The degree of cardiovascular risk is the major determinant in the decision to commence drug therapy. Current NCEP-ATP-III guidelines incorporate the Framingham 10-year absolute cardiovascular risk rates in identifying target LDL goals for patients with hyperlipidemia. The major risk factors (exclusive of LDL cholesterol) that modify LDL goals are cigarette smoking, hypertension (blood pressure > 140/90 mm Hg or on antihypertensive medication), low HDL cholesterol (< 40 mg/dL), family history of premature CHD (CHD in male first-degree relative < 55 years; CHD in female first-degree relative < 65 years), and age (men > 45 years; women > 55 years). HDL cholesterol > 60 mg/dL counts as a “negative” risk factor; its presence removes one risk factor from the total count. The presence of peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease, or diabetes is considered CHD equivalents. Patients are classified as low, intermediate, and high risk based on the number of their risk factors. The treatment goal and the threshold to initiate drug therapy differ between the three risk groups as illustrated in Table 1–2. Some authorities recommend an LDL goal of ≤ 70 mg/dL for very-high-risk patients (eg, a diabetic patient with recent myocardial infarction), a strategy that has been adapted by most cardiologists.
Table 1–2. LDL Treatment Goals ||Download (.pdf)
Table 1–2. LDL Treatment Goals
LDL Goal (mg/dL)
LDL Level at Which to Initiate Therapeutic Lifestyle Changes (mg/dL)
LDL Level at Which to Consider Drug Therapy (mg/dL)
CHD or CHD risk equivalent (10-year risk > 20%)
< 100 < 70 (optional)
2 risk factors (10-year risk < 20%)
10-year risk 10–20% > 130 10-year risk < 10% > 160
0–1 risk factor
The major limitation of the Framingham model is that this approach only measures a 10-year and not a lifetime risk of developing CAD. In addition, two major risk factors, diabetes and family history, are not included in the Framingham risk calculation. Therefore, it should be noted that the Framingham risk score may underestimate one's actual risk.
It should be emphasized that treating LDL to optimal target reduces the risk of coronary events but does not eliminate it completely. Patients with LDL at goal who are at very high risk may benefit from further testing to define their “residual risk” of coronary events. Levels of HDL, high-sensitivity C-reactive protein, and Lp(a); particle sizes/numbers; calcium scoring; and vascular intima imaging are useful tools in assessing this residual risk.
It may be reasonable to test serum Lp(a) in those with premature CAD, with a strong family history of premature CAD, or with recurrent disease despite statin treatment. Treatment consists of niacin, 1–3 g mostly in the long-acting form, and aspirin.
Low HDL is an independent risk factor for increased CVD and mortality, although a causal relationship has not been established. High HDL levels convey reduced coronary risk and are associated with a longevity syndrome. Low HDL levels can be caused by genetic mutations, as is the case with familial hypoalphalipoproteinemia, familial HDL deficiency, and Tangier disease. Acquired and often reversible causes include obesity, sedentary lifestyle, cigarette smoking, metabolic syndrome, hypertriglyceridemia, and certain drugs (β-blockers and steroids). These risk factors should be aggressively targeted. As of today, the studies have been inconclusive regarding increasing HDL with pharmacologic intervention and reducing the risk of CHD. In addition, NCEP-ATP-III guidelines highlight that LDL and non-HDL goals should be reached first before HDL goals are addressed.
Hypertriglyceridemia and Non-HDL Goals
Hypertriglyceridemia is common and is often associated with obesity, physical inactivity, high-carbohydrate diet, alcohol consumption, and cigarette smoking. Other conditions such as diabetes, metabolic syndrome, and renal disease, as well as drugs (particularly estrogens and protease inhibitors), are also contributory. Patients with hypertriglyceridemia are at increased risk of developing ASCVD. As with low HDL levels, it is unclear whether a causal relationship exists. Current NCEP-ATP-III treatment guidelines recommend reducing serum triglyceride levels in addition to lowering LDL values. Therapeutic lifestyle change should be the major treatment goal given the constellation of risk factors that contribute to the hypertriglyceridemic state.
In addition to aerobic exercise, dietary management should focus on carbohydrate reduction as well as restricting foods that have a high glycemic index. No dietary fat restriction is required, but the correct type of fat consumption should always be emphasized. Patients with extremely high triglyceride levels (> 1000 mg/dL) are at risk of developing acute pancreatitis due to high levels of circulating chylomicrons. In this subgroup of patients, all types of dietary fat should be restricted to reduce this risk. Fibrates, nicotinic acid, and fish oils are pharmacologic agents that can reduce triglyceride levels and are discussed separately. Table 1–3 categorizes triglyceride levels and summarizes NCEP-ATP-III guidelines for treating hypertriglyceridemia.
Table 1–3. Triglyceride Treatment Goals ||Download (.pdf)
Table 1–3. Triglyceride Treatment Goals
Triglyceride Levels (mg/dL)
Therapeutic lifestyle change (including weight reduction and aerobic exercise)
Therapeutic lifestyle change
Achieve primary LDL goal
Achieve secondary non-HDL goal
Consider pharmacologic therapy
Pharmacologic therapy to decrease triglyceride levels
Once < 500 mg/dL, address LDL goal
Non-HDL cholesterol is calculated by subtracting HDL from total cholesterol (TC – HDL). This fraction includes all apo B–containing (and therefore atherogenic) lipoprotein particles: LDL, Lp(a), IDL, and VLDL. This measure is useful in the setting of a raised triglyceride level (200–499 mg/dL). The goal non-HDL level is 30 mg/dL higher than the goal LDL level.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143–421. [PubMed: 12485966]
Despite the significant advances in medical treatment, CAD remains the leading cause of death worldwide. This is likely due to the increasing rates of obesity, diabetes, and metabolic syndrome. Therefore, any successful strategy to reduce CHD risk should emphasize weight loss, regular exercise, and a heart-healthy diet.
Dietary fats can be categorized into cholesterol, saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), polyunsaturated fatty acids (PUFAs), and trans-fatty acids. SFAs are mostly derived from animal products that raise both total and LDL cholesterol levels and are strongly associated with increased CVD. Trans-fatty acids result from commercial hydrogenation of PUFAs and decrease HDL levels and elevate LDL levels. Conversely, MUFAs and PUFAs have favorable effects on the lipid profile and may also delay atherosclerosis by limiting oxidization of LDL.
The American Heart Association–advocated diet, previously known as the “Step 1 Diet,” recommends that in addition to calorie restriction, there should be a shift in focus to the type of dietary fat consumed. Total fat should comprise no more than 30% (with 7% or less saturated fat) of daily caloric intake, and total cholesterol intake should be less than 300 mg/day.
Another highly successful dietary intervention is the modified Mediterranean diet (MMD). Rich in whole grains, beans, fish, and olive oil, the MMD has shown high adherence rates and a sustainable reduction of coronary events. Thus, diet and exercise remain the foundation of any successful lipid management program.
Kris-Etherton P, et al. AHA science advisory: Lyon Diet Heart Study. Benefits of a Mediterranean-style, National Cholesterol Education Program/American Heart Association Step I Dietary Pattern on Cardiovascular Disease. Circulation. 2001;103:1823–5. [PubMed: 11282918]
Mozaffarian D, et al. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2010;7:e1000252. [PubMed: 20351774]
Most patients with dyslipidemia will require targeted pharmacologic therapy to address their dyslipidemia. Statins are considered the cornerstone in treating dyslipidemia. Other drugs, however, are beneficial as an adjunctive or sole therapy in certain populations.
HMG-CoA Reductase Inhibitors (Statins)
Statins (simvastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, and lovastatin) are the most commonly used drugs in treating dyslipidemia. They are competitive inhibitors of HMG-CoA reductase, which is required for cholesterol biosynthesis. The decrease in intrahepatic cholesterol levels through this mechanism leads to an increase in LDL receptor expression and increased clearance of plasma LDL and decreased hepatic synthesis of VLDL and LDL. In addition, there is a modest increase in HDL levels. There is a synergistic effect when used in combination with either a cholesterol absorption inhibitor or a bile acid sequestrant, which can be helpful in optimizing LDL levels. They also appear to exert LDL independent anti-inflammatory effects on the endothelium and atherosclerotic plaques. For the most part, statins are well tolerated. Commonly reported side effects include myalgia, myositis reversible transaminitis, and rarely rhabdomyolysis.
Given their efficacy, potency, and tolerability, statins have been the focus of several large-scale prospective randomized studies over the last three decades, which have demonstrated relative cardiovascular risk reduction in primary prevention when compared to placebo. Secondary prevention has also been assessed in major trials (A-to-Z, PROVE-IT, TNT, IDEAL, and SEARCH) and formed the basis of the NCEP-ATP-III (2004) guidelines.
Ray KK, et al. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med. 2010;170(12): 1024–31. [PubMed: 20585067]
Cholesterol Absorption Inhibitors
Ezetimibe binds to and inhibits the protein Niemann-Pick C1-like 1 (NPC1L1) and inhibits the intestinal absorption of cholesterol. The net effect is a decrease in cholesterol reaching the liver and a subsequent increase in hepatocyte LDL receptor expression, thereby decreasing plasma LDL with no effect on HDL or triglyceride levels. Ezetimibe, the first drug in this class, decreases plasma cholesterol by 15–20% and has a synergistic effect when used in combination with a statin. Major side effects are rare, even when used together with a statin, but liver function should be monitored.
Fibric Acid Derivatives (Fibrates)
The major effects of the fibrate class of drugs (gemfibrozil and fenofibrate) are to reduce serum triglyceride levels and raise HDL levels. This effect is mediated by activation of nuclear peroxisome proliferator-activated receptor alpha (PPARα), which results in increased LPL activity and increased VLDL clearance. The elevation of HDL levels is mediated through PPARα-mediated synthesis of apo A-I and apo A-II. Gemfibrozil is indicated in secondary prevention of ASCVD in the setting of hypertriglyceridemia, low HDL, and normal LDL based on the Veterans Administration HDL Intervention Trial (VA-HIT). Common side effects include cholelithiasis, myalgias, and elevated transaminase levels. Combination therapy with statins is effective in treating elevated LDL as well as hypertriglyceridemia; however, fibrates, especially gemfibrozil, can decrease statin elimination and increase the risk of significant myositis and rhabdomyolysis.
Bile Acid Sequestrants (Resins)
Bile acid sequestrants interrupt the enterohepatic circulation through binding bile acids and preventing reuptake in the ileum. This results in a decrease in total body and intrahepatic cholesterol, leading to subsequent increase in LDL (apo B and apo E) receptor expression. The LDL receptors (apo B and apo E) then bind LDL cholesterol from the plasma, leading to further decrease in LDL levels. Resins are more effective when used together with a statin. Resins can increase VLDL levels and are therefore restricted to patients with relatively normal triglyceride levels.
Bile acid sequestrants are not absorbed from the gastrointestinal tract, and this reflects their side-effect profile. Bloating and constipation are common and dose dependent, which affects compliance. Bile acid sequestrants can also bind to and impair the absorption of other drugs such as digoxin, warfarin, β-blockers, thiazide diuretics, and fat-soluble vitamins. This effect can be minimized by administering other drugs 1 hour before or 4 hours after the bile acid sequestrant, but this can also affect compliance.
The available bile acid sequestrants, cholestyramine, colestipol, and colesevelam, are not systemically absorbed and thus can be used safely in pregnant patients, patients who are lactating, and children.
The predominant effect of niacin is to substantially increase HDL levels and decrease triglyceride levels. The mechanism by which niacin increases HDL levels remains unclear. Its effects on plasma triglyceride levels are mediated through enhanced LPL activity as well as inhibition of free fatty acid release from peripheral fat. The main obstacle with niacin therapy has been its tolerability. Common side effects include elevated transaminases, hyperglycemia, gastritis, and flushing. Taking aspirin 30 minutes prior to each dose may reduce flushing. Close monitoring of liver function is warranted due to the risk of niacin-induced hepatitis, which warrants discontinuation of therapy. An escalating dosing schedule can improve tolerability and compliance. Niacin has been shown to be effective in combination with a statin.
The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–67. [PubMed: 22085343]
Omega-3 Fatty Acids (Fish Oils)
Omega-3 polyunsaturated fatty acids are used in the treatment of hypertriglyceridemia. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the active compounds and are available over the counter and by prescription. They act through an uncertain mechanism to lower triglyceride levels at doses of 3-4 g/day. Fish oils are well tolerated at these doses but can prolong the bleeding time. Studies have shown morbidity and mortality benefit in secondary prevention with ingestion of 1 g of fish oil daily. Future studies are addressing the effects of fish oil on primary prevention. Consuming one to two servings of oily fish per week has been shown to reduce the risk of CVD in adult patients.
Treatment in Specific Patient Populations
Those who inherit only one copy of the defective gene (familial heterozygous hyperlipidemia) may respond well to high-dose statin therapy and diet and lifestyle modification. Those with severe forms of the disease may require apheresis, an extracorporeal therapy that removes LDL and returns the remainder of the blood to the patient.
The insulin-resistant state observed in type 2 diabetes mellitus is associated with hypertriglyceridemia as a result of increased circulating free fatty acids and decreased lipolysis. An increase in VLDL, IDL, and LDL is observed in addition to a decrease in HDL levels. Aggressive LDL reduction confers significant improvements in all-cause mortality in patients with type 2 diabetes mellitus as evidenced by the results from the CARE trial, the Heart Protection Study, and the CARDS study. Thus, type 2 diabetes mellitus is considered a CAD risk equivalent, and the NCEP-ATP-III treatment guidelines reflect these findings with an LDL target of less than 100 mg/dL (2.6 mmol/L) and an optimal target of less than 70 mg/dL (1.8 mmol/L).
Although an established risk factor for CVD, the link between dyslipidemia and cerebrovascular disease and stroke (cerebrovascular accident [CVA]) remains less clear. Regardless, statin therapy has been shown to be beneficial in both primary and secondary prevention. The HPS, CARE, and ASCOT-LLA trials all demonstrated CVA reduction with statin therapy, even in patients with cholesterol levels in the “normal” range. In addition, the SPARCL trial demonstrated that atorvastatin 80 mg daily reduced recurrent ischemic CVA in patients with a prior history of stroke or transient ischemic attack (TIA). It appears that the non–cholesterol-lowering benefits of statin therapy play a significant role in CVA reduction. This may explain why other lipid-lowering therapies have not shown CVA risk reduction benefits.
Hypothyroidism is commonly associated with hyperlipidemia due to decreased LDL receptor activity and with hypertriglyceridemia due to decreased LPL activity. Patients with dyslipidemia should have their thyroid function assessed. If hypothyroidism is diagnosed, treatment with thyroid replacement therapy will result in improvement in the lipid profile.