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Diabetes, Hypertension and the Metabolic Syndrome: Is There Anything New? Thomas D. Giles, M.D. New Orleans, LA

Diabetes, Hypertension and the Metabolic Syndrome: Is There Anything New? Thomas D. Giles, M.D. New Orleans, LA. Numbers of persons with diabetes will more than double by 2030. 40. 118% increase. 30.3. 30. US population with diabetes (millions). 20. 13.9. 10. 0. 2002. 2030. Year.

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Diabetes, Hypertension and the Metabolic Syndrome: Is There Anything New? Thomas D. Giles, M.D. New Orleans, LA

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  1. Diabetes, Hypertension and the Metabolic Syndrome: Is There Anything New? Thomas D. Giles, M.D. New Orleans, LA

  2. Numbers of persons with diabetes will more than double by 2030 40 118% increase 30.3 30 US population with diabetes(millions) 20 13.9 10 0 2002 2030 Year AHA. Heart Disease and Stroke Statistics–2005 Update.Wild S et al. Diabetes Care. 2004;27:1047-53.

  3. 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.

  4. The Metabolic Syndrome and Insulin Resistance

  5. 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.

  6. Metabolic syndrome diagnosis: ATP III emphasizes clinical practice • Risk factor Defining level • Abdominal obesity (in) Waist: Men >40 Women >35 • Triglycerides (mg/dL) ≥150 • HDL-C (mg/dL) Men <40 Women <50 • BP (mm Hg) ≥130/≥85 • Fasting glucose (mg/dL) ≥110 (ADA ≥100) NCEP ATP III. JAMA. 2001;285:2486-97.

  7. Plasma triglycerides >150 mg/dL* HDL-C <40 mg/dL* BP 140/90 mm Hg* Fasting glucose 100 mg/dL or previously diagnosed type 2 diabetes Metabolic syndrome diagnosis: IDF emphasizes central obesity International Diabetes Federation Central obesity • Plus any 2 of the following: • Defined according to waist circumference (ethnic- and gender-specific) www.idf.org. Accessed August 2005. *Or receiving specific treatment for this abnormality

  8. European37 32 Sub-Saharan African Middle Eastern South Asian35 32 South/Central American Chinese35 32 Japanese34 35 IDF ethnic- and gender-specific criteria for central obesity Waist circumference (inches) Men Women www.idf.org. Accessed August 2005.

  9. Metabolic syndrome diagnosis: WHO emphasizes central role of insulin resistance Insulin resistance • Type 2 diabetes, or • Impaired fasting glucose, or • If fasting glucose <110 mg/dL, glucose uptake below lowest quartile Plus any 2 of the following: • Antihypertensive medication and/or BP ≥140/90 mm Hg • Plasma triglycerides ≥150 mg/dL • HDL-C <35 mg/dL (men) or <39 mg/dL (women) • BMI >30 kg/m2 and/or waist-hip ratio >0.9 (men); >0.85 (women) • Urinary albumin excretion rate ≥20 µg/min or albumin-creatinine ratio ≥30 mg/g Grundy SM et al. Circulation. 2004;109:433-8.Adapted from Alberti KG, Zimmet PZ. Diabet Med.1998;15:539-53.

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

  11. Other markers of insulin resistance • Family history of type 2 diabetes or CAD • Overactive sympathetic nervous system • Uric acid Cohn GS et al. Am J Hypertens. 2005;18:1099-103.

  12. Over half of patients referred to cardiologists have insulin resistance syndrome Cardiac rehabilitation Acute MI 59 58 60 50 Patients withinsulin resistance syndrome (%) 40 20 0 N = 1912Savage, 2005 N = 235 Milani, 2003 N = 85 Curran, 2004 Savage PD et al. Am Heart J. 2005;149:627-31. Milani RV, Lavie CJ. Am J Cardiol. 2003;92:50-4. Curran PJ et al. J Am Coll Cardiol. 2004;43(suppl A):249A.

  13. Almost 70% of patients with first MI have IGT or undiagnosed diabetes N = 181 consecutive patients admitted to CCU 66 70 Undiagnosed diabetes 50 31 Patients (%) 30 Impaired glucose tolerance (IGT) 35 10 0 Glucose tolerance test results Norhammar A et al. Lancet. 2002;359:2140-4.

  14. Diagnosis of diabetes, IFG, and IGT Plasma glucose (mg/dL) Fasting 2-hr postload* Casual ≥200 – 140 to 199 (ADA) >140 to <200 (AACE) ≥126 100 to 125 (ADA) >110 to ≤126 (AACE) – Diabetes Impaired fasting glucose (IFG) Impaired glucose tolerance (IGT) ≥200 – – *Following equivalent of 75 g anhydrous glucose in water ADA. Diabetes Care. 2005;28(suppl 1):S4-36.AACE. Endocr Pract. 2003;9:240-52.

  15. Multidisciplinary consensus on managingmetabolic syndrome AHA / NHLBI / ADA • Modify lifestyle (weight loss, physical activity) • Assess risk • Framingham Risk Score • CRP (optional) • Reduce risk factors (ATP III, JNC 7, ADA) • Lipids, BP, thrombosis, glucose “There is growing interest in the possibility that drugs that reduceinsulin resistance will delay onset of type 2 diabetes and will reduceCVD risk when the metabolic syndrome is present.” Grundy SM et al. Circulation. 2004;109:551-6.

  16. Role of obesity in insulin resistance Caloric intake Sedentarylifestyle Geneticfactors Free fatty acids Glucose Lipids Oxidativestress Inflammation VisceralObesity Insulinresistance Adapted from Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.

  17. 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.

  18. 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.

  19. Insulin resistance increases risk of target organ damage in hypertension Without insulin resistance syndrome* N = 354 with untreated hypertension P = 0.003 59 60 45 40 Patients (%) P = 0.04 30 19 15 10 0 Microalbuminuria* LV hypertrophy With insulin resistance syndrome* Leoncini G et al. J Intern Med. 2005;257:454-60. *Modified ATP III definition

  20. Clinical manifestations of insulin resistance • Type 2 diabetes and glycemic disorders • Dyslipidemia • – Low HDL • – Small, dense LDL • – Hypertriglyceridemia • Hypertension • Endothelial dysfunction/inflammation (hsCRP) • Impaired thrombolysis • PAI-1 Insulin resistance Glucotoxicity Lipotoxicity  Adiponectin VisceralObesity Atherosclerosis Courtesy of Selwyn AP, Weissman PN.

  21. 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

  22. Potential role of PPAR activation in CV risk reduction Geneticbackground Food intake excess Physical inactivity Obesity Hyperglycemia Hyperinsulinemia Insulin Dyslipidemia Inflammation PPAR activation Hypercoagulation Hypertension resistance Atherosclerosis Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72.

  23. The PPAR Family

  24. PPAR activation: Newest strategy in CV risk reduction Hyperinsulinemia Hyperglycemia Insulin Dyslipidemia Inflammation PPAR activation Hypercoagulation Hypertension resistance Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72.

  25. TRIPOD: Evidence that insulin resistance causes -cell failure N = 266 Hispanic women with gestational diabetes randomized to troglitazone 400 mg or placebo for median 30 months • PPAR activation: 55% relative risk reduction for new-onset diabetes (HR 0.45; 0.25–0.83) • Effect was most prominent in women with initial increase in insulin sensitivity and accompanying large reduction in insulin output • Protection persisted 8 months after cessation of active treatment • PPAR activation associated with preserved -cell function TRIPOD = Troglitazone in Prevention of Diabetes Buchanan TA et al. Diabetes. 2002;51:2796-803.

  26. DPP: Improving insulin sensitivity/secretion prevents diabetes 30 Placebo Metformin Lifestyle Insulinsecretion(IGR) 25 20 Low Medium 15 High 10 5 Insulinsecretion(IGR) 0 High Low Medium Low Medium High Low Medium High Insulin sensitivity (1/fasting insulin) N = 3234 Diabetes hazard rate (per 100 pyr) pyr = person years IGR = insulin-to-glucose ratio DPP = Diabetes Prevention Program DPP Research Group. Diabetes. 2005;54:2404-14.

  27. PPAR activation blunts progression to diabetes Diabetes Prevention Program 15 Placebo Metformin 850 mg 10 Cumulative incidence (%) Lifestyle Troglitazone400 mg* 75% vs placeboP < 0.001 5 0 0.0 0.5 1.0 1.5 Years n = 2343 1568 237 739 DPP Research Group. Diabetes. 2005;54:1150-6. *Terminated early after 1.5 years

  28. CV implications of insulin resistance and PPAR activation Hyperglycemia Hyperinsulinemia Insulin Dyslipidemia Dyslipidemia Inflammation PPAR activation Hypercoagulation Hypertension resistance Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72.

  29. Importance of LDL particle density • In insulin resistance, LDL-C levels are similar or only slightly elevated vs general population • However, atherogenicity of LDL particles varies according to density – More dense = more atherogenic • Proportion of small, dense LDL particles greater in patients with insulin resistance or diabetes vs general population Miranda PJ et al. Am Heart J. 2005;149:33-45.

  30. Greater atherogenicity of small, dense LDL vs normal LDL Susceptible to oxidation Binds to arterial wallPenetrates arterial wall Toxic to endothelial cells Promotes PAI-1 production by endothelial cellsPromotes thromboxane production by endothelial cellsAccumulates Ca2+ in vascular smooth muscle cellsBinds to LDL scavenger receptor Adapted from Sniderman AD et al. Ann Intern Med. 2001;135:447-59.

  31. CV implications of insulin resistance and PPAR activation Hyperglycemia Hyperinsulinemia Insulin Inflammation Inflammation Dyslipidemia PPAR activation Hypertension Hypercoagulation resistance Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97:167-72.

  32. Adipokines: An overview CRP IL-6 PAI-1 Angiotensinogen Leptin Resistin MCP-1 Adiponectin Antiatherogenic Atherogenic Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H2031-41. Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9.

  33. Adiponectin associated with decreased risk of MI N = 18,225 men; 6-year follow-up 1.2 1.0 0.8 Relative 0.6 risk 0.4 0.2 0.0 1 2 3 4 5 Quintile of adiponectin (95% CI) g/mL 7.9 12.6 16.5 21.1 29.2 m Adjusted relative risk (P < 0.001) Lipid-adjusted relative risk (P < 0.02) Pischon T et al. JAMA . 2004;291:1730-7.

  34. Contrasting roles of CRP and PPAR on inflammation and insulin resistance Adipose tissue IL-6 Liver CRP PPAR  Glucose Insulinresistance Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H2031-41.

  35. Direct relationship of CRP to metabolic syndrome Women’s Health Study; N = 14,719 8 6 Median CRP(mg/L) 4 2 0 0 1 2 3 4 5 Components of the metabolic syndrome (n) n = 4086 3884 3152 2292 1135 170 Ridker PM et al. Circulation. 2003;107:391-7. Modified ATP III definition

  36. PPAR activation decreases CRP in patients with diabetes N = 357; 26 weeks Rosiglitazone 4 mg Rosiglitazone 8 mg Placebo 0 –10 Mean change from baseline(%) –20 –30 –40 P < 0.05 –50 27% P < 0.05 22% Haffner SM et al. Circulation. 2002;106:679-84.

  37. Benefits of combined insulin sensitizer therapy: Effects on CRP, PAl-1, and MMP-9 Weeks 8–24 MMP-9 30 * 22.2 20 10 Baseline(%) CRP PAl-1 0 –0.56 –10 –9.8 –14.35 * –20 P = 0.046 –30 –26.9 –32.76 P = 0.026 –40 P < 0.001 Metformin 2 g (n = 70) Metformin 1 g + rosiglitazone 8 mg (n = 57) Weissman PN et al. Diabetes. 2004;53(suppl 2):A28. *NS vs baseline

  38. PPAR activation improves renal endothelial function and reduces proteinuria N = 19 with type 2 diabetes with/without microalbuminuria P < 0.05 P < 0.05 140 133 120 Treatment with rosiglitazone was followed by 60% reductions in albuminuria and proteinuria in diabetic patients with microalbuminuria. 119 120 103 100 GFR(mL/min) 80 60 40 20 0 Placebo Rosiglitazone Nateglinide Rosiglitazone Microalbuminuria No microalbuminuria Pistrosch F et al. Diabetes. 2005;54:2206-11.

  39. Thiazolidinediones in patients with type 2 diabetes and HF AHA/ADA consensus statement summary • NYHA class I/II HF: Thiazolidinediones may be used cautiously, with initiation of treatment at the lowest dose and gradual dose escalation • Allow more time than usual to achieve target A1C • NYHA class III/IV HF: Thiazolidinediones should not be used at this time Nesto RW et al. Circulation. 2003;108:2941-8.

  40. Mortality benefit with combined insulin-sensitizing therapy 8872 acute MI patients, mean age 76.4 years, discharged on glucose-lowering medication No insulin sensitizer (n = 6641)Thiazolidinediones (n = 1273) Metformin (n = 819) TZD + MET (n = 139) 1.00 0.95 Proportion of patientssurviving 0.90 48% Relativerisk reduction 0.85 0.80 0 50 100 150 200 250 300 350 Days from discharge Inzucchi SE et al. Diabetes Care. 2005;28:1680-9.

  41. PROactive: Study design Objective: Assess the effects of pioglitazone on reducing macrovascular events in type 2 diabetes Design: Randomized double-blind, controlled outcome Population: N = 5238 with type 2 diabetes and history of macrovascular disease Treatment: Pioglitazone (up to 45 mg) or placebo Primary outcome: Composite of all-cause mortality, MI, ACS, coronary or peripheral revascularization, amputation, stroke Secondary outcomes: Individual components of primary outcome, CV mortality Follow-up:4 years Charbonnel B et al. Diabetes Care. 2004;27:1647-53. Dormandy JA et al. Lancet. 2005;366:1279-89.

  42. PROactive: Baseline CV history % Dormandy JA et al. Lancet. 2005;366:1279-89.

  43. PROactive: Reduction in primary outcome All-cause mortality, MI, ACS, coronary or peripheral revascularization, amputation, stroke 25 10% Relative risk reduction HR* 0.90 (0.80–1.02)P = 0.095 Placebo(572 events) 20 Pioglitazone(514 events) 15 Proportionof events(%) 10 5 0 0 6 12 18 24 30 36 Time from randomization Number at risk Pioglitazone 2488 2373 2302 2218 2146 348 Placebo 2530 2413 2317 2215 2122 345 *Unadjusted Dormandy JA et al. Lancet. 2005;366:1279-89.

  44. HPS and CARDS: Benefits of lowering LDL-C in diabetes Event rate (%) Δ LDL-C(mg/dL)* Statin better Placebo better Statin Placebo P HPS 0.73 34.8 9.4 9.3 5.8 12.6 13.5 9.0 <0.0001 0.0003 0.001 All diabetes 0.67 34.8 Diabetes, no CVD 0.63 46.4 CARDS 0.5 0.7 0.9 1 1.7 Relative risk *Statin vs placebo HPS = Heart Protection Study CARDS = Collaborative Atorvastatin Diabetes Study HPS Collaborative Group. Lancet. 2003;361:2005-16.Colhoun HM et al. Lancet. 2004;364:685-96.

  45. ASCOT-LLA: Atorvastatin reduces CV events in patients with diabetes and hypertension N = 2532, baseline LDL-C 128 mg/dL 14.0 Placebo 12.0 23% Risk reduction P = 0.036 10.0 8.0 % 6.0 Atorvastatin 10 mg 4.0 2.0 HR = 0.77 (0.61–0.98) 0.0 Years 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Number at risk 1258 1231 1209 1191 1171 1065 699 370 Placebo 1274 1237 1219 1200 1175 1058 714 375 Atorvastatin Nonfatal MI, CV mortality, UA, stable angina, arrhythmias, stroke, TIA, PAD, retinal vascular thrombosis, revascularization ASCOT-LLA = Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm Sever PS et al. Diabetes Care. 2005;28:1151-7.

  46. Steno-2 supports aggressive multifactorial intervention in type 2 diabetes Objective: Target-driven, long-term, intensified intervention aimed at multiple risk factors compared with conventional therapy Design: N = 160 patients with type 2 diabetes and microalbuminuria Intensive treatment targets: BP <130/80 mm Hg A1C<6.5% Total-C <175 mg/dL Triglycerides <150 mg/dL Gæde P et al. N Engl J Med. 2003;348:383-93.

  47. 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.

  48. 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.

  49. ABCs of coronary prevention Adapted from Cohen JD. Lancet. 2001;357:972-3.

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