1090807 -糖尿病盛行率&治療概況

1. Think twice for diabetes:
Cardio-renal or Renal-cardiac Benefits
of SGLT2i in diabetic patients
楊智超 醫師
腎臟科
高雄長庚紀念醫院
AUG 7th 2020

2. • The burden of diabetic kidney disease (DKD) and
cardiorenal syndrome
• Progression of DKD: glomerular blood pressure
matters!!
• Renal benefits of SGLT-2i: a wonder drug
• CVOTs of SGLT2i: The earlier, the longer, the better
• More cardiorenal benefits of SGLT-2i: Why and How
• Why Canagliflozin? : beneficial add-on effects of
GLP-1
2
Outline

4. 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
ChangeinGFRml/min
Microalbuminuria
Macroalbuminuria
Nelson RG. et al NEJM, 1996
10ml/min/yr
SLOW PROGRESSION ?

5. 5
Adapted from Gregg EW et al. N Engl J Med 2014;370:1514
Increased life expectancy and aging kidneys!!
Era of
SGLT2i
GLP1a
?
Rennal & IDNT 2001: Macroalbuminuric DKD

6. An ACE inhibitor or ARB, at the maximum tolerated dose indicated for BP
treatment, is the recommended first-line treatment for HTN in patients with
DM and UACR>300 mg/g creatinine (A) or 30–299 mg/g creatinine (B).
Diabetes Care 2020;43(Suppl.1): S111–S134
Cardiovascular Disease and Risk Management: Standards of Medical Care
in Diabetes—2020

7. Blood Pressure
Intraglomerular pressure
Albuminuria and GFR
CV-renal Outcome in
Diabetes
ARB
or
ACEI
Efferent arteriole tone

8. The Greater Changes in eGFR; the Better Protection from ARB
8 Kidney Int. 2011 Aug;80(3):282-7
RENAAL trial

9. 9
1st Golden Cross
Cardiology. 2013;126(3):175-86.
AKI
彎的過得去就是拓海，彎不過去就是填海
Poor cardiac output
Diuretics
Vasoconstrictor agents
SGLT2i

10. 10
Diabetes Obes Metab.2019;21:1237–1250.
SGLT2i is safer than diuretics and ACEI/ARB!!

11. For the purpose of scientific medical exchange only
Verma and McMurray (2018) Diabetologia DOI 10.1007/s00125-018-4670-7; Diabetes Obes Metab. 2018;20:479 – 487.
SGLT-2i may reduce mostIy interstitial fluid than
intravascuIar voIume
Loop diureticsSGLT-2 inhibitors
 Congestion relief without reducing arterial filling and perfusion
 Limit the reflex neurohumoral stimulation
Interstitial oedema
in congestive
heart failure

12. 12
Ohara et al. Diabetol Metab Syndr (2020) 12:37 https://doi.org/10.1186/s13098-020-00545-z
Dapagliflozin decreased the extracellular volume expansion
in patients with higher baseline ECW/TBW and BNP levels
Change in ECW/TBW after 7 days of dapagliflozin
in 36 DKD patients

13. • The burden of diabetic kidney disease (DKD) and
cardiorenal syndrome
• Progression of DKD: glomerular blood pressure
matters!!
• Renal benefits of SGLT-2i: a wonder drug
• CVOTs of SGLT2i: The earlier, the longer, the better
• More cardiorenal benefits of SGLT-2i: Why and How
• Why Canagliflozin? : beneficial add-on effects of
GLP-1
13
Outline

14. Renal Events by eGFR and Albuminuria : ADVANCE Study
Renal events: death as a result of kidney disease, requirement for dialysis or transplantation, or
doubling of serum creatinine to >2.26 mg/dL (200 μmol/L)
10,640 patients with T2DM; median follow-up of 4.3 years
eGFR, estimated glomerular filtration rate; HR, hazard ratio; T2DM, Type 2 diabetes mellitus; UAE, urinary albumin excretion
Ninomiya T, et al. J Am Soc Nephrol 2009;20:1813–1821
14

15. Glomerular hypertension, hyperfiltration and nephron loss
are key culprits in CKD progression
• CKD, chronic kidney disease; GFR, glomerular filtration rate
• Kanzaki G, et al. Hypertension Res 2015;38:633–641
GFR >90 ml/min GFR >135ml/min GFR <60ml/min GFR <30ml/min
Normal Hyperfiltration CKD Stage 3 CKD Stage 4
Courtesy M. Eynatten

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

17. 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.
Urinaryproteinexcretion
(mg/d)
Years
Glomerularfiltrationrate(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 excretionGFR

18. 18
Large glomerulus
large filtration surface
rapid sclerosis

19. 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!!

20. 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.
Case
• A 53 y/o man(173/cm/80kg) has medical history of DM more than 10 yrs, HTN
• DKD with macroalbuminuria(Bilateral nephromegaly, Cr 1.32, 57ml/min, UAER
6488 mg/g, Albumin 2.60 )

21. 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.
Urinaryproteinexcretion
(mg/d)
Years
Glomerularfiltrationrate(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 excretionGFR

22. Eur J Nutr. 2018 Apr;57(3):1083-1096.
14%35%
Glomerular hypertrophy/
hyperfiltration

23. High-Protein Diet Is Bad for Kidney Health
• HPD increases the risk of RHF and a rapid renal function decline in the general
population
Nephrol Dial Transplant. 2020 Jan 1;35(1):98-106.
• HPD was significantly associated with a more rapid kidney function
decline in post-MI patients.
Nephrol Dial Transplant . 2020 Jan 1;35(1):106-115.

24. Amino acid-induced hyperfiltration:
Amino acids
Branched-chain
amino/keto acids
cAMP
Glucagon
2
1
1 + 2
• Increased renal
plasma flow
• HyperfiltrationLang et al. (1995): Sem Nephrol, 15, 415-418
Progression of CKD: Hyperfiltration
Among the proteinogenic amino acids, there are
three BCAAs: leucine, isoleucine and valine
tubuloglomerular feedback

25. Macula densa

26. Am J Physiol Renal Physiol 309: F2–F23, 2015.

27. Am J Kidney Dis. 2016;67(3):483-498

28. SGLT2i
DAPA-CKD!!
Nephrol Dial Transplant. 2020;35(1):1-4.

29. • The burden of diabetic kidney disease (DKD) and
cardiorenal syndrome
• Progression of DKD: glomerular blood pressure
matters!!
• Renal benefits of SGLT-2i: a wonder drug
• CVOTs of SGLT2i: The earlier, the longer, the better
• More cardiorenal benefits of SGLT-2i: Why and How
• Why Canagliflozin? : beneficial add-on effects of
GLP-1
29
Outline

30. HemodynamicMetabolic SGLT2i

31. 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=0.031EstimatedGFR(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

32. 32

33. eGFR over 192 weeks
33
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.
11%
80% pts with ACEI/ARB; eGFR >30 ml/min; 100% CVD
N Engl J Med 2016; 375:323-334
Slop= 2 ml/min
Slop= 4~5ml/min

34. 34
Am J Nephrol. 2018 Jan; 46(6): 462–472. April 14, 2019 DOI: 10.1056/NEJMoa1811744
(<60ml/min 60%)
(macro 100%)

35. Cardiovascular Comorbidities,
5% Medicare sample, by Diabetes and CKD status, 1999-2000
Kidney International, Vol. 64, Supplement 87
(2003), pp. S24–S31
Safety issue of SGLT2i

36. 60% decline rate
RENAAL -4.3

37. 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??)

38. 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 hyperfiltration!!

39. 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)
Participantswithanevent
(%)
6 12 18 24 30 36 42
Placebo
Canagliflozin
Includes all treated patients through the end of the trial.
NS

40. 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)
Participantswithanevent
(%)
6 12 18 24 30 36 42
Placebo
Canagliflozin
Includes all treated patients through the end of the trial.
NS

41. 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
ACEi + ARB
DGFR = - ? ml/min/yr
Time to ESRD ?
© 2005. American College of Physicians.
SGLT2i

42. 252 required dialysis or transplantation or died of kidney disease
Lancet Diabetes Endocrinol. 2019 Nov;7(11):845-854.

43. CREDENCE: 50% CVD
3P MACE 4.87
HHF 2.53
57% CVD
eGfr<60 62%
Macroalbu 38%
4.39
1.45
100% CVD

44. European Heart Journal, ehz455
ESC/EAS dyslipidemia Guidelines 2019
Intensive care is needed for pts
with moderate to severe CKD !!
Moderate CKD (eGFR 30-59 ml/min)
Severe CKD (eGFR <30 ml/min)

45. 45
Post hoc analysis of CREDENCE
Circulation. 2019;140:739–750.

46. 10.1161/CIRCULATIONAHA.119.044359

47. 47
Effects of Canagliflozin on eGFR in Participants with
Baseline eGFR < 30 mL/min/1.73 m2
Prof. Carol Pollock presentation on IDF, 2019
Single nephron protection!!

48. • The burden of diabetic kidney disease (DKD) and
cardiorenal syndrome
• Progression of DKD: glomerular blood pressure
matters!!
• Renal benefits of SGLT-2i: a wonder drug
• CVOTs of SGLT2i: The earlier, the longer, the better
• More cardiorenal benefits of SGLT-2i: Why and How
• Why Canagliflozin? : beneficial add-on effects of
GLP-1
48
Outline

49. Patients’ CV-renal profile and SGLT2i effects on end-points
Baseline SBP~ 135-140 mmHg, 80%-100% pts with ACEI/ARB
DECLARE CANVUS EMPA-outcome
CREDENCE
~40% reduction
~40% reduction
Cardio-renal or
Renal-cardiac ?

50. 50
Lancet Diabetes Endocrinol 2019 Published Online September 5, 2019 http://dx.doi.org/10.1016/S2213-8587(19)30256-6
Effect of SGLT2i on substantial loss of kidney function, ESKD,
or death due to kidney disease, stratified by use of RAS blockade
• Residual renal risk is still high under RAS blockade!!
• SGLT2i can help and play as a starter!!

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

52. 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
140/90130/85
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

53. 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.

54. 54
• In diabetics versus non-diabetics, these were “identical” with
respective HRs of 0.75 and 0.73
Reduced EF<40%

55. 55
Circulation. 2019;139:2591–2593
33%

56. • The burden of diabetic kidney disease (DKD) and
cardiorenal syndrome
• Progression of DKD: glomerular blood pressure
matters!!
• Renal benefits of SGLT-2i: a wonder drug
• CVOTs of SGLT2i: The earlier, the longer, the better
• More cardiorenal benefits of SGLT-2i: Why and How?
• Why Canagliflozin? : beneficial add-on effects of
GLP-1
56
Outline

57. 57
Sano M. J Cardiol. 2018 May; 71(5): 471-476.

58. 58
Diabetes Care 2018;41:356–363
The strongest mediator was
hematocrit
A surrogate marker for
1. Recovery from reversible
tubulointerstitial injury!!
2. Preserved GFR and EF make
hemoconcentration possible!!

59. 59

60. 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.
Non-diabetic model

61. Therapeutic effect of EMPA against p-Cresol-induced oxidative stress, DNA damage and
mitochondrial damage
DNA damage: γ-H2AX
Mito integrity: mitochondrial cytochrome C (mit-Mito C),
Mito damage:cytosolic cytochrome C (cyt-Cyto C)
oxidative stress

62. Therapeutic effect of EMPA against p-Cresol induced injury in cell culture study
Apoptosis: double stain of Annexin IV/PI

63. • The burden of diabetic kidney disease (DKD) and
cardiorenal syndrome
• Progression of DKD: glomerular blood pressure matters!!
• Renal benefits of SGLT-2i: a wonder drug
• CVOTs of SGLT2i: The earlier, the longer, the better
• More cardiorenal benefits of SGLT-2i: Why and How
• Why Canagliflozin? : beneficial add-on effects of GLP-1
63
Outline

64. 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.
64
more natriuresis!!

65. Diabetes 2013 Oct; 62(10): 3324-3328.

66. 66
J Pharmacol Exp Ther 358:94–102, July 2016

67. Canagliflozin Reduce
Reabsorbtion
SGLT2
Inhibition
Blood
Sugar
Canagliflozin
Glucose
SGLT1
Inhibition Glucose Retention GLP-1
L-cellIntestine
Canagliflozin increase aGLP-1 through SGLT1 inhibition
67
More natriuresis?

68. Canagliflozin Lowers Postprandial Glucose and Insulin by DelayingIntestinal
Glucose Absorption in Addition to Increasing UrinaryGlucose Excretion
Endocrine Journal 2017, 64 (9), 923-931
68
Peptide tyrosine-tyrosine(PYY)抑制食慾
2~3x

69. Canagliflozin, dapagliflozin and empagliflozin
for treating type 2 diabetes: Network Meta-analysis 69
Health Technology Assessment, No. 21.2
HbA1c
BW

70. Canagliflozin, dapagliflozin and empagliflozin
for treating type 2 diabetes: Network Meta-analysis 70
Health Technology Assessment, No. 21.2
SBP

71. 71
More effective in
symptomatic HF!!
CANVAS: post hoc

72. 72
Diabetologia (2018) 61:2108–2117
Relative risk reduction of CV death and HHF
Interaction
p=0.02
More reasonable!!

73. 73Nature Reviews Nephrology (2017)
doi:10.1038/nrneph.2017.123
Metabolic
(repair glue)
Hemodynamic Natriuresis
(modest)

74. CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; eGFR=estimated glomerular filtration rate; UACR=urine albumin:creatinine ratio
Data presented as change from baseline [LSM (95%CI)]; Safety population, MMRM analysis; *p<0.05 and **p<0.001 vs. baseline; #p<0.05 vs. insulin glargine.
eGFR AND ALBUMINURIA Decline by Baseline Macroalbuminuria
Award 7
Beneficial renal effects of Glp-1a!!

75. Summary: Dulaglutide & Renal Outcomes
Dulaglutide
(N/100 py)
Placebo
(N/100 py)
HR (95%CI) P
Renal Composite Outcome 3.47 4.07 0.85 (0.77, 0.93) 0.0004
Components of Composite
First Macroalbuminuriaa 1.76 2.29 0.77 (0.68, 0.87) <0.0001
Sustained Decline in eGFR of ≥ 30% 1.79 2.00 0.89 (0.78, 1.01) 0.066
Chronic Renal Replacement 0.06 0.08 0.75 (0.39, 1.44) 0.39
Serious Renal Adverse Eventb 0.32 0.36 0.90 (0.67, 1.20) 0.46
Sensitivity Analyses
a) Sustained eGFR Decline ≥ 40% 0.66 0.93 0.70 (0.57, 0.85) 0.0004
Renal composite with this decline 2.36 3.10 0.76 (0.68, 0.84) <0.0001
b) Sustained eGFR Decline ≥ 50% 0.24 0.42 0.56 (0.41, 0.76) 0.0002
Renal composite with this decline 1.99 2.66 0.74 (0.66, 0.84) <0.0001
aACR > 33.9 mg/mmol (300 mg/g); bany reported AE linked to acute renal failure
Macroalb. Pts ?

76. HemodynamicMetabolic SGLT2i
GLP1a

77. 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!!

78. 78
SUSTAIN 6
Anti-atherosclerosis effect of GLP-1
-39%
-24%

79. 79
N Engl J Med 2017; 377:644-657
CANVAS trial
-10%

80. 80Stroke. 2017;48:1218-1225
Empareg outcome trial
+24%

81. Take home message

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

83. In the CREDENCE trial of patients with type 2
diabetes and chronic kidney disease, canagliflozin was
associated with a 30% reduction in the risk of the
primary composite endpoint, comprising end-stage
kidney disease, doubling of serum creatinine, and renal
serum creatinine, and renal or cardiovascular death, as
Pts with highest risk for both CV and renal disease!!

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

85. Hemodynamic
Cana
ACEi/ARB
Cana
Cana
metabolic
For kidney protection the earlier, the better

86. 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

87. DOI: 10.1016/j.jacc.2020.05.037

89. Thank you for listening!!