第2型糖尿病 降血糖藥物治療 (II) 嘉義基督教醫院新陳代謝科 游慧宜醫師

第2型糖尿病患之胰島素使用

impaired glucose tolerance and diabetes in obesity: a 6-year follow-up study of glucose metabolism 胰島素功能開始退化 近乎最大胰島素阻抗

Insulin secretion/insulin resistance index in NGT, IGT and T2DM subjects Lost 2/3 β-cell function Lost 80-85% β-cell function

UKPDS A1C <7% 3 years 6 years 9 years Metformin 45% 35% 15% SU 30% 20% Insulin 40% Follow up 14 years, 58% need insulin therapy

當第2型糖尿病患使用最大耐受量之 磺醯尿素類及雙胍類治療仍不能維持血糖控制目標… 1.增加第三種口服抗糖尿病藥物? 糖化血色素將下降大約0.5-1.5%。 當病人的糖化血色素>8%，可能無法達到控制指標。 2.增加胰島素? 糖化血色素將下降大約1.5-2.5% (基礎胰島素每天注射一次) Diabetes Care 29:554, 2006 Diabetes Care 29:1963, 2006

T2DM--加入第三種治療 -1.66% -1.51% P=0.14 *p<0.05 Baseline HbA1c *p<0.05 Diabetes Care 29:554, 2006

摘要：預期糖化血色素下降值 介入藥物 預期中的糖化血色素下降值

拒絕胰島素治療的關鍵障礙 畏懼低血糖 畏懼體重增加 畏懼打針 認為他們的疾病較嚴重 Barnett AH. Eur J Endocrinol 2004;151(Suppl.15):T3–T7

中華民國糖尿病學會制定 2006第二型糖尿病照護指引

第二型糖尿病整體治療的指導方針: 胰島素治療 國際糖尿病聯盟,2005 第二型糖尿病整體治療的指導方針: 胰島素治療 【三】 提供教育時應包括：繼續生活型態的管理和適當地自我監測。 基於安全因素考量，應由低劑量開始。 在明顯的血糖控制不良出現之前，即開始使用胰島素治療。 通常在使用最大劑量口服降血糖藥物時，糖化血色素 >7.5 %， 即考慮使用胰島素治療。 加入基礎胰島素治療時，應持續雙胍類藥物【metformin】使用， 亦可同時使用磺醯尿素類【sulfonylureas】藥物。

Common Insulin Regimens Background (Basal) Insulin + 2 Drugs Elevated FPG Stable daytime BG Overwhelmed Desire single injection Background and Mealtime Insulin  Sensitizer(s) Elevated fasting and/or post-meal A1C >11% Intensive control More flexibility Erratic schedule Premixed Insulin  Sensitizer(s) Elevated FPG Increasing daytime BG A1C >11% Decreased dexterity or visual acuity Regular schedule Glycemic Factors Patient Factors Key Points: Elevated fasting glucose indicates need for basal insulin to suppress gluconeogenesis overnight. With basal insulin, patient needs to be on at least one oral agent to address mealtime glucose excursions Elevated post-meal glucose indicates need for bolus insulin to cover meal related carbohydrate intake. Most common starting points are Basal Insulin and Mixed Insulin but both point to Basal/Bolus regimen of increased flexibility. Note page reference (3-5) to 4th edition Quick Guide to get people into the SDM materials. Insulin detemir is a new basal insulin that is expected to be approved by FDA by the end of 2005. Mazze, Strock, Simonson, Bergenstal. Staged Diabetes Management: A Systematic Approach, 2nd Edition Revised, 2007 Wiley Publishing, UK 13

Patient-Based Insulin Regimens A1C Medication Pattern Diet Hx Lifestyle Monitoring Basal only > 7.5 -10% OADs controlling PPG High FBG Small, regular meals Reluctance to do MDI Fasting Biphasic analog insulin > 7.5% OAD failure Glucose rises during the day Large suppers, small lunches Consistent daily routine; reluctance to do MDI Fasting and pre-supper (if insulin administered twice daily) Biphasic human insulin > 7.5% OAD failure Glucose rises during the day Isocaloric meals or large lunches Consistent daily routine; reluctance to do MDI Fasting and pre-supper (if insulin administered twice daily) Basal-bolus (MDI) > 7.5% OAD failure Can be matched to any pattern Can be matched to any diet Erratic schedule, motivated Frequent (minimum before meals and bedtime) Hirsch IB, et al Clin Diabetes 2005;23: 78-86

目前使用的胰島素製劑皮下注射的藥物動力學 開始期 高峰期 維持期 Rapid-acting (Aspart, Lispro) 10-15 min 60-90 min 4-5 hrs Short-acting (RI) 30-60 min 2-4 hrs 5-8 hrs Intermediate-Acting (NPH) 1-3 hrs Up to 18 hrs Long-acting analog (Glargine) 1.5-3 hrs No peak 20-24 hrs Long-acting analog (Detemire) Dose-dependent peak 9-24 hrs

Insulin Time Action Curves Rapid-Acting: Lispro, Aspart, Glulisine Short-Acting: Regular Intermediate: NPH Relative Insulin Effect Long-Acting: Glargine (Insulin Glargine) Detemir (Insulin Detemir) 2 4 6 8 10 12 14 16 18 20 Time (Hours) Bergenstal, “Effective insulin therapy,” International Textbook of Diabetes Mellitus vol 1. 3rd ed, Chichester NY, John Wiley and Sons, Inc., 2004:995-1015.

ADA/EASD 2008 Consensus Algorithm for Basal Insulin(基礎胰島素)Therapy in T2DM 開始使用中效(睡前)或長效胰島素(睡前或早晨) 起始劑量10 U或0.2 U/kg 空腹低血糖(<70 mg/dl) ：減少 睡前劑量4U位 總劑量之10%（>60 U/day） 監測空腹血糖，目標範圍：70-130 mg/dl 空腹血糖>130 mg/dl ：每3天增加2U 空腹血糖>180 mg/dl ：每3天增加4U Diabetes care 29: 1963, 2006

Starting Background (Basal) Insulin Background Insulin Dose 0.1 units/kg 0.2 units/kg Start with single dose of long-acting insulin (glargine or detemir) or intermediate-acting insulin (NPH) at bedtime Maintain oral agents (metformin, TZD,and/or sulfonylureas) Select starting insulin dose Mazze, Strock, Simonson, Bergenstal. Staged Diabetes Management Quick Guide 4th Edition Revised, 2007 © International Diabetes Center

步驟一：開始使用基礎胰島素 開始可使用…… - 睡前中效胰島素 - 睡前或早晨長效胰島素 胰島素治療方法應將病人的生活型態及飲食習慣列入考量

胰島素種類的考量因素 控制血糖的效果 長效與中效相當 血糖的穩定性 長效優於中效 低血糖的風險 長效低於中效 體重增加的幅度 注射時間的彈性 醫療費用 長效高於中效 筆型高於瓶裝（元/U） 外出方便性 筆型優於瓶裝

步驟一：開始使用基礎胰島素 監測空腹血糖及調整劑量，直到達目標範圍 - 目標範圍：3.89-7.22mmol/l (70-130mg/dl) - 典型的劑量是每3天增加2單位，假如空腹 >10mmol/l（>180mg/dl），可以加多一點的劑量 （例如：每3天加4單位 ）

每三天調整劑量法 Yki-Järvinen H et al. Diabetes, June 2004; 5(2). Abstract 2181-PO.

Adjusting Insulin Titration Guide If most BG are: Adjust insulin responsible: <70 mg/dL (3.9 mmol/L) Decrease by 1-3 units 70-120 mg/dL (3.9-6.7 mmol/L) No change 121-200 mg/dL (6.7-11.1mmol/L) Increase by 1-3 units >200 mg/dL (11.1 mmol/L) Increase by 3-5 units or 10% Make adjustments frequently, at least 1-2 times per week Provide the patient with self-titration guidelines to adjust insulin at home Doses need to be titrated on a regular basis Increase equally between doses if over 200 by 0.1 unit/kg For BG readings below 100, look at Table 6 as a guide for titrating insulin Guide to Starting and Adjusting Insulin for Type 2 Diabetes, © International Diabetes Center, 2008 Staged Diabetes Management Quick Guide 4th Edition Revised, 2007 © International Diabetes Center 23

強制調整劑量 開始劑量: 10單位睡前 前2天的自我監測空腹血糖數值之平均 胰島素的增加劑量 100–120 5.6–6.7 2 (mg/dL) (mmol/L) (U/day) 100–120 5.6–6.7 2 120–140 6.7–7.8 4 140–180 7.8–10 6 ≥180 10 8 Riddle et al. Diabetes Care 2003;26:3080–6

步驟一: 開始使用基礎胰島素… 假如有空腹低血糖發生於 < 3.89 mmole/l (70 mg/dl).. - 減少睡前劑量≧4單位 或減少總劑量之10%（每天劑量>60單位時） Diabetes care 29: 1963, 2006

Basal Plus Concept Meal time coverage is required when fasting blood glucose < 100 mg/dL (< 5.6 mmo/l), but A1C > 7% and / or Postprandial SMBG >140 mg/dL (> 7.5 mmol/l) 26

Adjusting Insulin for Background Regimen Use Titration Guide to adjust background insulin based on the pre-breakfast (AM) BG If most AM fasting BG >120 mg/dL (6.7 mmol/L) Titrate until fasting glucose at target BG If dose reaches 0.5-0.7 units/kg body weight, consider adding mealtime insulin If most AM fasting BG <120 mg/dL (6.7 mmol/L) and A1C remains above target Test pre-dinner and bedtime (or 2-hour post-dinner) and consider need for mealtime insulin Titrating background insulin focus on am fasting BG. Once you reach 0.5 units/kg body weight, explain to the patient that a RA insulin will need to be added If fasting BG is in target and A1C > 7%, it means that there are other timepoints throughout the day where the patient is having higher blood sugar. Ask them to do some post meal testing. This also helps them see that they're a partner with you in taking care of their diabetes. They provide you with importnat information which in turn helps you to make the best decision for them. Guide to Starting and Adjusting Insulin for Type 2 Diabetes, © International Diabetes Center, 2008 Staged Diabetes Management Quick Guide 4th Edition Revised, 2007 © International Diabetes Center 27

ADA/EASD 2008 Consensus Algorithm for Basal Plus(漸進式基礎-餐前治療)Insulin Therapy in T2DM 午餐前血糖在範圍之外，則增加早餐前速效胰島素劑量 空腹血糖在目標範圍 (70-130 mg/dl)內： 監測午餐前、晚餐前及睡前血糖 必要時增加第二次注射 起始劑量4 U or 0.1 units/kg 每3天增加2 U 晚餐前血糖在範圍之外，則增加午餐前速效胰島素劑量 2-3個月後糖化血色素≧7% 睡前血糖在範圍之外，則增加晚餐前速效胰島素劑量

步驟二：強化胰島素治療 如果空腹血糖在目標範圍內，但是糖化血色素≧7%， 則監測午餐前、晚餐前及睡前血糖，需增加第二次射。 如果午餐前血糖在範圍之外，則增加早餐前速效胰島素劑量。 如果晚餐前血糖在範圍之外，則增加早餐前中效胰島素或午 餐前速效胰島素劑量。 如果睡前血糖在範圍之外，則增加晚餐前速效胰島素劑量。

監測三餐前血糖： 若在範圍外，可能需要增加第三次注射 ADA/EASD 2008 Consensus Algorithm for Basal Plus(漸進式基礎-餐前治療)Insulin Therapy in T2DM 監測三餐前血糖： 若在範圍外，可能需要增加第三次注射 若糖化血色素持續≧7% ： 監測餐後2小時的血糖值，調整餐前速效胰島素劑量 2-3個月後糖化血色素≧7% 調整期間可能需要> 0.5-1年

步驟三：進一步強化胰島素治療 重複監測三餐前血糖，如果在範圍外，可 能需要增加第三次注射。 如果糖化血色素持續≧7% - 監測餐後2小時的血糖值 - 調整餐前速效胰島素劑量

漸進式基礎-餐前治療 現有的口服降血糖藥物繼續使用，開始加入一次基礎胰島素注射。 當空腹血糖能適當地控制達3-6 個月後，病人無法達到血糖控制目標， 就增加餐前胰島素控制。 最初，餐前胰島素治療可能僅需要使用在 一天中進食最大量的一餐， 或者使用在三餐中餐後血糖升幅最高的一餐。 隨時間之追蹤，可能需增加其他餐前胰島素注射，以維持日間血糖之 良好控制。

How to initiate multiple daily injection Starting dose= 0.4 - 0.5 U/kg Bolus dose (lispro/aspart)= 20% of starting dose at each meal Basal dose (glargine/Levemir)= 40% of starting dose given at bedtime or anytime

Starting Background and Mealtime Insulin A1C <9% A1C ≥9% Background Insulin Dose 0.1 units/kg (once daily) 0.2 units/kg Mealtime (divided evenly between meals) Total Insulin Dose 0.4 units/kg Mazze, Strock, Simonson, Bergenstal. Staged Diabetes Management Quick Guide 4th Edition Revised, 2007 © International Diabetes Center

Basal-Bolus Treatment Basal insulin requirement- -Best assessed by fasting glucose levels and glycemic curves with missed meals Adjusting Rapid-Acting Insulin- -Check BG before and 2hr after meal-- adjust dose of Lispro or Aspart until the readings within 20 mg/dl of each other -If dose is appropriate, but premeal BG is not in range-- Review BG patterns, adjust basal insulin dose or preceding prandial dose

Basal-Bolus Treatment Prandial insulin dose changes- Compensatory (correction) dose for pre-meal hyperglycemia. Most people need 1 unit of insulin to reduce BG 30-50 mg/dl. SF=1500/total daily dose (use RI) SF=1800/total daily dose (use Insulin Aspart or Lispro) Anticipatory based on planned meal and activity CI ratio=450/total daily dose (use RI) CI ratio=500 total daily dose (use Insulin Aspart or Lispro) 1:10 in Type 2 1:15 in Type 1

Ready for injected therapy Options to Individualize Therapy in Patients Failing Oral Anti-Hyperglycemic Therapy 1 shot basal Basal plus 2-3 shots Basal bolus 4 shots Ready for injected therapy Coverage: Only FPG Coverage: FPG PPG x 1-2 Coverage: FPG PPG x 3 OAD’s Mixed insulin QD Mixed insulin BID TID Coverage: FPG PPG x 1 Coverage: FPG PPG x 2 Coverage: FPG PPG x 3 Analog Premixes: More Options to Individualize and Fewer Injections

Starting Premixed Insulin A1C <9% A1C ≥9% Premixed Insulin Dose 0.1 units/kg (2 times/day) 0.2 units/kg total 0.2 units/kg 0.4 units/kg total Start with two doses; before breakfast and dinner Consider continuing or adding insulin sensitizer (metformin) Select starting dose and premixed insulin formulation Mazze, Strock, Simonson, Bergenstal. Staged Diabetes Management Quick Guide 4th Edition Revised, 2007 © International Diabetes Center

Premixed with Rapid Acting Insulin Regimen RA 25/30% + BI 75/70%  2009 International Diabetes Center

Starting a Background and Mealtime Insulin Regimen Sensitizers  2009 International Diabetes Center

Starting vs. Final Insulin Dose Typical Patient (Type 2 DM) Regimen Starting Dose (units) Common Final Dose (units) Background Insulin 0.2 units/kg (20 units) 0.5-0.7 units/kg (50-70 units) Premixed Insulin 0.2 units/kg BID (40 units total) 1.0-1.2 units/kg (100-120 units) Background & Mealtime Insulin 0.2 units/kg background 0.2 units/kg mealtime (40 units total) 220 lbs (100 kg) A1C 9% Mazze, Strock, Simonson, Bergenstal. Staged Diabetes Management Quick Guide 4th Edition Revised, 2007 © International Diabetes Center

Nutrition Guidelines for Insulin Insulin Regimen Meals Snacks Background Portion control Carbohydrate servings: Women: 2-4 per meal Men: 3-5 per meal Not needed If desired, keep small Premixed Eat at consistent times Eat consistent amounts of carbohydrate May be needed depending on schedule and insulin Background and Mealtime Start with consistent carbohydrate Can teach to adjust mealtime dose later If snack is eaten, add RA insulin to cover This slide demonstrates the key nutrition messages for the various insulin regimens described by Dr. Bergenstal. This information is also on Table 4 in the "Guide to Starting and Adjusting Insulin for Type 2 Diabetes". Note also on the algorithm, that on the right side-bar, there are initial nutrition messages given. For those patients put on a background insulin it helps glucose control if they control their carbohydrates throughout the day. A suggestion to get started is to tell the patient to have 3-4 carb choices per meal until they can consult with a dietitian For those patients on a premixed insulin it is important to eat meals at consistent times and consistent amount of carbs. Snacks may be needed depending on the insulin mix, for example if it's a Regular,NPH mix and patient schedule For the Background and mealtime regimen encourage the patient to start with a consistent carb intake at all meals. Generally snacks are not needed with this regimen. This regimen also allows for more flexibility in eating times and carb amounts. Once a patient is under control, you can teach what their insulin/carb ratio is which we'll adress later. This will add even more flexibility to their daily routine. *One carb serving = 15 grams of carbohydrate Guide to Starting and Adjusting Insulin for Type 2 Diabetes, © International Diabetes Center, 2008

每日注射兩次混合胰島素

每日注射兩次混合胰島素 胰島素在早餐前及晚餐前給予 中效胰島素(NPH)併用 短效胰島素(RI) 速效胰島素[Aspart (NovoRapid®)、Lispro (Humalog®)] 預混型胰島素(Novomix 30®、Humalog Mix25, 50®) 劑量:胰島素一天總劑量 早餐前：60%（短效或速效：中效=1：2） 晚餐前：40%（短效或速效：中效=1：1） 之後根據相對應的血糖值來調整

帶回之重要訊息 胰島素是使用最久的，研究最多的及最有效的 抗高血糖藥物，但可能導致體重增加（2-4公斤）， 和低血糖。 長效胰島素類似物的作用時間較長，沒有高峰期， 可以減少因使用NPH胰島素產生低血糖的風險。 預混型胰島素不建議用在調整劑量期間。

帶回之重要訊息(續) 起始胰島素治療，可用睡前中效胰島素，或者睡前或 早晨長效胰島素注射。 在2-3個月之後，假如空腹血糖是在目標範圍內，但 起始胰島素治療，可用睡前中效胰島素，或者睡前或 早晨長效胰島素注射。 在2-3個月之後，假如空腹血糖是在目標範圍內，但 是糖化血色素≧7%，檢查午餐前、晚餐前及睡前 血糖，取決其結果，加第二次注射。 在2-3個月之後，假如餐前血糖在目標範圍外，也 許需要加第三次注射；如果糖化血色素還是 ≧7%，則檢查餐後2小時血糖和調整餐前速效胰島素。

Incretin-based therapies In 1902, Bayliss and Starling proposed that intestinal mucosa contained a hormone which stimulated the exocrine secretion of the pancreas (“Secretin”). In 1932 La Barre proposed the name incretin for a hormone extracted from the upper gut mucosa which caused hypoglycemia and proposed possible therapy for diabetes. In 1939-1940, based on their studies, Leow et al concluded that the existence of incretins was “questionable.” No further research in this area was performed for about thirty years. In 1970, GIP was isolated and sequenced from intestinal mucosa The human Proglucagon gene was cloned in 1983 by G. Bell, et al, and the human proglucagon sequence was subsequently deduced. However, the entire GLP-1 molecule had no effect on insulin levels. It was found that only one specific sequence of GLP-1 has insulinotropic effect: GLP-1 (7-36) amide. It is rapidly inactivated to GLP-1 (9-36) by DPP-4 with a plasma half-life of only 1-2 minutes. GIP is also rapidly inactivated by DPP-4 to GIP (3-42). 48

M:\MWP-DPP-E43627_Core Platform_R5.ppt 二○一七年三月十九日 Incretins Regulate Glucose Homeostasis Through Effects on Islet Cell Function 攝食 Glucose dependent Insulin from beta cells (GLP-1 and GIP) Beta cells Insulin increases peripheral glucose uptake 腸道 活性 GLP-1 and GIP 分泌 incretin 腸激素 胰臟 The presence of nutrients in the gastrointestinal tract rapidly stimulates the release of incretins: GLP-1 from L cells located primarily in the distal gut (ileum and colon), and GIP from K cells in the proximal gut (duodenum).1,2 Collectively, these incretins exert several beneficial actions, including stimulating the insulin response in pancreatic beta cells and reducing glucagon production from pancreatic alpha cells when glucose levels are elevated.3,4 Increased insulin levels improve glucose uptake by peripheral tissues; the combination of increased insulin and decreased glucagon reduces hepatic glucose output.5 血糖控制 Glucagon from alpha cells (GLP-1) Glucose dependent Alpha cells Increased insulin and decreased glucagon reduce hepatic glucose output References Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004;145: 2653–2659. Zander M, Madsbad S, Madsen JL et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: A parallel-group study. Lancet 2002;359:824–830. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002;122:531–544. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483. Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483. 49 49

GLP-1為基礎的治療 食物刺激小腸L細胞分泌GLP-1 GLP-1有多重作用機轉 恢復胰島素對葡萄糖的第一與第二期分泌 延緩胃排空 抑制餐後升糖素之異常升高 有減重效果。有噁心、嘔吐副作用 在動物模式，可刺激貝它細胞增生與分化。 可預防糖尿病，或可阻止貝它細胞之持續衰竭 不太造成低血糖 Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. AUFehse F; Trautmann M; Holst JJ; Halseth AE; Nanayakkara N; Nielsen LL; Fineman MS; Kim DD; Nauck MA SOJ Clin Endocrinol Metab. 2005 Nov;90(11):5991-7. Epub 2005 Sep 6.   CONTEXT: First-phase insulin secretion (within 10 min after a sudden rise in plasma glucose) is reduced in type 2 diabetes mellitus (DM2). The incretin mimetic exenatide has glucoregulatory activities in DM2, including glucose-dependent enhancement of insulin secretion. OBJECTIVE: The objective of the study was to determine whether exenatide can restore a more normal pattern of insulin secretion in subjects with DM2. DESIGN: Fasted subjects received iv insulin infusion to reach plasma glucose 4.4-5.6 mmol/liter. Subjects received iv exenatide (DM2) or saline (DM2 and healthy volunteers), followed by iv glucose challenge. PATIENTS: Thirteen evaluable DM2 subjects were included in the study: 11 males, two females; age, 56 +/- 7 yr; body mass index, 31.7 +/- 2.4 kg/m2; hemoglobin A1c, 6.6 +/- 0.7% (mean +/- sd) treated with diet/exercise (n = 1), metformin (n = 10), or acarbose (n = 2). Controls included 12 healthy, weight-matched subjects with normal glucose tolerance: nine males, three females; age, 57 +/- 9 yr; and body mass index, 32.0 +/- 3.0 kg/m2. SETTING: The study was conducted at an academic hospital. MAIN OUTCOME MEASURES: Plasma insulin, plasma C-peptide, insulin secretion rate (derived by deconvolution), and plasma glucagon were the main outcome measures. RESULTS: DM2 subjects administered saline had diminished first-phase insulin secretion, compared with healthy control subjects. Exenatide-treated DM2 subjects had an insulin secretory pattern similar to healthy subjects in both first (0-10 min) and second (10-180 min) phases after glucose challenge, in contrast to saline-treated DM2 subjects. In exenatide-treated DM2 subjects, the most common adverse event was moderate nausea (two of 13 subjects). CONCLUSIONS: Short-term exposure to exenatide can restore the insulin secretory pattern in response to acute rises in glucose concentrations in DM2 patients who, in the absence of exenatide, do not display a first phase of insulin secretion. Loss of first-phase insulin secretion in DM2 patients may be restored by treatment with exenatide.   50

GLP-1 分泌與代謝 GLP-1 作用 GLP-1(9-36) 不活性 由腎臟移除 食物 DPP-IV GLP-1 (7-36) 活性 （半衰期約兩分鐘） 快速去活化 (>80% of pool) Plasma GLP-1 is secreted when meal contents are exposed to the intestine. A seminal paper published in the Spring of 1995 by Carolyn Deacon at the Panum Institute in Copenhagen showed clearly that once GLP-1 it is released into the circulation it is very rapidly inactivated by DPP-IV, a serine protease present throughout the vasculature. Additionally, both the intact and degraded peptide are removed from circulation by the kidneys, such that at any given time, only about 10 - 20 percent of GLP-1 is found in its intact, active form. Together, these removal pathways all but eliminate the ability of GLP-1 to exert its beneficial effects. GLP-1 作用 由腎臟移除 Deacon et al. Diabetes 1995; 44:1126 51

GLP-1 分泌與代謝 GLP-1的N端被DPP4破壞，半衰期很短，只有1-2分鐘，需要持續性的灌注才能達到穩定的藥效 因此需要研發 或抑制DPP4，延長內源性之GLP-1

GLP-1類似物 GLP-1類似物都需要注射，有每天一到兩針的exenatide（半衰期2.4小時）或兩週一針的長效型exenatide LAR等 刺激胰島素作用與它的劑量以及葡萄糖濃度有關 血糖低於72 mg/dl，它刺激胰島素分泌的作用就被抑制 它可與口服降糖藥如SU、metformin或glitazone，也可與胰島素併用 大約可降A1C 1% 副作用-常見的輕中度噁心、減重等 The molecular mechanism of action for GLP-1 as an insulinotropic agent as well as its extrapancreatic actions have been extensively reviewed by others [19 and 20]. On the β-cell, GLP-1 binds to GLP-1 receptor, a stimulatory G protein-coupled receptor activating adenylate cyclase. The activation of adenylate cyclase, in turn, increases the intracellular cyclic adenosine monophosphate (cAMP) concentration and subsequently activates protein kinase A (PKA). cAMP targets proteins that are insulin granular-associated, increasing the ability of a pool of granules to undergo exocytosis when intracellular calcium rises. The activation of PKA then also promotes adenosine triphosphate (ATP)-dependent potassium channel closure which works synergistically with elevated ATP generated from glucose, stimulates L-type calcium channels causing influx of extracellular calcium and promotes release of calcium from intracellular calcium stores, all of which result in exocytosis of insulin-containing granules [20]. 53

Exendin-4 39 氨基酸 53% 氨基酸與哺乳類雷同 作用在 GLP-1 受器 不易被 DPP-IV代謝 direct chemical synthesis Exenatide (Byetta)需注射，一天兩次 54

DPP4抑制劑 Sitagliptin 100mg qd 可口服 腎功能不全需要減量 約降A1C 0.6％ 原本糖尿病控制越不好的，效果較好 副作用 短期使用腸胃不適，稍微增加咽喉炎、泌尿道發炎、頭痛等 長期的安全性尚待觀察

J Clin Invest 117:24-32, 2007

GLP-1 analogs vs insulin

Exenatide與急性胰臟炎 2007-10-22衛生署：第二型糖尿病治療藥品Exenatide 美國FDA近日評估30件上市後安全性通報，發現第二型糖尿病治療藥品exenatide（商品名：Byetta）可能引起急性胰臟炎，故於2007年10月16日發布藥品安全資訊，提醒醫師倘若疑似病患罹患急性胰臟炎，應立刻中斷exenatide藥品之使用，倘若確認病患罹患急性胰臟炎，則不宜再繼續使用該藥品。病患若有無法解釋、持續且嚴重的腹痛應立即洽詢開立處方之醫師。 http://adr.doh.gov.tw

Exenatide可能引起急性腎衰竭 衛生署：Exenatide可能引起急性腎衰竭之不良反應 日期：2009-11-09 美國FDA於2009年11月2日發布含Exenatide藥品可能引起急性腎衰竭之安全資訊，並已核准其仿單更新標示。FDA從2005年4月至2008年10月，總共約有6百萬人使用Exenatide，共收到78件與該藥品有關之不良反應通報，其中62件發生急性腎衰竭，有些病人原先已存在腎臟方面的疾病，或者已潛在導致腎臟功能改變之風險因子。前述之不良反應，FDA已經請藥商加刊在藥品仿單中。 http://adr.doh.gov.tw

Sitagliptin與急性胰臟炎 衛生署：含Sitagliptin藥品可能引起急性胰臟炎之不良反應 建檔時間：2009/09/29 美國FDA於2009年9月25日發布藥品安全資訊，要求第二型糖尿病治療藥品Sitagliptin成分藥品（英文品名：JANUVIA及含Sitagliptin與Metformin之JANUMET）仿單應加刊上市後不良反應報告急性胰臟炎（acute pancreatitis），包括嚴重的出血性（hemorrhagic）和壞死性（necrotizing）胰臟炎。FDA建議醫師為病人處方該藥品時，宜同步監視其可能發生胰臟炎，尤其是在開始或增加劑量時，倘若懷疑病人發生胰臟炎時，應立即停藥。 http://adr.doh.gov.tw