糖尿病 香港 临床医师培训

Diabetes Mellitus: Pharmacotherapy & managementDr. Norman ChanType 2 Diabetes: A Complex Metabolic DisorderImpaired insulin secretionInsulin resistanceMacrovascular complications“INSULIN RESISTANCE SYNDROME”Microvascular complicationsCentral obesityHypertension DyslipidaemiaEstimates of Diabetes Prevalence in World Regions80 70Estimated prevalence (millions)19952000202560 50 40 30 20 10 0Africa Americas Eastern Med. Europe Southeast Western Pacific AsiaWHO Report 1997. World Health Organization. Geneva;1997.Impact of age on acute MI or death in diabetic and non-diabetic subjectsPopulation-based retrospective cohort study Diabetes N=379,003 No diabetes N=9,018,082 Ontario, Canada FU: April 1994 – March 2000 Entry into high risk category: (event rate equivalent to a 10-year risk of 20%) Diabetic men = 41.3 years Diabetic women = 47.7 yearsBooth GL, et al. Lancet 2006; 368:29-36Diabetes = Ageing 15 yearsDiabetic vascular complicationsIncreased prevalence of macrovascular and microvascular complications in type 2 diabetes3027.8 22.9Diabetes Normal glucose levels18.9Patients (%)2010109.89.59.16.17.92.16.61.1 1.81.81.7*0 Chronic kidney disease Foot problems Eye damage MI Chest pain CHD CHF StrokeMicrovascular complications*Data for prevalence of eye damage for individuals with normal glucose control not availableMacrovascular complicationsAACE. State of Diabetes Complications in America Report, 2007.Diabetes = coronary risk equivalent 7-Year Incidence of Fatal and Nonfatal MI50Incidence rate (%)45%40 30 20 10 0No Prior MI*(n=1,373)19%20%4%Prior MI No Prior MI* Prior MINon-diabeticDiabetic(n=1,059)*At baseline MI=myocardial infarction P<0.001 for prior MI vs. no prior MI and for diabetes vs. no diabetes Haffner SM, et al. N Eng J Med. 1998;339:229-234.Macrovascular risk starts early in diabetesIncreased risk of CV complications begins In the non-diabetic range of glucose disregulation1Normal Glucose intolerance DiabetesCVD Microvascular 1.0• Impaired glucose tolerance (IGT) appears first • HbA1C & fasting glucose are still normal at this stage 1,2 • Increased risk of CV complications begins before overt diabetes develops.3 • => Measurement of postprandial glucose allows early identification of at-risk individualsPlasma glucose level 1. Gerstein HC. Glucose: a continuous risk factor for cardiovascular disease. Diabet Med 1997;14(Suppl 3):S25-31. 2. Reaven GM et al. Does Hyperglycaemia or hyperinsulinemia characterize the patient with chemical diabetes? Lancet 1972;I;1247-1249. 3. Little RR et al. Relationship of glycosylated hemoglobin to oral glucose tolerance: implications for diabetes screening. Diabetes 1988;37:60-64.Relative riskCase studyMr. Wong Health check up WC 98cm BP 140/92 FPG 4.7 mmol/L TC 4.754/M WT 96kg BMI 38.6TG 4.9HDL 0.8LDL?ALT 128, GGT 108Case study OGTT 4.6 (fasting) 10.2 (2-hour)Ultrasound: Moderate fatty liver Carotid IMT: thinkened (1.2 cm) with plaquesCalcified plaque noted at LAD, DB,LCX and RCAGuidelinesTreatment goalsHbA1c< 7.0% (ADA) <6.5% (AACE/IDF)BP<130/80mmHg LDL<2.6 mmol/lHYPERGLYCEMIA AtherosclerosisClinical EventEndothelial dysfunctionEndothelial Inflammation Apoptosis activationFibrous cap Angiogenesis formationThrombosisChoudhury RP et al. Nat Rev Drug Disc 3:913-9, 2004time has come to move from a HgbA1c/fasting glucose-centered to a treatment paradigm that focuses on comprehensive glycemic controlDCCT FindingsLowering blood glucose reduced risk of:– Eye disease by 76% – Kidney disease by 50% – Nerve disease by 60%DCCT. New England Journal of Medicine, 329(14), September 30, 1993.Cumulative Incidence of New Clinical Albuminuria (> 300 mg/24 h) During EDICCumulative Incidence (%)12 10 8 6 483% risk reduction p < .0001ConventionalIntensive2 0 1-2 3-4 5-6 7-8EDIC YearJAMA 290:2159-2167, 2003DCCT/EDIC18Lowering HbA1C Reduces Risk of Microvascular ComplicationsIntensive Tx Group (HbA1c 7.0%) vs Conventional Tx Group (HbA1c 7.9%)-16P=0.052-21MI Retinopathy Cataract extraction Microvascular endpoint Albuminuria at 12 years Any diabetes related endpointP=0.015 P=0.046 P=0.009-34-24 -25P=0.00005-12P=0.029 -20 -30 -40 % Reduction in Risk -500-10UK Prospective Diabetes Study (UKPDS) Group (33). Lancet 1998; 352: 837–853DCCT/EDIC: Glycaemic control reduces complications in type 1 diabetesDCCT1 (6.5 years)Retinopathy Neuropathy NephropathyDCCT/EDIC2 (17 years)MI, stroke or death from CVD Any CVD event0 –10 –20Risk reduction (%)–30 –40 –5060% 54% 57% § 42% §–60 –70 –8076% *Retinopathy: primary prevention cohort (no retinopathy at baseline; n = 726); neuropathy, nephropathy: combined cohort (n = 715). Mean duration of follow-up shown *P < 0.001; P = 0.02§1DCCT.N Engl J Med 1993;329:977–986. 2DCCT/EDIC. N Engl J Med 2005;353:2643–2653.HbA1cThe lower the better???Effect of intensive glucose lowering in macrovascular complications of type 2 diabetic patientsVADTNon-fatal MI Non-fatal stroke CVD death Hospitalization for CHF Revascularization 0.87 (0.730 – 1.04)ACCORDADVANCEPrimary outcomeNon-fatal MI Non-fatal stroke CVD deathNon-fatal MI Non-fatal stroke CVD deathHazard Ratio for primary outcome (95% CI) Hazard Ratio for mortality (95% CI)*P=0.040.90 (0.78 – 1.04) 0.94 (0.84 – 1.06)1.065 (0.801 – 1.416)1.22 (1.01 – 1.46)*0.93 (0.83 – 1.06)l1CVD Trials in T2DM Patients90 + HEART 2D Proportion of Subjects with CVD (%) 60 ORGINN =12,612 A1C =6.5 % N =1115 A1C = 7.8 %BARI-2DN=2257 A1C =6.5 %50 PROactive 40 NAVIGATOR 30N = 9306 A1C = 5.8 %(N=5,238) A1C = 7.9 %VADT(N=1,791) A1C = 9.4 %ADVANCE(N=11,140) A1C = 7.5 %ACCORD(N=10,251) A1C = 8.3 %20 UKPDS N =5102 2 3RECORD(N=4,447) A1C = 8.0 %4 5 6 7 Duration of Diabetes (Years)8910UKPDS Group. Lancet. 1998;352:837 853; Home P, et al N Engl J Med 2007;357:28-38; Charbennel B. N Engl J Med 2007;357:28-38; ACCORD study group. N Engl J Med. 2008;358:2545 2559; ADVANCE study group. N Engl J Med. 2008;358:2560 2572; Duckworth W, et al. N Engl J Med. 2009;360:129 139. 23‒ ‒ ‒ ‒‒ ‒ ‒ ‒‒ ‒ ‒ ‒‒ ‒ ‒ ‒?tcerroc era eseht fi mrifnoc uoy nac esaelp ,seiduts laudividni eht rof secnerefer dedda evah eW :ztivobeL rosseforP7/3/9002 ,dnommah.ycul1 1 1llll 1 32 片 影 投 32 片 影 投 32 片 影 投 32 片 影 投Treat-to-target in diabetesThe earlier the better???The Rational of Early Combination TherapyBenefits of combination therapy --- Synergistic effects due to different mechanism --- Decreased side effects of medicationsDiet and exercise OAD monotherapy 10 OAD combinations 9 HbA1c (%) 8 7 6Campbell IW. Br J Cardiol 2000; 7:625–631.--- Improve drugs compliance then, improved glycemic controlOADs uptitrationOAD + basal insulinOAD + multiple daily insulin injectionsDuration of diabetes25UKPDS 10 Year Follow-up:Legacy Effect of Earlier Glucose ControlAfter median 8.5 years post-trial follow-up Aggregate Endpoint Any diabetes related endpoint Microvascular disease Myocardial infarction All-cause mortalityRRR: P:1997 12% 0.0292007 9% 0.040 24% 0.001 15% 0.014 13% 0.007RRR: 25% P: 0.0099 RRR: P: RRR: P:16% 0.052 6% 0.44RRR = Relative Risk Reduction, P = Log RankN Engl J Med 2008; Oct 9:35926Cardiovascular outcome in type 2 diabetes mellitus in the recent trials The earlier, the betterCV risk ↑9.5 9.0 8.5 8.0 A1C 7.5 7.0Build up Bad metabolic memoryDrive the risk for complicationsIntensive Tx in long duration DM patientIntensive Tx in early 6.5 DM patient6.0 2 5As long as possible6789101112131415The lower, the better The earlier, the betterYears after diabetes diagnosisThe lower, the Action Too late to takebetter ? ?S. Del Prato. Diabetologia (2009) 52:1219–1226.CV risk ↑Algorithm for Metabolic Management of Type 2 DiabetesA1C Goal ≤ 6.5%A1C 6.5 – 7.5%A1C 7.5 – 9.0%Symptoms No SymptomsA1C > 9.0%Drug Naive Under TreatmentMonotherapyMET DPP4 GLP-1 TZD AGI METDual TherapyGLP-1 or DPP4 + or TZD SU or Glinide INSULIN Other Agent(s)Dual or Triple TherapyGLP-1 INSULIN Other Agent(s)Dual TherapyGLP-1 or DPP4 MET + TZD Glinide or SU TZD MET + + GLP-1 or DPP4 AGI MET + or DPP4 + SU GLP-1 or DPP4 GLP-1 + TZDMET+TZD GLP-1 or DPP4 TZD2 - 3 Mos. Triple Therapy2 - 3 Mos. Triple TherapyMET + GLP-1 or DPP4 TZD + Glinide or SUTZD2 - 3 Mos.AGI -Glucosidase Inhibitor DPP4 DPP-4 Inhibitor GLP-1 Incretin Mimetic Met Metformin SU Sulfonylurea TZD Thiazolidinedione2 - 3 Mos.INSULIN Other Agent(s)INSULIN Other Agent(s)Adapted and modified from:Helena W. Rodbard, Paul Jellinger, et al. Endocrine Practice, 2009 Sept/Oct; 15 (6): 540 – 559 /pub/pdf/GlycemicControlAlgorithm.pdf29± ± ± ± ±or DPP4SU± ± ± ±α α α α± ± ± ±2 - 3 Mos.±± ± ± ±EASD/ADA Position StatementGuidelines for treatment of diabetesToo many Not truly evidence-based No ethnic considerations Written by a bunch politicians rather than clinicians Designed for population rather than individuals Cost saving (rather than patient care) top of agendaCurrent Treatment Regimens in Type 2 DiabetesPANCREASINSULIN SECRETIONSulphonylureas, Non-sulphonylureas Meglitinide familyMUSCLE PERIPHERAL & ADIPOSE GLUCOSE TISSUE UPTAKE &UTILIZATIONMetforminINSULIN REPLACEMENTInsulinINSULIN SENSITISINGThiazolidinediones (PPARγ agonists) γGLUCOSE ABSORPTIONα-glucosidase inhibitorsGLUCOSE PRODUCTIONMetforminINTESTINELIVERDeFronzo RA. Annals of Internal Medicine 1999;131:281–303. International Diabetes Federation (Europe). Diabetic Medicine 1999;16:716–730.DARTS: Cumulative Mortality Rates in 5 Study CohortsSulfonylureaMetforminEvans JMM et al. Diabetologia 49:930-936, 2006Metformin: The 1st line Choice Multiple mechanisms for vascular protection Metformin addresses CV risk by a range of mechanismsImprovedInsulin sensitivity1,2 Glycaemia1,2 Fibrinolysis3 Endothelial function4,5 Obesity managementReducedHypertriglyceridaemia2 AGE formation6 Clot stability3 Oxidative stress7 Atherogenesis8 DyslipidaemiaReduced cardiovascular riskDiabetes Metab (2003): 1Gianarelli R vol. 29:6S28-35; 2Després JP 29:6S53-61; 3Grant PJ ;29:6S44-52; 4Wiernsperger N 29:6S77-8; 5Schäfers RF 29:6S62-70; 6Beisswenger 29:6S95-103; 7Leverve XM 29:6S88-94; 8Mamputu JC 29:6S71-6;Metformin treatment in type 2 diabetes decreases Vitamin B12417304352 MonthsBMJ 2010; 340:c2181Molecular Targets of PPAR ActionYki-Jarvinen H. N Engl J Med 2004;351:1106–1118On May 2007– Myocardial infarction: Odds ratio 1.43, 95% CI 1.03-1.98, P=0.03 – CV death: Odds ratio 1.64, 95% CI 0.982.74, P=0.06Nissen SE, Wolski K. NEJM. 2007;356:Pioglitazone vs Placebo: Time to Main Secondary Endpoint* in PROactiveKaplan-Meier event rate0.15N events: Placebo Pioglitazone0.103-year estimate: 14.4% 12.3%358 / 2633 301 / 26050.05 HR Pioglitazone vs placebo 0.00 0 6 12 18 24 30 36 0.841 95% CI 0.722, 0.981 p value 0.0273Time from randomization (months)*Death, non-fatal MI (excluding silent MI) or strokeDormandy J et al. Lancet 2005;366:1279–1289Pioglitazone Reduced Risk of Subsequent Stroke in Patients with Prior Stroke PROactive（%） 12 10 8Event RatePlacebo PioglitazoneEvent sIncidence10.2% 5.6%51/49827/48647%（p=0.008）6 4HR Pioglitazone vs Placebo 95%CI p-value2 0N at Risk0.530.34, 0.850.008984 0952 6926 12903 18877 24849 30132 36Time from Randomisation（month） Wilcox RG. et al.：World Congress of Cardiology,Sep,2006,Barcelona.42Meta-analysis of Pioglitazone: Incidence of Death, MI, or Stroke•A total of 19 trials, 16,390 patients •Treatment duration ranged from 4 months to 3.5 years P<0.04 p=0.382.9 2.4 3.6 4.6Control (n=7,836) Pioglitazone (n=8,554)5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0Patients (%)p=0.082.0 1.5p=0.091.7 1.2No. of Patients Pioglitazone ControlDeath209 224MI131 159Death/MI309 357Stroke104 131Lincoff AM, et al. JAMA. 2007;298:1180-1188.TZDs & bone mineral densityDecreased matrix mineralisation Trabecular thinning, perforation and disruption Accumulation of microscopic damage Increased cortical porosityAcarbose delays carbohydrate absorptionWithout acarboseStomach Upper small intestineCarbohydratesWith acarboseCarbohydrate absorptionLower small intestineCarbohydrate absorptionCentral Obesity/中央肥胖 中央肥胖Anti-Diabetic therapiesClasses Weight HypoglycaemiaBiguanide TZD α-Glycosidase inhibitor Sulphonylurea Insulin DPP4-inhibitorDecrease Increase Neutral Increase Increase Neutralx x x √ √ xAnti-Diabetic therapiesClasses Biguanide TZDWeight Decrease IncreaseHypoglycaemia x x x √ √ x xα-Glycosidase inhibitor Neutral Sulphonylurea Insulin DPP4-inhibitor Incretin mimetic Increase Increase Neutral DecreaseDPP-4 Inhibitor versus SulfonylureaVildagliptin vs glimepiride as add on therapy to stable metformin therapy (mean dose 1898 mg/day; mean duration of treatment 3 yrs; mean baseline A1C = 7.3 % (6.5 to 8.5 %).) Vildigliptin 50 mg twice a day. Mean glimepiride dose 4.5 mg/day. 52 week dataVildigliptin Decrease A1C (%) Decrease in FPG (mmol/l) Weight change (kg) Incidence Hypoglycemia (percent of pts) Hypoglycemic events Severe hypoglycemic events 0.44 1.01 - 0.23 1.7 36 0 Glimepiride 0.53 1.14 +1.56 16.2 554 10Diabetes Obes Metab 11:157-166, 2009。