Managing Hyperlipidemia: An Evidence-Based Approach John Varras, MD For a CME/CEU version of this article please go to http://www.namcp.org/cmeonline.htm, and then click the activity title. Summary To best manage patients with hyperlipidemia, clinicians need to use an evidence- based approach. Based on the evidence, statins are the medications of choice for most patients who need lipid lowering therapy. The presence of various risk factors will determine the appropriate LDL goal for a particular patient. Some patients can benefit from aggressive lipid lowering. Key Points • Lifestyle changes are an important part of hyperlipidemia treatment. • Statins are the drug of choice for most patients with elevated LDL. • Side effects with statins are uncommon, but they do occur more frequently at higher doses. • It is optimal to have an LDL goal of less than 70 in high-risk patients and less than 100 in moderately high-risk patients. • Diabetic patients, those with acute coronary syndrome, and those with multiple or uncontrolled risk factors are at high risk for cardiovascular events and should be treated aggressively. AGGRESSIVELY TREATING HYPERLIPIDEMIA is a major secondary cause, especially of hyper- is an area where the biggest differences have been made triglyceridemia and low HDL.With hypothyroidism, in cardiovascular disease in the last few years. Lipids treating the thyroid disease may revert the lipids back play a significant role in the atherosclerotic process.1,2 to normal. Medications also can be a factor in elevated Low density lipoprotein (LDL) particles become locat- lipids.As an example, thiazides and beta-blockers can ed within the intima of the artery at areas of hemody- worsen lipid control. namic stress. The LDL particles undergo oxidative The National Cholesterol Education Program modification, which leads to uptake by the endothelial (NCEP) guidelines are used in the United States to cells and expression of inflammatory markers, which manage lipids disorders. 3 The most recent update to increases the likelihood of thrombus formation. these guidelines was published in 2004.4 According Inflammation induces the plaque to be unstable.When to these guidelines, patients are stratified based on unstable plaque ruptures, a thrombus forms. cardiac risk factors and coronary heart disease equiv- High-density lipoprotein (HDL) cholesterol has alents into low risk, moderate risk, moderately high the opposite effect. It has anti-atherogenic properties and high risk categories (Exhibit 3). 3,4 Each category and reverses cholesterol transports, helps in endothelial has individual goals. dysfunction, and reduces thrombosis. High HDL People at low risk for developing heart disease are cholesterol is a good thing, and when risk factors are the easiest to manage. One is considered low risk if he evaluated, providers can actually subtract a cardiac or she has zero to one risk factor in addition to a lipid risk factor if the patient has high HDL cholesterol. disorder.The goal LDL is less than 160 gm/dL. If the Treatment is not started based on one lipid measure- LDL is > 160 mg/dL, the patient is started on thera- ment. Two lipid measurements at least two weeks peutic lifestyle changes. Because lifestyle changes are apart and baseline tests to rule out secondary causes unlikely to produce a sufficient decline, medication is and to monitor liver function are needed. started if the LDL is greater than 190 mg/dL. Secondary causes of hyperlipidemias need to be Patients are considered to be at moderate risk for ruled out and treated if present (Exhibit 2). Diabetes developing heart disease if they have two or more www.namcp.org | Vol. 11, No. 2 | Journal of Managed Care Medicine 17 Exhibit 1: Atherosclerotic in the Human Artery Exhibit 2: Secondary Causes A C Thrombus 1. DM Thrombus Endothelium Smooth Ruptured cap muscle cell 2. Hypothyroidism Lipid-rich core B 3. Obstructive liver disease Proteases, prothrombotic 4. Chronic renal failure, nephrotics syndrome T cell factors Mast cell 5. Medications: progestins, estrogen, androgens, Macrophage corticosteriods, thiazides, beta-blockers, Microbes, protease inhibitors, isotretinoin, alcohol autoantigens, and tobacco inflammatory molecules risk factors in addition to a lipid issue. Their goal from their baseline lipids. This is achievable with LDL is less than 130 mg/dL. Therapeutic lifestyle standard doses of the statins. changes are started if LDL is greater than 130 and When treating patients with lipid disorders, LDL medication if greater than 160 mg/dL. cholesterol is the number one goal by the guidelines. The next group is patients at moderately high risk. Once LDL is controlled, non-HDL cholesterol can These are people with two plus risk factors, and an be addressed. Non-HDL cholesterol is total cholesterol estimated risk of developing heart disease in the next minus HDL. The patient’s non-HDL goal is their 10 years of 10 to 20 percent.Their goal LDL is 130 LDL goal plus 30. mg/dL. By the recent guideline updates, it is an Therapeutic lifestyle changes (TLC) are important option to treat these patients more aggressively to an in controlling lipids. All patients that are above goal LDL goal of less than 100.4 Patients with moderately cholesterol or even those with just multiple risk factors high risk and multiple risk factors or severe risk factors should be begun on TLC. that are uncontrolled would benefit from more In general, the patient should consume less than 25 aggressive treatment. to 30 percent of the calories from fat. Saturated fat The highest risk group already has coronary disease intake should be reduced and dietary cholesterol or one of its equivalents or two plus risk factors and should be less than 200 milligrams a day. Patient can an estimated ten year risk of greater than 20 percent. reduce their lipids by reducing fat intake, increasing The goal LDL for this group in general is an LDL fiber to 20 to 30 grams a day, adding plant stanols and less than 100, but there is the therapeutic option of sterols in their diet, losing weight, and exercising aer- treating them more aggressively to less than 70. obically at least 30 minutes the majority of days of Medications should be started in these patients if the the week. Patients with maximal TLC can lower LDL is greater than 100. If they are within the 70 to their LDL by 25 to 30 percent, which can get some 100 range,it also is an option to start them on treatment patients to their goal. then. Certain patients within this highest risk group For a lot of patients, medications will be necessary should be treated most aggressively. Patients who to achieve goal lipid values.The statins work by partially have acute coronary syndrome (ACS) are at the inhibiting HMG-CoA reductase, which is the rate- highest risk of having a cardiovascular event in the limiting step in cholesterol synthesis.They lower LDL near future. Patients with multiple risk factors or by 20 to 60 percent and increase HDL relatively severe poorly controlled risk factors also benefit from modestly (5 to 15 percent), and lower triglycerides. aggressive treatment. These medications reduce coronary events, cardiac The risk of coronary heart disease is log linear deaths, and the need for cardiovascular procedures. It associated with LDL cholesterol. For every 1 percent is unknown if the LDL lowering effect of statins pro- reduction in LDL, there is a relative risk reduction of vides the mortality benefit or if it is the other effects 1 percent.Trials show that this occurs even at LDLs of these agents.They have anti-inflammatory effects, of less than 100.The updated guidelines recommend enhance fibrinolysis, and reduce platelet function.The now that not only should patients get to their goal statins are the only lipid lowering class that has been LDL, they should have a 30 to 40 percent reduction shown to improve total mortality in primary and 18 Journal of Managed Care Medicine | Vol. 11, No. 2 | www.namcp.org secondary prevention.This is why statins are the drug niacin is available (Advicor®). Because it is an older of choice in patients with elevated LDL. medication, the outcomes based data is not as good as Although the agent of choice, they do have some that with statins. There are trials that show reduced adverse effects. Overall, statins are usually very well tol- coronary events, possible reduced total mortality in erated.The one-year discontinuation rate secondary to secondary prevention, and possibly reduced progression adverse effects is about 15 percent.This is much better of carotid disease when niacin is added to a statin. than for the other classes of lipid lowering agents. Unfortunately,there can be a lot of adverse effects. One of the biggest concerns with statins is myositis In general, niacin has a 46 percent discontinuation or muscle inflammation. Myalgias (muscle aches) rate for adverse effects.The biggest reason patients do occur in about 2 to 10 percent of patients, and in trials not tolerate niacin is flushing. Special formulations, this was fairly similar to placebo. slow dose adjustments, and aspirin can be used to Myositis is rare. It is seen in less than 0.5 of patients reduce the flushing. Hepatotoxicity has been report- and the worst case of this, rhabdomyolysis with acute ed. It is especially important for people not to take renal failure, is seen in less than 0.1 percent of over-the-counter niacin preparations because the patients. Rhabdomyolysis occurs most frequently in long acting over-the-counter preparations have been patients that are taking a statin combined with an associated with higher rates of hepatotoxicity. interacting medication. The fibric acid derivatives, gemfibrozil (Lopid®) and Elevated liver function tests are the other major fenofibrate (Tricor®), are another class of lipid lowering concern.With medium dose statins, the rate is prob- agents.They work as ligands for peroxisome profilera- ably about 1 percent of patients, and in high dose tor-activated receptors, which are similar to the mech- statins about 3 percent.