1. Targeting Insulin Resistance for Vascular Protection

2. Contents I.Vascular Consequences of Diabetes and Insulin Resistance II.CV Risk Reduction, Diabetes Prevention, and TZDs III.Clinical Imperatives When Treating Patients with Diabetes

3. Vascular Consequences of Diabetes and Insulin Resistance

4. One third of adults with diabetes are undiagnosed ~10% of US adults have diabetes/~20 million persons in 2005 Nearly one third don’t know they have diabetes 26% of US adults have impaired fasting glucose (IFG)* *100–125 mg/dL Cowie CC et al. Diabetes Care. 2006;29:1263-8. NIDDK. National Diabetes Statistics. www.diabetes.niddk.nih.gov. Total: 35% of US adults with diabetes or IFG ~73.3 million persons

5. Rising prevalence of diabetes Steinbrook R. N Engl J Med. 2006;354:545-8. Diagnosed diabetes in US, 1980–2004 Persons with diagnosed diabetes (millions) 15 10 5 0 1980198419881992199620002004 Year

6. CDC. www.cdc.gov. Parallel epidemics of diabetes and obesity Diabetes Obesity (BMI ≥30 kg/m 2 ) <4%4%–4.9%5%–5.9%>6% 10%–14%15%–19%20%– 24%>25% 20041994

7. 90% of patients with newly diagnosed diabetes are overweight or obese Geiss LS et al. Am J Prev Med. 2006;30:371-7. Obese (BMI ≥30) Overweight (BMI 25 to <30) Diabetes patients with BMI ≥25 kg/m 2 (%) National Health Interview Survey, 2003; N ≈ 31,000 aged 18 to 79 years 90%

8. IFG/IGT: Challenge for prevention US population (millions) NIDDK. National Diabetes Statistics. www.diabetes.niddk.nih.gov. ADA. Diabetes Care. 2006;29(suppl I):S4-48. Ages 40 to 74 years; US population estimates 2000 IGT = impaired glucose tolerance OGTT = oral glucose tolerance test Fasting plasma glucose (FPG) 100–125 mg/dL and/or 2-hr OGTT 140–199 mg/dL

9. “Ticking clock” hypothesis: Glucose abnormalities increase CV risk Nurses’ Health Study, N = 117,629 women, aged 30–55 years; follow-up 20 years (1976–1996) Hu FB et al. Diabetes Care. 2002;25:1129-34. Relative risk of MI or stroke* No diabetesBefore diabetes diagnosis After diabetes diagnosis Diabetes at baseline *Adjusted n = 1508 diabetes at baseline n = 5894 new-onset diabetes

10. DECODE: IGT increases mortality risk Diagnosed diabetes (n = 1275) Undiagnosed diabetes (n = 3071) Impaired glucose tolerance (n = 2766)* Normal glucose tolerance (n = 18,252)* Follow-up (years) Mortality hazard (%) DECODE Study Group. Lancet. 1999;354:617-21. *2-hour OGTT Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe N = 25,364 aged ≥30 years 20 10 0 02468

11. CHD risk appears to begin at low blood glucose levels N = 17,869 men, aged 40–64 years; follow-up 33 years Brunner EJ et al. Diabetes Care. 2006;29:26-31. *Relative to baseline group of all men with blood glucose <83 mg/dL 83 mg/dL OGTT blood glucose (mg/dL) 5472108 90126144162180 1.6 1.2 0.8 0.4 0.0 -0.4 CHD mortality (log hazard ratios)*

12. Continuum of CV risk: Reason for early intervention in patients with IFG/IGT Cardiovascular Health Study; N = 4014, age ≥65 years Smith NL et al. Arch Intern Med. 2002;162:209-16. CV events (hazard ratio*) ↑42% ↑36% ↑17% ↑54% ↑90% *Adjusted for age, sex, and race † Reference 1.6 1.4 1.2 1 0 2 1.6 1.2 1 0 1.8 1.4 † † ≤9293–9798–103104–111≥112≤103104–124125–146147–181≥182 FG (mg/dL)2-h glucose (mg/dL)

13. Even mild glucose elevations increase mortality in patients undergoing PCI Muhlestein JB et al. Am Heart J. 2003;146:351-8. N = 1612 with CAD; mean age 62 years Mortality (%) P-trend < 0.001 FG (mg/dL)<110110–125≥126 NFG = normal FG Undx DM2 = undiagnosed type 2 diabetes

14. IGT and undiagnosed DM2 are common in acute MI and stroke Norhammar A et al. Lancet. 2002;359:2140-4. Matz K et al. Diabetes Care. 2006;792-7. 2-hour OGTT 66 39 (n = 181)(n = 238) Myocardial infarctionStroke IGTUndiagnosed DM2

15. Risk of endothelial dysfunction increases at FG 110–125 mg/dL N = 579 without diabetes or prior CV disease Rodriguez CJ et al. Am J Cardiol. 2005;96:1273-7. *Unadjusted FMD = flow-mediated dilation % FG (mg/dL) <90 0 2 4 6 8 90–99 100–109110–125 P < 0.05 100 10 1 0 90–99100–109110–125 Odds ratio (95% Cl)* FG (mg/dL) (Referent = FG <90 mg/dL) FMD changeEndothelial dysfunction

16. Impaired macrovascular reactivity in people at risk for type 2 diabetes Caballero AE et al. Diabetes. 1999;48:1856-62. *vs relatives, IGT, diabetes Increase from baseline after cuff occlusion (%) 13.7 10.5 9.8 8.4 P < 0.01*

17. Insulin resistance: Risk factor for CV disease Kim J-a et al. Circulation. 2006;113:1888-904. Ridker P, Libby PJ. In Braunwald’s Heart Disease. 7th ed. Important feature of diabetes, obesity, glucose intolerance, and dyslipidemia Key component of CV disorders: hypertension, CAD, and atherosclerosis Independent risk factor for atherosclerosis Insulin resistance promotes atherosclerosis even before it produces diabetes

18. Insulin resistance and atherosclerosis Insulin resistance Genetic factors Acquired conditions Vasoconstriction INFLAMMATION Thrombosis ACCELERATED ATHEROSCLEROSIS Kim J-a et al. Circulation. 2006;113:1888-904.

19. Who has insulin resistance? DM2 1 HTN 3 Stroke 4 CHD 5 Refer to cardiol. 6 Age 40 to 74 7 1 Haffner et al. Diabetes. 1997. 2 McLaughlin et al. Am J Cardiol. 2005. 3 Reaven et al. N Engl J Med. 1996. 4 NIH. www.clinicaltrials.gov. 5 Lankisch et al. Clin Res Cardiol. 2006. 6 Savage et al. Am Heart J. 2005. 7 www.diabetes.niddk.nih.gov/. % Patients ↓HDL + ↑TG 2

20. IIIIIIIV Insulin resistance is an independent predictor of HF N = 1187 men, aged ≥70 years; follow-up 8.9 years Ingelsson E et al. JAMA. 2005;294:334-41. Inverse relationship between HF incidence and insulin sensitivity HF incidence/ 1000 person-years at risk* *Adjusted for HF risk factors † Quartiles of clamp glucose disposal rate (mg/kg body weight per min) Insulin resistance quartiles † 25 20 15 10 0 5

21. Insulin resistance increases risk of chronic kidney disease (CKD) N = 6453 without diabetes Odds ratio (highest vs lowest quartiles*) Chen J et al. J Am Soc Nephrol. 2003;14:469-77. *Multivariate adjusted CKD = GFR <60 mL/min per 1.73 m 2 HOMA-IR = Homeostasis model assessment of insulin resistance P = 0.001 P = 0.008

22. Development of insulin resistance in obesity- induced inflammation and stress Adapted from de Luca C, Olefsky JM. Nat Med. 2006;12:41-2. Macrophage Endocrine inflammatory signals Paracrine and autocrine inflammatory signals Fat insulin resistance Muscle insulin resistance Liver insulin resistance Systemic insulin resistance Overnutrition and genetics Dyslipidemia, hypertension, hyperglycemia Accelerated atherosclerosis

23. Visceral obesity CT scans from men matched for BMI and total body fat White = visceral fat area (VFA); black = subcutaneous fat Després J-P. Eur Heart J Suppl. 2006;8(suppl B):B4-12. Subcutaneous obesity Fat mass: 19.8 kg VFA: 96 cm 2 Visceral obesity Fat mass: 19.8 kg VFA: 155 cm 2 Visceral obesity drives CV risk progression independent of BMI

24. Visceral fat independently predicts mortality N = 291 men, mortality follow-up 2.2 years Kuk JL et al. Obesity. 2006;14:336-41. *Adjusted for age, follow-up time, and other fat measures Subcutaneous fat mass Visceral fat mass P 0.04 0.98 Mortality odds ratio (95% CI)* Waist circumference0.26 Liver fat 0.60 (0.25 – 1.44) 0.87 (0.56 – 1.37)0.55 0.99 (0.63 – 1.58) 1.81 (1.04–3.14)

25. CRP levels show positive correlation with visceral obesity P < 0.0001 vs * quintile 1; † quintile 2; ‡ quintile 3 Lemieux I et al. Arterioscler Thromb Vasc Biol. 2001;21:961-7. Després J-P. Eur Heart J Suppl. 2006;8(suppl B):B4-12. N = 159 men, mean age 43 yr; BMI 21.0–41.0 kg/m 2 Visceral fat areaWaist circumference CRP quintiles * * * * * * * * ‡ ‡ † † ‡ cm 2 cm 90 95 100 105 110

26. Shared CV risk between insulin resistance and visceral obesity Hypertension ↑SBP/DBP Absent nocturnal BP dipping Altered hemostasis ↑Fibrinogen ↑PAI-1 ↑Blood viscosity Renal changes Microalbuminuria ↑Uric acid Inflammation ↑CRP + other markers Endothelial dysfunction Insulin resistance and visceral obesity McFarlane SI et al. J Clin Endocrinol Metab. 2001;86:713-8. Dyslipidemia ↓HDL-C ↑Apo B Small dense LDL ↑TG

27. Metabolically active molecules link obesity and atherosclerosis CRP IL-6 PAI-1 Angiotensinogen Leptin Resistin MCP-1 TNFα Adiponectin 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. AtherogenicAntiatherogenic Adipocytokines (adipokines)

28. Antiatherogenic effects of adiponectin ↑ Endothelial vasodilation ↑ Nitric oxide ↑ Angiogenesis ↓ VCAM-1 ↓ TNF  level and proinflammatory effects ↓ Oxidized LDL effects on EC ↓ EC proliferation/migration ↓ Growth factor effects on SMC ↓ Neointimal thickening ↓ SMC proliferation EC = endothelial cells SMC = smooth muscle cells VCAM = vascular cell adhesion molecule Goldstein BJ, Scalia R. J Clin Endocrinol Metab. 2004;89:2563-8.

29. Visceral obesity and adiponectin Manigrasso MR et al. J Clin Endocrinol Metab. 2005;90:5876-9. Plasma adiponectin (µg/mL) 30 25 20 15 10 5 0 Non-obese Android (visceral) Obesity* status Gynoid (nonvisceral) P < 0.0001 P < 0.01 N = 104 women; 12-week follow-up Median *BMI > 28 kg/m 2

30. Inverse relationship between baseline adiponectin level and MI risk Pischon T et al. JAMA. 2004;291:1730-7. Multivariate adjusted (P Trend < 0.001)Multivariate + lipid adjusted (P Trend = 0.02) n = 798, case-control study; follow-up 6 years* IIIIIIIVV 0 0.2 0.4 0.6 0.8 1.0 1.2 Quintile of adiponectin 7.912.616.521.129.2 Median adiponectin (mg/L) Relative risk of MI (95% CI) *Health Professionals Follow-up Study

31. Shared metabolic abnormalities with insulin resistance and endothelial dysfunction GlucotoxicityLipotoxicityInflammation Insulin resistance Endothelial dysfunction Adapted from Kim J-a et al. Circulation. 2006;13:1888-904. Oxidative stress AGE formation Pro-inflammatory signaling Oxidative stress Pro-inflammatory signaling Pro-inflammatory factors Kinases/transcription factors AGE = advanced glycation end product

32. PPAR activation and atherosclerosis: A hypothesis Plutzky J. Science. 2003;302:406-7. Blunts atherosclerosis Indirect Fat, liver, skeletal muscle cells Ligand: Endogenous or synthetic Activated PPAR Reduces inflammation Direct Vascular and inflammatory cells  FFA  Glucose  Insulin sensitivity  Triglycerides  HDL  Atherogenic LDL  Cytokines  Chemokines  Cholesterol efflux  Adhesion molecules –– ––

33. Peroxisome proliferator-activator receptors (PPARs) PPAR , , and  belong to the nuclear hormone receptor superfamily PPAR agonists appear to play a critical role in regulating inflammation, lipoprotein metabolism, and glucose homeostasis Studies suggest that PPAR agonists exert antiatherogenic effects by inhibiting proinflammatory gene expression and enhancing cholesterol efflux PPAR agonists have potential in the treatment of obesity, diabetes, and atherosclerosis Li AC et al. J Clin Invest. 2004;114:1564-76. Blaschke F et al. Arterioscler Thromb Vasc Biol. 2006;26:28-40.

34. PPARs: Overview PPAR receptorMain tissue locationRegulates Alpha  Liver, skeletal muscle, heart, kidney Lipid metabolism (dyslipidemia) Inflammation/atherosclerosis Gamma  Fat cells, macrophagesInsulin sensitivity/glucose metabolism Inflammation/atherosclerosis Adipocyte differentiation Delta  Widespread, including skeletal muscle and fat cells Fatty acid oxidation Inflammation Blaschke F et al. Arterioscler Thromb Vasc Biol. 2006;26:28-40. Semple RK et al. J Clin Invest. 2006;116:581-9.

35. Beyond fat and glucose: Potential for CV benefits with PPAR  agonists PPAR  is expressed in cell types associated with CV disease –Vascular endothelial cells (EC) –Vascular smooth muscle cells (VSMC) –T-lymphocytes –Monocyte/macrophages –Cardiac myocytes –Renal tubule cells Monocytes Necrotic core Lumen VSMC Adapted from Marx N et al. Arterioscler Thromb Vasc Biol. 1999;19:546-51. Lumen EC

36. Obesity induces inflammatory changes in adipose tissue Wellen KE, Hotamisligil GS. J Clin Invest. 2003;112:1785-8.

37. Macrophage and adipocyte similarities Adipocyte Energy/lipids Inflammation Macrophage Inflammation Lipid storage Insulin resistance PPAR  and LXR oppose these actions in both macrophages and adipocytes Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115:1111-9. LXR = liver X receptor

38. Castrillo A, Tontonoz P. J Clin Invest. 2004;114:1538-40. PPAR signaling pathways influence macrophage gene expression and foam-cell formation Atherogenic inflammation PPAR  PPAR  PPAR  /  ABCG1 ABCA1 Cholesterol efflux  HDL acceptor Cholesterol efflux  ApoA1 acceptor ApoE, PLTP Atherosclerotic blood vessel Macrophage LXRα = liver X receptor α PLTP = phospholipid transfer protein LXR  ?

39. Campia U et al. Circulation. 2006;113:867-75. N = 80 with hypertension or hypercholesterolemia and no diabetes; change after 16 weeks PPAR  agonists improve endothelial vasodilation and decrease inflammation Pioglitazone 45 mg/d Placebo 100 200 400 600 500 400 300 0 Forearm blood flow (%  from baseline) Bradykinin (ng/min) All subjects Insulin resistant Insulin sensitive CRP (mg/L) 7 5 3 1 0 6 4 2 P = 0.0001 P = 0.38 P = 0.0008 P = 0.01 0

40. PPAR  agonists impact inflammatory markers and adiponectin N = 54 adults with metabolic syndrome and no diabetes; change after 12 weeks Samaha FF et al. Arterioscler Thromb Vasc Biol. 2006;26:624-30. *P = 0.002; † P = 0.027; ‡ P < 0.001 Change from baseline (%) * † ‡ PlaceboRosiglitazone 8 mg/d IL-6CRPAdiponectin

41. Added benefit of BP reduction with PPAR  agonists N = 87 with diabetes; PPAR  agonist added to glimepiride 4 mg/d; change after 12 months *P < 0.05 vs baseline Derosa G et al. Hypertens Res. 2005;28:917-24. Change in BP (mm Hg) SystolicDiastolic * * * * Pioglitazone 15 mg/dRosiglitazone 4 mg/d

42. PPAR  agonists increase collagen content – potentially improving plaque stability Meisner F et al. Arterioscler Thromb Vasc Biol. 2006;26:845-50. N = 24 without diabetes; change after 4 weeks in carotid endarterectomy samples P = 0.04 PlaceboRosiglitazone 8 mg/d

43. Potential vascular benefits of PPAR activation PPAR agonists  Thrombosis  Plaque stability  Cell recruitment and activation  Inflammatory response  Vasoconstriction  Cell migration  Foam cell formation  Cholesterol efflux  Atherogenesis Cariou B et al. Br J Diabetes Vasc Dis. 2005;5:126-32. Improved substrate metabolism