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

References

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