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Insulin Glargine in the Management of Hyperglycemia in Type 2 Diabetes 林志慶 醫師 M.D. Ph.D. 國立陽明大學醫學院內科學系 台北榮民總醫院內科部腎臟科.

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Presentation on theme: "Insulin Glargine in the Management of Hyperglycemia in Type 2 Diabetes 林志慶 醫師 M.D. Ph.D. 國立陽明大學醫學院內科學系 台北榮民總醫院內科部腎臟科."— Presentation transcript:

1 Insulin Glargine in the Management of Hyperglycemia in Type 2 Diabetes 林志慶 醫師 M.D. Ph.D. 國立陽明大學醫學院內科學系 台北榮民總醫院內科部腎臟科

2 Outline 1. Goal and guideline of Diabetes treatment 2. OADs mechanism and dose adjustment in Patients with Advanced Kidney Disease 3. Insulin therapy in Patients with Advanced Kidney Disease 2

3 Outline 1. Goal and guideline of Diabetes treatment 2. OADs mechanism and dose adjustment in Patients with Advanced Kidney Disease 3. Insulin therapy in Patients with Advanced Kidney Disease 3

4 UKPDS: Improving HbA 1c Control Reduced Diabetes-Related Complications 4 4 UKPDS=United Kingdom Prospective Diabetes Study. Data adjusted for age, sex, and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years. Stratton IM et al. UKPDS 35. BMJ 2000;321:405–412. EVERY 1% reduction in HbA 1c REDUCED RISK (P<0.0001) 1% Diabetes- related deaths Myocardial infarctions Microvascular complications Amputations or deaths from peripheral vascular disorders 21% 14% 37% 43% Relative Risk N=3642

5 2007 AJKD guidelines 5 5  Target HbA1c for people with diabetes should be < 7.0%, irrespective of the presence or absence of CKD. (A)  Lowering HbA1c levels to approximately 7.0% reduces the development of microalbuminuria. (Strong)

6 2007 AJKD guidelines 6 6  Lowering HbA1c levels to approximately 7.0% reduces the development of macroalbuminuria. (Moderate)  Lowering HbA1c levels to approximately 7.0% reduces the rate of decrease in GFR.(Weak)

7 Outline 1. Goal and guideline of Diabetes treatment 2. OADs mechanism and dose adjustment in Patients with Advanced Kidney Disease 3. Insulin therapy in Patients with Advanced Kidney Disease 7

8 糖尿病治療選擇 - 藥物治療 8 糖尿病 有九大類治療藥物 口服 1. 磺醯尿素類 Sulfonylurea(SU) 2. Meglitinides 3. 雙胍類 Biguanide 4. Thiazolidinediones(TZD) 5. α-glucosidase inhibitors 6. 腸泌素增強劑 (DPP-4 inhibitor) 固定劑量複方藥物 注射劑 7. 胰島素 insulin 8. 胰淀素 pramlintide* 9.GLP-1 作用劑 (exenatide) 吸入型胰島素 (inhaled insulin) 7.Exubera®* * 未在台灣上市

9 Major Targeted Sites of Oral Drug Classes 9 Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303; Inzucchi SE. JAMA 2002;287: ; Porte D et al. Clin Invest Med. 1995;18:247–254. DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones. Glucose absorption Hepatic glucose overproduction Impaired insulin secretion Insulin resistance Pancreas ↓ Glucose level Muscle and fat Liver Biguanides TZDs Biguanides Sulfonylureas Meglitinides TZDs α-Glucosidase inhibitors Gut DPP-4 inhibitors Biguanides 15

10 Sulfonylureas (SU) 2nd-generation  作用機轉:胰島素分泌促進劑 (secretagogues) 刺激尚有功能的 β 細胞釋放出胰島素  副作用 低血糖 ( 不論血糖高糖,皆會刺激胰島素分泌,因而增加低血糖 發生率 ) 體重增加、光敏感、噁心、頭疼、皮疹 DrugDoseDaily dose/Frequency (mg) Amaryl (glimepiride) 2mg1~4mg qd Glidiab/Minidiab (glipizide) 5mg2.5~40mg /day qd or bid Glurenorm (gliquidone) 30mg15~120 mg qd Euglucon/Daonil (glyburide) 5mg1.25~20 mg /day qd or bid Diamicron MR (gliclazide) 30mg 80mg 30~120/day 40~320/day 10

11 11 Name Duration (hr) 代謝 Glibenclamide (Diabitin ® ) 原形由肝臟代謝為弱活性,代謝物 60 %由膽汁排泄, 40 %由尿液排泄 Gliclazide (Diamicron ® MR) 原型由肝代謝為無活性,然後 %由腎排出, 20 %由糞便排出 Glipizide (Minidiab ® ) 原型由肝代謝為無活性,然後由腎 排出 Glimepiride (Amaryl ® ) 24 原形由肝代謝成弱活性, 2/3 由尿 液排出, 1/3 從糞便 Sulfonylureas (SU)

12 2007 AJKD guideline 12

13 Meglitinides  作用機轉 : 胰島素分泌促進劑 ; 隨餐血糖調節劑 與 SU 相近的方式刺激 insulin 分泌 快速吸收與作用迅速而短暫 (faster onset and shorter duration vs. SU) ,必需在進食前服藥 血糖量愈低,釋出的胰島素量愈少 降低餐後血糖濃度  副作用 低血糖 ( 但比 SU 比例少,因其為短效藥物 ) 、體重增加  製劑 DrugDose(mg)Daily dose/Frequency (mg) Starlix (nateglinide) times/day before meal Novonorm (repaglinide) 1mg0.5~4 administrated with meal 2,3,4 times/day 13

14 14 Name Duration (hr) 代謝 Nateglinide (Starlix ® ) 2-6 肝代謝, 16 %原型由腎排出 Repaglinide (NovoNorm ® ) 2-6 完全肝代謝,膽汁排出 Meglitinides CKD stage 3 and 4 CKD stage 5/ Dialysis

15 Brand nameNovonorm (1mg)Starlix (120mg) Glufast (10mg) Product name RepaglinideNateglinideMitiglinide Dose mg tid mg tid mg tid Administration time Before meal, min Before meal, 1-30 min Before meal, 5 min ; with meal T max hr hr17 mins T 1/ hr hr72 mins Metabolite enzyme CYP3A4 (major) 、 2C8CYP 2C9 (70%) 、 3A4(30%) CYP 2C9 < 25% UGT 1A 3 or 9 (74%) Drug interaction Gemfibrozil, macrolide, cyclosporin, -conazole, CCB, ator- & sim-vastatin Warfarin, phenytoin, Rosu- and flu-vastatin No significant interaction Metabolites in urine 8-10 %80-83 %93 % (inactive) Safety - hypoglycemia - GI intolerance % 2-5 % 5.5 % 3.2 % 5.6 % 1.4 % Efficacy - HbA 1C ( mg tid, 12 wks); -1.7 % (120 mg tid, 24 weeks); % (5~10 mg tid, 52 weeks); % BNHI price Daily cost ~

16 Biguanide  Metformin 作用機轉 (1) 降低肝臟中的葡萄糖合成作用 (gluconeogenesis) (2) 降低或延遲腸道的葡萄糖吸收,減少飯後血糖上升 (3) 增加週邊組織的胰島素敏感性  副作用 常見初期腸胃不適 ( 噁心嘔吐、食慾不振 ) 腎功能不全者罕見的乳酸中毒報告  上市產品 DrugDose (mg) Daily dose and Frequency (mg) Glucophage (metformin) ~2550mg/day bid or tid 16

17 Biguanide 17 Name Duration (hr) 代謝 Glucophage (metformin) 6-12 幾乎所有原型由腎排出

18 Thiazoldinediones (TZDs) 又稱為 PPAR-γ 作用劑  作用機轉 : 與脂肪、肌肉、肝臟細胞核的 PPAR-γ receptor 結合, 來增加肝臟、脂肪、肌肉細胞的胰島素敏感性  副作用 : 與劑量相關的體重增加 輕度至中度的水腫及水份滯留  特別注意 : 會引發體液滯留,不能用在第 III 及 IV 心衰竭病人 應定期檢測肝功能 (ALT 上昇至 >2.5 倍 UNL) 不可用於肝功能受損病人  上市產品 : DrugDose(mg)Daily dose /Frequency (mg) Avandia (rosiglitazone)4 or 84~8mg/day qd or bid Actos (Pioglitazone)3015~45mg qd 18 Thiazolidinediones (TZDs)

19 19 Name Duration 代謝 Avandia (rosiglitazone) Weeks 完全肝代謝成無活性產物,腎 臟排出 Actos (Pioglitazone) Weeks 完全肝代謝成無或弱活性產物, 腎臟排出 Thiazolidinediones (TZDs)

20 α-Glucosidase Inhibitor  作用機轉 抑制腸內 α-glucosidase 的作用 ( 分解碳水化合 物的一群酵素 ) ,使碳水化合物在腸道被分解 為單糖和吸收延遲 ; 可降低糖尿病患者飯後的血糖濃度  副作用 腸胃副作用 ( 腹痛、腹瀉、脹氣 )  上市產品 Drug Dose (mg) Daily dose and Frequency (mg) Glucobay (acarbose) 5050~100 mg tid 20

21 α-Glucosidase 抑制劑 : acarbose 21 Name Duration (hrs) 代謝 Acarbose 2-6 不被吸收 Miglitol 2-6 不被吸收 Information about the long-term use of acarbose in patients with reduced kidney function is sparse and its use in patients with later stage 3 and stages 4 and 5 CKDis not recommended.

22 Definition of Incretins “Intestine-derived factors that increase glucose-stimulated secretion of insulin ” In ● cre ● tin Intestine Secretion Insulin Creutzfeldt. Diabetologia. 1985;28:

23 Incretin Hormones Regulate Insulin and Glucagon Levels GLP-1 = glucagon-like peptide-1; GIP = glucose insulinotropic polypeptide Adapted from Kieffer T. Endocrine Reviews. 1999;20:876–913. Drucker DJ. Diabetes CarAdapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. e. 2003;26:2929–2940. Nauck MA et al. Diabetologia. 1993;36:741–744. Pancreas Gut Nutrient signals ● Glucose Hormonal signals GLP-1 GIP Glucagon (GLP-1) Insulin (GLP-1,GIP) Neural signals  cells  cells 23

24 Time, min IR Insulin, mU/L nmol/L The Incretin Effect Is Diminished in Individuals With Type 2 Diabetes Control Subjects (n=8) Patients With Type 2 Diabetes (n=14) Time, min IR Insulin, mU/L nmol/L Oral glucose load Intravenous (IV) glucose infusion Normal Incretin Effect Diminished Incretin Effect IR = immunoreactive Adapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag. Vilsbøll T, Holst JJ. Diabetologia 2004;47:357–

25 DPP-4 Inhibition  作用機轉  上市產品 25 Drug Dose (mg) Daily dose and Frequency (mg) JANUVIA (sitagliptin)100100mg QD ONGLYZA (saxagliptin)2.5-5mg2.5-5mg QD 釋出活性 Incretin GLP-1 與 GIP 進食 腸胃道 DPP-4 酵 素 無活性 GLP-1 X Sitagliptin ( DPP-4 抑 制劑) 胰臟 無活性 GIP β 細胞 α 細胞

26 DPP-4 Inhibition 26 Name Duration (hrs) 代謝 JANUVIA (Sitagliptin) 12-24hrs 70-80% 腎臟排出,無法被透析排 出 ONGLYZA (Saxagliptin) 24hrs 全由肝臟代謝成無或弱活性產物, 後從腎臟排出,可以被透析洗出 Onglyza:  Moderate or severe CKD, or ESRD under hemodialysis: 2.5mg QD(post-H/D)  PD: no data 1#QD 0.5# QD 0.25# QD

27 GLP-1 Analogues  作用機轉 產生類似 GLP-1 的作用  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  上市產品 DrugDose (mg) Daily dose and Frequency (mg) BYETTA (exenatide)5-10mcg BID 27

28 GLP-1 Analogues 28  BYETTA is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 mL/min)  caution in patients with renal transplantation.  Moderate renal impairment (30-50 mL/min): caution should be applied when initiating or increasing doses of Byetta from 5 mcg to 10 mcg REFERENCE: U.S. Food and Drug Administration ?

29 Renal Side Effects of Exenatide  11/02/2009 FDA:  From April 2005 through October 2008, FDA received 78 cases of altered kidney function (62 cases of acute renal failure and 16 cases of renal insufficiency), in patients using Byetta. (total number: 6.6 million) 29

30 Outline 1. Goal and guideline of Diabetes treatment 2. OADs mechanism and dose adjustment in Patients with Advanced Kidney Disease 3. Insulin therapy in Patients with Advanced Kidney Disease 30

31 Insulin Action: Comparison of New Insulin Analogs Regular Rapid (Lispro, Aspart) Insulin Level (  U/ml) Hours Intermediate (NPH) Long 31

32 Preparations Onset(h) Peak(h)Duration(h) Lispro/Aspart < Regular NPH Ultralente < 20 Glargine1 - 2 > 24 Action Profiles Modified after Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.

33 Insulin therapy in renal disease 33

34 Insulin therapy in renal disease 34 BiesenbachG, Raml A, Schmekal B, Eichbauer-SturmG:Decreased insulin requirement in relation to GFR in nephropathic Type 1 and insulin-treated Type 2 diabetic patients. DiabetMed 20:642–645, 2003

35 Insulin therapy in renal disease  The American College of Physicians recommended: 35 GFR (mL/min)Insulin mL/min25% decrease <10 mL/min50% decrease Haemodialysisrequire less exogenous insulin ( peripheral insulin resistance ↓)

36 Insulin therapy in renal disease  OBJECTIVE— Type 2 diabetic patients with end- stage renal disease (ESRD) on maintenance hemodialysis.  CONCLUSIONS— The present study has demonstrated a significant 25% reduction in basal insulin requirements No significant change in boluses Overall the reduction of total insulin requirements was 15% 36

37 Insulin therapy in renal disease ↓GFR:  RI (rapid-acting insulin analogs): ↑ half-life and maximal serum concentrations  NPH (Caution!): long-acting ‘‘basal’’ insulin like glargine  Insulin detemir : binding to serum albumin after injection so less predictable in patients with nephrotic syndrome and hypoalbuminema 37

38 The ADA Treatment Algorithm for the Initiation and Adjustment of Insulin

39 ADA-EASD Guidelines  Achievement of normal glycemic goals  Initial therapy with lifestyle intervention and metformin  Early addition of insulin therapy in patients who do not meet target goals  Rapid addition of and transition to new regimens, when glycemic goals are not achieved

40 Management of Type 2 Diabetes ADA-EASD  Check HbA1c every 3 months until < 7% and then at least every 6 months  Insulin regimens under lifestyle and diet control  Initiation and intensification of insulin due to effectiveness and low expense although 3 oral agents can be used

41 New ADA/EASD algorithm for T2DM: Basal insulin is recommended for insulin initiation Nathan et al. Diabetes Care At diagnosis: Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Sulfonylureas Lifestyle + Metformin + Intensive insulin Tier 1: well-validated therapies STEP 1STEP 2STEP 3 Tier 2: Less well validated therapies Lifestyle + Metformin + Pioglitazone No hypoglycaemia Oedema/CHF Bone loss Lifestyle + metformin + GLP-1 agonist No hypoglycaemia Weight loss Nausea/vomiting Lifestyle + metformin + Pioglitazone + Sulfonylurea Lifestyle + metformin + Basal insulin Nathan DM, et al. Diabetologia 2009;52:17−30

42 - Insulin is the most effective drug in lowering BG - Insulin should be started with basal insulin - Basal Insulin is proposed as early as after Metformin - Then consider stepwise addition of bolus insulin starting with one shot at selected meal - Premixes are not recommended as first line insulin therapy ADA-EASD Consensus Key messages on insulin

43 The basal–bolus insulin regimen Insulin (mU/L) 06:00 12:00 24:00 18: :00 BreakfastLunch Dinner Physiological insulin Basal insulin Prandial insulin Time Figure adapted from Kruszynska YT, et al. Diabetologia 1987;30:16–21 Normal Insulin Secretion: The Basal-Bolus Insulin Concept

44 Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001). Adapted from Hirsch I, et al. Clin Diabetes 2005;23:78–86. Time of day (hours) Plasma glucose (mg/dl) Normal Meal Plasma glucose (mmol/l) Treating Fasting Hyperglycemia Lowers the Entire 24-hour Plasma Glucose Profile Hyperglycaemia due to an increase in fasting glucose T2DM

45 Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001). Adapted from Hirsch I, et al. Clin Diabetes 2005;23:78–86. Time of day (hours) Plasma glucose (mg/dl) Normal Meal Plasma glucose (mmol/l) Hyperglycaemia due to an increase in fasting glucose T2DM Long-acting basal insulin Treating Fasting Hyperglycemia Lowers the Entire 24-hour Plasma Glucose Profile

46 ADA/EASD Consensus Algorithm for Type 2 Diabetes Mellitus Nathan D, et al. Diabetologia 2006;49:1711−21. Initiation of Basal Insulin: Start with bedtime intermediate-acting insulin, or bedtime or morning long-acting insulin Can initiate with 10 units or 0.2 units per kg ↑ 2 units every 3 days, if 180> FBS >130 mg/dl ↑ 4 units every 3 days if FBS >180 mg/dl If hypoglycaemia or FBS 60 units

47 Insulin Therapy for Type 2 Diabetes: Rescue, Augmentation, and Replacement of Beta-Cell Function

48  -Cell function (%) Postprandial Hyper- glycemia IGT Type 2 Diabetes Phase I Type 2 Diabetes Phase II –12–10–6– Years from diagnosis Adapted from Lebovitz H. Diabetes Rev 1999;7: Destiny of Type 2 Diabetes Pancreatic  -Cell Decline Over Time in UKPDS Type 2 Diabetes Phase III Insulin therapy Rescue Replacement Augmentation

49 Rescue therapy Using replacement regimens for several weeks May reverse glucose toxicity Augmentation therapy With basal insulin If some β- cell function remains Starting dose: u/kg/d or units of insulin/d = FBS (mmol) = FBS/18 (mg/dl) e.g. FPG 180mg/dl  10 units FPG 270mg/dl  15 units

50 Early Aggressive Insulin Therapy Study in Taiwan 60 newly diagnosed type 2 diabetic patients hospitalized patients with severe hyperglycemia were hospitalized and treated with intensive insulin injections for days. 50 patients randomized to insulin therapy and oral antidiabetic drugs after discharge for 6 months and a follow-up for further 6 months HbA1c and Beta-cell function were measured. Chen HS, et al. Diabetes Care 2008; 31:

51 Effect of Insulin vs. OADs on HbA1c in Newly Diagnosed T2DM HbA1c (%) P= Before therapy 6 months 12 months Insulin group Oral antidiabetic drug group P= Chen HS, et al. Diabetes Care 2008; 31:

52 Significantly Improved β -cell Function with Basal Insulin Assessed by OGTT Chen HS, et al. Diabetes Care 2008; 31: # # # # # # # # ** * * Time (minutes) Plasma insulin (  U/mL) OAD group, after 6-month treatment OAD group, at baseline Insulin group, after 6-month treatment Insulin group, at baseline *P<0.05 between groups #P<0.05 baseline vs. after treatment Insulin group OAD group

53 Replacement therapy With basal - bolus insulin (MDI) Required for β- cell exhaustion Starting dose : 0.5u/kg/d Basal 50-60% TDD Bolus 40-50% TDD (% of estimated calories for each meal) Fasting  Preprandial  Postprandial Adjustment

54 When to Consider Prandial Insulin A1C Versus FPG Target IncreaseBasal StartPrandial A1C (%) Fasting plasma glucose (mg/dL) Biphasic Basal plus Basal/bolus

55 Early Insulin Replacement in Type 2 DM May Preserve Beta-cell Function Glucose uptake  Insulin resistance  Lipolysis  Glucose output Early insulin replacement Reduced strain ? Reduced toxicity ? -> Sustained insulin secretion ? + After Gerstein & Rosenstock “ Beta-cell rest ”

56 Lantus (Insulin Glargine)

57 Insulin Glargine Structure  Asparagine at position A21 replaced by glycine –Provides stability  Addition of 2 arginines at the C-terminus of the B chain –Soluble at slightly acidic pH Lantus® (insulin glargine) EMEA Summary of Product Characteristics McKeage K et al. Drugs. 2001;61: Substitution Extension A chain B chain Asn 30 Gly ArgArg

58 Insulin Glargine vs NPH clear solution vs suspension NPH Glargine NPH NPH

59 Mechanism of Action Injection of an acidic solution (pH 4.0)  Microprecipitation of insulin glargine in sub- cutaneous tissue (pH 7.4)  Slow dissolution of free insulin glargine hexamers from microprecipitates (stabilised aggregates)  Protracted action  Protracted action Kramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61.

60 Time-Action Profile of Lantus vs. NPH Lepore et al. Diabetes 2000; 49: Plasma glucose

61 LEAD STUDY Lantus Evaluation in Asian type 2 Diabetics Inclusion criteria: Asian men and women with type 2 DM, insulin-naive Aged > 40 and  80 years Treatment with OADs for at least 3 months – Any sulfonylurea, as monotherapy or in combination with metformin or acarbose – Previous sulfonylurea dose  glimepiride 3 mg HbA 1c between 7.5% and 10.5% FBG >120 mg/dL (6.7 mmol/L) BMI kg/m 2 Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:

62 LEAD: Treatment regimen Subjects (n=448) were randomized to receive Bedtime insulin glargine +breakfast glimepiride (3mg) Bedtime NPH insulin + breakfast glimepiride (3 mg) Screening phase Week –4 to week –1 Week 0 (baseline) Week 24 (endpoint) Treatment phase Insulin starting dose: 0.15 U/kg/day Dose titration target: FBG < 120 mg/dL (6.7 mmol/L ) Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:

63 LEAD - Primary variable : change in HbA1c p= Insulin glargine (n=220) NPH insulin (n=223) Reduction in mean HbA1c (%) Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:

64 LEAD: change in mean daily blood glucose (FAS) Baseline Endpoint Insulin glargine (214) NPH insulin (219) Mean daily blood glucose (mg/dL) p= Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:

65 LEAD: Mean Basal Insulin Dose Mean initial dose of basal insulin* (IU/day) Mean basal insulin dose at endpoint (IU/day) Insulin glargine NPH insulin * Start dose recommended by protocol: 0.15 U/kg/day No difference between PP and FAS population Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:

66 LEAD: Hypoglycemic Events All Symptomatic Severe Nocturnal p<0.004 p< p<0.001 p<0.03 Insulin glargine NPH insulin Number of hypoglycemic episodes Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:

67 LACE: prospective, randomized real-life study of glargine + glulisine vs premixes n = 197 Randomization Initial assessment Follow-up assessments 3 month 6 month 9 month GLAR + GLU ± orals or ± other (as naturally occurring) Premix ± orals or ± other (as naturally occurring) Age  18 years HbA 1c  7% Type 2 diabetes BMI ≥ 26 Excluded if already taking exenatide or pramlintide Note: Inclusion – All patients eligible for BOTH insulin regimens Debit cards for all participants to cover additional, initial GLU copay so patients will have equal financial access to both treatment arms Lee et al. Poster presentation PS 085. Abstract EASD 2008 Wednesday 12.30, Poster session

68 LACE: glargine + glulisine vs premixes improved glycemic control with similar safety Insulin pre-treated patients with T2DM (n=197) Glargine + glulisine (n=106) Premixes (n=91) p Baseline HbA 1c (%)9.25 – Final adjusted HbA 1c (%) Change in HbA 1c (%)–2.27–1.68– Patients with hypoglycemia (last month) 36%43%NS Total insulin dose/day (U) Cost per day (all meds)10.82 (USD)12.06 (USD)0.209 Total cost (6 months) (USD) (USD) Cost difference–225 (USD) Lee et al. Poster presentation PS 085. Abstract EASD 2008

69 Before Lantus (2008/10/9) After Lantus (2009/11/26) FBS (mg/dl) / HbA1c (%) 237 / / 5.9 BUN/Creatinine (mg/dl) 38 / / 2.45 eGFR (ml/min/1.73m2) Urine Protein/Cr ratio Cholesterol/TG (mg/dl) 148/323125/111 HDL/LDL (mg/dl) 26/7628/80 Na/K (mEq/L) 139/3.9137/4 P (mg/dl) Albumin (g/dl) 3.54 Mr. King, 81 y/o male, diabetic nephropathy since 2008/ /10/14, initiating Lantus 24 units qd  FBS 130~160 mg/dl 2008/12/3, adding Novonorm 1.5# tid  FBS 100~120 mg/dl 2009/11/27, maintaining Lantus 26 units qd + Novonorm 1.5# tid Case of DMN: Insulin as Initial therapy

70 The Basal / Basal Plus strategy for T2DM Lifestyle changes OHA monotherapy and combinations Basal Add basal insulin and titrate Basal Plus Add prandial insulin at main meal Basal bolus Basal + three prandial FBG at target HbA 1c above target OHA=oral hypoglycemic agentAdapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257−64 Progressive deterioration of ß-cell function HbA 1c above target FBG above target HbA 1c above target FBG at target HbA 1c above target Stepwise intensification of treatment for continuity of control

71 Expected HbA1c Reduction in CKD Interventions Expected decrease in HbA1c Lifestyle 1 – 2 % Insulin 1.5 – 3.5 % Sulfonylureas (glurenorm) 1 – 2 % Glinides 1 – 1.5 % Sitagliptin 0.5 – 0.8 %  -glucosidase inhibitors 0.5 – 0.8 % Pioglitazones 0.5 – 1.4 % Nathan DM, et al. Diabetologia 2009;52:17−30

72 Summary: Treatment of DM in CKD  Novel diabetic medications are available in past few years.  Some require adjustment of dose or should be even avoided according to the patient’s renal function.  Metformin, 1st line Tx in patients with normal renal function, is contraindicated in CKD with Cr>1.5 (M) or 1.4 (F) mg/dL.  CKD stage 3/4: SU (glipizide, gliclazide, glimepiride), Glinides, TZD, DPP4i, α-glucosidase inhibitor, insulin  CKD stage 5 or ESRD: SU (glipizide, gliclazide), Glinide (repaglinide, mitiglinide), TZD, DPP4i, insulin  Judicious titration of medications and frequent monitoring of blood glucose to avoid severe adverse effects!

73 Summary for Basal Insulin Therapy  Tight glycemic control reduces risk of complications.  Earlier initiation of insulin helps achieve target of glycemic control.  Lantus, long-acting insulin analog, as a basal insulin therapy with: –Once daily, peakless, 24 hours basal insulin –Consistent efficacy in glycemic control –Less hypoglycemia than NPH insulin and premixed human insulin –Less adverse reactions than TZD add-on to OADs –Easy titration according to FPG to achieve target

74 Paradigm Link ™ Paradigm 512 ™ ) ) ) ) ) ) ) ) ) ) ) ) ) Wireless Diabetes Managing System: Insulin Pump (Paradigm 512) and Blood Glucose Monitor (Paradigm Link) 74

75 Thank You for Your Attention!

76 Expected HbA1c Reduction Interventions Expected decrease in HbA1c Lifestyle 1 – 2 % Insulin 1.5 – 3.5 % Metformin 1 – 2 % Sulfonylureas 1 – 2 % Pioglitazones 0.5 – 1.4 %  -glucosidase inhibitors 0.5 – 0.8 % Exenatide 0.5 – 1 % Glinides 1 – 1.5 % Pramlintide 0.5 – 1 % Sitagliptin 0.5 – 0.8 % Nathan DM, et al. Diabetologia 2009;52:17−30

77 Late Stage T2DM IGT Insulin resistance T2D Diagnosis NGT Beta-cell dysfunction 100% Relative Contributions of Diabetic Pathophysiologies Over Time Those who develop DM have lost ~50% of beta- cell function Beta-cell dysfunction determines the onset of hyperglycemia, glucose levels and disease progression, not insulin resistance Both beta-cell dysfunction + insulin resistance start years before diagnosis Hepatic glucose over-production NGT = normal glucose tolerance, IGT = impaired glucose tolerance, T2D = type 2 diabetes Bell D. Treat Endocrinol 2006; 5: ; Butler AE et al. Diabetes 2003;52: ; Del Prato S and Marchetti P. Diabetes Tech Therp 2004;6: Gastaldelli A, et al Diabetologia 2004:47:31-39; Mitrakou A, et al. N Engl J Med 1992; 326:22-29; Halter JB, et al. Am J Med 1985;79S2B:6-12

78 HOMA= Homeostasis model assessment. UKPDS Group. Diabetes 1995;44:1249―58. Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21 ― 5. Decline of  -cell function determines the progressive nature of T2DM (UKPDS)  -cell function % of Normal by HOMA Time (years) ―10―8―8―6―6―4―4―2― Time of diagnosis ? Pancreatic function = 50% of normal - 5% per yr

79 健康生活型態之飲食及運動 醣化血色素 < 9.0 % 之患者醣化血色素 ≧ 9.0 % 之患者 使用一種或二種口服抗糖尿病藥物 促胰島素分泌劑 雙胍類藥物 胰島素增敏劑 阿爾發葡萄醣苷酶抑制劑 二肽基肽酶 -4 抑製劑 使用二種或多種口服抗糖尿病藥物 促胰島素分泌劑 雙胍類藥物 胰島素增敏劑 阿爾發葡萄醣苷酶抑制劑 二肽基肽酶 -4 抑製劑 使用基礎 ( 及 / 或 ) 餐前胰島素 未達到控制目標時 增加不同種類的口服抗糖尿病藥物 或單獨使用胰島素 ( 或合併使用 ) 促胰島素分泌劑 雙胍類藥物 胰島素增敏劑 阿爾發葡萄醣苷酶抑制劑 二肽基肽酶 -4 抑製劑 增加不同種類的口服抗糖尿病藥物 或使用胰島素 增加不同種類的口服抗糖尿病藥物 或單獨使用胰島素 ( 或合併使用 ) 雙胍類藥物 胰島素增敏劑 阿爾發葡萄醣苷酶抑制劑 二肽基肽酶 -4 抑製劑 註 1: 適時調整口服糖尿病藥物和胰島素,希望使糖化血色素在 3-12 個月內達到治療的目標,若未達到治療目標,宜轉診至專科醫師。 註 2: 選擇降血糖藥物需依照病人個別情況而定,避免藥物所引起的低血糖。 註 3: 同時使用胰島素及胰島素增敏劑可能增加水腫的機會,並應同步注意病患的心臟功能變化。 使用基礎 ( 及 / 或 ) 餐前胰島素 增加不同種類的口服抗糖尿病藥物 或單獨使用胰島素 雙胍類藥物 胰島素增敏劑 阿爾發葡萄醣苷酶抑制劑 二肽基肽酶 -4 抑製劑 未達到控制目標時 2010 中華民國糖尿病學會臨床指引 79


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