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Hypertension in the Metabolic Syndrome

Hypertension in the Metabolic Syndrome. Thomas D. Giles, M.D. LSU Medical School New Orleans, LA. More Than 80% of Hypertensive Patients Have Additional Comorbidities. Men. Women. Comorbidities: Obesity Glucose intolerance Hyperinsulinemia Reduced HDL-C Elevated LDL-C Elevated TG

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Hypertension in the Metabolic Syndrome

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  1. Hypertension in the Metabolic Syndrome Thomas D. Giles, M.D. LSU Medical School New Orleans, LA

  2. More Than 80% of Hypertensive Patients Have Additional Comorbidities Men Women Comorbidities: • Obesity • Glucose intolerance • Hyperinsulinemia • Reduced HDL-C • Elevated LDL-C • Elevated TG • LVH One 26% Two 25% Two 24% One 27% Three 20% Three 22% None 17% None 19% ≥ Four 12% ≥ Four8% >50% have 2 or more comorbidities HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LVH, left ventricular hypertrophy; TG, triglycerides.Kannel WB. Am J Hypertens. 2000:13:3S-10S.

  3. Diabetes, Obesity, and the Metabolic Syndrome Are Prevalent ComorbiditiesAmong Hypertensive Patients • Hypertension is usually accompanied by other CV risk factors, including obesity, glucose intolerance, hyperinsulinemia, high LDL-C, and LVH • Assessment of CV risk in the hypertensive patient is based upon the presence of other CV risk factors in addition to BP levels Kannel WB. Am J Hypertens. 2000:13:3S-10S. Diabetes and Cardiovascular Disease Review. 2002;Issue 2. International Obesity Task Force Web site. www.obesite.chaire.ulaval.ca/iotf.htm Cameron AJ et al. Endocrinol Metab Clin North Am. 2004;33:351-375. Guidelines Committee. J Hypertens. 2003;21:1011-1053.

  4. Metabolic Syndrome: A Cluster of Disturbances • Abdominal obesity • Atherogenic dyslipidemia • Elevated blood pressure • Insulin resistance ± glucose intolerance • Atherothrombotic factors • Proinflammatory factors Expert Panel. JAMA. 2001;285:2486-2497.

  5. Diagnosis of the Metabolic Syndrome Presence of 3 of the following Waist circumference Men Women Triglycerides HDL-C Men Women BP Fasting glucose >40 inches>35 inches ≥150 mg/dL <40 mg/dL<50 mg/dL ≥130/85 mm Hg ≥110 mg/dL Expert Panel. JAMA. 2001;285:2486-2497.

  6. Metabolic Syndrome Definitions Compared BMI, body mass index; HDL, high-density lipoprotein; UAE, urinary albumin excretion. Expert Panel. JAMA. 2001;285:2486-2497. Einhorn D et al. Endocr Pract. 2003;9:237-252. Alberti KG et al. Diabet Med. 1998;15:539-553.

  7. Hyperglycemia Dyslipidemia Insulin deficiency Obesity Insulin resistance Hypertension Hyperinsulinemia Metabolic Syndrome

  8. Role of Abdominal Adipocytes in Insulin Resistance and Heart Disease Abdominal Adipocytes Liver Adipocytokines + Fatty Acids Insulin Resistance Metabolic Syndrome Heart Disease

  9. Subcutaneous Fat Abdominal Muscle Layer Intra-abdominal Fat Visceral Adiposity:The Critical Adipose Depot

  10. The Fat Cell Is More Than a Bag of Fat Lactate Cholesterolester Transfer Protein (CETP) Prostaglandin Angiotensinogen Phospholipid Transfer Protein (PLTP) Prostacyclin Fat Cell Monobutyrin Leptin Free Fatty Acids Adiponectin Plasminogen Activator Inhibitor (PAI-1) Galectin-12 TNF-a Adipsin (ASP) (complement 3a;D) IL-6 Lipoprotein Lipase (LPL) Adapted from Bray GA. Contemp Diagn Obes. 1998.

  11. Fat Cell Products and Hypertension áVisceral Fat Stores âHepatic Insulin Clearance á Portal FFA áPlasma Insulin Vascular Constriction áRenal Na+ Reabsorption Angiotensin II Angiotensinogen Angiotensin I Hypertension Bray GA. Contemp Diagn Obes. 1998.

  12. Etiology of Insulin Resistance  Circulating FFA Lipoatrophy, adipokines Weight gain, obesity Insulin Resistance The subnormal biologic response to agiven concentration of insulin Physical inactivity Genetics Aging Adipokines = cytokines secreted by adipose tissue.

  13. Pathways: Insulin Resistance Syndrome and Type 2 Diabetes Insulin Resistance Compensatory hyperinsulinemia “Inadequate” insulin response Type 2 Diabetes Insulin Resistance Syndrome CVD Retinopathy Nephropathy Neuropathy Hypertension Stroke PCOS NAFLD NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome. Einhorn D et al. Endocr Pract. 2003;9:237-252.

  14. Hypertension • Hyperinsulinemia can enhance renal sodium reabsorption and vascular reactivity • Angiotensinogen from fat cells can increase angiotensin II and thus blood pressure • Both systolic and diastolic blood pressure increase with increasing body mass index

  15. Inflammation, Abdominal Obesity, and Smoking as Predictors of Hypertension Odds ratio for developing hypertension during 11-year follow-up in 379 middle-age normotensive men* CI, confidence interval; CRP, C-reactive protein; NA, not applicable; OR, odds ratio.*Age adjusted. Niskanen L et al. Hypertension. 2004;44:859-865.

  16. Rise in Circulating Inflammatory Markers in Prehypertension Increase, prehypertensive vs normotensive Marker (%) P CRP 31 <0.01 TNF-α32 <0.05 Amyloid-α 9 <0.05 Homocysteine 6 <0.01 White blood cell count 10 <0.05 CRP, C-reactive protein; TNF-α, tumor necrosis factor-α.Chrysohoou C et al. Am J Hypertens. 2004;17:568-573.

  17. Mortality Is Strongly Associated With Systolic BP in Men With Type 2 Diabetes 250 Nondiabetic Diabetic 200 CV mortality 150 rate/ 10,000 100 person - yrs 50 0 <120 120 - 139 140 - 159 160 - 179 180-189 200 SBP (mm Hg) SBP, systolic blood pressure.Stamler J et al. Diabetes Care. 1993;16:434-444.

  18. CHD Risk Based on Major Risk Factors 40 37 35 30 27 25 Men Women Estimated 10-year rate (%) 25 20 20 13 15 8 10 5 5 5 0 A C D B Risk factors: Blood pressure (mm Hg) 120/80 140/90 140/90 140/90 Total cholesterol (mg/dL) 200 240 240 240 HDL cholesterol (mg/dL) 50 50 40 40 Diabetes No No Yes Yes Cigarettes No No No Yes Wilson PWF et al. Circulation. 1998;97:1837-1847. American Heart Association. Heart Disease and Stroke Statistics - 2004 Update.

  19. Use of Markers for Prediction of Risk for MI Among Healthy Middle-Aged Men* Lipoprotein(a) Total homocysteine TC Fibrinogen tPA antigen TC:HDL-C hs-CRP hs-CRP + TC:HDL-C 0 1.0 2.0 4.0 6.0 Relative risk for future MI hs-CRP, high-sensitivity C-reactive protein; MI, myocardial infarction; TC, total cholesterol.*Values based on men in the top compared with the bottom quartile for each marker.Ridker PM. Ann Intern Med. 1999;130:933-937.

  20. Clinical Management of the Metabolic Syndrome: Screening • Standard part of initial adult patient assessment • Include measurement of waist circumference in physical exam • Labs: • fasting glucose • full fasting lipid profile • Assess global risk of CHD • Future: may include other risk factors, eg, C-reactive protein, fibrinogen, and small, dense LDL Wong ND. Prev Cardiol. 2005;8:47-54.

  21. Clinical Management of the Metabolic Syndrome: Main Goals • Prevention of type 2 diabetes • Prevention of cardiovascular disease

  22. Clinical Management of the Metabolic Syndrome: NCEP Recommendations • Primary management of the metabolic syndrome should be to reverse its root causes: • overweight/obesity • physical inactivity • In addition, lipid and nonlipid risk factors associated with the metabolic syndrome should be appropriately treated • hypertension • prothrombic state • dyslipidemia NCEP, National Cholesterol Education Program. Expert Panel. Circulation. 2002;106:3143-3421.

  23. Clinical Management of the Metabolic Syndrome: Approaches • Therapeutic lifestyle changes • dietary restriction of calories, simple carbohydrates and saturated fats • increased dietary fiber • regular aerobic exercise • weight loss • Pharmacologic therapy • statins • fibrates • ACE inhibitors/ARBs • other agents? • What is the evidence?

  24. Clinical Management of the Metabolic Syndrome: Approaches • Therapeutic lifestyle changes • dietary restriction of calories, simple carbohydrates and saturated fats • increased dietary fiber • regular aerobic exercise • weight loss • Pharmacologic therapy • statins • fibrates • ACE inhibitors/ARBs • other agents? • What is the evidence?

  25. Lifestyle Interventions and Risk of Diabetes: Diabetes Prevention Program 70 58 60 50 Reduced incidence of diabetes (%) 40 31 30 20 10 0 Lifestyle modification Metformin N=3234 nondiabetic individuals.Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

  26. Prevention of Diabetes Through Lifestyle Changes Among Individuals With IGT: Finnish Diabetes Prevention Study 1.0 Intervention group 0.9 0.8 Cumulative probability ofremaining free of diabetes 0.7 Control group 0.6 Relative risk = 0.4 (P<0.001) 0.5 0.4 0 1 2 3 4 5 6 Year IGT, impaired glucose tolerance.Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350.

  27. ALLHAT: Incidence of New-Onset Diabetes at 4 Years* P .001 P = .04 11.6% 9.8% 8.1% % Chlorthalidone Amlodipine Lisinopril *43.2% lower onset of new diabetes with lisinopril compared to chlorthalidone (P .001 at 4 y). ALLHAT Officers and Coordinators. JAMA. 2002;288:2981-2997.

  28. CHARM-PreservedDevelopment of New-Onset Diabetes Number of cases HR Candesartan Placebo (CI) P value 47 77 0.60 0.005 (0.41-0.86) N=3025.CI, confidence interval; HR, hazard ratio. Yusuf S et al. Lancet. 2003;362:777-781.

  29. Effects of ACE Inhibition on the Development of Diabetes: HOPE 6 5.4 5 3.6 4 Diabetesincidence (%) 3 2 1 0 Ramipril Placebo Relative risk, 0.66; 95% confidence interval, 0.51-0.85; P<.001. Yusuf S et al. JAMA. 2001;286:1882-1885.

  30. Chinese Prevention Trial: Lifestyle Intervention, Acarbose, and Metformin Reduce Risk of Diabetes • 43% decrease in RR with diet + exercise • 88% decrease in RR with acarbose • 77% decrease in RR with metformin P = .09 P = .0002 P = .0001 Data from Yang W et al. Chin J Endocrinol Metab. 2001;17:131-136.

  31. 10 5 0 -5 -10 -15 -20 -25 -30 LIFEMajor Endpoints 7 Change inrelativerisk(%) -10 -11 -13* † † -25 -25 Primary endpoint CVmortality Stroke MI Total mortality New-onset diabetes *P=0.021; †P=0.001, losartan vs atenolol. Dahlöf B et al. Lancet. 2002;359:995-1003.

  32. Clinical Management of the Metabolic Syndrome: Approaches • Therapeutic lifestyle changes • dietary restriction of calories, simple carbohydrates and saturated fats • increased dietary fiber • regular aerobic exercise • weight loss • Pharmacologic therapy • statins • fibrates • ACE inhibitors/ARBs • other agents? • What is the evidence?

  33. Statin Therapy in CHD Patients:A Meta-Analysis 0 -10 -16% Rate(%) -20 -23% -25% All-cause mortality CHD mortality CHD mortality or nonfatal MI -30 -40 25 studies in meta-analysis; N=65,511.CHD, coronary heart disease; MI, myocardial infarction.Wilt TJ et al. Arch Intern Med. 2004;164:1427-1436.

  34. Statin Therapy in Patients With Diabetes AFCAPS/ TexCAPS LIPID 4S 0 -10 -20  in risk of major acute coronary event -30 -40 Total Diabetic -50 -60 Downs JR et al. JAMA. 1998;279:1615-1622; 4S Study Group. Lancet. 1994;344:1383-1389; LIPID Study Group. Lancet. 2002;359:1379-1387.

  35. Dyslipidemia in Metabolic Syndrome • Low HDL • High TG • Average to low LDL • Atherogenic lipoprotein particles • VLDL Remnants with apo CIII

  36. Anti-Atherogenic Effects of HDL HDL Inhibition of monocyte- adhesion mono- cyte HDL HDL LDL Endothelium LDL Cholesterol- efflux Inhibition of LDL-oxidation Ox LDL macro- phage foam cell HDL

  37. Gemfibrozil Effect on Lipids: VA-HIT Placebo Gemfibrozil 200 35 34 150 33 LDL cholesterol(mg/dL) HDL cholesterol(mg/dL) 100 32 50 31 0 30 0 1 2 3 4 5 0 1 2 3 4 5 Year Year 200 200 150 150 Total cholesterol(mg/dL) Triglycerides(mg/dL) 100 100 50 50 0 0 0 1 2 3 4 5 0 1 2 3 4 5 Year Year VA-HIT, Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial. Rubins HB et al. N Engl J Med. 1999;341:410-418.

  38. Gemfibrozil Effect on Fatal and Nonfatal CHD Events: VA-HIT 25 Placebo 20 15 Cumulativeincidence(%) Gemfibrozil 10 5 0 0 1 2 3 4 5 6 Year Rubins HB et al. N Engl J Med. 1999;341:410-418.

  39. Fenofibrate Versus Atorvastatin in Patients With Low HDL-C (<40 mg/dL) Randomized, Double-Blind Comparative Trial Atorvastatin 10 mg (12 weeks) n=68 +15.2% Fenofibrate 200 mg (12 weeks) n=57 +5.6% Baseline HDL-C Absolute Change in HDL-C, mg/dL Twice as many patients taking fenofibrate achieved an HDL-C of 40 mg/dL compared with patients taking atorvastatin. Després J-P, et al. J Intern Med. 2002;251:490-499.

  40. The PPAR Family

  41. Effects of Weight Loss (10Kg) on Systemic Hemodynamics Mean Arterial Pressure Total Peripheral Resistance Heart Rate Cardiac Output Percent NS - 5 -10 * ** * -15 * P < 0.01 pre-weight loss vs. ** P < 0.001 Ann. Int. Med. 1983; 98:315.

  42. Systolic Hypertension in the Elderly Program (SHEP): Influence of Diabetes on Cardiovascular Event Rates 35 Active treatment RR .66, 95% Cl .46 - .94 Placebo 30 25 20 5-Year Cumulative Event Rates for All Major Cardiovascular Events (%) RR .66, 95% Cl .55 - .79 15 10 5 0 Nondiabetes Diabetes RR, relative risk; Cl, confidence interval. Curb JD, et al. JAMA. 1996;276:1886-1892.

  43. Mortality and Morbidity in Non-Diabetic Patients SHEP SYST-EUR SHEP SYST-EUR -15 Rate in Placebo Group* Mortality 21.6 21.8 -34 -18 CV Endpoints 35.8 28.9 -30 -38 15.0 12.3 Stroke -19 -39 12.4 15.2 Coronary -22 -50% Active Better Placebo Better 50% -100% 0 *Number of endpoints / 1000 patient years

  44. Tight BP Control vs. Tight Glucose Control Microvascular Any DM Stroke DM Death Complications End Point 0 - -10 - -20 - Reduction in Risk (%) -30 - Tight Glucose Control -40 - Tight BP Control *P < 0.05 -50 - UKPDS. BMJ. 1998:317;703-712.

  45. Hypertension and DiabetesReduction in Total Mortality Captopril (UKPDS) Atenolol (UKPDS) Diuretic (SHEP) Nitrendipine (Syst-Eur) Nitrendipine (Syst-China) 0% 20% 40% 60% 80% 100%

  46. Multiple Risk Factor Intervention: The Steno-2 Study Intensive therapy Conventional therapy 80 P=0.01 P=0.21 70 P=0.019 60 50 P=0.001 Patients(%) 40 30 20 P=0.06 10 0 Glycosylatedhemoglobin<6.5% Cholesterol<175 mg/dL Triglycerides<150 mg/dL SBP<130 mm Hg DBP<80 mm Hg Gaede P et al. N Engl J Med. 2003;348:383-393.

  47. Multiple Risk Factor Intervention: The Steno-2 Study 60 P=0.007 50 Conventional therapy 40 Primarycomposite endpoint (%) 30 20 Intensive therapy 10 0 0 12 24 36 48 60 72 84 96 Follow-up (months) Gaede P et al. N Engl J Med. 2003;348:383-393.

  48. Summary: Hypertension in the Metabolic Syndrome • The metabolic syndrome predicts the development of both diabetes and CVD • Adolescents and adults (particularly those who are overweight or obese) should be assessed for metabolic syndrome • Lifestyle interventions have been shown to prevent (or delay the onset) of diabetes in individuals with impaired glucose tolerance

  49. Summary: Hypertension in the Metabolic Syndrome (cont’d) • Initial therapy for the metabolic syndrome should be dietary and exercise interventions • Conventional CV risk factors should also be identified and treated in persons with metabolic syndrome • Hypertension, in particular, should be treated aggressively.

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