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1、Willa Hsueh,M.D.Professor of MedicineChief,Division of Endocrinology,Diabetes,and Hypertension UCLA David Geffen School of Medicine Los Angeles,California,Cardiovascular Risk Continuum:Implications of Insulin Resistance and Diabetes,Diabetes is a vascular disease:Angiotensin II has been implicated i
2、n both the development of diabetes and its complications,Diabetes,Insulin-mediated glucose uptake,Skeletal muscle,Adipose,FFA Inflammatory Adipokines,Liver,Glucose production,Pancreas,Insulin production,Atherosclerosis,CAD,Stroke,Peripheral vascular disease,Diabetic Nephropathy,Albumin excretion,Dia
3、betic Retinopathy,VEGF neovascularization,Diastolic dysfunction,interstitial fibrosis heart failure,Cardiomyopathy,IL6,PAI-1,TNF,adiponectin,leptin,Insulin sensitivity,insulin resistance,Vascular inflammation,endothelial dysfunction,angiotensinogen,FFA,Adipocyte,Adipokines Mediate Insulin Resistance
4、 and Inflammation,Progression of Atherosclerosis in Insulin Resistance,Endothelial,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,Meta
5、bolic Syndrome,Impaired Glucose Tolerane,Type 2 Diabetes,Hsueh,WA,Law R.AJC,2003,Insulin Resistance,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
6、,13NH3,13NH3,13NH3,Dipyridamole(0.56 mg/kg),135,Rest,Quinones et al Ann Intern Med.,2004;140:700-8,Noninvasive Measurements of Myocardial Blood Flow:Positron Emission Tomography,0,25,45,70,90,115,CPT,DIP,Approaches that Improve Coronary Vasomotor Function in Insulin Resistance:,Insulin sensitizers:T
7、ZDs,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 on
8、set 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 hypertrophy,CHARM(Candesartan in Hea
9、rt Failure:Assessment of Reduction in Mortality and Morbidity):40%less new onset diabetes with candesartan in patients with heart failure,Inhibition of the Renin-angiotensin System Prevents Diabetes:,Mechanisms by Which ACEIs and ARBs Prevent Diabetes:,Improve endothelial function:Up to 40%of insuli
10、n-mediated glucose uptake may be endothelial dependent Allow fat cell differentiation Protect islet cells?Alter adipokine production?Alter liver glucose production,Angiotensin II,inflammation,oxidation,thrombosis,vascular growth and remodeling,hypertension,PPAR Ligands AT1 Receptor Blockers,reverse
11、cholesterol transport,Angiotensin II Activates Multiple Mechanisms Promoting Tissue Injury that are Antagonized by PPAR Ligands,Nuclear Receptors PPARs,Kidney proteinuria,Pancreas-cell protection,Blood Vessels atherosclerosis blood pressure,Eye neovascularization,Adipocyte inflammatory factors antii
12、nflammatory factors,glucose uptake in response to insulin,reverse metabolic syndrome,PPAR Impacts Multiple Aspects of Diabetes,Effects of PPARg Ligands on Atherosclerosis inAngII-Infused Male LDLR-/-Mice,PPARg Ligands Consistently Attenuates Albuminuria in Patients and Animal Models with Type 2 Diab
13、etes,Troglitazone 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 rec
14、eptor-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,Ligands PAI-1 expression Growth TGF effects on ECM production,Nicholas SB,et al Hypertension 37(Part 2):722-727,2001,PPARg Expressed
15、on Mesangial Cell,TRO Inhibits Capillary-Tube Formation,Control,TRO-treated,Murata et al.Invest Ophthalmol Vis Sci.41:2309-2317,2000,Retinal Neovascularization in Control and TZD-treated Hypoxic Mice,Telmisartan,Does it have dual activity to inhibit the AT1 receptor and activate PPAR?Kurtz TW,et al,
16、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 Strategie
17、s 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 fo
18、r developing type 2 diabetes,*Not effectively treated by current antihypertensive drugs*,Angiotensin II Receptor Blockers(ARBs),Hypertension,AII Receptor Blocker Telmisartan,PPAR Ligand Pioglitazone,PPAR,A cellular receptor that is a proven therapeutic target in the treatment of insulin resistance,d
19、iabetes,and the metabolic syndrome,Peroxisome proliferator activated receptor-gamma,PPAR Activators Approved for the Treatment of Type 2 Diabetes,Millions of Prescriptions Written,2,4,6,8,10,12,14,16,Telmisartan,Fold activation,5 micromolar,Ability of Different ARBs To Activate PPAR(S.C.Benson et al
20、.,Hypertension,43:993-1002,2004),Telmisartan is a Partial Agonist of PPAR,(Schupp et al.,Circulation,109:2054-2057,2004),Mechanism Whereby PPAR Activators Improve Insulin Resistance and the Metabolic Syndrome,PPAR Activator,Expression of Key Target Genes,Ability of Telmisartan to Activate Key Anti-D
21、iabetic Target Genes of PPAR,Gene Encoding PEPCK,(Benson et al.,Hypertension,43:993-1002,2004),It is also a PPAR Activator,-Telmisartan is Not Just an ARB-,Cellular differentiation assays,Target gene expression assays,Receptor transactivation assays,What is the clinical evidence that telmisartan can
22、 improve glucose and lipid metabolism as one would expect for a PPAR activator?,Studies in animal models of insulin resistance,Glucose,105,110,115,120,125,Week:,0,mg/dl,=,4,8,12,16,Insulin,10,15,20,25,30,Week:,0,uU/ml,=,4,8,12,16,Clinical Case Observations 52 year old male with the metabolic syndrom
23、e,20,20,Triglycerides,Telmisartan,60,80,100,120,140,Week:,0,4,mg/dl,=,8,12,16,Valsartan,Clinical Case Observations 52 year old male with the metabolic syndrome,20,Telmisartan,(Pershadsingh and Kurtz,Diabetes Care,27:1015,2004),Open Label,Post Marketing Surveillance Study of Telmisartan,40-80 mg/day
24、x 6 months,in 3,643 Diabetics(Michel et al.,Drug Safety,27:335-344,2004),-20,-10,mg/dl,Triglycerides,-30,0,Glucose,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 Hyperte
25、nsion&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),Telmisartan 80 mg/day(n=20),Losartan 50 mg/day(n=20),Randomized,P
26、arallel 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 G
27、lucose,Insulin,and Insulin Resistance FromBaseline in Patients with the Hypertension Metabolic Syndrome,Glucose,-8,-6,-4,-2,0,2,4,%change compared to baseline,Insulin,HOMA Index,Insulin Resistance,(G.Rosano et al.,VII Forum on the Renin-Angiotensin System,2004),It is also a PPAR Activator,-Telmisart
28、an is Not Just an ARB-,Cellular differentiation assays,Target gene expression assays,Receptor transactivation assays,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?,Preliminary c
29、linical studies,The Chemical Structures of ARBs,50,100,150,200,250,300,350,400,Telmisartan,Liters,Volume of Distribution of Different ARBs(Index of the Ability of a Drug to Enter Tissues Throughout the Body),450,500,Molecular Modeling of Telmisartan in the Ligand Binding Domain(LBD)of PPAR,Telmisart
30、an,(Benson et al.,Hypertension,43:993-1002,2004),Two Classes of PPAR Activators,Different effects on receptor activation&gene expression profiles,Clinical Implications:,Telmisartan is Both an ARB and a Selective PPAR Modulator,Treatment of the metabolic syndrome and the prevention of type 2 diabetes
31、,Prevention and treatment of atherosclerosis,Insulin resistance,Hypertension,Cell inflammation,Cell proliferation,Oxidative stress,Dyslipidemia,Telmisartan,PPAR pathways,Angiotensin pathways,Atherosclerosis,Activates,Blocks,ONTARGET and TRANSCEND,-Trial Designs-,ONTARGET,25,260,5,926,Telmisartan,Ram
32、ipril,Telmisartan,Ramipril,+,Telmisartan,Placebo,TRANSCEND,Cardiovascular and metabolic endpoints in high risk populations,SUMMARY,In preliminary clinical studies,telmisartan shows metabolic effects that distinguish it from other ARBs,Telmisartan is a dual ARB/selective PPAR modulator,Implications f
33、or prevention&treatment of the metabolic syndrome,type 2 diabetes,&atherosclerosis,New strategies for developing 3rd generation angiotensin II receptor blockers and PPAR activators,What Does the Future Hold for Cardiovascular Protection of Diabetic Patients?,Massimo Volpe Italy,Most Hypertensive Pat
34、ients Have Complex Hypertension,1 CV additional CV risk factor,No additional CV risk factor,COMPLEX HYPERTENSION HTN additional risk factor CAD,LVH Diabetes,Metabolic syndrome Renal Disease High-risk population,Framingham Offspring Study(men aged 18-74),Thrombosis 2003.ppt Copyright CMF Learning Sys
35、tems,Epidemics of Diabetes in Hypertension,A growing proportion of hypertensive patients have or develop metabolic syndrome or type 2 diabetes(1322%in different studies!),*,*,*,*,*,The Hypertension in Diabetes Study Group.J Hypertens 1993a;11:309-317.,*Statistically significant,hypertensive vs normo
36、tensive.LVH on ECG.,0,2,4,6,8,10,12,Prevalence(%),Myocardial infarction,Stroke/Transient ischemic attack,Left ventricular hypertrophy,Normotensive diabetic males Hypertensive diabetic males Normotensive diabetic females Hypertensive diabetic females,Hypertension and Type 2 Diabetes:a High-Risk Popul
37、ation,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 mmHg,Derived from Anderson et al.,Am Heart J 1991;121-293-8.,Patient 1,Patient 2,Patient 3,CVD risk threshold for hypertension treatment,Multifactor CV Risk(%
38、per yr),Blood Pressure threshold for equal benefit,Target Organ Disease and/or Diabetes,Multiple Risk Factors,only elevated Blood Pressure,High Risk,High BP,Low BP,Hypertension Treatment Based on Absolute CVD Risk,Intensity of treatment reflect progressive increase of the number and dosage of drugs,
39、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 Ri
40、sk,Single therapy,Intensity of drug treatment,Multiple therapy,modified from Am J Hyper 2002;15(10):917-23,MV 2004,Reduction of single or multiple Risk Factors generates a benefitproportional to the level of Risk,BP levels,Global CV Risk,Risk increases in relation to characteristics of individual.Sm
41、all reductions of Blood Pressure will produce larger absolute benefits in relation to level of risk.,New Paradigms in CVD and Diabetes,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 Eviden
42、ce Based Medicine(HOPE,IRMA 2,LIFE),Hypertension and Diabetes:General Guidelines,Lower Blood Pressure to target Get control of plasma glucose Block the renin-angiotensin system Use a statin Control modifiable Risk Factors,MV 2004,Antihypertensive Agents and Insulin Sensitivity Index*,%Change,*Data d
43、erived from various double-blind and open studies,Propranolol,Metoprolol,Atenolol,Pindolol,HCTZ,Isradipine,Furosemide,Diltiazem,Enalapril,Captopril,Prazosin,Doxazosin,Lithell HO.Diabetes Care 1991;14:203-209.Anderson PE,Lithell H.Am J Hypertens 1996;323-33.,083,Beta-blocker,Captopril,Ramipril,-50,-2
44、5,0,25,50,%,*P 0.05 compared to nondiabetics,Propensity to Development of Diabetes According to the Antihypertensive Drug,4944 M,Alderman M.et al.,Hypertension 1999,Rate/1000 person-years,6.11,7.5,Blood sugar(mmol/l),Baseline,In-treatment,Baseline,In-treatment,CVD,non-CVD,2.9,2.4,1.4,2.7,2.8,2.0,8.4
45、,10.1,15.2*,8.2,10.7,15.2*,Age-Gender-Adjusted CVD and Non-CVD Incidence Rates by Blood Sugar at Baseline and in Treatment in Treated Hypertensive Patients,Cardiovascular events in treated hypertensive subjects without diabetes(group A),new-onset diabetes(group B)and previously known diabetes(group
46、C),Verdecchia P.Hypertension 2004;43:963-9,Integrating Cardiorenal Care in DiabetesBlockade of AT1-Receptor,BP-dependent and Independent Effects,Renal Protection,Cardiovascular Protection,improves,improves,Average Number of Antihypertensive Agents Needed Per Patient to Achieve Target Systolic BP Goa
47、ls,Number of Medications,ALLHAT(138 mmHg)IDNT(138 mmHg)RENAAL(141 mmHg)UKPDS(144 mmHg)ABCD(132 mmHg)MDRD(132 mmHg)HOT(138 mmHg)AASK(128 mmHg),Trial/SBP achieved,Updated from Bakris GL.Am J Kidney Dis.2000,Does it Matter Which Drugs We Use in Combination?,Outcomes Data,Tolerability,New onset Diabetes
48、,Diuretics,ACE inhibitors,AT1-receptor blockers,Calcium antagonists,-blockers,-blockers,ESH/ESC Guidelines,J Hypertens 2003,Rational Non rational,Possible combinations of different classes of antihypertensive agents according to ESH-ESC Guidelines.Are They Valid in Diabetics?,New Onset Diabetes,Hype
49、rtension per se doubles the risk of developing new onset diabetes eta-blockers or diuretics increase the risk of new onset diabetes especially when combined(RR+19%)RAS blockade decreases new onset of diabetes,The Ideal Combination Therapy in Hypertension,Effective BP reduction at low doses Sound pat
50、hophysiological and pharmacodynamic rational Protection of associated Risk Factor Control of Target Organ Damage Control of events Well tolerated and few side effects,Antihypertensive therapy is the most effective preventive measure in diabetes,Monotherapy is rarely sufficient,Increased rational use
