In its simplest terms, the management of hyperlipidemia consists of matching the intensity of LDL-lowering therapy with the absolute risk: the higher the risk, the lower the target LDL level. This approach is based primarily on data from clinical trials and epidemiological studies, which, as mentioned previously, have suggested that a direct relationship exists between the level of LDL-C and the risk of CHD. The ATP III guidelines suggested measuring fasting lipoprotein levels in patients with hyperlipidemia and/or hyperlipoproteinemia. The clinician should also assess the patient for the presence of other risk factors (see Table 4-1) and the presence of clinical atherosclerotic disease, including clinical CHD, cerebrovascular or peripheral arterial disease, or abdominal aortic aneurysm. A risk calculator can help the clinician determine a patient’s 10-year risk for CHD based on these factors on a scale from lower risk to high risk. LDL treatment goals are determined based on the patient’s risk level. When treatment with a statin drug is indicated, the 2013 guidelines from the American College of Cardiology and the American Heart Association (ACC/AHA) recommend that patients be given the maximum tolerated intensity of the statin. Similarly, in 2016, the European Society of Cardiology recommended that each patient undergo a risk assessment (systematic coronary risk evaluation, or SCORE) and lowering of LDL cholesterol levels to 100 mg/dL in high-risk patients and 70 mg/dL in very-high-risk patients. These groups no longer advocate treatment to a preset generalized goal but instead recognize that any reduction in LDL-C is beneficial, and that some patients should be treated more aggressively because of their higher cardiovascular risk.
Therapeutic lifestyle changes, including dietary modifications, weight management, and increased physical activity, should be initiated. A diet high in fruits, vegetables, fiber, omega-3 fatty acids, and foods with a low glycemic index, and substituting monounsaturated fats for polyunsaturated or trans fats, have repeatedly been shown to lower cardiovascular risk. If LDL goals are not achieved by lifestyle changes alone, drug therapy should be introduced and, if necessary, advanced. Current US and European guidelines strongly support the use of statin drugs as the primary intervention. Tables 4-2 and 4-3 present information about specific drugs, their lipid-lowering effects, and possible adverse effects.
Table 4-2 Drugs Affecting Lipoprotein Metabolism
Table 4-3 Intensity of Statin Therapy With Daily Dosing
Once the goal LDL levels have been achieved, other lipid and nonlipid risk factors can be modified. Elevated triglyceride levels may respond to increased physical activity or weight management, but if the triglyceride levels are greater than or equal to 200 mg/dL after the LDL goal is reached, a secondary treatment goal would be a non–HDL-C (total – HDL) level of 30 mg/dL higher than the LDL goal.
Eckel RH, Jakicic JM, Ard JD, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129(25 Suppl 2):S76–99.
Catapano AL, Graham I, De Backer G, et al. 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2016; 37(39):2999–3058.
The Role of Statins
For virtually all patients whose LDL-C goals cannot be achieved by therapeutic lifestyle changes alone, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, more popularly known as statins, are the first choice for medical therapy. Multiple trials involving the use of statin drugs have reinforced the value of LDL-lowering therapy in reducing the risk of cardiometabolic disease. Moreover, the statins are the only class of oral drugs whose use has been shown to improve overall mortality in primary and secondary prevention. The Heart Protection Study, Myocardial Ischemia Reduction with Acute Cholesterol Lowering (MIRACL) study, and the PROVE IT study, among others, each demonstrated a decreased risk of major cardiovascular events in patients whose LDL-C levels had been lowered with statins. Findings from the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) suggest that statins—which are known to lower C-reactive protein levels in addition to having positive effects on hyperlipidemia—may decrease the risk of stroke, coronary artery disease, and death in apparently healthy persons without hyperlipidemia but with a Creactive protein level greater than 2.0 mg/L. The beneficial effects of statins arise from the reduction of LDL-C levels, stabilization of atherosclerotic plaques, and decreased atherogenic inflammation.
The 2013 ACC/AHA guidelines identified 4 patient groups likely to benefit from statin use:
individuals with clinical atherosclerotic cardiovascular disease (ASCVD)
individuals with LDL-C levels of ≥190 mg/dL
individuals aged 40–75 years with diabetes (but without ASCVD) and LDL-C levels of 70–189 mg/dL
individuals aged 40–75 years without diabetes or ASCVD with LDL-C levels of 70–189 mg/dL and an estimated 10-year ASCVD risk of >7.5%.
In these patients, the ACC/AHA recommendation is moderate to maximal intensity statin therapy (see Table 4-3), while those intolerant of high-intensity therapy or those at lower estimated cardiovascular risk may be treated with moderate intensity therapy. Current ESC and other international guidelines are similar, and they also recommend assessment of the risk for each patient with LDL-C goals tailored to the patient’s level of cardiovascular risk. Large studies have not established exact LDL-C goals, but many study authors recommend an LDL-C of less than 100 mg/dL for high-risk patients and less than 70 mg/dL in very-high-risk individuals.
Other drugs used to lower LDL-C levels (see Table 4-2) include nicotinic acid, bile acid sequestrants, fibric acids, and cholesterol absorption inhibitors. Although many of these drugs have been shown to lower LDL-C levels, there is a general lack of large randomized controlled trials demonstrating their effects on ASCVD or mortality. These drugs are often used worldwide; however, the most recent ACC/AHA and ESC guidelines do not support the use of these drugs in place of statins when statin therapy is effective and well tolerated. The role of these drugs when added to high-intensity statin treatment is still to be elucidated. A new class of injectable drugs consisting of monoclonal antibodies to proprotein convertase subtilisin kexin 9 (PCSK9-abs) shows promise in lowering LDL levels and reducing the risk of CV events, even when added to maximal statin therapy. Although the PCSK9-abs agents have been shown to reduce LDL-C levels by 60%–70%, their expense and delivery method (injection) have limited their outpatient use thus far.
Although statin drugs are largely safe and effective, patients taking them must be monitored for serious adverse effects, especially in the first few months of treatment. Adverse effects of statin use are rare but can include elevated hepatic transaminases, diarrhea, liver failure, polyneuropathy, and myopathy. Simvastatin should not be started at or increased to a dose of 80 mg per day because of the high risk of muscle injury. The risk of myopathy is also increased when simvastatin is used in conjunction with other medications, including amiodarone, some fibrates (gemfibrozil), and some calcium channel blockers. Cerivastatin was voluntarily withdrawn from the market after more than 52 reports of rhabdomyolysis and death related to its use. Pregnant women should not take statin drugs due to possible teratogenic effects.
Chou R, Dana T, Blazina I, Daeges M, Jeanne TL. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2016; 316(19):2008–2024.
ESC Clinical Practice Guidelines. European Society of Cardiology website. www.escardio.org/Guidelines/Clinical-Practice-Guidelines. Accessed February 21, 2019.
Stone NJ, Robinson JG, Lichtenstein AH, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129(25 Suppl 2):S1–S45.
Excerpted from BCSC 2020-2021 series: Section 1 - Update on General Medicine. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.