Low density lipoprotein medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Rim Halaby, M.D. [3]

Overview

While prior approaches to the management of LDL plasma concentration aimed towards treating the subjects with dyslipidemia to a target LDL concentration, the latest 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommends the treatment of blood cholesterol to decrease atherosclerotic cardiovascular disease rather than to a target LDL cut-off value. The 2013 ACC/AHA guidelines identified the following statin benefit groups: subjects with atherosclerotic cardiovascular disease, subjects with LDL ≥ 190 mg/dL, subjects with diabetes mellitus PLUS age 40-75 years PLUS LDL 10-189 mg/dL, and subjects with LDL 70-189 mg/dL PLUS estimated 10 year risk of atherosclerotic cardiovascular disease ≥ 7.5%. The pooled cohort equation should be used to estimate the 10 year risk of atherosclerotic cardiovascular disease and guide the treatment among subjects with no diabetes mellitus or atherosclerotic cardiovascular disease. Lifestyle changes is a critical component of the management of patients with elevated LDL whether they are administered or not lipid lowering drugs.

Treatment of High LDL

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol

Lifestyle changes is a critical component of the management of patients with elevated LDL whether they are administered or not lipid lowering drugs. Lifestyle changes include regular exercise, heart healthy diet, smoking cessation, and weight management.

While previous guidelines set cut-off values to initiate statin therapy among subjects with elevated LDL or high risk cardiovascular patients, the latest 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults no longer takes into consideration LDL cut-off concentration but rather identifies groups of patients among whom the benefit of statin outweighs the risk of adverse events. According to previous guidelines, subjects were treated to a target LDL of 70 or 100 mg/dL depending on whether statin is administered for primary or secondary prevention; however, the association between LDL lowering towards a target value and reduction in atherosclerotic cardiovascular disease is not clear in clinical trials. Therefore, according to the recent guidelines, the decision to administer statin therapy is individualized and is recommended only among subjects who most likely will benefit from it.

Statin Benefit Groups

The following groups are considered to benefit from statin therapy:

• Presence of atherosclerotic cardiovascular disease, defined as prior acute coronary syndrome, stable or unstable angina, coronary revascularization, non coronary arterial revascularization, stroke, transient ischemic attack, or peripheral artery disease
• LDL ≥ 190 mg/dL
• Diabetes mellitus PLUS age 40-75 years PLUS LDL 10-189 mg/dL
• LDL 70-189 PLUS estimated 10 year risk of atherosclerotic cardiovascular disease ≥ 7.5%

The estimated 10 year risk of atherosclerotic cardiovascular disease should be calculated every 4 to 6 years using the pooled cohort equation.

Intensity of Statin Therapy

Shown below is a table differentiating the different intensities of statin therapy.

High intensity statin therapy	Moderate to high intensity statin therapy	Low intensity statin therapy
Lowers LDL by ≥ 50%	Lowers LDL by 30-50%	Lowers LDL by <30%
Atorvastatin 40 or 80 mg Rosuvastatin 20 to 40 mg	Atorvastatin 10 to 20 mg Rosuvastatin 5 to 10 mg Simvastatin 20 to 40 mg Pravastatin 40 to 80 mg Lovastatin 40 mg Fluvastatin XL 80 mg to 40 mg bid Pitavastatin 2 to 4 mg	Simvastatin 10 mg Pravastatin 10 to 20 mg Lovastatin 20 mg Fluvastatin 20 to 40 mg Pitavastatin 1 mg

Rule Out Secondary Causes of Elevated LDL

Before the initiation of lipid lowering drugs, the following secondary causes of elevated LDL must be rules out and managed if present.

• Diet rich with saturated or trans fats
• Weight gain or anorexia
• Diuretics
• Cyclosporine
• Glucocorticoids
• Amiodarone
• Biliary obstruction
• Nephrotic syndrome
• Hypothyroidism
• Obesity
• Pregnancy

Treatment Algorithm

Shown below is an algorithm depicting the decision to treat with moderate or high statin therapy according to the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.

Does the patient have clinical atherosclerotic cardiovascular disease (ASCVD)

Yes

No

Is the patient ≤ 75 years and a candidate for high intensity statin?

What is the LDL concentration?

Yes

No

70-189 mg/dL

≥ 190 mg/dL

Administer high intensity statin

Administer moderate intensity statin

Does the patient have diabetes mellitus and is the age 40-75 years?

Administer high intensity statin

No

Yes

What is the 10 year risk of ASCVD?

What is the 10 year risk of ASCVD?

≥ 7.5%

< 7.5%

≥ 7.5%

< 7.5%

Administer moderate-high statin therapy

The benefit of statin is not clear Assess additional risk factors

Administer high intensity statin

Administer moderate intensity statin

Prior Guidelines

The National Cholesterol Education Program (NCEP) publishes the Adult Treatment Panel (ATP) guidelines for detection, evaluation, and treatment of hyperlipidemia in adults.

Adult Treatment Panel	Release History
I	1988
II	1993
III	2001
III Addendum (update)	2004
IV	2012

Other U.S. guidelines for the management of dyslipidemia are also present. LDL-C target ranges of the following guidelines are not different from the latest ATP guidelines:

• 2008: ADA/ACCF Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk
• 2011: AHA/ACC Guidelines for Secondary Prevention
• 2012: AACE Guidelines for the Management of Dyslipidemia and Prevention of Atherosclerosis
• 2013: ADA Standards of Medical Care in DM

Target Goal

• The American Heart Association, NIH and NCEP provide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk for heart disease. According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III published in 2001, the target goal for LDL-cholesterol after 9- to 12- hour fast are as follows:

Level mg/dL	Level mmol/L	Interpretation
<100	<2.6	Optimal LDL cholesterol, corresponding to reduced, but not zero, risk for heart disease
100 to 129	2.6 to 3.3	Near optimal LDL level
130 to 159	3.3 to 4.1	Borderline high LDL level
160 to 189	4.1 to 4.9	High LDL level
>190	>4.9	Very high LDL level, corresponding to highest increased risk of heart disease

• Nonetheless, ATP III guidelines emphasize on identification of clinical atherosclerotic disease and risk factors that predispose individuals to increased risk of coronary heart disease events. ATP III define clinical atherosclerotic disease as one of the following:
  • Clinical coronary heart disease
  • Symptomatic carotid artery disease (Transient ischemic attack or stroke of carotid origin)
  • Peripheral artery disease
  • Abdominal aortic aneurysm

• Categorization of risk and stratification of patients according to clinical atherosclerosis and risk factors play an integral part of ATP III guidelines. Accordingly, LDL-C target levels vary among various risk groups :

Risk Category (Number of Risk Factors)	10 Year Risk	LDL-C Goal (mg/dL)
0-1	<10%	<160
2+	≦20%	<130 (ATP III in 2001) Optional: <100 (Updated ATP III in 2004)
CHD or CHD Risk Equivalents	>20%	<100 (ATP III in 2001) Optional: <70 (Updated ATP III in 200)

• According to ATP III guidelines, the associated risk factors used to define LDL-C target include the following:
  • Age ≥ 45 years for men and ≥ 55 years for women
  • Smoking
  • Hypertension
  • HDL-C < 40 mg/dL
  • Family history (first degree relative) of premature coronary heart disease at age < 55 years in males or 65 years in females)

• On the contrary, HDL > 60 mg/dL is considered a reduction of 1 risk factor.

2004 Addendum ATP III

• In July 2004, an addendum to the NCEP ATP III guidelines was published following the emergence of data from 5 major clinical trials that addressed new issues and demonstrated novel findings and outcomes.

• Following the addendum, ATP III currently emphasizes on achieving at least 30-40% LDL-C reduction in treating high and moderately high risk patients.

• NCEP ATP IV Guidelines were expected to be published in 2009. However, ATP IV is still currently in the development process.

LDL Cut Off Level to Initiate Therapy

Risk Category	LDL Goal (mg/dL)	LDL Level to Initiate TLC (mg/dL)	LDL Level to Consider Drug Therapy (mg/dL)
CHD or CHD risk equivalents (10-year risk >20%)	<100	≥100	≥130
2+ major risk factors (10-year risk ≤20%)	<130	≥130	10-year risk 10-20% ≥130 10-year risk <10% ≥160
0-1 major risk factor	<160	≥160	≥190

Lifestyle Modifications

ATP III recommends the initiation of therapeutic lifestyle changes when LDL is above goal. ATP III recommends the following dietary lifestyle:

• Weight management
• Exercise
• Less than 7% of daily calories derived from saturated fat
• Daily cholesterol intake < 200 mg
• Daily intake of 10-25 g of soluble fiber intake and plant stanols/sterols intake of 2g

Lipid-Lowering Drugs

Shown below is a table that summarizes the mechanism of action, percent reduction of LDL and side effects of LDL-c lowering drugs.

Drug Class	Mechanism of Action	% LDL Reduction	Side Effect
Statins	Inhibit HMG-CoA Reductase, rate limiting enzyme of cholesterol synthesis	18-55	Hepatotoxicity Myositis
Bile Acid Sequestrants	Bind bile inhibiting entero-hepatic circulation	15-30	GI distress Nausea Constipation Impaired absorption of fat soluble vitamins and other drugs
Niacin ( Vitamin B3)	Inhibits lipolysis in adipose tissue	5-25	Facial flushing Hyperglycemia Hyperuricemia Hepatotoxicity
Fibrates	Upregulate lipoprotein lipase	5-20	Myositis Hepatotoxicity Gallstones
Ezetimibe	Inhibit intestinal cholesterol absorption (synergistic effect with statin)	17-20	GI distress Headache Atrial fibrillation Myalgia Constipation

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

Recommendations for Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults—Statin Treatment

Secondary Prevention

Class I

"1. High-intensity statin therapy should be initiated or continued as first-line therapy in women and men ≤75 years of age who have clinical ASCVD , unless contraindicated. (Level of Evidence: A)"

"2. In individuals with clinical ASCVD in whom high-intensity statin therapy would otherwise be used, when high-intensity statin therapy is contraindicated † or when characteristics predisposing to statin-associated adverse effects are present, moderate-intensity statin should be used as the second option if tolerated. (Level of Evidence: A)"

Class IIa

"1. In individuals with clinical ASCVD >75 years of age, it is reasonable to evaluate the potential for ASCVD risk-reduction benefits and for adverse effects and drug–drug interactions and to consider patient preferences when initiating a moderate- or high-intensity statin. It is reasonable to continue statin therapy in those who are tolerating it. (Level of Evidence: B)"

Primary Prevention in Individuals ≥21 Years of Age With LDL-C ≥190 mg/dL

Class I

"1. Individuals with LDL-C ≥190 mg/dL or triglycerides ≥500 mg/dL should be evaluated for secondary causes of hyperlipidemia. (Level of Evidence: B)"

"2.Adults ≥21 years of age with primary LDL-C ≥190 mg/dL should be treated with statin therapy (10-year ASCVD risk estimation is not required): Use high-intensity statin therapy unless contraindicated. For individuals unable to tolerate high-intensity statin therapy, use the maximum tolerated statin intensity. (Level of Evidence: B)"

Class IIa

"1. For individuals ≥21 years of age with an untreated primary LDL-C ≥190 mg/dL, it is reasonable to intensify statin therapy to achieve at least a 50% LDL-C reduction. (Level of Evidence: B)"

Class IIb

"1. For individuals ≥21 years of age with an untreated primary LDL-C ≥190 mg/dL, after the maximum intensity of statin therapy has been achieved, addition of a nonstatin drug may be considered to further lower LDL-C. Evaluate the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions, and consider patient preferences. (Level of Evidence: C)"

Primary Prevention in Individuals With Diabetes and LDL-C 70–189 mg/dL

Class I

"1. Moderate-intensity statin therapy should be initiated or continued for adults 40–75 years of age with diabetes. (Level of Evidence: A)"

Class IIa

"1. High-intensity statin therapy is reasonable for adults 40–75 years of age with diabetes with a ≥7.5% estimated 10-year ASCVD risk‖ unless contraindicated. (Level of Evidence: B)"

"2. In adults with diabetes, who are <40 years of age or >75 years of age, or with LDL <70 mg/dL it is reasonable to evaluate the potential for ASCVD benefits and for adverse effects and drug–drug interactions and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy. (Level of Evidence: C)"

Primary Prevention in Individuals Without Diabetes and With LDL-C 70–189 mg/dL

Class I

"1. The Pooled Cohort Equations should be used to estimate 10-year ASCVD‖ risk for individuals with LDL-C 70–189 mg/dL without clinical ASCVD ∗ to guide initiation of statin therapy for the primary prevention of ASCVD. (Level of Evidence: B)"

"2. Adults 40–75 years of age with LDL-C 70–189 mg/dL, without clinical ASCVD ∗ or diabetes, and with an estimated 10-year ASCVD ‖ risk ≥7.5% should be treated with moderate- to high-intensity statin therapy. (Level of Evidence: A)"

Class IIa

"1. It is reasonable to offer treatment with a moderate-intensity statin to adults 40–75 years of age, with LDL-C 70–189 mg/dL, without clinical ASCVD ∗ or diabetes, and with an estimated 10-year ASCVD ‖ risk of 5% to <7.5%. (Level of Evidence: B)"

"2. Before initiation of statin therapy for the primary prevention of ASCVD in adults with LDL-C 70–189 mg/dL without clinical ASCVD ∗ or diabetes, it is reasonable for clinicians and patients to engage in a discussion that considers the potential for ASCVD risk-reduction benefits and for adverse effects and drug–drug interactions, as well as patient preferences for treatment. (Level of Evidence: C)"

Class IIb

"1. In adults with LDL-C <190 mg/dL who are not otherwise identified in a statin benefit group, or for whom after quantitative risk assessment a risk-based treatment decision is uncertain, additional factors¶ may be considered to inform treatment decision making. In these individuals, statin therapy for primary prevention may be considered after evaluation of the potential for ASCVD risk-reduction benefits, adverse effects, and drug–drug interactions and consider patient preferences. (Level of Evidence: C)"

Safety

Class I

"1. To maximize the safety of statins, selection of the appropriate statin and dose in men and nonpregnant/nonnursing women should be based on patient characteristics, level of ASCVD∗ risk, and potential for adverse effects. Moderate-intensity statin therapy should be used in individuals in whom high-intensity statin therapy would otherwise be recommended when characteristics predisposing them to statin-associated adverse effects are present. Characteristics predisposing individuals to statin adverse effects include but are not limited to: Multiple or serious comorbidities, including impaired renal or hepatic function. History of previous statin intolerance or muscle disorders. Unexplained ALT elevations ≥3 times ULN. Patient characteristics or concomitant use of drugs affecting statin metabolism. Age >75 years. Additional characteristics that could modify the decision to use higher statin intensities might include but are not limited to: History of hemorrhagic stroke. Asian ancestry. (Level of Evidence: B)"

"2. Baseline measurement of hepatic transaminase levels (ALT) should be performed before initiation of statin therapy. (Level of Evidence: B)"

"3. Individuals receiving statin therapy should be evaluated for new-onset diabetes according to the current diabetes screening guidelines (91). Those who develop diabetes during statin therapy should be encouraged to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD events. (Level of Evidence: B)"

"4. Individuals receiving statin therapy should be evaluated for new-onset diabetes according to the current diabetes screening guidelines. Those who develop diabetes during statin therapy should be encouraged to adhere to a heart-healthy dietary pattern, engage in physical activity, achieve and maintain a healthy body weight, cease tobacco use, and continue statin therapy to reduce their risk of ASCVD events.. (Level of Evidence: B)"

Class III (No Benefit)

"1. CK should not be routinely measured in individuals receiving statin therapy. (Level of Evidence: A)"

"2. It may be harmful to initiate simvastatin at 80 mg daily or increase the dose of simvastatin to 80 mg daily. (Level of Evidence: A)"

Class IIa

"1. Baseline measurement of CK is reasonable for individuals believed to be at increased risk for adverse muscle events because of a personal or family history of statin intolerance or muscle disease, clinical presentation, or concomitant drug therapy that might increase the risk of myopathy. (Level of Evidence: C)"

"2. During statin therapy, it is reasonable to measure CK in individuals with muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or generalized fatigue. (Level of Evidence: C)"

"3. During statin therapy, it is reasonable to measure hepatic function if symptoms suggesting hepatotoxicity arise (e.g., unusual fatigue or weakness, loss of appetite, abdominal pain, dark-colored urine, or yellowing of the skin or sclera). (Level of Evidence: C)"

"4. For individuals taking any dose of statins, it is reasonable to use caution in individuals >75 years of age, as well as in individuals who are taking concomitant medications that alter drug metabolism, taking multiple drugs, or taking drugs for conditions that require complex medication regimens (e.g., those who have undergone solid organ transplantation or are receiving treatment for HIV). A review of the manufacturer’s prescribing information may be useful before initiation of any cholesterol-lowering drug. (Level of Evidence: C)"

"4. It is reasonable to evaluate and treat muscle symptoms, including pain, tenderness, stiffness, cramping, weakness, or fatigue, in statin-treated patients according to the following management algorithm: To avoid unnecessary discontinuation of statins, obtain a history of prior or current muscle symptoms to establish a baseline before initiation of statin therapy. If unexplained severe muscle symptoms or fatigue develop during statin therapy, promptly discontinue the statin and address the possibility of rhabdomyolysis by evaluating CK and creatinine and performing urinalysis for myoglobinuria. If mild to moderate muscle symptoms develop during statin therapy: Discontinue the statin until the symptoms can be evaluated. Evaluate the patient for other conditions that might increase the risk for muscle symptoms (e.g., hypothyroidism, reduced renal or hepatic function, rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy, vitamin D deficiency, or primary muscle diseases). If muscle symptoms resolve, and if no contraindication exists, give the patient the original or a lower dose of the same statin to establish a causal relationship between the muscle symptoms and statin therapy. If a causal relationship exists, discontinue the original statin. Once muscle symptoms resolve, use a low dose of a different statin. Once a low dose of a statin is tolerated, gradually increase the dose as tolerated. If, after 2 months without statin treatment, muscle symptoms or elevated CK levels do not resolve completely, consider other causes of muscle symptoms listed above. If persistent muscle symptoms are determined to arise from a condition unrelated to statin therapy, or if the predisposing condition has been treated, resume statin therapy at the original dose.. (Level of Evidence: B)"

Class IIb

"1. Decreasing the statin dose may be considered when 2 consecutive values of LDL-C levels are <40 mg/dL. (Level of Evidence: C)"

"2. For individuals presenting with a confusional state or memory impairment while on statin therapy, it may be reasonable to evaluate the patient for nonstatin causes, such as exposure to other drugs, as well as for systemic and neuropsychiatric causes, in addition to the possibility of adverse effects associated with statin drug therapy. (Level of Evidence: C)"

Nonstatin Safety Recommendations

Safety of BAS

Class III (No Benefit)

"1. BAS should not be used in individuals with baseline fasting triglyceride levels ≥300 mg/dL or type III hyperlipoproteinemia, because severe triglyceride elevations might occur. (A fasting lipid panel should be obtained before BAS is initiated, 3 months after initiation, and every 6 to 12 months thereafter.) (Level of Evidence: B)"

Class IIa

"1. It is reasonable to use BAS with caution if baseline triglyceride levels are 250 to 299 mg/dL, and evaluate a fasting lipid panel in 4 to 6 weeks after initiation. Discontinue the BAS if triglycerides exceed 400 mg/dL. (Level of Evidence: C)"

Safety of Cholesterol-Absorption Inhibitors

Class IIa

"1. It is reasonable to obtain baseline hepatic transaminases before initiation of ezetimibe. When ezetimibe is coadministered with a statin, monitor transaminase levels as clinically indicated, and discontinue ezetimibe if persistent ALT elevations ≥3 times ULN occur. (Level of Evidence: B)"

Safety of Fibrates

Class I

"1. Renal status should be evaluated before fenofibrate initiation, within 3 months after initiation, and every 6 months thereafter. Assess renal safety with both a serum creatinine level and an eGFR based on creatinine. (Level of Evidence: B)"

Class III (No Benefit)

"1. Gemfibrozil should not be initiated in patients on statin therapy because of an increased risk for muscle symptoms and rhabdomyolysis. (Level of Evidence: B)"

"2. Fenofibrate should not be used if moderate or severe renal impairment, defined as eGFR <30 mL/min per 1.73 m2, is present. If eGFR is between 30 and 59 mL/min per 1.73 m2, the dose of fenofibrate should not exceed 54 mg/day. If, during follow-up, the eGFR decreases persistently to ≤30 mL/min per 1.73 m2, fenofibrate should be discontinued. (Level of Evidence: B)"

Class IIb

"1. Fenofibrate may be considered concomitantly with a low- or moderate-intensity statin only if the benefits from ASCVD risk reduction or triglyceride lowering when triglycerides are ≥500 mg/dL are judged to outweigh the potential risk for adverse effects. (Level of Evidence: C)"

Safety of Omega-3 Fatty Acids

Class IIa

"1. If EPA and/or DHA are used for the management of severe hypertriglyceridemia, defined as triglycerides ≥500 mg/dL, it is reasonable to evaluate the patient for gastrointestinal disturbances, skin changes, and bleeding. (Level of Evidence: B)"

References

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