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 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. The 2013 ACC/AHA guidelines identifies 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.[1]
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.[1]
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.[1]
Statin Benefit Groups
The following groups are considered to benefit from statin therapy:[1]
- 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.[1]
Intensity of Statin Therapy
Shown below is a table differentiating the different intensities of statin therapy.[1]
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 10 mg Pravastatin 10 to 20 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.[1]
- 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.[1]
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 | ||||||||||||||||||||||||||||||||||
Monitor Statin Therapy
Shown below is an algorithm depicting the approach to monitoring statin therapy according to the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.[1]
Assess medication and lifestyle adherence Measure lipid panel (preferably fasting) | |||||||||||||||||||||||||||||||
Was there a response as anticipated? | |||||||||||||||||||||||||||||||
Yes | No | ||||||||||||||||||||||||||||||
Reinforced continued adherence Follow up in 3-12 months | |||||||||||||||||||||||||||||||
Was there a response as anticipated? | Was there an intolerance to the statin dose? | ||||||||||||||||||||||||||||||
Yes | No | No | Yes | ||||||||||||||||||||||||||||
Reinforced continued adherence Follow up in 3-12 months | Reinforce improved adherence PLUS Increase statin therapy intensity OR Administer an additional non-statin drug | Reinforced adherence Rule out causes of secondary high LDL Reinforce lifestyle changes | Manage the intolerance to statin | ||||||||||||||||||||||||||||
Follow up in 4-12 weeks | Follow up in 4-12 weeks | ||||||||||||||||||||||||||||||
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:[2]
Concentration mg/dL | Concentration mmol/L | Interpretation |
<100 | <2.6 | Optimal |
100 to 129 | 2.6 to 3.3 | Near optimal |
130 to 159 | 3.3 to 4.1 | Borderline high |
160 to 189 | 4.1 to 4.9 | High |
>190 | >4.9 | Very high |
- 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: [2]
- Clinical coronary heart disease
- Symptomatic carotid artery disease (Transient ischemic attack or stroke of carotid origin)
- Peripheral artery disease
- Abdominal aortic aneurysm[2]
- 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 :[2]
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)
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.==
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):
|
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:
Additional characteristics that could modify the decision to use higher statin intensities might include but are not limited to:
|
"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:
|
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 Niacin
Class I |
"1. Baseline hepatic transaminases, fasting blood glucose or hemoglobin A1c, and uric acid should be obtained before initiation of niacin, and again during up-titration to a maintenance dose and every 6 months thereafter. (Level of Evidence: B)" |
"2. In individuals with adverse effects from niacin, the potential for ASCVD benefits and the potential for adverse effects should be reconsidered before reinitiation of niacin therapy. (Level of Evidence: B)" |
Class III (No Benefit) |
"1. Niacin should not be used if hepatic transaminase elevations are higher than 2 to 3 times ULN. (Level of Evidence: B)" |
"2. Niacin should not be used if persistent severe cutaneous symptoms, persistent hyperglycemia, acute gout, or unexplained abdominal pain or gastrointestinal symptoms occur. (Level of Evidence: B)" |
"3. Niacin should not be used if new-onset atrial fibrillation or weight loss occurs. (Level of Evidence: B)" |
Safety of BAS
Class IIa |
"1. To reduce the frequency and severity of adverse cutaneous symptoms, it is reasonable to:
|
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.
|
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)" |
Recommendations for Monitoring, Optimizing, and Addressing Insufficient Response to Statin Therapy
Monitoring Statin Therapy
Class I |
"1. Adherence to medication and lifestyle, therapeutic response to statin therapy, and safety should be regularly assessed. This should also include a fasting lipid panel performed within 4–12 weeks after initiation or dose adjustment, and every 3–12 months thereafter. Other safety measurements should be measured as clinically indicated. (Level of Evidence: A)" |
Optimizing Statin Therapy
Class I |
"1. The maximum tolerated intensity of statin should be used in individuals for whom a high- or moderate-intensity statin is recommended but not tolerated. (Level of Evidence: B)" |
Insufficient Response to Statin Therapy
Class I |
"1. In individuals who have a less-than-anticipated therapeutic response or are intolerant of the recommended intensity of statin therapy, the following should be performed:
|
Class IIa |
"1.It is reasonable to use the following as indicators of anticipated therapeutic response to the recommended intensity of statin therapy. Focus is on the intensity of the statin therapy. As an aid to monitoring:
|
"2. In individuals who are candidates for statin treatment but are completely statin intolerant, it is reasonable to use nonstatin cholesterol-lowering drugs that have been shown to reduce ASCVD events in RCTs if the ASCVD risk-reduction benefits outweigh the potential for adverse effects. (Level of Evidence: B)" |
Class IIb |
"1. In individuals at higher ASCVD risk receiving the maximum tolerated intensity of statin therapy who continue to have a less-than-anticipated therapeutic response, addition of nonstatin cholesterol-lowering drug(s) may be considered if the ASCVD risk-reduction benefits outweigh the potential for adverse effects.
Higher-risk individuals include:
|
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH; et al. (2014). "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". J Am Coll Cardiol. 63 (25 Pt B): 2889–934. doi:10.1016/j.jacc.2013.11.002. PMID 24239923.
- ↑ 2.0 2.1 2.2 2.3 2.4 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (2001). "Executive Summary of The 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)". JAMA. 285 (19): 2486–97. PMID 11368702.