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乳鹭干
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1 慢性腎臟病與糖尿病藥物光田綜合醫院新陳代謝科曾士婷醫師藥物動力學 2 1

全球糖尿病盛行率盛行率改變 28.5% 兩者互動 31.8% 從 1 億 8 百萬到 4 億 2 千 2 百萬人人口結構改變 39.7% Lancet. 2016 Apr 5. pii: S0140-6736(16)00618-8. doi: 10.1016/S0140-6736(16)00618-8.

2 全球糖尿病盛行率盛行率改變 28.5% 兩者互動 31.8% 從 1 億 8 百萬到 4 億 2 千 2 百萬人人口結構改變 39.7% Lancet Apr 5. pii: S (16) doi: /S (16) Prevalence of diabetes in East Asian countries compared to the United States and Europe: Estimates for 2015 Country Diabetes prevalence in 2015 (%) Diabetes comparative prevalence in 2015 (%) Adults with undiagnosed diabetes (20-79) in 1,000s China Hong Kong Taiwan Singapore Japan Korea Australia USA UK IDF Diabetes Atlas I Seventh edition I Atlas, IDF Diabetes. 7th." International Diabetes Federation (2015). 2

Chronic Complications of DM Diabetic Retinopathy Leading cause of blindness in working age adults 1 Diabetic Nephropathy 30% of Type 1 Diabetes 40% of Type 2 Diabetes

cause of non-traumatic lower extremity amputations 5 1 Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99 S102. 2 Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94 S98.

5 Progression of DN Progression of diabetic nephropathy 25 Years from diagnosis of diabetes 20 15 10 5 Stage 2 Hypertension Stage 3 Proteinuria Stage 4 Rising

3 Chronic Complications of DM Diabetic Retinopathy Leading cause of blindness in working age adults 1 Diabetic Nephropathy 30% of Type 1 Diabetes 40% of Type 2 Diabetes Stroke 2 to 4 fold increase in cardiovascular mortality and stroke 3 Cardiovascular Disease 8/10 diabetic patients die from CV events 4 Diabetic Neuropathy Leading cause of non-traumatic lower extremity amputations 5 1 Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99 S Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94 S98. 3 Kannel WB, et al. Am Heart J 1990; 120: Gray RP & Yudkin JS. In Textbook of Diabetes Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78 S79. 5 Progression of DN Progression of diabetic nephropathy 25 Years from diagnosis of diabetes Stage 2 Hypertension Stage 3 Proteinuria Stage 4 Rising creatinine Stage 5 ESRD Hyperfiltration GBM thickening,mesengial expansion Stage 2 Microalbuminuria-BP rising 0 The kidney at a glance. 2000; Blackwell Science Ltd. 6 3

4 per million population 05/12/2017 Recommendations Diabetic Kidney Disease Optimize glucose control Optimize blood pressure control (<140/90 mmhg) Dietary protein intake Not dialysis dependent: 0.8 g/kg body weight per day. on dialysis: higher levels of dietary protein intake should be considered ACEI or ARB American Diabetes Association Standards of Medical Care in Diabetes. Microvascular complications and foot care. Diabetes Care 2016; 39 (Suppl. 1): S72-S80 Prevalence of ESRD Atlas of End-Stage Renal Disease in the United States 4

GFR (ml/min) 05/12/2017 Diabetes, the Leading

2008 9 The Progressive Nature of DN Type 2 DM

5 GFR (ml/min) 05/12/2017 Diabetes, the Leading Cause of ESRD in Taiwan since 2000 TSN Renal Registry1990~2001,Nephrology Dialysis Transplantation 23: Yang WC & Hwang SJ, The Progressive Nature of DN Type 2 DM (20-40%) J Clin Invest Feb;116(2): Time after diagnosis (yr) 10 5

6 Prediction Probability for Incidence or Progression of CKD After 5.5 years in T2DM For incidence of CKD For progression of CKD UACR (mg/g) UACR (mg/g) egfr CKD-EPI egfr CKD-EPI Modified from Clin J Am Soc Nephrol Aug 7;10(8): Predicted Probabilities for Death within 5.5 years in T2DM For death For death UACR (mg/g) UACR (mg/g) egfr CKD-EPI egfr CKD-EPI Modified from Clin J Am Soc Nephrol Aug 7;10(8):

7 Diabetic Nephropathy-DN GFR-Glomerular filtration rate Proteinuria 13 Stages of CKD 15 Stage Description GFR (ml/min/1.73m2) 1 Kidney damage with normal or GFR 2 Kidney damage with mild GFR 3 Moderate GFR Severe GFR Kidney failure < 15 NKF KDOQI GUIDELINES 7

8 Hyperglycemic Damage Pathway 13 Clinical diabetes, Vivian A. Fonseca, 2006 Type 1 DM Type 2 DM Hyperglycemia Metabolic change Reactive oxygen species Inflammatory cytokines Growth & apopototic factor Hemodynamic change Vasopressor peptide Sympathetic activation Elevation in blood pressure Diabetic Nephropathy (DN) Clinical Diabetes, Vivian A. Fonseca,

9 CKD 造成血糖異常之各項因素 37 1 CKD 造成血糖異常之各項因素糖監測困難

Diabetes and ESKD Reducing insulin requirements Difficult vascular access Accelerated macrovascular disease Advanced microvascular disease Frequent

10 Diabetes and ESKD Reducing insulin requirements Difficult vascular access Accelerated macrovascular disease Advanced microvascular disease Frequent sepsis Silent ischaemia 2-3 x death rate vs non-dm patients 20 Burnt-Out Diabetes Semin Dial March ; 27(2): doi: /sdi

11 Burnt-Out Diabetes 1. 營養不良糖尿病導致的胃腸消化不良 2. 因為腎臟對胰島素的清除率下降, 導致胰島素作用延長 3. 因為肝臟對胰島素的清除率下降, 導致胰島素作用延長 4. 因為腎臟萎縮降低腎臟的醣類再生作用 5. 累積一些毒素例如 guanidino compounds, 和 biguanide agents 構造相似 22 糖化血色素目標 01/Semin Dial March ; 27(2): doi: /sdi

12 與糖代謝有關的實驗室及臨床數據糖化血色素 (A1C) 空腹血糖 (AC sugar) 餐後血糖 (PC sugar) 血漿 C-peptide 濃度 C 血漿 insulin 濃度 A B 24 建議的血糖控制目標 Adapted from 中華民國糖尿病學會 2006 第 2 型糖尿病照護指引 p.9. 12

13 口口服抗糖尿病藥物 Oral Antidiabetic Drugs (OAD) 服抗糖尿病藥物 Oral Antidiabetic Drugs (OAD) 26 Nephrol Dial Transplant (2014) 29: /11/

口服降血糖藥物的種類胰島素分泌促進劑 (insulin secretagogues) 磺醯尿素 (sulfonylureas)

Biguanides) Glitazones (Thiazolidinediones, TZD) 阿爾發 - 葡萄糖甘酶抑制劑

Sites of Oral Drug Classes Pancreas Impaired insulin secretion Liver

glucose overproduction Biguanides TZDs DPP-4 inhibitors Glucose level

resistance TZDs Biguanides DPP-4=dipeptidyl peptidase 4;

In: Williams Textbook of Endocrinology. 10th ed.

14 口服降血糖藥物的種類胰島素分泌促進劑 (insulin secretagogues) 磺醯尿素 (sulfonylureas) Glinides ( 又稱 Meglitinides 類似物 ) 胰島素敏感劑 (insulin sensitizer) 雙胍類 ( Biguanides) Glitazones (Thiazolidinediones, TZD) 阿爾發 - 葡萄糖甘酶抑制劑 (α-glucosidase inhibitor ) 二肽基肽酶抑制劑 (DPP-4 Inhibitor) 28 Major Targeted Sites of Oral Drug Classes Pancreas Impaired insulin secretion Liver Sulfonylureas Meglitinides DPP-4 inhibitors Muscle and fat Hepatic glucose overproduction Biguanides TZDs DPP-4 inhibitors Glucose level Gut Glucose absorption α-glucosidase inhibitors Biguanides Insulin resistance TZDs Biguanides DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003: ; DeFronzo RA. Ann Intern Med. 1999;131: ; Inzucchi SE. JAMA 2002;287: ; Porte D et al. Clin Invest Med. 1995;18:

15 醫院常見之口服降血糖藥物 (1) Sulfonylurea 學名商品名劑量範圍 (mg/day) Peak level (h) Halflife (h) 代謝途徑 ( 腎 / 肝 ) 健保價 ( 元 ) Glipizide GliDiab / / 5mg Gliclazide Mezide /25 5/ 80mg Glibenclamide Gliben ~ / / 5mg Glimepiride Amaryl / / 2mg Meglitinide Repaglinide Novonorm / / 1mg D-phenylalanine derivative Nateglinide Starlix /10 7.3/ 120mg 30 醫院常見之口服降血糖藥物 (2) Biguanide 學名商品名劑量範圍 (mg/da y) Metformin Glibudon a-glucosidase Inhibitor Peak level (h) Halflife (h) 代謝途徑 ( 腎 / 肝 ) 健保價 ( 元 ) / / 500mg Acarbose Glucobay ~ ~ ~ 5.8/ 50mg Thiazolidinedio ne Rosiglitazone Avandia ~ 39/ 4mg Pioglitazone Actos /80 59/ 30mg 31 15

16 選擇口服降血糖藥物之考量原則需依據患者之病情胰島素分泌不足 ( Insulin deficiency) 或胰島素作用不良 ( Insulin resistance)? 血糖之高低與糖尿病症狀之嚴重程度飲食習慣與進食狀況肝腎心臟功能與併發之疾病自理生活之能力與居家照顧之品質藥物之療效低血糖等副作用的風險價格因素 32 胰島素分泌促進劑磺醯尿素 (sulfonylureas) A1C 降低約 1-2% 最大降糖效果通常在仿單建議最大劑量的 1/2~2/3 時便已達到 Glinides (Meglitinides analogue) A1C 降低約 0.8% 作用快速, 須隨餐服用, 可降低餐後高血糖短效, 較少低血糖副作用 Repaglinide 不可與 gemfibrozil 併用 33 16

17 SU 的作用機轉 34 Insulin Secretagogues 類 01/11/

18 SFU in CKD Depends on Renal or Hepatic metabolism Depends also on whether metabolites have hypoglycemic effects

19 38 Insulin Sensitizers 類 01/11/

常見腸胃道一過性副作用, 低劑量起始可避免 40 肝腎心肺功能不良不宜使用, 以免發生 Biguanide( 雙胍類 )

20 Metformin 常用於過重或肥胖的 ( 準 ) 糖尿病患者並不刺激胰島素分泌, 單獨使用少見低血糖副作用抑制肝糖新生與製造, 因而降低空腹血糖治療後不會增加體重可改善血脂肪異常, 對內皮細胞功能等心血管危險因子有正向的影響常見腸胃道一過性副作用, 低劑量起始可避免 40 肝腎心肺功能不良不宜使用, 以免發生 Biguanide( 雙胍類 ) 的作用機轉 1. Metformin 降低肝臟中的葡萄糖新生作用 3. 促進 GLUT4 移動到細胞表面而增加胰島素敏感性 2. 降低或延遲腸道葡萄糖吸收 20

21 Thiazolidinediones 活化 peroxisome proliferative-activated receptor-γ (PPAR-γ), 而增加胰島素之敏感度, 降低空腹血糖及血中胰島素濃度降糖效果較緩慢, 通常需 6 至 8 週才見成效需在內生或外源性胰島素存在下才有作用可改善內皮細胞功能, 發炎指摽等心血管疾患危險因子與 metformin 併用對改善胰島素阻抗性有加成作用常見副作用有體重增加水腫等, 需密切追蹤肝指數如 ALT, 若 ALT 值超過正常上限的三倍, 應停藥 42 重度心臟衰竭者不宜使用 43 21

23 46 Acarbose 抑制近端小腸澱粉及雙醣類之分解, 延緩葡萄糖的吸收, 降低飯後血糖胰島素濃度, 甚至空腹血糖不被腸胃道吸收 (<1%) 無體重增加之副作用副作用為輕至中度的脹氣腹瀉 ; 自低劑量起始可減緩 (start low, go slow) 低血糖僅出現於合併療法時, 須使用葡萄糖或牛奶治療使用於輕中度糖尿病之單一治療或合併治療可減低葡萄糖耐量異常患者轉變為第 2 型糖尿病的機率及發生心血管疾患的風險, 減緩頸動脈內膜厚度增加速率 (STOP-NIDDM) 可減低第 2 型糖尿病患者心肌梗塞風險 (MeRIA) 47 23

α-glucosidase inhibitors 類 01/11/2013 1 DPP-4 Inhibitor 二肽基肽酶抑制劑作用機轉抑制 DPP-4 酵素提昇 incretins 濃度, 包括 GLP-1 及 GIP 的濃度 incretins

24 α-glucosidase inhibitors 類 01/11/ DPP-4 Inhibitor 二肽基肽酶抑制劑作用機轉抑制 DPP-4 酵素提昇 incretins 濃度, 包括 GLP-1 及 GIP 的濃度 incretins 是體內平衡葡萄糖生理調節之內因系統一部份, 當血糖升高時,GLP-1 與 GIP 會提高胰臟 β 細胞合成及釋出胰島素作用 ;GLP-1 也會降低 α 細胞昇糖素分泌作用, 進而降低肝臟葡萄糖生成副作用對照性臨床研究中, 不論單一或合併療法, 表現出良好耐受性, 出現臨床不良反應而停藥者與安慰劑相當 49 24

25 50 DPP-4 Inhibitor 二肽基肽酶抑制劑 : 提升活性 incretin 濃度 Meal Intestinal GIP and GLP-1 release DPP-4 Enzyme DPP-4 Inhibitor GIP-(1-42*) GLP-1(7-36)* Intact (active) X Rapid Inactivation GIP-(3-42)* GLP-1(9-36)* metabolites GIP and GLP-1 Actions *Refers to amino acid number. Deacon CF et al. Diabetes. 1995;44:

26 Incretin-Based Insulin Secrtagogues 類 01/11/

27 27

Nephrol Dial Transplant (2014) 1 29: 1284 1300 低血糖副作用及策略危險因子老年營養狀況不佳餐無定時或合併有肝腎功能異常者低劑量起始高危險族群考慮使用 glinide

28 Nephrol Dial Transplant (2014) 1 29: 低血糖副作用及策略危險因子老年營養狀況不佳餐無定時或合併有肝腎功能異常者低劑量起始高危險族群考慮使用 glinide 腎功能不良者考慮短效具不活性代謝物由肝臟排除者尤佳, 可使用 glinide 餐無定時或常誤餐者, 可使用 glinide 注意藥物交互作用 Alcohol, anticoagulant, trimethoprim 57 28

29 抗糖尿病藥物胰島素 58 何時需使用胰島素? 第 1 型糖尿病患者第 2 型糖尿病患者空腹血糖超過 300 毫克 / 毫升和合併酮體血症或酮體尿症持續性出現空腹血糖超過 300 毫克 / 毫升和出現多尿多喝及體重減輕的症狀糖尿病酮酸血症患者肝腎功能不良的糖尿病患者因急性病症住院的糖尿病或高血糖患者口服抗糖尿病藥物療效不佳者願意接受胰島素做為第一線治療的患者妊娠性糖尿病患者無法以飲食控制者 59 糖尿病婦女懷孕時 29

60 Insulin in pt. on hemodialysis Insulin inhibitors dialyzable Insulin resistance diminishes after the start of dialysis. half-life of insulin is prolonged.

30 60 Insulin in pt. on hemodialysis Insulin inhibitors dialyzable Insulin resistance diminishes after the start of dialysis. half-life of insulin is prolonged. the potential for hypoglycemia with both oral agents and insulin increases in the presence of CKD (with the exception of gliquidone and glimepiride). Self-monitoring of blood glucose concentration is imperative. 30

31 正常人血糖與胰島素濃度曲線 Continuous basal insulin secretion Incremental prandial insulin secretion 62 Starting Dose 1 x Basal 10 IU (bedtime) FBG value in millimoles per liter 0.16 IU/Kg 1 x Premix 10 IU ( Presupper) 2 x Premix 10 IU ( Prebreakfast), 10 IU ( Presupper) MDI Individualized 63 31

32 Scheme for Adding Basal or Intermediate-Acting Insulin to Oral Agents Start with 5 10 units; increase by 2 3 units every 3 days until FPG is between 110 and 120 mg/dl 64 Clinic- vs. Patient-driven Titration of Basal Insulin --AT.LANTUS Study Mean FBG for the previous 3 consecutive days Increase in daily basal insulin glargine dose (U) Algorithm 1: Clinic-driven titration at every visit Algorithm 2: Patient-driven titration every 3 days 100 and <120 mg/dl ( 5.5 and <6.7 mmol/l) 120 and <140 mg/dl ( 6.7 and <7.8 mmol/l) 140 and <180 mg/dl ( 7.8 and <10 mmol/l) 180 mg/dl ( 10 mmol/l) Davies M et al. Diabetes Care 2005;28:

33 Self-Titration of Insulin Detemir: The PREDICTIVE 303 Study 303 Algorithm Sites: Patients to adjust dose every 3 days based on mean FPG values FPG (mg/dl) Basal Dose Adjustment < 80 Reduce detemir dose by 3U No change >110 Increase detemir dose by 3U Standard-of-Care sites: Physician to adjust dose based on standard-of-care Meneghini et al. Diabetes Obes Metab. 2007; 9: Key Learning Points There are clinical advantages of pens over vial-and-syringe dosing 1,2 You may need to consider features, advantages, and disadvantages of insulin pens as well as patient needs when selecting an insulin pen There are unique features in the insulin pens demonstrated today that may help you individualise care for your patients 1. Summers KH, et al. Clin Ther. 2004;26(9): Cobden D, et al. Pharmacotherapy. 2007;27(7):

34 Why Use an Insulin Pen? Patients with diabetes may benefit from modern insulin injection pens that provide an accurate way to inject insulin. 1 Clinical advantages of pens over vial-and-syringe dosing Ease of use 2 Social acceptability 2 Lifestyle adaptability 2 Reduced risk for hypoglycaemic events 3 Overall reduced healthcare costs 3 1. Hänel H, et al. J Diabetes Sci Technol. 2008;2(3): Summers KH, et al. Clin Ther. 2004;26(9): Cobden D, et al. Pharmacotherapy. 2007;27(7): Why Use an Insulin Pen? (continued) Insulin pens: Accurate dosing 1-4 Flexible 2,3,5,6 Convenient 2,3,5,6 Discreet 2,4,5,6 Easy to use Shelmet J, et al. Diabet Res Clin Pract. 2004;63(1): Hänel H, et al. J Diabetes Sci Technol. 2008;2(3): Korytkowski M, et al. Clin Ther. 2005;27(Suppl B):S89-S Lombardo F, et al. Acta Biomed. 2005;76(S3):S66-S Korytkowski M, et al. Clin Ther. 2003;25(11): Bohannon NJ, et al. Clin Ther. 2000;22(9): Fox C, et al. Practical Diabetes International. 2002;19(4):

Humalog KwikPen Humalog KwikPen is an easy-to-use, easy-to-inject pre-filled pen 1 For patients who want a portable device For patients desiring discreet insulin delivery Select Safety Information:

35 Humalog KwikPen Humalog KwikPen is an easy-to-use, easy-to-inject pre-filled pen 1 For patients who want a portable device For patients desiring discreet insulin delivery Select Safety Information: Pens and needles are for single-patient use only and should not be shared, even in healthcare facilities, as infection or disease can be spread from one person to another. Do not withdraw insulin from the pen. 1. Data on file, Lilly USA, LLC; KwikPen Design Validation User Study. HUM A. 70 Humalog KwikPen (continued) Humalog KwikPen has the following advantages: Easy to set the dose Easy to see numbers Easy to dispense maximum dose of 60 units* Easy to dispense dose* Easy to dial up and back down for dose correction Short thumb-reach at high doses Small, lightweight, and portable *Humalog KwikPen Design Validation User Study included adult male and female participants with type 1 and type 2 diabetes. Of the total 150 study participants, 56 were insulin-naïve, 42 were currently administering insulin with a vial and syringe, and 52 were experienced insulin pen users. Data on file, Lilly USA, LLC; KwikPen Design Validation User Study. HUM A

KwikPen 讓使用胰島素變得更容易喜好度分數 1 Overall satisfaction 10.9 89.1 Easy to Use Use in work,school or public setting 9.1 8.2 90.9 91.8 Vial & Syringe Humalog KwikPen Easy to Learn 7.8 92.

72 Laboratory Evaluation of Humalog KwikPen TM vs FlexPen : Study Design Ergonomic and glide force injection measurements were evaluated for a new prefilled insulin pen (Humalog KwikPen) and compared

36 KwikPen 讓使用胰島素變得更容易喜好度分數 1 Overall satisfaction Easy to Use Use in work,school or public setting Vial & Syringe Humalog KwikPen Easy to Learn Percentage of respondents 1 1 好學好用喜好度高重量輕 1. Ignaut et al. Diabet Educ 2009;35(5): Laboratory Evaluation of Humalog KwikPen TM vs FlexPen : Study Design Ergonomic and glide force injection measurements were evaluated for a new prefilled insulin pen (Humalog KwikPen) and compared to the currently available prefilled insulin pen (FlexPen) Humalog KwikPen containing Humalog Mix75/25 (75% insulin lispro protamine suspension and 25% insulin lispro injection) 1,2 FlexPen containing NovoLog Mix 70/30 (70% insulin aspart protamine suspension and 30% insulin aspart) 3 1 Ignaut DA et al. J Diabetes Sci Technol 2008;2(3): Humalog and Humalog KwikPen are registered trademarks of Eli Lilly and Company FlexPen is a registered trademark of Novo Nordisk A/S 73 36

Laboratory Evaluation of Humalog KwikPen TM vs FlexPen Ergonomic Testing Results Humalog KwikPen (A) FlexPen (B) Overall Length (in) 5.69 6.23 Weight w/ cap (g) 31.12 23.

J Diabetes Sci Technol 2008;2(3):533-537 Humalog and Humalog KwikPen are registered trademarks of Eli Lilly and Company FlexPen is a registered trademark of Novo Nordisk A/S 74 Laboratory Evaluation

37 Laboratory Evaluation of Humalog KwikPen TM vs FlexPen Ergonomic Testing Results Humalog KwikPen (A) FlexPen (B) Overall Length (in) Weight w/ cap (g) Diameter across cartridge holder (in) Data from Ignaut DA et al. J Diabetes Sci Technol 2008;2(3): Humalog and Humalog KwikPen are registered trademarks of Eli Lilly and Company FlexPen is a registered trademark of Novo Nordisk A/S 74 Laboratory Evaluation of Humalog KwikPen TM vs FlexPen Thumb Reach Distances Distance (in) Humalog KwikPen (A) FlexPen (B) At 30 units At 60 units Data from Ignaut DA et al. J Diabetes Sci Technol 2008;2(3): Humalog and Humalog KwikPen are registered trademarks of Eli Lilly and Company FlexPen is a registered trademark of Novo Nordisk A/S 75 37

of Humalog KwikPen TM vs FlexPen Injection Force Characteristics 30-Unit Dose 60-Unit Dose Maximum Glide Force (lbs) Humalog KwikPen FlexPen Humalog KwikPen FlexPen 3.42 ± 0.35 5.36 ± 0.76 3.61 ± 0.

38 Laboratory Evaluation of Humalog KwikPen TM vs FlexPen Thumb Reach Dialed Out to 60 Units Humalog KwikPen FlexPen Ignaut DA et al. J Diabetes Sci Technol 2008;2(3): Humalog and Humalog KwikPen are registered trademarks of Eli Lilly and Company FlexPen is a registered trademark of Novo Nordisk A/S 76 Laboratory Evaluation of Humalog KwikPen TM vs FlexPen Injection Force Characteristics 30-Unit Dose 60-Unit Dose Maximum Glide Force (lbs) Humalog KwikPen FlexPen Humalog KwikPen FlexPen 3.42 ± ± ± ± 0.77 Average Glide Force (lbs) 3.31 ± ± ± ± 0.66 Glide Force Variability at Plateau Curve (lbs) 0.30 ± ± ± ± 0.42 Data represent the mean ± standard deviation; All treatment comparisons were statistically significant, P< Data from Ignaut DA et al. J Diabetes Sci Technol 2008;2(3): Humalog and Humalog KwikPen are registered trademarks of Eli Lilly and Company FlexPen is a registered trademark of Novo Nordisk A/S 77 38

39 Laboratory Evaluation of Humalog KwikPen TM vs FlexPen Glide Force Profile Units 60 Units Glide Force (lbs) KwikPen FlexPen Time (s) Time (s) Abbreviation: s, seconds. Data from Ignaut DA et al. J Diabetes Sci Technol 2008;2(3): Humalog and Humalog KwikPen are registered trademarks of Eli Lilly and Company FlexPen is a registered trademark of Novo Nordisk A/S 78 Laboratory Evaluation of Humalog KwikPen TM vs FlexPen Key Results Summary FlexPen Lighter in weight Smaller in diameter at the cartridge holder Humalog KwikPen Shorter in overall length Shorter thumb reach Requires less effort to inject Provides smoother and more consistent delivery Ignaut DA et al. J Diabetes Sci Technol 2008;2(3): Humalog and Humalog KwikPen are registered trademarks of Eli Lilly and Company FlexPen is a registered trademark of Novo Nordisk A/S 79 39

Percentage of Respondents 05/12/2017 Humalog KwikPen vs NovoLog FlexPen Patient Preference Primary Objective: Response to the Final Preference Question (FPQ) Which Insulin Pen Would You Prefer?

40 Percentage of Respondents 05/12/2017 Humalog KwikPen vs NovoLog FlexPen Patient Preference Primary Objective: Response to the Final Preference Question (FPQ) Which Insulin Pen Would You Prefer? n=155 NovoLog FlexPen Humalog KwikPen 40 n= FPQ Ignaut DA, et al. Diabet Educ. 2009;35(5): Humalog KwikPen vs NovoLog FlexPen Secondary Objective To what extent do you agree that the pen just assessed has these features? Overall ease of use 1 Ease of holding in hand when injecting 1 Ease of pressing injection button when injecting dose 1,2 Adapted from J Diabetes Sci Technol, Ignaut DA, et al. Diabet Educ. 2009;35(5): Ignaut DA, et al. J Diabetes Sci Technol. 2008;2(3):

41 Percentage of Respondents Percentage of Respondents 05/12/2017 Humalog KwikPen vs NovoLog FlexPen Pen Use Scores Was the Pen Overall Easy to Use? Other Agree Strongly Agree n=147 n= n=38 n=46 n=39 n=13 NovoLog FlexPen Humalog KwikPen P=.006 Humalog KwikPen vs FlexPen for users who either agreed or strongly agreed. *IDAB Question 14. Ignaut DA, et al. Diabet Educ. 2009;35(5): Humalog KwikPen vs NovoLog FlexPen Pen Use Scores (continued) Was the Pen Easy to Hold in Your Hand When You Injected? Other Agree Strongly Agree n=62 n=122 n=48 n=49 n=29 NovoLog FlexPen n=153 Humalog KwikPen P=.002 Humalog KwikPen vs FlexPen for users who either agreed or strongly agreed. *IDAB Question 4. Ignaut DA, et al. Diabet Educ. 2009;35(5):

42 Percentage of Respondents 05/12/2017 Humalog KwikPen vs NovoLog FlexPen Pen Use Scores (continued) 100 Was It Easy to Press the Injection Button? Other Agree Strongly Agree n=78 n=106 n=48 n=47 n=34 n=150 0 NovoLog FlexPen Humalog KwikPen P<.001 Humalog KwikPen vs FlexPen for users who either agreed or strongly agreed. *IDAB Question 5. Ignaut DA, et al. Diabet Educ. 2009;35(5): 謝謝大家 85 42

表 1 慢性腎臟疾病分期第一期:腎臟之結構或功能性異常伴隨 GFR 正常或上升 GFR 90 ml/min/1.73m 2 第二期:腎臟之結構或功能性異常伴隨 GFR 下降 GFR 介於 60~89 ml/min/1.73m 2 第三期:中等 GFR 下降 GFR 介於 30~59 ml/min/

表 1 慢性腎臟疾病分期第一期:腎臟之結構或功能性異常伴隨 GFR 正常或上升 GFR 90 ml/min/1.73m 2 第二期:腎臟之結構或功能性異常伴隨 GFR 下降 GFR 介於 60~89 ml/min/1.73m 2 第三期:中等 GFR 下降 GFR 介於 30~59 ml/min/ 1,3 2,3 4,5 前言 (chronic kidney disease) 40-50% 30mg/24h( 1 中山醫學大學附設醫院家庭暨社區醫學部住院醫師 2 中山醫學大學附設醫院家庭暨社區醫學部主治醫師 3 中山醫學大學醫學系家庭暨社區醫學科 4 中山醫學大學附設醫院內分泌暨新陳代謝科主治醫師 5 中山醫學大學醫學系內科 Type 2 diabetes mellitus, Chronic