Willa Hsueh,M.D.Professor of MedicineProfessor of MedicineChief,Division of Endocrinology,Diabetes,and Hypertension Chief,Division of Endocrinology,Diabetes,and Hypertension UCLA David Geffen School of Medicine UCLA David Geffen School of Medicine Los Angeles,CaliforniaLos Angeles,CaliforniaCardiovascular Risk Continuum:Implications of Insulin Resistance and DiabetesDiabetes 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 IL6PAI-1TNF adiponectinleptinInsulin sensitivityinsulin resistanceVascular inflammationendothelial dysfunctionangiotensinogenFFAAdipokines Mediate Insulin Resistance and InflammationProgression 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 ResistanceFor 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 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 Tomography025457090115CPTDIPApproaches that Improve Coronary Vasomotor Function in Insulin Resistance:Insulin sensitizers:TZDs,PPAR ligands AT1 receptor blockers:ARBs Glucose control in type 2 diabetes:Metformin 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: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 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 LigandsNuclear 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 DiabetesEffects of PPAR Ligands on Atherosclerosis inAngII-Infused Male LDLR-/-MicePPAR 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,2003Ligands 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 CellTRO Inhibits Capillary-Tube FormationControlTRO-treatedMurata et al.Invest Ophthalmol Vis Sci.41:2309-2317,2000Retinal Neovascularization in Control and TZD-treated Hypoxic MiceTelmisartanDoes 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 Center for Consumer Freedom Identification of New Treatment Strategies for Insulin Resistance,Metabolic Syndrome and Hypertension Theodore W Kurtz USA 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*Angiotensin II Receptor Blockers(ARBs)Hypertension Insulin Resistance Dyslipidemia?H O O C N N N N O S N H O O N AII Receptor Blocker Telmisartan PPAR Ligand Pioglitazone 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 PPAR Activators Approved for the Treatment of Type 2 Diabetes Fatty Acids/TriglyceridesInsulin Sensitivity HDL Actos(Lilly/Takeda)(Avandia-GSK)Millions of Prescriptions Written2Losartan 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)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/LiterMechanism 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 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)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 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 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)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 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 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 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)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)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 OLMESARTAN MEDOXOMILThe Chemical Structures of ARBs 50100150200250300350400Telmisartan LitersVolume of Distribution of Different ARBs(