1、糖尿病治療之新趨勢糖尿病治療之新趨勢王朝弘王朝弘 醫師醫師內分泌暨新陳代謝科內分泌暨新陳代謝科馬偕醫院馬偕醫院92-11-2507:30 08:20 一、一、Introduction二二、Pathophysiology of Diabetes Mellitus三三、Treatment strategies四四、Clinical Trials五五、Drugs for Treatment六六、The Future七七、Questions&AnswersA)Current medicationsB)Insulin sensitizersC)Insulin therapy in T2DMD)Drugs
2、 interaction第一型糖尿病的疾病生理發展階段第一型糖尿病的疾病生理發展階段第一階段第一階段基因體質基因體質第二階段第二階段環境觸發環境觸發第三階段第三階段自家免疫啟動自家免疫啟動第四階段第四階段貝它細胞逐漸失能貝它細胞逐漸失能第五階段第五階段糖尿病顯現糖尿病顯現IMPAIREDGLUCOSETOLERANCEDYSLIPIDAEMIATYPE 2 DIABETESHYPERTENSIONFIBRINOLYSISURIC ACIDSYSTEMIC INFLAMMATIONLEPTINATHEROSCLEROSISENDOTHELIALDYSFUNCTIONCENTRALOBESITYI
3、NSULINRESISTANCELoss of Early-phase Insulin Release in Type 2 DiabetesWard WK et al.Diabetes Care 1984;7:491502NormalType 2 diabetes120100806040200300306090 120Time(minutes)300306090 120Time(minutes)Plasma insulin(U/ml)12010080604020020 g glucose20 gglucosePlasma insulin(U/ml)Pattern of insulin rele
4、ase is altered early in type 2 diabetes GeneticPredispositionEnvironmental factorsObesityAgeLifestyleInsulinResistanceInsulinSecretionCVDHTNStrokeLipiddisordersMany otherdiseasesIFG,IGT,T2DM+-celldefectMetabolic(Insulin Resistance)Syndrome-12-10-6-2 0 2 6 10 14 0255075100IGT PostprandialHyperglycemi
5、aType 2DiabetesPhase I Type 2Diabetes Phase IIType 2 Diabetes Phase IIIYears From DiagnosisBeta CellFunction (%)Stages of Type 2 DiabetesDiabetes Treatment GoalsPlasma Glucose(mg/dL)PreprandialPostprandialA1C(%)Normal110 140 6.0ADA901301807.0ACE/AACE110 140 160 8.0or+1 OHA+Insulin Insulin sensitizer
6、-glucosidase monotherapy Combination therapy(2 OHAs)7%850 mg b.i.d.IGTT2DM Exercise 150 min/wk 11%/yr N=1073 N=1082 N=1079 Risk reduction 58%risk reduction 31%UKPDSFor each 1%reduction in A1COver a 6-year period,53%of pts treated with sulfonylureas needed additional insulin therapyA 21%decrease in a
7、ny endpoint related to diabetes&in diabetes-related deathA 14%decrease in all-cause mortality&MIA 43%decrease in amputation or death from PVDA 37%decreased risk for microvascular complications 非藥物非藥物I.I.生活型態之改變生活型態之改變II.II.飲食飲食、營養之控制營養之控制III.III.規律之運動規律之運動Oral Antihyperglycemic AgentsAgentSulfonylur
8、easNateglinideRepaglinideMetforminPioglitazoneRosiglitazoneAcarboseMiglitolClassSulfonylureaNonsulfonylurea insulin secretagogueNonsulfonylurea insulin secretagogueBiguanideThiazolidinedioneThiazolidinedione-Glucosidase inhibitor-Glucosidase inhibitorMajor mechanism of actioninsulin secretionprandia
9、l insulin secretionprandial insulin secretioninsulin resistance(hepatic)insulin resistance(peripheral)insulin resistance(peripheral)Delays CHO absorption from G-I tractDelays CHO absorption from G-I tracta)MetforminPharmacological Agents(1.0)Action:Insulin resistance(plasma insulin conc.)by Insulin-
10、mediated muscle glucose uptake Insulin-mediated hepatic gluconeogenesis Translocation of glucose receptors to plasma membraneContraindications and PrecautionsMetforminHepatic disease,CHF(drugs treated)Hx of lactic acidosisRenal impartment GFRs(1.5mg/dl,women:1.4mg/dl)Alcohol ingestionShockSurgeryAgi
11、ng(80 years)c)Alpha-glucosidase inhibitors(AGIs)different mode of action from other drugsAction:Inhibit starch digestion in small intestine,&delaying glucose absorption Advantages:wt postprandial glycemia no risk of hypoglycaemia flatulence&bloatingDisadvantages:diarrheaPharmacological Agents(2.0)In
12、sulin 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 Sulfonylureas Non-sulfonylureasInsulin Secretagoguesd)Sulphonylureas powerful hypoglycemic ef
13、fectAction:Increase insulin secretion by closing Katp channels in pancreatic cellAdvantages:low cost no GI intolerance weight gainDisadvantages:secondary failure common risk of hypoglycaemiaPharmacological Agents(3.0)NovoNorm(4.3)Short acting Different binding site at SUR receptor Rapidly absorbed(p
14、eak 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 gainvs.PlaceboStarlix:使糖立釋使糖立釋 膜衣錠膜衣錠 60 毫克毫克(5.0)成分名：成分名：Nateglinide商品名：商品名：Starlix適應症：第適應症：第2型糖尿病型糖尿病(非胰島素依賴型糖尿病非胰島素依賴型糖尿病)最新一
15、類藥物：最新一類藥物：D-phenylalanine氨基酸衍生物，被氨基酸衍生物，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恢復人體本能胰島素分泌的能力的能力(mimic physical insulin release)臨床療效：明顯降低飯後血糖臨床療效：明顯降低飯後血糖(2hr-PPG)，糖化血色素糖化血色素(A1C)與空腹血糖與空腹血糖(FPG)，而不刺激胰臟而不刺激胰臟-細胞分泌過細胞分泌過度的胰島素度的胰島素快速生
16、效快速生效(Fast-on)；快速恢復；快速恢復(Fast-off)的作用的作用(5.1)Fast-on:(:(快速生效快速生效)作用，可重建糖尿病患喪失作用，可重建糖尿病患喪失的的 早期胰島素分泌功能。早期胰島素分泌功能。Fast-off:(快速恢復快速恢復)作用，可避免因高胰島素延作用，可避免因高胰島素延緩緩 而導致的低血糖危險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。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。不易造成高胰島素或低血糖之副作用。Sta
17、rlix(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)60180 mg
18、taken 130 before meal Hypoglycemia&wt gain low potential Monotherapy&combination therapy NovoNorm(1mg/#)Starlix(60mg/#)rapidly absorbed Peak plasma level within 1 within 45minBioavailability 65%70%plasma t1/2 1 h 0.5 1.9 hKatp-channel binding faster -affinity lowerMetabolism liver into inactive live
19、r(85-95%)substances to 3 6 less potent productsExcretion bile(major)urine(75%)urine 6%feces(10%)Maximal dose 16mg/d 540mg/d Contraindications and PrecautionsSulphonylureasT1DMPregnancy or breast-feedingDocumented hypersensitivitySevere hepatic or renal dysfunctionSevere,acute illness(e.g.,infection,
20、MI),surgery,stressb)Thiazolidinediones powerful hypoglycemic effectAction:Reduce insulin resistance by acting as PPAR g g agonists low risk of secondary failureAdvantages:lipids plasma insulin no risk of hypoglycaemia fluid retentionDisadvantages:weight gain?Hepatic dysfunction dilutional anemia hig
21、h costPharmacological Agents(6.0)Contraindications and PrecautionsThiazolidinediones T1DM Pre-existing hepatic disease *ALT 2.5 UNL *d/c,if ALT3 UNL,rising serum bilirubin *Hepatitis Sx(malaise,fatigue,nausea,vomiting,dark urine,abdominal pain,)Severe CHF(NYHA classes&)Premenopausal anovulatory woma
22、n unwanted pregnancy Hx of hypersensitivity to TZDs Drugs metabolized by CYP 3A4Drugs Interaction Sulphonylurea Effect *Antacids Gastric pH Enhanced Euglucon absorption *Cimetidine Tolbutamide hepatic metabolism *Fluconazole Plasma conc.*Gemfibrozil Protein displacement,need to dose of SU *Sulfinpyr
23、azone Tolbutamide hepatic metabolism&t 1/2 23 Effect *Alcohol Tolbutamide hepatic metabolism 2 *Rifampin Euglucon metabolism t 1/2&plasma drug conc.Oral Anti-diabetes Agents(1)Drugs InteractionMetformin *Alcohol Effects of metformin on lactate metabolism *Cimetidine Peak metformin plasma conc.*Eryth
24、romycin 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 Ranit
25、idine 60%(Miglitol)Oral Anti-diabetes Agents(2)Drugs InteractionThiazolidinediones *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.(5070%)of Terfenadine(Troglitazone)Oral
26、Anti-diabetes Agents(3)Comparison of Human Insulins and Insulin AnaloguesLispro/aspartHuman regularHuman NPH/LenteHuman UltralenteGlargine515min3060min12h2-4h1-2h122448UnpredictableFlat4681010201620About 24Insulin preparationOnset of actionPeak(h)Duration of action(h)*The time course of action of an
27、y 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.Premixed Insulin CombinationsComb
28、inationNovolog 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)Interval between dosing&meal initiation(min)102030153060Time of peak
29、activity(h after dosing)2.2+0.804.2+0.932.6(1.06.5)4.4(1.516)Role for Insulin Therapy in T2DM A disease of insulin deficiency continuing deterioration in-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 fai
30、lure Guidelines for optimal glucose control are going lower Potential for glucose lowering with insulin is unlimited Establishing StartingBasal and Bolus Doses50%BasalPre-Pump DosePump Starting Dose(70-75%of Pre-Pump Dose)50%BolusThe Majority of the Day is Spend in a Post-prandial&Post-absorptive St
31、ateBreakfastLunchDinner0:00 am4:00 amBreakfastPost-prandialPost-absorptiveFastingMonnier L.Eur J Clin Invest 2000;30(Suppl.2):311Acute in PG free radical,PAI-I hypercoagulability atherosclersis.Chronic PPG activation of protein kinase C in the endothelium endothelial dysfunction.Significances of Hyp
32、erglycemiaFPG=fasting plasma glucose;PPG=postprandial plasma glucoseAdapted from S Del Prato,2002Postprandial Glucose Spikes Significantly Affect A1CCombination Therapy Combo pill Glucovance(Glyburide+Metformin)1.25 mg/250 mg;2.5 mg/500 mg;5 mg/500 mg Metaglip(Glipizide+Metformin)2.5 mg/250 mg,2.5 m
33、g/500 mg,5 mg/500mg Avandamet(Avandia+Metformin HCl)1 mg/500 mg;2 mg/500 mg;4 mg/500 mg SUMetforminAcarbose TZDs(Starlix,NovoNorm)InsulinTrend in Treatment for DiabetesEarlier detection Prevention,focus on the metabolic risk factorsAggressive treatment Earlier use of insulinTotal treatment Poly-pharmacy and combo pillOptimal treatment goal Individualized(co-morbidity&complications)
