The Evidence for Current Cardiovascular Disease Prevention Guidelines: Cholesterol Management Evidence and Guidelines American College of Cardiology Best Practice Quality Initiative Subcommittee and Prevention Committee Classification of Recommendations and Levels of Evidence *Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as gender, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials. Even though randomized trials are not available, there may be a very clear clinical consensus that a particular test or therapy is useful or effective. †In 2003, the ACC/AHA Task Force on Practice Guidelines developed a list of suggested phrases to use when writing recommendations. All guideline recommendations have been written in full sentences that express a complete thought, such that a recommendation, even if separated and presented apart from the rest of the document (including headings above sets of recommendations), would still convey the full intent of the recommendation. It is hoped that this will increase readers’ comprehension of the guidelines and will allow queries at the individual recommendation level. Icons Representing the Classification and Evidence Levels for Recommendations I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III I IIa IIb III Evidence for Current Cardiovascular Disease Prevention Guidelines Cholesterol, Cholesterol Therapies, and Cholesterol Guidelines Lipoprotein Classes Chylomicrons, VLDL, and their catabolic remnants LDL HDL > 30 nm 20–22 nm 9–15 nm Potentially pro-inflammatory Potentially anti-inflammatory Sources: P. Barter. Role of Lipoproteins in Inflammation presentation, 2001. Available at http://www.lipidsonline.org/slides/slide01.cfm?&tk=18&dpg=3&x=293&43416. Doi H et al. Circulation 2000;102:670-676 Colome C et al. Atherosclerosis 2000;149:295-302 Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994 Role of Lipoproteins in Atherogenesis HDL High plasma LDL Endothelial injury LDL + VLDL LDL infiltration into intima Adherence of platelets Oxidative modification of LDL + Macrophages Release of PDGF Liver Cholesterol excreted LCAT APO-A1 Foam cells Fatty streak Other growth factors Advanced fibrocalcific lesion APO-A1=Apolipoprotein A1, HDL=High density lipoprotein, LCAT=Lecithin cholesterol acyltransferase, LDL=Low density lipoprotein, PDGF=Platelet-derived growth factor, VLDL=Very low density lipoprotein Attributable Risk Factors for a First Myocardial Infarction INTERHEART Study 100 90 PAR (%) 80 60 40 50 36 20 0 33 14 Smoking 12 Fruits/ Exercise Veg 18 7 Alcohol Hypertension 20 10 Diabetes Abdominal Psychoobesity social Lipids All 9 risk factors Lifestyle factors n=15,152 patients and 14,820 controls in 52 countries MI=Myocardial infarction, PAR=Population attributable risk (adjusted for all risk factors) Source: Yusuf S et al. Lancet. 2004;364:937-952 Change in Total Cholesterol Levels in the United States Over Time National Health and Nutrition Examination Survey (NHANES) Total Cholesterol mg/dl (mmol/L) age-adjusted percentage 100% 90% 80% 70% 60% 50% 40% >240 mg/dL (>6.21 mmol/L) 200-240 mg/dL (5.17-6.21 mmol/L) 30% <200 mg/dL (<5.17 mmol/L) 20% 10% 0% Source: Ford ES et al. Circulation 2009;120:1181-1188 Coronary Heart Disease Risk According to LDL-C Level Relative Risk for Coronary Heart Disease (Log Scale) 3.7 2.9 2.2 1.7 1.3 1.0 40 70 100 130 160 190 LDL-Cholesterol (mg/dL) CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol Source: Grundy S et al. Circulation 2004;110:227-239 Therapies to Lower Levels of LDL-C Class 3-Hydroxy-3-Methylglutaryl Coenzyme A (HMGCoA) reductase inhibitors [Statins] Bile acid sequestrants Cholesterol absorption inhibitor Nicotinic acid Dietary Adjuncts Drug(s) Atorvastatin (Lipitor) Fluvastatin (Lescol XL) Lovastatin (Mevacor) Pitavastatin (Livalo) Pravastatin (Pravachol) Rosuvastatin (Crestor) Simvastatin (Zocor) Cholestyramine (Questran) Colesevelam (Welchol) Colestipol (Colestid) Ezetimibe (Zetia) Niacin Soluble fiber Soy protein Stanol esters HMG-CoA Reductase Inhibitor: Mechanism of Action Inhibition of the cholesterol biosynthetic pathway Squalene synthase HMG-CoA Reductase Acetyl CoA HMGCoA Mevalonate Farnesyl pyrophosphate Dolichol Squalene Cholesterol Farnesyltransferase E,E,E-Geranylgeranyl pyrophosphate Farnesylated proteins Geranylgeranylated proteins Ubiquinones HMG-CoA Reductase Inhibitor: Mechanism of Action VLDL Cholesterol synthesis LDL receptor (B–E receptor) synthesis Intracellular Cholesterol VLDLR Apo B Apo E LDL-R–mediated hepatic uptake of LDL and VLDL remnants Serum LDL-C LDL Apo B Serum VLDL remnants Serum IDL Hepatocyte Systemic Circulation The reduction in hepatic cholesterol synthesis lowers intracellular cholesterol, which stimulates upregulation of the LDL receptor and increases uptake of non-HDL particles from the systemic circulation HDL=High density lipoprotein, LDL=Low density lipoprotein Source: McKenney JM. Selecting Successful Lipid-lowering Treatment presentation, 2002. Available at http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=4. HMG-CoA Reductase Inhibitor: Dose-Dependent Effect The Rule of 6’s Lovastatin 20/80* 28 Pravastatin 20/40* 27 12 6 35 Simvastatin 20/80* Fluvastatin 20/80* 19 12 12 37 Atorvastatin 10/80* Rosuvastatin 10/20† 18 46 Pitavastatin 1/4‡ 6 32 0 10 11 20 30 40 50 60 Each doubling of the statin dose produces an approximate 6% reduction in the LDL-C level Sources: *Illingworth DR. Med Clin North Am 2000;84-23-42 †Crestor Package Insert. http://www1.astrazeneca-us.com/pi/crestor.pdf ‡Livalo Package Insert. http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf HMG-CoA Reductase Inhibitor: Reduction in LDL-C A meta-analysis of 164 trials*†‡ Statin 10 mg/d 20 mg/d 40 mg/d 80 mg/d Atorvastatin 69 (37) 80 (43) 91 (49) 102 (55) Fluvastatin 29 (15) 39 (21) 50 (27) 61 (33) Lovastatin‡ 39 (21) 54 (29) 68 (37) 83 (45) Pravastatin 37 (20) 45 (24) 53 (29) 62 (33) Rosuvastatin§ 80 (43) 90 (48) 99 (53) 108 (58) Simvastatin 51 (27) 60 (32) 69 (37) 78 (42) *Standardized to LDL-C 186 mg/dL (mean concentration in trials) before Rx.† Independent of pre-Rx LDL-C ‡Maximum dose of 80 mg/day administered as two 40-mg tablets §Not FDA approved at 80 mg/day #Data presented as absolute reductions in LDL-C* (mg/dL) and percent reductions in LDL-C (in parentheses) ‡Although not included in this analysis, pitavastatin would be expected to achieve a 32%, 36%, and 43% mean reduction in LDL-C levels at the 1 mg, 2 mg, and 4 mg daily doses, respectively FDA=Food and Drug Administration, LDL-C=Low density lipoprotein cholesterol, Rx=Treatment Sources: Law MR et al. BMJ 2003;326:1423-1427 Livalo Package Insert. http://www.kowapharma.com/documents/LIVALO_PI_CURRENT.pdf HMG-CoA Reductase Inhibitor: Chronological Order of Event Driven Trials Study populations: Primary prevention Acute coronary syndromes (Secondary prevention) Chronic coronary heart disease (Secondary prevention) 1994 4S 2002 PROSPER 1995 WOSCOPS 2002 ALLHAT -LLA 1996 CARE 2002 ASCOT-LLA 1998 AFCAPS/TEXCAPS 2004 PROVE- IT 1998 LIPID 2004 A to Z 2001 MIRACL 2005 TNT 2002 HPS 2005 IDEAL 2008 JUPITER 2010 SEARCH HMG-CoA Reductase Inhibitor Evidence: Primary Prevention West of Scotland Coronary Prevention Study (WOSCOPS) 6,595 men with moderate hypercholesterolemia randomized to pravastatin (40 mg) or placebo for 5 years 31% RRR Rate of MI or CHD death (%) 9 7.5 6 5.3 3 0 P<0.001 Placebo Pravastatin A statin provides significant benefit in those with average cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: Shepherd J et al. NEJM 1995;333:1301-1307 HMG-CoA Reductase Inhibitor Evidence: Primary Prevention West of Scotland Coronary Prevention Study (WOSCOPS) Long-term follow-up at 5 and 10 years after conclusion of the study Risk of MI or CHD death (%) RRR=27%, p<0.001 RRR=18%, p<0.02 A statin provides long-term benefit in those with average cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: Ford I et al. NEJM 2007;357:1477-1486 HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TEXCAPS) 6,605 patients with average LDL-C levels randomized to lovastatin (2040 mg) or placebo for 5 years Rate of MI, unstable angina, or SCD (%) 37% RRR 6 5.5 4 3.5 2 0 P<0.001 Placebo Lovastatin A statin provides benefit in those with average LDL-C levels LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RRR=Relative risk reduction, SCD=Sudden cardiac death Source: Downs JR et al. JAMA 1998;279:1615–1622 HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial—Lipid Lowering Arm (ALLHAT-LLA) Cumulative rate % 10,355 patients with HTN and >1 CHD risk factor randomized to pravastatin (40 mg) or usual care for 5 years 18 Pravastatin Usual care 15 12 9 6 32% cross-over among patients with CHD 3 RR, 0.99; P=0.88 0 1 2 3 Years 4 5 6 The failure to demonstrate benefit with a statin may be the result of a high rate of cross over CHD=Coronary heart disease, HTN=Hypertension, RR=Relative risk Source: ALLHAT Collaborative Research Group. JAMA 2002;288:2998-3007 HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA) Cumulative incidence of MI and fatal CHD (%) 10,305 patients with HTN randomized to atorvastatin (10 mg) or placebo for 5 years 4 3 Atorvastatin 90 mg/dl* Placebo 126 mg/dl* 36% RRR 2 1 P=0.0005 0 0.0 0.5 1.0 1.5 2.0 Follow-up (yr) 2.5 3.0 3.5 A statin provides significant benefit in moderate- to high-risk individuals by lowering LDL-C levels below current goals *Post-treatment LDL-C level CHD=Coronary heart disease, HTN=Hypertension, LDL-C=Low density lipoprotein cholesterol, RRR=Relative risk reduction Source: Sever PS et al. Lancet. 2003;361:1149-1158 HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Relationship between LDL-C levels and event rates in select primary prevention statin trials CHD event rate (%) 10 Statin 8 Placebo WOSCOPS WOSCOPS 6 AFCAPS AFCAPS 4 ASCOT 2 ASCOT 0 –1 P=0.0019 55 75 95 115 135 155 175 195 LDL cholesterol (mg/dL) AFCAPS= Air Force/Texas Coronary Atherosclerosis Prevention Study, ASCOT= AngloScandinavian Cardiac Outcomes Trial—Lipid Lowering Arm, LDL-C=Low density lipoprotein cholesterol, WOSCOPS= West of Scotland Coronary Prevention Study Source: O’Keefe JH Jr et al. JACC 2004;43:2142-2146 HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Trial 7,832 men (age 40-70 years) and postmenopausal women (up to age 70 years) with total cholesterol levels of 220-270 mg/dL randomized to pravastatin (10-20 mg) or placebo for 5.3 years Number of adverse CV events* per 1000 person years 33% RRR 6 5.0 4 3.3 2 0 P=0.01 Placebo Pravastatin A statin provides benefit in those with high cholesterol levels *Composite of cardiac and sudden death, myocardial infarction, angina, and cardiac or vascular intervention CV=Cardiovascular Source: Nakamura H et al. Lancet 2006;368:1155-63 HMG-CoA Reductase Inhibitor Evidence: Primary Prevention Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) Cumulative incidence of CV death, MI, stroke, hospitalization for unstable angina, and arterial revascularization 0.00 0.04 0.08 17,802 men (>50 years) and women (>60 years) with LDL-C <130 mg/dL and hs-CRP >2 mg/L randomized to rosuvastatin (20 mg) or placebo for up to 5 years* Rosuvastatin Placebo 44% RRR P<0.00001, NNT=25 0 1 2 Follow-up (years) 3 4 A statin provides benefit in those with elevated hs-CRP levels *The study was stopped prematurely after 1.9 years CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction Ridker PM et al. NEJM 2008;359:2195-2207 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Trial event 15 15 Combined CV rate (%)* 3,086 pts with an ACS randomized to atorvastatin (80 mg) or placebo for 16 weeks 10 10 17.4% Placebo 14.8% Atorvastatin 55 0 0 RR=0.84, P=0.048 0 4 8 12 16 Weeks Acute intensive statin therapy provides significant CV benefit *Includes death, MI resuscitated cardiac arrest, recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. ACS=Acute coronary syndrome, CV=Caradiovascular Source: Schwartz GG et al. JAMA 2001;285:1711-1718 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT)—TIMI 22 Study Recurrent MI, cardiac death, UA, revascularization, or stroke 4,162 pts with an ACS randomized to atorvastatin (80 mg) or pravastatin (40 mg) for 24 months 30 16% RRR Pravastatin 25 Atorvastatin 20 15 10 5 0 P=0.005 3 6 9 12 15 18 21 24 27 30 Follow-up (months) Acute intensive statin therapy provides significant CV benefit ACS=Acute coronary syndrome, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction, UA=Unstable angina Source: Cannon CP et al. NEJM 2004;350:1495-1504 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Aggrastat to Zocor (A to Z) Trial 4,162 patients with an ACS randomized to simvastatin (80 mg) or simvastatin (20 mg) for 24 months Cumulative event rate (%)* 20 Placebo/Simvastatin 20 mg/day 15 Simvastatin 40/80 mg/day 10 5 HR=0.89, P=0.14 0 0 4 8 12 16 Time from randomization (months) 20 24 Acute intensive statin therapy does not provide CV benefit *Includes CV death, MI, readmission for an ACS, and CVA ACS=Acute coronary syndrome, CV=Cardiovascular, CVA=Cerebrovascular accident, MI=Myocardial infarction Source: de Lemos JA et al. JAMA 2004;292:1307-1316 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Scandinavian Simvastatin Survival Study (4S) 4,444 patients with angina pectoris or previous MI randomized to simvastatin (20-40 mg) or placebo for 5.4 years 30% RRR Mortality (%) 12 11.5 8.2 8 4 0 P<0.001 Placebo Simvastatin A statin provides significant benefit in those with average LDL-C levels LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RRR=Relative risk reduction Source: 4S Group. Lancet 1994;344:1383–1389 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Cholesterol and Recurrent Events (CARE) Study 4,159 patients with a history of MI randomized to pravastatin (40 mg) or placebo for 5 years Rate of MI or CHD death (%) 24% RRR 15 13.2 10.2 10 5 0 P=0.003 Placebo Pravastatin A statin provides significant benefit in those with average cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Srouce: Sacks FM et al. NEJM 1996;335:1001–1009 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) Study 9,014 patients with a history of MI or hospitalization for unstable angina randomized to pravastatin (40 mg) or placebo for 6.1 years 24% RRR CHD Death (%) 9 8.3 6.4 6 3 0 P<0.001 Placebo Pravastatin A statin provides significant benefit across a broad range of cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: LIPID Study Group. NEJM 1998;339:1349–1357 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Heart Protection Study (HPS) Event Rate Ratio (95% CI) Baseline LDL-C (mg/dL) Statin (n = 10,269) Placebo (n = 10,267) <100 282 (16.4%) 358 (21.0%) 100–129 668 (18.9%) 871 (24.7%) 130 1083 (21.6%) 1356 (26.9%) All patients 2033 (19.8%) 2585 (25.2%) Statin Better Statin Worse 0.76 (0.72–0.81) P<0.0001 0.4 0.6 0.8 1.0 1.2 1.4 A statin provides significant CV benefit regardless of baseline LDL-C level CAD=Coronary artery disease, CI=Confidence interval, CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol Source: HPS Collaborative Group. Lancet 2002;360:7-22 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) CHD death, non-fatal MI, stroke (%) 5,804 patients aged 70-82 years with a history of, or risk factors for, vascular disease randomized to pravastatin (40 mg) or placebo for 3.2 years 20 Placebo 10 Pravastatin 15% RRR, P=0.014 0 0 1 2 Years 3 4 A statin provides CV benefit in older men CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: Shepherd J et al. Lancet 2002;360:1623-1630 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Treating to New Targets (TNT) Trial 10,001 patients with stable CHD randomized to atorvastatin (80 mg) or atorvastatin (10 mg) for 4.9 years Major CV Event* (%) 0.15 22% RRR Atorvastatin (10 mg) 0.10 Atorvastatin (80 mg) 0.05 P<0.001 0.00 0 1 2 3 Years 4 5 6 High-dose statin therapy provides benefit in chronic CHD *Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: LaRosa JC et al. NEJM 2005;352:1425-35 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Trial Cumulative Hazard (%) 8,888 patients with a history of acute MI randomized to atorvastatin (80 mg) or simvastatin (20 mg) for 5 years 12 Simvastatin (20 mg) 8 Atorvastatin (80 mg) 4 HR=0.89, P=0.07 0 1 2 3 4 5 Years Since Randomization High-dose statin therapy does not provide CV benefit after a MI *Includes coronary death, hospitalization for nonfatal acute MI, or cardiac arrest with resuscitation CV=Cardiovascular, HR=Hazard ratio, MI=Myocardial infarction Source: Pedersen TR et al. JAMA 2005;294:2437-2445 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Relationship between LDL-C levels and event rates in secondary prevention statin trials of patients with stable CHD 30 4S Statin Placebo Event (%) 25 4S 20 LIPID CARE CARE HPS HPS TNT (atorvastatin 10 mg/d) TNT (atorvastatin 80 mg/d) LIPID 15 10 5 0 0 70 90 110 130 150 LDL-C (mg/dL) 170 190 210 CARE=Cholesterol and Recurrent Events Trial, CHD=Coronary heart disease, HPS=Heart Protection Study, LDL-C=Low density lipoprotein cholesterol, LIPID=Long-term Intervention with Pravastatin in Ischaemic Disease, 4S=Simvastatin Survival Study, TNT=Treating to New Targets Source: LaRosa JC et al. NEJM 2005;352:1425-1435 HMG-CoA Reductase Inhibitor Evidence: Secondary Prevention Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) 12,064 patients with a history of MI randomized to simvastatin (80 mg) or simvastatin (20 mg) for a mean of 6.7 years * High-dose statin therapy does not provide CV benefit after a MI *Includes coronary death, myocardial infarction, stroke, or arterial revascularization CHD=Coronary heart disease, MI=Myocardial infarction Source: SEARCH Collaborative Group. Lancet 2010;376:1658-1669 HMG-CoA Reductase Inhibitor Evidence: Degree of Benefit in Prevention Types Meta-analysis of randomized controlled trials comparing risk reductions between primary and secondary prevention patients Relative Risk Reduction Absolute Risk Reduction Number Needed To Treat Primary Secondary Primary Secondary Primary Secondary Major CHD events 29.2 20.8 1.66 2.4 60 33 Major CV events 14.4 17.8 0.37 0.8 268 125 Nonfatal MI 31.7 NA 1.65 NA 61 NA PCI or CABG 33.8 20.3 1.08 2.7 93 37 CABG=Coronary artery bypass graft surgery, CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, PCI=Percutaneous coronary intervention Source: Thavendiranathan P et al. Arch Intern Med 2006;166:2307-2313 HMG-CoA Reductase Inhibitor Evidence: Effect of Intensive Therapy Magnitude of event reduction among trials of intensive statin therapy Trial Population Duration (years) LDL-C Reduction (mg/dL) RR in Primary End Point (%) RR in MI or CHD Death (%) PROVE ITTIMI 22 ACS (N = 4162) 2 33 16 16 A to Z ACS (N = 4497) 2 14 11 15 TNT Stable CAD (N =10,001) 5 24 22 21 IDEAL Stable CAD (N = 8888) 5 23 11 11 Note: SI conversion factor: To convert LDL-C to mmol/L, multiply by 0.0259 ACS=Acute coronary syndrome, CAD=Coronary artery disease, CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol, MI=Myocardial infarction, RR=Relative reduction Source: Cannon CP et al. JAMA 2005;294:2492-2494 HMG-CoA Reductase Inhibitor Evidence: Effect of Intensive Therapy Cholesterol Treatment Trialists’ (CTT) Collaboration Control 15 Statin 21% relative risk reduction per mmol/L 16% relative risk reduction per 0.5 mmol/L 10 More statin 0 Five year risk of a major vascular event, % 20 Meta-analysis of 169,138 patients randomized to at least 2 years of statin therapy 0 1 2 3 4 5 LDL cholesterol level (mmol/L) There is a proportionate reduction in CV events with greater cholesterol reduction LDL- CV=Cardiovascular, LDL=Low density lipoprotein Source: Cholesterol Treatment Trialists’ Collaboration. Lancet 2010;376:1670-1681 HMG-CoA Reductase Inhibitor: Adverse Effects 74,102 subjects in 35 randomized clinical trials with statins • 1.4% incidence of elevated hepatic transaminases (1.1% incidence in control arm) • Dose-dependent phenomenon that is usually reversible Hepatocyte • 15.4% incidence of myalgias* (18.7% incidence in control arm) • 0.9% incidence of myositis (0.4% incidence in control arm) • 0.2% incidence of rhabdomyolysis (0.1% incidence in control arm) Skeletal myocyte *The rate of myalgias leading to discontinuation of atorvastatin in the TNT trial was 4.8% and 4.7% in the 80 mg and 10 mg arms, respectively Source: Kashani A et al. Circulation 2006;114:2788-2797 HMG-CoA Reductase Inhibitor: Adverse Effects Risk factors for the development of myopathy* Concomitant Use of Meds Other Conditions Fibrate Advanced age (especially >80 years) Nicotinic acid (Rarely) Women > Men especially at older age Cyclosporine Small body frame, frailty Antifungal azoles** Multisystem disease‡ Macrolide antibiotics† Multiple medications HIV protease inhibitors Perioperative period Nefazadone Alcohol abuse Verapamil, Amiodarone Grapefruit juice (>1 quart/day) *General term to describe diseases of muscles **Itraconazole, Ketoconazole †Erythromycin, Clarithromycin ‡Chronic renal insufficiency, especially from diabetes mellitus Source: Pasternak RC et al. Circulation 2002;106:1024-1028 Bile Acid Sequestrant: Mechanism of Action Gall Bladder Cholesterol 7- hydroxylase Conversion of cholesterol to BA BA Secretion Bile Acid Enterohepatic Circulation Liver Terminal Ileum BA Excretion Reabsorption of bile acids LDL Receptors VLDL and LDL removal LDL-C BA=Bile acid, LDL-C=Low density lipoprotein cholesterol, VLDL=Very low density lipoprotein Bile Acid Sequestrant Evidence: Efficacy at Reducing LDL-C 15 LDL-C HDL-C TG 10 % Change from baseline at week 24 10 5 0 3 † 5 0 -1 -5 -10 Placebo -15 Colesevelam 3.8 grams/day -15 * -20 *P<0.001 vs placebo †P=0.04 vs placebo HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride Source: Insull W et al. Mayo Clin Proc 2001;76:971-982 Bile Acid Sequestrant Evidence: Primary Prevention Lipid Research Clinics-Coronary Primary Prevention Trial (LRC-CPPT) 3,806 men with primary hypercholesterolemia randomized to cholestyramine (24 grams) or placebo for 7.4 years 19% RRR Rate of MI or CHD death (%) 9 8.6 7.0 6 3 0 P<0.05 Placebo Cholestyramine A bile acid sequestrant provides benefit in those with high cholesterol levels CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: The LRC-CPPT Investigators. JAMA 1984;251:351-364 Ezetimibe: Mechanism of Action Production in liver Absorption from intestine Bloodstream Dietary cholesterol LDL-C Cholesterol synthesis VLDL Biliary cholesterol Chylomicrons Fecal sterols and neutral sterols Ezetimibe Evidence: Efficacy at Reducing LDL-C 892 patients with primary hypercholesterolemia randomized to ezetimibe (10 mg) or placebo for 12 weeks LDL-C HDL-C Triglycerides +5.7 Mean % change from baseline to week 12 +5 0 +1.3 +0.4 –1.6 –5 –5.7 –10 Placebo –15 –16.9* Ezetimibe 10 mg –20 *p<0.01 compared to placebo HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Dujovne CA et al. Am J Cardiol 2002;90:1092-1097 Dietary Adjuncts Evidence: Efficacy at Reducing LDL-C Therapy Dose (g/day) Effect Dietary soluble fiber 5-10 (psyllium) LDL-C 10-15% Soy protein 20-30 LDL-C 5-7% Stanol esters 1.5-2 LDL-C 15-20% LDL-C=Low density lipoprotein cholesterol Sources: Kwiterovich Jr PO. Pediatrics 1995;96:1005-1009 Lichtenstein AH. Curr Atheroscler Rep 1999;1:210-214 Miettinen TA et al. Ann Med 2004;36:126-134 CHD Risk According to HDL-C Level Framingham Study CHD risk ratio 4.0 4.0 3.0 2.0 2.0 1.0 1.0 0 65 25 45 HDL-C (mg/dL) CHD=Coronary heart disease, HDLC=High-density lipoprotein cholesterol Source: Kannel WB. Am J Cardiol 1983;52:9B–12B Nicotinic Acid: Mechanism of Action Mobilization of FFA TG synthesis Apo B Apo B VLDL VLDL Serum LDL VLDL secretion LDL Hepatocyte Serum VLDL results in reduced lipolysis to LDL HDL Systemic Circulation Decreased hepatic production of VLDL and uptake of apolipoprotein A-1 results in reduced LDL cholesterol levels and increased HDL cholesterol levels FFA=Free fatty acid, HDL=High density lipoprotein, LDL=Low density lipoprotein, TG=Triglyceride, VLDL=Very low density lipoprotein Source: McKenney JM. Selecting Successful Lipid-lowering Treatments presentation, 2002. Available at http://www.lipidsonline.org/slides/slide01.cfm?tk=23&dpg=14 Nicotinic Acid Evidence: Effect on Lipid Parameters 30% 30 22% Mean change from Baseline HDL-C 15% 20 10 26% 30% 10% 0 –9% -10 -20 –14% –5% –17% –22% –11% -30 –21% LDL-C –28% -40 –35% -50 Triglyceride –39% –44% Dose (mg) 500 1000 1500 2000 2500 3000 HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol, TG=Triglyceride Source: Goldberg A et al. Am J Cardiol 2000;85:1100-1105 Nicotinic Acid Evidence: Secondary Prevention Coronary Drug Project (CDP) Survival (%) 8,341 men with previous myocardial infarction randomized to nicotinic acid (3 grams) or placebo for 15 years 100 90 80 70 60 5 0 40 Nicotinic Acid Nicotinic acid stopped Placebo P=0.0012 0 2 4 6 8 10 12 14 16 Years of follow-up Niacin provides long-term benefit following a MI MI=Myocardial infarction Source: Canner PL et al. JACC 1986;8:1245–1255 Nicotinic Acid Evidence: Secondary Prevention HDL-Atherosclerosis Treatment Study (HATS) 160 men with CAD, low HDL-C, and normal LDL-C randomized to simvastatin (1020 mg) + niacin (1000 mg bid), simvastatin (10-20 mg) + niacin (1000 mg bid) + antioxidants, antioxidants, or placebo for 3 years * ** ** Placebo (n=34) Niacin/Simvastatin (n=33) Placebo + Vitamins (n=39) Niacin/Simvastatin + Vitamins (n=40) A statin plus niacin provides benefit to men with CAD and low HDL-C levels *Includes cardiovascular death, MI, stroke, or need for coronary revascularization **p<0.01, but low absolute event rates CAD=Coronary artery disease, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Brown BG et al. NEJM 2001;345:1583-1592 Nicotinic Acid Evidence: Secondary Prevention Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact of Global Health Outcomes (AIM-HIGH) Trial Primary outcome (%)** 3414 patients with established CV disease randomized to niacin (up to 2000 mg/day) or placebo on a background of statin therapy for a mean of 3 years* 16.4% 20 Combination Therapy Monotherapy 16.2% 10 HR 1.02, p=0.79 0 0 1 2 3 4 Time (years) Niacin provides no benefit to those with CV disease and low HDL-C levels *The study was stopped prematurely **Composite of death from CHD, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary/cerebral revascularization CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol Source: AIM-HIGH Investigators. NEJM 2011;365:2255-2267 Nicotinic Acid Evidence: Secondary Prevention Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) Trial Major vascular events (%) 25,673 patients with established CV disease randomized to extended release niacin (up to 2000 mg/day) plus laropiprant (40 mg/day) or placebo on a background of statin therapy for a median of 3.9 years* 15.0% 14.5% 15 Placebo Niacin/Laropiprant 10 5 HR 0.96, p=0.29 0 0 1 2 3 4 Years of follow-up Niacin provides no benefit to those with CV disease and low HDL-C levels *The study was stopped prematurely CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol Source: Armitage J et al. Presented at Late Breaking Clinical Trials Session, ACC13, www.thrivestudy.org Cholesterol Ester Transfer Protein Evidence: Mechanism of Action LDL-R Liver F C SR-B1 CE CETP Vessel Wall LDL/VL DL CE Bile LCAT FC Free Cholesterol in Extrahepatic tissues HDL Inhibition of CETP limits the transfer of cholesterol esters from HDL particles to triglyceride-rich lipoproteins and results in elevated HDL cholesterol levels along with larger and less dense LDL cholesterol particles CE=Cholesterol ester, CETP=Cholesterol ester transfer protein, FC=Free cholesterol HDL=High density lipoprotein, LCAT=Lecithin carnitine acyl transferase, LDL=Low density lipoprotein, VLDL=Very low density lipoprotein Cholesterol Ester Transfer Protein Evidence: Secondary Prevention Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) Trial P=0.001 9 6 3 6.2 5.0 3 0 Atorvastatin Atorvastatin and Torcetrapib All-cause mortality (%) Primary end point** (%) 15,067 patients at high CV risk randomized to torcetrapib (60 mg/day) plus atorvastatin versus atorvastation alone for a median of 1.5 years* P=0.006 2 1.2 1 0 0.8 Atorvastatin Atorvastatin and Torcetrapib The CETP inhibitor, torcetrapib, is associated with increased CV risk *The trial was stopped prematurely **Composite of death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina CETP=Cholesterol ester transfer protein, CV=Cardiovascular Source: Barter PJ et al. NEJM 2007;357:2109-2122 Cholesterol Ester Transfer Protein Evidence: Secondary Prevention Dal-OUTCOMES Trial 15,871 patients with a recent ACS randomized to dalcetrapib (600 mg/day) or placebo for a median of 2.6 years Primary end point** (%) P=0.52 9 8.3 8.0 6 3 0 Placebo Dalcetrapib The CETP inhibitor, dalcetrapib, is associated with no CV benefit *The trial was stopped prematurely **Composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation ACS=Acute coronary syndrome, CETP=Cholesterol ester transfer protein, CV=Cardiovascular Source: Barter PJ et al. NEJM 2007;357:2109-2122 CHD Risk According to Triglyceride Levels Meta-analysis of 29 prospective studies evaluating the risk of CHD relative to triglyceride level (top third vs. bottom third) An elevated triglyceride level is associated with increased CHD risk CHD=Coronary heart disease Source: Sarwar N et al. Circulation 2007;115:450-458 Fibrate: Mechanism of Action TG VLDL LPL + Fibrate + Intestine IDL LDL-R Liver CE Mature HDL FC Nascent HDL FC CE Macrophage CE=Cholesterol ester, FC=Free cholesterol, HDL=High density lipoprotein, IDL=Intermediate density lipoprotein, LDL-R=Low density lipoprotein receptor, LPL=Lipoprotein lipase, TG=Triglyceride, VLDL=Very low density lipoprotein Fibrate Evidence: Effect on Lipid Parameters 180 patients with type IIa or IIb hyperlipidemia randomized to fenofibrate (100 mg three times daily) or placebo for 24 weeks 50 Type IIa hyperlipidemia Type IIb hyperlipidemia Mean % change from baseline 40 30 20 10 0 +11* LDL -30 -40 -50 TG HDL -10 -20 +15* LDL -6* TG HDL -20* -38* -45* *p<0.01 HDL=High density lipoprotein, LDL=Low density lipoprotein, TG=Triglyceride Source: Knopp RH et al. Am J Med 1987;83:50-9 % CHD Death/Nonfatal MI Fibrate Evidence: Primary and Secondary Prevention 42% Treatment arm 22% 22 Placebo 22*** 9% 17 66% 34% 2.7 4.1*** 13.6 15 13 8 2.7 HHS HHS* Primary Prevention Secondary Prevention *Post hoc analysis of subgroup with TG >200 mg/dL and HDL-C <42 mg/dL **Post hoc analysis of subgroup with TG 200 mg/dL and HDL-C <35 mg/dL ***Difference between placebo and Rx for primary endpoint was statistically significant (p < 0.05) HDL-C=High density lipoprotein cholesterol, TG=Triglyceride Sources: Frick MH et al. NEJM 1987;317:1237-1245 Manninen V et al. Circulation 1992;85:37-45 BIP Study Group. Circulation 2000;102:21-27 Rubins HB et al. NEJM 1999;341:410-418 Fibrate Evidence: Primary Prevention Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) 9,795 diabetic patients randomized to fenofibrate (200 mg) or placebo for 5 years 11% RRR CHD Death or Nonfatal MI (%) 9 6 5.9 5.2 3 0 P=0.16 Placebo Fenofibrate A fibrate does not provide significant additional benefit* in diabetics *Unadjusted for concomitant statin use CHD=Coronary heart disease, MI=Myocardial infarction, RRR=Relative risk reduction Source: Keech A et al. Lancet 2005;366:1849-1861 Fibrate Evidence: Primary and Secondary Prevention Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial 5,518 diabetic patients on statin therapy randomized to fenofibrate (160 mg) or placebo for 4.7 years CV death, nonfatal stroke or nonfatal MI (%/year) 8% RRR 3 2.4 2.2 2 1 0 P=0.32 Placebo Fenofibrate On a background of statin therapy, a fibrate does not reduce CV events in diabetics CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction Source: ACCORD study group. NEJM 2010;362:1563-1574 Effect of Pharmacotherapy on Lipid Parameters TC LDL-C HDL-C TG Patient tolerability - 19-37% - 25-50% + 4-12% - 14-29% Good - 13% - 18% + 1% - 9% Good Bile acid sequestrants - 7-10% - 10-18% + 3% Neutral or Poor Nicotinic acid - 10-20% - 10-20% + 14-35% - 30-70% Reasonable to Poor - 19% - 4-21% + 11-13% - 30% Good Therapy Statins* Ezetimibe Fibrates *Daily dose of 40mg of each drug, excluding rosuvastatin HDL-C=High-density lipoprotein cholesterol, LDL-C=Low-density lipoprotein cholesterol, TC=Total cholesterol, TG=Triglyceride Omega-3 Fatty Acids Evidence: Effect on Lipid Parameters 27 patients with hypertriglyceridemia and low HDL-C treated with omega-3 fatty acid (4 grams/day) for 7 months Triglyceride 0 Total Cholesterol % Reduction -10 -20 -21* -30 -40 -50 -46* *P<0.05 HDL-C=High-density lipoprotein cholesterol Source: Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18:723-731 Omega-3 Fatty Acids Evidence: Primary and Secondary Prevention Japan Eicosapentaenoic acid Lipid Intervention Study (JELIS) 18,645 patients with hypercholesterolemia randomized to EPA (1800 mg) with a statin or a statin alone for 5 years Years Omega-3 fatty acids provide CV benefit, particularly in secondary prevention *Composite of cardiac death, myocardial infarction, angina, PCI, or CABG CV=Cardiovascular, EPA=Eicosapentaenoic acid Source: Yokoyama M et al. Lancet 2007;369:1090-1098 Omega-3 Fatty Acids Evidence: Primary and Secondary Prevention Outcome Reduction with Initial Glargine Intervention (ORIGIN) 12,536 patients with IFG, IGT, DM, established CV disease, or CV risk factors randomized in 2 x 2 trial design to omega 3 fatty acids (at least 900 mg/day), insulin glargine (with a target fasting blood glucose <95 mg/dL) or placebo for a median of 6.2 years 2% RRR CV death (%) 15 10 9.3 9.1 5 0 P=0.72 Placebo Omega 3 fatty acids Low dose omega-3 fatty acids do not provide CV benefit in at risk individuals CV=Cardiovascular, DM=Diabetes mellitus, IFG=Impaired fasting glucose, IGT=Impaired glucose tolerance Source: ORIGIN Trial Investigators. NEJM 2012;367:309-318 Omega-3 Fatty Acids Evidence: Secondary Prevention Diet and Reinfarction Trial (DART) All cause mortality (%) 2,033 men with a history of a MI randomized to a diet of reduced fat with an increased ratio of polyunsaturated to saturated fat, increased fatty fish intake*, or increased fiber intake for 2 years 8.0% 7.0% 6.0% 5.0% 4.0% 3.0% Omega-3 Fatty Acids Placebo 2.0% 1.0% 0.0% Omega-3 fatty acids reduce all cause mortality** in men after a MI *Corresponds to 2.5 grams of EPA (PUFA) **p<0.05 EPA=Eicosapentaenoic acid, MI=Myocardial infarction Source: Burr ML et al. Lancet 1989;2:757-761 Omega-3 Fatty Acids Evidence: Secondary Prevention Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI-Prevenzione) Percent of patients 11,324 patients with a history of a MI randomized to omega-3 polyunsaturated fatty acids [PUFA] (1 gram), vitamin E (300 mg), both or none for 3.5 years 16 14 12 10 8 6 4 2 0 P=0.048 P=0.053 P=0.023 P=0.008 Omega-3 PUFA Placebo Death, NF MI, NF stroke (2 way) CV death, NF MI, and NF stroke Death, NF MI, NF stroke (4 way) CV death, NF MI, and NF stroke Omega-3 fatty acids provide significant CV benefit after a MI CV=Cardiovascular, MI=Myocardial infarction, NF=Non-fatal, PUFA=Polyunsaturated fatty acids Source: GISSI Investigators. Lancet 1999;354:447-455 Omega-3 Fatty Acids Evidence: Secondary Prevention OMEGA Trial Rate of reinfarction, stroke, or death* (%) 3,827 patients 3-14 days following a MI randomized to omega-3 fatty acids (460 mg EPA + 380 mg DHA) or placebo for 1 year 12 10.4 8.8 8 4 0 P=0.10 Placebo Fatty acids Omega-3 fatty acids provide no benefit following a MI in those with high utilization of risk reducing therapies *This is a secondary endpoint DHA=Docosahexaenoic acid, EPA=Eicosapentaenoic acid, MI=Myocardial infarction Source: Rauch B et al. Circulation 2010;122:2152-2159 Risk Assessment for LDL-C Lowering A risk assessment tool* is needed for individuals with >2 RFs 10-year CHD Risk 0 10 20 0-1 RFs 2 RFs CAD or Risk Equivalent** *Such as the Framingham Risk Score (FRS) **Includes DM, non-coronary atherosclerotic vascular disease, and >20% 10-year CHD risk by the FRS CAD=Coronary artery disease, CHD=Coronary heart disease, DM=Diabetes mellitus, RF=Risk factor Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497 Risk Stratification: Framingham Risk Score On Line Calculator Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Risk Assessment Tool. http://hp2010.nhlbihin.net/atpiii/calculator.asp Risk Stratification: Framingham Risk Score for Men Step 1: Age Points Years 20-34 35-39 Points -9 -4 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 0 3 6 8 10 11 12 13 Step 3: HDL-C Points HDL-C (mg/dl) >60 Points -1 50-59 40-49 <40 0 1 2 Age 20-39 0 4 7 9 11 Nonsmoker Smoker SBP (mm Hg) <120 120-129 130-139 140-159 >160 If untreated 0 0 1 1 2 If treated 0 1 2 2 3 Age 40-49 0 3 5 6 8 Age 50-59 0 2 3 4 5 Age 60-69 0 1 1 2 3 Age 70-79 0 0 0 1 1 Age 20-39 0 8 Age 40-49 0 5 Age 50-59 0 3 Age 60-69 0 1 Age 70-79 0 1 Step 6: Sum of Points Age Total Cholesterol HDL-C Systolic Blood Pressure Step 4: SBP Points Step 2: Total Cholesterol Points TC (mg/dl) <160 160-199 200-239 240-279 >280 Step 5: Smoking Status Points Smoking Status Point Total Step 7: 10-year CHD Risk Point Total <0 0 1 2 3 4 5 10-year Risk <1% 1% 1% 1% 1% 1% 2% Point Total 6 7 8 9 10 11 12 10-year Risk 2% 3% 4% 5% 6% 8% 10% Point Total 13 14 15 16 >17 10-year Risk 12% 16% 20% 25% >30% CHD=Coronary heart disease, HDL-C=High density lipoprotein cholesterol, SBP=Systolic blood pressure, TC=Total cholesterol Source: Framingham Heart Study. Hard Coronary Heart Disease (10-year risk). Available at http://www.framinghamheartstudy.org/risk/hrdcoronary.html. Risk Stratification: Framingham Risk Score for Women Step 1: Age Points Years 20-34 35-39 Points -7 -3 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 0 3 6 8 10 12 14 16 HDL-C (mg/dl) >60 50-59 40-49 <40 Points -1 0 1 2 Age 20-39 0 4 8 11 13 Nonsmoker Smoker SBP (mmHg) <120 120-129 130-139 140-159 >160 If untreated 0 1 2 3 4 If treated 0 3 4 5 6 Age 40-49 0 3 6 8 10 Age 50-59 0 2 4 5 7 Age 60-69 0 1 2 3 4 Age 70-79 0 1 1 2 2 Age 20-39 0 9 Age 40-49 0 7 Age 50-59 0 4 Age 60-69 0 2 Age 70-79 0 1 Step 6: Sum of Points Age Total Cholesterol HDL-C Systolic Blood Pressure Step 4: SBP Points Step 2: Total Cholesterol Points TC (mg/dl) <160 160-199 200-239 240-279 >280 Step 5: Smoking Status Points Step 3: HDL-C Points Smoking Status Point Total Step 7: 10-year CHD Risk Point Total <9 9 10 11 12 13 14 10-year Risk <1% 1% 1% 1% 1% 2% 2% Point Total 15 16 17 18 19 20 21 10-year Risk 3% 4% 5% 6% 8% 11% 14% Point Total 22 23 24 >25 10-year Risk 17% 22% 27% >30% CHD=Coronary heart disease, HDL-C=High density lipoprotein cholesterol, SBP=Systolic blood pressure, TC=Total cholesterol Source: Framingham Heart Study. Hard Coronary Heart Disease (10-year risk). Available at http://www.framinghamheartstudy.org/risk/hrdcoronary.html. Risk Stratification: Reynolds Risk Score On Line Calculator In addition to information collected as part of the Framingham Risk Score, the Reynolds Risk Score includes a hs-CRP level and a family history of premature CV disease in predicting one’s risk of adverse CV events Source: Reynolds Risk Score calculator. http://www.reynoldsriskscore.org/default.aspx ATP III LDL-C Goals and Cut-points for Drug Therapy Risk Category Consider Drug Therapy LDL-C Goal Initiate TLC High risk: CHD or CHD risk equivalents (10-year risk >20%) <100 mg/dL (optional goal: <70) 100 mg/dL >100 mg/dL (<100 mg/dL: consider drug options) Moderately high risk: 2+ risk factors* (10-year risk 10% to 20%) <130 mg/dL (optional goal: <100) 130 mg/dL >130 mg/dL (100-129 mg/dL: consider drug options) Moderate risk: 2+ risk factors* (10 year risk <10%) <130 mg/dL 130 mg/dL >160 mg/dL Lower risk: 0-1 risk factor* <160 mg/dL 160 mg/dL >190 mg/dL (160-189 mg/dL: LDL-C lowering drug optional) *Risk factors for CHD include: cigarette smoking, hypertension (blood pressure >140/90 mmHg or on antihypertensive medication, HDL-C <40 mg/dl (>60 mg/dl is a negative risk factor), family history of premature CHD, age >45 years in men or >55 years in women ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes Source: Grundy S et al. Circulation 2004;110:227-239 ATP III Classification of Other Lipoprotein Levels Total Cholesterol Level (mg/dl) Classification HDL-Cholesterol Level (mg/dl) Classification <200 Desirable >40 Minimum goal* 200-239 Borderline High 40-50 Desired goal* >240 High >50 High Triglyceride Level (mg/dl) Classification <150 Normal 150-199 Borderline High 200-499 High >500 Very High *These goals apply to men. For women, the minimum goal is >50 mg/dL HDL=High density lipoprotein Source: Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497 AHA Primary Prevention of CV Disease in DM Cholesterol Recommendations Primary Prevention • In adult patients, lipid levels should be measured at least annually and more often if needed to achieve goals. In adults <40 years of age with low-risk lipid values (LDL-C <100 mg/dL, HDL-C >50 mg/dL, and triglycerides <150 mg/dL), lipid assessments may be repeated every 2 years. • Lifestyle modification deserves primary emphasis for all individuals. Patients should focus on the reduction of saturated fat and cholesterol intake, weight loss (if indicated), and increases in dietary fiber and physical activity. These lifestyle changes have been shown to improve the lipid profile. AHA=American Heart Association, CV=Cardiovascular, DM=Diabetes mellitus, HDLC=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Buse JB et al. Circulation 2007;115:114-126 AHA Primary Prevention of CV Disease in DM Cholesterol Recommendations (Continued) Primary Prevention • In those >40 years of age without overt CVD, but with >1 major CVD risk factor*, the primary goal is an LDL-C level <100 mg/dL. If LDL-C lowering drugs are used, a reduction of at least 30-40% in LDL-C levels should be obtained. If the baseline LDL-C level is <100 mg/dL, statin therapy should be initiated based on risk factor assessment and clinical judgment. • In those <40 years of age without overt CVD, but at increased risk of CVD either by clinical judgment or by risk calculator, the LDL-C goal is <100 mg/dL, and LDL-C lowering drugs should be considered if lifestyle changes do not achieve the goal. *Includes cigarette smoking, hypertension [BP >140/90 mm Hg or use of antihypertensive medication], low HDL-C cholesterol [<40 mg/dL], and family history of premature CHD [CHD in male first-degree relative <55 years of age; CHD in female first-degree relative <65 years of age]. AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease, DM=Diabetes mellitus, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Buse JB et al. Circulation 2007;115:114-126 AHA and ADA Primary Prevention of CV Disease in DM Cholesterol Recommendations Primary Prevention • The ADA and AHA suggest different approaches to the management of HDL-C and triglyceride-associated CVD risk. • The AHA suggests that in patients with triglyceride levels of 200499 mg/dL, a non-HDL-C goal of <130 mg/dL is a secondary target. If triglycerides are >500 mg/dL, therapeutic options include a fibrate or niacin before LDL-C lowering therapy and treatment of LDL-C to goal after triglyceride-lowering therapy. A non HDL-C level <130 mg/dL should be achieved if possible • The ADA suggests lowering triglycerides to <150 mg/dL and raising HDL-C to <40 mg/dL. In women an HDL-C goal 10 mg/dL higher (>50 mg/dL) should be considered. ADA=American Diabetes Association, AHA=American Heart Association, CV=Cardiovascular, CVD=Cardiovascular disease, DM=Diabetes mellitus, HDLC=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Sources: Buse JB et al. Circulation 2007;115:114-126 American Diabetes Association. Diabetes Care 2010;33:S11-61 ADA Cholesterol Recommendations for Patients with Diabetes Mellitus Primary Prevention • In most adult patients, a fasting lipid profile should be measured at least annually. In adults with low-risk lipid values (LDL-C <100 mg/dL, HDL-C >50 mg/dL, and triglycerides <150 mg/dL), lipid assessments may be repeated every 2 years. • Lifestyle modification focusing on the reduction of saturated fat, trans fat, and cholesterol intake; increase of omega-3 fatty acids, viscous fiber, and plant stanols/sterols; weight loss (if indicated); and increased physical activity should be recommended to improve the lipid profile in patients with DM. ADA=American Diabetes Association, DM=Diabetes mellitus, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: American Diabetes Association. Diabetes Care 2010;33:S11-61 ADA Cholesterol Recommendations for Patients with Diabetes Mellitus (Continued) Primary and Secondary Prevention • Statin therapy should be added to lifestyle therapy, regardless of baseline lipid levels for diabetic patients: o With overt CV disease o Without CV disease who are over the age of 40 years and have >1 other CV disease risk factors • For patients at lower risk (without overt CV disease and <40 years of age), statin therapy should be considered in addition to lifestyle therapy if LDL-C remains >100 mg/dL or in those with multiple CV disease risk factors. ADA=American Diabetes Association, CV=Cardiovascular, LDL-C=Low density lipoprotein cholesterol Source: American Diabetes Association. Diabetes Care 2010;33:S11-61 ADA Cholesterol Recommendations for Patients with Diabetes Mellitus (Continued) Primary and Secondary Prevention • In individuals without overt CV disease, the primary goal is an LDL-C <100 mg/dL (2.6 mmol/L). • In individuals with overt CV disease, a lower LDL-C goal of <70 mg/dL (1.8 mmol/L), using a high dose of statin is an option. • If drug-treated patients do not reach the above targets on maximal tolerated statin therapy, a reduction in LDL-C of approximately 30-40% from baseline is an alternative therapeutic goal. • Triglyceride levels <150 mg/dL (1.7 mmol/L) and HDL-C >40 mg/dL (1.0 mmol/L) in men and >50 mg/dL (1.3 mmol/L) in women, are desirable. However, LDL-C targeted statin therapy remains the preferred strategy. ADA=American Diabetes Association, CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: American Diabetes Association. Diabetes Care 2010;33:S11-61 ADA Cholesterol Recommendations for Patients with Diabetes Mellitus (Continued) Primary Prevention • Triglyceride levels <150 mg/dL (1.7 mmol/L) and HDL-C >40 mg/dL (1.0 mmol/L) in men and >50 mg/dL (1.3 mmol/L) in women, are desirable. However, LDL-C targeted statin therapy remains the preferred strategy. • If targets are not reached on maximally tolerated doses of statins, combination therapy using statins and other lipid-lowering agents may be considered to achieve lipid targets but has not been evaluated in outcome studies for either CV disease outcomes or safety. • Statin therapy is contraindicated in pregnancy. ADA=American Diabetes Association, CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: American Diabetes Association. Diabetes Care 2010;33:S11-61 Cholesterol Management Recommendations (Continued) Secondary Prevention A lipid profile should be established in all patients, and for hospitalized patients, lipid-lowering therapy as recommended below should be initiated before discharge I IIa IIb III Lifestyle modifications including daily physical activity and weight management are strongly recommended for all patients Dietary therapy for all patients should include reduced intake of saturated fats (to <7% of total calories), trans fatty acids (to <1% of total calories), and cholesterol (to <200 mg/d) Source: Smith SC Jr. et al. JACC 2011;58:2432-2446 Cholesterol Management Recommendations (Continued) Secondary Prevention I IIa IIb III I IIa IIb III In addition to therapeutic lifestyle changes, statin therapy should be prescribed in the absence of contraindications or documented adverse effects An adequate dose of statin should be used that reduces LDL-C to <100 mg/dL AND achieves at least a 30% lowering of LDL-C I IIa IIb III Patients who have triglycerides >200 mg/dL should be treated with statins to lower non–HDL-C to <130 mg/dL Source: Smith SC Jr. et al. JACC 2011;58:2432-2446 Cholesterol Management Recommendations (Continued) Secondary Prevention I IIa IIb III I IIa IIb III I IIa IIb III Patients who have triglycerides >500 mg/dL should be started on fibrate therapy in addition to statin therapy to prevent acute pancreatitis If treatment with a statin (including trials of higher-dose statins and higher-potency statins) does not achieve the goal selected for a patient, intensification of LDL-C– lowering drug therapy with a bile acid sequestrant or niacin is reasonable For patients who do not tolerate statins, LDL-C–lowering therapy with bile acid sequestrants and/or niacin is reasonable Source: Smith SC Jr. et al. JACC 2011;58:2432-2446 Cholesterol Management Recommendations (Continued) I IIa IIb III Secondary Prevention It is reasonable to treat very high-risk* patients with statin therapy to lower LDL-C to <70 mg/dL I IIa IIb III I IIa IIb III In patients who are at very high risk* and who have triglycerides >200 mg/dL, a non–HDL-C goal of <100 mg/dL is reasonable The use of ezetimibe may be considered for patients who do not tolerate or achieve target LDL-C with statins, bile acid sequestrants, and/or niacin *Presence of established CVD plus 1) multiple major risk factors (especially diabetes), 2) severe and poorly controlled risk factors (especially continued cigarette smoking), 3) multiple risk factors of the metabolic syndrome (especially high triglycerides >200 mg/dL plus non-HDL-C >130 mg/dL with low HDL-C <40 mg/dL, and 4) patients with an ACS ACS=Acute coronary syndrome, CVD=Cardiovascular disease, HDL-C=High density lipoprotein cholesterol, LDL-C=Low density lipoprotein cholesterol Source: Smith SC Jr. et al. JACC 2011;58:2432-2446 Cholesterol Management Recommendations (Continued) Secondary Prevention I IIa IIb III For patients who continue to have an elevated non-HDL-C while on adequate statin therapy, consider niacin or fibrate therapy For all patients, it may be reasonable to recommend omega-3 fatty acids from fish or fish oil capsules (1 gram/day) for CV disease risk reduction CV=Cardiovascular, HDL-C=High density lipoprotein cholesterol Source: Smith SC Jr. et al. JACC 2011;58:2432-2446