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糖尿病治療之新趨勢

糖尿病治療之新趨勢. 王朝弘 醫師 內分泌暨新陳代謝科 馬偕醫院 9 2-11-25 07:30 ~08:20. 一、 Introduction 二 、 Pathoph ys iology of Diabetes Mellitus 三 、 Treatment strategies 四 、 Clinical Trials 五 、 Drugs for Treatment 六 、 The Future 七 、 Questions & Answers. A) Current medications B) Insulin sensitizers

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糖尿病治療之新趨勢

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  1. 糖尿病治療之新趨勢 王朝弘 醫師 內分泌暨新陳代謝科 馬偕醫院 92-11-25 07:30 ~08:20

  2. 一、Introduction 二、Pathophysiology of Diabetes Mellitus 三、 Treatment strategies 四、 Clinical Trials 五、Drugs for Treatment 六、The Future 七、Questions & Answers A) Current medications B) Insulin sensitizers C) Insulin therapy in T2DM D) Drugs interaction

  3. 第一型糖尿病的疾病生理發展階段 • 第一階段 基因體質 • 第二階段 環境觸發 • 第三階段 自家免疫啟動 • 第四階段 貝它細胞逐漸失能 • 第五階段 糖尿病顯現

  4. TYPE 2 DIABETES IMPAIRED GLUCOSE TOLERANCE HYPERTENSION CENTRAL OBESITY INSULIN RESISTANCE ATHEROSCLEROSIS DYSLIPIDAEMIA ENDOTHELIAL DYSFUNCTION URIC ACID FIBRINOLYSIS LEPTIN SYSTEMIC INFLAMMATION

  5. Loss of Early-phase Insulin Release in Type 2 Diabetes Pattern of insulin release is altered early in type 2 diabetes Normal Type 2 diabetes 120 100 80 60 40 20 0 120 100 80 60 40 20 0 20 gglucose 20 g glucose Plasma insulin (µU/ml) Plasma insulin (µU/ml) –30 0 30 60 90 120 –30 0 30 60 90 120 Time (minutes) Time (minutes) Ward WK et al. Diabetes Care 1984;7:491–502

  6. Metabolic (Insulin Resistance) Syndrome CVD Genetic Predisposition HTN Stroke Insulin Resistance Insulin Secretion Lipid disorders Many other diseases • Environmental factors • Obesity • Age • Lifestyle IFG, IGT, T2DM +β-cell defect

  7. Stages of Type 2 Diabetes 100 75 Beta Cell Function (%)   50    Postprandial Hyperglycemia Type 2 Diabetes Phase I IGT  Type 2 Diabetes Phase III  25 Type 2 Diabetes Phase II 0 -12 -10 -6 -2 0 2 6 10 14 Years From Diagnosis

  8. Diabetes Treatment Goals Plasma Glucose (mg/dL) Preprandial Postprandial A1C (%) Normal <110 <140 † <6.0 ADA 90~130 <180 <7.0 ACE/AACE <110 <140 † <6.5 *ACEE = American Association of Clinical Endocrinology; ACE = American College of Endocrinology; ADA = American Diabetes Association. †Two-hour postprandial

  9. Correlation between A1C & mean plasma glucose level Mean plasma glucose (mg/dl) 135 170 205 240 275 310 345 • A1C (%) • 6 • 7 • 8 • 9 • 10 • 11 • 12 ADA 2003

  10. Normal Physiology of Glucose Homeostasis Carbohydrate Gut Digestive enzymes Pancreas Regulation of lipolysis Blood Glucose Insulin Adiposetissue Glucose uptake, hepatic glucose production & storage of glycogen Muscle Liver Insulin-stimulated glucose uptake

  11. Stepped Management of Type 2 Diabetes

  12. Treatment Strategies FPG (mg/dl) A1C (%) + 1 OHA + Insulin or < 140 6.5~7.0 140~160 7.0~8.0 > 160 > 8.0 • Insulin sensitizer • -glucosidase • monotherapy • Combination • therapy • (2 OHAs)

  13. Finnish Diabetes Prevention Studymean duration of 3.2 years Intervention gr. Control gr. • n = 265 n = 257 • Specific dietary instruction oral or written information at baseline (diet & exercise) • Moderate exercise≧30min/d no specific individualized program • DM developed n=27 n=59 • DM developed 3%/yr 6%/yr • Risk of T2DM reduced by 58%

  14. Diabetes Prevention Program3 years of observation • Intense therapeutic lifestyle change ．Metformin ．Placebo • wt loss > 7% ．850 mg b.i.d. ．IGT→T2DM • Exercise > 150 min/wk 11%/yr • N=1073 ．N=1082 ． N=1079 • Risk reduction 58% ．risk reduction 31%

  15. UKPDS • For each 1% reduction in A1C • Over a 6-year period, ~53% of pt’s treated with sulfonylureas needed additional insulin therapy • A 21% decrease in any endpoint related to diabetes & in diabetes-related death • A 14% decrease in all-cause mortality & MI • A 43% decrease in amputation or death from PVD • A 37% decreased risk for microvascular complications

  16. 非藥物 • 生活型態之改變 • 飲食、營養之控制 • 規律之運動

  17. Oral Antihyperglycemic Agents Agent Sulfonylureas Nateglinide Repaglinide Metformin Pioglitazone Rosiglitazone Acarbose Miglitol Class Sulfonylurea Nonsulfonylurea insulin secretagogue Nonsulfonylurea insulin secretagogue Biguanide Thiazolidinedione Thiazolidinedione -Glucosidase inhibitor -Glucosidase inhibitor Major mechanism of action insulin secretion prandial insulin secretion prandial insulin secretion insulin resistance (hepatic) insulin resistance (peripheral) insulin resistance (peripheral) Delays CHO absorption from G-I tract Delays CHO absorption from G-I tract

  18. Action: Insulin resistance ( plasma insulin conc.) by • Insulin-mediated muscle glucose uptake • Insulin-mediated hepatic gluconeogenesis • Translocation of glucose receptors to plasma membrane Pharmacological Agents (1.0) a) Metformin

  19. Contraindications and PrecautionsMetformin • Hepatic disease, CHF (drugs treated) • Hx of lactic acidosis • Renal impartment — GFRs (<60ml/min) or Srcr (men:>1.5mg/dl, women:>1.4mg/dl) • Alcohol ingestion • Shock • Surgery • Aging (80 years)

  20. postprandial glycemia • wt Pharmacological Agents (2.0) c) Alpha-glucosidase inhibitors (AGIs) Action: Inhibit starch digestion in small intestine, & delaying glucose absorption Advantages: • different mode of action from other drugs • no risk of hypoglycaemia Disadvantages: • flatulence & bloating • diarrhea

  21. Insulin Secretagogues Sulfonylureas Non-sulfonylureas  Insulin Secretion 1st-phase No Yes 2nd-phase exaggerated No  Biological half-life Very short Starlix Short Tolbutamide NovoNorm Intermediate Glipizide, Diamicron, Amaryl long Euglucon, Diabenase  Hypoglycemic risk

  22. Pharmacological Agents (3.0) d) Sulphonylureas Action: Increase insulin secretion by closing Katp channels in pancreatic β cell Advantages: • powerful hypoglycemic effect • no GI intolerance • low cost Disadvantages: • weight gain • secondary failure common • risk of hypoglycaemia

  23. NovoNorm (4.3) Short acting Different binding site at SUR receptor Rapidly absorbed (peak ~45’) Action within 30’ 0.5 ~ 4.0 mg ac within 30’ Stimulate early-phase insulin secretion, subside ~ 4h Mean A1C ~ 1.7% Mean FPG ~ 61 mg/dl Liver metabolism ~100% Less hypoglycemia & wt gain ò vs. Placebo ò

  24. Starlix :使糖立釋 膜衣錠 60 毫克(5.0) • 成分名：Nateglinide • 商品名：Starlix® • 適應症：第2型糖尿病(非胰島素依賴型糖尿病) • 最新一類藥物：D-phenylalanine氨基酸衍生物，被 FDA證明可分泌早期胰島素的抗糖尿病藥物 • 作用機轉：可藉由高度選擇性地阻斷鉀離子管道(Katp channel)，恢復人體本能胰島素分泌的能力(mimic physical insulin release) • 臨床療效：明顯降低飯後血糖(2hr-PPG)，糖化血色素 (A1C)與空腹血糖(FPG)，而不刺激胰臟β-細胞分泌過 度的胰島素

  25. 快速生效(Fast-on)；快速恢復(Fast-off)的作用(5.1) • ‘Fast-on’ :(快速生效)作用，可重建糖尿病患喪失的 「早期胰島素」分泌功能。 • ‘Fast-off’: (快速恢復)作用，可避免因高胰島素延緩 而導致的低血糖危險 • Starlix®對血中葡萄糖濃度感受性非常明顯；當血糖 高時，作用明顯；反之血糖低時，則作用減低。 不易造成高胰島素或低血糖之副作用。

  26. Starlix (5.2) Rapidly absorbed & acting Significant selectivity on -cells & cardiac cells No accumulation or tissue retention with repeated administration Relatively low potential for drag-drug interactions Restoring early-phase insulin secretion No special dose adjustments (elderly, renal impairment) 60~180 mg taken 1’~30’ before meal Hypoglycemia & wt gain ─ low potential Monotherapy & combination therapy

  27. NovoNorm (1mg/#) Starlix (60mg/#) rapidly absorbed Peak plasma level within 1° within 45min Bioavailability 65% 70% plasma t1/2 ~1 h 0.5 ~1.9 h Katp -channel binding faster - affinity lower Metabolism liver into inactive liver (85-95%) substances to 3~6 less potent products Excretion bile (major) urine(75%) urine 6% feces (~10%) Maximal dose 16mg/d 540mg/d

  28. Contraindications and PrecautionsSulphonylureas • T1DM • Pregnancy or breast-feeding • Documented hypersensitivity • Severe hepatic or renal dysfunction • Severe, acute illness (e.g., infection, MI), surgery, stress

  29. plasma insulin • lipids Pharmacological Agents (6.0) b) Thiazolidinediones Action: Reduce insulin resistance by acting as PPARgagonists Advantages: • powerful hypoglycemic effect • low risk of secondary failure • no risk of hypoglycaemia • fluid retention Disadvantages: • weight gain • ? Hepatic dysfunction • dilutional anemia • high cost

  30. Contraindications and PrecautionsThiazolidinediones • T1DM • Pre-existing hepatic disease * ALT >2.5UNL * d/c, if ALT>3UNL, rising serum bilirubin * Hepatitis Sx (malaise, fatigue, nausea, vomiting, dark urine, abdominal pain, ……) • Severe CHF(NYHA classes Ⅲ & Ⅳ) • Premenopausal anovulatory woman — unwanted pregnancy • Hx of hypersensitivity to TZDs • Drugs metabolized by CYP 3A4

  31. Drugs Interaction Oral Anti-diabetes Agents (1) Sulphonylurea  Effect * Antacids Gastric pH  Enhanced Euglucon absorption * Cimetidine   Tolbutamide hepatic metabolism * Fluconazole   Plasma conc. * Gemfibrozil  Protein displacement , need to  dose of SU * Sulfinpyrazone   Tolbutamide hepatic metabolism &  t 1/2 2~3  Effect * Alcohol   Tolbutamide hepatic metabolism 2  * Rifampin  Euglucon metabolism   t 1/2 & plasma drug conc.

  32. Drugs Interaction Oral Anti-diabetes Agents (2) Metformin * Alcohol   Effects of metformin on lactate metabolism * Cimetidine   Peak metformin plasma conc. * Erythromycin  Severe cholestatic hepatitis reported (with chlorpropamide) * I-contrast dye  ARF, lactic acidosis -Glucosidase Inhibitors * Digestive enzyme preparations  Acarbose effect * Digoxin  Serum digoxin conc.  therapeutic effects * Inderal   Bioavailability of propranolol ~40% * Ranitidine   Bioavailability of Ranitidine ~60% (Miglitol)

  33. Drugs Interaction Oral Anti-diabetes Agents (3) Thiazolidinediones * Ketoconazone  Inhibit the metabolism of Actos * Oral pills   Plasma conc. (~30%) of ethinyl estradiol & norethindorne (Actos), watch for for flushes (estrogen def) * Terfenadine   Plasma conc. (~50~70%) of Terfenadine (Troglitazone)

  34. Comparison of Human Insulins and Insulin Analogues Duration of action (h) Insulin preparation Onset of action Peak (h) Lispro/aspart Human regular Human NPH†/Lente‡ Human Ultralente Glargine 5~15min 30~60min 1~2h 2-4h 1-2h 1~2 2~4 4~8 Unpredictable Flat 4~6 8~10 10~20 16~20 About 24 *The time course of action of any insulin may vary in different individuals or at different times in the same individual. Because of this variation, time frames should be considered general guidelines only. †Human insulin isophane suspension (or neutral protamine Hagedorn). ‡Human insulin zinc suspension.

  35. Premixed Insulin Combinations Interval between dosing & meal initiation (min) 10~20 30 15 30~60 Time of peak activity (h after dosing) 2.2+0.80 4.2+0.93 2.6 (1.0~6.5) 4.4 (1.5~16) Combination Novolog Mix 70/30 (70% insulin aspart protamine & 30% insulin aspart) Novolin 70/30 (70% insulin NPH & 30% insulin regular) Humalog Mix 75/25 (75% insulin lispro protamine & 25% insulin lispro) Humulin 70/30 (70% insulin NPH & 30% insulin regular)

  36. Role for Insulin Therapy in T2DM • A disease of insulin deficiency – continuing deterioration in β-cell function • Not good at diagnosing diabetes • All type 2 diabetes is not type 2 diabetes • Effects of OHAs are limited • Natural Hx of T2DM is OHA failure • Guidelines for optimal glucose control are going lower • Potential for glucose lowering with insulin is unlimited

  37. Establishing StartingBasal and Bolus Doses Pre-Pump Dose Pump Starting Dose (70-75% of Pre-Pump Dose) 50% Basal 50% Bolus

  38. Breakfast Dinner 0:00 am 4:00 am Breakfast Lunch Post-prandial The Majority of the Day is Spend in a Post-prandial & Post-absorptive State Post-absorptive Fasting Monnier L. Eur J Clin Invest 2000;30(Suppl. 2):3–11

  39. Significances of Hyperglycemia • Acute  in PG   free radical,  PAI-I  hypercoagulability  atherosclersis. • Chronic PPG  activation of protein kinase C in the endothelium  endothelial dysfunction.

  40. FPG + PPG Postprandial Glucose Spikes Significantly Affect A1C HbA1C = FPG = fasting plasma glucose; PPG = postprandial plasma glucose Adapted from S Del Prato, 2002

  41. Glucovance (Glyburide + Metformin) • 1.25 mg/250 mg; 2.5 mg/500 mg; 5 mg/500 mg Combination Therapy Combo pill • Metaglip (Glipizide + Metformin) • 2.5 mg/250 mg, 2.5 mg/500 mg, 5 mg/500mg • Avandamet (Avandia + Metformin HCl) • 1 mg/500 mg; 2 mg/500 mg; 4 mg/500 mg (Starlix, NovoNorm) SU Metformin Acarbose TZDs Insulin

  42. Trend in Treatment for Diabetes • Earlier detection  Prevention, focus on the metabolic risk factors • Aggressive treatment  Earlier use of insulin • Total treatment  Poly-pharmacy and combo pill • Optimal treatment goal  Individualized (co-morbidity & complications)

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