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Annals of Internal Medicine䊛

In the Clinic®

Dyslipidemia Prevention and Screening

D
yslipidemia is an important risk factor
for coronary artery disease and stroke. Diagnosis
Long-term, prospective epidemiologic
studies have consistently shown that persons
with healthier lifestyles and fewer risk factors for Treatment
coronary heart disease, and particularly those
with favorable lipid profiles, have reduced inci-
dence of coronary heart disease. Prevention Practice Improvement
and sensible management of dyslipidemia can
markedly alter cardiovascular morbidity and
mortality.

CME/MOC activity available at Annals.org.

Physician Writers doi:10.7326/AITC201712050


Laurie Kopin, EdD, MS, ANP
Charles J. Lowenstein, MD CME Objective: To review current evidence for prevention, screening, diagnosis, treatment,
From University of Rochester and practice improvement of dyslipidemia.
Medical Center, Rochester, Funding Source: American College of Physicians.
New York.
Disclosures: Drs. Kopin and Lowenstein, ACP Contributing Authors, have nothing to disclose.
Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms
.do?msNum=M17-2120.
With the assistance of additional physician writers, the editors of Annals of Internal Medi-
cine develop In the Clinic using MKSAP and other resources of the American College of
Physicians.
In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical
guidelines, please go to https://www.acponline.org/clinical_information/guidelines/.
© 2017 American College of Physicians

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Dyslipidemia is a major risk factor which is associated with the met-
for atherosclerotic cardiovascular abolic syndrome, is a major risk
disease (CVD). According to data factor for atherosclerotic CVD,
from 2009 –2012, more than 100 cerebrovascular accident, and
1. Mozaffarian D, Benjamin
EJ, Go AS, Arnett DK, million U.S. adults aged 20 years peripheral arterial disease (3)
Blaha MJ, Cushman M, or older have total cholesterol because it tends to increase lev-
et al; Writing Group Mem-
bers. Executive Summary: levels of 200 mg/dL (5.17 els of plasma triglycerides and
Heart Disease and Stroke mmol/L) or greater, and almost
Statistics—2016 Update: A low-density lipoprotein choles-
Report From the American 31 million have levels of 240
Heart Association. Circula- terol (LDL-C) and reduce levels of
tion. 2016;133:447-54. mg/dL (6.20 mmol/L) or greater.
high-density lipoprotein choles-
[PMID: 26811276] In 2016 alone, approximately
2. Nicholls S, Lundman P. terol (HDL-C) (4).
The emerging role of 660 000 persons in the United
lipoproteins in atherogen- States had a new coronary event
esis: beyond LDL choles-
terol. Semin Vasc Med. and approximately 305 000 had Large observational studies have
2004;4:187-95. [PMID:
a recurrent event (1). Epidemio- reported a strong, graded rela-
15478040]
3. Wild SH, Byrne CD, Tzou- logic data suggest that dyslipide- tionship between higher levels of
laki I, Lee AJ, Rumley A,
Lowe GD, et al. Metabolic mia can contribute to the risk for LDL-C, or lower levels of HDL-C,
syndrome, haemostatic an ischemic cerebrovascular acci- and increasing risk for athero-
and inflammatory mark-
ers, cerebrovascular and dent (2). Further, evidence is in- sclerotic coronary heart disease
peripheral arterial disease:
The Edinburgh Artery creasing that insulin resistance, (CHD) events (5, 6).
Study. Atherosclerosis.
2009;203:604-9. [PMID:
18804759]
4. Rodriguez-Colon SM, Mo
J, Duan Y, Liu J, Caulfield
Prevention and Screening
JE, Jin X, et al. Metabolic What preventive lifestyle Ultimately, increasing healthy
syndrome clusters and the
risk of incident stroke: the measures should clinicians lifestyles should reduce
atherosclerosis risk in
communities (ARIC) study. recommend to reduce risk for population-wide lipid levels and,
Stroke. 2009;40:200-5.
dyslipidemia? consequently, reduce the need
[PMID: 18927451]
5. Anderson KM, Castelli WP, Lifestyle changes can favorably for drug therapy.
Levy D. Cholesterol and
mortality. 30 years of affect total cholesterol, HDL-C, Who should be screened?
follow-up from the Fra-
mingham study. JAMA. LDL-C, and triglyceride levels. The age at which screening for
1987;257:2176-80. The American Heart Association dyslipidemia should start is con-
[PMID: 3560398]
6. Goldbourt U, Yaari S. (AHA) recommends that all troversial. No direct evidence
Cholesterol and coronary
heart disease mortality. A
adults consume a healthy diet, links lipid screening and subse-
23-year follow-up study of exercise regularly, and avoid to- quent treatment with reduced
9902 men in Israel. Arte-
riosclerosis. 1990;10: bacco smoke (7). However, the adverse outcomes from CVD or
512-9. [PMID: 2369362] U.S. Preventive Services Task stroke. In fact, in 2013 the Ameri-
7. Stone NJ, Robinson JG,
Lichtenstein AH, Bairey Force (USPSTF) points out that
Merz CN, Blum CB, Eckel can College of Cardiology (ACC)
lifestyle modifications, such as
RH, et al; American Col- and the AHA concluded that evi-
lege of Cardiology/Ameri- diet and physical activity, are un-
can Heart Association Task dence does not support LDL-C or
Force on Practice Guide- likely to substantially reduce lipid
lines. 2013 ACC/AHA
non–HDL-C levels as treatment
levels and that many patients
guideline on the treat- targets (7). According to the
ment of blood cholesterol with hyperlipidemia require
to reduce atherosclerotic USPSTF, clinicians should screen
cardiovascular risk in drugs to reach therapeutic
all men aged 35 years or older
adults: a report of the goals (8).
American College of Cardi- for lipid disorders and those
ology/American Heart
Association Task Force on Regardless of the presence of aged 20 –35 years if they are at
Practice Guidelines. Circu-
preexisting CHD, patients who increased risk for CHD. It strongly
lation. 2014;129:S1-45.
[PMID: 24222016] adopt these habits will have recommends screening women
8. Moyer VA; U.S. Preventive
Services Task Force. Behav- healthier lipid profiles and re- aged 45 years or older and rec-
ioral counseling interven- duce CHD risk. Because of their ommends screening women
tions to promote a health-
ful diet and physical higher baseline risk, patients with aged 20 – 45 years if they are at
activity for cardiovascular
disease prevention in
CHD or CHD risk– equivalent increased risk for CHD (9). Per-
adults: U.S. Preventive conditions (see the Box: Risk- sons with risk factors for CVD
Services Task Force recom-
mendation statement. Equivalent Conditions) may have (see the Box: Coronary Risk Fac-
Ann Intern Med. 2012; the most improvement in risk for tors), whose family history of
157:367-71. [PMID:
22733153] poor health outcomes. premature CHD or lipid abnor-

姝 2017 American College of Physicians ITC82 In the Clinic Annals of Internal Medicine 5 December 2017

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malities suggests a heritable lipid increased risk for CHD in adult-
disorder or who have evidence of hood, so behavioral lifestyle Risk-Equivalent Conditions
hyperlipidemia on physical ex- counseling is an important first • Acute coronary syndromes
amination are considered to have step to prevent or reduce abnor- • History of myocardial
infarction
increased risk for CHD. The USP- mal lipid levels in youths (12, 14). • Stable or unstable angina
STF makes no recommendation Lifestyle counseling is particularly • Coronary or other arterial
for or against routine screening important for young persons with revascularization
• Stroke
for lipid disorders in men aged 1 or more CVD risk factors and • Transient ischemic attack
20 –35 years or in women aged high LDL-C levels or who are • Peripheral arterial disease of
20 years or older who are not at overweight or obese with low atherosclerotic origin
increased risk for CHD (9). In con- HDL-C levels or high triglyceride
trast, the National Cholesterol levels. The American Academy of
Education Program Adult Treat- Pediatrics recommends consider-
Coronary Risk Factors
ment Panel III (NCEP-ATP III) rec- ing pharmacologic intervention
Nonmodifiable risk factors: Age,
ommends beginning screening to treat children whose LDL-C sex, family history, genetic
all adults at age 20 years, regard- level remains persistently high predisposition
less of CHD risk profile (10). This even after therapeutic lifestyle Modifiable risk factors: Smoking,
recommendation is based on the counseling (15). atherogenic diet, alcohol
rationale that screening pro- intake, physical activity,
Moderate-quality evidence sup- dyslipidemias, hypertension,
motes healthy behaviors, in- obesity, diabetes, metabolic
creases public awareness of cho- ports screening adults older than syndrome
lesterol, and identifies patients at 65 years. Total cholesterol level Emerging risk factors: Elevation
high risk for CHD (11). However, predicts CHD in elderly persons. in C-reactive protein;
the incremental yield and cost- Persons older than 65 years have fibrinogen; coronary artery
a higher baseline risk for CHD, calcification; homocysteine;
effectiveness of earlier universal lipoprotein(a); small, dense
screening versus risk factor– increasing their potential abso- LDL-C
based screening in young adults lute benefit from interventions to
is unclear. manage dyslipidemia (16). Re-
gardless of age, lipid levels
The USPSTF recommends rou- should be measured in patients
tine screening for overweight with known CHD or CHD risk– 9. U.S. Preventive Services
Task Force. Final Update
and obese persons younger than equivalent conditions (see Summary: Lipid Disorders
in Adults (Cholesterol,
20 years (12). The National Heart, the Box: Risk-Equivalent Dyslipidemia): Screening.
Lung, and Blood Institute (NHLBI) Conditions). July 2015. Accessed at
www.uspreventiveservices
recommends a more aggressive taskforce.org/Page/Docu-
screening policy that is also en- How and how often should ment/UpdateSummary
Final/lipid-disorders-in
dorsed by the American Acad- clinicians screen for -adults-cholesterol
-dyslipidemia-screening
emy of Pediatrics: No screening dyslipidemia? on 19 October 2017.
for children younger than 1 year; Most U.S. organizations recom- 10. National Cholesterol
Education Program
targeted screening of children mend screening all adults for (NCEP) Expert Panel on
Detection, Evaluation,
aged 1– 8 years if there is a family dyslipidemia at least every and Treatment of High
history of heart disease or high 5 years. The ACC/AHA recom- Blood Cholesterol in
Adults (Adult Treatment
cholesterol or if the child has mends that all adults aged 20 –78 Panel III). Third Report of
the National Cholesterol
other risk factors or a high-risk years have a fasting lipid profile Education Program
medical condition; targeted measured every 4 – 6 years if (NCEP) Expert Panel on
Detection, Evaluation,
screening of adolescents aged there is no atherosclerotic CVD and Treatment of High
Blood Cholesterol in
9 –16 years if there is a family his- and more often if this condition is Adults (Adult Treatment
tory of heart disease or high cho- present (7). The NCEP (ATP-III) Panel III) final report.
Circulation. 2002;106:
lesterol or the child has other risk recommends measurement of 3143-421. [PMID:
12485966]
factors or a high-risk medical the fasting lipid profile in adults 11. Cleeman JI, Grundy SM.
condition; and universal screen- aged 20 years or older every 5 National Cholesterol
Education Program rec-
ing of young adults aged 17 years (10). However, the USPSTF ommendations for cho-
lesterol testing in young
years or older (13). Untreated recommendations are more re- adults. A science-based
abnormal lipid levels in children strictive than those of the ACC/ approach. Circulation.
1997;95:1646-50.
and adolescents are linked to AHA and NCEP-ATP III—it recom- [PMID: 9118536]

5 December 2017 Annals of Internal Medicine In the Clinic ITC83 姝 2017 American College of Physicians

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mends universal lipid screening for guiding treatment but do not
for men older than 35 years every improve on risk prediction with
5 years, with shorter intervals for total and HDL-C levels (9).
persons with a history of elevated
lipid levels and longer intervals The updated 2013 ACC/AHA
for those not at increased risk guidelines concluded that the
with normal lipid levels; men evidence does not support
aged 20 –34 years at increased LDL-C or non–HDL-C levels as
risk for CHD should be screened treatment targets (7). The new
more often and women aged guidelines identify 4 groups of
20 years or older should be patients needing primary or sec-
screened if they are at increased ondary prevention in whom the
risk for CHD. Furthermore, the focus is now to reduce CVD
USPSTF accepts lipid profiles events by maximizing statin ther-
from both fasting and nonfasting
12. Moyer VA; U.S. Preven- apy to achieve the appropriate
tive Services Task Force. persons (9).
Screening for and man- reduction of LDL-C. The clinical
agement of obesity in
A study of fasting versus nonfasting total cho- guidelines emphasize the use of
adults: U.S. Preventive
Services Task Force rec- lesterol levels in 181 general internal medi- high-intensity statins for patients
ommendation state- cine outpatients found no clinically important
ment. Ann Intern Med. with atherosclerotic CVD to
2012;157:373-8. [PMID: differences between fasting and nonfasting re-
22733087]
achieve at least a 50% reduction
sults for total and HDL-C levels (16). Another
13. Expert Panel on Inte-
large cross-sectional population study that in LDL-C unless otherwise contra-
grated Guidelines for
Cardiovascular Health compared fasting and nonfasting lipid pro- indicated or if the patient has an
and Risk Reduction in
Children and Adoles- files for 33 391 persons aged 20 –95 years adverse reaction to statins. In
cents. Expert panel on reported that lipid profiles changed mini- cases of adverse reactions, a
integrated guidelines for
cardiovascular health and mally in response to normal food intake in moderate-intensity statin should
risk reduction in children persons in the general population and that
and adolescents: sum-
nonfasting levels also predicted cardiovas- be used (7).
mary report. Pediatrics.
2011;128 Suppl 5:S213- cular events (17).
56. [PMID: 22084329] In the absence of data to support
14. Grossman DC, Bibbins-
Domingo K, Curry SJ, The NCEP-ATP III advocates ini- a specific interval, screening ev-
Barry MJ, Davidson KW, tial screening with a fasting lipid ery 5 years seems to be reason-
Doubeni CA, et al; US
Preventive Services Task profile that includes measure- able in low-risk patients, because
Force. Screening for
Obesity in Children and ment of triglycerides and indirect lipid levels do not vary greatly
Adolescents: US Preven-
tive Services Task Force
calculation of LDL-C level (10). from year to year (7). Clinicians
Recommendation State- The USPSTF does not recom- might consider more frequent
ment. JAMA. 2017;317:
2417-2426. [PMID: mend triglyceride measurement screening for patients who have
28632874]
15. Barton M; US Preventive as part of a lipid profile evalua- lipid levels near treatment thresh-
Services Task Force. tion (9). Measurements of LDL-C olds or who develop new cardio-
Screening for obesity in
children and adoles- and triglyceride levels are useful vascular risk factors.
cents: US Preventive
Services Task Force rec-
ommendation state-
ment. Pediatrics. 2010; Prevention and Screening... Healthy diet, regular exercise, and avoid-
125:361-7. [PMID:
20083515] ance of tobacco can help patients preclude or reduce dyslipidemia. Evi-
16. Craig SR, Amin RV, Rus- dence supports routine screening for dyslipidemia in men aged 35
sell DW, Paradise NF.
Blood cholesterol screen- years or older and women aged 45 years or older. Screening at earlier
ing influence of fasting ages is warranted for children and adolescents with cardiovascular risk
state on cholesterol re-
sults and management factors or a clinical history suggestive of familial hyperlipidemia. Al-
decisions. J Gen Intern though authorities disagree on which cholesterol levels to measure and
Med. 2000;15:395-9.
[PMID: 10886474] at what age to begin testing, ACC/AHA and NCEP-ATP III guidelines
17. Langsted A, Freiberg JJ, recommend measuring a fasting lipid profile in all adults aged 20 years
Nordestgaard BG. Fast-
ing and nonfasting lipid or older every 5 years.
levels: influence of nor-
mal food intake on lip-
ids, lipoproteins, apolipo-
proteins, and
cardiovascular risk pre-
CLINICAL BOTTOM LINE
diction. Circulation.
2008;118:2047-56.
[PMID: 18955664]

姝 2017 American College of Physicians ITC84 In the Clinic Annals of Internal Medicine 5 December 2017

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Diagnosis
How should clinicians interpret Committee-8 guidelines for hy-
results of lipid screening in pertension. The incorporation of
relation to evaluating overall these guidelines enhances the
cardiovascular risk? tool's ability to accurately calcu-
When diagnosing dyslipidemia, late cardiovascular risk.
clinicians should estimate a pa- If whether to treat based on risk
tient's cardiovascular risk. Risk is uncertain after quantitative as-
assessment guides clinicians' de- sessment, family history, high-
cisions on treatment for primary sensitivity C-reactive protein lev-
prevention. Treatment is most els, coronary artery calcium
beneficial for patients with the score, and ankle– brachial index
highest risk. Calculation of risk can be considered. There is no
using specific equations is more recommendation for or against
accurate than using lipid levels adding any of the following to
alone or simply counting risk fac- assess risk for the first atheroscle-
tors. Several algorithms are used rotic CVD event: apolipoprotein
in the United States, including B levels, chronic kidney disease,
the Framingham Risk Score, the albuminuria, or cardiorespiratory
ACC/AHA Arteriosclerotic Car- fitness (7).
diovascular Disease Risk Estima-
tor, and the Reynolds Risk Score. What laboratory test results
Some experts believe that car- should clinicians obtain before
diovascular risk scores to predict starting therapy?
CVD lack validation, especially in The absolute benefit of begin-
populations outside the United ning medical therapy depends
States (18). Also, their use to on the patient's level of risk for
identify patients who will benefit CVD. Therefore, it is imperative
from pharmacologic agents and to risk-stratify the patient be-
to guide management of those cause potentially life-long ther-
with lipid disorders lacks predic- apy is being initiated. It is also
tive value because the current important to identify causes of
risk calculators may overestimate elevated cholesterol levels to ap-
risk (19). Many people believe propriately target diet and drug
that this can lead to overprescrib- therapy. Therefore, shared deci- 18. Selvarajah S, Kaur G,
ing and escalating doses of sta- sion making between the clini- Haniff J, Cheong KC,
Hiong TG, van der Graaf
tins and combinations of drugs cian and the patient is recom- Y, et al. Comparison of
that may result in adverse effects mended before beginning any the Framingham Risk
Score, SCORE and WHO/
without known beneficial treatment plan. ISH cardiovascular risk
prediction models in an
outcomes. Asian population. Int J
Dyslipidemia includes a large Cardiol. 2014;176:
An electronic tool for calculating range of lipid abnormalities and 211-8. [PMID:
25070380]
cardiovascular risk is publicly may involve a combination of 19. DeFilippis AP, Young R,
available through the ACC/AHA increased total cholesterol (≥240 Carrubba CJ, McEvoy
JW, Budoff MJ, Blumen-
(www.cvriskcalculator.com/). It mg/dL [6.20 mmol/L]), LDL-C thal RS, et al. An analysis
of calibration and dis-
calculates the 10-year risk for (>160 mg/dL [4.13 mmol/L]), and crimination among mul-
heart disease or stroke using the triglyceride levels (>200 mg/dL tiple cardiovascular risk
scores in a modern mul-
2013 ACC/AHA Guideline on [2.25 mmol/L]) or decreased tiethnic cohort. Ann
the Assessment of Cardiovascu- HDL-C (<40 mg/dL [1.03 mmol/ Intern Med. 2015;162:
266-75. [PMID:
lar Risk (7). In 2016, the calcula- L]). Although the screening rec- 25686167]
20. Sidhu D, Naugler C.
tor incorporated the USPSTF ommendations and the timing of Fasting time and lipid
guidelines for initiating aspirin testing vary by the given organi- levels in a community-
based population: a
therapy. Also, in 2015 and in zation, it is generally agreed that cross-sectional study.
2014 it incorporated the up- laboratory tests should include Arch Intern Med. 2012;
172:1707-10. [PMID:
dates from Joint National baseline measurement of total 23147400]

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cholesterol, LDL-C, HDL-C, and levels exceed 400 mg/dL (4.52
triglyceride levels. For patients mmol/L), follow-up assessment
with a history of CVD or those of fasting lipid levels should be
with a very high level of risk, tests considered (20).
that may be considered in addi-
tion to the baseline lipid profile The association of elevated tri-
include measurement of lipopro- glyceride levels with CAD
tein(a), apolipoprotein B, and seems to be stronger for
apolipoprotein A1. women than for men (23) be-
cause adjustment for other risk
The blood sample should be ob- factors in men (for example, di-
tained under fasting conditions abetes, HDL-C level, obesity)
(12 hours) if possible; however, a seems to explain this associa-
21. Taylor FC, Huffman M,
Ebrahim S. Statin therapy nonfasting sample provides mea- tion. The clinician should stratify
for primary prevention of sures of total cholesterol and patients based on fasting tri-
cardiovascular disease.
JAMA. 2013;310: HDL-C levels that vary little with glyceride levels as follows: nor-
2451-2. [PMID:
24276813]
fasting (20). The only exception is mal, less than 150 mg/dL (1.70
22. Miller M. Is hypertriglyc- if triglycerides exceed 400 mg/dL mmol/L); borderline high, 150 –
eridaemia an indepen-
dent risk factor for coro- (4.52 mmol/L) in which case a 199 mg/dL (1.70 –2.24 mmol/L);
nary heart disease? The fasting lipid profile is indicated. high, 200 – 499 mg/dL (2.26 –
epidemiological evi-
dence. Eur Heart J. Thus, in the vast majority of the 5.64 mmol/L); and very high,
1998;19 Suppl H:H18-
22. [PMID: 9717060] cases, a nonfasting lipid profile greater than 500 mg/dL (5.65
23. Sarwar N, Danesh J, provides acceptably accurate mmol/L).
Eiriksdottir G, Sigurdsson
G, Wareham N, Bingham measures for risk calculation. As
S, et al. Triglycerides and
mentioned, it is important that Persons with elevated triglycer-
the risk of coronary heart
disease: 10,158 incident the patient and provider make a ide levels are more likely to be
cases among 262,525
joint decision on whether to be- predisposed to the metabolic
participants in 29 West-
ern prospective studies. gin pharmacologic treatment be- syndrome. Elevated levels may
Circulation. 2007;115:
450-8. [PMID: cause the benefits can outweigh also result from reduced clear-
17190864]
the harms. For patients with a ance of triglyceride-rich lipopro-
24. Kuvin JT, Rämet ME,
Patel AR, Pandian NG, 10-year risk greater than 12%, teins or may identify persons with
Mendelsohn ME, Karas
clinical trials indicate that CVD other metabolic problems or del-
RH. A novel mechanism
for the beneficial vascu- risk can be decreased by 20% to eterious lifestyle habits in need of
lar effects of high-density
lipoprotein cholesterol: 30% with the use of a moderate- intervention (for example, diabe-
enhanced vasorelaxation
dose statin over a 5-year period tes, chronic renal failure, ne-
and increased endothe-
lial nitric oxide synthase (7, 21). phrotic syndrome, or alcohol use
expression. Am Heart J. disorder). Triglyceride levels
2002;144:165-72.
[PMID: 12094204] How should clinicians measure greater than 5.65 mmol/L (500
25. Gordon DJ, Probstfield and interpret triglyceride and
JL, Garrison RJ, Neaton mg/dL) are associated with pan-
JD, Castelli WP, Knoke HDL-C levels? creatitis and warrant treatment.
JD, et al. High-density
lipoprotein cholesterol
and cardiovascular dis- Triglyceride levels HDL-C levels
ease. Four prospective
American studies. Circu-
Triglyceride levels are a sec- HDL-C level is used to calculate
lation. 1989;79:8-15. ondary target for therapy. Nu- cardiovascular risk and is in-
[PMID: 2642759]
26. Lewington S, Whitlock G, merous prospective epidemio- versely associated with CVD and
Clarke R, Sherliker P, logic studies have shown that coronary death, independently
Emberson J, Halsey J,
et al; Prospective Studies increased triglyceride levels are from other traditional risk factors
Collaboration. Blood
cholesterol and vascular
related to an increased risk for (24). An HDL-C level less than
mortality by age, sex, CAD (22), and a meta-analysis 40 mg/dL (1.03 mmol/L) pre-
and blood pressure: a
meta-analysis of individ- of prospective studies found dicts an increase in atheroscle-
ual data from 61 pro- that high triglyceride levels are rotic events and for each
spective studies with
55,000 vascular deaths. an independent risk factor for 1-mg/dL (0.02-mmol/L) reduc-
Lancet. 2007;370:1829-
39. [PMID: 18061058]
CAD (23). Triglyceride levels tion it is estimated that coronary
27. Gencer B, Kronenberg F, must be tested in a fasting state risk increases by 2%–3% (25). In
Stroes ES, Mach F. Lipo-
protein(a): the revenant. to be accurate because they can addition, results from a meta-
Eur Heart J. 2017;38: increase by as much as 20% in a analysis showed a 30% reduc-
1553-1560. [PMID:
28329241] nonfasting state. If triglyceride tion in mortality when an in-

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crease (about 13 mg/dL [0.33 is important to risk-stratify pa-
mmol/L]) in HDL-C occurred tients with the use of risk algo- Drugs That Can Cause
(26). Low HDL-C levels are rithms, such as the ACC/AHA Dyslipidemia
caused most commonly by Arteriosclerotic Cardiovascular • Corticosteroids
acquired conditions, such as Disease Risk Estimator and the • Androgenic steroids
• Progestogens
smoking tobacco, obesity, inac- Reynolds Risk Score. Risk algo- • Thiazide diuretics
tivity, hypertriglyceridemia, rithms include lipid levels with • ␤-blockers
type 2 diabetes, and a high- some combination of other tra- • Retinoic acid derivatives
carbohydrate diet. Low HDL-C ditional risk factors, including • Oral estrogens
levels can also be caused by age, sex, family history of pre-
such drugs as ␤-blockers or an- mature coronary disease, smok-
drogenic steroids. Genetic ab- ing, hypertension, diabetes
normalities, including mutations mellitus, obesity, and a seden-
in genes encoding apoA-I, tary lifestyle.
LCAT, and ABC1, can also 28. Navarese EP, Kolodziejc-
What are the causes of
decrease HDL-C levels. zak M, Schulze V, Gurbel
secondary dyslipidemia, and PA, Tantry U, Lin Y, et al.
Effects of Proprotein
Before initiating drug therapy in how should clinicians diagnose Convertase Subtilisin/
Kexin Type 9 Antibodies
patients with an HDL-C level less them? in Adults With Hypercho-
than 40 mg/dL (1.03 mmoL/L), it Secondary causes of dyslipide- lesterolemia: A System-
atic Review and Meta-
is important to rule out other mia include hypothyroidism, ob- analysis. Ann Intern
possible contributing factors, structive liver disease, the ne-
Med. 2015;163:40-51.
[PMID: 25915661]
such as smoking tobacco; medi- phrotic syndrome, renal failure, 29. Eckel RH, Jakicic JM, Ard
JD, de Jesus JM, Hous-
cations (see the Box: Drugs That uncontrolled diabetes mellitus, ton Miller N, Hubbard
Can Cause Dyslipidemia); and and tobacco or alcohol use. Vari- VS, et al; American Col-
lege of Cardiology/Amer-
lifestyle habits, such as being ous drugs can also cause dyslipi- ican Heart Association
sedentary. Most treatment guide- demia (Box: Drugs That Can
Task Force on Practice
Guidelines. 2013 AHA/
lines do not recommend medica- Cause Dyslipidemia). ACC guideline on life-
style management to
tions to specifically increase reduce cardiovascular
HDL-C levels and prefer to advise It is important to address sec- risk: a report of the
American College of
lifestyle changes, which include ondary causes before starting Cardiology/American
weight loss, aerobic exercise, drug therapy, because treat- Heart Association Task
Force on Practice Guide-
and smoking cessation (7, 24). ment of the secondary cause lines. J Am Coll Cardiol.
2014;63:2960-84.
may render lipid-lowering ther-
What should clinicians look for apy unnecessary. Lipid-lowering
[PMID: 24239922]
30. Ernst ND, Sempos CT,
in the history and physical drugs may also be ineffective in Briefel RR, Clark MB.
Consistency between US
examination? persons with these conditions. dietary fat intake and
serum total cholesterol
History and physical examination If a drug is suspected as the concentrations: the Na-
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5 December 2017 Annals of Internal Medicine In the Clinic ITC87 姝 2017 American College of Physicians

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are proteins in lipid particles, and lism is suspected, especially in
measurement can be helpful be- conjunction with a history of
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be more accurate than measur- ease, lipoprotein(a) level can
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Krempf M, Bergeron J, macologic agents. When a ge- cause they have increased risk
Luc G, Averna M, et al; netic disorder of lipid metabo- for early CHD.
ODYSSEY LONG TERM
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and safety of alirocumab
in reducing lipids and
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N Engl J Med. 2015;
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36. Landray MJ, Haynes R,
Hopewell JC, Parish S,
further target interventions. History and physical examination should
Aung T, Tomson J, et al; focus on identifying CHD, cardiovascular risk factors, and potential sec-
HPS2-THRIVE Collabora- ondary causes of dyslipidemia. Specialized testing and specialty referral
tive Group. Effects of
extended-release niacin may be useful when familial hypercholesterolemia is suspected.
with laropiprant in high-
risk patients. N Engl J
Med. 2014;371:203-12.
[PMID: 25014686] CLINICAL BOTTOM LINE
37. Cannon CP, Blazing MA,
Giugliano RP, McCagg A,
White JA, Theroux P,
et al; IMPROVE-IT Investi-
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[PMID: 26039521]
38. Sabatine MS, Giugliano
What should clinicians advise Risk emphasizes a diet rich in
RP, Wiviott SD, Raal FJ, patients with dyslipidemia fruits, vegetables, nuts, and
Blom DJ, Robinson J,
et al; Open-Label Study about lifestyle changes? whole grains and use of monoun-
of Long-Term Evaluation
Patients with lipid disorders saturated oils (for example, olive
against LDL Cholesterol
(OSLER) Investigators. should be informed of the impor- oil and canola oil) as well as low-
Efficacy and safety of
evolocumab in reducing tance of behavioral lifestyle fat dairy products, poultry, and
lipids and cardiovascular
changes and should adopt these fish rather than animal products
events. N Engl J Med.
2015;372:1500-9. changes regardless of whether (29). The diet limits sweets,
[PMID: 25773607] sugar-sweetened beverages, and
39. National Insitutes of drug therapy is being prescribed.
Health, U.S. National red meat. A diet low in red meat
Library of Medicine. Use of the NCEP-ATP III Thera-
December 2016. Ac- and animal fat seems to substan-
peutic Lifestyle Change Diet can
cessed at https:// tially reduce risk, independent of
dailymed.nlm.nih.gov on result in a 5%–15% reduction in
29 September 2017. serum lipid levels (30). Moderate
40. Finegold JA, Manisty CH, LDL-C level (10). According to
Goldacre B, Barron AJ,
alcohol consumption, smoking
the National Health and Nutrition
Francis DP. What propor- cessation, weight reduction, and
tion of symptomatic side Examination Survey, a 15% re-
effects in patients taking regular exercise can increase
statins are genuinely duction in LDL-C could reduce
caused by the drug?
HDL-C by up to 10% (29).
Systematic review of
the need for cholesterol-lowering
randomized placebo- drugs from 14% to 5% of the Patients with dyslipidemia and a
controlled trials to aid
individual patient choice. population. The 2013 ACC/AHA normal BMI (18.5–24.9 kg/m2)
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24623264] ment to Reduce Cardiovascular and regular exercise to maintain

姝 2017 American College of Physicians ITC88 In the Clinic Annals of Internal Medicine 5 December 2017

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a healthy body weight and re- sion regarding lipid treatment,
duce lipid levels (12). Overweight discussing the risks and benefits
(BMI, 25–29.9 kg/m2) and obese as well as the costs of lipid-
(BMI, ≥30 kg/m2) patients should lowering medications.
reduce their caloric intake from
fats and simple carbohydrates The fourth step is to start treat-
and aim for at least 30 minutes of ment. A secondary prevention
physical activity on most days. A strategy is applied to patients
structured aerobic exercise pro- with clinical atherosclerotic CVD.
gram using large-muscle groups For secondary prevention, high-
(for example, running, walking, intensity statin therapy is
cycling, or swimming) greatly en- recommended.
hances weight reduction. Studies
A primary prevention strategy is
of weight loss with or without ex-
used for patients at high risk for 41. McKenney JM, Davidson
ercise suggest that exercise can MH, Jacobson TA, Guy-
cardiac events who do not have
optimize lipid levels (31). ton JR; National Lipid
clinical atherosclerotic CVD (7). Association Statin Safety
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The clinician and patient should These patients fall into 3 catego- Final conclusions and
set goals and select treatment ries: primary elevation of LDL-C recommendations of the
National Lipid Associa-
strategies for weight loss and risk to 190 mg/dL (4.91 mmol/L) or tion Statin Safety Assess-
ment Task Force. Am J
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nance counseling. Obese pa- an LDL-C level of 70 –189 mg/dL RD, Hessen SE, Liu L,
Victor MF. Achieving
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interventions and counseling for risk for atherosclerotic CVD 7.5% patients with coronary
artery disease. Am J
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Recent guidelines have empha- Lipid-lowering therapy should be 44. Link E, Parish S, Armit-
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S, Matsuda F, et al;
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cluded patients based on clinical for adults with clinical evidence of Dejager S, Yau C, Bé-
gaud B. Mild to moder-
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drug therapy, and the benefits and 46. Ferdowsian HR, Barnard
adhering to a heart healthy diet, ND. Effects of plant-
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healthy weight. [PMID: 19766762]
What options are available for 47. Sabaté J, Oda K, Ros E.
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The second step is to determine blood lipid levels: a
The options for drug treatment pooled analysis of 25
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risk. The 2013 ACC/AHA guide- Intern Med. 2010;170:

lines propose use of the Pooled guidelines from the ACC/AHA 821-7. [PMID:
20458092]
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Burke K, Knutsen SF,
tor based on several large clinical ferred drugs to lower lipids (7). Bennett H, Lindsted KD.
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Table. Drug Treatment for Lipid Disorders
Drug Class and Dose Benefits Side Effects Notes
Mechanism of Action
Statins (HMG-CoA Atorvastatin (10–80 Well-studied for Abnormal liver function Choice of drug for
reductases) mg/d) safety and efficacy tests (relatively elevated LDL
Partially inhibits Fluvastatin (20–40 mg in many trials: LDL uncommon). cholesterol based on
HMG-CoA reductase, every night or 80 mg cholesterol– Myositis/myalgias (use efficacy and safety.
the rate-limiting step extended-release lowering ranges with fibrates increases The 7 statins are
of cholesterol every night) from 22% to 63% risk). Rosuvastatin metabolized
synthesis. This depending on drug. should not be given differently, allowing
Lovastatin (10–40 mg with warfarin or substitution if side
induces LDL-receptor evening meal or
formation and the gemfibrozil. effects occur.
10–60 Sometimes used in
removal of LDL extended-release
cholesterol from combination with bile
every night) acid sequestrants to
blood.
Pravastatin (10–80 mg synergistically reduce
at bedtime) LDL cholesterol. If
Rosuvastatin (5–40 combined with a
mg/d) fibrate, monitor for
transaminase
Simvastatin (5–80 mg elevations. Do not use
evening meal) in pregnant or
Pitavastatin (2-4 mg/d) nursing women.
Contraindicated in
active liver disease.
Bile acid sequestrants Colestipol (2 scoops 2 Not absorbed. Unpleasant taste/texture, First-line drug to lower
Interrupt bile acid or 3 times per day) Long-term safety bloating, heartburn, cholesterol in
reabsorption Colsevelam established. LDL constipation, drug children and in
requiring bile acid hydrochloride (three cholesterol–lowering interaction (decreased women with
synthesis from 625 mg tablets 2 by 10% to 15%. by administrating child-bearing
cholesterol. times per day [3.8 g drugs 1 h before or 4 h potential. Second-line
total]) after meals). drug with statins to
Triglyceride levels synergistically induce
increase. LDL cholesterol
receptors. Do not use
if triglyceride levels
>3.39 mmol/L (>300
mg/dL) or in
gastrointestinal
motility disorder.
Fibrates Gemfibrozil (600 mg Best drugs for reducing Nausea, skin rash. Use Does not reliably
Reduce VLDL synthesis 2 times per day) triglyceride levels, with caution if renal reduce (and can
and lipoprotein Fenofibrate (45–145 lowers by 50% or insufficiency or increase) LDL
lipase. mg/d depending on more in many gallbladder disease. cholesterol level. Use
brand) patients. Increases cautiously with statins
HDL cholesterol level due to the possibility
by 15%. of myositis/myalgia.
Use with repaglinide
may cause severe
hypoglycemia.

Ezetimibe 10 mg once per day Reduces LDL Well-tolerated, but Can use with statins for
Selectively inhibits cholesterol level by contraindicated in further LDL
intestinal absorption 18%, triglyceride patients with liver cholesterol and
of cholesterol and level by 8%, and disease or elevated triglyceride level
related phytosterols. apoB by 16%. liver enzyme levels. reduction and to
increase HDL
cholesterol level. Do
not combine with
resins, fibrates, or
cyclosporine.

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Table—Continued
Drug Class and Dose Benefits Side Effects Notes
Mechanism of Action
Niacin Niacin (500–750 mg to Lowers LDL cholesterol Flushing of the skin, Drug of choice for
Largely unknown; 1–2 g every night of and triglyceride nausea, glucose combined
reduces hepatic extended-release levels 10% to 30%. intolerance, gout, liver hyperlipidemia and in
production of niacin) Most effective drug function test patients with low HDL
B-containing to raise HDL abnormalities, and cholesterol level.
lipoproteins. cholesterol level elevated uric acid. May Extended-release
Increases HDL (25% to 35%). increase preparations limit
cholesterol. homocysteine. flushing and liver
function test
abnormalities.
Long-acting OTC
niacin preparations
not recommended,
because they increase
the incidence of
hepatotoxicity.
Lowers lipoprotein(a).
Used in combination
with statins or bile
acid sequestrants in
patients with
combined
hyperlipidemia. Do
not use in pregnant
or nursing women.
Omega-3 fatty acids Lovaza 4 g/d Effective in controlling Dyspepsia, nausea. May Can increase LDL
Polyunsaturated fatty Omtryg 4.8 g/d triglyceride levels up increase bleeding cholesterol level in
acids inhibit hepatic Vascazen 4 g/d to 45%. Raises HDL time. Use cautiously in some patients with
triglyceride synthesis Epanova 2–4 g/d cholesterol level patients receiving increased triglyceride
and augment Vascepa (icosapent) 13%. anticoagulant therapy. levels.
chylomicron 2 g/d every 12 h Used as an adjunct Swallow capsule whole;
triglyceride with food to diet when do not break open,
clearance secondary triglycerides are dissolve, crush or
to increased activity greater than or equal chew.
of lipoprotein lipase. to 500 mg/dL. Safety and efficacy not
established in patients
<18 y.
ApoB antisense Mipomersen Indicated as an adjunct Measure baseline liver Administer on the same
oligonucleotide (Kynamro) 200 mg/mL to lipid-lowering function. Can cause day each week; if
SQ once weekly medications and diet elevated transaminases. dose is missed, the
to reduce LDL Check bilirubin, injection should be
cholesterol, apoB, aspartate given at least 3 d from
TC, and non-HDL transaminase, and the next weekly dose.
cholesterol in alanine transaminase if Inject SQ into
patients with nausea, vomiting, abdomen, thigh, or
homozygous familial abdominal pain, fever, outer area of upper
hypercholesterolemia. jaundice, lethargy or arm. Do no inject in
flu-like symptoms areas of active skin
develop. If greater than disease or injury such
2x ULN, consider as sunburn, rashes,
withholding. If greater inflammation,
than 5x the ULN, infections, or
withhold dose. psoriasis. Avoid
Recheck in 1 wk. tattooed or scarred
areas.
Requires refrigeration
(36–46 degrees F)
Allow to reach room
temperature for at
least 30 min prior to
administration.

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Table—Continued
Drug Class and Dose Benefits Side Effects Notes
Mechanism of Action
Ezetimibe and Ezetimibe, 10 mg Combination therapy Abnormal liver function Avoid use with fibrates,
simvastatin every night may improve patient tests. Myositis, myalgia. >1 g; niacin;
(combination drug) adherence. amiodarone; or
Both selectively inhibit Simvastatin, 10–80 mg Synergistic benefits. verapamil due to
the intestinal every night increased risk for
absorption of myopathy.
cholesterol and Contraindicated in liver
partially inhibit disease and in
HMG-CoA reductase. pregnant or nursing
women.
PCSK9 inhibitors Evolocumab (Repatha) Used as an adjunct to Mild or moderate Safety and efficacy not
Indicated as an adjunct 140 mg/mL SQ diet and maximally hepatic impairment. established in
to diet and other every 2 weeks or tolerated statin Mild or moderate renal children with
420 mg SQ once therapy for the impairment. heterozygous familial
LDL-lowering monthly Severe impairment has
therapies for treatment of adults hypercholesterolemia.
Alirocumab (Praluent) who have not been studied. In children younger
treatment of patients 75 mg/mL SQ every
with homozygous heterozygous familial than 13 y, safety and
2 wk or 300 mg SQ hypercholesterolemia efficacy is not
familial every 4 wk
hypercholesterolemia or clinical established.
who require atherosclerotic CVD, In young adults aged
additional lowering who require 13–17 y, administer as a
of LDL cholesterol additional lowering single dose of
of LDL cholesterol. 420 mg SQ monthly.
For those with Measure LDL cholesterol
homozygous familial levels 4–8 wk after
hypercholesterolemia initiating, since
who require response to therapy
additional lowering depends on the degree
of LDL cholesterol of LDL-receptor
after other agents function.
such as statins, When switching dosage
ezetimibe, and LDL regimens, administer
apheresis. the first dose of the new
regimen on the next
scheduled date of the
prior regimen.
Microsomal Lomitapide (Juxtapid) Indicated for those Available only through
triglyceride 5 mg–60 mg daily with homozygous restrictive access
transport protein familial programs due to the
inhibitor hypercholesterolemia potential for
to be used as an hepatotoxicity risk.
adjunct with other Administer with daily
lipid lowering agents supplements that
and LDL apheresis to contain vitamin E 400
reduce LDL IU, linoleic acid 200
cholesterol, TC, mg, ␣-linolenic acid
apoB, and non-HDL 210 mg.
cholesterol. Take once per day with a
glass of water, without
food, at least 2 h after
the evening meal as
food increases
gastrointestinal adverse
effects. Swallow whole,
do not crush, chew,
open, or dissolve.

apoB = apolipoprotein B; CVD = cardiovascular disease; HDL = high-density lipoprotein; HMG-CoA = 3-hydroxy-3-methylglutaryl
coenzyme A; LDL = low-density lipoprotein; OTC = over-the-counter; PCSK9 = proprotein convertase subtilisin/kexin type 9; SQ =
subcutaneous; TC = total cholesterol; ULN = upper limit of normal; VLDL = very low-density lipoprotein.

events in patients with preexist- ever, these drugs alone do not


ing atherosclerotic CVD and in decrease the risk for atheroscle-
patients at high risk for athero- rotic disease. For example,
sclerotic CVD. ezetimibe decreases LDL-C by tar-
geting the Niemann-Pick C1-like 1
Additional drugs have emerged as (NPC1L1) protein; however, no
agents to decrease lipids. How- clinical trial has shown that it alone

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can decrease cardiovascular Elevated Risk) trial showed that authors advocate routine liver
events (32), a finding also noted adding a PCSK9 inhibitor to exist- function tests before each
with PCSK9 inhibitors (33–35). Nia- ing moderate or high-dose statin follow-up visit, but statin-induced
cin, which was used by many clini- therapy improved a combined hepatotoxicity seems much less
cians to increase HDL-C and de- cardiovascular outcome (38). How- common than previously be-
crease triglyceride levels, is no ever, these drugs are expensive; lieved, so the American College
longer recommended for routine therefore, patients and clinicians of Physicians' guideline on treat-
dyslipidemia treatment. The HPS2- should discuss the cost– benefit ment for dyslipidemia does not
THRIVE (Heart Protection Study 2 ratio. recommend these tests in pa-
Treatment of HDL to Reduce the tients treated with statins (7). How-
Incidence of Vascular Events) When prescribing combination ever, when statin therapy is begun
showed that niacin has no clinical therapy, the clinician needs to be and during the first year of treat-
benefit (36) and causes such vigilant for drug interactions. Fi-
ment, liver function (aminotrans-
adverse reactions as glucose brates should be used with caution
ferase levels) should be measured
intolerance, gastrointestinal upset, when combined with statins, par-
at baseline, 3 months, and 12
musculoskeletal discomfort, skin- ticularly gemfibrozil, because they
months. Creatine kinase levels
related disorders (such as rash and compete with the statin for metab-
should also be measured at base-
flushing), headache, gout, and se- olism via the cytochrome P450
line for interpretation of future test
rious infections (36). system. This interaction may in-
results. Although the absolute
duce rhabdomyolysis (39).
benefit of statin therapy depends
Pharmacologic interventions that
What are the therapeutic goals on the patient's level of risk for
are not recommended for primary
prevention include fibrates, bile of treatment? CVD, there is potential for harm as
acid– binding resins, omega-3 fatty The first therapeutic goal is to im- well. Risk for serious liver injury is
acid supplements, plant sterols or prove the patient's lifestyle. The quite small if the statin dose is
stanols, and niacin. second goal is to decrease the risk moderate, but patients with ami-
for cardiovascular events. Reduc- notransferase levels greater than
When is combination drug ing absolute levels of LDL-C is no 3 times the normal levels should
therapy warranted? longer a therapeutic goal. The be evaluated for the net benefit of
Combination therapy should be 2013 ACC/AHA guidelines no lon- continuing statin therapy versus
considered in patients with se- ger base treatment decisions on adjusting or discontinuing treat-
verely elevated lipid levels that do these values; instead, they focus ment (40, 41). In 2012, the U.S.
not respond to maximum statin on identifying high- and medium- Food and Drug Administration
monotherapy. Recent trials show risk subgroups who would benefit concluded that serious liver injury
that adding specific agents to sta- from treatment aimed at reducing with statins is rare and unpredict-
tins can decrease LDL-C and car- cardiovascular risk (7). able in patients and, therefore,
diovascular events more than recommended that routine peri-
statins alone. For example, How should therapy be odic measurement of liver en-
IMPROVE-IT (Improved Reduction monitored? zymes does not seem to be effec-
of Outcomes: Vytorin Efficacy In- Most interventions to treat dyslipi- tive in detecting or preventing
ternational Trial) showed that add- demia require at least 6 months to liver dysfunction or myopathy.
ing ezetimibe to existing statin reduce the risk for CVD event rates
therapy improves a combined car- (7), and treatment is usually life- More frequent visits may be re-
diovascular end point (37). How- long. Regular follow-up is impor- quired to counsel about behav-
ever, the benefits of adding tant after initiation, but in the ab- ioral lifestyle changes, which gen-
ezetimibe were small; therefore, in sence of strong evidence to erally require extensive support
2016 the U.S. Food and Drug Ad- support a specific monitoring in- from the clinician to foster adher-
ministration decided that the re- terval, it seems reasonable to per- ence. Overall, only 39% of pa-
sults of IMPROVE-IT were not suffi- form a fasting lipid profile 6 weeks tients on drug therapy and 34% of
cient to recommend ezetimibe for after initiation of any new lipid- patients on dietary therapy reach
patients at high risk for atheroscle- lowering agent. During all their NCEP-ATP III goal (42). New
rotic CVD. HPS2-THRIVE showed follow-up visits, the clinician or additional drugs should be
that niacin has no clinical benefit should discuss adherence, identify added one at a time because if
and causes adverse reactions (36). side effects, and encourage life- adverse reactions occur, this
The FOURIER (Further Cardiovas- style changes. The frequency of method makes it easier to deter-
cular Outcomes Research with follow-up visits should depend on mine which drug caused the
PCSK9 Inhibition in Subjects with the patient's progress. Some problem. The recommendation is

5 December 2017 Annals of Internal Medicine ITC93 姝 2017 American College of Physicians

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that after the initial lipid-lowering therapy is associated with a small excess risk for complementary–alternative thera-
agent is started, the clinician elevated aminotransferase levels (risk difference pies should not substitute for drug
should reassess the fasting lipid [RD] per 1000 patients, 4.2 [95% CI, 1.5 to 6.9]) therapy in high-risk patients.
but not for myalgia (RD, 2.7 [CI, ⫺3.2 to 8.7]),
profile in 6 weeks to assess adher- When should clinicians consult
elevated creatine kinase levels (RD, 0.2 [CI,⫺0.6
ence (7). If lipids do not decrease to 0.9]), rhabdomyolysis (RD, 0.4 [CI, ⫺0.1 to a lipid specialist?
as expected, in addition to ad- 0.9]), or therapy withdrawal (RD, ⫺0.5 [CI, ⫺4.3
dressing adherence the clinician The clinician should consider con-
to 3.3]) (44). However, trial findings may differ
from the experience in actual clinical practice. sulting a lipid specialist for patients
should reinforce lifestyle modifica-
with lipid disorders that are rare or
tions and consider referral to a
In a prospective, observational cohort (PRIMO resistant to treatment. These spe-
lipid specialist (7). [Pexelizumab for Reduction in Infarction and Mortal- cific rare disorders require either
What are the side effects of ity] study) of nearly 8000 French patients aged 18 to special monitoring or complex
75 years who received high-dose statins for at least 3 regimens that are difficult to initi-
drug therapy? months, 10.1% developed muscular pain, with
The most common side effects of 24.2% of these reporting pain “all over” that often ate in a routine practice setting.
statins are myalgia, myositis, and caused a disruption in daily activities. The median Patients in this category may in-
elevated liver enzyme levels; how- time to developing muscular symptoms was 1 clude those with familial hyper-
ever, the frequency of serious month, but 80% of those who developed symptoms cholesterolemia, type 3 dyslipo-
events is low, and rhabdomyolysis did so within 3 months of initiating or intensifying proteinemia, very low HDL-C
is rare. The incidence of myopathy statin therapy (45). syndromes (HDL-C level 20 mg/dL
due to statins is 1 per 10 000 pa- [<0.5 mmol/L]), and resistant hy-
Clinicians should be vigilant for side
tients per year (43). A recent study pertriglyceridemia (triglyceride
effects when prescribing drugs for
discovered that variations in a level 1000 mg/dL [>11.3 mmol/
dyslipidemia. However, evidence is
gene encoding a transporter pro- L]). Also, patients at high risk for a
insufficient to establish clear recom-
tein are linked to many cases of mendations with regard to monitor- vascular event, such as those with
statin-induced myopathy (44). ing and managing side effects. vascular disease before age 45
Fibrates can cause nausea and When severe side effects occur, dis- years and patients with evidence
skin rash and must be used cau- continuation may be the only op- of disease progression despite
tiously with statins, because the tion. Clinicians and patients need to treatment, are candidates for re-
combination tends to increase the weigh the risks and benefits of ther- ferral to a lipid specialist. Patients
incidence of myositis and myalgia. apy with minor side effects. Because at very high risk may need multi-
The intestinal cholesterol metabolism of the various statins ple interventions to reduce
absorption-blocking drugs and differs, it may be reasonable to sub- LDL-C levels substantially below
the bile acid– binding resins tend stitute one statin for another if side the usual goals, to increase
to cause abdominal bloating and effects occur. HDL-C levels, or to identify and
constipation, although otherwise treat other lipid and nonlipid risk
they are generally well tolerated. What should clinicians advise factors. Current treatments to
Niacin, which is still prescribed by patients about the use of reduce LDL-C level are very effi-
some clinicians although not rec- complementary–alternative cacious; however, a poor re-
ommended for routine treatment therapies? sponse may prompt an examina-
of dyslipidemia, is the least well- Among commonly used alterna- tion for secondary causes, such
tolerated lipid-lowering agent. It tive therapies for controlling lipids, as unusual lipid and lipoprotein
can cause flushing, nausea, head- plant-based diets have been disorders, lack of adherence, or
ache, glucose intolerance, and shown to have some effectiveness other causes. If lipids do not de-
gout. Some of these effects can (46), as have nuts in moderation crease as expected, then adher-
be minimized with proper drug (47, 48). Some dietary changes ence issues and lifestyle modifi-
administration. To minimize flush- might affect serum lipid levels cations should be addressed and
ing, a non– enteric-coated aspirin merely by replacing fatty foods referral to a lipid specialist
can be taken 1 hour before the with healthier choices. However, should be considered (7).
evening dose along with a low-fat
snack. Patients should also avoid
hot beverages, baths, or showers Treatment... Treatment of dyslipidemia should always include modifica-
around the time of niacin dosing. tion of diet and exercise to optimize lipid levels. Clinicians should base
drug therapy decisions on the individual patient's risk for cardiovascular
A systematic review quantified the risks for mus- events and should select drugs that reduce that risk. Strong evidence sup-
culoskeletal, renal, and hepatic complications ports statin therapy for high-risk patients.
associated with statin therapy. After examining
data from 74 102 persons enrolled in 35 trials
and followed for up to 65 months, the authors CLINICAL BOTTOM LINE
concluded that, compared with placebo, statin

姝 2017 American College of Physicians ITC94 Annals of Internal Medicine 5 December 2017

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Practice Improvement
What measures do U.S. focus on dyslipidemia. In addition, should be started and which
stakeholders use to evaluate the voluntary Medicare Physicians screening tests should be used (7,
the quality of care for patients Quality Reporting Initiative pays 10). In addition, evidence-based
with dyslipidemia? physicians a bonus for reporting guidelines include a guideline from
on quality measures that apply to the American College of Physicians
In April 2005, the Ambulatory Care
their patients and includes a mea- on lipid control in patients with type
Quality Alliance released 26 health
sure related to lipid control in pa- 2 diabetes (46). A comprehensive
care quality indicators for clini-
tients with diabetes. listing of guidelines is available
cians, consumers, and health care through the National Guideline
purchasers to use in quality im- What do professional Clearinghouse at www.guidelines
provement efforts, public report- organizations recommend .gov. However, the most widely
ing, and pay-for-performance pro- regarding the care of patients used lipid guideline in the United
grams at www.aqaalliance.org. In with dyslipidemia? States is the 2013 ACC/AHA
May 2005, the Centers for Medi- guideline on blood cholesterol
As noted, several organizations offer
care & Medicaid Services en- treatment (http://circ.ahajournals
recommendations about dyslipide-
dorsed the development of these .org/content/early/2013/11/11/01
mia screening that differ with re-
indicators. Of the 26 indicators, 3 .cir.0000437738.63853.7a).
spect to the age at which screening

IntheClinic
In the Clinic Practice Guidelines
www.aace.com/files/lipid-guidelines.pdf

Tool Kit
Guidelines for prevention of cardiovascular disease by the
American Association of Clinical Endocrinologists and
the American College of Endocrinology.
www.healthquality.va.gov/guidelines/CD/lipids/
Guidelines from the U.S. Department of Veterans Affairs.
www.escardio.org/Guidelines/Clinical-Practice
Dyslipidemia -Guidelines/Dyslipidaemias-Management-of
Guidelines from the European Society of Cardiology.

Patient Information
www.lipid.org/practicetools/tools/tearsheets
Information and tear sheets on dyslipidemia and other
lipid disorders from the National Lipid Association.
http://pcna.net/clinical-tools/education-for-your
-patients/cholesterol
Information available in both English and Spanish from
the Preventive Cardiovascular Nurses Association.
https://medlineplus.gov/cholesterol.html
Information about cholesterol management from
Medline.

5 December 2017 Annals of Internal Medicine ITC95 姝 2017 American College of Physicians

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WHAT YOU SHOULD KNOW In the Clinic
Annals of Internal Medicine
ABOUT DYSLIPIDEMIA
What Is Dyslipidemia
(High Cholesterol)?
• Lipids are fatty substances in your blood.
These substances are called cholesterol and
triglycerides. It is normal to have some fats in
your blood.
• Sometimes the levels of fats in your blood can
get too high. This is called dyslipidemia or
high cholesterol.
• When you have too many fats in your blood,
they can build up and clog the blood vessels
in your heart. This can cause heart attack,
stroke, and other diseases.
What Are the Risk Factors?
You may be at higher risk for dyslipidemia if you:
• Are older than 65 years of age Sometimes lifestyle changes aren't enough.
• Have a family history of dyslipidemia There are several medicines available that
• Are a smoker help lower the fat levels in your blood. Many
• Eat an unhealthy diet people are prescribed one of several medi-
• Drink alcohol very frequently cines called statins. You and your doctor
• Do not exercise should work together to decide what medi-
• Are a person with high blood pressure, cine is right for you.
obesity, or diabetes
How Is It Diagnosed? Should I Be Screened?
• In general, women 45 years or older and men
Your doctor will ask you questions about your 35 years or older should be screened
current health and health history.
regularly.
• You may also get a physical exam.
• You may be screened at a younger age if you
• Your health care provider will give you a
blood test to check fat levels in your blood. have certain risk factors or family history of

Patient Information
This test may require you to not eat for a few dyslipidemia.
hours.
Questions for My Doctor
How Is It Treated? • Do I need to be screened for dyslipidemia?
Your doctor will work with you to create a plan for • What is the healthiest diet for me to eat?
your treatment. One part of your treatment will • Are there foods that I should not eat?
include making healthy changes, such as: • What is the best form of exercise for me?
• Eating a heart-healthy diet • What is the best medicine for me?
• Getting regular exercise • Does the medicine have side effects?
• Quitting smoking • Will this medicine interact with my other
• Losing weight if needed medicines?

For More Information


National Heart, Lung, and Blood Institute
www.nhlbi.nih.gov/health/resources/heart/heart-cholesterol-hbc
-what-html
Medline Plus
https://medlineplus.gov/ency/article/000403.htm

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