Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician Risk for atherosclerosis is 2 4 times greater in patients with diabetes CVD accounts for 65% of diabetic mortality >5% of patients with newly diagnosed type 2 diabetes already have CHD Accelerated atherosclerosis begins years prior to the diagnosis of diabetes Seven-Year Incidence of Fatal/Nonfatal MI 7-Year Incidence Rate of Myocardial Infarction 5 45 4 35 3 25 2 15 1 5 No diabetes Diabetes 45% P<.1 P<.1 18.8% 2.2% 3.5% n=134 n=69 n=89 n=169 No DM, No MI No DM, MI DM, No MI DM, MI DM=diabetes mellitus; MI=myocardial infarction Haffner SE et al. N Engl J Med. 1998;339:229-234. Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 1
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician 1. NIH-ONSET STUDY Proportion Alive following Acute MI.8.6.4.2 No diabetes No diabetes with prior MI Diabetes Diabetes with prior MI With diabetes=1536 Without diabetes=399. 1 2 3 Years 4 5 6 Mukamal KJ et al. Diabetes Care. 21;24:1422-1427. Dyslipidemia Hypertension Nephropathy Obesity / sedentary lifestyle Altered coagulation, platelet function, and fibrinolysis Hyperinsulinemia / hyperproinsulinemia / insulin resistance Cigarette smoking Hyperglycemia Results from the Multiple Risk Factor Intervention Trial (MRFIT) Adjusted CV Death Rate per 1, Person-Years 14 12 1 8 6 4 2 No diabetes Diabetes 1 2 All 3 Number of Risk Factors Stamler J et al. Diabetes Care. 1993;16:434-444. Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 2
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician Coronary Artery Disease (n=28) Position in Model First Second Third Fourth Fifth Variable Low-density lipoprotein cholesterol High-density lipoprotein cholesterol Hemoglobin A1C Systolic blood pressure Smoking P Value <.1.1.22.65.56 *Adjusted for age and sex. Turner RC et al. BMJ. 1998;316:823-828. Serum Concentration (mg/dl) 3 25 2 15 1 5 216 215 NHANES III N = 2844 Diabetes No Diabetes 131 137 143 51 41 245 Total-C LDL-C HDL-C TG Recommended ADA cutpoints Resnick HE et al. Diabetes Care. 2;23:176-18. American Diabetes Association. Diabetes Care. 26;29(suppl 1):S4-S42. Fat Cells Liver FFA CE IR X Insulin VLDL-TG Apo B Apo C-III CE VLDL (CETP) LDL (CETP) TG TG HDL SD LDL Apo A-1 Kidney (lipoprotein or hepatic lipase) Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 3
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician Media Intima Lumen LDL-C Lumen Lipid-rich core Fibrous cap Lumen Unstable Lipid-rich core Lumen Phase I: Initiation LDL-C plays a major role in initiating the development of atherosclerotic plaque Phase II: Progression Disease progression results in the remodeling of the vascular wall so that the size of the lumen does not change significantly Stable Phase III: Complication Extensive lipid accumulation and a greater inflammatory component can pose the threat of plaque rupture Libby P. In: Heart Disease: A Textbook of Cardiovascular Medicine. 6th ed. Philadelphia, PA: WB Saunders Co; 21:995-19. Libby P. J Intern Med. 2;247:349-358. 3.7 2.9 Relative Risk for Coronary Heart Disease (Log Scale) 2.2 1.7 1.3 1. 4 7 1 13 16 19 LDL-Cholesterol (mg/dl) Grundy S et al. Circulation. 24;11:227-239. 14 RCTs 18,686 with DM 71,37 without DM No differences by presence or absence of vascular disease, other risk factors, or baseline lipid levels CTT Collaborators. Lancet. 28;371:117-125. Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 4
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician HPS LDL-C Subgroup Analysis 175 LDL-C (mg/dl) 15 125 1 75 LDL-C 35% LDL-C 37% Placebo Simvastatin LDL-C 39% 4.5 4. 3.5 3. 2.5 2. LDL-C (mmol/l) 5 RR reduction (major vascular events): LDL-C <116 mg/dl LDL-C 116 135 mg/dl LDL-C >135 mg/dl (<3. mmol/l) (3. 3.5 mmol/l) (>3.5 mmol/l) 21% 26% 19% 1.5 Modified from Heart Protection Study Collaborative Group. Lancet. 22;36:7-22 Drug Dose (mg/d) LDL-C Reduction (%) Atorvastatin 1 39 Lovastatin 4 31 Pravastatin 4 34 Simvastatin 2 4 35 41 Fluvastatin 4 8 25 35 Rosuvastatin 5 1 39 45 For every doubling of the dose above the standard dose, an approximate 6% decrease in LDL-C level can be obtained. Grundy S et al. Circulation. 24;11:227-239. Cholesterol absorption inhibitor Ezetimibe Reduces cholesterol absorption by binding to intestinal cholesterol transporter Bile acid sequestrants (BAS) Colesevelam, cholestyramine, colestipol Bind to bile acids > increase excretion of cholesterol Increased hepatic removal of cholesterol via LDL receptor pathway Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 5
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician Mean Change from Untreated Baseline (%) 5 5 1 15 LDL-C TG (Median) HDL-C 1% % 1% 2% 8% 2 18% Placebo ( n=431) Ezetimibe 1 mg ( n=1288) *Pooled data. P.1 vs placebo. Lipoprotein and lipid effects 1 LDL-C: 15% to 3% Triglycerides: no change or HDL-C: 3% to 5% Reduce major coronary events and CHD deaths 1,2 Improved diabetic control (colesevelam) Adverse effects: 1,2 Gastrointestinal distress (bloating and constipation) Exacerbation of hypertriglyceridemia 1. NCEP ATP III. Circulation. 22;16:3143-3421. 2. Jacobson TA, et al. Am J Cardiol. 27;99(suppl 6A):47C-55C. Change from Baseline (%) 2 1-1 -2-3 -4-5 -6 LDL-C Total-C HDL-C TG 3 4 4 LDL-C and Total-C values are expressed as mean; HDL-C and TG values are expressed as median. P<.5 vs placebo P<.5 vs atorvastatin 1 mg -38-48 -53-27 -31-39 8 11 6 1-24 -1-33 Placebo Atorvastatin 1 mg/d Colesevelam 3.8 g/d + Atorvastatin 1 mg/d Atorvastatin 8 mg/d Hunninghake D et al. Atherosclerosis. 21;158:47-416. Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 6
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician Therapeutic lifestyle changes (TLC) Non HDL-C HDL-C Emerging biomarkers Other lipid risk markers Nonlipid risk markers Diet Limit saturated fats (<7% total calories), cholesterol (<2 mg/day), and trans fat Therapeutic options Omega-3 fatty acids Plant stanols/sterols Increased viscous fiber Regular physical activity Weight loss Smoking cessation Expert Panel. JAMA. 21;285:2486-2497. In patients with TG 2 mg/dl, the cholesterol content of TG-rich, atherogenic (remnant) lipoprotein particles is increased Measurement of non HDL-C (TC minus HDL-C) takes into account cholesterol in these particles (as well as LDL-C) Predictive for CHD Can be measured under nonfasting conditions Can be used as follow-up measurement Non HDL-C goal = LDL-C goal + 3 mg/dl Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 21;285:2486-2497. Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 7
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician Relative CHD Risk 2.5 2 1.5 1.5 <13 13 159 16 LDL-C (mg/dl) 2693 Men 311 Women 19 16 189 <16 Non HDL-C (mg/dl) Liu J et al. Am J Cardiol. 26;98:1363-1368. Risk Category Non HDL-C Goal (mg/dl) 1 RF <19 2 RFs (CHD risk 2%) <16 CHD or CHD risk equivalent <13 (CHD risk >2%) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 21;285:2486-2497. Risk Reduction (%) -1-2 -3-4 Nonfatal MI -24% P=.1 Macrovascular CVD -11% P=.35 Coronary Revasc. -21% P=.3 Angina -18% P=.4 Amputations -38% P=.11 Microvascular Retinal Laser Therapy -3% P=.3 Albuminuria -15% P=.2 Keech A et al. Lancet. 25;366:1849-1861. Keech A. Atherosclerosis Supplements. 26;7:342. Abstract. Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 8
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician N=5518 Mean Age: 62 yr Mean f/u: 4.7 yr The ACCORD Study Group. N Engl J Med. 21;1.156/NEJMoa11282 The ACCORD Study Group. N Engl J Med. 21;1.156/NEJMoa11282 Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 9
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician 3. Framingham Heart Study 2.5 Relative Risk of CHD after 4 Years 2. 1.5 1..5. 4525 1 16 65 22 85 HDL-C, mg/dl LDL-C, mg/dl CAD=coronary artery disease. Castelli WP. Can J Cardiol. 1988;4(suppl A):5A 1A. Reverse cholesterol transport Anti-oxidant effects Anti-inflammatory effects Antithrombotic effects Anti-apoptotic effects Promotion of NO production Endothelial function-enhancing effects Movva R et al. Clin Chem. 28:54:788-8. Barter P et al. N Engl J Med. 27;357:131-131. Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 1
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician 4 3 29 3 24 HDL-C 21 2 16 1 1-3 -8-13 -1-5 -16-12 -17-22 -21-2 -14 LDL-C -25-21 Lp(a) -3-26 -3-32 -4-44 -39 TG -5 BL 5 1 15 2 25* 3* *Greater than recommended daily doses. Change from Baseline (%) Kos Pharmaceuticals, Inc., Data on file, 23. AIM-HIGH Statin + niacin vs statin Patients with CVD and metabolic syndrome (n = ~33) HPS2-THRIVE Statin + niacin/laropiprant vs statin Patients with CVD (n = ~2,) Aim HDL-C with niacin while LDL-C with statin reduces CV events better than statin alone Design 34 patients with CVD and atherogenic dyslipidemia LDL-C treated with statin to 4 8 mg/dl Randomized to niacin vs placebo Stopped early by DSMB No difference in CV events, 32 mo Increase in ischemic strokes with niacin 28 (1.6%) niacin vs 12 (.7%) placebo AIM-High Investigators. Am Heart J. 211;161:471-477. NIH News Press Release www.nhlbi.nih.gov Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 11
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician Emerging lipid markers Apo B LDL particle size LDL particle number Lp(a) Emerging markers do not supplant LDL-C, HDL-C, or TG Non HDL-C (TC minus HDL-C) Easy to calculate; no added expense Lifestyle modifications (TLC) Primary goal LDL-C < 1 mg/dl If CVD, LDL-C < 7 mg/dl with high-dose statin is an option Statin therapy added to TLC, regardless of baseline LDL-C, if Overt CVD Age > 4 yr + 1 other CVD risk factors For patients at lower risk (age < 4 yr and without CVD or MRF) Consider statin if LDL-C > 1 mg/dl after TLC Reduction in LDL-C of ~3 4% alternative therapeutic goal, if LDL-C targets not achieved with maximum tolerated statin therapy Triglycerides < 15 mg/dl, HDL-C > 4 (men) > 5 (women) mg/dl desirable, but LDL-C targeted statin therapy preferred Combination therapy to achieve lipid goals may be considered, but not evaluated by CVD outcome or safety studies Diabetes Care. 211;34(suppl 1):S11-S61. Inflammatory markers C-reactive protein (CRP) Cytokines Homocysteine Fibrinogen Metabolic syndrome Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 12
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician An acute-phase reactant in blood Increases in inflammatory states Prognostic indicator in acute MI Predicts prospective coronary risk Better than LDL-C? May be predictor of risk for new diabetes 1. C-Reactive Protein 1. LDL Cholesterol Probability of Event-Free Survival.99.98.97.96 1st Quintile 2nd Quintile 3rd Quintile 4 th Quintile 5 th Quintile.99.98.97.96 1st Quintile 2nd Quintile 3rd Quintile 4 th Quintile 5 th Quintile 2 4 6 8 Years of Follow-up 2 4 6 8 Years of Follow-up Ridker PM et al. N Engl J Med. 22;347:1557-1565. LDL (mg/dl) 14 12 1 8 6 4 2 LDL-C decrease 5% at 12 months HDL (mg/dl) 6 5 4 3 2 1 HDL-C increase 4% at 12 months hscrp (mg/l) 5 4 3 2 1 hs-crp decrease 37% at 12 months 12 24 36 48 Months Ridker PM et al. N Engl J Med. 28;359:2195-227. TG (mg/dl) 14 12 1 8 6 4 2 TG decrease 17% at 12 months 12 24 36 48 Months Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 13
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician Cumulative Incidence.8.6.4.2 HR.56, 95% CI.46.69, P<.1 Number Needed to Treat (NNT ) = 25 ARR:.77 vs 1.36%/yr Placebo 251/891 Rosuvastatin 142/891. 1 2 3 4 Follow-up (years) Number at Risk -44% Rosuvastatin 891 8631 8412 654 3893 1958 1353 983 538 157 Placebo 891 8621 8353 658 3872 1963 1333 955 531 174 Ridker PM et al. N Engl J Med. 28;359:2195-227. Patients at intermediate risk (1% 2% risk of CHD per 1 years) hs-crp may help direct further evaluation, therapy in primary prevention Patients with stable coronary disease, acute coronary syndromes hs-crp measurement may be useful as independent marker of prognosis for recurrent events Not recommended for routine screening hs-crp = high-sensitivity CRP. Pearson TA et al. Circulation. 23;17:499-511. Clustering of abdominal obesity, atherogenic dyslipidemia, hypertension, and insulin resistance Defined as any 3 of the following risk factors Waist circumference >4" (men); >35" (women) TG 15 mg/dl HDL-C <4 mg/dl (men); <5 mg/dl (women) BP 13/ 85 mm Hg FPG 1 mg/dl Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 21;285:2486-2497. Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 14
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician 15 Cumulative Hazard (%) 1 5 Relative Risk = 3.55 Metabolic syndrome No metabolic syndrome 2 4 6 8 1 12 Follow-up (years) N=129 Lakka HM et al. JAMA. 22;288:279-2716. FREE FATTY ACIDS FREE FATTY ACIDS GLUCOSE Leptin Angiotensinogen Resistin Adiponectin (ACRP-3) TNF- PAI-1 Serum amyloid-a IL-6 CRP Estrogens Cortisol RBP4 Modified from Kahn BB, Flier JS. J Clin Invest. 2;16:473-481. Lau DCW et al. Am J Physiol Heart Circ Physiol. 25;288:H231-241. Wellen. KE, Hotamisligil GS. J Clin Invest. 25;115:1111-1119. Produces various adipocytokines, chemokines, and prothrombotic factors Results in insulin-resistant, proinflammatory, prothrombotic state Clinical endpoints Increased diabetes Increased cardiovascular disease Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 15
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician Identifies people at risk Allows targeting of specific risk factors May improve compliance May improve monitoring May improve therapy May be cost-effective Based on values of the following factors Age Smoking Total cholesterol HDL cholesterol Systolic blood pressure (including use of antihypertensive medication) Factors are the same for men and women but equations are different to reflect higher risk among men Integrate 1-year risk of hard CHD (MI or CHD death) Calculations can be done with online calculator available at http://hp21.nhlbihin.net/atpiii/calculator.asp?usertype=prof Use computer-assisted risk assessment tools Framingham CHD Risk Calculator Reynolds Risk Score UKPDS Risk Engine for Type 2 Diabetes Tear-off sheets for self-assessment of risk scores Training office personnel in assessment tools Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 16
Joslin Diabetes Forum 211: Optimizing Care for the Practicing Clinician Elkeles RS et al. Eur Heart J. 28;29:2244-2251. LDL-C remains the primary target of lipid-altering therapies in patients with diabetes Non HDL-C is a secondary target in patients with triglycerides >2 mg/dl The benefits of treatment of low HDL-C, Apo B, LDL particle size/number or Lp(a) remain to be determined Biomarkers may help to identify patients at high cardiometabolic risk, especially in those at high risk for developing diabetes Copyright 211 by Joslin Diabetes Center, Inc. All rights reserved. These materials may be used for personal use only. Any distribution 17