Cardio-Renal Protection in T2DM

1. 醫師公會 2022.01.06
沐康診所 高偉斌醫師
Cardio-Renal Protection in T2DM

2. 高偉斌醫師
• 高醫大醫學士 M84
• 高醫大附院內科及心臟科訓練
• 內科專科醫師
• 心臟血管專科醫師
• 介入性治療專科醫師
• 重症專科醫師
• 糖尿病衛教學會 合格衛教師
• 高醫心臟內科 主治醫師
• 高醫心臟加護病房專責醫師
• 聖功醫院 心臟內科 主治醫師
• 糖尿病照護網品質卓越獎 107,108,109
沐康診所
• 2012.06~
• 高雄市三民區河堤路318號
• 心臟內科 高偉斌 醫師
• 胸腔內科 連啟惇 醫師
• 內分泌科 黃昱甄 醫師
• 糖尿病照護網 106~
• 樂康醫療群

3. 「臺灣糖尿病年鑑2019第2型糖尿病」
台灣新診斷糖尿病患每年16萬

4. Vascular Health and Risk Management 2017:13 43–54
DPP-4 inhibitor

5. Petersen C.
Analyse des Phloridzins.
Annales Academie Science Francaise
1835;15: 178.
https://oreo.blog/ringocenter/

6. T2DM
CVOT
CKD
HF
EMPA-REG CANVAS DECALRE
CREDENCE
2015 2016 2017 2018 2019 2020 2021
DAPA-HF
DAPA-CKD
EMPEROR-R EMPEROR-P
23% HHF↓
14% 3P MACE ↓
30% ↓ Pri
32% ↓ESRD
26% ↓ Pri
18% ↓ CV death
31%↓ Pri
27%↓ HHF
25% ↓Pri
14% ↓ 3P MACE
38% ↓ CV Death
EMPULSE CHIEF-HF
39% ↓ Pri
36% ↓ ESRD

7. Diabetes Care VOLUME 45 | SUPPLEMENT 1 | PAGES S1–S264
Standards of Medical Care in Diabetes—2022

8. FIRST-LINE THERAPY depends on
comorbidities,
patient-centered treatment factors,
including cost and assess, and management needs
and generally includes
metformin and comprehensive lifestyle modification

12. CKD and albuminuria
e.g. > 200mg/dl creatine
CKD without albuminuria
e.g eGFR < 60ml/min/1.73m2
SGLT2
Evidence of reducing CKD pression in CVOTs
GLP1-RA
proven CVD benefit
or
SGLT2
Primary evidence of reducing CKD progression
or

13. CKD and albuminuria
e.g. > 200mg/dl creatine
CKD without albuminuria
e.g eGFR < 60ml/min/1.73m2
SGLT2
proven CVD evidence
GLP1-RA
proven CVD benefit
either

15. ASCVD HF Progression of DKD
Empagliflozin
Canagliflozin
Empagliflozin
Canagliflozin
Dapagliflozin
Ertugliflozin
Canagliflozin
Empagliflozin
Dapagliflozin

17. Sodium-dependent glucose cotransporters
鈉依賴型葡萄糖共同運輸蛋白
SGLT1
• 小腸吸收葡萄糖及半乳糖
• 腎臟近曲小管葡萄糖回收 (10%)
SGLT2
• 腎臟近曲小管葡萄糖回收
(90%)
World J Gastroenterol 2006 March 21; 12(11):1657-1670 https://doi.org/10.1038/ s41569-020-0406-8

18. SGLT2/SGLT1 selectivity of main SGLT inhibitors
Drug Design, Development and Therapy 2017:11 2905–2919
CAN-SLK-20210611

19. 經由阻斷部分腸道SGLT1 Canagliflozin 提高GLP-1
J Clin Med Res. 2017;9(9):745-753

20. 21
Canagliflozin 增加GLP-1濃度
Endocr J. 2017 Sep 30;64(9):923-931
Placebo
Placebo + CAN 100
Placebo + CAN 100 + TEN 25

21. 22
Canagliflozin Increases Postprandial Total Glucagon-Like Peptide 1 Levels
in the Absence of a-Glucosidase Inhibitor Therapy in Patients with Type 2
Diabetes
Diabetes Ther (2019) 10:2045–2059

22. Cardiovascular Drugs and Therapy
https://doi.org/10.1007/s10557-021-07291-y

23. Int. J. Mol. Sci. 2021, 22, 9852. https://doi.org/10.3390/ijms22189852

24. Int. J. Mol. Sci. 2021, 22, 9852. https://doi.org/10.3390/ijms22189852

25. Diabetes Care 2015;38:355–364 | DOI: 10.2337/dc13-2762

26. Canagliflozin長期降血糖效果優於Glimepiride
空腹血糖
治療一年後
空腹血糖Cana優於ＳＵ
Diabetes Care 2015;38:355–364 | DOI: 10.2337/dc13-2762

27. Canagliflozin provided durable glycemic improvements compared with glimepiride
canagliflozin長期的降糖效果優於Glimepiride
Diabetes Care 2015;38:355–364 | DOI: 10.2337/dc13-2762
治療一年後
A1C與SU相等
治療2年後
Cana A1C控制優於SU
A1C變化

28. Canagliflozin長期降血糖效果優於Glimepiride
Canagliflozin減少患者體重且降低血壓
體重
變化
體
重
5.1
%
血壓變化
收縮壓
-3.7
mmHg
Diabetes Care 2015;38:355–364 | DOI: 10.2337/dc13-2762

29. eGFR初期下降後回升之後腎功能保全
Diabetes Care 2015;38:355–364 | DOI: 10.2337/dc13-2762

30. 最常見的副作用為Genital infection
Diabetes Care 2015;38:355–364 | DOI: 10.2337/dc13-2762

31. CANA improved insulin resistance and decreased
visceral fat mass in Japanese patients with T2DM.
diabetes research and clinical practice 149 (2019) 140–146
Glucose
infusion
rate

32. Canagliflozin reduced body mass, fat mass and hepatic fat
content with- out significantly reducing muscle mass
J Diabetes Investig
2019; 10: 1004– 1011

33. Sezai et al. Cardiovasc Diabetol (2019) 18:76
https://doi.org/10.1186/s12933-019-0877-2

34. N Engl J Med 2017;377:644-57.
DOI: 10.1056/NEJMoa1611925

35. Inclusion
• T2DM with A1c ≥7.0% to ≤10.5%
• History or high risk of cardiovascular disease
• Age ≥30 y/o + documented symptomatic ASCVD
• Age ≥50 y/o with >= 2 risk
• duration of T2DM > = 10years or more,
• SBP >140 mmHg & under BP lowering treatment
• smoker,
• microalbuminuria or macroalbuminuria
• HDL < 39mg/dl
• eGFR > 30 ml/min/1.73m2 BSA

37. N Engl J Med 2017;377:644-57.DOI: 10.1056/NEJMoa1611925
A1C 體重
SBP DBP
–0.58%
–1.60 kg
–3.93 mm Hg
–1.39 mm Hg

38. Canagliflozin n= 5795 Placebo n = 4347 HR
Primary Endpoint 26.0 31.5 0.86 (0.75-0.97)
• CV death 11.6 12.8
• Nonfatal MI 9.7 11.6
• Nonfatal stroke 7.1 8.4
no. of participants per 1000 patient-yr
Canagliflozin
14%
3P-MACE
P=0.02 for superiority
N Engl J Med 2017;377:644-57.
DOI: 10.1056/NEJMoa161192

39. N Engl J Med 2017;377:644-57.DOI: 10.1056/NEJMoa1611925

40. SGLT2 inhibitor CVOT
3P MACE : Primary Endpoint
EMPA-REG CANVUS
DECLARE TIMI 58
14%
P=0.04
14%
P=0.02
7%
P=0.17

41. Hazard Ratio (95% CI)
0.60 (0.47–0.77)
0.73 (0.67–0.79)
0.78 (0.67–0.91)
0.67 (0.52–0.87)
CANA
N=5795
Placebo
N=4347
HHF 5.5 8.7
CV death
+HHF
16.3 20.8
⇡ albuminuria
89.4 128.7
eGFR↓ 40%,
replacement
renal death
5.5 9.0
no. of participants per 1000 patient-y
N Engl J Med 2017;377:644-57.
DOI: 10.1056/NEJMoa161192 Canagliflozin Better. Placebo Better
Canagliflozin於心血管高風險族群減少心衰竭及腎功能惡化

42. Canagliflozin在CANVUS研究降低心衰竭住院率33%
N Engl J Med 2017;377:644-57.DOI: 10.1056/NEJMoa1611925
心臟衰竭住院率 33%

44. Canagliflozin在CANVUS研究改善蛋白尿及腎臟預後
N Engl J Med 2017;377:644-57.DOI: 10.1056/NEJMoa1611925
14
%

45. KDIGO 2012
Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease
尿蛋白及過濾率
預測
慢性腎病病患
腎功能預後

46. 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

47. Ｍacroalbuminuria (>300) 警示腎絲球過濾率以每年10ml/min快速下降
-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 ?

48. 病患的 eGFR 與蛋白尿跟
all-cause death與CV mortality呈正相關
23. Lancet. 2010 Jun 12;375(9731):2073-81.
Early intervention is important to reduce mortality
≥300 mg/g
30-299 mg/g
<30 mg/g

49. Clin J Am Soc Nephrol 2: 581-590, 2007.
doi: 10.2215/CJN.03190906

50. TIMI Risk Score for Heart Failure in Diabetes (TRS-HFDM) in the Derivation Cohort
• 0 points (low risk)、1 point (intermediate risk)、2 points (high risk)、≥3 points (very high risk)
Circulation. 2019;140:1569–1577
eGFR <60 mL·min−1·1.73 m−2 represents chronic kidney disease. Urine albumin-to-creatinine ratio 30–300 mg/g represents moderately increased albuminuria, whereas >300 mg/g represents severely increased albuminuria. eGFR indicates
estimated glomerular filtration rate; HR, hazard ratio; TIMI, Thrombolysis in Myocardial Infarction; and TRS-HFDM, TIMI Risk Score for Heart Failure in Diabetes.
Circulation. 2019;140:1569–1577. DOI: 10.1161/CIRCULATIONAHA.119.042685
U-ACR也是心衰竭的重大危險因子

51. 政府建立公開資訊 糖尿病照護盡責指標

52. 現
實
很
蒼
白
～

53. Clin J Am Soc Nephrol 2: 581-590, 2007.
doi: 10.2215/CJN.03190906
U-ACR預測心血管疾病風險與心臟超音波相近
但我們以前只有ACEI/ARB藥物治療

54. 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
N Engl J Med 2001; 345:861-869

55. primary composite end point of a doubling of the base-line se-
rum creatinine concentration, the development of end- stage
renal disease, or death from any cause
N Engl J Med 2001;345:851-60
20%

57. •>= 30 y/o (63y/o)
•T2DM (A1C 6.5-12%) ( Duration 16Y)
•Chronic kidney disease (CKD)
•E-GFR : 30 to <90 ml /min/1.73m2 of BSA（56 )
•Albuminuria: u-ACR: >300 to 5000 (927)

58. Supplement to: Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N
Engl J Med 2019;380:2295-306. DOI: 10.1056/NEJMoa1811744

59. A1C – 0.11% BW -0.88kgw
SBP -2.38mmHg DBP - 1.44mmHg
Supplement to: Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N
Engl J Med 2019;380:2295-306. DOI: 10.1056/NEJMoa1811744

60. ESRD 32%

62. Presented at the 79th Scientific Sessions of the American Diabetes Association;
June 11, 2019; San Francisco, CA.
Acute and Long-term Effects on eGFR
-20
-18
-16
-14
-12
-10
-8
-6
-4
-2
0
0 26 52 78 104 130 156 182
LS
Mean
Change
(±SE)
in
eGFR
(mL/min/1.73
m
2
)
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
LS
mean
change
(
±
SE)
in
eGFR
(mL/min/1.73
m
2
)
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.

63. Diabetes Ther (2021) 12:499–508

65. 2021/3/1
DKD 治療新紀元 Canagliflozin
新適應症
糖尿病腎病變
巨量蛋白尿期
>300mg/gm
eGFR從>45下修至
>30mL/min/1.73 m2
Ref. TFDA Canaglu仿單資料
U-ACR

66. Cana Placebo HR P
CV Death + HHF 179 /2202 253 /2199 0.69 < 0.001
3P MACE 217 /2202 269 /2199 0.80 0.01
HHF 89 /2202 141 /2199 0.61 < 0.001
N Engl J Med 2019;380:2295-306.

67. CREDENCE is the first study to show positive of
CV primary prevention
71
Circulation. 2019 Aug 27; 140(9): 739–750.
CV death and hHF
-34% -15%
-26% -32%
Primary prevention Secondary prevention
Secondary prevention
Primary prevention
MACE: CV death, nonfatal MI, or nonfatal
stroke

68. N Engl J Med 2019;380:2295-306.

69. N Engl J Med 2019;380:2295-306.

70. Early Change in Albuminuria with Canagliflozin Predicts Kidney and
Cardiovascular Outcomes: A Post Hoc Analysis from the CREDENCE Trial
JASN 31: 2925–2936, 2020

71. Early Change in Albuminuria with Canagliflozin Predicts Kidney and
Cardiovascular Outcomes: A Post Hoc Analysis from the CREDENCE Trial
JASN 31: 2925–2936, 2020
(A) kidney composite outcome. (B) MACE outcome (C) HHF/CV death outcome

72. Effects of canagliflozin on anaemia in patients with type 2
diabetes and chronic kidney disease: a post-hoc analysis
from the CREDENCE trial
Lancet Diabetes Endocrinol 2020; 8: 903–14

73. Canagliflozin Improves Erythropoiesis in Diabetes
Patients with Anemia of Chronic Kidney Disease
DIABETES TECHNOLOGY & THERAPEUTICS
Volume 21, Number 12, 2019 DOI: 10.1089/dia.2019.0212

75. Journal of Cardiology 71 (2018) 471–476

76. Canagliflozin
T2DM +CV disease/Risk : 3-P MACE (MI , stroke CV death )
T2DM + DKD : ESRD, CV death, HHF
JACC VOL. 76, NO. 9; 2020:1117–45
2020 Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk
Reduction in Patients With Type 2 Diabetes: A Report of the American College of
Cardiology Solution Set Oversight Committee

77. JACC VOL. 76, NO. 9, 2020 SEPTEMBER 1, 2020:1117–45
禁忌症：
懷孕或哺乳
eGFR < 30ml/min
• 常規手術,至少術前三天起應停藥，避免酮酸血症
• 當血糖控制良好或有低血糖病史時起始SGLT inh應減輕或停止SU或Glinide ，及考慮減少20%的胰島素劑量
• 利尿劑在顧慮intravascular volume contraction時,可考慮停用或減少利尿劑
• 在截肢病史,周邊神經病變,嚴重周邊血管病變,糖尿病足潰瘍,及軟組織感染患者使用應特別小心
• 注意陰部黴菌感染,泌尿道感染
• 注意Euglycemic diabetic ketoacidosis
• 注意下肢潰瘍及軟組織感染

78. 衛生福利部中央健保署藥品給付規定

79. Diabetes Ther (2021) 12:313–328
Cost-Effectiveness of Canagliflozin Added to Standard of Care for
Treating Diabetic Kidney Disease (DKD) in Patients with Type 2 Diabetes
Mellitus (T2DM) in England: Estimates Using the CREDEM-DKD Model

80. Canagliflozin DKD 仿單 2021/3/1生效
eGFR
(mL/min/1.73 m2)
建議劑量
albuminuria≦300mg/day
(適應症 : T2DM)
albuminuria ˃300 mg/day
(適應症 : T2DM、DKD)
eGFR ³30 成人每日一次 Canagliflozin 100 mg
eGFR <30 不建議使用
透析病人 禁止投藥
適應症 : 1. 第二型糖尿病
2. 糖尿病腎病變(巨量蛋白尿期)

81. Take Home Massage -
改變糖尿病患的未來 ！Yes, We Can ！
•Ｕ-ACR 可預測糖尿病患腎臟,心臟疾病,及死亡率
•Canagliflozin 改善T2DM DKD病患心腎預後
• 大幅減少血液透析風險
• 減緩腎絲球過濾率衰退速度
• 大幅減少因心衰竭住院
• 有意義減少心血管相關死亡
測！
開！