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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92-11-2507:30 08:20,一、Introduction二、Pathophysiology of Diabetes Mellitus三、Treatment strategies四、Clinical Trials五、Drugs for Treatment六、The Future七、Questions&Answers,A)Current medicationsB)Insulin sensitizersC)Insulin therapy in T2DMD)Drugs interaction,第一型糖尿病的疾病生理發展階段,第一階段
2、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,IMPAIREDGLUCOSETOLERANCE,DYSLIPIDAEMIA,TYPE 2 DIABETES,HYPERTENSION,FIBRINOLYSIS,URIC ACID,SYSTEMIC INFLAMMATION,LEPTIN,ATHEROSCLEROSIS,ENDOTHELIALDYSFUNCTION,CENTRALOBESITY,INSULINRESISTANCE,Loss of Early-phase Insulin Release in Type 2 Diabetes,Ward WK e
3、t al.Diabetes Care 1984;7:491502,Normal,Type 2 diabetes,120100806040200,300306090120,Time(minutes),300306090120,Time(minutes),Plasma insulin(U/ml),120100806040200,20 g glucose,20 gglucose,Plasma insulin(U/ml),Pattern of insulin release is altered early in type 2 diabetes,GeneticPredisposition,Enviro
4、nmental factorsObesityAgeLifestyle,InsulinResistance,InsulinSecretion,CVD,HTNStroke,Lipiddisorders,Many otherdiseases,IFG,IGT,T2DM,+-celldefect,Metabolic(Insulin Resistance)Syndrome,-12,-10,-6,-2,0,2,6,10,14,0,25,50,75,100,IGT,PostprandialHyperglycemia,Type 2DiabetesPhase I,Type 2Diabetes Phase II,T
5、ype 2 Diabetes Phase III,Years From Diagnosis,Beta CellFunction(%),Stages of Type 2 Diabetes,Diabetes Treatment Goals,Plasma Glucose(mg/dL)PreprandialPostprandialA1C(%),Normal110 140 6.0,ADA901301807.0,ACE/AACE110 140 6.5,*ACEE=American Association of Clinical Endocrinology;ACE=American College of E
6、ndocrinology;ADA=American Diabetes Association.Two-hour postprandial,Correlation between A1C&mean plasma glucose level,A1C(%)6 7 8 9 10 11 12,Mean plasma glucose(mg/dl)135170205240275310345,ADA 2003,Normal Physiology of Glucose Homeostasis,Glucose uptake,hepatic glucose production&storage of glycoge
7、n,Insulin-stimulated glucose uptake,Regulation of lipolysis,Adiposetissue,Carbohydrate,Blood Glucose,Digestiveenzymes,Gut,Pancreas,Muscle,Liver,Insulin,Stepped Management of Type 2 Diabetes,Treatment Strategies,FPG(mg/dl)A1C(%),1401607.08.0,160 8.0,or,+1 OHA+Insulin,Insulin sensitizer-glucosidase,mo
8、notherapy,Combination therapy(2 OHAs),1406.57.0,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 exercise30min/d no specific individualized program DM develop
9、ed n=27 n=59 DM developed 3%/yr 6%/yr Risk of T2DM reduced by 58%,Diabetes Prevention Program 3 years of observation,Intense therapeutic lifestyle change Metformin Placebo wt loss 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%,UKPDS,For ea
10、ch 1%reduction in A1COver a 6-year period,53%of pts treated with sulfonylureas needed additional insulin therapy,A 21%decrease in any 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 micr
11、ovascular complications,非藥物,生活型態之改變飲食、營養之控制規律之運動,Oral Antihyperglycemic Agents,AgentSulfonylureasNateglinideRepaglinideMetforminPioglitazoneRosiglitazoneAcarboseMiglitol,ClassSulfonylureaNonsulfonylurea insulin secretagogueNonsulfonylurea insulin secretagogueBiguanideThiazolidinedioneThiazolidinedio
12、ne-Glucosidase inhibitor-Glucosidase inhibitor,Major mechanism of actioninsulin secretionprandial insulin secretionprandial insulin secretioninsulin resistance(hepatic)insulin resistance(peripheral)insulin resistance(peripheral)Delays CHO absorption from G-I tractDelays CHO absorption from G-I tract
13、,a)Metformin,Pharmacological Agents(1.0),Contraindications and PrecautionsMetformin,Hepatic disease,CHF(drugs treated)Hx of lactic acidosisRenal impartment GFRs(1.5mg/dl,women:1.4mg/dl)Alcohol ingestionShockSurgeryAging(80 years),c)Alpha-glucosidase inhibitors(AGIs),different mode of action from oth
14、er drugs,Action:Inhibit starch digestion in small intestine,&delaying glucose absorption,Advantages:,no risk of hypoglycaemia,flatulence&bloating,Disadvantages:,diarrhea,Pharmacological Agents(2.0),Insulin Secretion 1st-phase No Yes 2nd-phase exaggerated No Biological half-life Very short Starlix Sh
15、ort Tolbutamide NovoNorm Intermediate Glipizide,Diamicron,Amaryl long Euglucon,Diabenase Hypoglycemic risk,Sulfonylureas Non-sulfonylureas,Insulin Secretagogues,d)Sulphonylureas,powerful hypoglycemic effect,Action:Increase insulin secretion by closing Katp channels in pancreatic cell,Advantages:,low
16、 cost,no GI intolerance,weight gain,Disadvantages:,secondary failure common,risk of hypoglycaemia,Pharmacological Agents(3.0),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,su
17、bside 4h Mean A1C 1.7%Mean FPG 61 mg/dl Liver metabolism 100%Less hypoglycemia&wt gain,vs.Placebo,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 re
18、lease)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-細胞分泌過度的胰島素,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。,Starlix(5.2),Rapidly absorbed&acting Significant selecti
19、vity 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 taken 130 before meal Hypoglycemia&wt gain low potent
20、ial 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 liver(85-95%)substances to 36 less potent productsExcretio
21、n bile(major)urine(75%)urine 6%feces(10%)Maximal dose 16mg/d 540mg/d,Contraindications and PrecautionsSulphonylureas,T1DMPregnancy or breast-feedingDocumented hypersensitivitySevere hepatic or renal dysfunctionSevere,acute illness(e.g.,infection,MI),surgery,stress,b)Thiazolidinediones,powerful hypog
22、lycemic effect,Action:Reduce insulin resistance by acting as PPAR g agonists,low risk of secondary failure,Advantages:,no risk of hypoglycaemia,fluid retention,Disadvantages:,weight gain,?Hepatic dysfunction,dilutional anemia,high cost,Pharmacological Agents(6.0),Contraindications and PrecautionsThi
23、azolidinediones,T1DMPre-existing hepatic disease*ALT 2.5UNL*d/c,if ALT3UNL,rising serum bilirubin*Hepatitis Sx(malaise,fatigue,nausea,vomiting,dark urine,abdominal pain,)Severe CHF(NYHA classes&)Premenopausal anovulatory woman unwanted pregnancyHx of hypersensitivity to TZDsDrugs metabolized by CYP
24、3A4,Drugs Interaction,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 23 Effect*Alcohol Tolbutamide hepatic
25、 metabolism 2*Rifampin Euglucon metabolism t 1/2&plasma drug conc.,Oral Anti-diabetes Agents(1),Drugs Interaction,Metformin*Alcohol Effects of metformin on lactate metabolism*Cimetidine Peak metformin plasma conc.*Erythromycin Severe cholestatic hepatitis reported(with chlorpropamide)*I-contrast dye
26、 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),Oral Anti-diabetes Agents(2),Drugs Interaction,Thiazolidinediones
27、*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 Anti-diabetes Agents(3),Comparison of Human Insulins and Insulin Analogues,Lispro/a
28、spartHuman regularHuman NPH/LenteHuman UltralenteGlargine,515min3060min12h2-4h1-2h,122448UnpredictableFlat,4681010201620About 24,Insulin preparation,Onset of action,Peak(h),Duration of action(h),*The time course of action of any insulin may vary in different individuals or at different times in the
29、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 Combinations,CombinationNovolog Mix 70/30(70%insulin aspart protamine&30%insulin aspart)
30、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)102030153060,Time of peak activity(h after dosing)2.2+0.804.2+0.932.6(1.06.5)4.4(1.516),Role fo
31、r Insulin Therapy in T2DM,A disease of insulin deficiency continuing deterioration in-cell functionNot good at diagnosing diabetesAll type 2 diabetes is not type 2 diabetesEffects of OHAs are limitedNatural Hx of T2DM is OHA failureGuidelines for optimal glucose control are going lowerPotential for
32、glucose lowering with insulin is unlimited,Establishing StartingBasal and Bolus Doses,50%Basal,Pre-Pump Dose,Pump Starting Dose(70-75%of Pre-Pump Dose),50%Bolus,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
33、.2):311,Acute in PG free radical,PAI-I hypercoagulability atherosclersis.Chronic PPG activation of protein kinase C in the endothelium endothelial dysfunction.,Significances of Hyperglycemia,FPG=fasting plasma glucose;PPG=postprandial plasma glucose,HbA1C,=,Adapted from S Del Prato,2002,Postprandial
34、 Glucose Spikes Significantly Affect A1C,Combination 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 mg/500 mg,5 mg/500mg,Avandamet(Avandia+Metformin HCl)1 mg/500 mg;2 mg/500 mg;4 mg/500 mg,SUMetformin,Acarbose TZDs,(Starlix,NovoNorm),Insulin,Trend in Treatment for Diabetes,Earlier 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),
