Traditionally, clinicians and medical practitioners

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1 MANAGING DYSLIPIDEMIA THROUGH THE PA PATIENT RELATIONSHIP * John R. White, Jr, PharmD, PA-C ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in the Western world and in the United States. Despite the high and well-recognized mortality rate with CVD, as well as the epidemic levels of overweight and obesity and type 2 diabetes, most Americans are unable to successfully pursue behavioral changes that will reduce CVD risk (eg, regular exercise, better diet, smoking cessation, controlling hypertension and diabetes). In 2001, the Third Adult Treatment Panel of the National Cholesterol Education Program (NCEP ATP III) published updated guidelines on the treatment of abnormal cholesterol levels. Several key changes from ATP II profoundly affect the number of people eligible for lipid-lowering treatment. This article reviews the key changes in ATP III from ATP II and provides highlights on how these new guidelines affect physician-assistant practice through the use of 2 case studies. The challenge is to enable the patient to successfully pursue cholesterol reduction strategies and to convince the healthcare practitioner that preventing CVD is worth the time and effort in a busy office practice. (Adv Stud Med. 2003;3(9A):S864-S870) *Based on a presentation given by Dr White at a symposium held in conjunction with the American Academy of Physician Assistants 31st Annual Physician Assistant Conference. Professor, Primary Care Provider, Indian Health Service Clinic, and Professor, Department of Pharmacotherapy, Washington State University College of Pharmacy, Spokane, Washington. Address correspondence to: John R. White, Jr, PharmD, PA-C, Professor of Pharmacotherapy, Washington State University College of Pharmacy, PO Box 1495, Spokane, WA whitej@wsu.edu. Traditionally, clinicians and medical practitioners have maintained the view that coronary artery disease is caused by the arterial accumulation of cholesterol, leading to stenosis and, ultimately, occlusion. Our understanding of the pathophysiology underlying coronary artery disease shows that the process is more complex. Atherosclerosis is an inflammatory process involving several systems in the body. An atherosclerotic lesion can develop over decades and may be hidden as the arterial wall enlarges to compensate for the lesion, thus maintaining blood flow and being essentially invisible using standard imaging techniques. Narrowing of the lumen and flow limitation occur in more advanced stages. 1,2 This more complex pathophysiology offers an advantage; as we better understand the processes involved, we see numerous junctures for pharmacologic intervention that each process affords. EPIDEMIOLOGY Cardiovascular disease (CVD) is the leading cause of death in the Western world. It is a disease entity that encompasses many diagnoses, including hypertension, coronary heart disease (CHD), arrhythmias, chronic heart failure, and cerebral, peripheral, and renal vascular disease. According to the American Heart Association, approximately 13 million people in the United States have CHD, and about 1.4 million men and women die annually with CVD as a primary or contributing cause. 3 CVD caused 39.4% of deaths in 2000 (46.5% in men and 53.5% in women). It is a contributing cause in 60% of all deaths, and claims as many lives as the S864 Vol. 3 (9A) October 2003

2 next 5 leading causes of death combined (ie, cancer, chronic lower respiratory diseases, accidents, diabetes mellitus, and influenza and pneumonia). Those born in the United States today have about a 47% chance of dying from CVD versus about a 22% chance of dying from cancer. If CVD were eliminated, the average life span would increase by almost 7 years. 3 A fundamental question underlies these startling statistics: Why do such a large number of Americans have this disease? Although many factors contribute to CVD, including environment, inadequate healthcare, and genetic factors, an important answer is lifestyle: poor diet (high-fat/high-calorie foods, large portion sizes) and low physical activity, as well as obstacles to improvement (ie, nonexistent or unsafe walking areas; lack of healthy food choices, and extraordinary portion sizes in restaurants). PATHOPHYSIOLOGY A number of risk factors are associated with the pathophysiology of vascular disease. For CVD, they include dyslipidemia, hypertension, hyperglycemia, underlying genetics, smoking, and diabetes. These risk factors lead to a cumulative increase in oxidative stress through the creation of reactive oxygen species, which impact endothelial cells lining the lumen of arterial walls. As endothelial cells function abnormally over time, structural changes in the vascular system emerge in a process resulting in atherosclerosis. Remodeling includes structural alterations, such as abnormal vascular tone, smooth muscle cell growth, inflammatory cell infiltration, plaque growth, increased fibrinolysis, increased platelet aggregation, and increased inflammation. A remodeled arterial wall creates an environment that is conducive to occlusion by an atherosclerotic plaque, eventually leading to devastating outcomes, such as myocardial infarction (MI), stroke, and death. As mentioned earlier, however, these complicated processes and mechanisms in the development of CVD also offer numerous opportunities for therapeutic intervention. 1 (For a more detailed review on the atherosclerotic process, see the article by Dr Ferdinand, in this issue). TREATMENT CONCERNS Despite the high and well-recognized mortality rate with CVD, as well as epidemic levels of overweight and obesity and type 2 diabetes, most Americans have been unable to successfully achieve behavioral changes to reduce CVD risk (eg, regular exercise, better diet, smoking cessation, controlling hypertension and diabetes). Americans eat out of the home more often, and only 28% of US adults achieve the recommended levels of moderate or vigorous leisure-time physical activity. A full 29% report no regular physical activity outside of work. 4 It is difficult to initiate and incorporate lifestyle changes, but those who do will realize a significant change in health outcomes. The challenge is to help at-risk patients achieve these health benefits and to convince the healthcare practitioner that prevention of CVD is worth the time and effort in a busy office practice. In 2001, the Third Adult Treatment Panel of the National Cholesterol Education Program (NCEP ATP III) published updated guidelines on the treatment of abnormal cholesterol levels. Some of the key changes in ATP III are summarized in Table 1. ATP III now recommends a complete fasting lipoprotein profile (total cholesterol, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides) as the preferred initial test, rather than screening for total cholesterol and HDL cholesterol alone. Diabetes is classified as a CHD risk equivalent, indicating that those with type 2 diabetes have the same 10-year risk Table 1. NCEP ATP III: Key Changes from ATP II Recommends a fasting lipoprotein profile as initial test for high cholesterol Treats high levels of low-density lipoprotein cholesterol more aggressively for patients with diabetes Establishes new level at which a low level of high-density lipoprotein cholesterol becomes a major risk factor for cardiovascular disease Introduces therapeutic lifestyle changes treatment plan Identifies risk factors that define the metabolic syndrome Recommends more aggressive treatment for patients with elevated triglycerides Data from the Executive Summary of the Third Report of the National Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). 5 Advanced Studies in Medicine S865

3 of cardiovascular events as someone who has already had an MI the highest risk category. ATP III therefore recommends more stringent LDL cholesterol targets and more aggressive treatment of high cholesterol for patients with diabetes. ATP III also establishes a new level at which low HDL cholesterol becomes a risk factor for CVD and recommends treatment of elevated triglycerides. It also introduces 2 new concepts: the metabolic syndrome (also known as pre-diabetes, a potential risk factor for CVD; Table 2) and therapeutic lifestyle changes (TLC). TLC is recommended for any patient whose LDL level is above goal. 5 The implications of ATP III on the management of CVD risk are dramatic. By recommending more stringent LDL cholesterol goals, including other measures of dyslipidemia as therapeutic targets, identifying type 2 diabetes as a CHD risk equivalent, and actively identifying untreated and suboptimally treated patients, the number of patients who are candidates for lipidlowering therapy is nearly 3-fold higher, increasing from 13 million to 36 million. 6 According to the ATP III, LDL cholesterol targets are determined by the number of CHD risk factors, as shown in Table 3. Those with the lowest risk (ie, <10% risk of CHD in 10 years) should be treated to a target LDL cholesterol level below 160 mg/dl. Those with 2 or more risk factors should aim for LDL cholesterol levels below 130 mg/dl. Those with a greater than 20% CHD risk (which includes those with a CHD risk equivalent, such as type 2 diabetes, history of stroke, abdominal aneurysm, current vascular disease) should be treated to a target LDL cholesterol level below 100 mg/dl. The major risk factors that modify LDL cholesterol targets include age, cigarette smoking, family history, hypertension, and low (<40 mg/dl) HDL cholesterol levels (Table 4). Age as a risk differs between men and women (ie, >45 years for men, >55 years for women). Family history of premature CHD includes a first-degree male relative with a cardiac event at younger than 55 years of age or a firstdegree female relative who had a first event at younger than 65 years of age. One risk factor is subtracted from the total count if the HDL cholesterol level is above 60 mg/dl. For patients without established CHD or a CHD risk equivalent, the 10-year risk of CHD can be calculated using the Framingham Risk Calculator. The 2 treatment methods for lowering LDL cholesterol are lipid-lowering drug therapy and TLC. TLC emphasizes diet (low in saturated fat and cholesterol), Table 2. NCEP ATP III Definition of the Metabolic Syndrome 3 OF THE FOLLOWING 5 CHARACTERISTICS: Abdominal obesity (waist circumference) >40 in (men) >35 in (women) Triglycerides 150 mg/dl High-density lipoprotein cholesterol <40 mg/dl (men) <50 mg/dl (women) Blood pressure 130/ 85 mm Hg Fasting glucose 110 mg/dl Adapted from the Executive Summary of the Third Report of the National Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). JAMA. 2001;285(19): Table 3. NCEP ATP III: Major Risk Factors Affecting LDL Cholesterol Goals Age Men >45 years Women >55 years Cigarette smoking Family history of premature CHD Male first-degree relative aged <55 years Female first-degree relative aged <65 years Hypertension Blood pressure >140/90 mm Hg Currently receiving antihypertensive medication Low HDL cholesterol <40 mg/dl* Diabetes is a CHD risk equivalent *HDL cholesterol 60 mg/dl counts as a negative risk factor; its presence removes 1 risk factor from the total. LDL = low-density lipoprotein; CHD = coronary heart disease; HDL = high-density lipoprotein. Adapted from the Executive Summary of the Third Report of the National Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). JAMA. 2001;285(19): S866 Vol. 3 (9A) October 2003

4 The Framingham Risk Calculator is used to determine the 10-year risk of CHD. It is available in print format, on the Internet ( or as a free program that can be downloaded onto personal digital assistants from the National Heart, Lung, and Blood Institute ( treated to goal in the primary care setting. No difference in success rate was observed between men (37%) and women (39%), and success rate was not affected by height, weight, place of residence, whether the patient had medical insurance, or education (in low- or highrisk groups). However, in those with CHD, higher levels of education increased the success rate (44% for Table 4. NCEP ATP III: Risk Categories Dictating LDL Cholesterol Goals weight loss, and increased physical activity. The 10- year estimated risk and number of risk factors determine the target LDL cholesterol levels. Table 5 outlines the cutoff points based on risk category. In short, TLC is recommended for anyone whose LDL level is above the goal level. Drug therapy is recommended if TLC has not reduced LDL cholesterol to recommended levels after 3 months. In the highestrisk patients (ie, CHD or CHD risk equivalent), the target LDL level is below 100 mg/dl. Drug therapy is not formally recommended unless the LDL level is 130 mg/dl or above but may be considered in those with LDL levels of 100 to 129 mg/dl, based on clinical judgement. 5 OPTIMIZING TREATMENT Despite the published guidelines and the programs to educate healthcare practitioners on the importance of treating high cholesterol early and aggressively in appropriate patients, an enormous disparity remains between knowledge and application. A recent study of 4888 patients receiving lipid-lowering therapy from their primary care physicians (n = 606) showed that only 38% of patients had achieved NCEP ATP III target goals of LDL cholesterol after 3 months of treatment. However, 95% of the physicians stated they were aware of the NCEP guideline classification of cholesterol levels and follow them in practice. The patients who reached LDL goals were primarily low-risk patients at onset. Almost 70% of low-risk patients reached LDL goals compared with 37% of medium-risk patients; only 18% of patients with established CHD those who need it most reached target LDL levels. On average, only 38% of patients were Risk Category LDL Goal (mg/dl) CHD/CHD risk equivalents (>20% risk) <100 Multiple ( 2) risk factors (10% to 20% risk) < risk factor (<10% risk) <160 LDL = low-density lipoprotein; CHD = coronary heart disease. Adapted from the Executive Summary of the Third Report of the National Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). JAMA. 2001;285(19): Table 5. NCEP ATP III: LDL Cholesterol Goals and Cutoff Points for TLC and Lipid-Lowering Drug Therapy Based on Risk Category LDL Level at LDL Level at LDL Goal Which to Initiate Which to Consider Risk Category (mg/dl) TLC (mg/dl) Drug Therapy (mg/dl) CHD or CHD risk equivalents (10-yr risk >20%) < ( , drug optional) 2 risk factors (10-yr risk 20%) < yr risk 10% to 20%: yr risk <10%: risk factor < ( , drug optional) LDL = low-density lipoprotein; TLC = therapeutic lifestyle change; CHD = coronary heart disease. Adapted from the Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). JAMA. 2001;285(19): Advanced Studies in Medicine S867

5 those with a college degree or higher, 40% for those with some college or technical school education, 37% for high school graduates, and 32% for those who completed some high school). 7 A team approach to disease management is becoming more common with virtually all chronic diseases as the benefits are being realized. Therefore, a team approach to hyperlipidemia would also be useful. Traditionally, the primary relationship has been between the physician and the patient or the physician assistant (PA) and the patient. A healthcare team, however, would also reap the benefits of nurses and pharmacists knowledge and experience. In the Indian Health Service Clinic, pharmacists have a portable device to measure cholesterol levels on any patient at any time. In addition, students routinely examine patients charts and identify hyperlipidemic individuals who are untreated. The students contact the patients to arrange appointments at the clinic. Cholesterol levels are measured at the pharmacy, and by the prescriptive authority protocol, patients are treated for hyperlipidemia if required. Similarly, the nurses have been empowered to obtain lipid levels from patients. If the patient presents with a cold, the nurse can order a cholesterol check on the patient as they are being triaged, if he or she determines it necessary. Because PAs are predominantly in family practice, general practice, or internal medicine, they are in the front line of managing chronic diseases and encounter many patients with hyperlipidemia. With the NCEP ATP III guidelines, PAs also encounter many previously unidentified patients who are at risk for CHD and are undertreated with regard to cholesterol levels. It is the challenge of the PA to understand the risks associated with CVD, to appreciate the importance of preventing CVD (primary and secondary), and to incorporate the guidelines into practice. CONCLUSION CVD is the leading cause of death in the Western world. Hyperlipidemia is dramatically underdiagnosed and, when diagnosed, is often undertreated. The ATP III guideline update provides stringent treatment targets for the management of hyperlipidemia. More aggressive management is encouraged to avoid the common and costly cardiovascular events associated with CHD. Clearly, primary care providers are in an excellent position to identify the majority of these patients and to manage hyperlipidemia. CASE STUDIES CASE 1 A 52-year-old man with no significant medical history presents to a primary care physician for a pre-employment physical examination. He takes no medications but has smoked 1.5 packs of cigarettes per day for the past 25 years. His blood pressure is 161/95 mm Hg, and he is moderately obese (body mass index [BMI], 31 kg/m 2 ). His family history is positive for premature CHD; his father died from an MI at age 53 years. WORKUP The electrocardiogram (ECG) and chest radiograph are normal. Urinalysis is normal, and complete blood cell count is within normal limits. A chemistry profile reveals that the patient s fasting blood glucose levels, electrolytes, renal function, and hepatic function are within normal limits. His lipid profile reveals the following: total cholesterol, 182 mg/dl; LDL cholesterol, 138 mg/dl; HDL cholesterol, 50 mg/dl; and triglycerides, 190 mg/dl. DISCUSSION According to the NCEP ATP III guidelines, this patient s risk factors include a strong family history of CHD, current cigarette smoking (heavy), age, and high blood pressure. He would therefore be categorized as having more than 2 risk factors. His obesity, although not part of the ATP III guidelines, also places him at risk for CHD. The next step would be to calculate the patient s 10-year risk (using the Framingham risk calculator) of CHD; the result shows a 10-year risk between 10% and 20%, making him an intermediate-risk patient. Intuitively, we see that this patient is at increased risk, but calculation of his risk will identify his recommended treatment goals. For those with more than 2 risk factors and 10% to 20% 10-year risk, the target LDL cholesterol level is below 130 mg/dl. S868 Vol. 3 (9A) October 2003

6 The patient s LDL cholesterol level is 138 mg/dl. The practitioner is faced with the question of whether to initiate lipid-lowering therapy, institute TLC, or both. In this patient, it is recommended to start TLC first for 3 months, then reassess. In most cases, pharmacotherapy will be necessary. Arguments can be made for or against starting with pharmacotherapy immediately. The practitioner must determine the chances of success with prescribing TLC based on the practitioner s knowledge of and relationship with the patient. Failing TLC may reinforce the patient s idea that TLC is a waste of time and that drug therapy will take care of the problem. However, appropriate resources should be used if available dietitians are helpful in giving patients a well-defined plan for dietary changes. One strategy is to encourage patients to slowly make changes, often one at a time. TLC requires followup, patience, persistence, and a willingness to accept relapse. In those who can comply, the benefits are rewarding to both patient and provider. TLC is useful with or without lipid-lowering drugs. The Figure shows a model offered by NCEP on the treatment strategies using TLC. It is important to remember that guidelines are guidelines, not rules of law. They are intended for primary prevention in the general public. They take into account the cost of treating all who might benefit from lipid-lowering therapy and attempt to identify those who would obtain the most benefit, without disrupting the healthcare economy. The true art of medicine considers the individual patient and his or her lifestyle, needs, socioeconomic factors, education, personality, and complete medical history. CASE 2 A 51-year-old woman with an 8-year history of type 2 diabetes presents for a routine physical. She is obese (BMI, 36 kg/m 2 ), is a nonsmoker, and has no personal or family history of CHD. Her blood pres- Figure. Model of Steps in TLC from NCEP ATP III Visit 1 Begin lifestyle therapies Visit 2 Evaluate LDL response If LDL goal not achieved, intensify LDL-lowering therapy 6 weeks 6 weeks Visit 3 Evaluate LDL response If LDL goal not achieved, consider adding drug therapy Every 4-6 mos Visit N Monitor adherence to TLC Emphasize reduction of saturated fat and cholesterol intake Encourage moderate physical activity Consider referral to a dietician Reinforce reduction in saturated fat/cholesterol intake Consider adding plant stenols/sterols Increase fiber intake Consider referral to a dietician Initiate therapy for metabolic syndrome Intensify weight management and physical activity Consider referral to a dietician TLC = therapeutic lifestyle change; LDL = low-density lipoprotein. Adapted from the Executive Summary of the Third Report of the National Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III). JAMA. 2001;285(19): Copyright 2001, American Medical Association. All rights reserved. Advanced Studies in Medicine S869

7 sure is 133/90 mm Hg, for which she is taking an angiotensin-converting enzyme inhibitor (enalapril). She is also taking metformin. WORKUP Her ECG reveals a few premature ventricular contractions but is otherwise normal. Her chest radiograph is also normal. Urinalysis reveals microproteinuria. Her complete blood cell count is normal, but her fasting blood glucose level is 142 mg/dl, and her hemoglobin A 1c is 7.9% her diabetes is moderately controlled. Kidney and hepatic function tests are within normal limits. Her lipid profile is as follows: total cholesterol, 194 mg/dl; LDL cholesterol, 141 mg/dl; HDL cholesterol, 40 mg/dl; and triglycerides, 154 mg/dl. DISCUSSION This patient s 10-year risk can be calculated from the Framingham charts, but the presence of type 2 diabetes automatically puts her in the highest-risk category (diabetes is a CHD risk equivalent), thus defining her target LDL cholesterol level as below 100 mg/dl. The next step in this patient s treatment would be to initiate both TLC and pharmacologic therapy. At this time, during the development of the treatment plan, her other risk factors should be assessed, and strategies for removing or reducing those risk factors should be reviewed. REFERENCES 1. Pepine CJ. Why vascular biology matters. Am J Cardiol. 2001;88(suppl):5K-9K. 2. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med. 1987; 316(22): American Heart Association. Heart Disease and Stroke Statistics 2003 Update. Dallas, Tex: American Heart Association; Available at: org/statistics. Accessed August 25, Cooper R, Cutler J, Desvigne-Nickens P, et al. Trends and disparities in coronary heart disease, stroke, and other cardiovascular diseases in the United States: findings of the National Conference on Cardiovascular Disease Prevention. Circulation. 2000;102(25): Executive summary of the Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (ATP III). JAMA. 2001;285(19): Grundy SM. Clinical application of ATP III guidelines. Lipid Management. 2001;6(3). Published by the National Lipid Education Council. Available at: org/content/newsletter/vol6no3/pg1.asp. Accessed August 25, Pearson TA, Laurora I, Chu H, Kafonek S. The lipid treatment assessment project (L-TAP): multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med. 2000;160(4): S870 Vol. 3 (9A) October 2003