC2020.
T2D 68%
Mean age 62
Mean eGFR 43
Mean UACR ~950

48. DAPA-CKD
CV outcomes by primary & secondary prevention
5.5/100 pt-
yr
5.2/100 pt-
yr
1.7/100 pt-
yr
1.4/100 pt-
yr
AHA 2020

49. 2020 Taiwan: Treatment algorithm in diabetic patients
Mono- and dual therapy
Multiple
risk factors
CHD HF
Stage 3
CKD
Stroke
HbA1c target (%) <7 <7 <7.5 <7 <7
Monotherap
y
1st choice Metformin Metformin SGLT2i SGLT2i Metformin
2nd choice Metformin TZD
Dual therapy 1st choice
Metformin
+ SGLT2i
Metformin
+ SGLT2i
SGLT2i +
metformin
SGLT2i +
metformin
Metformin
+
TZD
2nd choice
Metformin
+ GLP-1 RA
3rd choice
Metformin
+
TZD

50. 2020 KDIGO
Comprehensive care in
patients with diabetes
and CKD

51. 2021 ADA: Comorbidities-oriented
Metformin + Lifestyle

52. 2021 ADA: Comorbidities-oriented
Metformin + Lifestyle

53. 2021 ADA: Comorbidities-oriented
Metformin + Lifestyle

54. 2021 ADA: Factors to consider when selecting SGLT2
inhibitors in adults with T2D
CV effects Renal effects
Additional considerations
ASCVD HF
Progression
of CKD
Benefit:
empagliflozi
n,
canagliflozin
Benefit:
empagliflozi
n,
canagliflozin,
dapagliflozin
Benefit:
canagliflozin,
empagliflozi
n,
dapagliflozin
,
• Should be discontinued before any
scheduled surgery to avoid potential
risk of DKA
• DKA risk (all agents in T2D)
• Risk of bone fracture (canagliflozin)
• Genitourinary infection
• Risk of volume depletion,
hypotension
• ↑LDL-C
• Risk of Fournier’s gangrene

55. Conclusion
• CANVAS showcased CV and renal benefits of
canagliflozin in T2D patients.
• CREDENCE demonstrated significant improvements in
renal and CV outcomes in patients with T2D +
macroalbuminuria treated with canagliflozin.
• Monitor renal status, including eGFR and albuminuria in
your T2D patients.
• Get with the guideline!