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METABOLIC SYNDROME DIABETES & HYPERTENSION

METABOLIC SYNDROME DIABETES & HYPERTENSION. Thomas D. Giles, M.D. Louisiana State University Medical School New Orleans, Louisiana . Top Three Countries for Diabetes. Data from King H et al. Diabetes Care . 1998;21:1414-1431. . CV Mortality Risk Doubles with Each 20/10 mm Hg BP Increment*.

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METABOLIC SYNDROME DIABETES & HYPERTENSION

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  1. METABOLIC SYNDROME DIABETES & HYPERTENSION Thomas D. Giles, M.D. Louisiana State University Medical School New Orleans, Louisiana

  2. Top Three Countries for Diabetes Data from King H et al. Diabetes Care. 1998;21:1414-1431.

  3. CV Mortality Risk Doubles withEach 20/10 mm Hg BP Increment* 8 7 6 5 CVmortalityrisk 4 3 2 1 0 115/75 135/85 155/95 175/105 SBP/DBP (mm Hg) *Individuals aged 40-69 years, starting at BP 115/75 mm Hg. CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressure Lewington S, et al. Lancet. 2002; 60:1903-1913. JNC VII. JAMA. 2003.

  4. Association of SBP and CV Mortalityin Men With Type 2 Diabetes 250 Nondiabetic Diabetic 200 CVmortalityrate/10,000 person-yr 150 100 50 0 <120 120-139 140-159 160-179 180-199 ≥200 SBP (mm Hg) CV, cardiovascular; SBP, systolic blood pressure. Stamler J et al. Diabetes Care. 1993;16:434-444.

  5. Any end point related to diabetes (P<0.0001) 4.0 Death related to diabetes (P<0.0001) 3.5 All-cause mortality (P<0.0001) 3.0 2.5 2.0 1.5 1.0 0.5 0 110 120 130 140 150 160 170 End Point Hazard Ratios Associated With Increase in SBP Hazard ratio Updated mean SBP (mm Hg) Adler A et al. BMJ. 2000;321:412–419.

  6. Characteristics of Adults 20 Years With Previously Diagnosed Diabetes NHANES 1999-2000 P Characterisitic NHANES III Mean body mass index Obese (%) Hypertension Taking antihypertensive medication Hypercholesterolemia Taking lipid-controlling medication 29.9 41.6 54.8 77.0 44.9 27.7 32.3 54.6 51.4 85.2 54.5 56.1 .002 .008 .32 .05 .02 <.001 Saydah SH et al. JAMA. 2004;291:335-342.

  7. Percentage of Adults With Recommended Levels of Vascular Disease Risk Factors in NHANES III and NHANES 1999-2000 NHANES III (n=1204) NHANES 1999-2000 (n=370) 60 50 Adults (%) 40 30 20 10 0 HbA1c Level <7% BP <130/80 mm Hg Total Cholesterol Level <200 mg/dL (5.18 mmol/L) Vascular Disease Risk Factors Saydah SH et al. JAMA. 2004;291:335-342.

  8. Metabolic Syndrome: NCEP/ATP III Definition Presence of at least 3 of 5 risk factors: • Abdominal obesity • Elevated blood pressure • Elevated fasting glucose • Elevated triglycerides • Low HDL-C Third Report of the National Cholesterol Education Program Expert Panel. Executive Summary; May 2001. NIH # 01-3670.

  9. No Data <4% 4%-6% 7%-8% 9%-10% >10% Prevalence of Diabetes among US Adults, 1991 and 2001 Diabetes 1991 2001 Mokdad AH, et al., JAMA, 2003:289;76-80.

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

  11. Diagnostic Criteria for Diabetes, IFG, and IGT (mg/dL) 8.5 Diabetes 7.5 126 Fasting Glucose (mmol/L) IFG IFG + IGT 6.5 110 Normal glucose IGT 5.5 4.5 3.5 2.5 4.5 6.5 8.5 10.5 12.5 14.5 7.0 11.1 140 200 (mg/dL) 2-h Postload Glucose (mmol/L) IFG = impaired fasting glucose. American Diabetes Association. Diabetes Care. 2003;26(suppl 1):S5-S20.

  12. 45 40 Men (n=4265) Women (n=4559) 35 30 25 20 15 10 5 0 20-29 30-39 40-49 50-59 60-69 70 ? Metabolic Syndrome: Prevalence Increases With Age 47 million or 23% of US Adults Have Metabolic Syndrome Prevalence, % Age, yr Adapted from: Ford ES, et al. JAMA. 2002;287:356-359.

  13. 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

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

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

  16. 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.

  17. Cardiometabolic Syndrome: Large (Insulin resistant) Fat Cells • ( ↑Central Fat) • (Fatty liver(NASH) (↑CRP) • (Endothelial Dysfunction) • ↑Small, dense LDL • ↑triglyceridemia • ↓HDL • Hypertension • PAI-1/PA • Albuminuria Enhanced Lipolysis > FreeFA  IL- 6, TNF- @, and RAS ActivationReduced Adiponectin VisceralObesity Atherosclosis

  18. 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.

  19. 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

  20. Mortality and Morbidity in Diabetic Patients SHEP SYST-EUR SYST-EUR SHEP -25 Rate in Placebo Group* Mortality 45.1 35.6 -55 -34 CV Endpoints 63.0 57.6 -22 -59 26.6 Stroke 28.8 -56 -73 21.3 32.2 Coronary -57 Placebo Better Active Better 50% -100% 0 -50% *Number of endpoints / 1000 patient years

  21. HOT Study: Risk of Morbidity and Mortality in Diabetic Hypertensive Patients 90 mmHg Myocardial Infarction 80 mmHg Major CV Events Stroke CV Mortality Total Mortality | | | | 0 1 2 3 4

  22. 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.

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

  24. JNC 7 Classification and Management of Blood Pressure Considerations for Initial Therapy DBP* mm Hg Lifestyle modification SBP* mm Hg Category Without Compelling Indications With CompellingIndications No antihypertensive drug indicated Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combo 2-drug combofor most (usually thiazide-type diuretic and ACEI or ARB or BB or CCB) Normal Prehypertension Stage 1 Hypertension Stage 2 Hypertension <120 120–139 140–159 ≥160 and <80 or 80–89 or 90–99 or ≥100 Encourage Yes Yes Yes Drug(s) for compelling indications† Drug(s) for the compelling indications† Other antihypertensivedrugs (diuretics, ACEI, ARB, BB, CCB) as needed SBP, systolic blood pressure; DBP, diastolic blood pressure; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, beta blocker; CCB, calcium channel blocker. *Treatment determined by highest BP category. **Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. †Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg. Chobanian AV et al. JAMA. 2003;289:2560–2572.

  25. JNC 7 Compelling Indications for Specific Antihypertensive Agents Based on Favorable Outcome Data From Clinical Trials BB ACEI ARB CCB AA Diuretic CHF Post-MI CAD risk Diabetes mellitus Renal disease Recurrent strokeprevention                      BB, beta blocker; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker;CCB, calcium channel blocker; AA, aldosterone antagonist; CHF, chronic heart failure;MI, myocardial infarction; CAD, coronary artery disease; DM, diabetes mellitus Chobanian AV et al. JAMA. 2003;289:2560–2572.

  26. ISHIB Blood Pressure TargetsInternational Society on Hypertension In Blacks 140/90 mmHg for uncomplicated hypertension 130/80 mmHg for patients with diabetes or nondiabetic renal disease and proteinuria >1 g/d Combination antihypertensive therapy if SBP 15 mmHg or DBP 10 mmHg above target <140/90 mmHg (eg, 130/80 mmHg) with history of cardiovascular event, stroke, or TIA; or evidence of target organ damage, including microalbuminuria; or CHD or high risk for CHD Douglas JG et al. Arch Intern Med. 2003;163:525–541.

  27. Hypertension and DiabetesAmerican Diabetes Association “There is a strong epidemiological connection between hypertensionin diabetes and adverse outcomes of diabetes. Clinical trialsdemonstrate the efficacy of drug therapy versus placebo in reducingthese outcomes and in setting an aggressive blood pressure–loweringtarget of <130/80 mmHg.” Arauz-Pacheco C et al. Diabetes Care. 2003;26(suppl):S80–S82.

  28. ADA Guidelines For Management of Hypertension in Adults With Diabetes Systolic Diastolic Goal (mmHg) <130 <80 Behavioral therapy alone 130–139 80–89 (maximum 3 months) then add pharmacologic treatment Behavioral therapy + 140 90 pharmacologic treatment Arauz-Pacheco C et al. Diabetes Care. 2003;26(suppl):S80–S82.

  29. CAPPP Study: Results • 13% risk reduction in diabetes Conventional Captopril P <.04 P <.001 Data from Hansson L et al. Lancet. 1999;353:611-616.

  30. SOLVD: Enalapril Reduces New-Onset Diabetes Risk in CHF Patients • 16.5% absolute risk reduction in development of diabetes No. of New Diabetes Cases P <.0001 N = 291 Vermes E et al. Circulation. 2003;107:1291-1296.

  31. SOLVD: Enalapril Reduces Diabetes Risk in CHF Patients With IFG Patients With IFG at Baseline (n = 55) 100 Enalapril • 45% risk reductionP <.0001 75 % Diabetes-Free 50 Placebo 25 0 1 2 3 4 5 Time (y) Vermes E et al. Circulation. 2003;107:1291-1296.

  32. LIFE Study: Results P <.05 • 25% decrease in RR P <.001 Dahlöf B et al. Lancet. 2002;359:995-1003.

  33. CHARM-Preserved Development of new diabetes Number of cases HR p-value Candesartan Placebo (CI) 47 77 0.60 0.005 (0.41-0.86)

  34. 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.

  35. Multiple Antihypertensive Agents Are Needed to Achieve Target BP No. of antihypertensive agents Trial Target BP (mm Hg) 1 2 3 4 UKPDS DBP <85 ABCD DBP <75 MDRD MAP <92 HOT DBP <80 AASK MAP <92 IDNT SBP <135/DBP <85 ALLHAT SBP <140/DBP <90 DBP, diastolic blood pressure; MAP, mean arterial pressure; SBP, systolic blood pressure. Bakris GL et al. Am J Kidney Dis. 2000;36:646-661. Lewis EJ et al. N Engl J Med. 2001;345:851-860. Cushman WC et al. J Clin Hypertens. 2002;4:393-404.

  36. JNC VII on Combination Therapy • “When BP is more than 20/10 mm Hg above goal, consideration should be given to initiating therapy with two drugs, either as separate prescriptions or in fixed-dose combinations.” • “Failure to titrate or combine medications, despite knowing the patient is not at goal BP, represents clinical inertia and must be overcome.” JNC VII. JAMA. 2003.

  37. CONCLUSION • Diabetes, the metabolic syndrome and hypertensionconstitute a particularly dangerous combination as regards cardiovascular morbidity and mortality. • The primary therapeutic goal is to reduce blood pressure. • The ACE inhibitors and ARBs may have additional properties that warrant their use in diabetes and the metabolic syndrome, whereas thiazide diuretic monotherapy may not.

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