替米沙坦與代謝綜合征學(xué)習(xí)教案

1、會計學(xué)1替米沙坦與代謝替米沙坦與代謝(dixi)綜合征綜合征第一頁，共69頁。IL6PAI-1TNF adiponectinleptinInsulin sensitivityinsulin resistanceVascular inflammationendothelial dysfunctionangiotensinogenFFAAdipokines Mediate Insulin Resistance and Inflammation第2頁/共69頁第二頁，共69頁。Progression of Atherosclerosis in Insulin ResistanceEndothelia

2、l 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,

3、2003 Insulin Resistance第3頁/共69頁第三頁，共69頁。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頁/共69頁第四頁，共69頁。13NH3 13NH3 13NH3 Dipyridamole (0.56 m

4、g/kg)135RestQuinones et al Ann Intern Med., 2004; 140:700-8 025457090115CPTDIP第5頁/共69頁第五頁，共69頁。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頁/共69頁第六頁，共69頁。

5、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

6、 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 on

7、set diabetes with candesartan in patients with heart failureInhibition of the Renin-angiotensin System Prevents Diabetes:第7頁/共69頁第七頁，共69頁。Mechanisms by Which ACEIs and ARBs Prevent Diabetes:Improve endothelial function: Up to 40% of insulin-mediated glucose uptake may be endothelial dependent Allow

8、fat cell differentiation Protect islet cells ?Alter adipokine production ?Alter liver glucose production 第8頁/共69頁第八頁，共69頁。PPAR Ligands AT1 Receptor Blockers Angiotensin II Activates Multiple Mechanisms Promoting Tissue Injury that are Antagonized by PPAR Ligands第9頁/共69頁第九頁，共69頁。Kidney proteinuria Pa

9、ncreas -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頁/共69頁第十頁，共69頁。Effects of PPAR Ligands on Athe

10、rosclerosis inAngII-Infused Male LDLR-/- Mice第11頁/共69頁第十一頁，共69頁。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

11、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. Bak

12、ris et al J Human Hypertension, 2003第12頁/共69頁第十二頁，共69頁。Ligands PAI-1 expression Growth TGF effects on ECM productionNicholas SB, et al Hypertension 37( Part 2):722-727, 2001 第13頁/共69頁第十三頁，共69頁。TRO Inhibits Capillary-Tube FormationControlTRO-treatedMurata et al. Invest Ophthalmol Vis Sci. 41:2309-231

13、7, 2000Retinal Neovascularization in Control and TZD-treated Hypoxic Mice第14頁/共69頁第十四頁，共69頁。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 ONTARGET: Telmisartan Ramipr

14、il 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頁/共69頁第十五頁，共69頁。 Center for Consumer Freedom 第16頁/共69頁第十六頁，共69頁。Identification of New Treatment Strategies for Insulin Resistance, Metabolic Syndrome and Hype

15、rtension Theodore W Kurtz USA 第17頁/共69頁第十七頁，共69頁。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

16、diabetes *Not effectively treated by current antihypertensive drugs* 第18頁/共69頁第十八頁，共69頁。Angiotensin II Receptor Blockers (ARBs)Hypertension Insulin Resistance Dyslipidemia ? ? 第19頁/共69頁第十九頁，共69頁。H O O C N N N N O S N H O O N AII Receptor Blocker Telmisartan PPAR Ligand Pioglitazone 第20頁/共69頁第二十頁，共69

17、頁。第21頁/共69頁第二十一頁，共69頁。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頁/共69頁第二十二頁，共69頁。2Losartan 46810121416Eprosartan Irbesartan Valsartan Candesartan Telmisartan

18、Fold activation Olmesartan 5 micromolar Ability of Different ARBs To Activate PPAR (S.C. Benson et al., Hypertension, 43:993-1002, 2004) 第23頁/共69頁第二十三頁，共69頁。Telmisartan is a Partial Agonist of PPAR (Schupp et al., Circulation, 109:2054-2057, 2004)0,11101000510152025 Pioglitazone TelmisartanLuciferas

19、e activity x-fold induction over vehicle treated cellsPioglitazone Telmisartan mol/Liter第24頁/共69頁第二十四頁，共69頁。 PPAR Activator Expression of Key Target Genes Receptor complex DBD PPAR DNA response elements CytoplasmNucleus RXR 第25頁/共69頁第二十五頁，共69頁。Ability of Telmisartan to Activate Key Anti-Diabetic Tar

20、get 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頁/共69頁第二十六頁，共69頁。It is also a PPAR Activator- Telmisartan is Not Just an ARB - u Cellular differentiation assaysu Target gene expression ass

21、aysu 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頁/共69頁第二十七頁，共69頁。Valsartan 160 mg/day Telmisartan 80 mg/day Glucose 105 110 115 12

22、0 125 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頁/共69頁第二十八頁，共69頁。Triglycerides Telmisartan 60 80 100 120 140 Week:04mg/dl= 81216Valsartan Clinical Case Ob

23、servations 52 year old male with the metabolic syndrome 20Telmisartan (Pershadsingh and Kurtz, Diabetes Care, 27:1015, 2004) 第29頁/共69頁第二十九頁，共69頁。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) -

24、20- 10mg/dl Triglycerides - 300Glucose 第30頁/共69頁第三十頁，共69頁。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 Researc

25、h, 2004) Hypertensive Diabetics After 12 months, compare changes in insulin, glucose, and triglyceride levels from baseline 第31頁/共69頁第三十一頁，共69頁。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

26、control140 20 60 100 40 80 120 mg/dl BeforeBeforeBeforeTelmisartan 40 mg/day140 20 60 100 pAfter* P.05 第32頁/共69頁第三十二頁，共69頁。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

27、 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頁/共69頁第三十三頁，共69頁。Changes in Glucose, Insulin, and Insulin Resistance FromBaseline in Patients with the Hypertension

28、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頁/共69頁第三十四頁，共69頁。It is also a PPAR A

29、ctivator- 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 o

30、ral dosing? u Preliminary clinical studies 第35頁/共69頁第三十五頁，共69頁。OLMESARTAN MEDOXOMILThe Chemical Structures of ARBs 第36頁/共69頁第三十六頁，共69頁。50100150200250300350400Telmisartan LitersVolume of Distribution of Different ARBs (Index of the Ability of a Drug to Enter Tissues Throughout the Body) 450500Valsart

31、an Olmesartan Losartan Losartan Metabolite Candesartan Irbesartan 第37頁/共69頁第三十七頁，共69頁。Molecular Modeling of Telmisartan in the Ligand Binding Domain (LBD) of PPAR Telmisartan(Benson et al., Hypertension, 43:993-1002, 2004) 第38頁/共69頁第三十八頁，共69頁。 Two Classes of PPAR Activators Conventional PPAR Activat

32、ors 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頁/共69頁第三十九頁，共69頁。Clinical

33、 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頁/共69頁第四十頁，共69頁。 第41頁/共69頁第四十一頁，共69頁。ONTARGET and TRANSCEND - Trial Designs -ONTARGET 25,260 5,926 Telmisar

34、tan Ramipril Telmisartan Ramipril + Telmisartan Placebo TRANSCEND Cardiovascular and metabolic endpoints in high risk populations 第42頁/共69頁第四十二頁，共69頁。第43頁/共69頁第四十三頁，共69頁。What Does the Future Hold for Cardiovascular Protection of Diabetic Patients? Massimo Volpe Italy 第44頁/共69頁第四十四頁，共69頁。Most Hyperte

35、nsive Patients Have Complex Hypertension 1 CV additional CV risk factorNo additional CV risk factorCOMPLEX HYPERTENSION HTN additional risk factor CAD, LVH Diabetes, Metabolic syndrome Renal Disease High-risk populationFramingham Offspring Study (men aged 18-74)Thrombosis 2003.ppt Copyright CMF Lear

36、ning Systems第45頁/共69頁第四十五頁，共69頁。Epidemics of Diabetes in Hypertension A growing proportion of hypertensive patients have or develop metabolic syndrome or type 2 diabetes (1322% in different studies!) 第46頁/共69頁第四十六頁，共69頁。* * * * * The Hypertension in Diabetes Study Group. J Hypertens 1993a;11:309-317

37、.* 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

38、Hypertension and Type 2 Diabetes: a High-Risk Population第47頁/共69頁第四十七頁，共69頁。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. 035455020

39、30Referencegroup5 year CVD risk per 100 persons TC=7mmol/L& smokermale402510155& diabetes60 yrs& HDL=1mmol/L3%1%6%12%18%24%33%44%第48頁/共69頁第四十八頁，共69頁。Patient 1Patient 2Patient 3CVD risk threshold for hypertension treatmentMultifactor CV Risk (% per yr)Blood Pressure threshold for equal be

40、nefitTarget 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 (a

41、spirin, 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 Mul

42、tiple therapymodified from Am J Hyper 2002; 15 (10): 917-23第49頁/共69頁第四十九頁，共69頁。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 Pressu

43、re will produce larger absolute benefits in relation to level of risk.New Paradigms in CVD and Diabetes 第50頁/共69頁第五十頁，共69頁。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 M

44、edicine (HOPE, IRMA 2, LIFE) 第51頁/共69頁第五十一頁，共69頁。Hypertension and Diabetes:General GuidelinesLower Blood Pressure to target Get control of plasma glucose Block the renin-angiotensin system Use a statin Control modifiable Risk Factors MV 2004第52頁/共69頁第五十二頁，共69頁。Antihypertensive Agents and Insulin Sen

45、sitivity Index* % Change*Data derived from various double-blind and open studiesPropranolol Metoprolol Atenolol Pindolol HCTZIsradipine Furosemide Diltiazem Enalapril Captopril Prazosin Doxazosin Lithell HO. Diabetes Care 1991;14:203-209. Anderson PE, Lithell H. Am J Hypertens 1996; 323-33.第53頁/共69頁

46、第五十三頁，共69頁。Beta-blocker Captopril Ramipril -50 -25 0 25 50 % * P 0.05 compared to nondiabetics Athhosel Risk StudyCAPP Study HOPE Study Propensity to Development of Diabetes According to the Antihypertensive Drug第54頁/共69頁第五十四頁，共69頁。第55頁/共69頁第五十五頁，共69頁。Verdecchia P. Hypertension 2004;43:963-9第56頁/共69

47、頁第五十六頁，共69頁。Integrating Cardiorenal Care in DiabetesBlockade of AT1-Receptor improvesimproves第57頁/共69頁第五十七頁，共69頁。Average Number of Antihypertensive Agents Needed Per Patient to Achieve Target Systolic BP GoalsNumber of Medications ALLHAT (138 mmHg) IDNT (138 mmHg) RENAAL (141 mmHg) UKPDS (144 mmHg)

48、ABCD (132 mmHg) MDRD (132 mmHg) HOT (138 mmHg) AASK (128 mmHg)Trial/SBP achievedUpdated from Bakris GL. Am J Kidney Dis. 2000第58頁/共69頁第五十八頁，共69頁。Does it Matter Which Drugs We Use in Combination? Outcomes Data Tolerability New onset Diabetes 第59頁/共69頁第五十九頁，共69頁。DiureticsACE inhibitorsAT1-receptor blo

49、ckersCalcium antagonists-blockers-blockersESH/ESC Guidelines, J Hypertens 2003 Rational Non rationalPossible combinations of different classes of antihypertensive agents according to ESH-ESC Guidelines. Are They Valid in Diabetics?第60頁/共69頁第六十頁，共69頁。New Onset Diabetes Hypertension per se doubles the

50、 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第61頁/共69頁第六十一頁，共69頁。The Ideal Combination Therapy in HypertensionEffective BP reduction at low doses Sound pathophys

51、iological and pharmacodynamic rational Protection of associated Risk Factor Control of Target Organ Damage Control of events Well tolerated and few side effects第62頁/共69頁第六十二頁，共69頁。 Antihypertensive therapy is the most effective preventive measure in diabetes Monotherapy is rarely sufficient Increase

52、d rational use of combination therapy is the key to improving blood pressure control The type of drugs used in combination influences the BP lowering effect of the combination, the adverse event profile and may ultimately influence morbidity and mortalitySummary I 第63頁/共69頁第六十三頁，共69頁。Cardiovascular and Renal Protection Wit