1130525--家醫計畫2.0糖尿病照護研討會-社團法人高雄市醫師公會.pdf

家庭醫師整合性照護計畫 2.0
暨代謝症候群防治計畫
之介紹與分享元成診所
陳登旺醫師
2024/05/25(六）

2
OUTLINE
家庭醫師整合性照護計畫
家庭醫師整合性照護計畫 1.0 VS 2.0
代謝症候群防治計畫

113年家庭醫師整合性照護計畫說明及問答集
感謝中央健康保險署高屏業務組及陳宏麟醫師提供

4
921震災後衛生醫療重建工作
的經驗，讓我對於結合身體、心
理與社會面向的「全人健康照護」
有更深入的體會。如果要落實照
護民眾身心健康，不能只依賴醫
師，必須將其他醫療專業及健康
相關人員組織起來，形成健康支
持網絡，營造支持國民健康的環
境，鼓勵民眾負起自我健康照護
的責任才能克竟全功，社區醫療
群即是組織「健康社區支持網
絡」,協助民眾提高健康照護技
能最重要的一股力量。
2006/11/01·作者/林芝安·出處/康健雜誌第96期
故台大醫學院院長謝博生教授圖片來源 / 蕭
世英

最初期家庭醫師整合性照護計畫
民國92年
以高屏區為例 :
高雄市:3群
高雄縣:1群
屏東縣:1群

計畫目的
一:建立家庭醫師制度，提供民眾周全性、協調性與持續
性的醫療照護，同時提供家庭與社區健康服務，以落實全
人、全家、全社區的整合照護。
二:以民眾健康為導向，建立以病人為中心、家庭為核心、
社區為範疇的健康照護觀念，提升醫療服務品質。
三:為全民健康保險法實施家庭責任醫師制度奠定基礎。
鼓勵民眾負起自我健康照護的責任

12
高齡長期共病多

13

*家醫2.0醫療群診所年度結束前需完成相關受訓課程
*年度已獲 P4P品質獎勵金之個案不重複給付

家醫計畫1.0VS 2.0有三大差異
1:DM/DKD/CKD照護費提升
DM/CKD照顧良好 : 增加250元DKD照顧良好 :增加750元
3:合乎三條件 :績效獎勵費 550點:保障1點一元
A.評核指標分數 90分以上
B.「VC-AE」>275元/人
C.醫療群內每一醫師均完成家醫2.0課程
2:特定疾病會員控制良好或進步 VPN 自動抓資料
且同一會員可重複計算

1.無慢性病
學習、了解照護慢性病 (DKD修滿8學分)
與群內其他有慢性病診所一起努力
家醫1.0VS 家醫2.0
2.有慢性病患但未加入 DM或CKD共照網:
照顧好就有機會拿獎勵金也會增加診所競爭力
3.已加入CKD未加入DM共照網:
考慮醫護加入共照網->大幅增加診所照護品質、競爭力
DM人數50以上150以下:考慮聘請兼職營養衛教師
DM人數150人以上:考慮聘請專職營養衛教師

4.已加入DM照護未加入CKD OR DKD
或已有DM照護及收案 CKD但未合併成 DKD
補齊學分盡速兩者都參加，盡速合併管理成DKD照護，
診所效益加乘 !
家醫1.0VS 家醫2.0
5.已有DM、CKD、DKD照護及收案
加強品質管理得到更多獎勵金
協助其他診所，讓更多民眾接受良好照護
走入社區 :宣導正確醫療觀念
強化民眾自我照護能力
提供全人、全家、全社區的健康照護

全民健保代謝症候群防治計畫

113年新陳代謝防治計畫說明及問答
(感謝陳宏麟醫師提供 )

預防重於治療 :但一直被忽略
29
鶡冠子·卷下·世賢第十六》
魏文王之問扁鵲耶？
曰：「子昆弟三人其孰最善為醫？」
扁鵲曰：「長兄最善，中兄次之，扁鵲最為下。」
魏文侯曰：「可得聞邪？」
扁鵲曰：「長兄於病視神，未有形而除之，故名不出於家。
中兄治病，其在毫毛，故名不出於閭。若扁鵲者，鑱血脈，
投毒藥，副肌膚，閒而名出聞於諸侯。」

健康
疾病前期 (亞健康)
疾病發生

真的健康嗎 ?
31
50歲男性:無三高家族史，無慢性病，有規則運動
體脂率： 20% ，不喝含糖飲料
空腹血糖:89
糖化血色素 5.7

32

33

改變不健康的飲食和生活型態是最基本的
六大營養素，熱量計算
醣類計算、蛋白質、脂肪
規律的運動
不斷教育 , 從小就有這些觀念，落實
執行
肥胖、糖尿病、高血壓、中風、心肌梗塞 …一定大
大減少
預防慢性病怎麼做？

收案經驗
收案來源:
1:門診慢性病患
2:肥胖(尤其“中廣”病患)
3:有抽血報告病患
4:發揮福爾摩斯精神 !!
越懂得分享，越是有成就

初收案注意事項
1：年齡一定要 20到64歲有健保民眾
2：六項一定要有三項符合規定或者糖化血
色素5.7~6.4%(90天內報告均可 )
3：至少有 AC，CHO，TG，HDL四項數據，
VPN才可以完成輸入 (輸入完成才可申報 )
4:DM，DKD，透析病患不可收案，
CKD 可以

第一年:2000點第二年:1100點
不含檢驗費

追蹤及年度案規則：
1：p7501收案後70天就可收p7502(可以用電話 )
2：在收p7501時最好能夠約病人第 3個月或第6個月回來
抽血追蹤，年度要收 P7503才符合規定。
3：收P7503定要有三個月內抽血資料 (但不可以與 P7502
同一筆)至少需含AC、TG、HDL
4:P7501 or P7503仍需病患親自門診才能收案，但當天單
純執行代謝收案就醫序號請以 MSPT 掛號，無部份負擔！
5：以HBa1C異常收案者每次檢驗輸入還是得須有
HBa1C跟AC（但如在168天內驗HBa1C是否會被核刪？
需注意！也可診所自行吸收！）

113年代謝症候群防治計畫變革
112年原內容 113年修訂內容
VPN資料登錄必填約50欄位調降至26個
資訊系統優化不知是否異常狀況
11303開始申報後，每個月會產
生異常報表。
年度評估 (P7503C)
(追蹤管理費 3次
(含)(P7502C)以上且
收案時檢驗異常項目
一年內至少追蹤一次 )
檢驗異常項目未追蹤， VPN仍
可輸入
檢驗異常項目未追蹤， VPN不
可輸入

積極個案健康指導及衛教
•強調改善危險因子的重要性
•血壓量測之 722 指導
•提供適當介入 (營養、運動衛教 )
•減少危險因子改善預後
有錢好辦事
用錢辦好事

家庭醫師強化疾病早期前端管理
資料來源 :國民健康署

54
執行率7.06 %0.2205億/ 3.08億
93%的費用就消失了

未加入診所可能考量
1：對健保局的不滿：消極抵制健保局推動的方案
學分課程一直增加 ,很容易達標（就當修執照學分）
收案：規則了解其實收案簡單， VPN:簡化很多，很容易上手了！
會有健康諮詢的民眾
醫療群診所合作
學習慢性病照顧是未來的趨勢
2：診所以急性病為主很少慢性病患
此方案主要為國民健康署所推動，經費也來自於國民健康署
大家努力下或可減少許多慢性病、失能，點值反而會增加
3：參加還需認證，且收案規則複雜 VPN輸入耗人力

健保台灣的驕傲 !
58
治病!
致病!
論量計酬

台灣糖尿病之父林瑞祥教授曾說 :
控制好一個糖尿病病人等於挽救了一個家庭！
同樣的
讓一個民眾免於慢性病，避免失能、健康老化
不只挽救一個家庭也可提升台灣醫療體系 !
更可以讓自己“義”“利”兼得！

60
THANKS FOR YOUR ATTENTION!

113年家庭醫師整合性照護計畫
說明及問答集
感謝中央健康保險署高屏業務組
及陳宏麟醫師提供
113年新陳代謝防治計畫說明及
問答
(感謝陳宏麟醫師提供 )

Management of Patients
with Diabetes and
Chronic Kidney Disease
建工萬川診所
林昆德醫師

Outline
Introduction of Chronic kidney disease (CKD)
Interaction between diabetes and CKD
Goals of Care
Challenges in managing patients with diabetes and CKD
Postprandial glucose in CKD
Premixed insulin in managing patients with diabetes and CKD
New co-formulation IDeg-Asp in managing diabetes with CKD

Introduction of
Chronic kidney disease (CKD)
3

CKD is defined as GFR <60 mL/min per 1.73 m
2
or
markers of kidney damage, or both, of at least
3 months duration
Webster AC, et al. Lancet. 2017 Mar 25;389(10075):1238 -1252.
CKD, chronic kidney disease; GFR, glomerular filtration rate
Criteria of CKD, according to international guidelines
Either one, or both, of the following two criteria for at least 3 months:
GFR <60mL/min per 1.73m²
(categories: G3a-5)
Markers of kidney damage (1 or more):
Albuminuria
(albumin: creatinine ratio
[ACR] ≥30mg/g)
Urinary sediment
abnormality
Electrolyte or other
abnormality due to
tubular disorder
Abnormalities on
histology
Structural
abnormalities detected
by imaging
History of a kidney
transplantation

Persistent albuminuria categories
A1 A2 A3
Normal to mildly increased
Moderately
increased
Severely increased
<30 mg/g
<3 mg/mmol
30-300 mg/g
3-30 mg/mmol
>300 mg/g
>30 mg/mmol
GFR category
(ml/min per 1.73 m
2
)
Description and range
G1 Normal or high ≥90
Low risk
Moderately
increased risk
High risk
G2 Mildly to decreased 60-89
G3a Mildly to moderately decreased 45-59 Moderately increased risk High risk
G3b Moderately to severely decreased 30-44 High risk
Very high riskG4 Severely decreased 15-29
G5 Kidney failure <15
CKD is classified based on CGA, and can
progress to ESRD
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int. 2022 Nov;102(5S):S1-S127.
Green, low risk (if no other markers of kidney disease, no CKD); yellow, moderately increased risk; orange, high risk; red, veryhigh risk.
Prognosis of CKD by GFR and albuminuria category: KDIGO 2012
CKD, chronic kidney disease; CGA, Cause, GFR category (G1 –G5), and Albuminuria category (A1–A3); ESRD, End Stage Renal Disease;GFR,glomerular filtration rate; KDIGO, Kidney
Disease: Improving Global Outcomes
CKD is classified based on CGA
C G A
Cause
GFR category
(G1–G5)
Albuminuria category
(A1–A3)

CKD is common among Taiwan adults but
many are unaware of their condition
1. Tsai MH, et al. Nephron. 2018;140(3):175-184. 2. Webster AC, et al. Lancet. 2017 Mar 25;389(10075):1238 -1252.
CKD, chronic kidney disease; PY, person-years
Sign and symptom of CKD
2
Prevalence and incidence of CKD
1
The Keelung Community-based Integrated Screening (KCIS)
program from 1999-2009
Many people are
asymptomatic
Present after
chance findings from
screening tests,
or
until the advanced
stages
15.46
9.06
0
5
10
15
20
25
CKD
stage 1-5
CKD
stage 3-5
Prevalence (%)
27.21
16.89
0
5
10
15
20
25
30
35
CKD
stage 1-5
CKD
stage 3-5
Incidence (per 1,000 PY)
Prevalence Incidence

Taiwan has relative high disease burden of
CKD worldwide
GBD Chronic Kidney Disease Collaboration. Lancet. 2020 Feb 29;395(10225):709 -733.
CKD, chronic kidney disease; DALY, disability-adjusted life-year.
Age-standardized rate of DALYs for chronic kidney disease in 2017
Age-standardized DALY rate
per 100,000 population
100-199
200-299
300-399
400-499
500-999
≥1500
1000-1499
400-499

3,317
2,529
2,138
1,972
1,824
1,689
1,673
1,558
1,485
1,337
1,314
1,295
1,284
1,279
1,258
1,237
1,235
1,209
1,183
1,079
1,078
1,068
1,050
990
968
968
961
958
953
950
936
932
932
916
904
865
854
833
806
800
790
754
751
751
750
720
670
661
659
635
624
624
593
541
512
422
319
300
211
206
189
178
119
05001,0001,5002,0002,5003,0003,500
Romania
Chile
Brunei
Indonesia
United States
Colombia
Bosnia and Herzegovina
Hungary
ESRDprevalence
per million population/year
Kuwait
Singapore
Taiwan
Spain
Rep. of Korea
Hong Kong
New Zealand
Japan
Portugal
Belgium, Dutch-sp.
Belgium, French-sp.
Jalisco (Mexico)
Brazil
Thailand
Country
Canada
Qatar
Turkey
Denmark
Malaysia
Argentina
France
Greece
Finland
Israel
Austria
Bangladesh
Estonia
Uruguay
Czech Republic
Italy
Netherlands
Australia
kazakhstan
Sweden
Bulgaria
Iran
United Kingdom^
Switzerland
South Africa
Norway
Scotland
Poland
Serbia
Macedonia
Lithuania
Saudi Arabia
Egypt
Iceland
Morocco
Latvia
Albania
Russia
Philippines
Ukraine
Oman
476
411
393
378
338
319
290
286
261
227
227
227
223
197
194
194
188
182
180
179
165
162
160
159
158
156
154
153
152
147
144
144
140
135
131
125
121
121
119
119
118
115
115
115
114
112
112
108
105
103
99
95
87
80
77
73
57
56
47
28
26
0 100 200 300 400 500
Finland
Turkey
Country
Jalisco (Mexico)
Sweden
Thailand
South Africa
Argentina
ESRDincidence
per million population/year
New Zealand
Malaysia
Taiwan
Ukraine
Iceland
Spain
Brunei
Colombia
Serbia
United States
Philippines
Singapore
Japan
Rep. of Korea
Greece
Portugal
Chile
Czech Republic
Hungary
Canada
Brazil
Israel
Norway
Bosnia and Herzegovina
Belgium, French-sp.
Italy
Belgium, Dutch-sp.
Morocco
France
Poland
Hong Kong
Romania
Uruguay
Indonesia
Denmark
Australia
Bulgaria
Scotland
Macedonia
Saudi Arabia
Austria
Kuwait
Lithuania
Qatar
United Kingdom^
Iran
Netherlands
Switzerland
Estonia
Albania
Laatvia
Russia
Egypt
Bangladesh
Taiwan has the highest prevalence and
incidence of ESRD in the world in 2017
Wang AY, et al. Kidney Int Rep. 2019 Sep 23;4(11):1523 -1537.
Prevalence rate
*
Incidence rate
*
*Unknown for China where data are available only for HD
ESRD, End Stage Renal Disease
Highest in the world
Incidence
476
per million
population/year
Prevalence
3,317
per million
population/year

DM is the leading cause of CKD and ESRD
1. Centers for Disease Control and Prevention.Chronic Kidney Disease in the United States, 2021. 2. Wang JS, et al. J Diabetes Investig. 2021 Dec;12(12):2112-2123. 3. 2020 台灣腎
病年報.
9
BP, blood pressure; CKD, chronic kidney disease; DM, diabetes mellitus; ESRD, End Stage Renal Disease
Reported causes of new cases of ESRDRisk factors for developing CKD
1
Most common causes
39.0%
26.0%
15.0%
5.0%
15.0%
Diabetes
HBP
Glomerulonephritis
Other cause*
Unknown cause
High BP
Heart disease
Obesity
Family history
of CKD
Inherited
kidney disorder
Past damage to
the kidneys
Older age
N=785,883
(all ages, 2018)
US Renal Data System
Diabetes
Other causes
United States
1
Diabetic
kidney disease
A primary leading cause
of ESRD
2
* Included polycystic kidney disease, among other causes
Taiwan
2,3
46.2%
Diabetes
Diabetes predominated
the incidence of ESRD
New cases of ESRD in 2018
3

Prevalence of CKD in diabetes is high
worldwide and in Taiwan
1. Centers for Disease Control and Prevention.Chronic Kidney Disease in the United States, 2021. 2. Lin YC, et al. J Formos Med Assoc. 2018 Aug;117(8):662-675.
BP, blood pressure; CKD, chronic kidney disease; DM, diabetes mellitus; ESRD, end-stage renal disease
Prevalence of CKD with DM in Taiwan
2
Prevalence of CKD with DM in US
1
Hyperglycemia Kidney disease May have CKD
1
Data from The Bureau of Health Promotion Annual Report
in 2011
1/5
9.5%
15.4%
in patients
with DM
Adults with DM Adults with high BP
1/3

DKD usually occurs in patients with T1DM and T 2DM
without long-termadequate glycemic control
1
1.LinYC, et al. J Formos Med Assoc. 2018 Aug;117(8):662-675. 2. Wang JS, et al. J Diabetes Investig. 2021 Dec;12(12):2112-2123. 3. Anders HJ, et al. Nat Rev Nephrol. 2018
Jun;14(6):361-377.4. Alicic RZ, et al. Clin J Am Soc Nephrol. 2017 Dec 7;12(12):2032-2045.
CKD, chronic kidney disease; DKD, diabetic kidney disease; DM, diabetes mellitus; ESRD, end-stage renal disease; GFR, glomerular filtration rate; NDKD, concomitant nondiabetic kidney disease;
T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus
Duration of diabetes, in years, is presented on thehorizontal axis
4
.
*
Kidney complications: anemia, bone and mineral metabolism, retinopathy, and neuropathy.
CKD and DM
3
DKD is classified as moderate -to-severe CKD
2
GFR <60 mL/min per 1.73m²
DKD
Diabetes-related
causes of CKD
NDKD
Combinations
The Conceptual model of the natural history of DKD
4
Diagnosis
Years
2 5 10 20 30
Hyperglycemia
Cellular injury Mesangial expansion, glomerulosclerosis, tubulointerstitial fibrosis and inflammation
Microalbuminuria Macroalbuminuria
GFR Normal Low ESRDHigh
Hypertension
Cardiovascular disease, infections, death
Kidney complications
*

Patients with kidney failure have high symptom
burden affecting nearly all body systems
Kalantar-Zadeh K, et al. Nat Rev Nephrol. 2022 Mar;18(3):185-198.
Early-stage CKD:stages 1 to 3a
eGFR>45 ml/min/1.73 m
2
Advanced CKD :stages 4
eGFR <30 ml/min/1.73 m
2
Kidney failure (ESRD):stages 5
The burden of unpleasant symptoms across progressive stages of chronic kidney disease
Declining GFR Emerging Symptoms Declining RRF
Worsening
Uraemia
Worsening
Comorbidities
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GFR, glomerular filtration rate; RRF, residual renal function
Adapted from figure 1.
Stage 1-2 Stage 5, 5D and 5TStage 4Stage 3
Worsening uraemicsymptoms
•Cognitive dysfunction
•Anorexia
•Sexual dysfunction
Mild symptoms and
those relating to
underlying
comorbidities
•Sleep disorders
•Facial or peripheral
oedema
Variable symptoms
•Anxiety
•Depression
•Worsening oedema
•Constipation
More severe symptoms
•Fluid overload
•Pruritus
•Fatigue
•Muscle cramps
•Restless legs
•Cognitive dysfunction
•Nausea and vomiting
Symptoms deterioration
•Cardiopulmonary symptoms
•Gastrointestinal symptoms
•Bleeding diatheses
•Worsening pruritus
Increasing burden of uraemicsymptoms

疾病別名稱
醫療費用
（億元
*
）
就醫人數
（萬人）
平均每人
就醫費用
（元）
慢性腎臟疾病 533.16 39.7 134,157
第2型糖尿病 309.60 153.6 20,150
齒齦炎及牙周疾病 180.03 906.1 1,987
齲齒 166.46 577.9 2,880
本態性（原發性）高血壓 140.27 179.2 7,829
來院接受抗腫瘤治療
†
134.05 7.7 173,783
呼吸衰竭 125.16 4.1 302,361
慢性缺血性心臟病 122.66 38.2 32,083
思覺失調症 115.09 10.6 108,473
支氣管及肺惡性腫瘤 110.12 6 183,000
Diabetes accounts for more than 40% of
new cases of ESRD in Taiwan
1
1.2020 台灣腎病年報 .2.中國時報 .10大燒錢國病出爐！慢性腎病年耗 533億奪第一 . https://www.chinatimes.com/newspapers/20200712001388 -260114?chdtv.Accessed 14Jun2022.
2019年十大燒錢疾病
2
十大燒錢國病出爐！慢性腎病年耗 533 億奪第一
2
ESRD, end-stage renal disease
*
費用以健保點值 1 點1 元計算
†各種癌症治療，例如放、化療或免疫療法、緩和照護等

Interaction between diabetes
and CKD
14CKD, chronic kidney disease

CKD is associated with disturbances of glucose
metabolism including insulin resistance and glucose
intolerance
Williams ME, Garg R. Am J Kidney Dis. 2014 Feb;63(2 Suppl 2):S22 -38.
Several factors contribute to hyperglycemia, which may coexist with hypoglycemia
Overview of glucose/insulin homeostasis in CKD
CKD, chronic kidney disease
Decreased kidney function
Deficient
catecholamine
release
Lower renal insulin
degradation
Uremic toxins
Secondary
hyperparathyroidism
Decreased renal
gluconeogenesis
Uremic malnutrition
Decreased
insulin clearance
Lower hepatic
insulin degradation
Increased
insulin resistance
Decreased
insulin production
Glycemic
dysregulation
Hypoglycemia Hyperglycemia
Muscle protein
breakdown
Glucose load
from dialysate
Peritonealdialysis
Hemodialysis
Mechanical effects
of filling volume
Loss of appetite
Low
1,25(OH)
2Vitamin D

Kidney disease predominantly accounts for the
increased mortality observed in T2DM
Afkarian M, et al. J Am Soc Nephrol. 2013 Feb;24(2):302-8.
Absolute differences in mortality risk were estimated using linear regression and were adjusted for age, sex, and race. Standardized 10-year all-cause cumulative incidences were estimated for the mean levels of the
covariates in the study population.
10-year cumulative mortality in T2DM by kidney disease manifestation
GFR, glomerular filtration rate; NHANES, Third National Health and Nutrition Examination Survey; T2DM, type 2 diabetes mellitus
4.1%
17.8%
23.9%
47.0%
Standardized ten
-
year
cumulative incidence of
mortality
0
10
20
30
40
50
60
70
No
kidney disease
Albuminuria Impaired GFR
Albuminuria &
Impaired GFR
Background mortality
In persons without diabetes or
kidney disease (reference group)
Excess mortality
Above the reference group
15,046 participants in the NHANES III

Diabetes is associated with increased mortality
in patients on dialysis in Taiwan
The dialytic patients with diabetes have higher mortality than those without diabetes
Tien KJ, et al. Diabetes Care. 2013 Oct;36(10):3027-32.
CKD, chronic kidney disease; DM, diabetes mellitus; ESRD, end-stage renal disease
Crude overall survival curves after initiation of dialysis in ESRD dialysis patients
22,693 20,740 18,655 16,803 12,987 9,739 7,011 4,270 2,672 1,081
3,337 3,075 2,724 2,390 1,902 1,453 1,069 714 408 175
25,231 22,058 18,368 15,205 10,411 6,865 4,347 2,585 1,432 627
Non-DM
New-onset DM
Pre-existing DM
Number at risk
0
Survival time (years)
1 2 3 4 5 6 7 8 9
0
0.2
0.4
0.6
0.8
Cumulative survival rate
Non-DM
Log rank test, p<0.001
New-onset DM
Pre-existing DM
1.0

Prognosis of dialysis +/-DM is worse than
most neoplastic diseases
1. Nordio M, et al. Am J Kidney Dis. 2012 Jun;59(6):819-28. 2. ERA-EDTA Annual Report 2019, https://www.era-online.org/registry/AnnRep2019.pdfAccessed 24Jun2022.
Comparison of 5-year relativesurvival of most important cancers with long-term dialysis
1,2
DM, diabetes mellitus; ERA, European Renal Association; EDTA, European Dialysis and Transplantation Association
*
5-year adjusted survival in a difference study based on data from the ERA-EDTA Registry.
Prostate cancer
Thyroid cancer
Breast cancer
Hodgkin lymphoma
Bladder cancer
Non-Hodgkin lymphoma
Kidney cancer
Colorectal cancer
Leukemia
Chronic Dialysis without DM
Myeloma
Dialysis with diabetes
2*
Heart failure
Stomach cancer
Esophageal cancer
Lung cancer
Pancreatic cancer
46.3%
55%
0 10 20 30 40 50 60 70 80 90 100
5-year survival (%)

Death
0
HbA1cValue(%)
6 7 8 9 10 11
0.9
1.0
1.2
1.4
1.6
1.8
High (>8-9%) and lower (<6 -6.5%) HbA
1C
are associated with increased mortality risk
in diabetic patients with CKD or on dialysis
1. Shurraw S, et al. Arch Intern Med. 2011 Nov 28;171(21):1920 -7. 2. Rhee CM, et al. Semin Dial. 2014 Mar;27(2):135-45.
CKD, chronic kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; HR, hazard ratio; HbA
1C, glycated hemoglobin
The optimal target HbA
1Crange for
diabetic dialysis patients appears to be different
from the general population
2
Histogram of observed HbA
1Cvalues
in people with stage 3 to 4 CKD
1
HR
20
16
12
8
4
0
Population (%)
4
HbA1cValue (%)
Risk of death
5 6 7 8 9 10 11 12
Diabetics without CKD
Diabetic dialysis patients
HbA
1C: 6-8%
Recommended
targetA1c for
dialysis patients
HbA
1C: <6%
Bunt-out
diabetes
23,296 patients with DM and an eGFR <60.0 mL/min/1.73 m
2
54,757 DaVita hemodialysis patients

Goals of Care
20

HbA
1Cgoal attainment remains suboptimal
among individuals With T2DM
1. Carls G, et al. Diabetes Ther. 2017 Aug;8(4):863-873. 2. de Pablos-Velasco P, et al. Clin Endocrinol (Oxf). 2014 Jan;80(1):47-56.
BEL, Belgium; FRA,France; GER, Germany; GRE, Greece; HbA
1C, glycated hemoglobin;IT, Italy;NED, the Netherlands; NHANES, National Health and Nutrition Examination Survey; SP, Spain; T2DM,
type 2 diabetes mellitus; TUR, Turkey; UK, the United Kingdom.
50.9
0
10
20
30
40
50
60
70
Patients Not at HbA
1c
<7%, %
US
PANORAMA (Europe)
2
: NHANES (US)
1
:
2011–2014
HbA
1cNot at <7.0%
May 2009-April 2010
HbA
1cNot at <7.0%
38.2
42.3
36.2
32.9
28.3
25.9
39.8
52.0
40.3
TURBEL FRA GER GRE IT NED SP UK

More than half T2DM had suboptimal glycemic
control in Taiwan
The 4th Quality Survey (2018) of Diabetes Control by TADE.
HbA
1C, glycated hemoglobin; T2DM, type 2 diabetes mellitus
T2DM control rate in Taiwan (2002 -2018)
21.1
43.5
32.3
21.7
34.5
16.6
44.1
10.8
0
5
10
15
20
25
30
35
40
45
Patients (%)
HbA
1C<7% HbA
1C≥9%
2002 20112006 2018
N=5,855

DM is a silent disorder in the early
disease course
1. Colagiuri S, et al. Diabetes Care. 2002 Aug;25(8):1410-7. 2. Simonson GD, et al. Diabetes manage. (2011)1(2), 175-189.
DM, diabetes mellitus; T2DM, type 2 diabetes mellitus
Natural history of T2DM
1
Decline in β-cell function, which begins as early as 12 years before diagnosis and continues
throughout the disease process
2
250
200
150
100
50
0
-15 -10 -5 0 5 10 20 2515 30
Relative function
250
200
150
100
50
0
Glucose
(mg/dL)
Prediabetes metabolic
syndrome
Onset of
diabetes
Years
Insulin resistance
Insulin level
Fasting glucose
Postmealglucose
Beta-cell fuction
Insulin action

24
CKD is a progressive disease and acts as a CV
risk multiplier
1,2
Figure adapted from Tonneijck L et al. 2017
UACR, urine albumin-to-creatinine ratio; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; T2D, type 2 diabetes
See slide notes for references
By the time treatment for CKD is initiated, it is often too late
Time
Whole kidney GFR (ml/min/1.73 m
2
)
180
100
60
0
UACR
(mg/mmol)
500
100
20
3
0
GFR
UACR
Nephron
mass
100%
0%
UACR 3 mg/mmol
eGFR 60 ml/min/1.73 m
2
By the time hypertension
or T2D are diagnosed, structural
kidney damage may already be
underway
3,4
Patients with CKD are 3×more likely
to have a CV event
5
Early screening and interventioncan slow the progression of CKD and
reduce CV risk and related outcomes
1,8
By the time eGFR fallsbelow
60 ml/min/1.73 m
2
significant damage may be present
6,7
PC-TW-105557-2023Aug22

Earlier intervention in T2DM associated with lower
long-term microvascular and macrovascular
complications
1. UKPDS Group. Lancet.1998 Sep 12;352(9131):837 -53. 2. Holman RR, et al. N Engl J Med. 2008 Oct 9;359(15):1577-89. 3. ADVANCE Collaborative Group. N Engl J Med.2008 Jun 12;358(24):2560-72.4.
Wong MG, et al. Diabetes Care. 2016 May;39(5):694-700. 5. Actionto Control Cardiovascular Risk in Diabetes Study Group.N Engl J Med.2008 Jun 12;358(24):2545-59.6. The ACCORD Study Group. N Engl
J Med. 2011 Mar 3;364(9):818-28. 7. The ACCORD Study Group. Diabetes Care. 2016 Jul;39(7):1089 -100. 8. Duckworth W, et al. N Engl J Med.2009 Jan 8;360(2):129-39. 9. Hayward RA, et al. N Engl J
Med. 2015 Jun 4;372(23):2197-206.
FPG, fasting plasma glucose; HbA
1C, glycated hemoglobin; MI, myocardial infarction; T2DM, type 2 diabetes mellitus
Disease progression
UKPDS
1,2
(n=3,867)
ADVANCE
3,4
(n=11,140)
ACCORD
5,6,7
(n=10,251)
VADT
8,9
(n=1,791)
Duration of diabetes (years) 0 8 10 11.5
Mean baseline HbA
1C(%) 7.08 7.5 8.3 9.4
Mean baseline FPG (mmol/L) 8.0 8.5 9.7 11.4
Mean age (years) 53 66 62 60
Follow-up period post-trial (years) 10 5.4 4-5 10
Microvascular complications ▼ ▼
▼
(retinopathy)
=
(▼worsening of
albumin excretion)
Macrovascular complications ▼(MI) =
=
(▼nonfatal MI, ▲death)
▼

Improved glycemic control reduced risk of
long-term complications in T2DM
Stratton IM, et al. BMJ. 2000 Aug 12;321(7258):405 -12.
FU, follow up; HbA
1C, glycated hemoglobin; MI, myocardial infarction; T2DM, type 2 diabetes mellitus; UKPDS, United Kingdom Prospective Diabetes Study
•There is a direct relation between the risk of complications of diabetes and glycaemia over time
•The rate of increase of risk for microvascular disease with hyperglycemia is greater than that for
macrovascular disease
21 21
14 14
12
37
43
0
10
20
30
40
50
Percentage (%)
Death related
to diabetes
Any end point
related to diabetes All cause mortality StrokeMI
Microvascular
end point
Amputation or
death from
peripheral
vascular disease
p<0.0001 p<0.0001
p<0.0001 p<0.0001 p=0.035
p<0.0001
p<0.0001
Reduction of risk per 1% decrease in HbA
1C
N=5,102, T2DM
UKPDS study, conventional glucose control (primarily with diet) vs.
intensive treatment (sulphonylureaor insulin)
Median FU=10 years

Early intensive diabetes therapy prevent CKD
progression
The DCCT/EDIC Research Group. N EnglJ Med. 2011 Dec 22;365(25):2366 -76.
CI, confidence interval; CKD, chronic kidney disease; DCCT/EDIC, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications;FU, follow up; GFR, glomerular filtration rate
Early intensive diabetes therapy significantly reduced long-term risk of impaired GFR by 50%
Cumulative incidence of an impaired GFR, according to treatment group
Type 1 DM; DCCT: N=1,441;EDIC: N=1,375DCCT/EDIC trial
*
Aim of achieving HbA
1C<6.05%; insulin injections ≥ 3 daily.
†
Aim of preventing symptoms of hyperglycemia and hypoglycemia; insulin injections 1 or 2 daily.
DCCT: median FU=6.5 years; EDIC: median FU=22 years
Conventional
therapy
*
Intensive
therapy
†
Cumulative incidence
of impaired GFR
(%)
Years since Randomization
0 5 10 15 20 25
711 704 684 672 619 108
730 719 697 657 594 90
Intensive therapy
†
Conventional therapy
*
No. at risk
0
5
10
15
Risk
-50%
[18, 69]
p=0.006

Intensive glucose control improved
kidney outcomes in T2DM
PerkovicV, et al. Kidney Int. 2013 Mar;83(3):517-23.
Kaplan–Meier curves depicting the incidence of ESRD
CI, confidence interval; CKD, chronic kidney disease; DM, diabetes mellitus; ESRD, end-stage renal disease; HbA1C, glycated hemoglobin; HR, hazard ratio; T2DM, type 2 diabetes mellitus
*
Standard glucose control strategy: target HbA1C levels defined by local guidelines.
†
Intensive blood glucose control strategy: aiming for a HbA1C ≤6.5%.
N=11,140; intensive therapy (n=5,571) vs.
Standard therapy (n=5,569)
ADVANCE trial Median of 5 years follow up
0 6 12 18 24 30 36 42 48 54 60 66
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Follow-up (months)
5,571 5,489 5,394 5,294 5,172 2,753
5,569 5,501 5,383 5,280 5,156 2,814
Intensive therapy
†
Standard therapy
*
No. at risk
Cumulative incidence
(%)
Conventional
therapy
*
Intensive
therapy
†
Risk
-65%
0.35 [0.15, 0.83]
p=0.01

The latest guidelines recommend
optimize glucose control to reduce the risk or
slow the progression of CKD
American Diabetes Association. Diabetes Care 2023;46(Suppl. 1):S191–S202.
CKD, chronic kidney disease
CKD
Treatment
Recommendations
11.2 Optimize glucose control to reduce the risk or slow the
progression of chronic kidney disease. (GRADE: A)

Albuminuria and eGFR should be
monitored regularly in diabetes patients
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate
CKD
Screening
Recommendations
11.1aAt least annually, urinary albumin (e.g., spot urinary albumin-to-
creatinine ratio) and estimated glomerular filtration rate should be
assessed in patients with type 1 diabetes with duration of ≥5 years
and in all patients with type 2 diabetes regardless of treatment.
(GRADE: B)
11.1b In people with established diabetic kidney disease, urinary albumin
(e.g., spot urinary albumin-to-creatinine ratio) and estimated
glomerular filtration rate should be monitored 1–4 times per year
dependingon the stage of the disease.(GRADE: B)
American Diabetes Association. Diabetes Care 2023;46(Suppl. 1):S191–S202.

HbA
1Ctarget in patients with prevalent CKD and
substantial comorbidity should be individualized
CKD, chronic kidney disease; HbA
1C, glycated hemoglobin; LEO, level of evidence
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int. 2022 Nov;102(5S):S1-S127.
Recommendation
2.2.1Safe achievement of lower HbA
1Ctargets (e.g., <6.5% or <7.0%) may be
facilitated by CGM or SMBG and by selection of glucose-lowering agents that are not
associated with hypoglycemia
Factors guiding decisions
on individual HbA
1C
targets
<6.5% HbA1c <8.0%
CKD G1 Severity of CKD CKD G5
Absent/minor Macrovascular complications Present/severe
Few Comorbidities Many
Life expectancyLong Short
Present Hypoglycemia awareness Impaired
Available Resources for hypoglycemia management Scarce
Low Propensity of treatment to cause hypoglycemia High

Challenges in managing
patients with diabetes
and CKD
32CKD, chronic kidney disease

Mainly degraded in theliver
during the first pass effect
Kidney plays an important role in insulin
clearance in DM
Pecoits-Filho R, et al. DiabetolMetabSyndr. 2016 Jul 28;8:50.
Schematic presentation of the clearance of insulin
DM, diabetes mellitus
Pancreas
Insulin
~50%
Insulin
receptor
Adipose
tissue
Muscle
Kidney
Insulin
receptor
Adipose
tissue
Muscle
Kidney
Liver
30%~80%
Endogenous insulin Exogenous insulin
Mainly degraded in the Kidney,
enters the systemic circulation directly,
without first passing through the liver.
Insulin
Liver
Exogenous
insulin

CKD is an independent risk factor of
hypoglycemia
Moen MF, et al. Clin J Am Soc Nephrol. 2009 Jun;4(6):1121-7.
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate
CKD is a risk for hypoglycemia, with or without diabetes
Risk for hypoglycemia of varying severity
N=243,222, CKD(defined as eGFR <60 mL/min/1.73 m
2
)
0
1
2
3
4
5
6
7
8
9
類別1
類別2
類別3
類別4
3.28
1.66
1.53
1
7.21
3.56
1.58
1
8.43
4.09
1.62 1
Incident rate ratios
All p-values <0.0001, (95% CI)
Glucose <50 mg/dL
Glucose <60 and ≥50 mg/dL
Glucose <70 and ≥60 mg/dL
+CKD, +Diabetes -CKD, +Diabetes +CKD, -Diabetes
Ref:
-CKD, -Diabetes

The first clinical practice guideline for patients
with diabetes and CKD was published in 2020
35
1.Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int. 2020 Oct;98(4S):S1 -S115.2.de Boer IH, et al. Kidney Int. 2020 Oct;98(4):839-848.
2020年第一次
出此議題治療指引

HbA
1Cremains the glycemic biomarker of choice
in advanced CKD and is recommended
by the latest KDGIO
1
1. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int. 2022 Nov;102(5S):S1 -S127.2. Speeckaert M, et al. Nephrol Dial Transplant. 2014 Dec;29(12):2167-77.
CKD, chronic kidney disease; EPO,erythropoietin, HbA
1C, glycated hemoglobin; KDIGO, Kidney Disease: Improving Global Outcomes
Glycated albumin
1,2
HbA
1C
2
False elevation False reduction
•Carbamylated hemoglobin
•Iron deficiency
•Vitamin B12 deficiency
•Decreased erythropoiesis
•Alcoholism
•Chronic renal failure
•Decreased erythrocyte pH…
•After administration of
erythropoietin, iron or
vitamin B12
•Erythrocyte lifespan▼
•Hemoglobinopathies….
⚫Amarkerof long-term glycemic concentrations
⚫Having excellent standardization of HbA
1Cassays
Briefer timeframe Not influence by…
Reflect glycemia
in 2-4weeks
than HbA
1C
•Gender
•Erythrocyte lifespan
•Erythropoietin therapy
•Serum albumin concentration
Biasedby… Worse correlations
with glycemia
•Low serum protein
•Malnutrition
•Peritoneal dialysis
•Age
•Albuminuria
in most cases
Glycemic monitoring
Recommendation
2.2.1We recommend using hemoglobin A
1c (HbA
1c) to monitor glycemic control in
patients with diabetes and CKD (1C).

Insulin is potent in glucose-lowering and can
be used across all eGFR levels
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int. 2022 Nov;102(5S):S1-S127.
AGI, alpha-glucosidase inhibitor; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; DPP4i, dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; GLP1RA,
glucagon-like peptide-1 receptor agonist; SGLT2i, sodium–glucose cotransporter-2 inhibitor; SU, sulfonylurea; T2D, type 2 diabetes; TZD, thiazolidinedione
Patient factors influencing the selection of glucose -lowering agent
other than SGLT2i and metformin in T2D and CKD
Preference, comorbidity or other characteristic
High-risk
ASCVD
Potent
glucose-
lowering
Avoid
hypoglycemia
Avoid
Injections
Weight
loss
Low cost
eGFR < 15 ml/min
per 1.73 m
2
or
treatmentwith dialysis
Heart
failure
Less-suitable medications
•DPP4i
•TZD
•AGI
•SU
•Insulin
•GLP1RA
•Insulin
•SU
•Insulin
•TZD
•GLP1RA
•DPP4i
•Insulin
•SU
•AGI
•TZD
More-suitable medications
•GLP1RA
•GLP1RA
•Insulin
•GLP1RA
•DPP4i
•TZD
•AGI
•GLP1RA
•SU
•TZD
•AGI
•DPP4i
•Insulin
•TZD
•GLP1RA
•DPP4i
•TZD
•Oral GLP1RA
•SU
•AGI

Postprandial glucose in CKD
40CKD, chronic kidney disease

DM-CKD population
41
Rahhal MN, et al. J Clin Endocrinol Metab. 2019 Nov 1;104(11):4949-4966.
More carbohydrate
?
Low protein diet
due to uremic
symptoms and signs
Less food intake
(large variation
in different stages)
Complicated
glucose homeostasis

The genetic background of East Asians
makes them more and differentially susceptible
to diabetes than Caucasians
1
1. Kodama K, et al. Diabetes Care. 2013 Jun;36(6):1789-96. 2. Kahn SE, et al. Diabetes. 1993;42:1663-72.
IGR, impaired glucose regulation; T2DM, type 2 diabetes mellitus
Study cohort(N =3,813)
*
AIR: acute insulin response, reflects the secretion of insulin by the pancreas and can be interpreted as β-cell function.
Adults with normal glucose tolerance
(non-diabetic)
1,2
Better
β
-
cell
function
worse
β
-
cell
function
AIR
g
(
pmol
/L)
0 5 10 15 20 25 30
ISI (10
-5
min
-1
per
pmol/L)
1400
1000
800
200
0
1200
400
600
1800
1600
Hyperbolic relationship between ISI and AIR
g
East Asian
Caucasian
African
Study by Kodama K, et al
1
Study by Kahn SE, et al
2
More insulin
sensitive
Less insulin
sensitive
Factor of impact on
insulin sensitivity and insulin response
(=β-cell function
1
)
Ethnicity
1
Insulin responses to glucose (AIR
*
)
1
East Asians are more
susceptible to diabetes
1
Lower AIR
in healthy East Asians
Higher AIR
in Africans
Higher AIR
in Caucasians

β-cell mass and function in the glycemic continuum
evolve differently in Caucasians and East Asians
YagihashiS, et al. J Diabetes Investig. 2016 Mar;7(2):155-65.
IGT, impaired glucose tolerance; IFG, impaired fasting glucose;T2DM, type 2 diabetes mellitus
β cell function
(IRI, CPR, HOMAβ)
β cell mass
(β cell volume density)
Normal IGT, IFG Non-insulin requiringInsulin requiring
Intact islet
β-cell deplete islet
Healthy non-diabetic controls
American type 2 diabetes
(obese type)
Japanese type 2 diabetes
(lean type)
•β‐cell function and mass initially increases to compensate for insulin resistance in non-Asians
•This dynamic is blunted in East Asians
Natural history of T2DM and differences
Healthy non-diabetic controls
American type 2 diabetes
(obese type)
Japanese type 2 diabetes
(lean type)
100
50
0
(%)
0
1.0
2.0
3.0
4.0
Healthy Prediabetic Diabetic (mild-moderate) Diabetic severe
(%)

Genetic factors are associated with decrease
in β-cell function in East Asians
1. Ma RC, et al. Diabetologia. 2013 Jun;56(6):1291-305. 2. Tokuyama Y, et al. Metabolism. 2006 Feb;55(2):213-6.3. Artner I, et al. Diabetes. 2006 Feb;55(2):297-304.
Ngn3, neurogenin3; MafB, MAF BZIP transcription factor B; Pax4/6, paired box gene 4/6
Expression pattern of MafBduring α-and β-cell
differentiation
3
Hormone
positive
cells
Ngn3
MafB
Pax6
MafB
Pax6
MafB
Pax4/6
MafB
Pax6
Endocrine
Progenitor cell
Mature β-cell α-cell
East Asians
1
Variation near
PAX4 gene
(Meta analysis)
The differentiation
and maturation of
β-cell function
Associate
Japanese
2
Carrying PAX4mutationspatients:
severe defects in insulin secretion
2
Hong Kong
and
Shanghai
1
Identified other genes linked to
β-cell function

Carbohydrates contribute about 60 -65% energy
per person per day in Taiwan
SchmidhuberJ, et al. Lancet Planet Health. 2018 Aug;2(8):e353-e368.
Carbohydrates contribution of macronutrients to energy availability by country in 2013
<55%
55% to <60%
60%to<65%
65% to<70%
70% to<75%
75% to <80%
≥80%
Energy per person per day
60-65%

中西飲食大不同
聖誕大餐
烤雞8g
烤洋芋21g
火腿3g
起司盤5g
聖誕蛋糕 120g
沙拉5g
水果（五人份）80g
年夜飯
佛跳牆97.2g
糖醋魚68g
高粱酒香腸 25g
烏魚子炒飯 245g
白菜滷20g
紅燒蹄膀 59.4g
煎蘿蔔糕 45g
<242g 514g

PPG was a predominant contributor to
excess hyperglycemia in Asian than Caucasian
*
Significant difference between Fasting glucose and postprandial glucose.†Significant difference from all other quintiles.
1. Monnier L, et al. Diabetes Care. 2003;26(3):881-885. 2.Wang JS, et al. Diabetes Metab Res Rev. 2011;27(1):79-84.
Fasting glucose postprandial glucose
Taiwan
2
Caucasian
1
Fasting glucose postprandial glucose
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<7.3 7.3-8.4 8.5-9.2 9.3-10.2 >10.2
Contribution (%)
HbA
1c Range(%)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
<7.1 7.1-7.5 7.6-8.0 8.1-8.7 8.8-12.7
Contribution (%)
HbA
1c Quintiles(%)
*
†
†

Maintaining daily protein intake for healthy people in
those with diabetes and CKD is recommended by
KDIGO and Taiwan clinical practice guideline
1,2
1.Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int. 2022 Nov;102(5S):S1 -S127. 2.2019台灣糖尿病腎臟疾病臨床照護指引
Average protein content of foods in grams
1
CKD, chronic kidney disease; HbA
1C, glycated hemoglobin; KDIGO, Kidney Disease: Improving Global Outcomes
Animal proteins Plant proteins
Meat, poultry, fish,
seafood, eggs
28 g (1 oz)
=
6-8 g protein
Dairy, milk, yogurt,
cheese
Recommendation
3.1.1We suggest maintaining a protein intake of 0.8 g protein/kg (weight)/d for those
with diabetes and CKD not treated with dialysis (2C)
1
.
3.1.2Patients treated with hemodialysis, and particularly peritoneal dialysis, should
consume between 1.0 and 1.2 g protein/kg (weight)/d
1
.
1egg
=
6-8 g protein
250 ml(8 oz)
=
8-10 g protein
28 g (1 oz)
cheese
=
6-8 g protein
Legumes, dried beans,
nuts, seeds
100 g (0.5 cup)
cooked
=
7-10 g protein
100g (0.5 cup)
cooked
=
3-6 g protein
Whole grains,
cereals
Starchy vegetables,
breads
2.4g protein

Competing needs for nutritional management
can make appropriate protein intake challenging
53
KDOQI. Am J Kidney Dis. 2007 Feb;49(2 Suppl 2):S12 -154.
CKD, chronic kidney disease;DM, diabetes mellitus;PPG, postprandial plasma glucose.
When protein intake is limited…
“Caloric distribution” of other macronutrients
must be addressed
Nonprotein
calories
(90% of total)
According to the National Academy of Sciences, Institute of Medicine
Low-glycemic
index foods
(a measure of type of carbohydrate)
Decrease
postprandial hyperglycemia
Improve
overall blood glucose control
≤30%
Dietary fats
Up to60%
Complex
carbohydrates
Glycemic effects
are determined strongly by…..
Total amount of
carbohydrate
Higher PPG!?
More carbohydrate in DM -CKD…

Premixed insulin in managing
patients with diabetes
and CKD
54CKD, chronic kidney disease

Insulin is traditionally the treatment of choice
for nondialysis and dialysis CKD patients
1
1. Betô nico CC, et al. Clinics (Sao Paulo). 2016 Jan;71(1):47-53. 2.Tien KJ, et al. J Diabetes Investig. 2019 May;10(3):560-570. 3.BernsJS, Glickman JD. UpToDate.
https://www.uptodate.com/contents/management -of-hyperglycemia-in-patients-with-type-2-diabetes-and-advanced-chronic-kidney-disease-or-end-stage-kidney-disease.Accessed 7Mar2022.
CKD, chronic kidney disease; T2DM, type 2 diabetes mellitus
Insulin therapy is eventually indicated for most patients,
owing to progressive loss of pancreatic β-cell function in T2DM
2
Non-Dialysis CKDpatients
Same as for the general diabetic population
3
Dialysis CKDpatients
=
The indications and principle for initiating insulin therapy for…….

American Diabetes Association. Diabetes Care 2023;46(Suppl. 1):S140–S157.
Use of premixed insulin or split insulin regimen
is recommended for treatment intensification
if signals of overbasalizationpresent
Recommendations
9.12Recommendation for treatment intensification for patients not meeting
treatment goals should not be delayed (GRADE: A)
9.14 Clinicians should be aware of the potential for overbasalizationwith
insulin therapy. Clinical signals that may prompt evaluation of
overbasalizationinclude basal dose more than ~0.5 IU/kg/day, high
bedtime-morning or postpreprandialglucose differential,
hypoglycemia (aware or unaware), and high glycemic variability.
Indication of overbasalizationshould prompt reevaluation to further
individualize therapy. (GRADE: E)

Use of premixed insulin or split insulin regimen
is recommended for treatment intensification
if signals of overbasalizationpresent (cont.)
GLP1RA, glucagon-like peptide-1 receptor agonist; GIP, glucose-dependent insulinotropic polypeptide.
If injectable therapy is needed to reduce A1C
Consider GLP-1 RA or GIP/GLP-1 RA in most patients prior to insulin
INITIATION: Initiate appropriate starting dose for agent selected (varies within class)
TITRATION: Titrate to maintenance dose (varies within class)
Add basal insulin or bedtime NPH insulin
Better managed with an A.M. dose of a long-acting basal insulin if the individual develops hypoglycemia and/or frequently
forgets to administer NPH in the evening
If above A1C target
Assess adequacy of basal insulin dose
Consider clinical signals to evaluate for overbasalizationand need to consider adjunctive therapies
[e.g., basal dose more than ~0.5 units/kg/day, elevated bedtime-morning and/or post-preprandialdifferential,
hypoglycemia (aware or unaware), high variability]
Consider self-mixed/split insulin regimen
Can adjust NPH and short/rapid-acting insulins separately
If already on GLP-1 RA or dual GIP and
GLP-1 RA or if these are
not appropriate OR insulin is preferred
If on bedtime NPH, consider
converting totwice-daily NPH regimen
If above A1C target
Stepwise additional injections of
prandial insulin
Consider twice daily
premixed insulin regimen
If above A1C target
Consider GLP-1 RA or
dual GIP and GLP-1 RA
If above A1C target
Add prandial insulin
American Diabetes Association. Diabetes Care 2023;46(Suppl. 1):S140–S157.

Premixed insulin provides benefits of more
physiological, fewer injections, flexible injection
timing, and better PPG control than basal insulin
1
1. Garber AJ, et al. Diabetes Obes Metab. 2007 Sep;9(5):630 -9. 2. Wu T, et al. Diabetes Ther. 2015 Sep;6(3):273-87.
PPG, postprandial plasma glucose
Patient factors to consider when deciding whether to use premix insulin
analog or basal insulin for initiation
2
Considerations
at initiation
Considerations
for future intensification
No
Yes
Prefers fewer
injections
Comfortable
with more
frequent
injections
Poor Good
Patient preference regarding
number of injections
Prefers less
frequent
monitoring
Patient preference regarding
self-monitoring of
blood glucose
Patient ability to inject
(e.g., cognitive ability,
manual dexterity, need for carer)
Favors premix
Favors
basal-bolus
Favors premix
Favors
basal-bolus
>54 mg/dL
(>3 mmol/L)
<18 mg/dL
(<1 mmol/L)
What is the postprandial increment?
Is the patient likely to manage
basal-bolus therapy when
intensification is needed?
Is there a large carbohydrate
intake at one or two meals?
Yes
Is the patient's lifestyle predictable
(e.g., eatingpattern, working hours)?
Yes
No
No

Biphasic insulin offer maximum HbA
1C
reductions
-1.28
-1.91
-1.08
-1.22
-1.12
-1.61
-0.74 -0.72
-0.96
-0.77
-0.64
-1.21
-2.0
-1.5
-1.0
-0.5
0.0
Extenatide
LAR
Prandial
insulin
Δ
HbA
1C
(%)
DPP-4
inhibitors
Basal
insulin Glinides
Biphasic
insulin
Basal
bolus
GLP-1
agnoists AGI TZD SUs Metformin
Subjects
(N)
21,615 11,921 2,597 2,967 5,783 668 1,12013,847 6,655 4,8275,895 1,050
Patient factors influencing the selection of glucose -lowering agent
Esposito K, et al. Diabetes Obes Metab. 2012 Mar;14(3):228-33.
AGI, α-glucosidase inhibitor; DPP-4, dipeptidyl peptidase-4; GLP-1, GLP-1, glucagon-like peptide-1; HbA
1C, glycated hemoglobin; LAR, long-acting release; SUs, sulphonylureas; TZD, thiazolidinediones

BIAsp30is abiphasic premixed insulin analogue
that has dual-action PK profiles and targets both FPG
and PPG
1,2
Physiological insulin profile
Soluble insulin aspart
Protamine crystallised insulin aspart
BIAsp 30
1. Rizvi AA, et al. Eur Med J Diabetes. 2016;4(1):74-83. 2. Garber AJ, et al. Diabetes Obes Metab. 2006 Jan;8(1):58-66. 3. Garber AJ, et al. Diabetes Obes Metab. 2007 Sep;9(5):630 -9. 4. Hirsch IB. N Engl J
Med. 2005 Jan 13;352(2):174-83. 5. Liebl A, et al. Drugs. 2012 Jul 30;72(11):1495-520.
BIAsp, biphasic insulin aspart; BIA, biphasic insulin analogues; FPG, fasting plasma glucose;PK, pharmacokinetic; PPG, postprandial plasma glucose; RAA, rapid-acting analogues
Adapted from figure 1A, Garber AJ, et al. Diabetes Obes Metab. 2007 Sep;9(5):630 -9 and figure 2,Hirsch IB. N Engl J Med. 2005 Jan 13;352(2):174-83.
Physiological prandial serum insulin profile with
superimposed theoretical profile of BIAsp30
3,4
•BIAs are composed of
a single type of RAA
1
Dual-action PK profiles
Premixed
human insulin
3
•Combining a short-acting peak and
a longer basal component
1
vs.
Schematic presentation
BIAsp30
aspart
Characteristics of BIAsp30
More physiological
PK profile
biphasic human insulin
andbasalinsulin
5
vs.

BIAsp30 has rapid absorption and higher peak
concentration reflected in more rapid and pronounced
glucose-lowering effect than BHI 30
Jacobsen LV, Sø gaardB, Riis A.Eur J Clin Pharmacol. 2000 Aug;56(5):399-403.
•BIAsp30 provides an early meal-related insulin peak followed by a smooth protracted profile
resulting from the protaminatedfraction of the insulin
•BIAsp30 has a similar duration of action of basal component as BHI 30
BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; SEM, standard error of the mean
Mean (±2 SEM) serum glucoseprofiles
in healthy volunteers
after a single subcutaneous injection
Mean(±2 SEM) serum insulinprofiles
in healthy volunteers
after a single subcutaneous injection
Serum insulin (mUI
-
1
)
Time of Day
***
p<0.0001; n=24
20
15
10
5
0
8:0011:0014:0017:0020:0023:002:005:008:00
25
BHI 30
***
BIAsp30
Serum glucose (mmol
l
1
)
8:00
3
3.5
4
4.5
5
5.5
11:0014:0017:0020:0023:002:005:008:00
BHI 30
BIAsp30
Time of Day

Twice-daily BIAsp30 reduced more 48 -h
average glucose, PPG and MAGE than BHI 30
without hypoglycemia in T2DM
1
1. OhtaA, et al. J Diabetes Investig. 2011 Oct 7;2(5):406-11. 2. LieblA, et al. Drugs R D. 2018 Mar;18(1):27-39.
BB, before breakfast; BD, before dinner; BL, beforeLunch; BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; MAGE, mean amplitude of glucose excursion; PPG, postprandial glucose; SD, standard
deviation; T2DM,type 2 diabetes mellitus
Average glucose profile
by 48-h continuous glucose monitoring
between BHI 30 and BIAsp30
2
Comparison of 48-h average glucose and MAGE
between BHI 30 and BIAsp30
1
*p<0.05.
mg/dLmg/dL
Average glucose MAGE
0
50
100
150
200
BHI 30 BIAsp30
*
180
160
140
120
100
80
60
40
20
0
BHI 30 BIAsp30
*
0
100
150
200
250
300
0
6
8
10
16
12
14
18
n=12
Mean±SD
mg/dL
mmol/L
*
*
*
BIAsp 30 BHI 30

BIAsp 30 reduced HbA
1Cmore efficiently than
IGlar
1
1. RysP, et al. Int J Clin Pract. 2014 Mar;68(3):304-13. 2. LieblA, et al. Drugs R D. 2018 Mar;18(1):27-39.
BIAsp, biphasic insulin aspart; BID, twice daily; CI, confidence interval; HbA
1C, glycated hemoglobin; IGlar, insulin glargine; MAGE, mean amplitude of glucose excursion; OAD, oral antidiabetic drugs; OD, once
daily; PPG, postprandial glucose; RCT, randomized controlled trials;SD, standard deviation; T2DM, type 2 diabetes mellitus; WMD, weighted mean difference
BIAsp30 added to OAD therapy results in a better glycemic control as compared with IGlarin T2DM patients
1
Meta-analysis showing weighted mean difference in HbA
1Cfor BIAsp30 vs. IGlar
2
Strojek2009
Yang 2012
Kann2006
Ligthelm2011
Raskin2005
Subtotal (BIAsp30 BID)
Total
Study or
sub-category
BIAsp30
N Mean SD
225
X
X
X
X
X
128
132
117
X
-1.30
-2.79
X
X
1.19
IGIar
N Mean SD
232
x
X
X
X
X
127
127
116
X
-1.20
-2.36
X
X
1.18
28.13
28.74
13.58
16.26
13.29
-0.16( 0.30; -0.02)
-0.12(-0.25; 0.02)
-0.50 ( 0.80; -0.20)
-0.06 (-0.32; 0.20)
-0.43 (-0.73; -0.13)
100.0 -0.21(-0.35; -0.08)
WMD (95% CI)
Random-effects model
Weight
%
WMD (95% CI)
Random-effects model
Q = 5.68, d = 2
(p = 0.658)I
2
= 65%
-0.32 (-0.60; -0.04)
Subtotal (BIAsp30 OD) -0.14 (-0.24; -0.04)
Q= 0.16.d=1
(p = 0.687) 12 =0%
Initiating insulin
therapy with BIAsp30
BIAsp 30 vs. IGlar added to at least one OAD
in T2DM patients (N=1,758)
Meta-analysis of 5 RCTs Followed for 24–28 weeks
Favors BIAsp30 Favors IGIar
-0.7 -0.35 0 0.35 0.7

BIAsp 30 reduced prandial glucose increment to a
greater extent than basal insulin IGlar without rise in
severe hypoglycemic risk
RysP, et al. Int J Clin Pract. 2014 Mar;68(3):304-13.
BIAsp, biphasic insulin aspart; CI, confidence interval; IGlar, insulin glargine; OAD, oral antidiabetic drugs; RCT, randomized controlled trials;SD, standard deviation; T2DM, type 2 diabetes mellitus; WMD,
weighted mean difference
•The difference of severe hypoglycemic episodes: 1% vs. 1%; OR=0.88 (0.31;2.53)
•BIAsp30 added to OAD therapy results in a better glycemic control as compared with IGlar
in T2DM patients
Weighted mean difference in mean prandial glucose increment between BIAsp30 and IGlar
Test for heterogeneity: Q -0.67. df=2 (p=0.7137), I
2
=0.00%
Test overall effect Z=-5.34 (p<0.0001)
Kann2006
Ligthelm2011
Raskin2005
Studyor
sub-category
Total
128
132
117
25.20
X
32.47
25.20
X
51.04
N Mean SD
BIAsp30
N Mean SD
IGIar
127
127
116
39.60
X
43.20
32.40
X
53.06
Weight(%)
WMD (95% CI)
Random-effects model
57.17
26.58
16.25
-14.40 [-21.53, -7.27]
-17.76 [-28.20, -7.29]
-10.73 [-24.10, 2.64]
-14.70 [-20.09, -9.31]100.00
-20-10 0 10 20
WMD [95% CI]
fixed effects model
Initiating insulin
therapy with BIAsp30
BIAsp 30 vs. IGlar added to at least one OAD
in T2DM patients (N=1,758)
Meta-analysis of 5 RCTs Followed for 24–28 weeks
Favors BIAsp30Favors IGIar

BIAsp30 can benefit patients with poor glycemic
control on basal insulin regimens -Efficacy
Haddad J, et al. Diabetes Ther. 2013 Dec;4(2):309-19.
Change in effectiveness outcomes after
24 weeks of treatment with BIAsp30
Mean plasma HbA
1Camong patients switching to
BIAsp30 from IGlar
Adapted from figure 1.
BIAsp, biphasic insulin aspart; CI, confidence interval; FPG, fasting plasma glucose; GLA, insulin glargine group; HRQoLhealth-related quality of life; HbA
1C, glycated hemoglobin; IGlar, insulin glargine; OGLDs,
oral glucose-lowering drugs; PPG, post-prandial plasma glucose; SD, standard deviation; VAS, visual analogue scale
Adapted from table 3.
GLA group
N
Baseline
(SD)
Change at
24 weeks (SD)
p
HbA
1c 894 9.7(1.7) -1.9 (1.7) <0.001
HbA
1c mmol 83 (19) -21 (18) <0.001
FPG (pre-breakfast)
mmol/l
956 10.4(3.4) -2.9 (3.7) <0.001
PPG (post-breakfast)
mmol/l
710 15.0 (4.2) -4.6 (4.4) <0.001
PPG (post-lunch)
mmol/l
146 13.8 (4.4) -4.5 (4.5) <0.001
PPG (post-dinner)
mmol/l
127 13.1 (3.9) -4.3 (4.3) <0.001
HRQoL, VAS 92363.4 (15.8) +10.3 (17.2) <0.001
N=2,818
A1chieve study-sub-analysis:switch to therapy with BIAsp30 (±OGLDs)
from basal insulin regimens under routine clinical practice after 24 weeks treatment
GLA group
HbA
1c
(%)
10.5
9.5
8.5
7.5
6.5
5.5
4.5
3.5
p<0.01
Baseline (at the start of BIAsp30) Week 24
Switching to BIAsp30
from basal insulin

BIAsp30 can benefit patients with poor glycemic
control on basal insulin regimens -Safety
Haddad J, et al. Diabetes Ther. 2013 Dec;4(2):309-19.
There was statistically significant improvement in HbA
1C, FPG and PPG, and quality of life with significant
reduction of hypoglycemic events after 24 weeks treatment of switching tpBIAsp30 from basal insulin
Safety outcomes before and after 24 weeks of treatment with BIAsp30
Adapted from table 2.
BIAsp, biphasic insulin aspart; FPG, fasting plasma glucose; HbA
1C, glycated hemoglobin; OGLDs, oral glucose-lowering drugs; PPG, post-prandial plasma glucose
N=2,818
A1chieve study-sub-analysis:switch to therapy with BIAsp30 (±OGLDs)
from basal insulin regimens under routine clinical practice after 24 weeks treatment
% Patients with at least one event (event/person -year)
Baseline (n=1,395) 24 weeks (n=1,200) p
Hypoglycemia (overall) 12.3 (3.10) 9.9 (2.98) <0.05
Hypoglycemia (major) 1.2 (0.16) 0.08 (0.01) <0.001
Hypoglycemia (nocturnal) 5.4(1.03) 3.9 (0.88) <0.05
Switching to BIAsp30
from basal insulin

Slightly more patients achieved HbA
1C<7.0% and
significant lower nocturnal hypoglycemia rate using
BIAsp30 vs. basal-plus regimen
Vora J, et al. Diabetes Obes Metab. 2015 Dec;17(12):1133 -41.
BID, twice daily; BIAsp, biphasic insulin aspart; CL, confidence limit; CI, confidence interval; HbA
1C, glycated hemoglobin; ITT, intention-to-treat; IGlar, insulin glargine; OD, once daily
*
Non-inferiority was inferred if the upper one-sided 97.5% CL for the difference in adjusted mean change in HbA
1Cwas<0.4%.
†
Patients with no data (5 in basal plus and 10 in biphasic) were classed as not achieving target for the statistical analysis.
Adapted from table 2.
T2DM and
HbA
1C7.5–11%(N=335)
LanScapetrial:randomized (1:1) to either BIAsp30 BID at breakfast
and evening meal or to IGlarOD plus a single injection of insulin glulisine
at the largest meal (basal-plus regimen)
Basal plus Biphasic insulin Difference
Change in HbA
1C(per protocol population, n=288)
LS mean change in HbA16,% (mnol/mol) (95% CI) -1.00 (-10.9) -1.22 (-13.3)
Difference in adjusted mean change HbA1c, %
(upper one-sided 97.5% CL.)
*
(-1.13, -0.87) (-1.35, -1.08) 0.21 (0.38)
Achieve target HbA
1C<7.0% or 53 mmol/mol (ITT population, n=335)
Participants achievingtarget, n (%) 35 (20.6)
Participants not achieving target, n (%)
†
130 (76.5) 109 (66.1)
Odds ratio ( 95% CI) 0.65 (0.37, 1.12)
pvalue 0.12
Nocturnal hypoglycemia (events/patient -year) 5.7 3.6 0.019
Summary of the efficacy results
Intensification of therapy:
BIAsp30 vs. basal-plus

BIAsp30 is cost effectiveness vs. other insulin
therapies in both insulin-naïve and insulin-experienced
patients
LieblA, et al. Drugs R D. 2018 Mar;18(1):27-39.
Cost effectiveness of BIAsp30
Adapted from table 1.
BHI, biphasic human insulin; BIAsp, biphasic insulin aspart; BID, twice daily administration; ICER, incremental cost-effectiveness ratio; IDegAsp, co-formulation of insulin degludec+ insulin aspart; Iglar, insulin
glargine; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drug; QALY, quality-adjusted life-year; RCT, randomized controlled trial; T2DM, type 2 diabetes mellitus
Health-
economic study
Clinical data source
Country setting
Health-economic
medal time horizon
Study endpoint summary
BIAsp30 in insulin-naive patients
Shafieet al.
•A
1chieve-observational study
•BIAsp30 Vs. OADs, 24 weeks,
T2DM (n=8,879)
•India, Indonesia,-Saudi Arabia,
Algeria, Tunisia, Morocco
•IMS CORE Diabetes model,
30 years and 1 year
Switching to BIAsp30 was cost effective in
both the long and short term across all
country settings
Switching to BIAsp30 from other insulin
Gupta et al.
•A
1chieve observational study
•BIAsp30 vs. BHI 30, IGlar, or
NPH insulin, 24 weeks, T2DM
(n=2,027)
•India, Indonesia, Saudi Arabia
•IMS CORE Diabetes model,
30 years and 1 year
Switching to BIAsp30 was cost effective in
both the long and short term across all
country settings
Switching to BIAsp30 from basal-bolus therapy
Farshchiet al.
•RCT
•BIAsp30 BID vs. basal-bolus
therapy with NPH insulin +
regular human insulin, 48 weeks,
T2DM (n=174)
•Iran
•Direct and indirect costs
estimated, 48 weeks
•Treatment with BIAsp30 had significantly
higher QALYs (p=0.011)
•ICER dominant for BIAsp30

New co-formulation IDeg-Asp
in managing diabetes
with CKD
69CKD, chronic kidney disease; IAsp, insulin aspart; IDeg, insulin degludec

Ryzodeg
®
is a combination of two soluble insulin
analogues (30% IAspand 70% IDeg) to provide both
basal and mealtime insulin coverage in one injection
1
1. Haahr H, et al. Clin Pharmacokinet. 2017 Apr;56(4):339-354. 2. LieblA, et al. Drugs R D. 2018 Mar;18(1):27-39.
•Ryzodeg
®
has a clearer separation of the prandial and basal components, resulting in a more distinct
mealtime peak because it includes only the soluble form of IAsp
2
•The novel basal component leads to flatter and more consistent insulin levels for patients
2
Conditions simulating the subcutaneous environment
IAsp, insulin aspart; IDeg, insulin degludec
Mode of absorption of Ryzodeg
®1
Subcutaneous
tissue
IAsp
hexamers
Capillary
IAsp
monomers
IDeg
monomers
IDeg
dihexamers
IDeg
multihexamers
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
Absorbance unit
4567891011121314
Minutes
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
Absorbance unit
4567891011121314
Minutes
Multihexamers
Monomers
Monomers
Multihexamers
30%
IAsp
70%
IDeg
IDegalone IAspalone Ryzodeg
®
There is no need for resuspension prior to injection
due to the existence of its insulin components as separate and
stable soluble forms in the formulation.
1
The combination of two separate insulin analogues (IDegand IAsp) does not
change the pharmacological properties of the individual components
1

Ryzodeg
®
provided superior long-term glycemic
control compared to IGlarand numerically lower
hypoglycemia rate
OnishiY, et al.Diabetes Obes Metab. 2013 Sep;15(9):826 -32.
CI, confidence interval;ETD, estimated treatment difference; HbA
1C, glycated hemoglobin; IGlar, insulin glargine; NS, no significance; RR, relative risk; T2DM, type 2 diabetes mellitus;
OHA:oralantidiabetic treatments
Cumulative number of
confirmed hypoglycemic episodes
Mean change from baseline in HbA
1C
Change from baseline in HbA
1c
(%
-
point)
Mean number of episodes
(per subject)
0.0
0.5
1.0
1.5
Weeks since randomization
0 4 8 12 16 20 24
A phase 3 clinical trial (BOOST JAPAN)
-1.5
-1.0
-0.5
0.0
Weeks since randomization
0 4 8 12 16 20 24
ETD(IDegAsp-IGlar)
-0.28
[-0.46, -0.10]
p<0.01
RR(IDegAsp-IGlar)
0.73
[0.50, 1.08]
p=NS
Ryzodeg
®
for inadequate
control with OHA
Once daily of Ryzodeg® (n=147) vs. IGlar(n=149)
in insulin-naïve T2DM with ≤2 OHA
Ryzodeg
®
IGlar
Ryzodeg
®
IGlar

Ryzodeg
®
provided effective overall glycemic control
and superior FPG control comparable to BIAsp30
Christiansen JS, et al. J Diabetes. 2016 Sep;8(5):720-8.
BIAsp, biphasic insulin aspart; BID, twice-daily; CI, confidence interval; FPG, Fasting plasma glucose;HbA
1C, glycated hemoglobin; OADs, oral antidiabetic drugs; T2DM, type 2 diabetes mellitus
Reduction in FPG over time during BID treatment
with Ryzodeg
®
and BIAsp30
Reduction in HbA
1Cover time during BID treatment
with Ryzodeg
®
and BIAsp30
HbA
1c
(%)
0.0
6.5
7.0
7.5
8.0
8.5
9.0
02468101214161820222426
Time (weeks)
HbA
1c
(mmol/mol)
0.0
47.5
53.0
58.5
63.9
69.4
74.9
FPG (mmol/L)
0.0
5.5
6.5
7.5
8.5
9.5
02468101214161820222426
Time (weeks)
FPG (mg/dL)
0
99
117
135
153
175
A combined analysis of 2 phase 3a clinical trials
(BOOST
®
: INTENSIFY PREMIX I and BOOST
®
: INTENSIFY ALL)
Treatment differences
0.00%
[-0.11, 0.10]
p=NS
Ryzodeg
®
for inadequate control
with basal or premixed insulin
INTENSIFY PREMIX I (Global population, n=446) and INTENSIFY ALL (Asian,
n=422) of Ryzodeg
®
twice daily vs. BIAsp30 twice daily in insulin users
with advanced T2DM
INTENSIFY ALL: Inadequately controlled on basal, premixed or self-mixed insulin +/-metformin
INTENSIFY PREMIX I:Inadequately controlled with premixed or self-mixed insulin +/-OADs
Treatment differences
-1.12mmol/L
[-1.38, -0.85]
p<0.0001
Ryzodeg
®
BID
(N=364)
BIAsp30 BID
(N=504)
Ryzodeg
®
BID
(N=364)
BIAsp30 BID
(N=504)

Ryzodeg
®
resulted in significantly lower rates of
overall and nocturnal hypoglycemia than BIAsp30
The rates of overall confirmed, nocturnal confirmed, and severe hypoglycemic events
were lower with Ryzodeg
®
, particularly during the maintenance period (≥16 weeks to end of trial)
Christiansen JS, et al. J Diabetes. 2016 Sep;8(5):720-8.
Cumulative rate of nocturnal confirmed hypoglycemia Cumulative rate of overall confirmed hypoglycemia
BIAsp, biphasic insulin aspart; BID, twice-daily; CI, confidence interval
0 2 4 6 8 101214161820222426
Time (weeks)
Cumulative episodes per subject
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
0 2 4 6 8101214161820222426
Time (weeks)
Cumulative episodes per subject
0.0
0.2
3.0
0.6
0.8
1.0
1.2
Full trial period
-19%
p=0.03
Ryzodeg
®
for inadequate control
with basal or premixed insulin
Full trial period
-57%
p=0.0001
Ryzodeg
®
BID
BIAsp30 BID
Ryzodeg
®
BID
BIAsp30 BID

Ryzodeg
®
retains a consistent efficacy profile in
patients with different baseline characteristics
Haluzík M, et al. Diabetes Obes Metab. 2018 Jul;20(7):1585-1592.
Ryzodeg
®
has the benefit of similar HbA1C levels and lower EOT FPG levels vs. comparators
BMI, body mass index; BIAsp, biphasic insulin aspart; BID, twice-daily; EOT, end of trial; FPG, Fasting plasma glucose;HbA
1C, glycated hemoglobin; IAsp, insulin aspart; IDeg, insulin degludec;
OADs, oral antidiabetic drugs
FPG at EOT by baseline FPG, diabetes duration
and BMI
HbA
1Cat EOT stratified by HbA
1C category,
diabetes duration and BMI
Ryzodeg
®
Comparators
Baseline FPG
mmol/L (mg/dL)
Baseline BMI
(kg/m
2
)
Diabetes duration
(years)
8.0
0.0
7.0
6.0
5.0
4.0
EOT FPG (mmol/L)
<5.5
(<99)
≥5.5-<7.0
(≥99-<126)
≥7.0-<10.0
(≥126-<180)
≥10.0
(≥180)
≤30 >30≤10 >10
EOT FPG
(mg/dL)
154
0
134
114
94
70
*
**
*
** ** **
**
8.0
7.5
0.0
7.0
6.5
6.0
5.5
5.0
4.5
4.0
EOT HbA
1c
53-58.5
(7.0-7.5)
≥58.5-<58.5
(≥7.5-<8.5)
≥69.4-<74.9
(≥8.5-<9.0)
≥74.9
(≥9.0)
Baseline HbA
1c
Mmol/mol (%)
≤30 >30
Baseline BMI
(kg/m
2
)
≤10 >10
Diabetes duration
(years)
EOT HbA
1c
(mmol/mol)
63.9
0.0
53.9
43.9
33.9
23.9
161102474286183126293183 430298681399 607393504304 11555206112463324323200 430298681399 607393504304
A meta-analysis
of 5 clinical
trials
N= N=
Ryzodeg
®
Comparators
START TWICE DAILY
vs.
Ryzodeg
®
BID + metformin
BIAsp 30 BID +metformin
INTENSIFY PREMIX
vs.
Ryzodeg
®
BID ±OADs
BIAsp 30 BID ±OADs
INTENSIFY ALL
vs.
Ryzodeg
®
BID ±OADs
BIAsp 30 BID ±OADs
SIMPLE vs STEP-
WISE TWICE DAILY
vs.
Simple
Step-wise titration of
Ryzodeg
®
BID ±OADs
TWICE DAILY vs
BASAL-BOLUS
vs.
Ryzodeg
®
BID ±OADs
IDegonce daily + IAsp(2-4
injections/day) ±OADs

Ryzodeg
®
retains a consistent safety profile in
patients with different baseline characteristics
Ryzodeg
®
twice daily has the advantages of significantly lower rates of confirmed and nocturnal confirmed
hypoglycemia vs comparators across different baseline characteristic and category groups
Haluzík M, et al. Diabetes Obes Metab. 2018 Jul;20(7):1585-1592.
Nocturnalconfirmed hypoglycemia
stratifiedHbA
1Ccategory,diabetes duration and BMI
Confirmed hypoglycemia
stratifiedHbA
1Ccategory,diabetes duration and BMI
BMI, body mass index; HbA
1C, glycated hemoglobin
*
p<0.05;
**
p<0.01;
***
p<0.0001
Baseline
category
Baseline group Rate ratio [95%CI]
N, Ryzodeg
®
/
Comparators
HbA
1c
mmol/mol
53-<58.5 (7.0-7.5%) 0.66[0.46, 0.96]
*
161/102
≥58.5-<69.4 (≥7.5-<8.5%) 0.72 [0.58, 0.91]
**
474/286
≥69.4-<74.9 (≥8.5-9.0%) 0.68 [0.49, 0.93]
*
183/126
≥74.9 (≥9.0%) 0.74 [0.55, 1.00]
*
293/183
Diabetes
duration
≤10 years 0.61 [0.47, 0.79]
**
430/298
>10 years 0.76 [0.64, 0.90]
**
681/399
BMI
≤30 kg/m
2
0.81 [0.67, 0.98]
*
607/393
>30 kg/m
2
0.55 [0.45, 0.68]
***
504/304
Baseline
category
Baseline group Rate ratio [95%CI]
N, Ryzodeg
®
/
Comparators
HbA
1c
mmol/mol
53-<58.5 (7.0-7.5%) 0.54[0.33, 0.88]
*
161/102
≥58.5-<69.4 (≥7.5-<8.5%) 0.43 [0.30, 0.63]
***
474/286
≥69.4-<74.9 (≥8.5-9.0%) 0.41 [0.23, 0.72]
**
183/126
≥74.9 (≥9.0%) 0.36 [0.22, 0.59]
***
293/183
Diabetes
duration
≤10 years 0.31 [0.47, 0.49]
***
430/298
>10 years 0.48 [0.36, 0.62]
***
681/399
BMI
≤30 kg/m
2
0.43 [0.31, 0.60]
***
607/393
>30 kg/m
2
0.38 [0.27, 0.53]
***
504/304
1010.11010.1
Favors Ryzodeg
®
Favors Comparator Favors Ryzodeg
®
Favors Comparator

The pharmacological properties of Ryzodeg
®
are maintained in those with renal impairment
Pharmacokinetic results after dosing of IDegor IAspalone in patients with renal impairment
should also be representative for Ryzodeg
®
1. Kiss I, et al. Clin Pharmacokinet. 2014 Feb;53(2):175-83.2. Holmes G, et al. Br J Clin Pharmacol. 2005 Nov;60(5):469-76.
Mean plasma concentration -vs.-time profiles
for IAspfollowing subcutaneous injection
2
Simulated mean IDegconcentrations
at steady state
1
BMI, body mass index; HbA
1C, glycated hemoglobin; IAsp, insulin aspart; IDeg, insulin degludec
10,000
0.0
9,000
8,000
7,000
6,000
5,000
4,000
3,000
2,000
1,000
IDeg
serum concentration
(
pmol
/L)
Time since injection (hours)
024681012141618202224
Renal function
group
Severe
Moderate
Mild
Normal
60
0
50
40
30
20
10
Mean
IAsp
concentration
(
mU
/L)
Time (mins)
0 200 400 600 800 1,0001,2001,4001,600
Severe
Moderate
Mild
Normal
Degree of
renal impairment

Intensified insulin treatment using premixed or novel insulin
coformulations, such as Ryzodeg
®
, which target both fasting and
postprandial hyperglycemia, might be beneficial in Asian T2DM
1
1. Yang W, et al. Diabetes Ther. 2022 Feb;13(2):311-323. 2. Zhang XM, et al. Diabetes Metab Res Rev. 2018 Nov;34(8):e3062.
BG, blood glucose; T2DM, type 2 diabetes mellitus
Blood glucose excursion Adjusted blood glucose profiles
*
p<0.001
BG excursion and postprandial BG are higher among East Asian patients with T2DM than Caucasian patients
2
Pooled analysis for East Asian and Caucasian injection ‐naive patients with inadequate glycemic
control after oral antihyperglycemic medication
2
5
0
4
2
1
3
Blood glucose excursion
(mmol/L)
Breakfast Lunch Dinner Daily
*
*
*
*
15
8
14
13
12
11
10
9
Blood glucose
(mmol/L)
Daily
Pre Post Pre Post Pre Post PostPre
DinnerLunchBreakfast
**
*
Caucasian East AsianCaucasian East Asian
*

Ryzodeg
®
is useful for those failing to achieve glycemic
control despite optimisingcurrent non-insulin
therapies or with basal or premixed insulins
Glastras SJ, et al. J Clin Med. 2020 Apr 11;9(4):1091.
BID, twice daily; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; OAD, oral antidiabetic drug; OD, once daily; SGLT2i, sodium-glucose cotransporter-2 inhibitor;
TID, three times daily; T2DM, type 2 diabetes mellitus; BG, blood glucose
Situations where Ryzodeg
®
could be considered in T2DM patients requiring insulin therapy
Basal insulin
OD, BID
Ryzodeg®OD/BID
OD to BID
Ryzodeg®
OD to BID
Ryzodeg®
OD to BID
Ryzodeg
®
OD to BID
Ryzodeg
®
OD to BID
Ryzodeg
®
Premixed insulin OD, BID, TID
Basal-plus/
Basal-bolus
Ryzodeg
®
OD/BID
Switch to
Ryzodeg®
OD/BID
Switch to
Ryzodeg
®
OD/BID
Switch to
Ryzodeg
®
OD/BID
Premixed insulin
OD, BID, TID
Treatment intensification options with Ryzodeg
®
Insulin initiation
Poor
glycemic
control
on
multiple
OADs +/-
GLP-1
RAs

Conclusion
1. Tien KJ, et al. Diabetes Care. 2013 Oct;36(10):3027-32. 2. American Diabetes Association. Diabetes Care. 2023;46(Suppl. 1):S191–S202; 3. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes
Work Group. Kidney Int. 2022 Nov;102(5S):S1-S127. 4. Rizvi AA, et al. Eur Med J Diabetes. 2016;4(1):74-83. 5. Garber AJ, et al. Diabetes Obes Metab. 2006 Jan;8(1):58-66. 6. RysP, et al. Int J Clin Pract.
2014 Mar;68(3):304-13. 7. LieblA, et al. Drugs R D. 2018 Mar;18(1):27-39.8.Haluzík M, et al. Diabetes Obes Metab. 2018 Jul;20(7):1585-1592; 9. Glastras SJ, et al. J Clin Med. 2020 Apr 11;9(4):1091.
BIAsp, biphasic insulin aspart; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; FPG, Fasting plasma glucose;HbA
1C, glycated hemoglobin; IAsp, insulin aspart; IDeg, insulin degludec;
OAD, oral antidiabetic drugs; PPG, postprandial plasma glucose; T2DM, type 2 diabetes mellitus
Diabetes with CKD
reduced the progression of
renal function decline
2
•Potent in glucose-lowering
•Can be used across all eGFR levels
3
BIAsp30
-a biphasic premixed insulin analogue
Ryzodeg
®
-new co-formulation IDegAsp
Non-inferiority in glycemic control (HbA
1C)
vs. BIAsp 30
7
increased morbidity and mortality
1
Optimal glycemic control Insulin
⚫Dual-action PK profiles and targets both FPG and PPG
4,5
⚫A safe, effective, and simple-to-use insulin
for initiation and intensification after 15-year clinical use
worldwide
7
⚫Cost effective in T2DM
7
⚫Added to OADs results in a better glycemic control
without rise in hypoglycemic risk vs. basal insulin in
T2DM patients
6
For T2DM patients in need of
insulin initiation or intensification
8,9
Flexibility
in dose timing
Better
PPG control
Lower
hypoglycemia risk

開啟糖尿病患者早期
治療對話框
吉泰內科診所
辛世杰

Outline
Dia-besity
GLP-1 RAs recommended as initial therapy for T2D by current guidelines
Rybelsus
®
, the only oral GLP-1 RA approved for treatment of T2D
Efficacy and benefits of GLP-1 RAs in T2D:
•Improvement of glycemic control
•Effective weight management
•Reduction of complications
Safety across PIONEER series
Rybelsus
®
, also proven by real-world data
Special considerations and summary
GLP-1 RA, glucagon-like peptide-1 receptor agonist; T2D, type 2 diabetes.

胖..的人多嗎？

Header
肥胖是國安問題？

有沒有健康的胖(微肉肉)？

Hazard ratios of metabolic syndrome were
➢BMI 23-24.9: 4.68 (2.22-9.86)
➢BMI 25-26.9:8.82(4.01-19.4)
➢BMI>27:24.4(12.3-48.4)
Each kg/m
2
BMI gained:
Increased 18%HTN
Increased 26%Metabolic syndrome

Diabetes and Obesity

Novo Nordisk
®
•In particular, the prevalence of CVD or high risk
factors for CVD was significantly increased even
in the non-obese population with BMI ≥23
kg/m
2
11
Endocrinol Metab2015;30:514-521

AACE -2023

Obesity has higher risk of T2DM.
Fatdiabetic patients have higher risk of complications.

<24
24-27 27-30
>30

糖尿病患的體重管理 –ADA 2024

GLP-1 RAs offer significant weight loss in T2D
Weight loss effects for different therapies at 1 year or as specified
GLP-1 RA, glucagon-like peptide 1 receptor agonist; T2D, type 2 diabetes.
Blü her M, et al. Diabetes ObesMetab. 2023 Aug;25(8):2058-2072.
Bariatric surgery
Pharmacotherapy +
Lifestyle intervention
Lifestyle intervention
Gastric
bypass
Sleeve
gastrectomy
Gastric
band
Adapted from figure 1.
Weight loss
(%)
0 3 5 10 15 20 25 30 35

Novo Nordisk
®
Waist circumference
1
-14.4 cm
Systolic blood pressure
1
-5.7mmHg
HbA
1cimprovements
1
-0.43%
Placebo: -5.2 cm Placebo: -1.6 mmHg Placebo: -0.1%
Triglycerides
1
-19%
C-reactive protein
1
-57%
Prediabetes remission*
1
80%*
Placebo: -7.8% Placebo: 3.7% Placebo: 37%
*Exploratory endpoint, proportion of patients who reverted to normoglycemia (according to American Diabetes Glycemic category)byend of trial.
HbA1c, glycated hemoglobin.
1. Garvey WT et al. Nat Med. 2022;28:2083-91; 2. Yuen MM et al. Obesity Week 2016. Oct 31–Nov 4 2016. New Orleans: T-P-3166.
What is the value of new generation
pharmacotherapy beyond weight management? Effective chronic weight
management improves
cardiometabolic
risk factors
Improvement in cardiometabolic risk factors
has the potential for long-term health benefits,
preventing or improving obesity related
complications (e.g. cardiovascular diseases)
and improving overall health.
Improvements in
health must go beyond the
number on the scale
Obesity is a gateway
disease to obesity-related
complications
2
Maintenance of weight loss
15.2%weight reduction

Novo Nordisk
®
*T2D remission rates have been found to plateau at 20-25% total weight loss where 25% total weight loss did not confer additionalbenefits
BP, blood pressure; CV, cardiovascular; GERD, gastro-oesophageal reflux disease; HbA1c, glycated hemoglobin; HFpEF, heart failure with preserved ejection fraction; NAFLD; non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; OSAS, obstructive sleep apnoea
syndrome; PCOS, polycystic ovary syndrome; T2D, type 2 diabetes; TG, triglycerides.
1. Horn D et al. Postgrad Med. 2022;134:359–75; 2. Garvey WT et al. EndocrPract. 2016;22(Suppl. 3):1–203; 3. Look AHEAD Research Group, Gregg EW et al. Lancet Diabetes Endocrinol. 2016;4:913–21; 4. Lean ME et al. Lancet. 2018;391:541–51; 5. SundströmJ et al.
Circulation. 2017;135:1577–85; 6. BenraouneF & Litwin SE. CurrOpinCardiol. 2011;26:555–61; 7. MeerasaA & Dash S. Diabetes Care 2022;45:28–30;8.Teasdale, N et al.Int J Obes2007;31:153–160; 9.Ryan DH and YockeySR. CurrObesRep 2017;6:187–94.
Most PwOcan achieve
significant weight loss,
health benefits and
improved QoL
Improvements in
health must go beyond the
scale
Increased weight loss is
associated with
improvements in obesity
comorbidities
1-5
Greater sustained weight loss leads to
improved health benefits in obesity related
complications.
Greater weight loss leads to improved health
How can we improve health and
quality of life in people with obesity?
Magnitude of weight loss (%)
Weight loss leads to overall health improvements in:
✓Hypertension
1
✓Hyperglycemia
1
✓PCOS
1
✓NAFLD
1
✓CV mortality
3
✓T2D remission
4
✓Hepatic steatosis
5
✓OSAS
1
✓GERD
1
✓NASH
1
✓Cardiovascular disease
1
✓Urinary stress incontinence
2
✓Knee osteoarthritis
1
✓Prevention of T2D
1
✓Dyslipidemia
15–10%
10–15%
15–20%
>20%
✓HFpEF
6
✓Advanced T2D remission
7,8*
✓Postural instability
9
0–5%

我已經有糖尿病了，減重有幫助嗎？

Effects of weight loss on mechanisms of hyperglycemiain people
with obesity and T2D
Values are expressed as means ±SE (except for age, expressed as mean ±SD) *P< .01. †P< .001. ‡N= 5. §P< .05
SD, standard deviation; SE, standard error; T2D, type 2 diabetes
Henry et al. Diabetes. 1986;35(9):990–8 Copyright and all rights reserved. Material from this publication has been used with the permission of AmericanDiabetes Association
What are the quantitative effects of weight loss on metabolic parameters?
Clinical and metabolic characteristics Before treatment After treatment
Age (yr)
Sex
Duration of diabetes (yr)
Therapy of diabetes
54 ±4
5 male, 3 female
7 ±2
7 on hypoglycemicagents,
1 on no treatment
Weight (kg)
Body mass index (kg/m
2
)
Fasting plasma glucose (mg/dl)
Total glycosylated hemoglobin(%)
102.9 ±5.1
34.4 ±1.8
277 ±21
11.9 ±0.8
86.1 ±3.7*
28.7 ±1.0*
123 ±8†
7.5 ±0.4*
Fasting plasma cholesterol (mg/dL)
Fasting plasma triglyceride (mg/dL)
Fasting serum free fatty acids (μeq/L)‡
Fasting serum insulin (μU/mL)
Fasting serum glucagon (pg/mL)
Adipocyte cell volume (pL)
Adipocyte cell surface area (x 10
4
μm
2
)
181 ±14
351 ±124
791 ±87
17 ±4
229 ±15
851 ±91
4.30 ±0.31
135 ±12*
125 ±22*
379 ±35§
15±2
141 ±12†
475 ±48†
2.92 ±0.20†
1986
16%
weight
loss

Weight management in T2D patients led to
remission and improved CV outcomes
AHEAD, Action for Health in Diabetes; AMI, acute myocardial infarction; BMI, body mass index; CVD, cardiovascular disease; DiRECT, Diabetes Remission Clinical Trial; HbA
1C, glycated hemoglobin; T2D, type 2
diabetes.
1. Lean ME, et al. Lancet. 2018 Feb 10;391(10120):541 -551. 2.Lean ME, et al. Lancet Diabetes Endocrinol. 2019 May;7(5):344-355.
3. Look AHEAD Research Group, et al. Lancet Diabetes Endocrinol. 2016 Nov;4(11):913 -921.
Study DiRECT
1,2
Look AHEAD
3
Patients T2D adult patients with BMI 27–45 kg/m
2
(N=298) Overweight and obese (BMI >25 kg/m
2
) adults with T2D (N=4,834)
Groups Weight management program vs. best-practice care by guidelines
Diabetes support and educationvs. intensive lifestyle intervention
for 4 years
Duration 2 year 10.2 years
Results
Weight management group:
•Diabetes remission 46% ,with oddsratio 19.7 (p<0.0001)
at 1
st
year
1
•Diabetes remission 36%, with oddsratio 25.82 (p<0.0001)
at 2
nd
year
2
(Definedas HbA
1cless than 6·5% after at least 2 months off all
antidiabetic medication)
1
•Primary outcome rate ratio ↓21% (p<0.05)
(Definedas first occurrence ofnon-fatal AMI or stroke,
hospitalized angina, or CVD death.)
•Secondary outcome rate ratio ↓24% (p<0.05)
(Primary endpoint plus coronary artery bypass grafting, carotid
endarterectomy, percutaneous coronary intervention,
hospitalization for congestive heart failure, peripheral vascular
disease, or total mortality)
DiRECT
1,2
Look AHEAD
3

DiRECT: Achieving and maintaining weight loss is critical for
diabetes remission
1. Lean ME et al. Lancet. 2018;391:541–51; 2. Lean ME et al. Lancet Diabetes Endocrinol. 2019;7:344–355; 3. Al-MrabehA, et al; Lancet DiabetesEndocrinol2020; 8:939-48.
“Interpretation: These data show for the
first time…reversibility of the abnormal
pancreas morphology of type 2 diabetes by
weight loss-induced remission”
At 1
year
1
achieved diabetes
remission 46%
Weight loss of 10–15 kg: 57%achieved diabetes remissions
Weight loss of ≥15 kg: 86%achieved diabetes remissions
Maintained ≥10 kg weight
loss
24% 11%
Maintained ≥15 kg weight
loss
At 2 years
2
At 2 years
2
Achieved diabetes remission
64% 70%
Achieved diabetes remission
In responders (remission)
3
:
Increase in pancreas volume
Normalized regularity of
pancreatic borders
Increase in maximal
insulin secretion
Reprinted from The Lancet Diabetes & Endocrinology. Vol. 8, Al-MrabehA, Hollingsworth KG, Shaw JAM, McConnachieA, Sattar
N, Lean MEJ, Taylor R.
2-year remission of type 2 diabetes and pancreas morphology: a post-hoc analysis of the DiRECTopen-label, cluster-randomised
trial, Pages 939-48., Copyright (2022), with permission from Elsevier

早期，積極的減重可以預防
甚至逆轉糖尿病

Dia-besity
1.GLP-1RA
2.SGLT2inhibitor

GLP-1 RAs recommended as
an appropriate initial therapy for
T2D by current guidelines
GLP-1 RA, glucagon-like peptide-1 receptor agonist; T2D, type 2 diabetes.

Evidence from CVOTs in patients with T2D has shown that SGLT2 inhibitors
and GLP-1 RAs have beneficial effects on CV outcomes
EMPA-REG
OUTCOME
1
(empagliflozin)
CANVAS
Program
2,3
(canagliflozin)
DECLARE-
TIMI 58
4
(dapagliflozin
)
ELIXA
5
(lixisenatide)
LEADER
6
(liraglutide)
EXSCEL
7
(exenatide)
SUSTAIN-6
8
(injectable
semaglutide)
Harmony
Outcomes
9
(albiglutide)
PIONEER 6
(oral
semaglutide)
10
REWIND
(dulaglutide)
11
Highlights indicate that the upper bound limit of the confidence interval for the active versus placebo comparison is below unity
Non-fatal
MI
HR 0.87
(95% CI 0.70, 1.09)
p=0.23*
HR 0.89
(95% CI 0.73, 1.09)
‡
HR 0.89
(95% CI 0.77, 1.01)
‡
HR 1.03
(95% CI 0.87, 1.22)
p=0.71*
HR 0.88
(95% CI 0.75, 1.03)
p=0.11*
HR 0.97
(95% CI 0.85, 1.10)
‡,††
HR 0.74
(95% CI 0.51, 1.08)
p=0.12*
HR 0.75
(95% CI 0.61, 0.90)
p=0.003*
HR 1.18
(95% CI 0.73, 1.90)
‡
HR 0.96
(95% CI 0.79, 1.16)
p=0.65*
Non-fatal
stroke
HR 1.24
(95% CI 0.92, 1.67)
p=0.16*
HR 0.90
(95% CI 0.71, 1.15)
‡
HR 1.01
(95% CI 0.84, 1.21)
‡
HR 1.12
(95% CI 0.79, 1.58)
p=0.54*
HR 0.89
(95% CI 0.72, 1.11)
p=0.30*
HR 0.85
(95% CI 0.70, 1.03)
‡, ††
HR 0.61
(95% CI 0.38, 0.99)
p=0.04*
NR
HR 0.74
(95% CI 0.35, 1.57)
‡
HR 0.76
(95% CI 0.61, 0.95)
p=0.017*
CV death
or HHF
HR 0.66
(95% CI 0.55, 0.79)
p<0.001*
HR 0.78
(95% CI 0.67, 0.91)
p=0.002*
HR 0.83
(95% CI 0.73, 0.95)
p=0.005*
NR NR NR NR
HR 0.85
(95% CI 0.70, 1.04)
p=0.113*
NR NR
HHF
HR 0.65
(95% CI 0.50, 0.85)
p=0.002*
HR 0.67
(95% CI 0.52, 0.87)
‡
HR 0.73
(95% CI 0.61, 0.88)
‡
HR 0.96
(95% CI 0.75, 1.23)
p=0.75*
HR 0.87
(95% CI 0.73, 1.05)
p=0.14*
HR 0.94
(95% CI 0.78, 1.13)
‡
HR 1.11
(95% CI 0.77, 1.61)
p=0.57*
NR
HR 0.86
(95% CI 0.48, 1.55)
‡
HR 0.93
(95% CI 0.77, 1.12)
p=0.46
*
CV
death**
HR 0.62
(95% CI 0.49, 0.77)
p<0.001*
HR 0.87
(95% CI 0.72, 1.06)
‡
HR 0.98
(95% CI 0.82, 1.17)
‡
HR 0.98
(95% CI 0.78, 1.22)
p=0.85*
HR 0.78
(95% CI 0.66, 0.93)
p=0.007*
HR 0.88
(95% CI 0.76, 1.02)
‡
HR 0.98
(95% CI 0.65, 1.48)
p=0.92*
HR 0.93
(95% CI 0.73, 1.19)
p=0.578*
HR 0.49
(95% CI 0.27, 0.92)
‡
HR 0.91
(95% CI 0.78, 1.06)
p=0.21*
3P-MACE
HR 0.86
(95% CI 0.74, 0.99)
p=0.04
HR 0.86
(95% CI 0.75, 0.97)
p=0.02
†
HR 0.93
(95% CI 0.84, 1.03)
p=0.17
HR 1.02
(4P-MACE)
(95% CI 0.89, 1.17)
p=0.81
HR 0.87
(95% CI 0.78, 0.97)
p=0.01
HR 0.91
(95% CI 0.83, 1.00)
p=0.06
HR 0.74
(95% CI 0.58, 0.95)
p=0.02
§
HR 0.78
(95% CI 0.68, 0.90)
p=0.0006
HR 0.79
(95% CI 0.57, 1.11)
p=0.17
HR 0.88
(95% CI 0.79, 0.99)
p=0.026

最新2024 ADA第2型糖尿病藥物治療流程圖
延續ADA/EASD共識
30
https://diabetesjournals.org/care/issue/46/Supplement_1.

GLP-1 RAs are recommended as
appropriate initial therapy for T2D
to achieve and maintain glycemic and weight control
Adapted from American Diabetes Association Professional Practice Committee. Diabetes Care. 2024 Jan 1;47(Suppl 1):S158 -S178 figure 9.3 and Davies MJ, et al. Diabetes Care. 2022 Nov 1;45(11):2753-2786 figure 3.
ADA, American Diabetes Association; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; CVOT, cardi ovascular outcomes trial; DPP-4i, dipeptidyl peptidase 4 inhibitor; EASD, European
Association for the Study of Diabetes; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HF, heart failure; SGLT2i, sodium-glucose cotransporter 2 inhibitor; T2D, type 2 diabetes; TZD, thiazolidinedione.
1. American Diabetes Association Professional Practice Committee. Diabetes Care. 2024 Jan 1;47(Suppl 1):S158 -S178. 2. Davies MJ, et al. Diabetes Care. 2022 Nov 1;45(11):2753-2786.
2024 ADA/2022 ESAD
guidelines

GLP -1 RA 新的健保規範
節錄自陳志宏醫師

Rybelsus 取得糖尿病用藥第一線之適應症
原適應症：搭配飲食及運動療法，⽤於治療⾎糖控制不良的第⼆型糖尿病成⼈病⼈，
以改善⾎糖控制
–若病⼈因耐受不良或有禁忌症⽽不適合使⽤ metformin，可做為單⼀療法
–與其他糖尿病藥物合併使⽤。
新適應症：單一療法或與其他糖尿病治療藥物併用，治療控制不佳的第⼆型糖尿病
成⼈病⼈，作為飲食及運動之外的輔助治療。
Approval date: 2-Jan-2024
TFDA許可證及仿單係統已更新

03
Rybelsus
®
, the only oral
GLP-1 RA approved for
treatment of T2D
GLP-1 RA, glucagon-like peptide-1 receptor agonist; T2D, type 2 diabetes.

With SNAC as absorption enhancer, Rybelsus
®
was
as effective as s.c.semaglutide in glycemic control
GLP-1, glucagon-like peptide-1; s.c., subcutaneous; sema, semaglutide; SNAC, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate.
1. Anderson A, et al. Drugs. 2021 Jun;81(9):1003-1030. 2. Overgaard RV, et al. Cell Rep Med. 2021 Sep 3;2(9):100387.
Oral semaglutide
1
94%homology to human GLP-1
Plasma t
½of approximately 1 week
HisAib Thr ThrSerPheGluGly Asp
Val
Ser
SerTyrLeuGluGlyAlaAla GlnLys
Phe
Glu
IleAlaTrpLeu GlyVal GlyArgArg
8
26
34
Amino acid substitution prevents C-18 fatty
acid binding at wrong site
Amino acid substitution protects against
DPP-4 degradation
Spacer and C-18 fatty di-acid
chain provide strong binding to
albumin
Spacer
COOH
Absorption enhancer (SNAC)
Increases bioavailabilityof oraladministration
Sodium N-(8-(2-hydroxybenzoyl) Amino) Caprylate
O
O
O
-
Na
+
H
N
OH
Semaglutide exposure
via different routes of administration
2

04
Efficacy and benefits of
early and long-term use of
GLP-1 RAs in T2D
GLP-1 RA, glucagon-like peptide-1 receptor agonist; T2D, type 2 diabetes.

04-1
Improvement of glycemic control

Early glycemic control leads to
persistent legacy effects on reducing complications
UKPDS T2D (N=5,102 in 1977, N=484 in 2021)
1977 -2021
Intensive glycemic control vs.
conventional diet control
1997
(UPKDS 33)
2007
(UKPDS 80)
2021
(UKPDS 44-year FU)
Median follow-up 10.0 years 16.9 years 17.4 years
Any diabetes-related endpoint
12%
(p=0.029)
9%
(p=0.040)
10%
(p=0.016)
Myocardial infarction
16%
(p=0.052)
15%
(p=0.014)
15%
(p=0.0074)
Microvascular disease
25%
(p=0.0099)
24%
(p=0.001)
26%
(p<0.0001)
All-cause mortality 6% 13% 11%
Relative risk reduction of endpoints
FU: follow-up; RRR, relative risk reduction; SU, sulfonylurea; T2D, type 2 diabetes; ; UKPDS, UK Prospective Diabetes Study.
Holman RR. Presented at EASD Congress 2022. Session S22. https://www.easd.org/media-centre/#!resources/clinical-outcomes-at-44-years-do-the-legacy-effects-persist. Accessed
22Jan2024.
UKPDS:
44-year follow-up

Rybelsus
®
was effective
in reducing HbA
1Cin all types of T2D patients
a
HbA
1C reduction was not the primary endpoint in PIONEER 6 or 7.
b
event-driven trial: efficacy outcomes were not analyzed statistically.
*
p<0.05 for the estimated treatment difference with oral semaglutidevs. placebo and/or
active comparator;
†
p<0.05 for the estimated treatment difference with comparator vs. oral semaglutide 3 mg.
Change in HbA
1C–End of treatment in the PIONEER trials, by the treatment policy estimand
CKD, chronic kidney disease; CVD, cardiovascular disease; dula, dulaglutide; empa, empagliflozin; HbA
1C, glycated hemoglobin; imp, impairment; lira, liraglutide; met, metformin; OAD, oral antidiabetic drug; pbo,
placebo; sema, semaglutide; SGLT2i, sodium-glucose co-transporter-2 inhibitor; sita, sitagliptin; SU, sulfonylurea; T2D, type 2 diabetes.
Thethi TK, et al. Diabetes Obes Metab. 2020 Aug;22(8):1263-1277.
PIONEER
programme

Asian patients in some PIONEER trials
achieved greater HbA
1C reduction with Rybelsus
®
An exploratory subgroup analysis evaluated the effect of race on HbA
1C and body weight reductions at the end of treatment in PIONEER trials
AA, African American; flex, flexible dose; HbA
1C, glycated hemoglobin; Ins, insulin; Met, metformin; OAD, oral antidiabetic drug; SGLT2i, sodium-glucose co-transporter-2 inhibitor; SU, sulfonylurea; T2D, type 2
diabetes.
Desouza C, et al. Diabetes 2020;69(Supplement_1):930 -P.
Change in HbA
1C from baseline to end of treatment, by race
*
p<0.05 unadjusted two-side test of treatment by subgroup interaction.
†
Baseline data are for the oral semaglutide14 mg arm, and were generally similar to the comparator arm.
PIONEER
Sub-analysis by race

Efficacy and safety of Rybelsus
®
in T2D Chinese patientsOral semaglutide3 mg
Diet and
exercise
Week:
N=521
Randomization
(1:1:1:1)
Screening Dose escalation
End of
treatment
Follow-up
visit
–5–4 –10 4 8 26 31
Run-in
3 mg Oral semaglutide7 mg
Placebo
3 mg Oral semaglutide14 mg7 mg
HbA
1C, glycated hemoglobin; T2D, type 2 diabetes.
Key inclusion criteria:
•Adults aged ≥18years
(≥20 years if in Taiwan)
•Diagnosed with T2D with HbA
1c7.0–10.0%
and not receiving any anti-diabetic drugs
•After the 4-week run-in period, participants
with HbA
1c7.0–9.5% were randomized
PIONEER
11 & 12
PIONEER 11
1
PIONEER 12
2
Key inclusion criteria:
•Adults aged ≥18years (≥20 years if in
Taiwan)
•Diagnosed with T2D for ≥60days prior to
screening
•On a stable dose of metformin for ≥60 days
prior to screening
•HbA
1C 7.0–10.5%
N=130
N=130
N=130
N=131
N=361
N=360
N=361
N=359
1. Wang W, et al. Presented at the International Diabetes Federation conference, 5-8 December 2022. Abstract number: LI2022 -0613.
2. Ji L, et al. Presented at the International Diabetes Federation conference, 5-8 December 2022. Abstract number: LI2022 -0780.

Rybelsus
®
significantly reduced HbA
1C
in T2D Chinese patients
Estimated mean change in HbA
1C at week 26
of treatment-naïve patients
1
CI, confidence interval; ETD, estimated treatment difference; HbA
1C, glycated hemoglobin; T2D, type 2 diabetes.
PIONEER
11 & 12
Estimated mean change in HbA
1C at week 26
of patients uncontrolled with metformin
2
1. Wang W, et al. Presented at the International Diabetes Federation conference, 5-8 December 2022. Abstract number: LI2022 -0613.
2. Ji L, et al. Presented at the International Diabetes Federation conference, 5-8 December 2022. Abstract number: LI2022 -0780.

GLP-1 RAs are as effective as insulin
in achieving and maintaining target HbA
1Clevels
CI, confidence interval; DPP-4i, dipeptidyl peptidase 4 inhibitor; GLP-1 RA, glucagon-like peptide 1 receptor agonist; GRADE, the Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness
Study; HbA
1C, glycosylated hemoglobin; HR, hazard ratio; SU, sulfonylurea; T2D, type 2 diabetes.
GRADE Study Research Group, et al. N Engl J Med. 2022 Sep 22;387(12):1063 -1074.
GRADE
T2D <10 years (N=5,047)
receiving metforminHbA
1C 6.8-
8.5%
5 years
•GLP-1 RA (liraglutide) (n=1,262)
•Basal insulin (glargine U-100)
(n=1,263)
•SU (glimepiride)(n=1,254)
•DPP-4i(sitagliptin)(n=1,268)
Primary metabolic outcome (patient % of HbA
1C≥7%)
100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6
Years since randomization
Cumulative incidence (%)
No, contributing data over time
5047
p<0.001 by log-rank test
66
1202
DPP-4i (n=1,268)
SU (n=1,254)
Basal insulin (n=1,263)
GLP-1 RA (n=1,262)
77.4%
72.4%
67.4%
68.2%
1.37
*
(1.27-1.48)
1.01 (0.93-1.09)
0.87
*
(0.80-0.94)
0.84
*
(0.78-0.91)
HR vs.
with all other treatments combined(95% CI)
Participants no.
(%)
*
p≤0.001
GRADE

Novo Nordisk
®
44
Rybelsus有很好的降血糖效果，特別是東方人。
那什麼時候開始使用呢？

Earlier initiation of Rybelsus
®
results
inmore people reaching glycemic targets
n 7699 8392 70105 8296
PIONEER 1
Post-hoc analysis
A post-hoc analysis of the PIONEER 1 study to assess the efficacy of oral semaglutide vs placebo in people with T2D duration ≤1 year and >1 year for comparison
HbA
1C, glycated hemoglobin; T2D, type 2 diabetes.
Goldenberg R, et al. Can J Diabetes. 2021 Nov;45(7_Supplement):S28 -S29.
Proportions of patients (HbA
1C ≤6.5%) Proportions of participants (HbA
1C <7%)
54.4
58.1
68.3
29.2
25.9
41.7
67.8
13.2
0
20
40
60
80
100
Oral
semaglutide
3 mg
Proportions of patients
(%)
Oral
semaglutide
7 mg
Oral
semaglutide
14 mg
Placebo
Diabetes duration ≤1Diabetes duration >1
n 7699 8392 70105 8296
69.1
79.7
83.3
46.2
50.6
63.9
78.2
22.1
0
20
40
60
80
100
Proportions of patients
(%)
Oral
semaglutide
3 mg
Oral
semaglutide
7 mg
Oral
semaglutide
14 mg
Placebo
Earlier is better ！

Key to reach glycemic goal
1.Right medication (efficacy and durability)
2.Timing (early start and early combination)

04-2
Effective weight management

Rybelsus
®
was effective
in reducing body weight in all types of T2D patients
Change in body weight –End of treatment in the PIONEER trials, by the treatment policy estimand
a
Event-driven trial: efficacy outcomes were not analyzed statistically.
*
p<0.05 for the estimated treatment difference with oral semaglutidevs. placebo and/or active comparator.
CKD, chronic kidney disease; CVD, cardiovascular disease; dula, dulaglutide; empa, empagliflozin; imp, impairment; lira, liraglutide; met, metformin; OAD, oral antidiabetic drug; pbo, placebo; sema, semaglutide;
SGLT2i, sodium-glucose co-transporter-2 inhibitor; sita, sitagliptin; SU, sulfonylurea; T2D, type 2 diabetes.
Thethi TK, et al. Diabetes Obes Metab. 2020 Aug;22(8):1263-1277.
PIONEER
programme

Rybelsus
®
significantly reduced body weight
in T2D Chinese patients
Estimated mean change in body weight
at week 26 of treatment -naïve patients
1
CI, confidence interval; ETD, estimated treatment difference; HbA
1C, glycated hemoglobin; T2D, type 2 diabetes.
PIONEER
11 & 12
Estimated mean change in body weight at week 26
of patients uncontrolled with metformin
2
1. Wang W, et al. Presented at the International Diabetes Federation conference, 5-8 December 2022. Abstract number: LI2022 -0613.
2. Ji L, et al. Presented at the International Diabetes Federation conference, 5-8 December 2022. Abstract number: LI2022 -0780.

04-3
Reduction of complications

GLP-1 RAs significantly reduce risks for MACE
in T2D patients with increased CV risks
CI, confidence interval; CV, cardiovascular; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HF, heart failure; HR, hazard ratio; I
2
, heterogeneity; MACE, major adverse cardiovascular events; MI, myocardial
infarction.
Sattar N, et al. Lancet Diabetes Endocrinol. 2021 Oct;9(10):653-662.
Harmony
Outcomes
(N=9,463)
LEADER
(N=9,340)
EXSCEL
(N=14,775)
PIONEER 6
(N=3,183)
SUSTAIN 6
(N=3,297)
REWIND
(N=9,901)
AMPLITUDE -O
(N=4,076)
ELIXA
(N=6,068)
Meta-analysis(N=60,080)
MACE
14%
p<0.0001
HR 0.86
[95% CI 0.80, 0.93]
(I
2
=44.5%, p=0.082)
Hospitalizations
for HF
11%
p=0.013
HR 0.89
[95% CI 0.82, 0.98]
(I
2
=3.0%, p=0.41)
Fatal or
non-fatal stroke
17%
p=0.0002
HR 0.83
[95% CI 0.76, 0.92]
(I
2
=0.0%, p=0.64)
Fatal or
non-fatal MI
10%
p=0.020
HR 0.90
[95% CI 0.83, 0.98]
(I
2
=26.9%, p=0.21)
CV death
13%
p=0.0010
HR 0.87
[95% CI 0.80, 0.94]
(I
2
=13.4%, p=0.33)

Potential multiple mechanisms of CV risk reduction
in T2D by Rybelsus
®
Rybelsus
®
CV risk reduction
▼Atherosclerosis
▼Inflammation
1,2
▲Lipid homeostasis
3,4
▼Body weight
3,4
▼Blood pressure
3,4
▼HbA
1c
3,4
CV, cardiovascular; HbA
1C, glycated hemoglobin; T2D, type 2 diabetes.
1. ArodaV, et al. Diabetes Care. 2019 Sep;42(9):1724-1732. 2. RodbardHW, et al. Diabetes Care. 2019 Dec;42(12):2272-2281. 3.MarsoSP, et al. N Engl J Med. 2016 Nov
10;375(19):1834-1844. 4. Husain M, et al. N Engl J Med. 2019 Aug 29;381(9):841-851.

GLP-1 RAs shown to have a time-dependent
cardiovascular protective effect
“Positive” correlation between MACE ARR
and time of exposure to GLP -1 RAs
“Negative” correlation between MACE HR
and time of exposure to GLP -1 RAs
AMPLITUDE-O, Effect of Efpeglenatideon Cardiovascular Outcomes; ARR, absolute risk reduction; CVOT, cardiovascular outcomes trial; ELIXA, the Evaluation of Lixisenatidein Acute Coronary Syndrome; EXSCEL,
Exenatide Study of Cardiovascular Event Lowering; GLP-1 RA; Glucagon-like peptide-1 receptor agonists; HR, hazard ratio; LEADER,Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular
Outcome Results; MACE, major adverse cardiovascular events; SUSTAIN -6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutidein Subjects With Type 2 Diabetes; HARMONY,
Harmony Outcomes trial; REWIND, Dulaglutide and Cardiovascular Outcomes in Type 2 Diabetes.
Caruso I, et al. Diabetes Care. 2022 Feb 1;45(2):e30-e31.
Correlation between percentage of time of exposure to GLP -1RA and the risk of MACE in CVOTs
Longer is better ！

Cardiovascular safety of Rybelsus
®
in T2D patients in PIONEER 6
PIONEER 6
T2D patients with high CV risk (N=3,183) Median 15.9 months Oral semaglutidevs. placebo
CI, confidence interval; CV, cardiovascular; T2D, type 2 diabetes.
Husain M, et al. N Engl J Med. 2019 Aug 29;381(9):841-851.
Cardiovascular outcome

Rybelsus
®
demonstrated the significant
effects of improving cardiometabolic risk factors
CVOT, cardiovascular outcomes trial; HbA
1C, glycated hemoglobin; LDL, low-density lipoprotein; SBP, systolic blood pressure; s.c., subcutaneous.
ArodaVR, et al. Presented at the Hybrid 58th EASD Annual Meeting on 21 December 2022.
*
p<0.05 for estimated odds ratio vs comparator.
**
p<0.001 for estimated odds ratio vs comparator;
***
p≤0.0001 for estimated odds ratio vs comparator.
†
p<0.05 for estimated odds ratio vs placebo only in PIONEER 4.
‡
p<0.05
for estimated odds ratio vs liraglutide only in PIONEER 4.
§
Time to primary endpoint: 26 weeks for PIONEER 1–5 and 8.
Proportion of patients achieving improvements in cardiometabolic risk factors
PIONEER 1-8
Post-hocanalysis

Rybelsus
®
significantly reduced
multiple CV risk factors in T2D patients
Proportion of patients achieving multiple improvements
CV, cardiovascular; CVOT, cardiovascular outcomes trial; LDL, low-density lipoprotein; SBP, systolic blood pressure; s.c., subcutaneous; T2D, type 2 diabetes.
ArodaVR, et al. Presented at the Hybrid 58th EASD Annual Meeting on 21 December 2022.
Besides the four endpoints in the previous page, the post-hoc analysis also include an increase or no worsening of estimated glomerular filtration rate change ≥0 mL/min/1.73 m2 as an endpoint.
*
p<0.05 for estimated odds ratio vs comparator.
**
p<0.001 for estimated odds ratio vs comparator.
***
p≤0.0001 for estimated odds ratio vs comparator.
†
p<0.05 for estimated odds ratio vs placebo only in PIONEER 4.
‡
p<0.05
for estimated odds ratio vs liraglutide only in PIONEER 4.
§
Time to primary endpoint: 26 weeks for PIONEER 1–5 and 8.
PIONEER 1-8
Post-hocanalysis
Improve multiple risk factors (A1c, BW, SBP and LDL-C)

CVOTs have been conducted with semaglutide
in T2D patients: SUSTAIN 6 and PIONEER 6
CKD, chronic kidney disease; CV, cardiovascular; CVOT, cardiovascular outcome trial; MACE, major adverse cardiovascular event s; MI, myocardial infarction; R, randomization;
SoC, standard of care; T2D, type 2 diabetes.
1. Marso SP, et al. N Engl J Med. 2016 Nov 10;375(19):1834 -1844. 2. Husain M, et al. N Engl J Med. 2019 Aug 29;381(9):841-851.
SUSTAIN 6
1
Time and event-driven
0.5 or 1.0 mg semaglutide+ SoC
Placebo + SoC
n=3,297
Treatment duration 104weeks
PIONEER 6
2
Event-driven
14 mg oralsemaglutide + SoC
Placebo + SoC
n=3,183
Continuation until accrual of at least 122events (first
occurrence of MACE)
Similarities
1,2
Inclusion criteria:
•Age ≥50 years and established CV
disease or CKD or
•Age≥60 years and CV risk factors
Endpoint:
•Time to first occurrence of MACE,
defined as CV death, non-fatal MI,
or non-fatal stroke
Differences
1,2
PINOEER 6:
•A shorter trial duration
•Smaller number of events
R
R
Median follow-up: 2.1 years
Number of MACE recorded: 254
Median follow-up: 1.3 years
Number of MACE recorded: 137
Riskreduction of MACE:
1
26%
Riskreduction of MACE:
2
21%
SUSTAIN 6 vs. PIONEER 6
ConfirmsCV safety and
superiority of semaglutidevs.placebo
ConfirmsCV safety and
non-inferiority of semaglutidevs.placebo

Semaglutidesignificantly reduces
MACE risk in a broad range of T2D population
Relative risk of MACE as a function of baseline CV risk
CI, confidence interval; CV, cardiovascular; CVOT, cardiovascular outcomes trial; HR, hazard ratio; MACE, major adverse cardiovascular events; T2D, type 2 diabetes.
Husain M, et al. Cardiovasc Diabetol. 2020 Sep 30;19(1):156.
HR for treatment effect (semaglutidevs comparator) and 95% CI estimated using a stratified Cox proportional hazards model including effects of treatment, CV riskscore and interaction between both. The x-axis shows the CV
risk score derived from subjects’ baseline characteristics in the semaglutidetrials. Data on graph cut off at the 5th and 95th percentile of the whole dataset. Hazard ratio value of 1.00 is indicated byahorizontal dashed line.
Underlying histograms: distribution of subjects in the glycemic efficacy trials or CVOTs across baseline CV risk scores (histogram data for 439 subjects not shown, as these subjects had a CV risk score of <–3.0 or >0.0).
SUSTAIN and PIONEER
Pooled analysis

Safety across PIONEER series
05

The most frequent AEs were mild -to-moderate
and transient gastrointestinal disturbances
19.5 19.8
44.0
26.1
12.0
9.0
36.4
30.8
34.0
41.0
36.0 36.5
12.0 15.0
20.4
7.3
36.4
14.0
15.0
6.0
48.0
14.0
24.0
10.0
18.9
16.9 17.0
4.0
0.0
10.0
20.0
30.0
40.0
50.0
PIONEER 5
Renal
26 weeks
PIONEER 3
vs sitagliptin
78 weeks
Proportion of subjects (%)
PIONEER 7
Flex
52 weeks
PIONEER 1
monotherapy
26 weeks
PIONEER 2 vs
empagliflozin
52 weeks
PIONEER 4
vs liraglutide
52 weeks
PIONEER 6 PIONEER 8
insulin
52 weeks
PIONEER 9
*
52 weeks
PIONEER 10
52 weeks
14.8
4.0
NR
Sema
7
mg
3
mg
14
mg
Pbo SemaEmpa
14
mg
25
mg
Sema
7
mg
3
mg
14
mg
Sita
100
mg
SemaLiraPbo
14
mg
1.8
mg
Sema
14
mg
Pbo Sema
14
mg
Pbo Sema
14
mg
Sita
100
mg
Sema
7
mg
3
mg
14
mg
Pbo Sema
7
mg
3
mg
14
mg
Lira
0.9
mg
Sema
7
mg
3
mg
14
mg
Dula
0.75
mg
Pbo
Proportion of patients with gastrointestinal AEs ( nausea, vomiting & diarrhea )
AE, adverse event; Dula, dulaglutide; Empa, empagliflozin; Lira, liraglutide; NR, not recorded; Sema, semaglutide; Sita, sitagliptin; Pbo, placebo.
Smits MM, et al. Front Endocrinol (Lausanne). 2021 Jul 7;12:645563.
PIONEER
programme

06
Rybelsus
®
, also proven
by real-world data

Metabolic risk factors assessment of Rybelsus
®
in a real-world Japanese study
DPP-4, Dipeptidyl peptidase-4; GLP-1 RA, glucagon-like peptide-1 receptor agonist; SGLT2, Sodium-glucose cotransporter 2; T2D, type 2 diabetes.
YanaiH, et al. CardiolRes. 2022 Oct;13(5):303-308.
A retrospective study using an
electronic medical record to
obtain information about
patients
T2D patients who have not been
treated with injectable glucose-
lowering drugs previously
Metabolic parameters were
compared at baseline with data at 3
and 6 months after starting of
Rybelsus
®
Initiated treatment with
oral semaglutidefrom
March 2021 to June
2022
Baseline characteristics (N=47)
Age (mean) 58.2 years old
Male sex 25 (53.2%)
Treatment for T2D at baseline
DPP-4 inhibitors 30 (63.8%)
Metformin 35 (74.5%)
SGLT2 inhibitors 39 (83.0%)
Sulfonylurea 8 (17.0%)
⍺-glucosidase inhibitors 7 (15.0%)
Pioglitazone 17 (36.2%)
Insulin 3 (6.4%)
GLP-1 analogues
Subcutaneous semaglutide
Dulaglutide
11 (23.4%)
8 (17.0%)
3 (6.4%)
Adapted from table 1.
REAL Japan

Rybelsus
®
demonstrated significant improvements in
HbA
1C, body weight, SBP, LDL-C and UACR
Changes in metabolic parameters from baseline in all patients
ALT, alanine aminotransferase; AST, aspartate ami-notransferase; eGFR, estimated glomerular filtration rate; GGT, gamma-glutamyl transferase; HbA
1C, glycated hemoglobin; HDL-C, high-density lipoprotein
cholesterol; LDL-C, low-density lipoprotein cholesterol; non-HDL-C, non-high-density lipoprotein cholesterol; SBP, systolic blood pressure; TG, triglyceride; UA, uric acid; UACR, urinary albumin to creatinine ratio.
YanaiH, et al. CardiolRes. 2022 Oct;13(5):303-308.
*
p<0.1.
**
p<0.05 vs. baseline.
Significantly reduce (after 6M):
•Body weight(2.4kg)
•SBP
•HbA1c
•LDL-C
•Non-HDL-C
•UACR

Cardiovascular prevention of GLP -1 RAs
in real-world T2D population
BMI, body mass index; CV, cardiovascular; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA
1C, glycated hemoglobin; T2D, type 2 diabetes.
PicciniS, et al. Cardiovasc Diabetol. 2023 Mar 25;22(1):69.
Baseline characteristics
Primary prevention
(without history of CV diseases)
n=395
Secondary prevention
(with history of CV diseases)
n=155
Age, years 61.6 ±10.1 66.3 ±7.8
Male sex 193 (48.86%) 119 (76.77%)
BMI, kg/m
2
34.2 ±5.8 32.2 ±5.9
Diabetes duration, years 8 (0-48) 11 (0-50)
HbA
1c, % 8.22 ±1.36 7.87 ±1.33
Duration of follow up, years 5.0 (0.25-10.8) 3.6 (0-10.3)
Duration of GLP-1 treatment, years 3.2 (0-10.8) 2.5 (0-10.3)
GLP-1 RA discontinuation 159 (40.25%) 63 (40.65%)
Top 3 reasons for discontinuation
GI symptoms
Inefficacy
Noncompliance
50 (31.4%)
74 (46.5%)
11 (6.9%)
24 (38.1%)
25 (40.0%)
3 (4.8%)
A retrospective cohort study
using electronic medical records in a single hospital
T2D patients who first received a GLP-1 RA for the first time
between 12/1/2009 and 12/31/2019 were split into two groups
based on with or without history of CV diseases
Follow-up data until
12/31/2021 were
included
Adapted from table 1 and table 3.

Early discontinuation of GLP-1 RA was associated with
a higher risk for MACE
GLP-1 RA; Glucagon-like peptide-1 receptor agonists; HbA
1C, glycated hemoglobin; MACE, major adverse cardiovascular events.
The main composite CV outcome (MACE) included non -fatal myocardial infarction or unstable angina,
non-fatal stroke, all-cause death
PicciniS, et al. Cardiovasc Diabetol. 2023 Mar 25;22(1):69.
Results are adjusted by year.
The anti-inflammatory and anti -atherogenic effects of GLP-1 RAs, which lead to
plaque stabilization over time, may potentially explain the time -dependent risk reduction
Cardiovascular events during follow -up
MACE results
(multivariable time-dependent Cox regression analysis)

Special considerations

Wake up fastingand takeyour RYBELSUS
®
tablet with
up to half a glass of water (approximately 120 mL )
Wait at least 30 minutes before eating,
drinking or taking any other oral medication
Have your first meal and drink of the day and
take any other medications you need
a
The3 mg dose is intended for treatment initiation and is not effective for glycemic control.
RYBELSUS® package insert. Plainsboro, NJ: Novo Nordisk Inc; April 2021.
DO not split, crush, or chew.
Swallow RYBELSUS
®
whole
30
mins
+
Administration of RYBELSUS
®

Patient profiles and outcomes
BMI, body mass index; CKD, Chronic kidney disease; FSG, fasting serum glucose; GI, gastrointestinal; GLP -1 RA, glucagon-like peptide 1 receptor agonist;
HbA
1C, glycosylated hemoglobin; TITR, time in tighter range
Patient profiles 12 weeks
50years old
Weight
BMI
HbA
1C
FSG
TITR
OnXigduo
80kg
26.73kg/m
2
7.4%
108mg/dL
GI side effect
76.4kg
25.52kg/m
2
6.7%
94mg/dL
Change
(from baseline)
3.6kg
-1.21kg/m
2
-0.7%
-14mg/dL
nausea

您以為這樣就結束了嗎？

Reduce 24%kidney disease progression, renal or CV death

13.3%

Take home messages
Dia-besityand weight management
Early, aggressive BW reduction (TLC, pharmacotherapy
or surgery)
Oral semaglutide–Rybelsus
空腹服用 , water < 120 ml, fasting at least 30 mins
Semaglutideis not only Semaglutide

Thanks

1130525--家醫計畫2.0糖尿病照護研討會-社團法人高雄市醫師公會.pdf

About This Presentation

Slide Content

Tags

Categories

Download

Quick Actions

Statistics

Related Slideshows

1130525--家醫計畫2.0糖尿病照護研討會-社團法人高雄市醫師公會.pdf

About This Presentation

Slide Content

Slide 1

Slide 2

Slide 3

Slide 4

Slide 5

Slide 6

Slide 12

Slide 13

Slide 15

Slide 24

Slide 25

Slide 26

Slide 27

Slide 28

Slide 29

Slide 30

Slide 31

Slide 32

Slide 33

Slide 34

Slide 41

Slide 42

Slide 44

Slide 49

Slide 51

Slide 52

Slide 53

Slide 54

Slide 57

Slide 58

Slide 59

Slide 60

Slide 61

Slide 62

Slide 63

Slide 64

Slide 65

Slide 66

Slide 67

Slide 68

Slide 69

Slide 70

Slide 71

Slide 72

Slide 73

Slide 74

Slide 75

Slide 76

Slide 77

Slide 78

Slide 79

Slide 80

Slide 81

Slide 82

Slide 83

Slide 84

Slide 85

Slide 86

Slide 87

Slide 88

Slide 89

Slide 90

Slide 91

Slide 92

Slide 93

Slide 94

Slide 95

Slide 96

Slide 97

Slide 98

Slide 99

Slide 100

Slide 101

Slide 102

Slide 103

Slide 104

Slide 105