2. Click to add title
2
• CKD and CVD: Accelerated HF, atherosclerosis and arteriosclerosis
Outline
3. Patients with CKD should be considered to be in the highest
risk category, ie, a CHD risk equivalent, for risk factor
management.
• KDOQI Clinical Practice Guidelines for Managing Dyslipidemias in
Chronic Kidney Disease
4. CRM, cardio-renal-metabolic; LV, left ventricular
Adapted from Dzau VJ et al.5
1. Sarafidis PA et al. J Cardiometab Syndr 2006;1:58; 2. Ronco C. Contrib Nephrol 2010;164:33; 3. Banerjee S and Panas R. Hellenic J Cardiol 2017;58:342;
4. Leon BM and Maddox TM. World J Diabetes 2015;6:1246; 5. Dzau VJ et al. Circulation 2006;114:2850
Diseases of the CRM systems share many of
the same risk factors1
4
Progression of interrelated diseases (T2D, CV disease, HF and CKD) can occur due to dysfunction
of the CRM systems, which, in turn, may lead to an increased risk of CV death2–4
= Diabetes and metabolic risk factors
= Kidney disease
= CV disease
PC-TW-102542
Bad metabolic memory
CKD HF CVD
5. Click to add title
5
Worse renal function with higher CAD and CV death
1. PLoS Med. 2007 Sep;4(9):e270. 2. Circulation. 2021 Mar 16;143(11):1157-1172.
Lower eGFR with higher risk of CVD mortality
及時護腎，維持eGFR>75
Lower eGFR with higher risk of coronary disease
及時護腎，維持eGFR>70
Keep GFR as normal as possible!!
6. 6
All-cause mortality risks were significantly higher across all levels
of estimated GFR, proteinuria for early DKD group
Early DKD had higher mortality
across all eGFR levels
Early DKD had higher mortality
across all levels of proteinuria
Wen CP, Chang CH et al. Kidney Int. 2017 Aug;92(2):388-396.
A total of 512,700 subjects were identified; among them, 27,455 (5.4%) had diabetes. One-third of those with
diabetes (9067 or 33.3%) had early DKD. Approximately 50,977 participants (9.9%) had early CKD without diabetes.
~2 fold risk ~2 fold risk
Keep albuminuria as normal as possible, too !!
7. - 7 -
CVD in patients with or without CKD
https://abdominalkey.com/cardiovascular-disease-in-chronic-kidney-disease/#bib15
Chapeter 82, Cardiovascular Disease in Chronic Kidney Disease
「腰子若壞，人生是黑白的；腰子若好，人生是彩色的」
8. Structural and Functional Changes in Human Kidneys
with Healthy Aging
8
JASN October 2017, 28 (10) 2838-2844
9. J Am Soc Nephrol 28: 1023–1039, 2017. doi: 10.1681/ASN.2016060666
Glomerular Hyperfiltration in Diabetes
9
13. 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.
Mean age~55y/o
14. First-Line therapy is metformin and comprehensive lifestyle
Indicators of high-risk or established
ASCVD, CKD, HF
Consider independently of baseline A1C,
Individualized A1C target, or metformin use
+ASCVD/
Indicators
of high risk
+HF +CKD
Compelling need to
minimize
hypoglycemia
Compelling need to
minimize weight gain
or promote weight
loss
Cost is a
major issue
If A1C above individualized target proceed as below
No
共病考量需先評估病患是否合併有 ASCVD (or high risk)，CKD，HF
在治療用藥上，就需要獨立於血糖控制的考量
1
2
Adapted from 2021 ADA guidelines
SGLT2i fits all, esp. for renal
protection!!
15. Click to add title
15
• Prevalence of kidney disease in patients with CVD
Outline
17. Click to add title
17
34% ACS patients suffered from CKD in Taiwan
CKD is defined as eGFR<60
Data from Taiwan Acute Coronary Syndrome Full Spectrum Registry (n=3183); Heart Vessels. 2015 Jul;30(4):441-50.
18. Click to add title
18
45% patients underwent PCI suffered from CKD in Taiwan
CKD was defined as eGFR<60
1394 patients who underwent PCI and 45.3% had CKD; 1676 patients treated with PCI and 45.8% had CKD
1. BMC Cardiovasc Disord. 2017 Sep 11;17(1):242. 2. Sci Rep . 2018 Dec 5;8(1):17673.
19. 2
19
Relative risks of 1-year
preserved RF vs Renal failure Ccr < 60)
Archives of Cardiovascular Disease (2015) 108, 554—562
20. Click to add title
20
CKD had additive effect on adverse long-term outcomes in
patients receiving PCI
CKD is defined as eGFR<60, n=1394
BMC Cardiovasc Disord. 2017 Sep 11;17(1):242.
21. Click to add title
21
CKD is important risk factor for AKI in patients with PCI
11.4倍
Int J Med Sci 2018; 15(5):528-535.
82,186 patients admitted for ACS and receiving
PCI from the Taiwan National Health Insurance
Research
22. 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
23. Click to add title
23
Incidence of heart failure after acute coronary syndromes
Am Heart J. 2013 Mar;165(3):379-85.e2.
Cumulative 1-year HF rates among STEMI, NSTEMI, and UA
24. Click to add title
24
Prevalence of HF in ACS patients with/without CKD
Medicina (Kaunas). 2020 Mar 8;56(3):118.
25. Click to add title
25
Association of renal function and all-cause mortality
in HF patients
All-cause mortality in patients with HF by eGFR
Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials
J Am Coll Cardiol. 2019 Dec, 74 (23) 2893–2904.
Death by cause in patients with HF by eGFR
及時護腎，維持eGFR>60
26. Nature Reviews Nephrology volume 15, pages159–175 (2019)
Uraemic cardiomyopathy is characterized by diastolic dysfunction and marked left ventricular
hypertrophy with profound ventricular fibrosis.
Treatments that are effective in other cardiomyopathic conditions such as antihypertensive
drugs improve clinical outcomes in uraemic cardiomyopathy only modestly at best.
27. Click to add title
27
hHF: heart failure hospitalizations
J Am Soc Nephrol. 2015 Mar;26(3):715-22.
HF increases the risk of ESRD
29. 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 ?
31. Levey AS, et al. Kidney Int. 2011;80:17-28
Save kidneys=effective primary and secondary prevention
Macro-DKD needs most intensive cardiorenal protection!!
32.
33. Click to add title
33
• Advantages of canagliflozin on SGLT 1&2 inhibitions
Outline
34. 34
MACE Reduction : Only for Secondary Prevention
Population
www.thelancet.com Published online November 10, 2018
http://dx.doi.org/10.1016/S0140-6736(18)32590-X
The p value for subgroup differences was 0.0501
6.5 7.2 4.2
36. 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.
36
more glucosuria &
natriuresis!!
38. Canagliflozin, dapagliflozin and empagliflozin
for treating type 2 diabetes: Network Meta-analysis 38
Health Technology Assessment, No. 21.2
HbA1c
BW
39. Canagliflozin, dapagliflozin and empagliflozin
for treating type 2 diabetes: Network Meta-analysis 39
Health Technology Assessment, No. 21.2
SBP
41. Prespecified Cox proportional-hazard regression analyses were performed for subgroups of patients with respect to
the primary outcome (first occurrence of death from CV causes, nonfatal MI, or nonfatal stroke). P values signify tests
of homogeneity for between-group differences with no adjustment for multiple testing. The percentages of patients
with a first primary outcome between the randomization date and the date of last follow-up are shown. There were
missing data for BMI in 5 patients in the liraglutide group and 4 in the placebo group and for the duration of diabetes
in 11 patients in the liraglutide group and 8 in the placebo group.
Presented at the American Diabetes Association 76th Scientific Sessions, Session 3-CT-SY24. June 13 2016, New Orleans, LA, USA.
Primary outcome: Subgroup analyses
LEADER trial: 81% CVD
CVD/CKDPrimary cohort with benefit
42. 42
CV risk 33% in DKD patient (stage III)
N Engl J Med 2016;374:311-22. DOI: 10.1056/NEJMoa1603827
43. Renal outcomes from CVOTs
REWIND, LEADER and SUSTAIN 6
*RRT is defined as either dialysis or renal transplantation
CI, confidence interval; eGFR, estimated glomerular filtration rate; ESRD, end stage renal disease
1. Gerstein HC et al. Lancet 2019; 394(10193):131–138; 2. Mann JFE et al. N Engl J Med 2017; 377(9):839–848; 3. Marso et al. N Engl J Med 2016; 375:1834-1844.
REWIND (Dulaglutide)1: Composite renal outcome
Macroalbuminuria, sustained ≥30% decline in eGFR, or new chronic
RRT*
Time from randomisation (years)
0 1 2 3 4 5 6
50
40
30
20
10
0
Cumulative
risk
(%)
HR: 0.85
(95% CI: 0.77; 0.93)
Dulaglutide: 848 events, placebo:
970 events
p=0.0004
Dulaglutide 1.5 mg
Placebo
SUSTAIN 6 (Semaglutide)3: Composite renal outcome
Macroalbuminuria, doubling of serum creatinine
or ESRD
0
2
4
6
8
10
0 8 16 24 32 40 48 56 64 72 80 88 96 104
Semaglutide
Placebo
HR 0.64 (0.46–0.88)
p=0.005
Time from randomisation (weeks)
LEADER (Liraglutide)2: Composite renal outcome
Macroalbuminuria, doubling of serum creatinine, ESRD or renal death
Time since randomisation (months)
Cumulative
risk
(%)
0 6 12 18 24 30 36 42 48 54
0
2
4
6
8
10
Cumulative
risk
(%)
HR: 0.78
95% CI (0.67–0.92)
p=0.003
10
8
6
4
2
0
0 6 12 18 24 30 36 42 48 54
Liraglutide
Placebo
SUSTAIN 6: 83% CVD
REWIND: 30% CVD LEADER: 81% CVD
15% 22% 36%
44. Time to categorical eGFR reduction
Post-hoc pooled analysis of LEADER AND SUSTAIN 6(Macro-DKD got most benefits?)
CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio.
Presented at the 56th European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Congress, 13–16 June 2019, Budapest, Hungary.
Reduction in
eGFR
Sema/lira
pooled (N)
Placebo pooled
(N)
HR
(95% CI)
p-value
Overall pooled population
30% 791 848 0.92 (0.84; 1.02) 0.1005
40% 378 432 0.86 (0.75; 0.99) 0.0386
50% 185 229 0.80 (0.66; 0.97) 0.0233
57% 121 135 0.89 (0.69; 1.13) 0.3423
eGFR ≥30 to
<60 mL/min/1.73 m2 and
micro-or macroalbuminuria
30% 151 196 0.65 (0.53; 0.81) <0.0001
40% 89 120 0.64 (0.48; 0.84) 0.0013
50% 51 78 0.57 (0.40; 0.81) 0.0017
57% 34 53 0.56 (0.37; 0.87) 0.0093
eGFR
≥60 mL/min/1.73 m2 or
normoalbuminuria
30% 579 591 0.99 (0.88; 1.10) 0.7982
40% 245 270 0.91 (0.76; 1.08) 0.2810
50% 101 118 0.86 (0.66; 1.12) 0.2598
57% 58 61 0.95 (0.67; 1.37) 0.7961
0.2 0.4 0.6 0.8 1 1.2 1.4
Favours placebo
Favours semaglutide/liraglutide
Semaglutide
Liraglutide
49. Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes
mellitus and chronic kidney disease: A systematic review and meta-analysis Diabetes
Obes Metab. 2019; 21: 1237– 1250.
53. (31.2%, BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs,
including a diuretic)
54. 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?
55. 55
More effective in
symptomatic HF!!
CANVAS: post hoc
Relative risk reduction of CV death and HHF
Diabetologia (2018) 61:2108–2117
62. Click to add title
62
• Save kidneys = effective primary and secondary preventions!!
Outline
63. J Am Soc Nephrol 28: 1023–1039, 2017. doi: 10.1681/ASN.2016060666
Glomerular Hyperfiltration in Diabetes
63
ARB yes/SGLT2i great!!
ARB No! but SGLT2i Yes!
64. N Engl J Med 2001; 345:870-878
Data from the IRMA2 Program BP 153/90
UAE 55 ug/min
Ccr 110 ml/min
65. JASN November 2019, 30 (11) 2229-2242;
Data from the CANVAS Program(65% CVD)
The earlier, the better!!
~3
~1
~1
66.
67. 67
Diabetes Ther. 2020 Dec 18. doi: 10.1007/s13300-020-00953-4. Online ahead of print
Estimated eGFR values used to project the delay in time to dialysis*
by treatment in the CREDENCE trial**
* eGFR of 10 ml/min/1.73 m2
** overlaid with observed data
RENNAL&IDNT
2-3 years
56
68. Renal Safety: CREDENCE
Number of participants
with an event, n
Canagliflozin
(N = 2200)
Placebo
(N = 2197)
Hazard ratio
(95% CI)
All renal-related AEs 290 388 0.71 (0.61–0.82)
Hyperkalemia 151 181 0.80 (0.65–1.00)
Acute kidney injury 86 98 0.85 (0.64–1.13)
Favors Canagliflozin Favors Placebo
0.5 1.0 2.0
Includes all treated participants through 30 days after last dose.
76. First-Line therapy is metformin and comprehensive lifestyle
Indicators of high-risk or established
ASCVD, CKD, HF
Consider independently of baseline A1C,
Individualized A1C target, or metformin use
+ASCVD/
Indicators
of high risk
+HF +CKD
Compelling need to
minimize
hypoglycemia
Compelling need to
minimize weight gain
or promote weight
loss
Cost is a
major issue
If A1C above individualized target proceed as below
No
共病考量需先評估病患是否合併有 ASCVD (or high risk)，CKD，HF
在治療用藥上，就需要獨立於血糖控制的考量
1
2
Adapted from 2021 ADA guidelines
Canagliflozin fits all !!
