替米沙坦與代謝綜合征

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

2、Resistance and Diabetes,Diabetes is a vascular disease: Angiotensin II has been implicated in both the development of diabetes and its complications,Diabetes,? Insulin-mediated glucose uptake,Skeletal muscle,Adipose,?

3、 FFA ? Inflammatory Adipokines,Liver,? Glucose production,Pancreas,? Insulin production,Atherosclerosis,CAD, ? Stroke, ? Peripheral vascular disease,Diabetic Nephropathy,? Albumin excretion,Diabetic Retinop

4、athy,? VEGF ? ? neovascularization,Diastolic dysfunction, interstitial fibrosis ? heart failure,Cardiomyopathy,,,?,?,?,?,?,?,?,?,,IL6,,PAI-1,,,TNF?,,adiponectin,leptin,,,Insulin sensitivity,,insulin resistance,,Vascul

5、ar inflammation,,,endothelial dysfunction,,,,,,,angiotensinogen,FFA,,,Adipocyte,Adipokines Mediate Insulin Resistance and Inflammation,,Progression of Atherosclerosis in Insulin Resistance,,Endothelial,Dysfunction,TG,

6、 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 S

7、yndrome,,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:

8、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),135’,Rest,Quinones et al Ann Intern Med., 2004; 140:700-8,Noninvasive

9、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: TZDs, PPAR? ligands AT

10、1 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 hyp

11、ertension,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

12、): 25% less new onset diabetes with losartan compared to atenolol in patients with hypertension and left ventricular hypertrophy,CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity): 4

13、0% 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:

14、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 II,inflammation,oxi

15、dation,thrombosis,vascular growth and remodeling,hypertension,PPAR? Ligands AT1 Receptor Blockers,,reverse cholesterol transport,,,,,,Angiotensin II Activates Multiple Mechanisms Promoting Tissue Injury that are Antago

16、nized by PPAR? Ligands,Nuclear Receptors PPARs,,Kidney ? proteinuria,,Pancreas ?-cell protection,,Blood Vessels ? atherosclerosis ? blood pressure,,,,Eye ? neovascularization,Adipocyte ? inflammatory factors anti

17、inflammatory 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 Lig

18、ands Consistently Attenuates Albuminuria in Patients and Animal Models with Type 2 Diabetes,Troglitazone ameliorates albuminuria in streptozotocin-induced diabetic rats. Fujii, M et al. Metabolism, 1997 Effect of trogli

19、tazone 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

20、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

21、Hypertension 37( Part 2):722-727, 2001,PPARg Expressed 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

22、 Control and TZD-treated Hypoxic Mice,Telmisartan,Does 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

23、 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,Identifi

24、cation 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, & Increa

25、sed 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 antihypertensiv

26、e 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

27、resistance, diabetes, 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

28、,16,,Telmisartan,Fold activation,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, 10

29、9:2054-2057, 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-Diabetic Tar

30、get 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,Rece

31、ptor transactivation assays,What is the clinical evidence that telmisartan can improve glucose and lipid metabolism as one would expect for a PPAR? activator?,Studies in animal models of insulin resistance,,,Glucose,,,

32、,,,,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 syndrome,,,20,,20,,,,Triglycerides,,,T

33、elmisartan,,,,,,,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, 27:10

34、15, 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,- 10,mg/dl,,,Triglycerides,,- 30,0,Glucose,,,T

35、elmisartan 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 (De

36、Rosa 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 Resea

37、rch, 2004),,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,Chan

38、ges 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 FromBa

39、seline 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-Angioten

40、sin System, 2004),,It is also a PPAR? Activator,- Telmisartan is Not Just an ARB -,Cellular differentiation assays,Target gene expression assays,Receptor transactivation assays,Studies in animal models,Why is Telmisartan

41、 the only ARB that can clearly activate PPAR? when tested at concentrations that can be achieved with conventional oral dosing?,Preliminary clinical studies,,The Chemical Structures of ARBs,,,,,50,,,,,100,150,200,250,3

42、00,350,400,,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 (L

43、BD) of PPAR?,Telmisartan,,(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

44、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,,Insulin resistance,Hypertension,Cell inflammation

45、,Cell proliferation,Oxidative stress,Dyslipidemia,Telmisartan,PPAR? pathways,Angiotensin pathways,,Atherosclerosis,Activates,Blocks,,ONTARGET and TRANSCEND,- Trial Designs -,,,,,,,,,,,,ONTARGET,25,260,5,926,Telmisarta

46、n,Ramipril,Telmisartan,Ramipril,+,Telmisartan,Placebo,TRANSCEND,Cardiovascular and metabolic endpoints in high risk populations,,SUMMARY,In preliminary clinical studies, telmisartan shows metabolic effects that distin

47、guish it from other ARBs,Telmisartan is a dual ARB/selective PPAR? modulator,Implications for prevention & treatment of the metabolic syndrome, type 2 diabetes, & atherosclerosis,New strategies for developing

48、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 Patients Have Complex Hyperten

49、sion,≥ 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 Offspri

50、ng Study (men aged 18-74),,,Thrombosis 2003.ppt Copyright CMF Learning Systems,Epidemics of Diabetes in Hypertension,A growing proportion of hypertensive patients have or develop metabolic syndrome or type 2 diabetes (

51、13–22% in different studies!),,,,,,,,,,*,*,,,,*,,,,,,*,*,The Hypertension in Diabetes Study Group. J Hypertens 1993a;11:309-317.,* Statistically significant, hypertensive vs normotensive. ? LVH on ECG.,,,,,,,,,,,,0,2,4

52、,6,8,10,12,Prevalence(%),Myocardial infarction,Stroke/Transient ischemic attack,Left ventricular hypertrophy?,,Normotensive diabetic males Hypertensive diabetic males Normotensive diabetic females Hypertensive

53、 diabetic females,,,,,,,,,,,,,,,,,,,,,,,,,,,,Hypertension and Type 2 Diabetes: a High-Risk Population,Reference group: female aged 50 years, TC=4 mmol/L, HDL=1.6 mmol/L, non smoker, no diabetes, at SBP levels of 110,

54、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 (% per yr),Bl

55、ood 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

56、 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

57、rather to absolute risk level in individual subjects. Components of treatment are chosen based on the identification of different risk factors in individuals.,,Low Risk,Single therapy,Intensity of drug treatment,Multip

58、le 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 relat

59、ion 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,Does it Matter How You Reduce Blood Pressure

60、 in Type 2 Diabetes and Metabolic Syndrome?,Yes, according to Hypertension and Diabetes Guidelines Yes, according to Evidence Based Medicine (HOPE, IRMA 2, LIFE…),Hypertension and Diabetes:General Guidelines,Lower Bl

61、ood 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 deri

62、ved 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.

63、 Anderson PE, Lithell H. Am J Hypertens 1996; 323-33.,083,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Beta-blocker,C

64、aptopril,Ramipril,,,,,,,-50,-25,0,25,50,%,* 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 p

65、erson-years,< 6.11,6.11-7.4,≥ 7.5,Blood sugar (mmol/l),Baseline,In-treatment,Baseline,In-treatment,CVD,non-CVD,,,2.9,2.4,1.4,2.7,2.8,2.0,8.4,10.1,15.2 *,8.2,10.7,15.2 *,,Age-Gender-Adjusted CVD and Non-CVD Incidence

66、 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 dia

67、betes (group 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,i

68、mproves,Average Number of Antihypertensive Agents Needed Per Patient to Achieve Target Systolic BP Goals,Number of Medications,ALLHAT (138 mmHg) IDNT (138 mmHg) RENAAL (141 mmHg) UKPDS (144 mmHg) ABCD