DYSLIPIDEMIA: AN UPDATE

Introduction      
     Atherosclerosis is recognized as pervasive in Western societies, an inevitable consequence of aging and a by-product of the evolutionary success of medical science over the ages in prolonging life in modern society to a point where atherosclerosis and ensuing cardiovascular disease (CVD) have become far more significant as causes of death than simple infections. CVD, in fact, is currently responsible for as much as 40% of all deaths in the United States, with a staggering estimated annual price tag of some 260 billion dollars. While ultimate causes of CVD are admittedly complex and often involve multiple underlying disease states and contributing factors, atherosclerosis is undeniably a primary factor in the overwhelming majority of non-congenital CVD.
     Likewise, dyslipidemia is one of the more obvious contributing factors to both atherosclerosis and thrombus formation, not only promoting the formation of atherosclerotic plaques, but enhancing the likelihood of unstable ischemic events. The prevailing relative absence of dyslipidemia and CVD, even in old age, in a few selected other societies with significantly different dietary and lifestyle factors remains proof that atherogenesis is a disease process largely preventable in most cases, at least in theory.
     Dyslipidemia thus remains a primary clinical focus of the medical industry in both prevention and management of CVD, as a multi-faceted approach consisting of blood pressure control, regular exercise, management of body weight, limitation of dietary lipid intake, and pharmaceutical reduction of blood lipid levels. This combination of tactics has consistently proven to reduce risks of fatal CVD events.

Treatment Guidelines
     The National Cholesterol Education Program (NCEP) has recently issued a third update of its recommendations for detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III, or ATPIII); and the US Preventive Services Task Force (USPSTF) 2001 recommendations for screening and treatment of hypercholesterolemia include primary prevention for individuals without CVD, and secondary prevention for those with CVD.

USPSTF Recommendation Designations for Screening
* "A" recommendation -- Very good evidence of improved health outcomes and evidence that benefits of treatment substantially outweigh associated risks: routine cholesterol screening of all men aged 35 years or older and all women aged 45 years or older.
* "B" recommendation -- Fair evidence of improved outcomes and clear evidence that benefits outweigh risks: Men 20 to 35 and women 20 to 45 with other risk factors for CVD like diabetes, family history of early myocardial infarction, family history of hypercholesterolemia, or multiple risk factors, like smoking and hypertension.
* "C" recommendation: Fair evidence of improved outcomes with balance of benefit vs risk is too close to justify a general recommendation.
* "D" recommendation: Evidence that intervention is ineffective, or that if effective, potential harm of treatment outweighs the potential benefits.
* "I" recommendation: Insufficient data for recommending for or against providing the treatment.

     ATP III guidelines focus on risk assessment to determine aggressiveness of intervention, using number of risk factors to determine LDL cholesterol goals.

Risk Factors
* Tobacco use
* Hypertension, even if normalized by anti-hypertensive therapy
* HDL cholesterol below 40 mg/dL, (though HDL over 60 mg/dL is considered a beneficial factor)
* Family history of premature coronary heart disease: Documented CVD in first-degree male relative under 55 years of age or female under 65 years
* Age: Men over the age of 45 and women over 55

Therapeutic Goals for LDL Target Levels
* Zero or one risk factor: Target level is 160 mg/dL or lower. Consider drug therapy if over 190 mg/dL.
* Two or more risk factors: Target level is 130mg/dL or lower. Consider drug therapy if over 160 mg/dL.
* Patients with two or more risk factors may be further evaluated for 10-year risk of CHD by assessing variables of age, gender, total and HDL cholesterol levels, tobacco use, systolic blood pressure, and current antihypertensive medication. LDL target level for these patients is 100 mg/dL or lower with drug therapy indicated where LDL is 130 mg/dL or higher.

Management
     Lifestyle changes are the obvious first therapeutic choice in almost any case of dyslipidemia, as side effects and regimen compliance tend to become significant issues with almost any medical intervention, especially with long-term therapy.
     A patient-specific regimen of regular exercise is an essential first step, since exercise itself tends to improve dyslipidemia to some degree even in the absence of other intervention; and it also generally improves glucose tolerance, with a commensurate direct effect on hypertension. Exercise also tends to help control obesity, whose significant contribution to dyslipidemia is as obvious as its connection to hypertension. In the obese patient, the circulatory system must pump through literally miles more capillaries through increased resistance, so any reduction in body fat can improve atherosclerotic prognosis. Regular aerobic exercise of large muscle groups can be expected to reduce levels total cholesterol, LDL, VLDL, and triglycerides, while increasing HDL cholesterol.
     Similarly, smoking cessation can not only reduce lipid levels, but reduce blood pressure as well; and while moderate consumption of alcohol has actually been shown beneficial in managing lipid levels and blood pressure, efforts to reduce overconsumption cannot be overemphasized.
     Dietary changes are also considered first-line therapy, reducing intake of saturated fats and cholesterol, while increasing intake of plant stanols or sterols to 2 to 3 grams per day. Found in vegetable oils, nuts, corn, rice, and in many yellow or orange fruits and vegetables, these substances are not absorbed, but can significantly decrease cholesterol absorption simply by being present in the intestine. Intake of soluble fibers should also be increased to 10-25 grams per day. Step-1 diets limit caloric intake from saturated fats to 8 to 10% and cholesterol intake to a maximum of 300 mg per day; Step-2 diets limit caloric intake from saturated fats to below 7% and daily cholesterol intake to a maximum of 200 mg per day.
      While the benefits of lifestyle measures are uncontested, even drastic changes may produce only marginal beneficial changes. Undoubtedly, genetic tendencies play a significant role in lipid levels for a great many patients, and this may limit the effectiveness of lifestyle changes for many patients. Even more significant, though, is the issue of practicality of such lifestyle changes. Removing habits a patient finds enjoyable, however self-destructive they may be, is often very difficult; and while changing one’s dietary habits may sound like a very logical and simple step to take, decades of cooking and eating habits can be challenging changes for an individual, especially when such dietary changes affect an entire family’s eating habits. Thus, this issue of compliance is the primary reason for failure of such measures to control lipid levels for most patient populations.

Medical Management
     Bile acid sequestrants, fibric acid derivatives, and nicotinic acid all have their appropriate places in dyslipidemia therapy; but the HMG CoA reductase inhibitors, the “statins,” have unquestionably revolutionized treatment of lipid disorders, with their relatively favorable side effect profile and their remarkable effectiveness at producing broad and drastic improvements in lipid profiles for the vast majority of patients. While drastic lifestyle changes might be expected to bring about as much as a 15% change in lipid levels, it is not unusual for only low to moderate doses of statins to produce twice that change for many patients. With common once-daily dosing, it is little wonder the statins have become the backbone of dyslipidemia therapy. While other agents might be better choices for dyslipidemia involving primarily triglycerides, the HMG CoA reductase inhibitors seem to be more effective overall and are the drugs of choice for those patients whose disorders involve total and/or LDL cholesterol, or those plus triglycerides.
    As with almost any medical management issue, the optimum individual choice usually involves a combination of every effort to make appropriate lifestyle changes coupled by what is largely an educated guess as to which agent will be both most effective and best-tolerated by the individual. Agents, though, that produce significant bothersome side effects can be expected to be less effective overall due to compliance issues.
     The fibric acids are known for causing dyspepsia, myopathies, and increased incidence of gallstones; nicotinic acid is noted for causing flushing, hyperglycemia, hyperuricemia, dyspepsia, and hepatotoxicity; and bile acid sequestrants are noted for causing generalized gastrointestinal symptoms including constipation. Myopathies, and specifically rhabdomyolysis, are certainly valid concerns with all except the bile acid sequestrants, but these events are actually rare with all such agents at reasonable doses and without combinations. The highly publicized hepatotoxic events associated with cerivastatin that prompted its removal from the market generally involved combinations with either other statins or fibric acid derivatives clearly recommended against in prescribing information.

Monitoring
      Monitoring of all lipid levels is essential throughout therapy; and since the HMG CoA reductase inhibitors, the fibric acid derivatives, and nicotinic acid all have a tendency to alter hepatic function, liver function tests are also essential with these agents. Evaluation of therapeutic efforts should generally be done at six-week intervals, from lifestyle changes to dosage adjustments and additions to medical regimens. When initial measures prove inadequate to attain therapeutic goals at any stage, the importance of lifestyle changes should be reinforced and level of intensity of such interventions may be considered; and either dosage increase of initial therapeutic agent or addition of a bile acid sequestrant or nicotinic acid should be considered.
     A number of home monitors are now commercially available for the patient to monitor his own cholesterol levels on a daily basis, which promises to help facilitate efficacy, especially of lifestyle modifications. To avoid commercial bias in this article, the reader is encouraged to simply do an Internet search by entering “home monitor” and “cholesterol” as search parameters in almost any good search engine. Most available options seem reasonably reliable and affordable for the patient striving for optimum daily control by lifestyle measures.
     Assessing liver function (LFTs) prior to initiating therapy with HMG CoA reductase inhibitors is essential, as the wisdom of their utilization with existing liver damage must be carefully weighed. LFTs should also be reassessed periodically during therapy, and especially when doses are increased or when combinations are utilized. Care should also be taken to minimize the risk of hepatic impairment by coadministration of other therapeutic agents used for other conditions, in order to avoid drug interactions that might inhibit metabolism or elimination of statins (or other agents with hepatotoxic potential) or exacerbate their potential for hepatotoxicity or myopathies. Atorvastatin , lovastatin , and simvastatin are metabolized extensively by the CYP3A4 enzyme system and thus may interact with CYP3A4 inhibitors; while fluvastatin is primarily metabolized by CYP2C9, making it vulnerable to interactions with CYP2C9 inhibitors.

References
1. LaRosa, J. Chemoprevention of Coronary Atherosclerosis: The Role of Lipid Interventions. A Position Paper of the American Council on Science and Health. Available at: http://www.medscape.com/viewarticle/430061. Accessed April 7, 2002.
2. The HMG-CoA Reductase Inhibitors – New Safety Concerns? Available at: http://www.medscape.com/viewarticle/420890. Accessed April 7, 2002.
3. High Cholesterol and Dyslipidemia – New Treatments, February 8, 2002. Available at: http://www.ccspublishing.com/journals2/dyslipidemia.htm. Accessed April 7, 2002.
4. McKenney, J. New Guidelines for Managing Hypercholesterolemia. Available at: http://www.medscape.com/viewarticle/406726_print. Accessed April 7, 2002.
5. Atherosclerosis and Dyslipidemia. Available at: http://www.diabetic-lifestyle.com/articles/apr99 whats 1.htm. Accessed April 7, 2002.