替米沙坦与代谢综合征.pptx

Diabetes is a vascular disease:Angiotensin II has been implicated in both the development of diabetes and its complicationsDiabetes Insulin-mediated glucose uptake Skeletal muscle Skeletal muscle Adipose Adipose FFA Inflammatory AdipokinesLiver Liver Glucose productionPancreas Pancreas Insulin production Atherosclerosis Atherosclerosis CAD,Stroke,Peripheral vascular diseaseDiabetic Diabetic Diabetic NephropathyNephropathyNephropathy Albumin excretionDiabetic Diabetic RetinopathyRetinopathy VEGF neovascularizationDiastolic dysfunction,interstitial fibrosis heart failureCardiomyopathyCardiomyopathy 第1页/共69页IL6PAI-1TNF adiponectinleptinInsulin sensitivityinsulin resistanceVascular inflammationendothelial dysfunctionangiotensinogenFFAAdipokines Mediate Insulin Resistance and Inflammation第2页/共69页Progression of Atherosclerosis in Insulin ResistanceEndothelial Dysfunction TG,HDL-C sd LDL-C Hypertension Uric Acid PAI-1 Inflammation Thrombosis Oxidation Atherosclerosis Atherosclerosis Unstable plaque Inflammation,Fibrosis Cap Thrombosis and Rupture Event Hyperinsulinemia Metabolic Syndrome Impaired Glucose Tolerane Type 2 Diabetes Hsueh WA,Law R.AJC,2003 Insulin Resistance第3页/共69页For individuals born in 2000:Males 32.8%Females 38.5%Estimated loss of life expectancy if diagnosed at age 40:Males 11.6 years Females 14.3 years Narayan JAMA 2003 Lifetime Risk for Diabetes in the US 第4页/共69页13NH3 13NH3 13NH3 Dipyridamole(0.56 mg/kg)135RestQuinones et al Ann Intern Med.,2004;140:700-8 Noninvasive Measurements of Noninvasive Measurements of Myocardial Blood Flow:Positron Emission TomographyMyocardial Blood Flow:Positron Emission Tomography025457090115CPTDIP第5页/共69页Approaches that Improve Coronary Vasomotor Function in Insulin Resistance:Insulin sensitizers:TZDs,PPAR ligands AT1 receptor blockers:ARBs Glucose control in type 2 diabetes:Metformin 第6页/共69页VALUE(Valsartan Antihypertensive Long-Term Use Evaluation):23%less new onset diabetes with valsartan compared to amlodipine in patients with hypertension HOPE(Heart Outcomes Prevention Evaluation):32%less new onset diabetes with ramipril compared to placebo in high cardiovascular risk patients LIFE(Losartan Intervention for Endpoint Reduction in Hypertension):25%less new onset diabetes with losartan compared to atenolol in patients with hypertension and left ventricular hypertrophyCHARM(Candesartan in Heart Failure:Assessment of Reduction in Mortality and Morbidity):40%less new onset diabetes with candesartan in patients with heart failureInhibition of the Renin-angiotensin System Prevents Diabetes:第7页/共69页Mechanisms by Which ACEIs and ARBs Prevent Diabetes:Improve endothelial function:Up to 40%of insulin-mediated glucose uptake may be endothelial dependent Allow fat cell differentiation Protect islet cells?Alter adipokine production?Alter liver glucose production 第8页/共69页Angiotensin IIAngiotensin IIinflammationinflammationoxidationoxidationthrombosisthrombosisvascular growth vascular growth and remodelingand remodelinghypertensionhypertensionPPAR Ligands AT1 Receptor Blockers reverse reverse cholesterol cholesterol transporttransportAngiotensin II Activates Multiple Mechanisms Promoting Tissue Injury that are Antagonized by PPAR Ligands第9页/共69页Nuclear Receptors Nuclear Receptors PPARsPPARsKidney proteinuria Pancreas -cell protection Blood Vessels atherosclerosis blood pressureEye neovascularizationAdipocyte inflammatory factors antiinflammatory factorsglucose uptake in response to insulin,reverse metabolic syndromePPAR Impacts Multiple Aspects of Diabetes第10页/共69页Effects of PPAR Ligands on Atherosclerosis inAngII-Infused Male LDLR-/-Mice第11页/共69页PPAR Ligands Consistently Attenuates Albuminuria in Patients and Animal Models with Type 2 DiabetesTroglitazone ameliorates albuminuria in streptozotocin-induced diabetic rats.Fujii,M et al.Metabolism,1997 Effect of troglitazone on microalbuminuria in patients with incipient diabetic nephropathy.Imano,E et al.Diabetes Care,1998 Expression and function of peroxisome proliferator-activated receptor-y in mesangial cells.Nicholas et al Hypertension,2001 Rosiglitazone reduces urinary albumin excretion in type II diabetes.Bakris et al J Human Hypertension,2003第12页/共69页Ligands PAI-1 expression Growth TGF effects on ECM productionNicholas SB,et al Hypertension 37(Part 2):722-727,2001PPARPPAR Expressed on Mesangial Cell Expressed on Mesangial Cell第13页/共69页TRO Inhibits Capillary-Tube FormationControlTRO-treatedMurata et al.Invest Ophthalmol Vis Sci.41:2309-2317,2000Retinal Neovascularization in Control and TZD-treated Hypoxic Mice第14页/共69页TelmisartanDoes it have dual activity to inhibit the AT1 receptor and activate PPAR?Kurtz TW,et al,Hypertension 43:993-1002,2004Schupp M.,et al,Circulation 109:2054-7,2004 ONTARGET:Telmisartan Ramipril in high risk patients CV endpoints,new onset type 2 diabetes,nephropathy,cognition Unger T.,Am J.Cardiol 91(suppl):28G-34G,2003 第15页/共69页 Center for Consumer Freedom 第16页/共69页Identification of New Treatment Strategies for Insulin Resistance,Metabolic Syndrome and Hypertension Theodore W Kurtz USA 第17页/共69页Hypertension:More Than Just High BP Metabolic Syndrome Insulin resistance,Dyslipidemia,&Increased BP Affects 15-25%of individuals in industrialized populations 2-4 fold risk in cardiovascular mortality 5-9 fold risk for developing type 2 diabetes*Not effectively treated by current antihypertensive drugs*第18页/共69页Angiotensin II Receptor Blockers(ARBs)Hypertension Insulin Resistance Dyslipidemia?第19页/共69页H O O C N N N N O S N H O O N AII Receptor Blocker Telmisartan PPAR Ligand Pioglitazone 第20页/共69页PPAR A cellular receptor that is a A cellular receptor that is a provenproven therapeutic therapeutic target in the treatment of insulin resistance,target in the treatment of insulin resistance,diabetes,and the metabolic syndromediabetes,and the metabolic syndrome Peroxisome proliferator activated receptor-gammaPeroxisome proliferator activated receptor-gamma 第21页/共69页PPAR Activators Approved for the Treatment of Type 2 Diabetes Fatty Acids/TriglyceridesInsulin Sensitivity HDL Actos(Lilly/Takeda)(Avandia-GSK)Millions of Prescriptions Written第22页/共69页2Losartan 46810121416Eprosartan Irbesartan Valsartan Candesartan Telmisartan Fold activation Olmesartan 5 micromolar Ability of Different ARBs To Activate PPAR (S.C.Benson et al.,Hypertension,43:993-1002,2004)第23页/共69页Telmisartan is a Partial Agonist of PPAR (Schupp et al.,Circulation,109:2054-2057,2004)Luciferase activity x-fold induction over vehicle treated cellsPioglitazone Telmisartan mol/Liter第24页/共69页Mechanism Whereby PPARMechanism Whereby PPAR Activators Activators Improve Insulin Resistance and the Metabolic Improve Insulin Resistance and the Metabolic SyndromeSyndrome PPAR Activator Expression of Key Target Genes Receptor complex DBD PPAR DNA response elements CytoplasmNucleus RXR 第25页/共69页Ability of Telmisartan to Activate Key Anti-Diabetic Target Genes of PPAR Gene Encoding PEPCK Telmisartan 22.5 micromolar 3Val Irb 14Fold activaitonCan Olm Epro Exp(Benson et al.,Hypertension,43:993-1002,2004)第26页/共69页It is also a PPAR Activator-Telmisartan is Not Just an ARB-u Cellular differentiation assaysu Target gene expression assaysu Receptor transactivation assaysWhat is the clinical evidence that telmisartan can improve glucose and lipid metabolism as one would expect for a PPAR activator?u Studies in animal models of insulin resistance 第27页/共69页Valsartan 160 mg/day Telmisartan 80 mg/day Glucose 105 110 115 120 125 Week:0 mg/dl=481216Valsartan Telmisartan Insulin 10 15 20 25 30 Week:0 uU/ml=481216Clinical Case Observations 52 year old male with the metabolic syndrome 2020Telmisartan Telmisartan 第28页/共69页Triglycerides Telmisartan 60 80 100 120 140 Week:04mg/dl=81216Valsartan Clinical Case Observations 52 year old male with the metabolic syndrome 20Telmisartan (Pershadsingh and Kurtz,Diabetes Care,27:1015,2004)第29页/共69页Open Label,Post Marketing Surveillance Study of Telmisartan,40-80 mg/day x 6 months,in 3,643 Diabetics(Michel et al.,Drug Safety,27:335-344,2004)-20-10mg/dl Triglycerides-300Glucose 第30页/共69页Telmisartan 40 mg/day(n=40)Placebo control(n=40)Eprosartan 600 mg/day(n=39)Double-Blind,Placebo-Controlled Study of the Metabolic Effects of Telmisartan in Patients with Mild Hypertension&Type 2 DM(DeRosa et al.Hypertension Research,2004)Hypertensive Diabetics After 12 months,compare changes in insulin,glucose,and triglyceride levels from baseline 第31页/共69页Effects on Triglycerides(DeRosa et al.Hypertension Research,2004)After After 40 80 120 mg/dl Eprosartan 600 mg/day140 20 60 100 40 80 120 mg/dl Placebo control140 20 60 100 40 80 120 mg/dl BeforeBeforeBeforeTelmisartan 40 mg/day140 20 60 100 pAfter*P.05 第32页/共69页Telmisartan 80 mg/day(n=20)Losartan 50 mg/day(n=20)Randomized,Parallel Study Comparing Telmisartan to Losartan in Patients with the Metabolic Syndrome 40 Patients Hypertension Metabolic Syndrome Changes from baseline in fasting glucose,insulin,and oral glucose tolerance after 3 months (G.Rosano et al.,VII Forum on the Renin-Angiotensin System,2004)第33页/共69页Changes in Glucose,Insulin,and Insulin Resistance FromBaseline in Patients with the Hypertension Metabolic Syndrome Glucose-8-6-4-2 0 2 4%change compared to baseline Losartan Telmisartan p0.05 Insulin Losartan Telmisartan p0.06 HOMA Index Losartan Telmisartan p0.05 Insulin Resistance(G.Rosano et al.,VII Forum on the Renin-Angiotensin System,2004)第34页/共69页It is also a PPAR Activator-Telmisartan is Not Just an ARB-u Cellular differentiation assaysu Target gene expression assaysu Receptor transactivation assaysu Studies in animal models Why is Telmisartan the only ARB that can clearly activate PPAR when tested at concentrations that can be achieved with conventional oral dosing?u Preliminary clinical studies 第35页/共69页OLMESARTAN MEDOXOMILThe Chemical Structures of ARBs 第36页/共69页50100150200250300350400Telmisartan LitersVolume of Distribution of Different ARBs(Index of the Ability of a Drug to Enter Tissues Throughout the Body)450500Valsartan Olmesartan Losartan Losartan Metabolite Candesartan Irbesartan 第37页/共69页Molecular Modeling of Telmisartan in the Ligand Binding Domain(LBD)of PPAR Telmisartan(Benson et al.,Hypertension,43:993-1002,2004)第38页/共69页 Two Classes of PPAR Activators Conventional PPAR Activators Selective PPAR Modulators Pioglitazone Rosiglitazone Telmisartan nTZDpa(Merck)Weight gain Yes No Fluid retention Yes No Marked adipogenesis Yes No Improve glucose&lipid metabolism Yes Yes Different effects on receptor activation&gene expression profiles 第39页/共69页Clinical Implications:Telmisartan is Both an ARB and a Selective PPAR Modulator Treatment of the metabolic syndrome and the prevention of type 2 diabetes Prevention and treatment of atherosclerosis第40页/共69页Insulin Insulin resistanceresistanceHypertensionHypertensionCell Cell inflammationinflammation Cell Cell proliferationproliferation Oxidative Oxidative stressstress DyslipidemiaDyslipidemiaTelmisartan PPARPPAR pathwayspathways Angiotensin pathwaysAngiotensin pathways AtherosclerosisAtherosclerosis ActivatesActivatesBlocksBlocks第41页/共69页ONTARGET and TRANSCEND-Trial Designs-ONTARGET 25,260 5,926 Telmisartan Ramipril Telmisartan Ramipril+Telmisartan Placebo TRANSCEND Cardiovascular and metabolic endpoints in high risk populations 第42页/共69页SUMMARY In preliminary clinical studies,telmisartan showsIn preliminary clinical studies,telmisartan shows metabolic effects that distinguish it from other ARBs metabolic effects that distinguish it from other ARBs Telmisartan is a dual ARB/selective PPARTelmisartan is a dual ARB/selective PPAR modulator modulator Implications for prevention&treatment of the Implications for prevention&treatment of the metabolic syndrome,type 2 diabetes,&atherosclerosis metabolic syndrome,type 2 diabetes,&atherosclerosis New strategies for developing 3rd generation New strategies for developing 3rd generation angiotensin II receptor blockers and PPAR angiotensin II receptor blockers and PPAR activators activators 第43页/共69页What Does the Future Hold for Cardiovascular Protection of Diabetic Patients?Massimo Volpe Italy 第44页/共69页Most Hypertensive Patients Have Complex Hypertension 1 CV additional CV risk factorNo additional No additional CV risk factorCV risk factorCOMPLEX HYPERTENSION COMPLEX HYPERTENSION HTN additional risk factor HTN additional risk factor CAD,LVH CAD,LVH Diabetes,Metabolic syndrome Diabetes,Metabolic syndrome Renal Disease Renal Disease High-risk population High-risk populationFramingham Offspring Study Framingham Offspring Study(men aged 18-74)(men aged 18-74)Thrombosis 2003.ppt Thrombosis 2003.ppt Copyright CMF Learning SystemsCopyright CMF Learning Systems第45页/共69页Epidemics of Diabetes in HypertensionA growing proportion of hypertensive patients have or develop metabolic syndrome or type 2 diabetes(1322%in different studies!)第46页/共69页*The Hypertension in Diabetes Study Group.J Hypertens 1993a;11:309-317.*Statistically significant,hypertensive vs normotensive.LVH on ECG.0 2 4 6 8 10 12 Prevalence(%)Myocardial infarction Stroke/Transient ischemic attackLeft ventricular hypertrophy Normotensive diabetic males Hypertensive diabetic males Normotensive diabetic females Hypertensive diabetic females Hypertension and Type 2 Diabetes:a High-Risk Population第47页/共69页Reference group:female aged 50 years,TC=4 mmol/L,HDL=1.6 mmol/L,non smoker,no diabetes,at SBP levels of 110,120,130,140,150,160,170&180 mmHgDerived from Anderson et al.,Am Heart J 1991;121-293-8.03545502030Referencegroup5 year CVD risk per 100 persons TC=7mmol/L&smokermale402510155&diabetes60 yrs&HDL=1mmol/L3%1%6%12%18%24%33%44%第48页/共69页Patient 1Patient 2Patient 3CVD risk threshold for hypertension treatmentMultifactor CV Risk(%per yr)Blood Pressure threshold for equal benefitTarget Organ Disease and/or DiabetesMultiple Risk Factorsonly elevated Blood PressureHigh RiskHigh BPLow BPHypertension Treatment Based on Absolute CVD RiskIntensity of treatment reflect progressive increase of the number and dosage of drugs,including antihypertensive agents and cotreatment(aspirin,statins,antidiabetics,etc.).It is not related to levels of blood pressure but rather to absolute risk level in individual subjects.Components of treatment are chosen based on the identification of different risk factors in individuals.Low RiskSingle therapyIntensity of drug treatment Multiple therapymodified from Am J Hyper 2002;15(10):917-23第49页/共69页MV 2004Reduction of single or multiple Risk Factors generates a benefitproportional to the level of Risk BP levelsGlobal CV RiskRisk increases in relation to characteristics of individual.Small reductions of Blood Pressure will produce larger absolute benefits in relation to level of risk.New Paradigms in CVD and Diabetes 第50页/共69页Does it Matter How You Reduce Blood Pressure in Type 2 Diabetes and Metabolic Syndrome?Yes,according to Hypertension and Diabetes Guidelines Yes,according to Evidence Based Medicine(HOPE,IRMA 2,LIFE)第51页/共69页Hypertension and