Dyslipidemia: What Every Resident Should Know

Med Study Lipoproteins Hyperlipoproteinemia Chylomicrons, VLDL, IDL, LDL, & HDL Hyperlipoproteinemia Familial syndromes Evaluation of hyperlipidemia Treatment of hyperlipidemia Guidelines, diet, & drugs

MKSAP Physiology & metabolism Diagnosis Management Secondary causes Increased LDL Increased triglycerides Decreased HDL

Pathways of Lipid Transport Figure 1. Pathways of Lipid Transport. Cholesterol is absorbed from the intestine and transported to the liver by chylomicron remnants, which are taken up by the low-density lipoprotein (LDL)-receptor-related protein (LRP). Hepatic cholesterol enters the circulation as very-low-density lipoprotein (VLDL) and is metabolized to remnant lipoproteins after lipoprotein lipase removes triglyceride. The remnant lipoproteins are removed by LDL receptors (LDL-R) or further metabolized to LDL and then removed by these receptors. Cholesterol is transported from peripheral cells to the liver by high-density lipoprotein (HDL). Cholesterol is recycled to LDL and VLDL by cholesterol-ester transport protein (CETP) or is taken up in the liver by hepatic lipase. Cholesterol is excreted in bile. The points in the process that are affected by the five primary lipoprotein disorders -- familial hypertriglyceridemia (FHTG), familial combined hyperlipidemia (FCHL), remnant removal disease (RRD, also known as familial dysbetalipoproteinemia), familial hypercholesterolemia (FH), and hypoalphalipoproteinemia -- are shown. The effects of drug therapy can also be understood from these pathways. Statins decrease the synthesis of cholesterol and the secretion of VLDL and increase the activity of LDL receptors. Bile-acid-binding resins increase the secretion of bile acids. Nicotinic acid decreases the secretion of VLDL and the formation of LDL and increases the formation of HDL. Fibrates decrease the secretion of VLDL and increase the activity of lipoprotein lipase, thereby increasing the removal of triglycerides. Adapted from Knopp.12 Knopp, R. H. N Engl J Med 1999;341:498-511

Primary Lipoprotein Disorders Amenable to Treatment with Diet and Drug Therapy Table 1. Primary Lipoprotein Disorders Amenable to Treatment with Diet and Drug Therapy. Knopp, R. H. N Engl J Med 1999;341:498-511

Pathophysiologic Events Culminating in the Clinical Syndrome of Unstable Angina Figure 1. Pathophysiologic Events Culminating in the Clinical Syndrome of Unstable Angina. Numerous physiologic triggers probably initiate the rupture of a vulnerable plaque. Rupture leads to the activation, adhesion, and aggregation of platelets and the activation of the clotting cascade, resulting in the formation of an occlusive thrombus. If this process leads to complete occlusion of the artery, then acute myocardial infarction with ST-segment elevation occurs. Alternatively, if the process leads to severe stenosis but the artery nonetheless remains patent, then unstable angina occurs. Yeghiazarians, Y. et al. N Engl J Med 2000;342:101-114

JAMA 2001; 285: 2486-2497

NCEP Reports ATP I (1988) ATP II (1994) ATP III (2001) Prevention of CHD among patients with high LDL (160) or borderline high LDL (130-159) with multiple (2) risk factors ATP II (1994) Intensive management of LDL (100) among patients with established CHD ATP III (2001) Prevention of CHD among high-risk patients DM as a CHD risk equivalent Use of Framingham risk score Therapeutic lifestyle changes

NCEP - ATP III JAMA 2001; 285: 2486-2497

Question #1 How often should the average adult patient have his or her lipids measured?

Routine Testing Adults ≥ 20 yo should have a fasting lipid panel measured every 5 years If the specimen is non-fasting, then only the TC and HDL values can be used Obtain a fasting lipid panel if… TC ≥ 200 mg/dl, or HDL ≤ 40 mg/dl JAMA 2001; 285: 2486-2497

Question #2 What is the formula for calculating LDL from total cholestrol (TC), HDL, & triglycerides (TG)?

Calculation of LDL LDL = TC – [HDL + (TG  5)] TC = HDL + LDL + VLDL (TG  5) is an estimate of VLDL Formula is not reliable if TG > 400 mg/dl

Question #3 What are 5 potential causes of “secondary dyslipidemia” that should be ruled out before to initiating lipid-lowering therapy?

Secondary Dyslipidemia Diabetes mellitus Hypothyroidism Obstructive liver disease Chronic renal failure Drugs Anabolic steroids, corticosteroids, progestins, thiazides, protease inhibitors, Cyclosporine, Sertraline (Zoloft), Isotretinoin (Accutane) JAMA 2001; 285: 2486-2497

Secondary Dyslipidemia Increased LDL Obesity Hypothyroidism Nephrotic syndrome Biliary cirrhosis Thiazide diuretics Pregnancy Increased triglycerides Obesity Diabetes Hypothyroidism Chronic kidney disease Alcohol Thiazide diuretics Corticosteroids Nonselective -blockers Estrogen Pregnancy MKSAP 13

Question #4 According to ATP III, what are the 3 categories of risk that modify LDL goals?

Categories of Risk CHD and CHD risk equivalents Multiple (2+) risk factors Few (0-1) risk factors

Question #5 According to ATP III, which conditions are considered to be CHD risk equivalents?

CHD Risk Equivalents Other forms of atherosclerotic disease Peripheral arterial disease Abdominal aortic aneurysm Symptomatic carotid artery disease Diabetes mellitus Multiple risk factors that confer a 10-year risk for CHD >20% Framingham point score

Question #6 According to ATP III, what are the 5 major CVD risk factors that modify LDL goals?

Major Risk Factors Age Family history of premature CHD Men  45 yo Women  55 yo Family history of premature CHD Males < 55 yo Females < 65 yo Cigarette smoking Hypertension (>140/90 mmHg or on meds) Low HDL (< 40 mg/dl)

Question #7 For which of the following patients should you calculate a Framingham point score in order guide your lipid-lowering therapy? A 50 yo man with CHD A 60 yo woman with diabetes mellitus A 50 yo man who smokes cigarettes A 60 yo woman without any other risk factors

Multiple Risk Factors Patients with  2 risk factors Framingham point score Ten-year risk for CHD > 20% 10-20% < 10%

Question #8 According to ATP III, what is the LDL goal for each of the 3 categories of risk? CHD or CHD risk equivalent Multiple (2+) risk factors Few (0-1) risk factors

LDL Goals JAMA 2001; 285: 2486-2497

LDL Goals Diabetes mellitus Chronic kidney disease LDL < 100 ADA Guidelines (2005) Chronic kidney disease KDOQI Guidelines (2003)

Question #8 According to ATP III, what are the LDL cutpoints for initiating therapeutic lifestyle changes and drug therapy for each category of risk? CHD or CHD risk equivalent Multiple (2+) risk factors Few (0-1) risk factors

LDL Cutpoints JAMA 2001; 285: 2486-2497

Question #10 According to ATP III, which therapeutic lifestyle changes (TLC) should physicians recommend to patients with dyslipidemia?

Therapeutic Lifestyle Changes Low-fat diet Refer to a nutritionist www.nutrition.gov Increased physical activity www.fitness.gov Weight reduction www.nhlbi.nih.gov/health/public/heart/obesity/lose_wt/index.htm JAMA 2001; 285: 2486-2497

Model of Steps in Therapeutic Lifestyle Changes (TLC) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA 2001;285:2486-2497. Copyright restrictions may apply.

Question #11 Which of the following classes of drugs can lower LDL the most? Bile acid sequestrants Fibric acids Nicotinic acid Statins (HMG CoA reductase inhibitors)

LDL Lowering-Drugs Statins 18-55% Bile acid sequestrants 15-30% Atorvastatin (Lipitor) & Simvastatin (Zocor) Bile acid sequestrants 15-30% Cholestyramine (Questran) & Colestipol (Colestid) Nicotinic acid 5-25% Niacin ER (Niaspan) Fibic acid 5-20% Fenofibrate (Tricor) & Gemfibrozil (Lopid)

Characteristics of Statins Table 4. Characteristics of Statins. Knopp, R. H. N Engl J Med 1999;341:498-511

Circulation 2004; 110: 227-239

Progression of Drug Therapy in Primary Prevention Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA 2001;285:2486-2497. Copyright restrictions may apply.

Circulation 2004; 110: 227-239

Recent Clinical Trials HPS Lancet 2002; 360: 7-22 PROSPER Lancet 2002; 360: 1623-1630 ALLHAT-LLT JAMA 2002; 288: 2998-3007 ASCOT-LLA Lancet 2003; 361: 1149-1158 PROVE IT – TIMI 22 N Engl J Med 2004; 350: 1495-1504

Heart Protection Study 20,536 adults age 40-80 yo with CHD, PAD, or diabetes mellitus Simvastatin (Zocor) 40 mg qd v placebo Follow-up = 5 years LDL  132.6 to 89.7 mg/dl Primary outcomes All-cause mortality RR  13% (12.9% v 14.7%) Vascular mortality RR  17% (7.6% v 9.1%) CHD mortality RR  18% (5.7% v 6.9%) Lancet 2002; 360: 7-22

Prospective Study of Pravastatin in the Elderly at Risk 5,804 adults age 70-82 yo with, or at risk of, CVD Pravastatin (Pravachol) 40 mg qd v placebo Follow-up = 3.2 years LDL  148.2 to 97.8 mg/dl Primary outcome Composite of CHD death, non-fatal MI, and fatal or nonfatal stroke RR  15% (14.1% v 16.2%) Lancet 2002; 360: 1623-1630

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial – Lipid-Lowering Trial 10,355 adults ≥ 55 yo with HTN and ≥ 1 other CHD risk factor Pravastatin (Pravachol) 40mg qd v placebo Follow-up = 4.8 years LDL  145.6 to 104 mg/dl No difference in the primary outcomes All-cause mortality CVD death CHD events and stroke  9% (stat. nonsignif.) JAMA 2002; 288: 2998-3007

Anglo-Scandinavian Cardiac Outcomes Trial – Lipid-Lowering Arm 10,305 adults aged 40-79 yo with HTN Atorvastatin 10mg po qd v placebo Follow-up = 3.3 years LDL  132.6 to 90.5 mg/dl Primary outcome Composite of fatal CHD and nonfatal MI RR  36% (6% v 9.4%) Lancet 2003; 361: 1149-1158

Pravastatin or Atorvastatin Evaluation and Infection Therapy 4,162 adults ≥ 18 yo hospitalized for ACS Atorvastatin (Lipitor) 80mg qd v Pravastatin (Pravachol) 40 mg qd Follow-up = 2 years LDL values Atorvastatin  106 to 62 mg/dl Pravastatin  106 to 95 mg/dl Primary outcome Composite of all-cause mortality, MI, unstable angina, revascularization, and stroke RR  16% (22.4% v 26.3%) N Engl J Med 2004; 350: 1495-1504

Circulation 2004; 110: 227-239

Lancet 2005; 366: 1267-1278

CTT (2005) 14 RCTs of statins published 1994-2004 90,056 subjects 55% had HTN 47% had CHD 21% had DM Mean follow-up = 4.7 years Mean baseline LDL = 147.8 mg/dl Mean decrease in LDL after 1 yr = 42.5 mg/dl Lancet 2005; 366: 1267-1278

CTT (2005)

CTT (2005) Risk reduction per 1 mmol/L (39 mg/dl) decrease in LDL cholesterol: All-cause mortality 12% CHD death 19% Major coronary events 23% Coronary revascularization 24% Ischemic stroke 19% Major vascular events 21% No significant increase in the risk of cancer or rhabdomyolysis Lancet 2005; 366: 1267-1278

Question #12 What is the incidence of elevated liver transaminase levels with statin use?

Hepatotoxicity PROSPER: ALT & AST > 3X ULN HPS: ALT > 2X ULN Pravastatin 0.0003% v placebo 0.0003% HPS: ALT > 2X ULN Simvastatin 1.8% v placebo 1.6% PROVE IT: ALT > 3X ULN Atorvastatin 3.3% v Pravastatin 1.1%

Question #13 What is the incidence of skeletal muscle toxicity with statin use? Myalgias Elevated creatinine kinase (CK) Rhabdomyolysis

Myotoxicity Myalgias Elevated CK > 4X ULN Elevated CK > 10X ULN PROSPER: Prava. 0.01% v placebo 0.01% PROVE IT: Atorva. 3.3% v Prava. 1.1% Elevated CK > 4X ULN HPS: Simva. 0.30% v placebo 0.19% Elevated CK > 10X ULN PROSPER: Prava. 0% v placebo 0% Rhabdomyolysis HPS: Simva. 0.05% v placebo 0.03% PROVE IT: Atorva. 0% v Prava. 0%

Question #14 According to ATP III, what are the five clinical features of the metabolic syndrome?

JAMA 2001; 285: 2486-2497

Question #13 Which of the following classes of drugs can lower triglycerides (TG) the most? Bile acid sequestrants Fibric acids Nicotinic acid Statins (HMG CoA reductase inhibitors)

TG-Lowering Drugs Fibic acid 20-50% Nicotinic acid 20-50% Fenofibrate (Tricor) & Gemfibrozil (Lopid) Nicotinic acid 20-50% Niacin ER (Niaspan) Statins 7-30% Atorvastatin (Lipitor) & Simvastatin (Zocor) Bile acid sequestrants No change Cholestyramine (Questran) & Colestipol (Colestid)

Question #14 Which of the following classes of drugs can raise HDL the most? Bile acid sequestrants Fibric acids Nicotinic acid Statins (HMG CoA reductase inhibitors)

HDL-Raising Drugs Nicotinic acid 15-35% Fibic acid 10-20% Niacin ER (Niaspan) Fibic acid 10-20% Fenofibrate (Tricor) & Gemfibrozil (Lopid) Statins 5-15% Atorvastatin (Lipitor) & Simvastatin (Zocor) Bile acid sequestrants 3-5% Cholestyramine (Questran) & Colestipol (Colestid)

JAMA 2001; 285: 2486-2497

Lipid-Lowering Medications and Effects on HDL Cholesterol Levels Table 1. Lipid-Lowering Medications and Effects on HDL Cholesterol Levels. Ashen, M. D. et al. N Engl J Med 2005;353:1252-1260

Question #15 What is the role of Ezetimibe (Zetia) in lipid-lowering drug therapy?

Role of Ezetimibe Inhibits intestinal absorption of cholesterol Dose = 10 mg po qd Ezetimibe alone  LDL 18-20%, whereas Ezetimibe + Simvastatin  LDL 44-61% J Am Coll Cardiol 2002; 40: 2125-2134 Mayo Clin Prac 2004; 79: 620-629 Ezetimibe added to statin therapy helped 71% of patients achieve their target LDL Mayo Clin Prac 2005; 80: 587-595 No RCTs with clinical outcomes

Question #14 What is “intensive” statin therapy?

Intensive Statin Therapy PROVE IT – TIMI 22 N Engl J Med 2004; 350: 1495-1504 REVERSAL JAMA 2004; 291; 1071-1080 A to Z JAMA 2004; 292: 1307-1316 IDEAL JAMA 2005; 294: 2437-2445 TNT N Engl J Med 2005; 352: 1425-1435

Treating to New Targets 10,001 adults aged 35-75 yo with CHD Atorvastatin (Lipitor) 10 mg qd v 80 mg qd Follow-up = 4.9 years LDL values 10 mg  98 to 101 mg/dl 80 mg  99 to 77 mg/dl Primary outcome  22% Composite of CHD death, nonfatal MI, resuscitation from cardiac arrest, and fatal or nonfatal stroke N Engl J Med 2005; 352: 1425-1435

References “Executive Summary of the Third Report of the National Cholesterol Education Panel (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).” JAMA 2001; 2486-2497. http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm Grundy SM, et al. “Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.” Circulation 2004; 110: 227-239. Cholesterol Treatment Trialists’ Collaborators. “Efficacy and Safety of Cholesterol-Lowering Treatment: Prospective Meta-analysis of Data from 90,056 Participants in 14 Randomized Trials of Statins.” Lancet 2005; 366: 1267-1278.

References Knopp RH. “Drug Treatment of Lipid Disorders.” N Engl J Med 1999; 341: 498-511. Ashen MD, Blumenthal RS. “Low HDL Cholesterol Levels.” N Engl J Med 2005; 353: 1252-1260.