The era of SGLT2i has come for DKD

內科部腎臟科楊智超醫師

• The burden of diabetic kidney disease (DKD) and the
coming era of SGLT2i
• Progression of DKD: glomerular blood pressure
matters!!
• Renal benefits of SGLT-2i: a wonder drug
• CVOTs of SGLT2i: The earlier, the longer, the better
but never too late!!
• Why Canagliflozin? : beneficial add-on effects of
GLP-1
2
Outline

0
500,000
1,000,000
1,500,000
2,000,000
2007
2008
2009
2010
2011
2012
2013
2014
2015
2016
DM pt >60 yr
Estimated 2017 DM patients by IDF2
Prevalence of Diabetes In Past 10 years1 (2007-2016)
Patients (n)
1. 衛生福利部國民健署歷年統計2.International Diabetes Federation, 2015Diabetes Atlas. https://www.idf.org/e-library/epidemiology-research/diabetes-atlas/13-diabetes-atlas-seventhedition.html.
56%
51%
How BIG is Diabetes in Taiwan ?
What is the proportion of elderly age ?

4
Diabetic kidney disease, we face today in Taiwan
~78,000 hemodialysis patients in Taiwan in 2017
49.3% are diabetic patients
1. 2017 Annual Report on Kidney Disease in Taiwan. http://www.tsn.org.tw/UI/L/TWRD/ebook_2017%E5%B9%B4%E5%A0%B1.pdf
2. Am J Kidney Dis. 2018 Jun;71(6):884-895.
3. Acta Nephrologica 2009; 23: 90-95
30-40% of patients with diabetes develop
diabetic nephropathy.
In Taiwan, about 39.7% of patients
with type 2 diabetes have diabetic
nephropathy

Nephrol Dial Transplant (2008) 23: 3977–3982
Nephrology 22, Suppl. 4 (2017) 3–8
2017 Annual Report on Kidney Disease in Taiwan.
ESRD
The era of SGLT2i: Renal endpoint postponded!!
腎臟終點出現在生命終點之前!!

Development of Macroalbuminuria Heralds Rapid Decline in
Glomerular Filtration in Type II Diabetes
-50
-40
-30
-20
-10
0
1 1.5 2 2.5 3 3.5 4
Time years
Change
in
GFR
ml/min
Microalbuminuria
Macroalbuminuria
Nelson RG. et al NEJM, 1996
10ml/min/yr
SLOW PROGRESSION
Or Compensation ?

20
25
30
35
40
Losartan -4.29 ml/min/year
P=0.002
Placebo
-5.05 ml/min/year
-1.55 ml/min
-2.28 ml/min
P=0.031
Estimated
GFR
(ml/min)
0 6 12 18 24 30 36 42
Time (month)
RENAAL: Relationship between initial eGFR change and
subsequent long-term renal function decline
Holtkamp et al. Kid Int 2011
Residual renal risk is still high by using RAS blockade!!
sCr doubling 25%
ESRD 28% 100% macro DKD
0.76

.
Zhang Z et al. JASN 2005;16:1775-1780
2x Cr, ESRD, or death
RENAAL Study
NNT
82
30
24
14

The Greater Changes in eGFR; the Better Protection from ARB
10 Kidney Int. 2011 Aug;80(3):282-7
RENAAL trial
2020 ADA--------
An ACEi or ARB, at the
maximum tolerated
dose indicated for BP
treatment, is
recommended for HTN
in pts with DM and
UACR>300 mg/g

For training purposes only.
Dulaglutide has received positive opinion from the CHMP; however, there is no guarantee it will receive regulatory approval and become commercially available in your affiliate.
Levey AS, et al. Kidney Int. 2011;80:17-28
CV-renal outcome in CKD:
Each ml GFR counts in macro!!
1. Rennal & IDNT: 100% macro
2. Empareg-outcome: 11% macro with egfr>60 ml/min可保護的腎絲球較多!!
3. Credence 100% macro, mean egfr 56可保護的腎絲球較少,但延緩崩壞!
4. Dapa-CKD: 90% macro with 11% egfr>60 ml/min(1+2)

Mechanistic concept of the effects of RAS and SGLT-2 inhibition
on intraglomerular pressure.
CKJ: Clinical Kidney Journal 11(6):749-761

13
Golden Cross
Cardiology. 2013;126(3):175-86.
AKI
Poor cardiac output
Diuretics
Vasoconstrictor agents
SGLT2i+RAASi ?

14
Diabetes Obes Metab.2019;21:1237–1250.
SGLT2i is safer than diuretics and ACEI/ARB!!

Cox regression analyses in patients treated with ≥1 dose of study drug. Interaction p-value is for test of homogeneity of treatment group difference between subgroups with no adjustment for
multiple tests. Data for patients who did not have an event were censored on the last day they were known to be free of the outcome. Albuminuric DKD defined as UACR >300 mg/g with
any eGFR [CKD-EPI]; non-albuminuric DKD group defined as eGFR <60 ml/min/1.73 m2 and UACR ≤300 mg/g; all others group defined as eGFR ≥60 ml/min/1.73 m2 or UACR ≤300 mg/g.
CV, cardiovascular; DKD, diabetic kidney disease; eGFR, estimated glomerular filtration rate; HHF, hospitalisation for heart failure; UACR; urinary albumin-to-creatinine ratio.
16
Empagliflozin Placebo Hazard ratio
(95% CI)
Hazard ratio
(95% CI)
Interaction
p-value
n event/N % n event/N %
CV death
All patients 172/4687 3.7 137/2333 5.9 0.62 (0.49, 0.77)
0.2567
Albuminuric DKD 42/509 8.3 36/260 13.8 0.54 (0.35, 0.85)
Non-albuminuric DKD 47/850 5.5 29/440 6.6 0.86 (0.54, 1.37)
All others 82/3276 2.5 72/1617 4.5 0.55 (0.40, 0.76)
HHF
All patients 126/4687 2.7 95/2333 4.1 0.65 (0.50, 0.85)
0.7087
Albuminuric DKD 32/509 6.3 24/260 9.2 0.58 (0.34, 0.99)
All others 62/3276 1.9 42/1617 2.6 0.72 (0.49, 1.07)
All-cause hospitalisation
All patients 1725/4687 36.8 925/2333 39.6 0.89 (0.82, 0.96)
0.3408
Albuminuric DKD 237/509 46.6 139/260 53.5 0.77 (0.62, 0.94)
All others 1093/3276 33.4 575/1617 35.6 0.91 (0.82, 1.01)
0.25 0.5 1 2
CV outcomes in patients with albuminuric vs non-albuminuric DKD vs all
others
Favours empagliflozin Favours placebo
18
90
50
NNT
26
250
166

EMPA-REG OUTCOME post-hoc analyses
2020 ADA

Intraglomerular blood pressure is derived from
Systemic blood pressure
Afferent arteriole tone
Efferent arteriole tone
N Engl J Med 2017; 377:1765-1776
SGLT2i
RAAS blockade

era of SGLT2i has come
• Progression of DKD/CKD: glomerular blood pressure
matters!!
GLP-1
21
Outline

eGFR over 192 weeks
22
Mixed model repeated measures analysis using all data from patients treated with ≥1 dose of study drug
(modified intent-to-treat approach). eGFR by Chronic Kidney Disease Epidemiology Collaboration formula.
eGFR, estimated glomerular filtration rate.
80% pts with ACEI/ARB; eGFR >30 ml/min; 100% CVD
N Engl J Med 2016; 375:323-334
Slope= 5.9ml/min
Slope= 1.14 ml/min
RENAAL 0.76/yr
及早，快速累積腎臟保護紅利是關鍵!!
4.76

Natural history of diabetic nephropathy
Functional Hyperfiltration Microalbuminuria, hypertension Albuminuira, declining GFR
Vora JP, et al. In: Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. New York: Mosby; 2000.
Urinary
protein
excretion
(mg/d)
Years
Glomerular
filtration
rate
(GFR)
(mL/min)
0
150
100
50
5 10 15 20 25
Incipient diabetic
nephropathy
Pre Overt diabetic
nephropathy
End-stage
renal disease
1 2 3 4 5
200
1000
5000
20
Urinary protein excretion
GFR
SGLT2i
SGLT2i?

24
Circulation. 2019;140:303–315
The alterations of glomerular hyperfiltration and
permeability by empagliflozin in diabetic mice

25
Large glomerulus
large filtration surface
rapid sclerosis
SGLT2i
SGLT2i
SGLT2i
ESRD

For training purposes only.
Dulaglutide has received positive opinion from the CHMP; however, there is no guarantee it will receive regulatory approval and become commercially available in your affiliate.
JASN April 2017, 28 (4) 1023-1039
Silent loss
Save diabetic kidneys: The earlier, the better!!
Single nephron protection!!
SGLT2i

SGLT2i
Nephrol Dial Transplant. 2020;35(1):1-4. Kidney Int Rep (2017) 2, 251–260

Am J Kidney Dis. 2016;67(3):483-498
SGLT2i
Uremic toxin

Diabetes 2013 Oct; 62(10): 3324-3328.
SGLT2i works in non-DM, too!!
Why?

matters!!
GLP-1
30
Outline

The hidden beauty of SGLT2i !!
31
Reduce glucose reabsorption
by SGLT2 inhibition
Reduce intraglomerular
pressure
Reduce tubular
workload
Reduce renal
inflammation

32
Sano M. J Cardiol. 2018 May; 71(5): 471-476.

33
Diabetes Care 2018;41:356–363
The strongest mediator was
hematocrit

35
A surrogate marker for
1. Recovery from reversible
tubulointerstitial injury!!
2. Preserved GFR and EF make
hemoconcentration possible!!

matters!!
GLP-1
36
Outline

CV(HF!!) and Renal protection start soon after Na-Glu excretion !!
(albuminuria)
N Engl J Med 2016; 375:323-334

38
Data are reported for week 6 in CANVAS and week 13 in CANVAS-R.
Circulation. 2018;138:1537–1550.
Data From the CANVAS Program
80% pts with ACEI/ARB; mean eGFR =77 ml/min; median UACR 12.4 mg/g
The earlier, the better
1.47
1.09
1.05
1.35

39
Am J Nephrol. 2018 Jan; 46(6): 462–472. April 14, 2019 DOI: 10.1056/NEJMoa1811744
(<60ml/min 60%)
(macro 100%)

252 required dialysis or transplantation or died of kidney disease
Lancet Diabetes Endocrinol. 2019 Nov;7(11):845-854.
Canaglu 對最高腎風險的族群帶來有效保護!!

CREDENCE: 50% CVD
3P MACE 4.87
HHF 2.53
57% CVD
eGfr<60 62%
Macroalbu 38%
4.39
1.45
100% CVD
Canaglu 對最高心血管風險的族群帶來有效保護!!

60% decline rate
eGFR 56
UAER 927
2.74

CREDENCE: canagliflozin ARB
Journal of nephrology 24(5):569-80
JASN 31: 1128–1139, 2020
Cana + ARB ~ 70-80% albuminuria reduction!!

Hazard ratio
(95% CI) P value
Primary composite outcome 0.70 (0.59–0.82) 0.00001
Doubling of serum creatinine 0.60 (0.48–0.76) <0.001
ESKD 0.68 (0.54–0.86) 0.002
eGFR <15 mL/min/1.73 m2
0.60 (0.45–0.80) –
Dialysis initiated or kidney transplantation 0.74 (0.55–1.00) –
Renal death 0.39 (0.08–2.03) –
CV death 0.78 (0.61–1.00) 0.0502
CV death or hospitalization for heart failure 0.69 (0.57–0.83) <0.001
CV death, MI, or stroke 0.80 (0.67–0.95) 0.01
Hospitalization for heart failure 0.61 (0.47–0.80) <0.001
ESKD, doubling of serum creatinine, or renal death 0.66 (0.53–0.81) <0.001
Summary of Key Renal and CV Outcomes
Favors Canagliflozin Favors Placebo
0.25 0.5 1.0 2.0 4.0
Baseline SBP 140mmHg; 100% Macro, 60% GFR<60 ml/min and 50% CVD
(risk is as high as 100% CVD population??)

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
再爛的腎臟還是會有好的腎絲球
Single nephron protection!!
Never too late for Cana!!

JASN 31: 1128–1139, 2020
14.3 M
11.2 M
8.7 M
A Secondary Analysis of the CREDENCE Randomized
Trial
40%

48
Diabetes Ther. 2020 Dec 18. doi: 10.1007/s13300-020-00953-4. Online ahead of print
Estimated eGFR values used to projectthe delay in time to dialysis*
by treatment in the CREDENCEtrial**
* eGFR of 10 ml/min/1.73 m2
** overlaid with observed data

10.1161/CIRCULATIONAHA.119.044359

Keep flood out is better than pour water out!!
SGLT2i ACEI/ARB

JASN October 2018, ASN.2018010103;

Long-term Decline in GFR is Correlated
With Poor Control of Blood Pressure:
9 Studies on Nephropathy Progression
–14
–12
–10
–8
–6
–4
–2
0
95 97 99 101 103 105 107 109 111 113 115 117 119
MAP (mmHg)
GFR
(ml/min/yr)
(mmHg)
Untreated HTN
140/90
130/85
Graph: (Bakris GL. J Clin Hypertens. 1999)
Trials: (Parving HH, et al. Br Med J. 1989) (Viberti GC, et al. JAMA. 1993) (Klaur S, et al. N Engl J Med. 1993*) (Herbert L, et al.
Kidney Int. 1994) (Lebovitz H, et al. Kidney Int. 1994) (Moschio G, et al. N Engl J Med. 1996*) (Bakris GL, et al. Kidney
Int. 1996) (Bakris GL, et al. Hypertension. 1997) (GISEN Group, Lancet. 1997)
121
*Trials marked by * are non-diabetic renal disease patients.
125/75 mmHg
if proteinuria
>1g/day
+SGLT2i
Untreated HTN and DM

matters!!
GLP-1
54
Outline

Structure and selectivity profiles for SGLT2 over
SGLT1
Empagliflozin
Canagliflozin
Dapagliflozin
Selectivity
SGLT-1 : SGLT-2
1:2500
1:1200
1:160
Singh AK et al. Indian J Endocrinol Metab. 2015 Nov-Dec;19(6):722-30.
55
more natriuresis!!

Canagliflozin Reduce
Reabsorbtion
SGLT2
Inhibition
Blood
Sugar
Canagliflozin
Glucose
SGLT1
Inhibition Glucose Retention GLP-1
L-cell
Intestine
Canagliflozin increase aGLP-1 through SGLT1 inhibition
56
More natriuresis?

Canagliflozin, dapagliflozin and empagliflozin
for treating type 2 diabetes: Network Meta-analysis 57
Health Technology Assessment, No. 21.2
HbA1c
BW

Canagliflozin, dapagliflozin and empagliflozin
for treating type 2 diabetes: Network Meta-analysis 58
Health Technology Assessment, No. 21.2
SBP

Hypertension. 2016;68:1355–1364

Hypertension. 2016;68:1355–1364
A+C+cana!!

62
J Clin Hypertens. 2014; 16(2): 115–121.
6 mmHg 70%

Hemodynamic
Metabolic SGLT2i
GLP1a
Dual effects of
Canagliflozin!!

64
KDIGO 2020 CLINICAL PRACTICE GUIDELINE FOR DM MANAGEMENT IN CKD
Kidney International (2020) 98, S1–S115

GLP-1a/DPP4i: seal glue
+
SGLT2i+ARB/ACEi: wrench
to decrease the flow and
pressure
In macroalbuminuria
Complementary effect!!
Broken pipe needs wrench and seal glue!
CREDENCE pts!!

心衰竭病史、巨量蛋白尿、eGFR<60增加hHF相對風險2-4倍
n X2 Adjusted
Hazard Ratio
95% Confidence
Intervals
P
Previous heart failure 1986 231.99 4.18 3.48-5.02 <0.01
Albumin/creatinine ratio >33.9 mg/mmol 1638 119.26 3.66 2.90-4.62 <0.01
Albumin/creatinine ratio 3.4 to ≤33.9 mg/mmol 4426 35.77 1.89 1.54-2.34 <0.01
Estimated glomerular filtration rate ≤60 mL/min 4602 49.86 2.00 1.65-2.42 <0.01
Age ≥75y 2192 24.92 1.70 1.38-2.09 <0.01
Previous myocardial infarction 5933 15.62 1.47 1.21-1.78 <0.01
Non-Hispanic 12327 10.71 1.56 1.20-2.04 <0.01
Established cardiovascualr disease 12344 8.81 1.64 1.18-2.28 <0.01
Saxagliptin 7916 7.77 1.29 1.08-1.54 0.01
Female 5205 6.93 0.76 0.62-0.93 0.01
Dyslipidemia 11213 4.63 1.27 1.02-1.59 0.03
Circulation 2014; 130: 1579-1588
Risk Factors for hHF in the Overall SAVOR-TIMI 53 Population

J Am Coll Cardiol. 2018, 71 (11 Supplement) A921.
PRIOR HEART FAILURE (HF) HOSPITALIZATION AND 30-DAY AND 1-YEAR
OUTCOMES IN PATIENTS WITH HF AND PRESERVED EF
27% 33%

Due to the progressive nature of HF, patients cannot be perceived as
‘stable’
Mortality
Cardiac
function
and
Quality
of life Decompensation/
hospitalization
Chronic decline1
Disease progression
1. Adapted from Gheorghiade et al. Am J Cardiol 2005;96:11G–17G; 2. Ahmed et al. Am Heart J 2006;151:444–50; 3. Gheorghiade and Pang. J Am Coll Cardiol
2009;53:557–73; 4. Holland et al. J Card Fail 2010;16:150–6; 5. Muntwyler et al. Eur Heart J 2002;23:1861–6
Frequency of decompensation and risk of mortality increase,1–5 with acute events and
sudden death occurring at any time
Canagliflozin?

69
More effective in
symptomatic HF!!
CANVAS: post hoc
Relative risk reduction of CV death and HHF
Diabetologia (2018) 61:2108–2117

70
Circulation. 2019;139:2591–2593
33%
30%

71
SUSTAIN 6
Anti-atherosclerosis effect of GLP-1
-39%
-24%

2020 ACC expert consensus: Cana 同時保護腎，心，血管!!
CREDENCE trial

73
N Engl J Med 2017; 377:644-657
CANVAS trial
-10%

DOI: 10.1016/j.jacc.2020.05.037

Cana 同時保護腎，心，血管!!

Eur Heart J. 2012 Sep;33(17):2135-42
SGLT2i
Non-diabetic HF
Non-diabetic CKD

Curr Opin Nephrol Hypertens 2017, 26:345–350
SGLT2i
High BP&protein or obesity
induced hyperfiltration
High protein related
Uremic toxin

Hemodynamic
Cana
ACEi/ARB
Cana
Cana
metabolic
For kidney protection the earlier, the better but never too late!!
Renal-cardio Benefits!!
GLP-1

Effect on eGFR (CANVAS vs CREDENCE)
80
Mean eGFR 76 ml/min
Mean ACR 12mg/gCr
Mean eGFR 56 ml/min
Mean ACR 923 mg/gCr
Secondary renal outcomes of the
CANVAS/CANVAS R study
CREDENCE study
N Engl J Med 2017; 377:644-657; 21. N Engl J Med 2019; 380:2295-2306; CAN-20200324.No2
The earlier, the better Never too late

SGLT2 inhibition: Class effect
SGLT1 inhibition: Canagliflozin only!

ACEi- or ARB-Based Regimens
for Diabetic Nephropathy Do Not
Go Far Enough!
ACEi or ARB
DGFR = - 6 ml/min/yr
Time to ESRD 6.6 yrs
Time (yrs)
ESRD
50
2 4 6 8 10
No ACEi/ARB
or BP control
DGFR = - 10 ml/min/yr
Time to ESRD 4 yrs
40
30
20
10
© 2005. American College of Physicians.
SGLT2i
RAAS blockade + GLP-1a
RAAS blockade + Cana

DKD治療新紀元
自2021/3月，Canaglu核准
糖尿病腎病變適應症
巨量蛋白尿期 : Albuminuria >
300
mg/day
eGFR從45下修至
30
mL/min/1.73 m2
Ref. TFDA Canaglu仿單資料
83

SGLT2i eGFR 說明
Canagliflozin eGFR<30不建議持續使用
Dapagliflozin eGFR30-45的CHF病人可以使用
eGFR<45不建議持續使用(T2DM)
Empagliflozin eGFR<30不建議持續使用
Ertugliflozin eGFR<60不建議持續使用
台灣仿單比較 : eGFR範圍

No. at risk
Placebo 2197 2169 2131 2065 1766 1177 658 182
Canagliflozin 2200 2163 2118 2071 1788 1228 667 202
Lower Extremity Amputation
0
5
10
15
20
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)
Participants
with
an
event
(%)
6 12 18 24 30 36 42
Placebo
Canagliflozin
Includes all treated patients through the end of the trial.
NS

0
5
10
15
20
25
0 26 52 78 104 130 156 182
Months since randomization
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)
Participants
with
an
event
(%)
6 12 18 24 30 36 42
Placebo
Canagliflozin
Includes all treated patients through the end of the trial.
NS

Safety by Diabetes Status
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; dAE with the following criteria confirmed by the investigator: i) symptoms of severe impairment in consciousness or behaviour, ii) need of external assistance, iii) intervention to treat
hypoglycemia, iv) prompt recovery of acute symptoms following the intervention.
AE = adverse event; T2D = type 2 diabetes;
Wheeler D. Presented at: ASN – Kidney Week 2020; October 22 – October 25, 2020.
Safety outcomesa, %
With T2D Without T2D
Dapagliflozin
(n=1453)
Placebo
(n=1450)
Dapagliflozin
(n=696)
Placebo
(n=699)
Discontinuation due to AE 5.6 6.5 5.2 4.1
Any serious AE 33.2 38.8 21.6 23.9
AE of interest
Amputationb
Any definite or probable
diabetic ketoacidosis
Fracturec HR=1.29
Renal related adverse eventc
Major hypoglycemiad
Volume depletionc
2.4
0
4.5
8.3
1.0
6.3
2.6
0.1
3.5
10.2
1.9
4.9
0
0
2.9
4.9
0
5.0
0.1
0
2.6
5.7
0
2.7
For reactive use only. This slide includes information for the purpose of scientific medical exchange only. AstraZeneca has no intention to promote its drugs outside of it approved indications.
DAPA-CKD:

Cell Metab. 2020 Sep 1;32(3):404-419.e6.

Diabetes Care 2020 Mar; 43(3): 508-
511.

The era of SGLT2i has come for DKD

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