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Global Distribution of Diabetes, WHO 2011

Metabolic Syndrome, Diabetes and Cardiovascular Disease: Strategies for Management Nathan D. Wong, PhD, FACC, FAHA Professor and Director, Heart Disease Prevention Program, Division of Cardiology, University of California, Irvine Past President, American Society of Preventive Cardiology.

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Global Distribution of Diabetes, WHO 2011

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  1. Metabolic Syndrome, Diabetes and Cardiovascular Disease: Strategies for ManagementNathan D. Wong, PhD, FACC, FAHAProfessor and Director, Heart Disease Prevention Program, Division of Cardiology, University of California, IrvinePast President, American Society of Preventive Cardiology

  2. Global Distribution of Diabetes, WHO 2011

  3. Diabetes: A Growing ChallengePrevalence in the United States Diagnosed Diabetes % of Population # of Patients in Millions Centers for Disease Control and Prevention, Division of Diabetes Translation. National Diabetes Surveillance System. Available at http://www.cdc.gov/diabetes/statistics.

  4. Age-Adjusted Prevalence of Type 2 DM: California Adults Aged >18 Including Hispanic and Asian Subgroups 2009 N.D. Wong, California Health Interview Survey (unpublished)

  5. Diabetes Mellitus: Lifetime Risk Narayan et al. JAMA 2003;290:1884-1890.

  6. Postprandial glucose Natural History of Type II Diabetes Mellitus Years from diagnosis 0 10 5 15 -10 -5 Onset Diagnosis Insulin resistance Insulin secretion Fasting glucose Microvascular complications Macrovascular complications Pre-diabetes Type II diabetes Ramlo-Halsted BA et al. Prim Care. 1999;26:771-789 Nathan DM et al. NEJM 2002;347:1342-1349

  7. Diagnostic Criteria for Glycemic Abnormalities FPG 2-Hour PG on OGTT Hemoglobin A1C Diabetes Mellitus Diabetes Mellitus Diabetes Mellitus 126 mg/dL 200 mg/dL 6.5% 7.0 mmol/L 11.1 mmol/L Impaired Glucose Tolerance Prediabetes Prediabetes 100 mg/dL 5.6 mmol/L 140 mg/dL 6.0% 7.8 mmol/L Normal Normal Normal To convert mg/dL to mmol/L multiply mg/dl by 0.055 FPG=Fasting plasma glucose, PG=Plasma glucose, OGTT=Oral glucose tolerance test The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2001;24:S5-S20 American Diabetes Association. Diabetes Care 2010;33:S11-61

  8. Causes of Mortality in Patients With Diabetes

  9. Diabetes and CVD • Atherosclerotic complications responsible for • 80% of mortality among patients with diabetes • 75% of cases due to coronary artery disease (CAD) • Results in >75% of all hospitalizations for diabetic complications • 50% of patients with type 2 diabetes have preexisting CAD. (This number may be less now that more younger people are diagnosed with diabetes.)  • 1/3 of patients presenting with myocardial infarction have undiagnosed diabetes mellitus Lewis GF. Can J Cardiol. 1995;11(suppl C):24C-28C Norhammar A, et.al. Lancet 2002;359;2140-2144

  10. Most Cardiovascular Patients Have Abnormal Glucose Metabolism GAMI n = 164 EHS n = 1920 CHS n = 2263 18% 27% 31% 35% 37% 37% 36% 45% 34% Prediabetes Type 2 Diabetes Normoglycemia GAMI = Glucose Tolerance in Patients with Acute Myocardial Infarction study; EHS = Euro Heart Survey; CHS = China Heart Survey Anselmino M, et al. Rev Cardiovasc Med. 2008;9:29-38.

  11. Mechanisms by which Diabetes Mellitus Leads to Coronary Heart Disease Insulin Resistance Dyslipidemia HTN Endothelial dysfunction  LDL  TG  HDL Thrombosis  PAI-1  TF  tPA Disease Progression Hyperglycemia Inflammation  AGE  Oxidative stress  IL-6  CRP  SAA Infection  Defensemechanisms  Pathogen burden Subclinical Atherosclerosis Atherosclerotic Clinical Events AGE=Advanced glycation end products, CRP=C-reactive protein, CHD=Coronary heart disease HDL=High-density lipoprotein, HTN=Hypertension, IL-6=Interleukin-6, LDL=Low-density lipoprotein, PAI-1=Plasminogen activator inhibitor-1, SAA=Serum amyloid A protein, TF=Tissue factor, TG=Triglycerides, tPA=Tissue plasminogen activator Biondi-Zoccai GGL et al. JACC 2003;41:1071-1077.

  12. Risk of Cardiovascular Events in Patients withDiabetes: Framingham Study _________________________________________________________________ _________________________________________________________________ Age-adjusted Biennial Rate Age-adjusted Per 1000Risk Ratio Cardiovascular EventMen WomenMen Women Coronary Disease 39 21 1.5** 2.2*** Stroke 15 6 2.9*** 2.6*** Peripheral Artery Dis. 18 18 3.4*** 6.4*** Cardiac Failure 23 21 4.4*** 7.8*** All CVD Events 76 65 2.2*** 3.7*** Subjects 35-64 36-year Follow-up **P<.001,***P<.0001

  13. Cardiovascular Risk Factors are the Top 6 Leading Causes of Death

  14. Metabolic Syndrome: Clustering of Interconnected Metabolic Risk Factors Obesity Insulin Resistance + Hyperglycemia Hypertension Atherogenic Dyslipidemia

  15. IDF/IAS/NHLBI/AHA/WHF Joint Scientific Statement on Diagnosis of Metabolic Syndrome (Alberti et al. Circulation 2009) (>=3 criteria required for diagnosis)

  16. Alberti et al. Circulation 2009

  17. Intra-abdominal (Visceral) FatThe dangerous inner fat! Front Visceral AT Subcutaneous AT Back

  18. Abdominal Adiposity Is Associated With Increased Risk of Diabetes P value for trend <0.001 Relative Risk of Diabetes Waist Circumference (in) Carey VJ, et al. Am J Epidemiol. 1997;145:614-619

  19. Metabolic Syndrome and Diabetes in Relation to CHD, CVD, and Total Mortality: U.S. Men and Women Ages 30-74 (Risk-factor Adjusted Cox Regression) NHANES II Follow-up (n=6255) *** *** *** *** *** *** *** *** * ** *** *** Malik and Wong, et al., Circulation 2004. * p<.05, ** p<.01, **** p<.0001 compared to none

  20. Metabolic Syndrome and CVD Risk: Meta-Analysis: Mottillo et al. JACC 2010 • 951,083 pts in 83 studies • Little variation in risk between definitions • Relative risk: • 2.35 (2.20-2.73) for CVD events • 2.40 (1.87-3.08) for CVD mortality • 1.58 (1.39-1.78) for all-cause mortality • 1.99 (1.61-2.46) for myocardial infarction • 2.27 (1.80-2.85) for stroke Those with metabolic syndrome, without diabetes, maintained high CVD risk (RR=1.75, 95% CI=1.19-2.58)

  21. Type 2 Diabetes and CHD 7-Year Incidence of Fatal/Nonfatal MI (East West Study) P<0.001 P<0.001 45.0% 20.2% 18.8% 7-Year Incidence Rate of MI 3.5% No Diabetes Diabetes CHD=coronary heart disease; MI=myocardial infarction; DM=diabetes mellitus Haffner SM et al. N Engl J Med. 1998;339:229-234.

  22. Is DM really a CHD Risk Equivalent? Meta-Analysis of 38,578 subjects (Bulugahapitiya et al. Diabetic Med 2008) DM without prior MI has a 43% lower risk of developing total CHD events compared to those without DM with prior MI, suggesting DM is not a coronary risk equivalent.

  23. 32% of men and 48% of women are at calculated low to intermediate risk Global Risk Assessment in DM: US adults 2003-2006 10-year Total CVD Risk by Gender(Wong ND et al., Diab Vas Dis Res 2012)

  24. 2013 Prevention Guidelines ASCVD Risk Estimator Available at www.cardiosource.com

  25. Screening for Coronary Disease in Diabetes: When and How (Ali and Maron, Clinical Diabetes 2006) “ Screening patients according to traditional risk factors and current guidelines alone will frequently fail to identify CHD, thus losing the opportunity for early diagnosis and intensified management” “A more aggressive approach to identifying asymptomatic coronary disease should therefore be considered in this (diabetic) patient population”

  26. Annual CHD Event Rates (in %) by Calcium Score Events by CAC Categories in Subjects with DM, MetS, or Neither Disease(Malik and Wong et al., Diabetes Care 2011) Coronary Heart Disease Coronary Artery Calcium Score ACCF/AHA 2010 Guideline: CAC Scoring for CV risk assessment in asymptomatic adults aged 40 and over with diabetes (Class IIa-B)

  27. DIAD Randomized Clinical Trial of Stress MPI Screening (Young, Inzucchi et al. JAMA 2009) • Randomized NIH multicenter trial examining whether screening for myocardial ischemia using adenosine-stress MPI in 1123 persons with type 2 DM and no symptoms of CAD. • Only 22% were positive for myocardial ischemia with only 6% have moderate or large defects • 5-year 2.9% cumulative event rate (0.6% per year), much lower than expected Event rates similar in those screening (2.7%) vs. not screened (3.0%) (p=0.73) (authors note the study only had 20% power to detect a 20% difference between groups)

  28. The authors conclude that screening for inducible ischemia in asymptomatic patients with T2DM cannot be advocated for 4 reasons: • The yield of significant inducible ischemia is very low • Overall cardiac event rates are low • Routine screening does not appear to affect overall outcome • Routine screening would be prohibitively expensive • The much lower than expected event rates makes the study inconclusive in demonstrating the lack of efficacy of screening for subclinical CVD DIAD Study (continued)

  29. But should we be using stress MPI to screen for CVD in all pts with DM? • Stress MPI is meant to identify short-term risk due to functional deficit, rather than long-term prognosis such as that identified by a test to quantify atherosclerotic burden such as coronary calcium • The radiation and costs are much higher for MPI as compared to coronary calcium, suggesting MPI might be best reserved for those DM at highest risk

  30. ADA 2007 Consensus Statement (Bax et al. Diab Care 2007) “If coronary calcium testing is performed, it appears reasonable to proceed with further testing in diabetic patients with calcium scores >400…….using single photon emission tomography to assess myocardial perfusion or stress echocardiography to assess ischemic wall motion abnormalities”

  31. Prevalence of Inducible Ischemia Associated with Presence of Metabolic Abnormality and Coronary Calcium Score (Wong et al., Diabetes Care 2005; 28: 1445-50 ) P=0.032 P=0.018 P<0.0001 for trend across CCS groups for both metabolic abnormality present and absent; similar relation for those with metabolic syndrome excluding diabetes ACCF/AHA 2010 Guideline: Stress MPI may be considered for advanced CV risk assessment in asymptomatic adults with diabetes or when previous risk assessment testing suggests a high risk of CHD, such as a CAC score of 400 or greater (Class IIb – Level of Evidence C)

  32. Does Screening for CVD Improve Outcomes?Beneficial Role of Coronary Multidetector CT Screening for 5-Year All-Cause Mortality among Asymptomatic DM Patients (H Kyung Yang et al., ADA 2014) • Asymptomatic T2DM subjects • 774 received coronary MDCT and 1548 matched controls did not get screened • Groups similar except longer duration DM and higher A1c in screened group • After 31 month median follow-up, greater lipid decreases and statin prescription in screened group • Coronary angiography and revascularization higher in MDCT group

  33. Beneficial Role of Coronary Multidetector CT Screening for 5-Year All-Cause Mortality among Asymptomatic DM Patients (Yang et al., ADA 2014) All cause mortality at 5 years lower in the MDCT (4.5%) vs. non-MDCT (6.8%) group, p=0.02 Authors conclude “MDCT may play a beneficial role as a screening test to detect advanced macrovascular complications in asymptomatic T2DM patients and to increase survival rate”

  34. Coronary Artery Calcium and Cardiovascular Events in Diabetes: Implications for Primary Prevention Therapies:The Multi-Ethnic Study of Atherosclerosis (MESA) Michael G. Silverman1, Michael J. Blaha1, Matthew J. Budoff2, Ron Blankstein3, Roger S. Blumenthal1, Harlan Krumholz4, Juan J. Rivera5, Arthur Agatston6, Nathan D. Wong7, Steven Shea8, John McEvoy1, Khurram Nasir1, 6 1 Johns Hopkins Ciccarone Center for Prevention of Heart Disease, Baltimore, MD 2 Division of Cardiology, Harbor-UCLA Medical Center, Torrance, CA 3 Brigham and Women's Hospital Non-invasive CV Imaging Program, Boston, MA 4 Yale University School of Medicine, New Haven, CT 5 Division of Cardiology, University of Miami, Miami, FL 6 Center for Prevention and Wellness, Baptist Health South Florida, Miami, FL 7 UC Irvine Heart Disease Prevention Program, Irvine, CA 8 College of Physicians and Surgeons, Columbia University, New York, NY Presented at AHA 2012 Presented by: Michael Silverman

  35. Estimated 5 year NNT with Statin NNT calculated using 21% RR reduction Chen Y-H, Feng R, Chen Z-W. Exp Clin End Diab 2012; 120: 116-120. Cholesterol Treatment Trialists’ Collaboration, Lancet 2008; 371: 117-25

  36. Summary of Care: ABC's for Providers

  37. Treating the ABCs Reduces Diabetic Complications 1 UKPDS Study Group (UKPDS 33). Lancet. 1998;352:837-853. 2 Hansson L, et al. Lancet. 1998;351:1755-1762. 3 UKPDS Study Group (UKPDS 38). BMJ. 1998;317:703-713. 4 Grover SA, et al. Circulation. 2000;102:722-727. 5 Pyŏrälä K, et al. Diabetes Care. 1997;20:614-620.

  38. Benefit of Comprehensive, Intensive Management: STENO 2 Study Treatment Goals: Intensive TLC HgbA1c <6.5% Cholesterol <175 Triglycerides <150 BP <130/80 Primary End Point=CV events (%) 60 Conventional Therapy 50 n =80 Intensive Therapy 40 30 20 n =80 10 0 12 24 36 48 60 72 84 96 0 Months of Follow Up Gaede, P. et al, NEJM 2003;348:390-393

  39. Percent of CHD Events Over 10 Years Prevented in US Adults with T2DM, According to Individual and Composite Risk Factor Control (Wong ND, et al., Am J Cardiol 2014)

  40. Achieving Risk Factor Targets and CVD Event Risk in Diabetes (Wong et al. ADA 2014) • Potential effects of multifactorial risk factor control are not well-quantitated. • We examined if being at target for LDL-C, HbA1c, and BP, individually and together, is associated with lower CHD/CVD rates. • 2,160 multiethnic adults with DM without prior CVD from the ARIC, Jackson, and MESA prospective studies followed for 11 years. • We examined event risk in those at target for LDL-C (<100 mg/dl), HbA1c (<7%), and blood pressure (BP) (<130/80 mmHg) according to American Diabetes Association guidelines. • Overall, 39.0%, 42.8%, 30.5%, and 6.8% of subjects were at target for LDL-C, HbA1c, and BP, and all three factors • Being at composite target (vs one or more factors not at target) was associated with a significantly reduced risk of CHD (HR=0.46, 95% CI = 0.25-0.87) and CVD (HR=0.66, 95% CI=0.45-0.98) events. • Optimal levels of lipids, blood pressure, and glucose control together are uncommon in persons with DM, but are associated with substantially lower CHD and CVD risks.

  41. Control of DM Risk Factors in a Large Multipayer Outpatient Population in Northern California (n=15,826) (Holland et al., J Diab Complic 2013) Individual control of HbA1c, BP, and LDL ranged from 42-78% in Asians Composite control of HbA1c, BP, and LDL ranged from 21-27% in Asians

  42. Diabetes Mellitus: Effect of Aspirin n= 533 3711 4502 2368 1031 1276 2539 Endpoint 5 yr MI 7 yr MI 1 yr MCE 5 yr CV Death 4 yr MCE 7yr MCE 4 yr MCE # Events 26 vs 11 283 vs 241 502 vs 415 183 vs 133 20 vs 22 117 vs 116 86 vs 68 p<0.002 p=NS p < 0.001 p=.04 p<0.05 p=NS p=NS NS=Not Significant 1. Steering Committee of the Physicians' Health Study Research Group. NEJM 1989;321:129-35 2. ETDRS Investigators. JAMA 1992;268:1292 3. Antiplatelet Trialists' Collaboration. BMJ 1994; 308:81 4. Harpaz D et al. Am J Med 1998;105:494 3. Sacco M et al. Diabetes Care 2003;26:3264 4. Belch J et al. BMJ 2008; 337:a1840 5. Ogawa H et al. JAMA 2008; 300: 2134

  43. Recommendations:Antiplatelet Agents (1) • Consider aspirin therapy (75–162 mg/day) (C) • As a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%) • Includes most men >50 years of age or women >60 years of age who have at least one additional major risk factor • Family history of CVD • Hypertension • Smoking • Dyslipidemia • Albuminuria ADA. VI. Prevention, Management of Complications. Diabetes Care 2013;36(suppl 1):S32-S33.

  44. Recommendations:Antiplatelet Agents (2) • Aspirin should not be recommended for CVD prevention for adults with diabetes at low CVD risk, since potential adverse effects from bleeding likely offset potential benefits (C) • 10-year CVD risk <5%: men <50 and women <60 years of age with no major additional CVD risk factors • In patients in these age groups with multiple other risk factors (10-year risk5–10%), clinical judgment is required (E) ADA. VI. Prevention, Management of Complications. Diabetes Care 2013;36(suppl 1):S33.

  45. Recommendations:Antiplatelet Agents (3) • Use aspirin therapy (75–162 mg/day) • Secondary prevention strategy in those with diabetes with a history of CVD (A) • For patients with CVD and documented aspirin allergy • Clopidogrel (75 mg/day) should be used (B) • Combination therapy with aspirin (75–162 mg/day) and clopidogrel (75 mg/day) • Reasonable for up to a year after an acute coronary syndrome (B) ADA. VI. Prevention, Management of Complications. Diabetes Care 2013;36(suppl 1):S33-S34.

  46. Diabetes Mellitus (Type II): Effect of Intensive Glycemic Control United Kingdom Prospective Diabetes Study (UKPDS) 10-Year Follow-Up Sulphonylurea vs. Conventional Therapy Insulin vs. Conventional Therapy Intensive glycemic control in DM reduces the long-term risk of myocardial infarction Holman RR et al. NEJM 2008;359:1577-89

  47. Glycemic Legacy? N Engl J Med 2008;359:1577-89.

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