Hypercholesterolemia

Updated 2014 Aug 19 10:49:00 AM: review of low-density lipoprotein cholesterol (Lancet 2014 Aug
16) view updateShow more updates

Related Summaries:
Familial hypercholesterolemia
Dietary interventions for cardiovascular disease prevention
Statins for prevention of cardiovascular disease
Lipid-lowering pharmacotherapy overview

General Information
Description:
condition characterized by elevated total cholesterol, low-density lipoprotein cholesterol or non-high-
density lipoprotein cholesterol levels
risk factor for cardiovascular disease
this topic deals with nonfamilial forms of hypercholesterolemia; see also Familial hypercholesterolemia
Also called:
hypercholesterolemia may also be called
o hypercholesterolaemia
o pure hypercholesterolemia
o Fredrickson Type IIa hyperlipoproteinemia
o hyperbetalipoproteinemia
o group A hyperlipidemia
o low-density lipoprotein hyperlipoproteinemia
mixed hypercholesterolemia (hypercholesterolemia with hypertriglyceridemia) may also be called
o broad-betalipoproteinemia
o floating-betalipoproteinemia
o Fredrickson Type IIb hyperlipoproteinemia
o Fredrickson Type III hyperlipoproteinemia
o hypercholesterolemia with endogenous hyperglyceridemia
o hyperbetalipoproteinemia with prebetalipoproteinemia
o combined hyperlipidemia
Types:

Phenotype
Lipoproteins(s)
Elevated
Serum Cholesterol
Level
Serum Triglyceride
Level Atherogenicity
I Chylomicrons
Normal to mildly
increased Very severely increased None
IIa LDL Moderately increased Normal Severe
IIb LDL and VLDL Moderately increased Moderately increased Severe
III IDL Moderately increased Severely increased Severe
IV VLDL
Normal to mildly
increased Moderately increased Mild to Moderate
V VLDL and chylomicrons
Normal to mildly
increased Very severely increased Mild to Moderate
Abbreviations: HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein;
VLDL, very-low-density lipoprotein.

* HDL cholesterol levels not considered.
Phenotype
Lipoproteins(s)
Elevated
Serum Cholesterol
Level
Serum Triglyceride
Level Atherogenicity

Reference - N Engl J Med 1967 Jan 5;276(1):34 full-text
Fredrickson Classification of Dyslipidemias*:
Epidemiology
Incidence/Prevalence:
eleventh most common diagnosis made during family physician visits
o based on analysis of patient visits to family physicians in United States 1995-1998 in National
Ambulatory Medical Care Survey
o hypercholesterolemia diagnosis coded in 2.8% of visits
o Reference - Ann Fam Med 2004 Sep-Oct;2(5):411 Texto completo de EBSCOhost full-text
high cholesterol reported in 35% of adults having cholesterol screening in United States
in 2009
o based on national survey data in United States
o Reference - MMWR Morb Mortal Wkly Rep 2012 Sep 7;61:697 Texto completo de
EBSCOhost full-text
30-year risk for developing high low-density lipoprotein (LDL) cholesterol is 50% among
United States adults
o based on cohort of 4,701 Framingham Offspring study participants
o estimated 30-year risks for various dyslipidemias
> 80% for "borderline-high" LDL cholesterol ( 130 mg/dL [3.4 mmol/L])
50% for "high" LDL cholesterol ( 160 mg/dL [4.1 mmol/L])
25% women and 65% men for "low" high-density lipoprotein (HDL) cholesterol (< 40 mg/dL
[1 mmol/L])
o Reference - Am J Med 2007 Jul;120(7):623
10% prevalence of elevated non-high-density lipoprotein (HDL) cholesterol in children
aged 6-19 years in United States in 2007-2010
o based on cohort of 4,957 children aged 6-19 years from National Health and Nutrition Examination
Survey (NHANES) during 2007-2010
o prevalence of serum lipids during 2007-2010
elevated total cholesterol ( 200 mg/dL [5.2 mmol/L]) in 8.1%
elevated non-HDL cholesterol ( 145 mg/dL [3.8 mmol/L]) in 10%
low HDL cholesterol (< 40 mg/dL [1 mmol/L]) in 14.8%
o Reference - JAMA 2012 Aug 8;308(6):591, editorial can be found in JAMA 2012 Aug 8;308(6):621
prevalence of elevated total and LDL cholesterol in children and adolescents may be as
high as 10.7% depending on threshold used
o based on cohort of 9,868 children aged 6-17 years from National Health and Nutrition Examination
Survey 1999-2006
o 10.7% prevalence of elevated total cholesterol (cut point 200 mg/dL or 5.2 mmol/L)
o 6.6% prevalence of elevated LDL cholesterol (cut point 130 mg/dL or 3.4 mmol/L) in 2,724
adolescents aged 12-17 years
o estimated that only 0.8% of adolescents exceed LDL threshold for considering for pharmacological
treatment by current AAP guideline
o Reference - Circulation 2009 Mar 3;119(8):1108 full-text
Possible risk factors:
spouse with hyperlipidemia associated with increased risk of hyperlipidemia
o based on cohort study
o 8,386 married couples aged 30-74 evaluated
o presence of spouse with hyperlipidemia had adjusted odds ratio 1.44 (95% CI 1.19-1.75)
o Reference - BMJ 2002 Sep 21;325(7365):636 full-text, commentary can be found in BMJ 2003 Feb
15;326(7385):396
Associated conditions:
hypertriglyceridemia
association with subclinical hypothyroidism controversial
o based on cohort studies
o hypercholesterolemia may be associated with subclinical hypothyroidism
based on cohort of 1,191 patients aged 40-60 years
10.3% prevalence of subclinical hypothyroidism among patients with total cholesterol > 309
mg/dL (8 mmol/L)
Reference - Clin Endocrinol (Oxf) 1999 Feb;50(2):217 Texto completo de EBSCOhost
o subclinical hypothyroidism may not be associated with abnormal lipid levels
based on cohort of 8,218 adults > 40 years old in United States
subclinical hypothyroidism not associated with abnormal lipid levels after adjusting for
confounding factors
Reference - Ann Fam Med 2004 Jul-Aug;2(4):351 Texto completo de EBSCOhost full-
text
Etiology and Pathogenesis
Causes:
contributions to elevated cholesterol levels may be
o genetic
o dietary
o metabolic (including medical conditions and drugs)
History and Physical
History:
Chief concern (CC):
asymptomatic
Past medical history (PMH):
ask about history of
o cardiovascular disease
o liver disease
o thyroid disease
o medication use
Family history (FH):
ask about family history of hypercholesterolemia
ask about family history of cardiovascular disease
Social history (SH):
ask about diet, exercise
Physical:
General physical:
calculate body mass index
Diagnosis
Making the diagnosis:
overall cardiovascular risk is essential component in consideration of whether a specific cholesterol
level warrants treatment
(
1
,
2
)

current guidelines de-emphasize target numbers for low-density lipoprotein (LDL) cholesterol and
focus on targeting treatment to patients at increased risk for cardiovascular disease who derive benefit
from treatment
(
3
,
4
)

prior classification of LDL cholesterol levels
(
1
)

o LDL cholesterol < 100 mg/dL (2.59 mmol/L) considered optimal
o LDL cholesterol 100-129 mg/dL (2.59-3.34 mmol/L) considered above optimal
o LDL cholesterol 130-159 mg/dL (3.37-4.13 mmol/L) considered borderline high
o LDL cholesterol 160-189 mg/dL (4.14-4.89 mmol/L) considered high
o LDL cholesterol 190 mg/dL (4.90 mmol/L) considered very high
Differential diagnosis:
metabolic syndrome
diabetes mellitus type 2
hypothyroidism
nephrotic syndrome
obstructive liver disease
(
1
)

chronic kidney disease
drugs
o anabolic steroids
o possibly thiazide-type diuretics
o corticosteroids
o protease inhibitors
Testing overview:
fasting lipid profile
(
1
,
3
)

o total cholesterol
o high-density lipoprotein (HDL) cholesterol
o triglycerides
o low-density lipoprotein (LDL) cholesterol
LDL cholesterol may be measured directly or calculated
LDL cholesterol (calculated) = total cholesterol - (HDL cholesterol + triglycerides/5)
calculation not valid if triglycerides > 400 mg/dL (4.52 mmol/L)
fasting time may have minimal impact on lipid levels (level 2 [mid-level] evidence)
testing recommended to rule out secondary causes of hyperlipidemia
(
1
)

o fasting blood glucose
o thyroid-stimulating hormone
o liver function tests
o creatinine
Blood tests:
Lipid profile:
conventional testing is fasting lipid profile
(
1
,
3
)

o total cholesterol
o high-density lipoprotein (HDL) cholesterol
o triglycerides
o low-density lipoprotein (LDL) cholesterol
LDL cholesterol may be measured directly or calculated
LDL cholesterol (calculated) = total cholesterol - (HDL cholesterol + triglycerides/5)
calculation not valid if triglycerides > 400 mg/dL (4.52 mmol/L)
nonfasting triglyceride levels may be about 10%-20% higher than fasting triglyceride levels, while
cholesterol levels may not vary with fasting state, based on study with 209,180 persons
cardiovascular risk by lipid panel appears similar in fasting and nonfasting patients
o based on meta-analysis and 2 cohort studies in Denmark
o meta-analysis of 68 prospective studies with 302,430 people without initial vascular disease
hazard ratios for cardiovascular disease at least as strong in participants who did not fast as
in those who did
Reference - JAMA 2009 Nov 11;302(18):1993 full-text
o 2 cohort studies in Denmark
33,391 participants aged 20-95 years with lipid levels < 3 standard deviations from mean
analyzed in cross-sectional study
795 considered fasting defined as last meal 8 hours before test
analysis done by grouping patients by hourly time brackets since last meal
maximum difference in mean lipid levels comparing nonfasting participants to 795
participants with fasting measurements
-0.2 mmol/L (-7.8 mg/dL) for total cholesterol (p < 0.001)
-0.2 mmol/L (-7.8 mg/dL) for LDL cholesterol (p < 0.001)
-0.1 mmol/L (-3.9 mg/dL) for HDL cholesterol (p < 0.001)
0.3 mmol/L (26.7 mg/dL) for triglycerides (p < 0.001)
prospective cohort of 9,319 participants (57% women) aged 20-93 years without
cardiovascular disease at baseline followed for 14 years
all participants had nonfasting lipid measurements
cardiovascular events in 1,166 participants (12.5%)
participants stratified into tertiles by lipid levels
increasing tertiles associated with increasing incidence of cardiovascular events (p <
0.001)
Reference - Circulation 2008 Nov 11;118(20):2047 full-text
seasonal variation reported in serum cholesterol levels and may significantly affect
diagnosis of hypercholesterolemia in women
o based on longitudinal study
o 517 healthy volunteers had lipid levels tested every 3 months for 1 year
o mean total cholesterol 222 mg/dL (5.75 mmol/L) in men and 213 mg/dL (5.52 mmol/L) in women
o amplitude of seasonal variation 3.9 mg/dL (0.1 mmol/L) in men and 5.4 mg/dL (0.14 mmol/L) in
women with peak in winter
o in men
rate of total cholesterol 240 mg/dL (6.22 mmol/L) was 30% in summer and 32% in winter
(not significant)
rate of LDL cholesterol 160 mg/dL (4.14 mmol/L) was 34% in both winter and summer
o in women
rate of total cholesterol 240 mg/dL (6.22 mmol/L) was 19% in summer and 28% in winter
(p < 0.001)
rate of LDL cholesterol 160 mg/dL (4.14 mmol/L) was 22% in summer and 29% in winter
(p = 0.005)
o Reference - Arch Intern Med 2004 Apr 26;164(8):863, commentary can be found in Arch Intern
Med 2004 Dec 13/27;164(22):2505, Int J Cardiol 2005 Sep 15;104(1):101
use of direct LDL cholesterol measurements may lead to overtreatment
o based on cohort study
o 464 patients had lipid panel with calculated LDL and direct LDL cholesterol measurements
o direct LDL cholesterol measurements were 18% higher than calculated LDL measurements at 100
mg/dL (2.6 mmol/L) and would lead to overtreatment if treatment based on LDL levels
o Reference - J Fam Pract 2002 Nov;51(11):972 Texto completo de EBSCOhost, correction
can be found in J Fam Pract 2002 Dec;51(12):1079
Other lipid parameters:
higher LDL particle number may be associated with increased risk for cardiovascular
disease
o based on systematic review of 24 studies investigating relation between LDL subfractions and
cardiovascular disease outcomes
o 10 studies with 8,806 patients used analytical methods available for clinical use
o higher LDL particle number associated with increased risk for cardiovascular disease compared
with other LDL subfractions
o review limited by heterogeneity in
specific tests analyzed
analytical methods used
patient populations
outcomes measured
o Reference - Ann Intern Med 2009 Apr 7;150(7):474 Texto completo de EBSCOhost
circulating levels of oxidized LDL strongly associated with angiographically documented
coronary artery disease
o based on cohort study of 504 patients tested immediately before coronary angiography
o Reference - N Engl J Med 2005 Jul 7;353(1):46
Non-lipid blood tests:
testing recommended to rule out secondary causes of hyperlipidemia
(
1
)

o fasting blood glucose
o thyroid-stimulating hormone
o liver function tests
o creatinine
Treatment
Treatment overview:
cholesterol-lowering treatment depends on overall cardiovascular risk, but specific recommendations
and approaches to risk estimation vary
o patients with existing cardiovascular disease (secondary prevention) uniformly considered high-
risk and do not require risk calculation
o American College of Cardiology/American Heart Association (ACC/AHA) guidelines in United States
recommend use of Pooled Cohort Equations to estimate 10-year risk of atherosclerotic
cardiovascular disease
DynaMed commentary -- Pooled Cohort Equations may overestimate cardiovascular risk (level
2 [mid-level] evidence)
o National Institute for Clinical Excellence (NICE) guidelines in United Kingdom use any of several
calculators (adjusted Framingham risk equation, QRISK, and ASSIGN) to estimate 10-year risk of
cardiovascular disease (coronary heart disease and stroke)
lifestyle changes recommended by both ACC/AHA and NICE include
o dietary changes including reduced intake of saturated fats
o increased physical activity (30-40 minutes of moderate intensity 3-5 days/week)
ACC/AHA and NICE have different thresholds for 10-year cardiovascular disease risk for when statin
therapy is recommended
Risk Category Statin Therapy Recommended if
Reasonable to Consider Statin Therapy
if
Clinical atherosclerotic
cardiovascular disease
Age 20-75 years (ACC/AHA Class I,
Level A)
Age > 75 years (ACC/AHA Class IIa,
Level B)
LDL-C 190 mg/dL (4.91
mmol/L)
Age 21 years (ACC/AHA Class I,
Level B) NA
Diabetes and LDL-C 70-189
mg/dL (1.81-4.9 mmol/L)
Age 40-75 years (ACC/AHA Class I,
Level A)
Age 21-40 years or > 75 years (ACC/AHA
Class IIa, Level C)
Age 40-75 years and LDL-C
70-189 mg/dL (1.81-4.9
mmol/L)
Estimated 10-year risk of atherosclerotic
cardiovascular disease 7.5%
(ACC/AHA Class I, Level A)
Estimated 10-year risk of atherosclerotic
cardiovascular disease 5% to < 7.5%
(ACC/AHA Class IIa, Level B)
Abbreviation: ACC/AHA, American College of Cardiology/American Heart Association; LDL-C, low-density
lipoprotein cholesterol.
ACC/AHA Recommendations on Statin Therapy:
Risk Category Drug Recommendations
Existing cardiovascular disease (secondary
prevention)
o Simvastatin 40 mg/day for all adults with cardiovascular
disease
o Increase to 80 mg/day if either of
acute coronary syndrome
inability to attain total cholesterol < 4 mmol/L (154
mg/dL) or LDL-C < 2 mmol/L (77 mg/dL)
10-year cardiovascular disease risk > 20% o Start simvastatin 40 mg/day
10-year cardiovascular disease risk < 20%
o Optimizing all other modifiable cardiovascular risk factors
o Statin not recommend
Abbreviations: LDL-C, low-density lipoprotein; NICE, National Institute for Health and Clinical Excellence.
NICE Recommendations on Statin Therapy:
statins are drugs of first choice for pharmacotherapy of hypercholesterolemia
o statins reduce mortality and myocardial infarction in adults with coronary heart disease (level 1
[likely reliable] evidence)
o lipid-lowering therapy (primarily with statins) is effective for primary and secondary prevention of
major coronary events in patients with diabetes (level 1 [likely reliable] evidence)
o in patients without cardiovascular disease (primary prevention)
statins reduce cardiovascular disease events and stroke (level 1 [likely reliable] evidence) and
may reduce all-cause mortality (level 2 [mid-level] evidence)
absolute benefit from statins for primary prevention depends more on overall risk than
cholesterol levels; see below for estimates of benefit at different risk levels
alternative drugs or add-on therapies
o fibric acid derivatives
may reduce risk for coronary events (level 2 [mid-level] evidence)
combination of fibrates and statins may improve lipid profiles more than monotherapy (level 3
[lacking direct] evidence) but associated with increased risk for rhabdomyolysis (level 2 [mid-
level] evidence)
o niacin may reduce risk for myocardial infarction, stroke, and transient ischemic attack in patients
with coronary artery disease (level 2 [mid-level] evidence), but addition of niacin may not reduce
cardiovascular events in patients with cardiovascular disease on treatment to control low-density
lipoprotein (LDL) cholesterol levels (level 2 [mid-level] evidence)
o ezetimibe improves lipid profile but not shown to improve clinical outcomes (level 3 [lacking
direct] evidence)
o bile acid-binding resins
cholestyramine may reduce composite outcome of coronary mortality and nonfatal myocardial
infarction in men with hypercholesterolemia and without known coronary artery disease (level
2 [mid-level] evidence)
o herbs and dietary supplements
evidence for clinical benefit exists for red yeast rice 600 mg twice daily (contains statins)
(level 2 [mid-level] evidence)
evidence for lowering cholesterol levels exists with guggulipid, policosanol, artichoke leaf
extract, fenugreek, and Arjuna (level 3 [lacking direct] evidence)
follow-up recommendations vary
o ACC/AHA recommends monitoring fasting lipid profile 4-12 weeks after dose change, and every 3-
12 months
o NICE does not recommend routine lipid monitoring after decision to start statin for primary
prevention
Recommendations:
American College of Cardiology/American Heart Association (ACC/AHA) 2013 guidelines:
ACC/AHA recommendations on statin therapy
(
4
)

o selecting patients for statin therapy
use Pooled Cohort Equations to estimate 10-year atherosclerotic cardiovascular disease risk
for patients without clinical atherosclerotic cardiovascular disease or low-density lipoprotein
(LDL) > 190 mg/dL (4.91 mmol/L) to guide initiation of statin therapy (ACC/AHA Class I,
Level B)
Pooled Cohort Equations CV Risk Calculator can be downloaded (in form of interactive
spreadsheet with display for patient) from American Heart Association
DynaMed commentary -- Pooled Cohort Equations may overestimate cardiovascular
risk (level 2 [mid-level] evidence)
statin therapy recommended for 4 groups of adults 21 years old for whom statin therapy
has randomized trial evidence of reduction in atherosclerotic cardiovascular disease events
patients 75 years old with clinical atherosclerotic cardiovascular disease (history of
myocardial infarction, acute coronary syndrome, stable or unstable angina, coronary or
other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial
disease of presumed atherosclerotic origin) (ACC/AHA Class I, Level A)
patients with LDL cholesterol 190 mg/dL (4.91 mmol/L) (ACC/AHA Class I, Level B)
patients aged 40-75 years with diabetes (type 1 or 2) and LDL cholesterol 70 mg/dL
(1.81 mmol/L) (ACC/AHA Class I, Level A)
patients aged 40-75 years with estimated 10-year risk of atherosclerotic cardiovascular
disease 7.5% and LDL cholesterol 70 mg/dL (1.81 mmol/L) (ACC/AHA Class I, Level
A)
reasonable to consider statin therapy (but less strongly recommended) upon evaluating
potential for benefits, adverse effects, drug-drug interactions, and patient preferences in
patients with
clinical atherosclerotic cardiovascular disease and > 75 years old (ACC/AHA Class IIa,
Level B)
diabetes and aged 21-40 years or > 75 years old (ACC/AHA Class IIa, Level C)
estimated 10-year risk of atherosclerotic cardiovascular disease 5% to < 7.5% and aged
40-75 years with LDL cholesterol 70-189 mg/dL (1.81-4.9 mmol/L) and without diabetes
or clinical atherosclerotic cardiovascular disease (ACC/AHA Class IIa, Level B)
no recommendation made regarding starting or discontinuing statins in patients with
New York Heart Association (NYHA) class II-IV ischemic systolic heart failure
chronic kidney disease on maintenance hemodialysis
o treatment targets no longer recommended
no recommendations made for or against specific LDL cholesterol or nonhigh-density
lipoprotein cholesterol (non-HDL-C) targets for primary or secondary prevention of
atherosclerotic cardiovascular disease
decreasing statin dose may be considered if LDL cholesterol < 40 mg/dL on 2 consecutive
values (ACC/AHA Class IIb, Level C)
o statin dosing
intensity of statin dosing
high-intensity statin therapy defined as dosing associated with mean reduction in LDL
cholesterol 50%
moderate-intensity statin therapy defined as dosing associated with mean reduction in
LDL cholesterol 30% to < 50%
low-intensity statin therapy defined as dosing associated with mean reduction in LDL
cholesterol < 30%
Statin High-intensity Moderate-intensity Low-intensity
Atorvastatin
80 mg (40 mg may be used if 80 mg not
tolerated) 10 mg, 20 mg** NA
Fluvastatin NA 80 mg*
20 mg**, 40
mg**
Lovastatin NA 40 mg 20 mg
Pitavastatin NA 2 mg**, 4 mg** 1 mg**
Pravastatin NA 40 mg, 80 mg** 10 mg, 20 mg
Rosuvastatin 20 mg, 40 mg** 5 mg **, 10 mg NA
Simvastatin Avoid*** 20 mg, 40 mg 10 mg**
* All doses listed are once daily except for moderate-intensity fluvastatin which is given as 40 mg
twice daily or fluvastatin extended-release 80 mg once daily.

** All doses listed are FDA approved, but doses with ** are not shown in randomized trials to reduce
major cardiovascular events.

*** Simvastatin 80 mg once daily NOT recommended due to risk for myopathy and rhabdomyolysis
(ACC/AHA Class III Harm, Level A)
Statin Intensity (Daily Dosing*):
high-intensity statin therapy recommended (unless contraindicated or increased risk for
statin-associated adverse effects) in patients with
clinical atherosclerotic cardiovascular disease and < 75 years old (ACC/AHA Class I,
Level A)
diabetes mellitus, aged 40-75 years, and estimated 10-year atherosclerotic
cardiovascular disease risk 7.5% (ACC/AHA Class IIa, Level B)
LDL cholesterol 190 mg/dL (4.91 mmol/L) (ACC/AHA Class I, Level B)
reasonable in this group to intensify statin therapy to achieve 50% LDL
cholesterol reduction (ACC/AHA Class IIa, Level B)
addition of nonstatin drug may be considered after maximum intensity of statin
therapy achieved (ACC/AHA Class IIb, Level C)
moderate-intensity statin therapy recommended in patients with increased risk for statin-
associated adverse effects, based on factors such as (ACC/AHA Class I, Level B)
multiple or serious comorbidities, including impaired renal or hepatic function
history of statin intolerance or muscle disorders
unexplained alanine transaminase (ALT) elevations > 3 times upper limit of normal
patient characteristics or concomitant use of drugs affecting statin metabolism
> 75 years old
moderate-intensity statins recommended for
patients with diabetes mellitus not meeting criteria for high-intensity statin therapy
(ACC/AHA Class I, Level A)
estimated 10-year risk of atherosclerotic cardiovascular disease 5% to < 7.5% and aged
40-75 years with LDL cholesterol 70-189 mg/dL (1.81-4.9 mmol/L) and without diabetes
or clinical atherosclerotic cardiovascular disease (ACC/AHA Class IIa, Level B)
moderate- or high-intensity statin therapy recommended for other patients aged 40-75 years
with estimated 10-year risk of atherosclerotic cardiovascular disease 7.5% and LDL
cholesterol 70-189 mg/dL (1.81-4.9 mmol/L) (ACC/AHA Class I, Level A)
additional factors that may support use of high-intensity statin therapy include
history of hemorrhagic stroke
Asian ancestry
maximum tolerated intensity recommended for patients who do not tolerate indicated
intensity (ACC/AHA Class I, Level B)
o blood test monitoring for statin use
although target treatment levels no longer recommended, monitoring fasting lipid profile (4-
12 weeks after starting or changing dose, then every 3-12 months) recommended to monitor
therapeutic response and reinforce adherence to medication and lifestyle changes (ACC/AHA
Class I, Level A)
creatine kinase (CK)
should not be routinely measured in patients receiving statin therapy (ACC/AHA Class III
No Benefit, Level A)
baseline CK measurement is reasonable for patients at increased risk for adverse muscle
events (ACC/AHA Class IIa, Level C)
CK measurement during statin therapy is reasonable in patients with muscle symptoms
including pain, tenderness, stiffness, cramping, weakness, or generalized fatigue
(ACC/AHA Class IIa, Level C)
if mild-to-moderate muscle symptoms, discontinue statin until symptoms evaluated, then
restart if muscle symptoms resolve; if symptoms recur, discontinue statin and once
resolved start low dose of different statin (ACC/AHA Class IIa, Level B)
if unexplained severe muscle symptoms or fatigue, discontinue statin and check CK,
creatinine, and urinalysis for myoglobinuria (ACC/AHA Class IIa, Level B)
hepatic ALT levels
perform baseline ALT measurement before starting statin therapy (ACC/AHA Class I,
Level B)
during statin therapy, it is reasonable to measure hepatic function if symptoms
suggesting hepatotoxicity arise (such as unusual fatigue or weakness, loss of appetite,
abdominal pain, dark colored urine, or yellowing of skin or sclera) (ACC/AHA Class IIa,
Level C)
screen for new-onset diabetes mellitus per current guidelines (ACC/AHA Class I, Level B)
o Reference - ACC/AHA 2013 Guideline on the Treatment of Blood Cholesterol to Reduce
Atherosclerotic Cardiovascular Risk in Adults (J Am Coll Cardiol 2014 Jul 1;63(25 Pt B):2889 PDF,
also published in Circulation 2014 Jun 24;129(25 Suppl 2):S1)
(
4
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ACC/AHA recommendations on lifestyle modifications
(
6
)

o recommended dietary pattern (ACC/AHA Class I, Level A)
emphasizes intake of vegetables, fruits, and whole grains
includes low-fat dairy products, poultry, fish, legumes, nontropical vegetable oils, and nuts
limits intake of sweets, sugar-sweetened beverages, and red meats
adapted to appropriate calorie requirements, personal and cultural food preferences, and
nutrition therapy for other medical conditions (including diabetes mellitus)
may be achieved by following plans such as Dietary Approaches to Stop Hypertension
(DASH) dietary pattern, United States Department of Agriculture (USDA) Food Pattern, or
AHA Diet
o advise adults to engage in aerobic physical activity to reduce LDL cholesterol and non-high-
density lipoprotein cholesterol (ACC/AHA Class IIa, Level A)
3-4 physical activity sessions/week
average duration 40 minutes/session
activity should be moderate-to-vigorous intensity
o additional recommendations for adults who would benefit from LDL cholesterol lowering
reduce percent of calories from saturated fat to goal of 5%-6% (ACC/AHA Class I, Level A),
based on moderate strength of evidence for modest reduction in LDL cholesterol
reduce percent of calories from trans fat (ACC/AHA Class I, Level A), based on moderate
strength of evidence for modest reduction in LDL-C
o additional recommendations for adults who would benefit from blood pressure (BP) lowering
lower sodium intake (ACC/AHA Class I, Level A), based on high-to-moderate strength of
evidence for small reduction in BP and low strength of evidence for reduction in
cardiovascular disease
combine DASH dietary pattern with lower sodium intake (ACC/AHA Class I, Level A)
consider specific sodium intake restrictions (ACC/AHA Class IIa, Level B), based on high-to-
moderate strength of evidence for small reduction in BP
consume 2,400 mg of sodium/day
further reduction of sodium intake to 1,500 mg/day is desirable (associated with greater
reduction in BP)
reduce intake by 1,000 mg/day even if desired daily sodium intake is not yet achieved
o Reference - 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk (J
Am Coll Cardiol 2014 Jul 1;63(25 Pt B):2960 PDF, also published inCirculation 2014 Jun
24;129(25 Suppl 2):S76)
(
6
)

National Institute for Clinical Excellence (NICE) 2008 guidelines (United Kingdom):
lifestyle recommendations for people at high-risk of, or with, cardiovascular disease
o cardioprotective diet
total fat intake 30%, saturated fats 10%, and dietary cholesterol < 300 mg/day
replace saturated fats with monounsaturated and polyunsaturated fats
5 portions of fruits and vegetables per day
2 portions of fish per week, including oily fish
o physical activity of at least moderate intensity for 30 minutes/day at least 5 days/week
o achieve and maintain healthy weight
o limit alcohol consumption to 3-4 units/day in men and 2-3 units/day in women
o smoking cessation
primary prevention of cardiovascular disease
o before offering lipid modification therapy for primary prevention, all other modifiable
cardiovascular disease risk factors should be considered and their management optimized if
possible
baseline blood tests and clinical assessment should be performed
comorbidities and secondary causes of dyslipidemia should be treated
o statin therapy is recommended as part of management strategy for primary prevention of
cardiovascular disease for adults who have a 20% 10-year risk of developing cardiovascular
disease which should be estimated by
using an appropriate risk calculator
NICE does not recommend a specific risk calculator
potential options include adjusted Framingham risk equation, QRISK, and ASSIGN
or by clinical assessment for people for whom an appropriate risk calculator is not available
or appropriate (for example, older people, people with diabetes, or people in high-risk ethnic
groups)
o statin therapy dosing and monitoring
treatment for primary prevention of cardiovascular disease should be initiated with
simvastatin 40 mg
lower dose of simvastatin or alternative preparation such as pravastatin may be chosen if
potential drug interactions or simvastatin 40 mg is contraindicated
once statin started for primary prevention, repeat lipid measurement is unnecessary
monitoring on statin therapy should include liver function (transaminases) at baseline, 3
months, and 12 months
o consider ezetimibe for patients with primary hypercholesterolemia (markedly elevated LDL
cholesterol levels with other forms of cholesterol remaining normal) if
contraindications to statin
intolerance of statin
o drugs which may be considered if statins not tolerated
fibrates
anion exchange resins
o interventions not recommended for primary prevention
target for total or LDL cholesterol
omega-3 fatty acid supplements
plant sterols or stanols
nicotinic acid
combination therapy of statin with any of fibrate, anion exchange resin, nicotinic acid, or fish
oil supplement
secondary prevention of cardiovascular disease
o lipid modification therapy should be offered and should not be delayed by management of
modifiable risk factors
blood tests and clinical assessment should be performed
comorbidities and secondary causes of dyslipidemia should be treated
o statin therapy is recommended for adults with clinical evidence of cardiovascular disease
start treatment with simvastatin 40 mg
lower dose of simvastatin or alternative preparation such as pravastatin may be chosen if
potential drug interactions or simvastatin 40 mg is contraindicated
consider increasing to simvastatin 80 mg (or drug of similar efficacy and acquisition cost) if
total cholesterol < 4 mmol/L (154 mg/dL) or LDL cholesterol < 2 mmol/L (77 mg/dL) is not
attained
patients with acute coronary syndrome should be treated with a higher intensity statin
any decision to offer a higher intensity statin should take into account informed preference,
comorbidities, multiple drug therapy, and the benefit and risks of treatment
monitoring on statin therapy should include liver function (transaminases) at baseline, 3
months, and 12 months
o consider ezetimibe for patients with primary hypercholesterolemia (markedly elevated LDL
cholesterol levels with other forms of cholesterol remaining normal) if
contraindications to statin
intolerance of statin
inability to control total or LDL cholesterol level, but guideline development group did not
reach consensus of use of specific targets
o drugs which may be considered if statins not tolerated
fibrates
nicotinic acid
anion exchange resins
Reference - NICE 2008 clinical guidelines and evidence review for lipid modification: cardiovascular
risk assessment and the primary and secondary prevention of cardiovascular disease (NICE 2008 May
PDF, revised March 2010)
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Pediatric recommendations (National Heart, Lung, and Blood Institute):
see NHLBI integrated guidelines for pediatric cardiovascular risk reduction
Diet:
American Heart Association 2006 diet and lifestyle recommendations to reduce cardiovascular risk
(generally supported by 2013 AHA/ACC recommendations)
o balance calorie intake and physical activity to achieve or maintain healthy body weight
o consume diet rich in vegetables and fruits, and choose whole-grain, high-fiber foods
o consume fish, especially oily fish, at least twice weekly
o limit intake of saturated fat, trans fat, and cholesterol
o minimize intake of beverages and foods with added sugars
o choose and prepare foods with little or no salt
o consume alcohol in moderation (for those who drink)
fat modification
o American Heart Association and FDA Food Advisory Committee both recommend limiting trans
fatty acid intake to < 1% total calories; increased trans unsaturated fatty acids (trans fat) intake
associated with increased risk of coronary heart disease (level 2 [mid-level] evidence)
o long-term reduction of saturated fat intake may reduce cardiovascular events but not mortality in
men (level 2 [mid-level] evidence)
o replacing saturated fats with polyunsaturated fats (but not with monounsaturated fats or
carbohydrates) may be associated with reduced risk of coronary artery disease (level 3 [lacking
direct] evidence)
o dietary substitution of saturated fatty acids with omega-6 linoleic acid (without omega-3 fatty
acids) might increase risk of cardiovascular mortality (level 2 [mid-level] evidence)
fish and omega-3 fatty acids
o omega-3 fatty acid supplementation (including nonprescription and dietary forms) does not
appear effective for primary or secondary prevention of cardiovascular disease (level 2 [mid-level]
evidence), but evidence is inconsistent and limited by wide confidence intervals in estimates of
efficacy
o increasing fish consumption may be associated with decreased risk for coronary heart disease and
stroke (level 2 [mid-level] evidence), but advice to increase fish oil intakehas uncertain effects on
cardiac mortality in patients with heart disease (level 2 [mid-level] evidence)
o omega-3 fatty acids (Omacor or Lovaza capsule) 1 g/day does not reduce mortality or risk for
cardiovascular events in patients with impaired glucose tolerance or diabetes and high risk for
cardiovascular events (level 1 [likely reliable] evidence)
increased fruit and vegetable intake associated with decreased risk for cardiovascular disease (level 2
[mid-level] evidence), but insufficient evidence to determine whether interventions to increase fruit
and vegetable consumption has benefit for primary prevention of cardiovascular disease
increasing dietary fiber intake associated with reduced risk of coronary heart disease and
cardiovascular disease (level 2 [mid-level] evidence)
regular consumption of sugar-sweetened beverages ( 1 standard serving size per day) may be
associated with increased risk of coronary heart disease in women (level 2 [mid-level] evidence)
evidence for specific foods or supplements
o consumption of processed meat associated with increased risk of coronary heart disease and
diabetes mellitus; red meat not associated with increased risk (level 2 [mid-level] evidence)
o nut consumption associated with reduced coronary heart disease risk (level 2 [mid-level]
evidence); walnuts and almonds may be associated with improved lipid levels (level 3 [lacking
direct] evidence)
o soy protein and isoflavones appear to have minimal effect on cholesterol levels (level 3 [lacking
direct] evidence)
o light-to-moderate alcohol consumption associated with decreased risk of all-cause mortality,
coronary heart disease mortality, and myocardial infarction (level 2 [mid-level] evidence)
o tea consumption associated with reduced risk for myocardial infarction and reduced cardiovascular
mortality (level 2 [mid-level] evidence)
o moderate coffee consumption associated with reduced risk of cardiovascular disease (level 2 [mid-
level] evidence)
o flavonoid content of chocolate may reduce risk of cardiovascular mortality (level 2 [mid-level]
evidence)
o whole flaxseed and lignan supplements (but not flaxseed oil) reported to reduce total and low-
density lipoprotein (LDL) cholesterol levels in certain populations (level 3 [lacking direct] evidence)
o plant stanols or sterols 2 g/day may reduce LDL cholesterol by 10% (level 3 [lacking direct]
evidence)
sodium restriction may reduce blood pressure modestly in hypertensive patients (by 5-10/2-3 mm Hg)
and minimally in normotensive patients (level 3 [lacking direct] evidence), but unknown whether
reduced salt intake reduces cardiovascular morbidity or mortality (level 2 [mid-level] evidence)
o higher salt intake might increase risk of stroke (level 2 [mid-level] evidence)
o individual response to sodium restriction not consistent (level 3 [lacking direct] evidence)
Mediterranean diet associated with lower mortality and lower rate of cardiovascular events in patients
with cardiac disease (level 2 [mid-level] evidence)
Dietary Approaches to Stop Hypertension (DASH) diet reduces blood pressure, lipid levels, and
homocysteine levels (level 3 [lacking direct] evidence); increased adherence to DASH-style diet
associated with reduced risk for cardiovascular mortality, myocardial infarction, and stroke (level 2
[mid-level] evidence)
vitamin and mineral supplementation not shown to reduce risk for cardiovascular disease
o vitamin and antioxidant supplements do not appear to reduce risk for cardiovascular disease (level
2 [mid-level] evidence)
o inconsistent evidence regarding calcium supplementation and increased risk for cardiovascular
disease
o higher potassium intake and higher magnesium intake associated with decreased risk of
cardiovascular disease in observational studies (level 2 [mid-level] evidence)
see Dietary interventions for cardiovascular disease prevention for details
no randomized trials identified evaluating low-fat diets in adults with acquired
hypercholesterolemia
o based on Cochrane review
o Reference - Cochrane Database Syst Rev 2011 Feb 16;(2):CD007957 Texto completo de
EBSCOhost
Activity:
American College of Cardiology/American Heart Association (ACC/AHA) recommends advising adults to
engage in aerobic physical activity to reduce low-density lipoprotein cholesterol and nonhigh-density
lipoprotein cholesterol (ACC/AHA Class IIa, Level A)
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o 3-4 physical activity sessions/week
o average duration 40 minutes/session
o activity should be moderate-to-vigorous intensity
see also Physical Activity Guidelines for Americans
progressive resistance training reported to improve low-density lipoprotein (LDL)
cholesterol and other lipoprotein and lipid measures (level 3 [lacking direct] evidence)
o based on systematic review without clinical outcomes
o systematic review of 29 studies with 1,329 adults evaluated the effect of 4 weeks of progressive
resistance training on lipoproteins and lipids
o significant improvement with progressive resistance training in
LDL cholesterol
nonhigh-density lipoprotein (HDL) cholesterol
total cholesterol
total cholesterol/HDL cholesterol ratio
triglycerides
o Reference - Prev Med 2009 Jan;48(1):9
moderate intensity walking may reduce weight and total cholesterol/HDL cholesterol ratio
in men with hypercholesterolemia (level 2 [mid-level] evidence)
o based on randomized trial
o 67 men (mean age 55.1 years) with hypercholesterolemia randomized to brisk walking (burning
300 kcal/walk) vs. control for 12 weeks
o comparing walking group vs. control
significant reduction in total cholesterol/HDL cholesterol ratio
significant reduction in weight (-1.4 kg [-3.1 lb], 95% CI -2.43 kg to -0.38 kg [-5.4 lb to 0.8
lb])
borderline reduction in triglycerides
o Reference - Prev Med 2008 Jun;46(6):545
more intensive diet and exercise interventions may be more effective at lowering
cholesterol and weight (level 2 [mid-level] evidence)
o based on small randomized trial
o 47 patients with dyslipidemia were randomized to 1 of 4 groups for 3 months
standard lifestyle recommendations (National Cholesterol Education Program [NCEP] Step I
diet and regular exercise)
Step I diet plus supervised aerobic exercise
Step II diet and regular exercise
Step II diet and supervised aerobic exercise
o 41 patients completed the study
o no significant changes in weight or lipid profile measures studied for standard group
o more intensive interventions reduced LDL cholesterol (-6%) and weight (-1.7 kg to -3.7 kg [-3.7 lb
to -8.2 lb])
o Reference - Prev Med 2002 Jul;35(1):16
diet and exercise both contribute to decreasing LDL cholesterol (level 3 [lacking direct]
evidence)
o based on randomized trial without clinical outcomes
o 180 postmenopausal women aged 45-64 years and 197 men aged 30-64 years with low HDL
cholesterol (< 44-59 mg/dL, 1.1-1.5 mmol/L) and moderately elevated LDL cholesterol (125-210
mg/dL, 3.2-5.4 mmol/L) were randomized to NCEP Step II diet, aerobic exercise, both diet and
exercise, or control group with no intervention for 1 year
o LDL cholesterol significantly reduced only in diet plus exercise group, with reductions of 14.5-20
mg/dL (0.38-0.5 mmol/L)
o Reference - N Engl J Med 1998 Jul 2;339(1):12, commentary can be found in N Engl J Med 1998
Nov 19;339(21):1552
increased exercise capacity (fitness) and statin use associated with decreased risk of
mortality in veterans with dyslipidemia (level 2 [mid-level] evidence)
o based on prospective cohort study
o 10,043 veterans (mean age 59 years) with dyslipidemia who participated in exercise tolerance test
between 1986 and 2011 were followed for median 10 years
50% were receiving statin therapy
42% had a history of cardiovascular disease
o one metabolic equivalent (MET) defined as energy expended at rest (approximately equivalent to
oxygen consumption of 3.5 mL/kg/minute)
o 23% overall mortality during follow-up
o mortality 18.5% with statins vs. 27.7% without statins (p < 0.0001)
Exercise Capacity Statin Use No Statin Use
Least fit (peak MET 5) Reference Adjusted HR 1.35 (95% CI 1.17-1.54)
Moderately fit (peak MET 5-7) Adjusted HR 0.65 (95% CI 0.56-0.75) Adjusted HR 1.02 (95% CI 0.88-1.12)
Fit (peak MET 7-9) Adjusted HR 0.41 (95% CI 0.34-0.49) Adjusted HR 0.81 (95% CI 0.69-0.96)
Highly fit (peak MET > 9) Adjusted HR 0.3 (95% CI 0.21-0.41) Adjusted HR 0.53 (95% CI 0.44-0.65)
Abbreviations: HR, hazard ratio; MET, one metabolic equivalent.
Mortality Risk Decreased as Exercise Capacity Increased:
o Reference - Lancet 2013 Feb 2;381(9864):394, editorial can be found in Lancet 2013 Feb
2;381(9864):356
Counseling:
discussing coronary risk with patient might further reduce low-density lipoprotein (LDL)
cholesterol levels in some patients (level 3 [lacking direct] evidence)
o based on randomized trial without clinical outcomes
o 3,053 patients with dyslipidemia randomized to receive calculated coronary risk profile (1-page
computer printout) every 3 months vs. usual care for 1 year
o risk profile freely available from McGill Cardiovascular Health Improvement Program
o comparing risk profile vs. usual care
lipid targets reached in 55.2% vs. 52.2% (not significant), but differences significant in
subgroups with highest risks
mean change in total cholesterol at 1 year -58.4 mg/dL vs. -54.5 mg/dL (1.51 mmol/L vs.
1.41 mmol/L) (mean difference between groups -3.9 mg/dL [-0.1 mmol/L], p = 0.02)
mean change in LDL cholesterol at 1 year -51.2 mg/dL vs. -48 mg/dL (-1.33 mmol/L vs. -1.24
mmol/L) (mean difference between groups -3.3 mg/dL [-0.085 mmol/L], p = 0.02)
mean change in calculated 10-year coronary risk at 1 year -5.9% vs. -5.3% (mean difference
-0.6%, p = < 0.001, NNT 167 to prevent 1 coronary event over 10 years)
o Reference - CHECK-UP study (Arch Intern Med 2007 Nov 26;167(21):2296), editorial can be found
in Arch Intern Med 2007 Nov 26;167(21):2286, commentary can be found in Arch Intern Med
2008 Aug 11;168(15):1719
Medications:
Statins:
statins inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting step in
cholesterol synthesis
primary role of statins is cardiovascular disease prevention
o statins are drugs of first choice for lipid lowering in patients at increased risk for cardiovascular
disease
o statins reduce mortality and myocardial infarction in adults with coronary heart disease (with or
without hypercholesterolemia) (level 1 [likely reliable] evidence) and reduce subsequent
cerebrovascular events in adults with history of stroke or transient ischemic attack (TIA) (level 1
[likely reliable] evidence)
o lipid-lowering therapy (primarily with statins) is effective for primary and secondary prevention of
major coronary events in patients with diabetes (level 1 [likely reliable] evidence)
o for patients without known cardiovascular disease (primary prevention)
statins reduce cardiovascular disease events and stroke (level 1 [likely reliable] evidence)
and may reduce all-cause mortality (level 2 [mid-level] evidence)
absolute benefit from statins for primary prevention of heart disease depends more on
overall risk than cholesterol levels
10-year Risk of CVD
Events
NNT for CVD
Events
NNT for Myocardial
Infarction
NNT for
Stroke
NNT for
Mortality
5% 80 139 455 500
7.5% 54 93 303 334
10% 40 70 228 250
15% 27 47 152 167
20% 20 35 114 125
Abbreviations: CVD, cardiovascular disease; NNT, number needed to treat for 10 years to prevent 1
outcome.
NNT for Statins for 10 Years:
guidelines vary regarding threshold for using statins for primary prevention
American College of Cardiology/American Heart Association (ACC/AHA) recommends
statin therapy if 10-year risk of cardiovascular disease 7.5% (ACC/AHA Class I, Level
A) with consideration at risk 5% to < 7.5% (ACC/AHA Class IIa, Level B)
National Institute for Health and Clinical Excellence (NICE) recommends statin therapy if
10-year risk of cardiovascular disease 20%
o statins have inconsistent evidence for effect on overall and cardiovascular mortality in patients
aged 70-82 years
o see Statins for prevention of cardiovascular disease for details
comparative efficacy of statins for reduction in cardiovascular disease events may relate more to
intensity of dosing than to specific agent used (level 2 [mid-level] evidence)
other potential clinical benefits of statins include
o in heart failure, atorvastatin may decrease all-cause mortality and hospitalization for worsening
heart failure (level 2 [mid-level] evidence), but these benefits not found with simvastatin (level 2
[mid-level] evidence) or rosuvastatin (level 1 [likely reliable] evidence)
o statins may reduce blood pressure (level 3 [lacking direct] evidence)
o statins may be associated with reduced risk for venous thromboembolism (level 2 [mid-level]
evidence)
adverse effects include
o adverse effects may include mild transient gastrointestinal symptoms, muscle pain, rash,
headache, sleep disturbances, anxiety, irritability, fatigue, pruritus
o statins not associated with risk of cancer in meta-analyses which do not adjust for patient age,
but statins may be associated with increased cancer risk in older patients (level 2 [mid-level]
evidence)
o statins associated with low rate of myopathy (1 per 10,000 person-years) and rhabdomyolysis (3-
4 per 100,000 person-years), but rate 6-10 times higher with concomitant fibrates
o statins associated with small increase in incidence of elevated hepatic transaminases compared to
placebo (level 3 [lacking direct] evidence)
recommended laboratory monitoring includes fasting lipid profile 4-12 weeks after dose changes and
every 3-12 months (ACC/AHA Class I, Level A), baseline liver function tests (alanine transaminase
[ALT]) (ACC/AHA Class I, Level B), and screening for new-onset diabetes (ACC/AHA Class I, Level B),
but no evidence to support clinical benefit of routine monitoring
red yeast rice preparations contain statins and reduce low-density lipoprotein cholesterol (LDL-C)
(level 3 [lacking direct] evidence); Xuezhikang extract may reduce mortality and reinfarction following
myocardial infarction (level 2 [mid-level] evidence)
see Statins for details
Fibric acid derivatives:
fibrates include
o gemfibrozil (Lopid)
o bezafibrate (Bezalip, not available in United States)
o fenofibrate (Antara, Lofibra, Tricor, generic)
used mainly to lower triglycerides and increase high-density lipoprotein cholesterol (HDL-C)
may increase or decrease low-density lipoprotein cholesterol (LDL-C)
fibrates may reduce risk for coronary events (level 2 [mid-level] evidence)
fibrates may decrease risk for nonfatal myocardial infarction in patients refractory to or intolerant of
statins (level 2 [mid-level] evidence)
combination of fibrates and statins may improve lipid profiles more than monotherapy (level 3 [lacking
direct] evidence) but associated with increased risk for rhabdomyolysis (level 2 [mid-level] evidence)
gemfibrozil reduces risk for myocardial infarction and possibly stroke and coronary mortality in
patients with coronary artery disease and low HDL-C (level 1 [likely reliable] evidence)
see Fibric acid derivatives for details
American College of Cardiology/American Heart Association (ACC/AHA) safety recommendations when
using fibrates
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o do not use gemfibrozil with statins due to risk for muscle symptoms and rhabdomyolysis
(ACC/AHA Class III Harm, Level B)
o consider fenofibrate with low- to moderate-intensity statin only if benefits (cardiovascular risk
reduction or lowering of triglyceride levels > 500 mg/dL) are judged to outweigh risks (ACC/AHA
Class IIb, Level C)
o evaluate renal status before starting fenofibrate, within 3 months, then every 6 months on
fenofibrate (ACC/AHA Class I, Level B)
do not use fenofibrate if estimated glomerular filtration rate < 30 mL/minute/1.73
mg
2
(ACC/AHA Class III Harm, Level B)
do not exceed fenofibrate 54 mg/day if estimated glomerular filtration rate 30-59
mL/minute/1.73 mg
2
(ACC/AHA Class III Harm, Level B)
Niacin:
water-soluble B-complex vitamin (vitamin B3) used to improve lipid profile for cardiovascular risk
reduction
also called nicotinic acid, available under many brand names
addition of niacin to simvastatin increases high-density lipoprotein cholesterol (HDL-C) but does not
reduce cardiovascular events in patients with cardiovascular disease and controlled low-density
lipoprotein cholesterol (LDL-C) (level 1 [high-quality] evidence)
niacin may reduce risk for myocardial infarction, stroke, and transient ischemic attack in patients with
coronary artery disease (level 2 [mid-level] evidence)
addition of extended-release niacin/laropiprant to statin-based therapy increases risk of serious
adverse events and does not decrease risk of major vascular events in patients with vascular disease
(level 1 [likely reliable] evidence)
immediate-release niacin taken with meals; extended-release niacin taken at bedtime following low-fat
snack
avoid concomitant alcohol or hot drinks to reduce risk of flushing or pruritus
dosing for cardiovascular disease prevention
o initial dose 500 mg once daily at bedtime using extended-release niacin
o may increase by 500 mg increments at 4-week intervals
o maximum dose 2 g/day
o higher doses using immediate-release niacin have been used for marked lipid abnormalities
contraindicated if active liver disease, persistent elevated serum transaminases, active peptic ulcer
disease, or arterial bleeding
do not use different niacin formulations interchangeably
adverse effects include flushing, headache, abdominal pain, diarrhea, dyspepsia, nausea, vomiting,
pruritus, rash, hepatotoxicity (liver function test monitoring recommended), myopathy, decreased
glucose tolerance, increased prothrombin time, decreased platelet counts, and hyperuricemia
Pregnancy Category C, not recommended during breastfeeding
see Niacin for details
ACC/AHA safety recommendations when using niacin
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o obtain hepatic transaminases, fasting blood glucose or HbA1c, and uric acid at baseline, during
up titration to maintenance dose, and then every 6 months (ACC/AHA Class I, Level B)
o do not use niacin if any of
hepatic transaminase levels > 2-3 times upper limit of normal (ACC/AHA Class III Harm,
Level B)
persistent severe cutaneous symptoms, persistent hyperglycemia, acute gout, or unexplained
abdominal pain or gastrointestinal symptoms occur (ACC/AHA Class III Harm, Level B)
occurrence of new-onset atrial fibrillation or weight loss (ACC/AHA Class III Harm, Level B)
o if adverse effects from niacin, reconsider potential benefits and adverse effects before restarting
niacin (ACC/AHA Class I, Level B)
o dosing strategies to reduce risk and severity of adverse cutaneous symptoms (ACC/AHA Class IIa,
Level C)
starting at low dose and titrating over weeks as tolerated
if extended-release niacin used, starting with 500 mg/day and increasing no more than
weekly to maximum 2,000 mg/day over 4-8 weeks
if immediate-release niacin used, stating with 100 mg 3 times daily and increasing to 3
g/day in 2-3 divided doses
taking niacin with food
taking aspirin 325 mg 30 minutes before taking niacin
Ezetimibe:
ezetimibe is a cholesterol absorption inhibitor
brand names Zetia or Vytorin (in combination with simvastatin) in United States, Ezetrol in Canada
FDA approved for primary hypercholesterolemia, mixed dyslipidemia, homozygous
familial hypercholesterolemia, and homozygous familial sitosterolemia
efficacy for clinical outcomes not clearly established
o ezetimibe/simvastatin might reduce ischemic stroke and coronary revascularization in patients
with chronic kidney disease (level 2 [mid-level] evidence), but comparison with simvastatin alone
not established
o ezetimibe/simvastatin may not reduce rate of cardiovascular events in patients with aortic
stenosis (level 2 [mid-level] evidence)
o addition of ezetimibe to simvastatin is ineffective for reducing arterial plaque growth (level 3
[lacking direct] evidence)
o ezetimibe improves lipid profiles (level 3 [lacking direct] evidence)
o addition of ezetimibe 10 mg/day to statin therapy or fenofibrate further reduces low-density
lipoprotein cholesterol level (level 3 [lacking direct] evidence)
dosing
o 10 mg once daily
o give 2 hours before or 4 hours after bile acid sequestrant
do not use if moderate or severe hepatic impairment
not recommended in children < 10 years, due to lack of safety and efficacy data
Pregnancy Category C (combination ezetimibe/simvastatin [Vytorin] is Category X due to simvastatin)
adverse effects include back pain, arthralgia, diarrhea, sinusitis, abdominal pain, cough, pharyngitis,
viral infection, fatigue; hypersensitivity reactions have been reported
ezetimibe/simvastatin (Vytorin) potentially associated with increased incidence of cancer (level 2 [mid-
level] evidence), perhaps attributable to simvastatin
see Ezetimibe for details
reasonable to check baseline hepatic transaminases before starting ezetimibe and monitor when
ezetimibe used with statin therapy (ACC/AHA Class IIa, Level B)
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Evolocumab:
Evolocumab is a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor
addition of evolocumab to lipid-lowering therapy reduces low density lipoprotein
cholesterol levels in patients with hyperlipidemia (level 3 [lacking direct] evidence)
o based on nonclinical outcome from randomized trial
o 1,485 patients aged 18-75 years with hyperlipidemia had open-label run-in period of lipid-
lowering background therapy with diet alone, diet plus atorvastatin 10 mg daily, atorvastatin 80
mg alone daily, or atorvastatin 80 mg daily plus ezetimibe 10 mg daily for 4-12 weeks prior to
randomized treatment (treatment determined by previous statin use and cardiovascular risk and
could be adjusted every 4 weeks)
o 905 patients with low density lipoprotein (LDL) cholesterol level 75 mg/dL after run-in were
randomized to evolocumab 420 mg subcutaneously vs. placebo once every 4 weeks for 1 year
o lipid-lowering background therapy was continued throughout trial
o comparing evolocumab vs. placebo
mean change in LDL cholesterol overall -50.1% vs. +6.8% (p < 0.001)
LDL cholesterol < 70 mg/dL in 82.3% vs. 6.4% (p < 0.05)
adverse events in 74.8% vs. 74.2% (not significant)
o most common adverse events were nasopharyngitis, upper respiratory tract infection, influenza,
and back pain
o evolocumab associated with significantly
decreased apolipoprotein B, non-high density lipoprotein cholesterol, lipoprotein a, and
triglyceride levels
increased high density lipoprotein cholesterol and apolipoprotein A1 levels
o no significant differences in effect of evolocumab comparing different run-in treatment groups
o Reference - DESCARTES trial (N Engl J Med 2014 May 8;370(19):1809)
addition of evolocumab to moderate- or high-intensity statin therapy associated with
greater reduction in low-density lipoprotein cholesterol levels (level 3 [lacking direct]
evidence)
o based on nonclinical outcome from randomized trial without intention-to-treat analysis
o 2,067 patients aged 18-80 years with primary hypercholesterolemia and mixed dyslipidemia were
randomized to 4-week lipid-stabilization period with moderate- vs. high-intensity statin regimens
o 1,899 of these patients were then randomized to evolocumab (140 mg subcutaneously once
every 2 weeks vs. 420 mg once monthly) vs. ezetimibe 10 mg/day orally vs. matching placebos
for 12 weeks
o evolocumab associated with significantly decreased LDL-C levels at 10-12 weeks compared to
placebo (reduction 63%-75% depending upon dosing and statin regimen)
ezetimibe (38%-54% depending upon dosing and statin regimen)
o adverse events similar among groups (no p values reported)
o most common adverse events with evolocumab were back pain, arthralgia, headache, and muscle
spasms
o Reference - LAPLACE-2 trial (JAMA 2014 May 14;311(18):1870)
Bile acid-binding resins:
bile acid-binding resins also called bile acid sequestrants, anion exchange resins
available drugs include
o cholestyramine (Prevalite, Questran, generic) 4-8 g orally twice daily
o colesevelam (Welchol) 3.75 g (6 tablets) once daily or 1.875 g (3 tablets) twice daily
o colestipol (Colestid, generic) 2-16 g/day using tablets or 5-30 g/day (1-6 packets or scoops per
day) using granules for oral suspension
o colestilan (not available in United States, Cholebine in Japan)
drug class effects
o can lower LDL-C levels but may increase triglyceride levels (level 3 [lacking direct] evidence)
o interferes with absorption of many drugs given 2 hours before or 4-6 hours after bile acid-binding
resins
cholestyramine may reduce composite outcome of coronary mortality and nonfatal myocardial
infarction in men with hypercholesterolemia and without known coronary artery disease (level 2 [mid-
level] evidence)
colesevelam labeled for use in type 2 diabetes in addition to use in hypercholesterolemia; colesevelam
may reduce LDL-C, glucose, and HbA1c levels (reducing HbA1c by about 0.5%) (level 3 [lacking
direct] evidence)
colestipol (tablets or granules) reduce total and LDL-C levels (level 3 [lacking direct] evidence) but
granules may be poorly tolerated (level 3 [lacking direct] evidence)
colestilan associated with improved glycemic control and reduced LDL-C levels in patients with type 2
diabetes (level 3 [lacking direct] evidence)
see Bile acid-binding resins for details
American College of Cardiology/American Heart Association (ACC/AHA) safety recommendations when
using bile acid sequestrants
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4
)

o do not use bile acid sequestrants if baseline fasting triglyceride levels 300 mg/dL or type III
hyperlipoproteinemia (ACC/AHA Class III Harm, Level B)
o use caution if baseline fasting triglyceride levels 250-299 mg/dL (ACC/AHA Class IIa, Level C)
recheck fasting lipid profile in 4-6 weeks
discontinue if triglyceride level > 400 mg/dL
Herbs and dietary supplements:
herbs and dietary supplements with evidence for clinical benefit include (level 2 [mid-level] evidence)
o red yeast rice 600 mg twice daily (contains statins)
herbs and dietary supplements with evidence for lowering cholesterol levels include (level 3 [lacking
direct] evidence)
o guggulipid
o policosanol
o artichoke leaf extract
o fenugreek
o Arjuna (Terminalia arjuna)
herbs and dietary supplements which appear ineffective for lowering cholesterol levels include (level 3
[lacking direct] evidence)
o garlic
see Lipid-lowering pharmacotherapy overview
Surgery and procedures:
partial ileal bypass associated with reduced mortality (compared to diet alone) in patients
with hypercholesterolemia and myocardial infarction (level 2 [mid-level] evidence)
o based on randomized trial with allocation concealment not stated
o 838 patients aged 30-64 years with single myocardial infarction and hypercholesterolemia (total
cholesterol level > 220 mg/dL [5.69 mmol/L] or > 200 mg/dL [5.17 mmol/L] with low-density
lipoprotein cholesterol > 140 mg/dL 3.62 mmol/L]) were randomized to partial ileal bypass plus
diet instruction vs. diet instruction alone
o patients were encouraged not to take cholesterol-lowering medications during the trial
o mean follow-up 14.7 years (range 12.2-20 years)
o comparing ileal bypass vs. diet
overall mortality 20% vs. 25.4% (p = 0.049, NNT 19)
mortality from atherosclerotic coronary artery disease 11.6% vs. 16.8% (p = 0.03, NNT 20)
o Reference - POSCH trial (Arch Intern Med 1998 Jun 8;158(11):1253)
o estimated 25-year survival in POSCH trial was 57% after surgery vs. 51% after diet control (Ann
Surg 2010 Jun;251(6):1034)
Consultation and referral:
dietitian
o advice from dietitian associated with modest short-term reductions in blood
cholesterol compared to advice from doctor, but no evidence of greater efficacy than
nurses or self-help resources (level 3 [lacking direct] evidence)
based on Cochrane review of trials with methodologic limitations and mostly surrogate
outcomes
systematic review of 12 randomized trials comparing 727 patients receiving advice from
dietitians, 515 patients receiving advice from other health professionals (mostly doctors), and
551 patients using self-help resources
all 12 trials had methodologic limitations including limited reporting of randomization method
and allocation concealment
participants receiving advice from dietitians had greater reduction in blood cholesterol than
participants receiving advice only from doctors (-0.25 mmol/L [-10 mg/dL], 95% CI -0.37
mmol/L to -0.12 mmol/L [-14 mg/dL to -5 mg/dL]) in analysis of 4 trials with 664 patients; all
trials in this comparison were limited to < 6 months duration
most other comparisons were not significant, except dietitian counseling associated with
greater weight reduction than counselor in 1 trial with 52 patients (-5.8 kg [ -12.8 pounds],
95% CI -8.91 kg to -2.69 kg [-19.6 lbs to -5.9 lbs])
Reference - Cochrane Database Syst Rev 2003;(3):CD001366 Texto completo de
EBSCOhost (review updated 2008 Oct 20)
o dietitian counseling can significantly lower cholesterol at 3 months and (with less
effect) at 12 months (level 3 [lacking direct] evidence)
based on randomized trial without clinical outcomes
trial excluded from Cochrane review CD001366
136 middle-aged patients with hypercholesterolemia (mean total cholesterol 252 mg/dL [6.5
mmol/L], mean low-density lipoprotein (LDL) cholesterol 177 mg/dL [4.6 mmol/L])
randomized to usual care by specially trained physicians vs. counseling by dietitians (2-4
sessions over 3 months) following physician assessment
comparing physicians vs. dietitians at 3 months
total cholesterol lowered by 5% vs. 9%
LDL cholesterol lowered by 7% vs. 12%
comparing physicians vs. dietitians at 12 months
total cholesterol lowered by 1% vs. 5%
LDL cholesterol lowered by 3% vs. 7%
Reference - Am J Med 2000 Nov;109(7):549
pharmacist
o enhanced pharmacist care associated with reduced cholesterol levels (especially LDL
cholesterol levels) in patients with hypercholesterolemia (level 3 [lacking direct]
evidence)
based on systematic review without clinical outcomes
systematic review of 21 randomized trials comparing enhanced pharmacist care vs. standard
care in patients with hypercholesterolemia
enhanced pharmacist care defined as pharmacist intervention including assessment of
therapy, education, and/or adherence
enhanced pharmacist care associated with
reduced LDL cholesterol level (10.7 mg/dL [0. 28 mmol/L], 95% CI 4.6-16.9 mg/dL
[0.12-0.44 mmol/L]) in analysis of 9 trials with 960 patients, results limited by
heterogeneity
reduced total cholesterol level (15.2 mg/dL [0.4 mmol/L], 95% CI 6.4-24 mg/dL [0.17-
0.62 mmol/L]) in analysis of 10 trials with 1,196 patients, results limited by heterogeneity
reduced triglycerides (23 mg/dL [0.26 mmol/L], 95% CI 8.9-37.2 mg/dL [0.1-0.42
mmol/L]) in analysis of 9 trials with 1,082 patients
increased rate of achieving target lipid parameters (odds ratio 2.46, 95% CI 1.43-4.25) in
analysis of 8 trials with 2,089 patients
no significant differences in high-density lipoprotein (HDL) cholesterol level
Reference - Pharmacotherapy 2012 Mar;32(3):222
o collaborative care involving physicians and pharmacists not associated with greater
decrease in LDL cholesterol compared with usual care among patients with
dyslipidemia (level 3 [lacking direct] evidence)
based on cluster randomized trial without clinical outcomes (not in systematic review)
15 clusters representing 77 physicians and 108 pharmacists randomized to provide
collaborative care vs. usual care
collaborative care was healthcare team intervention including visits every 2 months
usual care was physicians requesting laboratory tests and adjusting lipid-lowering
pharmacotherapy, pharmacists dispensing medications and providing usual counseling
included were 225 patients with dyslipidemia taking no more than 1 lipid-lowering medication
at study initiation
evaluation visits conducted at baseline and 12 months
Reference - TEAM study (CMAJ 2010 Mar 23;182(5):447 Texto completo de
EBSCOhost full-text)
Other management:
lifestyle interventions identified which have evidence for reduction in low-density
lipoprotein (LDL) cholesterol levels (level 3 [lacking direct] evidence)
o weight loss, based on 1 meta-analysis and 32 randomized trials
o exercise, based on 5 meta-analyses
o counseling, based on 15 randomized trials
o alcohol consumption (1-2 drinks/day), based on 4 randomized trials
o yoga/tai chi, based on 2 randomized trials
o meditation, based on limited evidence with 3 randomized trials
o smoking cessation, based on limited evidence with 2 randomized trials
o Reference - J Fam Pract 2007 Jun;56(6):483 Texto completo de EBSCOhost
addition of lifestyle change intervention to red yeast rice (in patients with
hypercholesterolemia not receiving statins) may not further lower low-density lipoprotein
cholesterol at 1 year (level 3 [lacking direct] evidence) but may promote modest weight
loss (level 2 [mid-level] evidence)
o based on randomized trial with high dropout rate
o 220 patients aged 21-80 years with low-density lipoprotein cholesterol (LDL-C)100-210 mg/dL
(2.59 - 5.43 mmol/L) randomized to lifestyle change intervention vs. usual care
o lifestyle change intervention included 3.5-hour weekly sessions for 12 weeks led by cardiologist
and including
nutrition education including promotion of modified Mediterranean diet by dietitian
education on health benefits of exercise, stretching, and light strength training by exercise
physiologist
conclusion with exposure to different relaxation techniques (including tai chi, meditation, and
yoga)
recommendations for continued adherence to lifestyle strategies for 1 year, and monthly
meetings to provide study medication
o at baseline all patients had discontinued 1 statin due to myalgias or refused statin therapy
o all patients received
red yeast rice 1,800 mg orally twice daily
separate randomization to phytosterols 900 mg orally twice daily vs. placebo
o 70% completed trial and all patients were included in intention-to-treat analyses
o comparing lifestyle change intervention vs. usual care
mean weight change at 1 year -2.3 kg (-5.1 lbs) vs. -0.3 kg (-0.7 lbs) (p < 0.001)
mean change in LDL cholesterol at 12 weeks -51 mg/dL (-1.32 mmol/L) vs. -42 mg/dL (-1.09
mmol/L) (p = 0.006)
mean change in LDL- cholesterol at 1 year -42 mg/dL (-1.09 mmol/L) vs. -38 mg/dL (-0.99
mmol/L) (not significant)
o no significant differences in high-density lipoprotein cholesterol at any time point
o Reference - Am Heart J 2013 Jul;166(1):187
multidisciplinary lifestyle program may be as effective as simvastatin for lowering LDL
cholesterol levels (level 3 [lacking direct] evidence)
o based on randomized trial without clinical outcomes
o 79 patients with hypercholesterolemia meeting Adult Treatment Panel III criteria for primary
prevention using statin therapy were randomized to multidisciplinary lifestyle program
vs. simvastatin 40 mg daily for 12 weeks
multidisciplinary lifestyle program included fish oil supplements, red yeast rice supplements,
3.5-hour weekly meetings, education, relaxation instruction (including yoga and tai chi),
aerobic exercise instruction from exercise physiologist, and modified Mediterranean diet as
instructed by dietitian
simvastatin group received drug and handout on diet and lifestyle recommendations from
American Heart Association
o 74 patients (94%) completed study
o significant mean reduction from baseline occurred in both groups for LDL cholesterol, total
cholesterol, and triglycerides
o mean reductions comparing multidisciplinary program vs. simvastatin
LDL cholesterol 42.4% vs. 39.6% (not significant)
total cholesterol 32.4% vs. 27.3% (not significant)
triglycerides 29.2% vs. 9.3% (p = 0.003)
o Reference - Mayo Clin Proc 2008 Jul;83(7):758 Texto completo de EBSCOhost,
commentary can be found in Mayo Clin Proc 2008 Oct;83(10):1187 Texto completo de
EBSCOhost, Mayo Clin Proc 2008 Nov;83(11):1294
o DynaMed commentary -- red yeast rice contains 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-
CoA) reductase inhibitors (statins)
Follow-up:
recommended follow-up differs in United States and United Kingdom guidelines
American College of Cardiology/American Heart Association (ACC/AHA) guidelines (United States)
o blood test monitoring for statin use
(
4
)

although target treatment levels no longer recommended, monitoring fasting lipid profile (4-
12 weeks after starting or changing dose, then every 3-12 months) recommended to monitor
therapeutic response and reinforce adherence to medication and lifestyle changes (ACC/AHA
Class I, Level A)
creatine kinase (CK)
should not be routinely measured in patients receiving statin therapy (ACC/AHA Class III
No Benefit, Level A)
baseline CK measurement is reasonable for patients at increased risk for adverse muscle
events (ACC/AHA Class IIa, Level C)
CK measurement during statin therapy is reasonable in patients with muscle symptoms
including pain, tenderness, stiffness, cramping, weakness, or generalized fatigue
(ACC/AHA Class IIa, Level C)
if mild-to-moderate muscle symptoms, discontinue statin until symptoms evaluated, then
restart if muscle symptoms resolve; if symptoms recur, discontinue statin and once
resolved start low dose of different statin (ACC/AHA Class IIa, Level B)
if unexplained severe muscle symptoms or fatigue, discontinue statin and check CK,
creatinine, and urinalysis for myoglobinuria (ACC/AHA Class IIa, Level B)
hepatic alanine transaminase levels (ALT)
perform baseline ALT measurement before starting statin therapy (ACC/AHA Class I,
Level B)
during statin therapy, it is reasonable to measure hepatic function if symptoms
suggesting hepatotoxicity arise (such as unusual fatigue or weakness, loss of appetite,
abdominal pain, dark colored urine, or yellowing of skin or sclera) (ACC/AHA Class IIa,
Level C)
screen for new-onset diabetes mellitus per current guidelines (ACC/AHA Class I, Level B)
o if not in risk group warranting statin use (and more frequent assessment)
(
5
)

reasonable to repeat cardiovascular risk assessment every 4-6 years in adults without
atherosclerotic cardiovascular disease (ACC/AHA Class IIa, Level B), including
assessment of traditional atherosclerotic cardiovascular disease risk factors (age, sex,
total and high-density lipoprotein cholesterol, systolic blood pressure, use of
antihypertensive therapy, diabetes, and current smoking) at ages 20-79 years
estimation of 10-year atherosclerotic cardiovascular disease risk at ages 40-79 years
use race- and sex-specific Pooled Cohort Equations to estimate 10-year atherosclerotic
cardiovascular disease risk in non-Hispanic African Americans and non-Hispanic white patients
aged 40-79 years without clinical atherosclerotic cardiovascular disease (ACC/AHA Class I,
Level B)
Pooled Cohort Equations CV Risk Calculator can be downloaded (in form of interactive
spreadsheet with display for patient) from American Heart Association
DynaMed commentary -- Pooled Cohort Equations may overestimate cardiovascular
risk (level 2 [mid-level] evidence)
for populations other than African Americans and non-Hispanic white patients, use of
sex-specific Pooled Cohort Equations for non-Hispanic white patients may be considered
(ACC/AHA Class IIb, Level C)
if risk-based treatment decision is uncertain after quantitative risk assessment, consider
assessment of 1 of (ACC/AHA Class IIb, Level B)
family history
high-sensitivity C-reactive protein (hs-CRP)
coronary artery calcium (CAC) score
ankle-brachial index (ABI)
no recommendation made for or against addition of any of the following to risk assessment of
first atherosclerotic cardiovascular disease event
apolipoprotein B
chronic kidney disease
albuminuria
cardiorespiratory fitness
assessing 30-year or lifetime atherosclerotic cardiovascular disease risk based on traditional
risk factors may be considered in adults aged 20-59 years without atherosclerotic
cardiovascular disease and who are not at high short-term risk (ACC/AHA Class IIb, Level C)
National Institute for Health and Clinical Excellence (NICE) guidelines (United Kingdom)
(
3
)

o if patient is started on a statin for primary prevention, repeat lipid measurement is unnecessary
o baseline liver enzymes (transaminases) should be measured
before starting a statin
within 3 months of starting treatment
after 12 months of therapy
not again unless clinically indicated.
o clinical judgement and patient preference should guide the review of drug therapy and whether to
review the lipid profile
Complications and Prognosis
Complications:
elevated cholesterol in younger men (ages 35-39 years) associated with increased long-
term risk for cardiovascular and total mortality
o based on cohort study
o 64,205 men aged 35-39 years followed for 16 years plus 2 other studies of 12,283 men aged 18-
39 years followed for 25-34 years
o increasing total cholesterol level associated with strong graded independent risk for total mortality
and cardiovascular disease
o total cholesterol > 240 mg/dL (6.2 mmol/L) compared with cholesterol < 200 mg/dL (5.2 mmol/L)
associated with significantly increased risk for total mortality, corresponding to reduced life
expectancy of 3.8-8.7 years
o Reference - JAMA 2000 Jul 19;284(3):311, editorial can be found in JAMA 2000 Jul 19;284(3):365
Prognosis:
relationship between serum cholesterol and coronary heart disease (CHD) mortality in
middle-aged men is continuous, graded, and strong
o based on cohort study
o 356 222 men aged 35-57 years who were free of history of hospitalization for myocardial
infarction were evaluated
o compared to men in lowest quintile of cholesterol levels (< 182 mg/dL [< 4.71 mmol/L]), age-
adjusted relative risks for CHD mortality were
1.29 for second quintile (cholesterol 182-202 mg/dL [4.71-5.22 mmol/L])
1.73 for third quintile (cholesterol 203-220 mg/dL [5.25-5.69 mmol/L])
2.21 for fourth quintile (cholesterol 221-244 mg/dL [5.72-6.31 mmol/L])
3.42 for highest quintile (cholesterol 245 mg/dL [ 6.34 mmol/L])
o Reference - JAMA 1986 Nov 28;256(20):2823
non-high-density lipoprotein (HDL) cholesterol may be a better predictor for
cardiovascular mortality than low-density lipoprotein (LDL) cholesterol
o based on prospective cohort study
o 4,462 persons aged 40-64 years followed for mean 19 years
o Reference - Arch Intern Med 2001 Jun 11;161(11):1413, editorial can be found in Arch Intern Med
2001 Jun 11;161(11):1379, commentary can be found in Arch Intern Med 2002 Jan
14;162(1):108
elevated cholesterol levels do not predict mortality in elderly
o total cholesterol and LDL cholesterol levels do not have substantial prognostic
significance in elderly without cardiovascular disease
based on prospective cohort study
1,954 men and 2,931 women without myocardial infarction or stroke were followed for mean
7.5 years
436 had coronary event, 332 had ischemic stroke, 104 had hemorrhagic stroke, 1,096 died
total cholesterol and LDL cholesterol levels only marginally predicted myocardial infarction or
ischemic stroke
lower HDL cholesterol levels strongly associated with increased risk of myocardial infarction
(in men and women) and ischemic stroke (in men)
associations between lipid levels and hemorrhagic stroke or mortality were weak
Reference - J Am Geriatr Soc 2004 Oct;52(10):1639 Texto completo de EBSCOhost,
commentary can be found in Am Fam Physician 2005 Sep 1;72(5):892
o LDL cholesterol levels had non-linear relationships (differing with gender) with
mortality and cardiovascular disease in elderly i
based on prospective cohort study of 3,120 Caucasian subjects > 65 years old followed for up
to 12 years in northern Italy
Reference - J Am Geriatr Soc 2005 Dec;53(12):2159 Texto completo de EBSCOhost
o low cholesterol levels (and not high cholesterol levels) associated with increased
mortality in elderly
based on prospective cohort study
3,572 Japanese American men aged 71-93 years followed for 20 years
only low cholesterol (< 4.65 mmol/L) was significantly associated with mortality
Reference - Lancet 2001 Aug 4;358(9279):351 Texto completo de EBSCOhost,
commentary can be found in Lancet 2001 Dec 1;358(9296):1903 Texto completo de
EBSCOhost
DynaMed commentary -- low cholesterol levels may have been a marker for poor nutrition or
general status in this cohort)
Prevention and Screening
Screening:
Screening in adults:
when screening is done
o total and high-density lipoprotein (HDL) cholesterol levels (fasting or non-fasting samples) are
preferred tests in USPSTF, ACC/AHA, and NICE guidelines summarized below
o role of screening is primarily to inform cardiovascular risk assessment; lipid-lowering therapy
recommendations are based on overall cardiovascular risk
United States Preventive Services Task Force (USPSTF) recommendations for screening for lipid
disorders in adults
o USPSTF strongly recommends routine screening in men 35 years old (USPSTF Grade A)
o USPSTF strongly recommends screening in women 45 years old if at increased risk for coronary
heart disease (USPSTF Grade A)
o USPSTF recommends screening in men aged 20-35 years and in women aged 20-45 years if at
increased risk for coronary heart disease (USPSTF Grade B)
o no recommendation for or against routine screening in men aged 20-35 years or women 20
years old who are not at increased risk for coronary heart disease (USPSTF Grade C)
o preferred screening tests for dyslipidemia are total cholesterol and HDL cholesterol on nonfasting
or fasting samples
o Reference - USPSTF 2008 Jun
American College of Cardiology/American Heart Association (ACC/AHA) 2013 guideline on
cardiovascular risk assessment
(
5
)

o reasonable to assess traditional atherosclerotic cardiovascular disease risk factors every 4-6 years
in adults aged 20-79 years without atherosclerotic cardiovascular disease (ACC/AHA Class IIa,
Level B)
traditional atherosclerotic cardiovascular disease risk factors include age, sex, total and high-
density lipoprotein (HDL) cholesterol, systolic blood pressure, use of antihypertensive
therapy, diabetes, and current smoking
reasonable to estimate 10-year atherosclerotic cardiovascular disease risk in adults 40-79
years without atherosclerotic cardiovascular disease
o for estimation of 10-year atherosclerotic cardiovascular disease risk
use of race- and sex-specific Pooled Cohort Equations recommended in non-Hispanic African
Americans and non-Hispanic white patients aged 40-79 years without clinical atherosclerotic
cardiovascular disease (ACC/AHA Class I, Level B)
Pooled Cohort Equations CV Risk Calculator can be downloaded (in form of interactive
spreadsheet with display for patient) from American Heart Association
DynaMed commentary -- Pooled Cohort Equations may overestimate cardiovascular
risk (level 2 [mid-level] evidence)
for populations other than African Americans and non-Hispanic white patients, use of sex-
specific Pooled Cohort Equations for non-Hispanic white patients may be considered
(ACC/AHA Class IIb, Level C)
o assessing 30-year or lifetime atherosclerotic cardiovascular disease risk based on traditional risk
factors may be considered in adults aged 20-59 years without atherosclerotic cardiovascular
disease and who are not at high short-term risk (ACC/AHA Class IIb, Level C)
o if risk-based treatment decision is uncertain after quantitative risk assessment, consider
assessment of 1 of (ACC/AHA Class IIb, Level B)
family history
high-sensitivity C-reactive protein (hs-CRP)
coronary artery calcium (CAC) score
ankle-brachial index (ABI)
o no recommendation made for or against addition of any of the following to risk assessment of
first atherosclerotic cardiovascular disease event
apolipoprotein B
chronic kidney disease
albuminuria
cardiorespiratory fitness
o Reference - 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk (J Am Coll Cardiol
2014 Jul 1;63(25 Pt B):2935 PDF, also published in Circulation 2014 Jun 24;129(25 Suppl 2):S49)
National Institute for Health and Clinical Excellence (NICE) guidance
(
3
)

o for primary prevention of cardiovascular disease in primary care, systematic strategy should be
used to identify people aged 40-74 years who are likely to be at high risk
o prioritize people for full formal risk assessment if estimated 10-year risk of cardiovascular disease
20%
o risk equations should be used to assess cardiovascular disease risk
risk equations should not be used for patients already considered high risk due to
preexisting coronary heart disease, angina, stroke, transient ischemic attack or
peripheral vascular disease
familial hypercholesterolemia or other monogenic disorder of lipid metabolism
diabetes
both total and HDL cholesterol should be measured to achieve best estimate of
cardiovascular disease risk equations (non-fasting specimens are sufficient for risk
estimation)
o before starting lipid modification therapy for primary prevention (indicated if 10-year risk of
cardiovascular disease 20%) people should have at least 1 fasting lipid sample to measure total
cholesterol, low-density lipoprotein (LDL) cholesterol, HDL cholesterol, and triglycerides
estimated 418 persons need to be screened with lipid profile to prevent 1 death in 5 years if detection
of dyslipidemia followed by treatment with pravastatin (BMJ 1998 Aug 1;317(7154):307 full-text)
nonfasting triglyceride levels may be about 10%-20% higher than fasting triglyceride
levels, while cholesterol levels may not vary with fasting state
o based on cross-sectional study
o 209,180 persons with lipid profile completed after known fasting durations were analyzed
o across fasting intervals stratified by hours of fasting there was minimal variation for mean levels
of
total cholesterol
high-density lipoprotein (HDL) cholesterol
calculated low-density lipoprotein (LDL) cholesterol (which varied up to 10%)
o mean triglyceride levels appeared to vary with fasting duration
in men with < 8 hours of fasting, mean triglyceride levels ranged from 150.6 mg/dL to 165.6
mg/dL (1.7 mmol/L to 1.87 mmol/L)
in men with 8 hours of fasting, mean triglyceride levels ranged from 117.7 mg/dL to 134.9
mg/dL (1.33 mmol/L to 1.52 mmol/L)
in women with < 7 hours of fasting, mean triglyceride levels ranged from 122.5 mg/dL to
134.4 mg/dL (1.38 mmol/L to 1.52 mmol/L)
in women with 7 hours of fasting, mean triglyceride levels ranged from 107.3 mg/dL to
114.1 mg/dL (1.21 mmol/L to 1.29 mmol/L)
o Reference - Arch Intern Med 2012 Dec 10;172(22):1707, editorials can be found in Arch Intern
Med 2012 Dec 10;172(22):1710, Arch Intern Med 2012 Dec 10;172(22):1705
Screening in children:
for screening recommendations in children and adolescents, see NHLBI integrated guidelines for
pediatric cardiovascular risk reduction
American Academy of Pediatrics (AAP) clinical report on lipid screening and cardiovascular health in
childhood
o recommendations include
increased physical activity and dietary changes for children at risk of overweight or obesity
screening between age 2-10 years in children with
family history of dyslipidemia or premature cardiovascular disease
dyslipidemia
unknown family history
other cardiovascular disease risk factors
o consider pharmacologic intervention in patients 8 years old with
LDL cholesterol 190 mg/dL (4.9 mmol/L)
LDL cholesterol 160 mg/dL (4.1 mmol/L) and family history of early heart disease or 2
other risk factors present
LDL cholesterol 130 mg/dL (3.4 mmol/L) if diabetes mellitus
o limitations of recommendations
no data to predict risk of cardiovascular disease as an adult based on cholesterol levels in
children
insufficient data to support specific evidence-based recommendation for cholesterol
screening in children
insufficient data to support specific evidence-based recommendation for specific age to
implement pharmacologic treatment
o Reference - Pediatrics 2008 Jul;122(1):198 full-text or at National Guideline Clearinghouse 2009
May 18:13438, commentary can be found in BMJ 2008 Jul 23;337:a886
USPSTF recommendations
o insufficient evidence to recommend for or against routine screening for lipid disorders in children
(USPSTF Grade I recommendation)
o Reference - Pediatrics 2007 Jul;120(1):e215 full-text, supporting systematic review can be found
in Pediatrics 2007 Jul;120(1):e189 full-text
fasting may have clinically insignificant effect on measurements of total cholesterol, LDL-
C, and HDL-C in children
o based on cross-sectional study from National Health and Nutrition Survey (NHANES) 1999 to
2008
o 12,744 children aged 3-17 years (mean age 11 years) with 1 fasting or nonfasting lipid
measurement evaluated
o adjusted mean difference per hour fasting
0.17 mg/dL (0.0044 mmol/L) for total cholesterol (approximately 2 mg/dL [0.0518 mmol/L]
higher after 12-hour fast vs. postprandial lipid measurement)
0.46 mg/dL (0.0119 mmol/L) for LDL-C (approximately 6 mg/dL [0.1554 mmol/L] higher
after 12-hour fast vs. postprandial lipid measurement)
0.08 mg/dL (0.002 mmol/L) for HDL-C (approximately 1 mg/dL [0.0259 mmol/L] higher after
12-hour fast vs. postprandial lipid measurement)
o Reference - Pediatrics 2011 Sep;128(3):463 full-text, commentary can be found in Evid Based
Med 2012 Aug;17(4):133
family history does not appear useful for selecting children for hypercholesterolemia
screening (level 2 [mid-level] evidence)
o based on 2 cohort studies
o 20,266 children (mean age 10.9 years) had fasting lipid profiles and family history questionnaire
71.4% had positive family history
8.3% had dyslipidemia (LDL cholesterol 160 mg/dL [4.1 mmol/L])
1.2% with dyslipidemia met criteria for possible pharmacologic intervention
28.6% without positive family history
9.5% had dyslipidemia
1.7% with dyslipidemia met criteria for possible pharmacologic intervention
Reference - Pediatrics 2010 Aug;126(2):260 full-text
o cohort of 2,475 Quebec youths aged 9-16 years
4.8% had high LDL cholesterol defined as LDL cholesterol 130 mg/dL (3.4 mmol/L)
25.6% had positive parent history
parent history had 41% sensitivity, 75% specificity, 8% positive predictive value, and 96%
negative predictive value for identifying high LDL cholesterol
Reference - Pediatrics 2004 Jun;113(6):1723 Texto completo de EBSCOhost full-text,
commentary can be found in Pediatrics 2005 Jan;115(1):195 Texto completo de
EBSCOhost full-text, Am Fam Physician 2005 Mar 15;71(6):1203
Guidelines and Resources
Guidelines:
Guideline comparison:
guideline developers using less rigorous methods tend to promote more aggressive interventions,
based on systematic review of 12 guidelines for managing hypertension, 12 guidelines for
hyperlipidemia, 5 guidelines for cholesterol screening, and 4 guidelines for coronary heart disease
prevention (J Fam Pract 2002 Nov;51(11):963 Texto completo de EBSCOhost)
United States guidelines:
guidelines in adults
o American College of Cardiology/American Heart Association (ACC/AHA) guidelines on
treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults can be
found in Circulation 2014 Jun 24;129(25 Suppl 2):S1, also published in J Am Coll Cardiol
2014 Jul 1;63(25 Pt B):2889 PDF, synopsis of major recommendations can be found in Ann
Intern Med 2014 Mar 4;160(5):339 Texto completo de EBSCOhost
assessment of cardiovascular risk can be found in J Am Coll Cardiol 2014 Jul 1;63(25 Pt
B):2935 PDF
lifestyle management to reduce cardiovascular risk can be found in Circulation 2014 Jun
24;129(25 Suppl 2):S76, also published in J Am Coll Cardiol 2014 Jul 1;63(25 Pt B):2960 PDF
o American Heart Association (AHA) scientific statements on
triglycerides and cardiovascular disease can be found in Circulation 2011 May
24;123(20):2292 full-text
managing abnormal blood lipids can be found in Circulation 2005 Nov 15;112(20):3184 full-
text
o Michigan Quality Improvement Consortium (MQIC) guideline on screening and management
of hypercholesterolemia can be found at MQIC 2013 Aug PDF National Guideline Clearinghouse
2014 Mar 17:47289
o National Heart, Lung, and Blood Institute (NHLBI) guideline on high blood cholesterol in adults
(National Cholesterol Education Program Adult Treatment Panel III) can be found in Circulation
2002 Dec 17;106(25):3143 PDF or at NHLBI 2002 Sep PDF, update can be found in Circulation
2004 Jul 13;110(2):227 full-text
o Institute for Clinical Systems Improvement (ICSI) guideline on lipid management in adults can be
found at ICSI 2013 Nov PDF or at National Guideline Clearinghouse 2014 May 26:47783
o American Association of Clinical Endocrinologists (AACE) guideline on diagnosis and treatment of
dyslipidemia and prevention of atherosclerosis can be found in Endocr Pract 2012 Mar
1;18(0):1 PDF or at National Guideline Clearinghouse 2012 Dec 24:37693, executive summary
can be found in Endocr Pract 2012 Mar-Apr;18(2):269
o Endocrine Society (ENDO) clinical practice guidelines on evaluation and treatment of
hypertriglyceridemia can be found at ENDO 2012 PDF or in J Clin Endocrinol Metab 2012
Sep;97(9):2969 full-text or at National Guideline Clearinghouse 2013 Jan 14:38432
o Veterans Affairs/Department of Defense (VA/DoD) clinical practice guideline on management of
dyslipidemia can be found at VA/DoD 2006 PDF
o University of Michigan Health System (UMHS) guideline on screening and management of lipids
can be found at UMHS 2014 May PDF
o United States Preventive Services Task Force (USPSTF) guideline on screening for lipid disorders
in adults can be found in USPSTF 2008 Jun
guidelines in children and adolescents
o National Heart, Lung, and Blood Institute (NHLBI) integrated guideline on cardiovascular health
and risk reduction in children and adolescents can be found at NHLBI Oct 2012 PDF, summary
can be found at NHLBI Oct 2012 PDF
o USPSTF guideline on screening for lipid disorders in children can be found in Pediatrics 2007
Jul;120(1):e215 full-text, supporting systematic review can be found inPediatrics 2007
Jul;120(1):e189 full-text
o American Academy of Pediatrics (AAP) clinical report on lipid screening and cardiovascular health
in childhood can be found in Pediatrics 2008 Jul;122(1):198 full-text, commentary can be found
in BMJ 2008 Jul 23;337:a886
guidelines in specific patient populations
o American Diabetes Association (ADA) position statement on standards of medical care in
diabetes can be found in Diabetes Care 2014 Jan;37 Suppl 1:S14, executive summary can be
found in Diabetes Care 2014 Jan;37 Suppl 1:S5
o American College of Physicians (ACP) evidence-based guideline on lipid control in management of
type 2 diabetes mellitus can be found in Ann Intern Med 2004 Apr 20;140(8):644 Texto
completo de EBSCOhost full-text, supporting systematic review can be found in Ann Intern
Med 2004 Apr 20;140(8):650 Texto completo de EBSCOhost full-text, commentary can be
found in Am Fam Physician 2004 Aug 15;70(4):775, ACP J Club 2004 Nov-Dec;141(3):65
Texto completo de EBSCOhost, Am Fam Physician 2005 Feb 1;71(3):588, Ann Intern Med
2005 Nov 1;143(9):673 Texto completo de EBSCOhost
o National Kidney Foundation (K/DOQI) clinical practice guidelines on
management of dyslipidemias in patients with kidney disease can be found in Am J Kidney
Dis 2003 Apr;41(4 Suppl 3):I
managing dyslipidemias in kidney transplant patients can be found in Am J Transplant
2004;4 Suppl 7:13 full-text
o Health Care for the Homeless Clinician's Network guideline on treatment and recommendations
for homeless patients with hypertension, hyperlipidemia, and heart failure can be found
at National Guideline Clearinghouse 2010 Sep 27:15643
o Academy of Nutrition and Dietetics (AND) evidence-based nutrition practice guideline on
vegetarian nutrition can be found at AND 2011 Sep
United Kingdom guidelines:
National Institute for Health and Care Excellence (NICE) guidance on cardiovascular risk assessment
and modification of blood lipids for primary and secondary prevention of cardiovascular disease can be
found at NICE 2008 May PDF, revised 2010 March
NICE guidance on ezetimibe for treatment of primary (heterozygous-familial and non-
familial) hypercholesterolaemia can be found at NICE 2007 Nov:TA132 PDF
Canadian guidelines:
Canadian Cardiovascular Society (CCS) 2012 updated guideline on diagnosis and treatment of
dyslipidemia for prevention of cardiovascular disease in adults can be found in Can J Cardiol 2013
Feb;29(2):151 PDF or at National Guideline Clearinghouse 2013 Nov 18:46910
European guidelines:
European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on
o management of dyslipidaemias can be found in Eur Heart J 2011
Jul;32(14):1769 PDF, Atherosclerosis 2011 Jul;217(1):3 or in Rev Esp Cardiol 2011
Dec;64(12):1168.e1 full-text [Spanish]
o management of dyslipidaemia in cardiovascular prevention can be found in Rev Med Liege 2012
Mar;67(3):118 [French]
Basque Health System - Osakidetza 2008 clinical practice guideline on management of lipids as
cardiovascular risk factor can be found at Osakidetza 2008 PDF (reaffirmed 2013 Jun) or at National
Guideline Clearinghouse 2011 Jan 31:15711
Finnish Medical Society Duodecim evidence-based guideline on treatment of dyslipidaemias can be
found at National Guideline Clearinghouse 2011 Jul 4:24712
Comit Espaol Interdisciplinario para la Prevencin/Espanola de Arteriosclerosis (Interdisciplinary
Spanish Committee on Cardiovascular Prevention/Spanish Atherosclerosis Society [CEIPC/SEA])
consensus document on dyslipidemias: a pending challenge in cardiovascular prevention can be found
in Med Clin (Barc) 2011 Jun 11;137(1):30.e1 [Spanish]
Nouvelle socit franaise dathrosclrose/Socit Franaise de Pdiatrie (NFSA/SFP)
recommendations for hypercholesterolemic children can be found in Presse Med 2011
Feb;40(2):138 [French] or in Arch Pediatr 2011 Feb;18(2):217 [French]
Asian guidelines:
Chinese expert recommendations on attaining goal for treatment of hypercholesterolemia in clinical
practice can be found in Zhonghua Xin Xue Guan Bing Za Zhi 2010 Apr;38(4):294 [Chinese]
Chinese expert consensus statement on prevention and treatment of dyslipidemia in children and
adolescents can be found in Zhonghua Er Ke Za Zhi 2009 Jun;47(6):426 [Chinese]
Australian and New Zealand guidelines:
National Heart Foundation of Australia and Cardiac Society of Australia and New Zealand position
statement on lipid management can be found in Heart Lung Circ 2005 Dec;14(4):275
African guidelines:
South African Heart Association/Lipid and Atherosclerosis Society of Southern Africa (S A
Heart/LASSA) consensus statement on dyslipidaemia can be found in S Afr Med J 2012 Feb 23;102(3
Pt 2):178
Review articles:
review can be found in BMJ 2008 Aug 21;337:a993, commentary can be found in BMJ 2008 Sep
3;337:a1493, BMJ 2008 Sep 16;337:a1681, BMJ 2008 Sep 16;337:a1669
review of low-density lipoprotein cholesterol can be found in Lancet 2014 Aug 16;384(9943):607
review of pharmacologic treatment of hyperlipidemia can be found in Am Fam Physician 2011 Sep
1;84(5):551 Texto completo de EBSCOhost full-text
review of treatment of cholesterol abnormalities can be found in Am Fam Physician 2005 Mar
15;71(6):1137 Texto completo de EBSCOhost full-text, commentary can be found in Am Fam
Physician 2006 Mar 15;73(6):973 Texto completo de EBSCOhost full-text
Applied Evidence review of treatment of hyperlipidemia can be found in J Fam Pract 2002
Apr;51(4):370 Texto completo de EBSCOhost
review of dyslipidemia can be found in Am Fam Physician 1998 May 1;57(9):2192
review of drug treatment of lipid disorders can be found in N Engl J Med 1999 Aug
12;341(7):498 (author may have conflict of interest [N Engl J Med 2000 Feb 24;342(8):586]),
commentary can be found in N Engl J Med 1999 Dec 23;341(26):2020
review of investigating mixed hyperlipidemia can be found in BMJ 2011 Aug 25;343:d5146
review of lifestyle, diet, dietary supplements and botanicals in management of hyperlipidemia can be
found in Altern Ther Health Med 2003 May-Jun;9(3):28 Texto completo de EBSCOhost
review of screening children for hyperlipidemia can be found in J Fam Pract 2006 Aug;55(8):723
Texto completo de EBSCOhost
review of dietary therapy in children can be found in Am Fam Physician 2000 Feb 1;61(3):675,
editorial can be found in Am Fam Physician 2000 Feb 1;61(3):633
MEDLINE search:
to search MEDLINE for (Hypercholesterolemia) with targeted search (Clinical Queries),
click therapy, diagnosis, or prognosis
Patient Information
information on cholesterol from American Heart Association
information on cholesterol from Centers for Disease Control and Prevention
handouts from American Academy of Family Physicians on
o high cholesterol or in Spanish
o cholesterol and children or in Spanish
o cholesterol-lowering medications or in Spanish
o lifestyle changes to lower your cholesterol or in Spanish
ICD-9/ICD-10 Codes
ICD-9 codes:
272.0 pure hypercholesterolemia
272.2 mixed hyperlipidemia
V77.91 screening for lipoid disorders
ICD-10 codes:
E78.0 pure hypercholesterolaemia
E78.2 mixed hyperlipidaemia
E78.4 other hyperlipidaemia
References
General references used:
1. 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 Dec
17;106(25):3143-421 PDF or at NHLBI 2002 Sep PDF
2. Grundy SM, Cleeman JI, Merz CN, et al; National Heart, Lung, and Blood Institute; American
College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for
the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 Jul
13;110(2):227-39 full-text
3. Cooper A, Nherera L, Calvert N, et al. (2008) Clinical Guidelines and Evidence Review for Lipid
Modification: cardiovascular risk assessment and the primary and secondary prevention of
cardiovascular disease. London: National Collaborating Centre for Primary Care and Royal College of
General Practitioners. NICE 2008 May PDF, revised March 2010.
4. Stone NJ, Robinson J, Lichtenstein AH, et al. 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 Jun
24;129(25 Suppl 2):S1-45, also published in J Am Coll Cardiol 2014 Jul 1;63(25 Pt B):2889 PDF
5. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA Guideline on the Assessment of
Cardiovascular Risk: A Report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S49-73, also published in J Am
Coll Cardiol 2014 Jul 1;63(25 Pt B):2935 PDF
6. Eckel RH, Jakicic JM, Ard JD, et al. 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 Jun 24;129(25 Suppl 2):S76-99, also published in J Am
Coll Cardiol 2014 Jul 1;63(25 Pt B):2960 PDF
Recommendation grading systems used:
American College of Cardiology/American Heart Association (ACC/AHA) grading system for
recommendations
o classifications of recommendations
Class I - procedure or treatment should be performed or administered
Class IIa - reasonable to perform procedure or administer treatment, but additional studies
with focused objectives needed
Class IIb - procedure or treatment may be considered; additional studies with broad
objectives needed, additional registry data would be useful
Class III - procedure or treatment should not be performed or administered because it is not
helpful or may be harmful
Class III ratings may be subclassified as Class III No Benefit or Class III Harm
o levels of evidence
Level A - data derived from multiple randomized clinical trials or meta-analyses
Level B - data derived from single randomized trial or nonrandomized studies
Level C - only consensus opinions of experts, case studies, or standard of care
o References
2013 ACC/AHA guideline on treatment of blood cholesterol to reduce atherosclerotic
cardiovascular risk in adults (Circulation 2014 Jun 24;129(25 Suppl 2):S1), also published in J
Am Coll Cardiol 2014 Jul 1;63(25 Pt B):2889 PDF
2013 ACC/AHA guideline on lifestyle management to reduce cardiovascular risk (Circulation
2014 Jun 24;129(25 Suppl 2):S76), also published in J Am Coll Cardiol 2014 Jul 1;63(25 Pt
B):2960 PDF
United States Preventive Services Task Force (USPSTF) grades of recommendation (June 2007-June
2012)
o Grade A - USPSTF recommends the service with high certainty of substantial net benefit
o Grade B - USPSTF recommends the service with high certainty of moderate net benefit or
moderate certainty of moderate-to-substantial net benefit
o Grade C - clinicians may provide the service to select patients depending on individual
circumstances, however, only small benefit is likely for most individuals without signs or symptoms
o Grade D - USPSTF recommends against providing the service with moderate-to-high certainty of
no net benefit or harms outweighing benefits
o Grade I - insufficient evidence to assess balance of benefits and harms
o Reference - USPSTF Grade Definitions
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