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

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

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

UKPDS: Improving HbA1c Control Reduced Diabetes-Related Complications EVERY 1% reduction in HbA1c 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 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. 4

2007 AJKD guidelines 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) 5

2007 AJKD guidelines 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) 6

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

M:\MWP-DPP-E43627_Core Platform_R5.ppt 糖尿病治療選擇-藥物治療 二○一七年四月十四日 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 糖尿病 有九大類治療藥物

Major Targeted Sites of Oral Drug Classes M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日 Major Targeted Sites of Oral Drug Classes Glucose absorption Hepatic glucose overproduction Impaired insulin secretion Insulin resistance Pancreas ↓Glucose level Muscle and fat Liver Biguanides TZDs Sulfonylureas Meglitinides α-Glucosidase inhibitors Gut DPP-4 inhibitors Purpose: To provide a broad overview of the key mechanisms and targeted sites of available anti-hyperglycaemic drug classes. Take-away: Different drug classes with different but complementary mechanisms may be suitable for combination therapy to address multiple pathophysiologies and improve HbA1c control. DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones. 15 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;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254. References 1. DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. Ann Intern Med. 1999;131:281–303. 2. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483. 3. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002;287:360-372. 4. Porte D Jr, Kahn SE. The key role of islet dysfunction in type 2 diabetes mellitus. Clin Invest Med. 1995;18:247–254. 5. Data on file, MSD. 6. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patient with type 2 diabetes. J Clin Endocrinol Metab. 2006;9:4612–4619. 15

Sulfonylureas (SU) 2nd-generation M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日 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 Drug Dose Daily dose/Frequency (mg) Amaryl (glimepiride) 2mg 1~4mg qd Glidiab/Minidiab (glipizide) 5mg 2.5~40mg /day qd or bid Glurenorm (gliquidone) 30mg 15~120 mg qd Euglucon/Daonil (glyburide) 1.25~20 mg /day qd or bid Diamicron MR (gliclazide) 80mg 30~120/day 40~320/day

Sulfonylureas (SU) 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 Glibenclamide Name Duration (hr) 代謝 Glibenclamide (Diabitin®) 12-18 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60-80％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

2007 AJKD guideline

M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日 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 Drug Dose(mg) Daily dose/Frequency (mg) Starlix (nateglinide) 120 120 3 times/day before meal Novonorm (repaglinide) 1mg 0.5~4 administrated with meal 2,3,4 times/day

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

Brand name Novonorm (1mg) Starlix (120mg) Glufast (10mg) Product name Repaglinide Nateglinide Mitiglinide Dose 0.5-4 mg tid 60-120 mg tid 2.5-10 mg tid Administration time Before meal, 15-30 min 1-30 min 5 min；with meal Tmax 0.5-1 hr 0.25-1 hr 17 mins T 1/2 1-1.8 hr 1.25-2.9 hr 72 mins Metabolite enzyme CYP3A4 (major)、2C8 CYP 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   16-31 % 2-5 % 5.5 % 3.2 % 5.6 % 1.4 % Efficacy - HbA1C (0.25-4 mg tid, 12 wks); -1.7 % (120 mg tid, 24 weeks); - 0.7 % (5~10 mg tid, 52 weeks); - 1.5 % BNHI price 4.98 6.5 4.87 Daily cost 14.94 ~ 59.76 19.5 14.61

M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日 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 Drug Dose (mg) Daily dose and Frequency (mg) Glucophage (metformin) 500 1000~2550mg/day bid or tid

M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日 Biguanide Name Duration (hr) 代謝 Glucophage (metformin) 6-12 幾乎所有原型由腎排出

M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日 Thiazolidinediones (TZDs) 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: Drug Dose(mg) Daily dose /Frequency (mg) Avandia (rosiglitazone) 4 or 8 4~8mg/day qd or bid Actos (Pioglitazone) 30 15~45mg qd

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

α-Glucosidase Inhibitor M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日 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) 50 50~100 mg tid

α-Glucosidase抑制劑: acarbose M:\MWP-DPP-E43627_Core Platform_R5.ppt α-Glucosidase抑制劑: acarbose 二○一七年四月十四日 Name Duration (hrs) 代謝 Acarbose 2-6 不被吸收 Miglitol Alpha-Glucosidase inhibitors act by suppressing the enzyme responsible for metabolizing complex carbohydrates in the small intestine. They slow or block the breakdown and absorption of carbohydrates and certain sugars thereby delaying entry of glucose into liver and muscle tissue. Side Effects include flatulence, diarrhea and abdominal pain. Hypoglycemia may result if taken with a secretagogue or insulin. The use of alpha-Glucosidase inhibitors is contra-indicated in patients with renal dysfunction, inflammatory bowel disease, colonic ulceration or cirrhosis. They should not be used in patients with serum creatinine levels >2.0 mg/dL. This class of medications is not used much in US. Generic and brand names for common Alpha-Glucosidase inhibitors include Precose for acarbose and Glyset for miglitol. 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.

Definition of Incretins 二○一七年四月十四日 Definition of Incretins “Intestine-derived factors that increase glucose-stimulated secretion of insulin ” In ● cre ● tin Intestine Secretion Insulin Creutzfeldt. Diabetologia. 1985;28:565.

Incretin Hormones Regulate Insulin and Glucagon Levels Pancreas Gut Nutrient signals ● Glucose Hormonal signals GLP-1 GIP Glucagon (GLP-1) Insulin (GLP-1,GIP) Neural signals  cells  cells Purpose: To provide a high level overview of the incretin axis. Take-away: In response to the oral ingestion of glucose, the gut releases incretin hormones, which in turn stimulate insulin from the pancreatic β cells and suppress glucagon release from α cells. 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. References 1. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999; 20:876–913. 2. Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91. 3. D’Alessio DA, Vahl TP. Glucagon-like peptide 1: Evolution of an incretin into a treatment for diabetes. Am J Physiol Endocrinol Metab. 2004;286:E882–E890. 4. Gautier JF, Fetita S, Sobngwi E, Salaün-Martin C. Biological actions of the incretins GIP and GLP-1 and therapeutic perspectives in patients with type 2 diabetes. Diabetes Metab. 2005;31:233–242. 5. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 6. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1(7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744.

The Incretin Effect Is Diminished in Individuals With Type 2 Diabetes 二○一七年四月十四日 The Incretin Effect Is Diminished in Individuals With Type 2 Diabetes Control Subjects (n=8) Patients With Type 2 Diabetes (n=14) Diminished Incretin Effect Normal Incretin Effect 0.6 0.5 0.4 0.3 0.2 0.1 0.6 0.5 0.4 0.3 0.2 0.1 80 60 40 20 80 60 40 20 nmol/L nmol/L IR Insulin, mU/L IR Insulin, mU/L 60 120 180 60 120 180 Time, min Time, min Oral glucose load Intravenous (IV) glucose infusion 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;47:357–366. References: 1. Vilsbøll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 2004;47:357–366. 2. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986;29:46–52.

M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日 DPP-4 Inhibition 作用機轉 上市產品 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 GIP β細胞 α細胞 Drug Dose (mg) Daily dose and Frequency (mg) JANUVIA (sitagliptin) 100 100mg QD ONGLYZA (saxagliptin) 2.5-5mg 2.5-5mg QD

M:\MWP-DPP-E43627_Core Platform_R5.ppt DPP-4 Inhibition M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日 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 1#QD 0.5# QD 0.25# QD Onglyza: Moderate or severe CKD, or ESRD under hemodialysis: 2.5mg QD(post-H/D) PD: no data

M:\MWP-DPP-E43627_Core Platform_R5.ppt GLP-1 Analogues M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日 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 Drug Dose (mg) Daily dose and Frequency (mg) BYETTA (exenatide) 5-10mcg BID

M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年四月十四日 GLP-1 Analogues 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 ?

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)

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

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

Action Profiles Preparations Onset(h) Peak(h) Duration(h) Lispro/Aspart < 0.25 1 - 2 3 - 4 Regular 0.5 - 1 2 - 4 6 - 8 NPH 1 - 3 5 - 7 13 - 16 Ultralente 2 - 4 8 - 14 < 20 Glargine 1 - 2 > 24 A variety of human insulins that can be incorporated into a basal-bolus regimen that mimicks natural islet cell function are available1 Genetically engineered short-acting human insulin preparations generally show a rapid onset of action and duration of action ranging from 3 to 4 hours1 Lantus® (insulin glargine) activity is peakless and has an onset of action beginning 1 to 2 hours after subcutaneous injection1 Lantus has demonstrated a duration of activity that is almost twice as long as that of NPH2 The absorption of Lantus, which has a 24-hour duration of action, is prolonged without unwanted peaks3 and thus mimicks physiologic basal insulin more closely than does NPH Modified after Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002. 1. Leahy JL. Intensive insulin therapy in type 1 diabetes mellitus. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002. 2. Bolli GB, Di Marchi RD, Park GD, Pramming S, Koivisto VA. Insulin analogues and their potential in the management of diabetes mellitus. Diabetologia. 1999;42:1151-1167. 3. Lantus® (insulin glargine) US Prescribing Information. Bridgewater, NJ: Aventis Pharmaceuticals; 2002.

Insulin therapy in renal disease

Insulin therapy in renal disease 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

Insulin therapy in renal disease The American College of Physicians recommended: GFR (mL/min) Insulin 50-10 mL/min 25% decrease <10 mL/min 50% decrease Haemodialysis require less exogenous insulin ( peripheral insulin resistance ↓)

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%

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

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

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

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

New ADA/EASD algorithm for T2DM: Basal insulin is recommended for insulin initiation At diagnosis: Lifestyle + Metformin + Basal insulin + Sulfonylureas + Intensive insulin Tier 1: well-validated therapies STEP 1 STEP 2 STEP 3 Tier 2: Less well validated therapies + Pioglitazone No hypoglycaemia Oedema/CHF Bone loss Lifestyle + metformin + GLP-1 agonist Weight loss Nausea/vomiting + Sulfonylurea Nathan et al. Diabetes Care 2008. Nathan DM, et al. Diabetologia 2009;52:17−30

ADA-EASD Consensus Key messages on insulin - 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 The following three-step approach to achieving and maintaining glycemic control is recommended. This graphic shows the relative glucose-lowering potential of all commonly used antidiabetes agents. Step 1 – initial therapy should be a combination of lifestyle intervention and metformin therapy. Metformin is the first-choice pharmacological intervention because of its efficacy, absence of weight gain and hypoglycemia, high level of acceptance, and low cost. Step 2 – additional therapy within 2–3 months of the initiation therapy or whenever HbA1c goal is not achieved. Basal insulin therapy should be considered for patients with HbA1c levels > 8.5% because insulin is the most effective glucose-lowering agent and can achieve reductions of up to 2.5%. Hospitalisation is not required to initiate insulin or adjust therapy. The patient is the key player and should be trained and empowered with the guidance of healthcare professionals. Step 3 – further adjustments to achieve glycemic targets. This involves initiation of basal insulin if not previously used or intensification of insulin therapy using prandial insulin to control postprandial glucose excursions. In some cases another oral agent may be added but this is often ineffective and can be relatively expensive. Nathan DM, et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 2006;49:1711–21.

Normal Insulin Secretion: The Basal-Bolus Insulin Concept The basal–bolus insulin regimen Breakfast Lunch Dinner Physiological insulin Prandial insulin 45 Basal insulin 30 Insulin (mU/L) 15 06:00 12:00 18:00 24:00 06:00 Time Figure adapted from Kruszynska YT, et al. Diabetologia 1987;30:16–21

Treating Fasting Hyperglycemia Lowers the Entire 24-hour Plasma Glucose Profile 400 20 T2DM 300 15 Plasma glucose (mg/dl) 200 Hyperglycaemia due to an increase in fasting glucose Plasma glucose (mmol/l) 10 100 5 Normal In patients with T2DM, excess exposure to hyperglycaemia is caused by an increase in fasting plasma glucose concentrations. Specifically targeting fasting hyperglycaemia will therefore lower the entire 24-hour plasma glucose profile and should be a primary aim of therapy. Hirsch I, et al. Clin Diabetes 2005;23:78–86. Meal Meal Meal 06.00 10.00 14.00 18.00 22.00 02.00 06.00 Time of day (hours) 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.

Treating Fasting Hyperglycemia Lowers the Entire 24-hour Plasma Glucose Profile 400 20 300 15 Plasma glucose (mg/dl) 200 T2DM Hyperglycaemia due to an increase in fasting glucose Plasma glucose (mmol/l) 10 100 5 Normal Long-acting basal insulin In patients with T2DM, excess exposure to hyperglycaemia is caused by an increase in fasting plasma glucose concentrations. Specifically targeting fasting hyperglycaemia will therefore lower the entire 24-hour plasma glucose profile and should be a primary aim of therapy. Hirsch I, et al. Clin Diabetes 2005;23:78–86. Meal Meal Meal 06.00 10.00 14.00 18.00 22.00 02.00 06.00 Time of day (hours) 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.

ADA/EASD Consensus Algorithm for Type 2 Diabetes Mellitus 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 <70 mg/dl, ↓ bedtime dose by 4 units, or 10% if dose >60 units Nathan D, et al. Diabetologia 2006;49:1711−21.

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

Type 2 Diabetes Phase III Destiny of Type 2 Diabetes Pancreatic -Cell Decline Over Time in UKPDS 100 Insulin therapy 75 Rescue -Cell function (%) Augmentation 50 Replacement 25 Postprandial Hyper- glycemia Type 2 Diabetes Phase I Type 2 Diabetes Phase II Type 2 Diabetes Phase III IGT –12 –10 –6 –2 2 6 10 14 Years from diagnosis Adapted from Lebovitz H. Diabetes Rev 1999;7:139-153.

Augmentation therapy Rescue therapy May reverse glucose toxicity Using replacement regimens for several weeks May reverse glucose toxicity Augmentation therapy With basal insulin If some β- cell function remains Starting dose: 0.15-0.2u/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

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 10-14 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: 1927-1932.

Effect of Insulin vs. OADs on HbA1c in Newly Diagnosed T2DM Insulin group Oral antidiabetic drug group 11.89 11.33 14 P=0.002 P=0.009 12 6.78 7.84 6.33 7.50 10 HbA1c (%) 8 6 4 2 Before therapy 6 months 12 months Chen HS, et al. Diabetes Care 2008; 31: 1927-1932.

Significantly Improved β-cell Function with Basal Insulin Assessed by OGTT 140 120 100 80 60 40 20 0 30 60 90 120 # * Time (minutes) Plasma insulin (mU/mL) OAD group, after 6-month treatment OAD group, at baseline Insulin group, after 6-month treatment Insulin group, at baseline Insulin group OAD group *P<0.05 between groups #P<0.05 baseline vs. after treatment Chen HS, et al. Diabetes Care 2008; 31: 1927-1932.

Replacement therapy Required for β- cell exhaustion 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

When to Consider Prandial Insulin A1C Versus FPG 240 Increase Basal 210 180 Fasting plasma glucose (mg/dL) Start Prandial 150 Biphasic Basal plus Basal/bolus Target 120 6 7 8 9 10 A1C (%)

Early Insulin Replacement in Type 2 DM May Preserve Beta-cell Function  Glucose output “ Beta-cell rest ” ? + Early insulin replacement Reduced strain ? Reduced toxicity ? -> Sustained insulin secretion -glucosidase inhibitors (e.g. acarbose) – delay digestion and absorption of carbohydrates in the gastrointestinal tract.1,2 Sulfonylureas and meglitinides – stimulate insulin secretion from the pancreas.1,2 Biguanides (e.g. metformin) – suppress liver glucose output, enhance insulin sensitivity in the liver and stimulate insulin-mediated glucose disposal. They do not stimulate insulin secretion.1,2 Thiazolidinediones – decrease insulin resistance in fat, muscle and liver. In addition, they improve estimates of -cell function.1,2 1Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40. 2Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329. Glucose uptake  Insulin resistance  Lipolysis After Gerstein & Rosenstock

Lantus (Insulin Glargine)

Insulin Glargine Structure Substitution Extension A chain B chain 1 15 10 5 20 Asn 30 Gly Arg 19 25 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. 2002. McKeage K et al. Drugs. 2001;61:1599-1624.

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

Injection of an acidic solution (pH 4.0)  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 Kramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61.

Time-Action Profile of Lantus vs. NPH Plasma glucose Lepore et al. Diabetes 2000; 49: 2142-2148

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 HbA1c between 7.5% and 10.5% FBG >120 mg/dL (6.7 mmol/L) BMI 20-35 kg/m2 Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:111-118

LEAD: Treatment regimen Subjects (n=448) were randomized to receive Bedtime insulin glargine+breakfast glimepiride (3mg) Bedtime NPH insulin + breakfast glimepiride (3 mg) Week –4 to week –1 Week 0 (baseline) Week 24 (endpoint) Screening phase 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; 76:111-118

LEAD - Primary variable : change in HbA1c Insulin glargine (n=220) NPH insulin (n=223) -1.2 -1 -0.8 -0.6 -0.4 -0.2 Reduction in mean HbA1c (%) - 0.77 - 0.99 p=0.0319 Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:111-118

LEAD: change in mean daily blood glucose (FAS) p=0.0018 - 94 - 80 Baseline Endpoint 50 100 150 200 250 300 276 269 189 182 Mean daily blood glucose (mg/dL) Insulin glargine (214) NPH insulin (219) Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:111-118

LEAD: Mean Basal Insulin Dose Mean initial dose Mean basal of basal insulin* insulin dose at endpoint (IU/day) (IU/day) Insulin glargine 9.6 32.1 NPH insulin 9.8 32.8 * 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; 76:111-118

LEAD: Hypoglycemic Events 200 400 600 800 1000 1200 p<0.004 p<0.0003 p<0.001 Number of hypoglycemic episodes p<0.03 All Symptomatic Severe Nocturnal Insulin glargine NPH insulin Pan C-Y et al. Diabetes Res Clin Pract 2007; 76:111-118

Follow-up assessments LACE: prospective, randomized real-life study of glargine + glulisine vs premixes Age  18 years HbA1c  7% Type 2 diabetes BMI ≥ 26 Excluded if already taking exenatide or pramlintide GLAR + GLU ± orals or ± other (as naturally occurring) n = 197 Premix ± orals or ± other (as naturally occurring) Randomization Initial assessment 3 month 6 month 9 month Follow-up assessments 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 1003. EASD 2008 Wednesday 12.30, Poster session

Glargine + glulisine (n=106) LACE: glargine + glulisine vs premixes improved glycemic control with similar safety Glargine + glulisine (n=106) Premixes (n=91) p Baseline HbA1c (%) 9.25 – Final adjusted HbA1c (%) 6.93 7.52 0.009 Change in HbA1c (%) –2.27 –1.68 Patients with hypoglycemia (last month) 36% 43% NS Total insulin dose/day (U) 74 85 0.267 Cost per day (all meds) 10.82 (USD) 12.06 (USD) 0.209 Total cost (6 months) 1933.20 (USD) 2158.74 (USD) Cost difference –225 (USD) Insulin pre-treated patients with T2DM (n=197) Lee et al. Poster presentation PS 085. Abstract 1003. EASD 2008

Case of DMN: Insulin as Initial therapy Mr. King, 81 y/o male, diabetic nephropathy since 2008/10 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 Before Lantus (2008/10/9) After Lantus (2009/11/26) FBS (mg/dl) / HbA1c (%) 237 / 13.2 103 / 5.9 BUN/Creatinine (mg/dl) 38 / 2.42 29 / 2.45 eGFR (ml/min/1.73m2) 27.7 27 Urine Protein/Cr ratio 1.3 1.49 Cholesterol/TG (mg/dl) 148/323 125/111 HDL/LDL (mg/dl) 26/76 28/80 Na/K (mEq/L) 139/3.9 137/4 P (mg/dl) 3.0 3.6 Albumin (g/dl) 3.5 4

The Basal / Basal Plus strategy for T2DM Stepwise intensification of treatment for continuity of control FBG at target HbA1c above target FBG at target HbA1c above target Basal bolus Basal + three prandial FBG above target HbA1c above target Basal Plus Add prandial insulin at main meal HbA1c above target Basal Add basal insulin and titrate OHA monotherapy and combinations Lifestyle changes Progressive deterioration of ß-cell function OHA=oral hypoglycemic agent Adapted from Raccah et al. Diabetes Metab Res Rev 2007;23:257−64

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 % a-glucosidase inhibitors 0.5 – 0.8 % Pioglitazones 0.5 – 1.4 % ADA: Managing hyperglycemia in T2DM This consensus approach to management of hyperglycemia is intended to offer guidance in choosing the most appropriate therapy for patients with T2DM. Lifestyle intervention to decrease weight and increase activity is the initial step in T2DM management and metformin is the initial medication used. An A1C ≥7% should serve as a call to rapid action to initiate or change therapy and intensify treatment to achieve and maintain glycemic levels as close to the nondiabetic range as possible. Combinations of 3 oral agents can be used, although early initiation and intensification of insulin therapy may be beneficial because of efficacy and cost. Choices of antihyperglycemic agents are based primarily on relative glucose-lowering efficacy, nonglycemic effects of medications that may reduce long-term complications, safety profiles, tolerability, and cost.(1) Agents not referred to in this algorithm (eg, DPP-IV inhibitors) are relatively less effective choices for lowering A1C.(2) Nathan DM, et al. Diabetologia 2009;52:17−30 1. Nathan DM et al. Diabetologia. 2006;49:1711-21. 2. Nathan DM. N Engl J Med. 2007;356:437-40.

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!

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

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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 % a-glucosidase inhibitors 0.5 – 0.8 % Exenatide 0.5 – 1 % Glinides 1 – 1.5 % Pramlintide 0.5 – 1 % Sitagliptin 0.5 – 0.8 % ADA: Managing hyperglycemia in T2DM This consensus approach to management of hyperglycemia is intended to offer guidance in choosing the most appropriate therapy for patients with T2DM. Lifestyle intervention to decrease weight and increase activity is the initial step in T2DM management and metformin is the initial medication used. An A1C ≥7% should serve as a call to rapid action to initiate or change therapy and intensify treatment to achieve and maintain glycemic levels as close to the nondiabetic range as possible. Combinations of 3 oral agents can be used, although early initiation and intensification of insulin therapy may be beneficial because of efficacy and cost. Choices of antihyperglycemic agents are based primarily on relative glucose-lowering efficacy, nonglycemic effects of medications that may reduce long-term complications, safety profiles, tolerability, and cost.(1) Agents not referred to in this algorithm (eg, DPP-IV inhibitors) are relatively less effective choices for lowering A1C.(2) Nathan DM, et al. Diabetologia 2009;52:17−30 1. Nathan DM et al. Diabetologia. 2006;49:1711-21. 2. Nathan DM. N Engl J Med. 2007;356:437-40.

Relative Contributions of Diabetic Pathophysiologies Over Time Both beta-cell dysfunction + insulin resistance start years before diagnosis Beta-cell dysfunction determines the onset of hyperglycemia, glucose levels and disease progression, not insulin resistance Those who develop DM have lost ~50% of beta-cell function Hepatic glucose over-production Relative Contributions of Diabetes Pathophysiologies Over Time This is a conceptual slide about the relative contributions of diabetic pathophysiologies, beta-cell dysfunction, insulin resistance, and hepatic glucose overproduction. Build 1-From UKPDS, at the time of diagnosis of type 2 diabetes and 6 years afterwards about 50% and 73% of beta-cell function has been lost, respectively.1 This and other data2,3 has led to the projection that beta-cell dysfunction begins in individuals with normal glucose tolerance (NGT) more than 10 years before diagnosis.1 Beta-cell dysfunction is progressive with time.3,4 Build 2-Insulin resistance, like beta-cell dysfunction, begins years before diagnosis4 Build 3-Insulin resistance develops rapidly. It has been shown that there is no significant difference between the level of insulin resistance found in individuals with impaired glucose tolerance (IGT) and that found in type 2 diabetes patients.3 Although insulin resistance is known to drive metabolic deterioration in the development of type 2 diabetes, beta-cell dysfunction ultimately determines the onset of hyperglycemia and is a major factor associated with progressively rising plasma glucose levels and disease progression.3,5 Basal hepatic glucose output did not differ significantly between NGT and IGT groups.6 It has been shown that during type 2 diabetes increases in hepatic glucose production correlate with the increases in fasting glucose levels.7 100% Beta-cell dysfunction 100% Insulin resistance NGT IGT T2D Diagnosis Late Stage T2DM NGT = normal glucose tolerance, IGT = impaired glucose tolerance, T2D = type 2 diabetes Bell D. Treat Endocrinol 2006; 5:131-137; Butler AE et al. Diabetes 2003;52:102-110; Del Prato S and Marchetti P. Diabetes Tech Therp 2004;6:719-731 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 References: Bell DSH. The case for combination therapy as first-line treatment for type 2 diabetic patients. Treat Endocrinol 2006;5:131–137. Butler AE, Jansen J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52:102–110. Del Prato S and Marchetti P. Targeting insulin resistance and beta-cell dysfunction: The role of thiazolidinediones. Diabetes Tech Ther 2004;6:719–131. Gastaldelli A, Ferranninni E, Miyazaki Y, et al. Beta-cell dysfunction and glucose intolerance: Results from the San Antonio metabolism (SAM) study. Diabetologia 2004;47:31–39. Rhodes CJ. Type 2 diabetes—A matter of β-cell life and death? Science 2005; 307:380–384. Mitrakou A, Kelley D, Mokan M, et al. Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 1992;326:22–29. Halter JB, Ward WK, Porte D, et al. Glucose regulation in non-insulin-dependent diabetes mellitus: Interaction between pancreatic islets and the liver. Am J Med 1985;79S2B:6–12.

Decline of -cell function determines the progressive nature of T2DM (UKPDS) 100 Time of diagnosis ? % of Normal by HOMA -cell function 80 - 5% per yr 60 Pancreatic function = 50% of normal 40 20 Six-year follow-up data from the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated the decline in -cell function with T2DM over time. At the time of diagnosis, -cell function is already reduced by about 50% and continues to decline regardless of therapy. Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21―5. UKPDS Group. Diabetes 1995;44:1249―58. ―10 ―8 ―6 ―4 ―2 2 4 6 Time (years) 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.

健 康 生 活 型 態 之 飲 食 及 運 動 2010 中華民國糖尿病學會臨床指引 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 使用基礎 (及/或) 餐前胰島素 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 未達到控制目標時 未達到控制目標時 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 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。 2010 中華民國糖尿病學會臨床指引