Annals of Internal MedicineT

In the ClinicT

Dyslipidemia
D
yslipidemia is an important risk factor for
coronary artery disease and stroke. All per-
sons with dyslipidemia should be advised
to focus on lifestyle interventions, including regular Screening
aerobic exercise, a healthy diet, maintenance of a
healthy weight, and abstinence from smoking. In
addition to lifestyle interventions, lipid-lowering Clinical Evaluation
therapy should be considered for persons at mod-
erate to high risk for atherosclerotic cardiovascular Treatment
disease based on validated risk equations. Statin
therapy is the first-line medical treatment for dys-
lipidemia due to its effectiveness and favorable
adverse effect profile, but newer treatments pro-
vide additional tools for clinicians to effectively
treat dyslipidemia.

CME/MOC activity available at Annals.org.

Physician Writers doi:10.7326/AITC202306200

Marios Arvanitis, MD
Charles J. Lowenstein, MD
Johns Hopkins University
School of Medicine, Baltimore,
Maryland (M.A., C.J.L.)
This article was published at Annals.org on 13 June 2023.
CME Objective: To review current evidence for screening, clinical evaluation, and
treatment of dyslipidemia.
Funding Source: American College of Physicians.

Acknowledgment: The authors thank Laurie Kopin, EdD, MS, ANP, coauthor of
the previous version of this In the Clinic.

Disclosures: All relevant financial relationships have been mitigated. Disclosures

can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.
do?msNum=M22-2604.

With the assistance of additional physician writers, the editors of Annals of

Internal Medicine 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/.
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 Atherosclerotic cardiovascular disease smoking status, and other comorbid con-
1. Dai H, Much AA, Maor E, et (ASCVD) is the leading cause of death ditions in addition to lipid levels. Medical
al. Global, regional, and
national burden of ischae- worldwide (1). Dyslipidemia is a major therapy and lifestyle interventions are
mic heart disease and its risk factor for ASCVD. “Dyslipidemia” is generally recommended for persons at
attributable risk factors,
1990–2017: results from an umbrella term that encompasses all high risk, and lifestyle interventions
the Global Burden of
Disease Study 2017. Eur disorders of lipid metabolism. The most alone are recommended for those
Heart J Qual Care Clin commonly measured lipid particles with low estimated risk. The 2018
Outcomes. 2022;8:50-60.
[PMID: 33017008] include total cholesterol, triglycerides, guidelines on management of blood
2. Grundy SM, Stone NJ,
Bailey AL, et al. 2018 AHA/ low-density lipoprotein cholesterol (LDL- cholesterol from the American College
ACC/AACVPR/AAPA/ABC/ C), high-density lipoprotein cholesterol of Cardiology (ACC) and the American
ACPM/ADA/AGS/APhA/
ASPC/NLA/PCNA guideline (HDL-C), and more recently lipoprotein Heart Association (AHA) recommend
on the management of
blood cholesterol: a report (a) [Lp(a)]. With few exceptions, primarily considering additional factors, known
of the American College of linked to genetic disorders, treatment as ASCVD risk enhancers (see the Box:
Cardiology/American Heart
Association Task Force on and prevention of dyslipidemia do not ASCVD Risk Enhancers), when deciding
Clinical Practice Guidelines.
Circulation. 2019;139: depend only on lipid thresholds but how to treat patients at intermediate
e1082-e1143. [PMID: instead take into account individual risk risk (2). Similar risk-enhancing factors
30586774]
3. Mach F, Baigent C, for ASCVD. Estimation of risk for ASCVD were proposed in the 2019 European
Catapano AL, et al.; ESC
Scientific Document Group. is based on equations that incorporate Society of Cardiology (ESC) guidelines
2019 ESC/EAS guidelines traditional risk factors, including age, sex, (3).
for the management of
dyslipidaemias: lipid modi-
fication to reduce cardiovas-
cular risk. Eur Heart J.
2020;41:111-188. [PMID:
31504418]
4. Arnett DK, Blumenthal RS,
Screening
Albert MA, et al. 2019 ACC/ Who should be screened? randomized controlled trials (RCTs) for
AHA guideline on the pri-
mary prevention of cardio- All major clinical practice guidelines statin therapy for primary prevention is
vascular disease: executive
agree on screening for persons aged weak for persons older than 75 years
summary: a report of the
American College of
40 to 75 years with or without known and recommend clinical assessment of
Cardiology/American Heart
Association Task Force on risk factors for ASCVD (Appendix risk status and a discussion between
Clinical Practice Guidelines.
Table, available at Annals.org) (2–5). the clinician and the patient to guide
J Am Coll Cardiol.
2019;74:1376-1414. screening and treatment decisions.
[PMID: 30894319] The exact age at which screening for
5. Visseren FLJ, Mach F,
Smulders YM, et al.; ESC
dyslipidemia should start is controver- A systematic literature review by the CTT
National Cardiac Societies. sial. According to the U.S. Preventive (Cholesterol Treatment Trialists’) collab-
2021 ESC guidelines on
cardiovascular disease pre- Services Task Force (USPSTF), clinicians oration found that 14 483 (8%) persons
vention in clinical practice.
Eur Heart J. should screen all persons aged 40 to among 28 statin therapy trials were
2021;42:3227-3337.
75 years for lipid disorders (6). The older than 75 years at the time of ran-
[PMID: 34458905]
6. Bibbins-Domingo K, USPSTF makes no recommendation for domization and the effects of statins in
Grossman DC, Curry SJ, et
al.; US Preventive Services or against routine screening for lipid reducing major vascular events were
Task Force. Statin use for
disorders in persons aged 20 to 39 years similar among different age groups (7).
the primary prevention of
cardiovascular disease in
adults: US Preventive
who are not at increased risk for coro- The ESC guidelines acknowledge the
Services Task Force recom- nary heart disease (CHD) (6). In contrast, findings of the CTT review but note that
mendation statement.
JAMA. 2016;316:1997- the 2019 ACC/AHA guidelines for pri- evidence of benefit in this age group is
2007. [PMID: 27838723] mary prevention recommend consider-
7. Fulcher J, O'Connell R, less direct among persons who do not al-
Voysey M, et al.; ing screening of all adults at age 20 ready have occlusive vascular disease
Cholesterol Treatment
Trialists' (CTT) years, regardless of CHD risk profile (4). and point to the ongoing STAREE (Statin
Collaboration. Efficacy and
safety of LDL-lowering ther-
The rationale is that screening can guide Therapy for Reducing Events in the
apy among men and discussions about intensity of lifestyle Elderly) trial for a potential answer to that
women: meta-analysis of
individual data from interventions, treatment of nonlipid risk question (8).
174,000 participants in 27
randomised trials. Lancet.
factors, and consideration of lifetime or
2015;385:1397-1405. 30-year risk estimation (4). How often should clinicians screen for
[PMID: 25579834] dyslipidemia?
8. Kirkpatrick JN, Bernacki
GM. Primary prevention Clinical guidelines agree that the evi- Most U.S. organizations recommend
statins in older patients:
the good news or the bad dence for screening persons older screening for dyslipidemia every 5 years
news first? [Editorial]. J Am than 75 years is limited. The ACC/AHA on average. The ACC/AHA recommends
Coll Cardiol. 2020;76:28-
30. [PMID: 32616159] guidelines note that evidence from that all adults aged 20 to 75 years have a

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fasting lipid profile measured every 4 to How should clinicians measure and
6 years if there is no ASCVD and more interpret lipid levels?
often if it is present (2). Similarly, the LDL-C levels
USPSTF recommendations state that it LDL-C is the most well-studied proathero-
is reasonable to measure a lipid profile genic lipoprotein. Estimation of circulating
every 5 years, although the recommended LDL-C levels is usually based on other
age range for screening is more restrictive, measured parameters of the standard
as previously outlined (6). lipid tests (total cholesterol, HDL-C, tri-
How should screening for glycerides). Large observational studies
dyslipidemia be done? have reported a strong, graded rela- 9. Mangione CM, Barry MJ,
tionship between higher LDL-C levels Nicholson WK, et al.; US
Preventive Services Task
All clinical guidelines agree that non- and increased risk for atherosclerotic Force. Statin use for the pri-
fasting lipid screening is acceptable. CHD events (14, 15), an effect that has mary prevention of cardio-
vascular disease in adults:
Fasting has minimal influence on LDL-C been replicated by several RCTs of US Preventive Services Task
Force recommendation
levels but decreases triglyceride levels LDL-C–reducing medications (16–18). statement. JAMA.
2022;328:746-753.
by an average of 27 mg/dL in most [PMID: 35997723]
Triglyceride levels
persons. Although the USPSTF does 10. Martin SS, Blaha MJ,
Triglyceride levels were recognized as Elshazly MB, et al.
not make specific recommendations Comparison of a novel
on measuring triglycerides in primary ASCVD risk enhancers by the 2018 method vs the Friedewald
equation for estimating
prevention (9), both the ESC and the ACC/AHA guidelines (Box: ASCVD low-density lipoprotein
cholesterol levels from
Risk Enhancers). Prospective epidemio-
ACC/AHA (2, 3) recommend measuring the standard lipid profile.
logic studies have shown that increased JAMA. 2013;310:2061-
triglycerides as part of the lipid panel, 2068. [PMID: 24240933]
triglyceride levels are related to increased 11. Sampson M, Ling C, Sun
and the ACC/AHA further suggests that Q, et al. A new equation
risk for coronary artery disease (CAD) for calculation of low-den-
a fasting lipid panel should be obtained
(19), and a meta-analysis of prospective sity lipoprotein choles-
if the nonfasting triglyceride level is studies found that high triglyceride lev-
terol in patients with
normolipidemia and/or
above 400 mg/dL. The LDL-C level is a els are an independent risk factor for hypertriglyceridemia.
JAMA Cardiol.
calculated value in routine lipid profiles. CAD (20). 2020;5:540-548. [PMID:
32101259]
The calculation was traditionally based 12. Craig SR, Amin RV,
on the Friedewald formula, but that for- The association between elevated triglyc- Russell DW, et al. Blood
cholesterol screening
mula is now known to produce inaccurate eride levels and CAD seems to be influence of fasting state
on cholesterol results and
LDL-C estimates in people with hypertri- management decisions. J
Gen Intern Med.
glyceridemia, and alternative equations, 2000;15:395-399.
ASCVD Risk Enhancers*
such as the ones validated by Martin • Family history of premature ASCVD
[PMID: 10886474]
13. Langsted A, Freiberg JJ,
and colleagues (10) and Samson and • Persistently elevated LDL-C level ≥160 Nordestgaard BG. Fasting
and nonfasting lipid lev-
colleagues (11), have been shown to be mg/dL els: influence of normal
• Chronic kidney disease (estimated glomer- food intake on lipids, lipo-
more accurate. These alternative equa- ular filtration rate <59 mL/min/1.73 m2) proteins, apolipoproteins,
tions are now recommended by the • Metabolic syndrome (increased waist cir- and cardiovascular risk
prediction. Circulation.
ACC/AHA and the ESC and have been cumference, triglyceride level >150 2008;118:2047-2056.
mg/dL, elevated blood pressure, elevated [PMID: 18955664]
adopted by multiple laboratories. glucose level, and low HDL-C level are fac- 14. Anderson KM, Castelli
tors; presence of 3 confirms the diagnosis) WP, Levy D. Cholesterol
and mortality. 30 years of
A study of 181 general internal medicine • Persistently elevated triglyceride level follow-up from the
≥175 mg/dL Framingham study.
outpatients found no clinically important • High-sensitivity C-reactive protein level JAMA. 1987;257:2176-
differences between fasting and non- ≥2 mg/L 2180. [PMID: 3560398]
15. Goldbourt U, Yaari S.
fasting results for total and HDL-C levels • Lp(a) level >125 nmol/L Cholesterol and coronary
(12). Another large cross-sectional pop- • Apolipoprotein B level ≥1.3 g/L heart disease mortality. A
• Ankle–brachial index <0.9 23-year follow-up study of
ulation study that compared fasting and • Conditions specific to women (e.g., 9902 men in Israel.
Arteriosclerosis.
nonfasting lipid profiles in 33 391 per- preeclampsia, premature menopause) 1990;10:512-519.
• Inflammatory diseases (especially rheu- [PMID: 2369362]
sons aged 20 to 95 years reported that 16. Ridker PM, Danielson E,
matoid arthritis, psoriasis, HIV)
lipid profiles changed minimally in • Ethnicity (e.g., South Asian ancestry) Fonseca FA, et al.;
JUPITER Study Group.
response to normal food intake in the * Adapted from the 2018 ACC/AHA Rosuvastatin to prevent
vascular events in men
general population and that nonfasting guidelines on the management of blood and women with elevated
levels also predicted cardiovascular cholesterol (2). C-reactive protein. N Engl
J Med. 2008;359:2195-
events (13). 2207. [PMID: 18997196]

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 stronger for women than for men (21). by the ACC/AHA. The ESC makes a
Persons with elevated triglyceride lev- strong recommendation for measuring
17. Ridker PM, MacFadyen
els are more likely to be predisposed apoB in all persons, particularly those
JG, Fonseca FA, et al.; to metabolic syndrome. Triglyceride with hypertriglyceridemia, diabetes, met-
JUPITER Study Group.
Number needed to treat levels greater than 500 mg/dL are abolic syndrome, or very low LDL-C lev-
with rosuvastatin to pre- associated with pancreatitis and war- els. The ACC/AHA guidelines agree that
vent first cardiovascular
events and death among rant treatment and evaluation for fami-
men and women with low measuring apoB is reasonable to refine
lial hypertriglyceridemia (2).
low-density lipoprotein
cholesterol and elevated
risk estimates in persons with triglyceride
high-sensitivity C-reactive HDL-C levels levels above 200 mg/dL but do not
protein: justification for
the use of statins in pre- HDL-C level is inversely associated with broadly recommend routine apoB mea-
vention: an intervention
trial evaluating rosuvasta-
CVD and coronary death independent surement. Similarly, non-HDL cholesterol
tin (JUPITER). Circ of other traditional risk factors (22). An can better estimate the total number of
Cardiovasc Qual
Outcomes. 2009;2:616- HDL-C level less than 40 mg/dL in men circulating atherogenic particles and can
623. [PMID: 20031900]
18. Sabatine MS, Giugliano
and 50 mg/dL in women predicts an help evaluate risk in persons with high tri-
RP, Keech AC, et al.; increase in atherosclerotic events, and glyceride levels (3).
FOURIER Steering
Committee and for each 1-mg/dL reduction, coronary
Investigators. Evolocumab risk is estimated to increase by 2% to Lp(a) levels
and clinical outcomes in
patients with cardiovascu- 3% (23). However, a causal link between Lp(a) is a lipoprotein particle that is sim-
lar disease. N Engl J Med. ilar to LDL-C in size and structure but
2017;376:1713-1722. low HDL-C level and ASCVD has not
[PMID: 28304224] been confirmed by Mendelian random- contains an Lp(a) particle that is cova-
19. Miller M. Is hypertriglycer-
idaemia an independent ization studies (24) or RCTs studying lently attached to its apoB component.
risk factor for coronary
heart disease? The epide- HDL-C–increasing medications (25, 26). Lp(a) is not part of the standard lipid
miological evidence. Eur
Heart J. 1998;19 Suppl
Thus, most treatment guidelines do not panel and must be measured sepa-
H:H18-22. [PMID: recommend medications specifically to rately. Lp(a) levels are primarily geneti-
9717060]
20. Sarwar N, Danesh J, increase HDL-C levels and instead advise cally determined (>90% heritability in
Eiriksdottir G, et al.
Triglycerides and the risk
lifestyle interventions for ASCVD preven- recent studies) (28) and are recognized
of coronary heart disease: tion in those patients (2). as a risk-enhancing factor (see the Box:
10,158 incident cases
among 262,525 partici-
Apolipoprotein B levels
ASCVD Risk Enhancers). However, rec-
pants in 29 Western pro-
spective studies. Apolipoprotein B (apoB) is the major ommendations for routine testing of
Circulation.
2007;115:450-458. structural component of very-low-den- Lp(a) are not strong, owing primarily to
[PMID: 17190864]
sity lipoprotein, LDL, and triglyceride- the lack of specific therapies for Lp(a).
21. Stone NJ, Robinson JG,
Lichtenstein AH, et al.; rich remnant particles. All lipoproteins The ESC issued a class IIa recommen-
American College of
Cardiology/American that contain apoB contain a single mol- dation for measuring Lp(a) in all per-
Heart Association Task sons at least once in their lifetime,
Force on Practice ecule of it, so measuring apoB directly
Guidelines. 2013 ACC/ in plasma estimates the number of circu- whereas the ACC/AHA guidelines include
AHA guideline on the
treatment of blood choles- lating atherogenic lipoprotein particles. a relative indication for Lp(a) testing in per-
terol to reduce athero-
sclerotic cardiovascular ApoB has been more strongly associated sons with a family history of premature
risk in adults: a report of
the American College of
with ASCVD risk than all other measured ASCVD or those with a personal history of
Cardiology/American or estimated lipid components (27) and ASCVD that is not explained by major risk
Heart Association Task
Force on Practice is considered an ASCVD risk enhancer factors.
Guidelines. J Am Coll
Cardiol. 2014;63:2889-
2934. [PMID: 24239923]
22. Kuvin JT, Rämet ME, Patel
AR, et al. A novel mecha-
Screening... Evidence-based guidelines recommend routine screening for dyslipidemia in
nism for the beneficial persons aged 40 to 75 years. Screening at earlier ages may be considered, especially in peo-
vascular effects of high- ple with cardiovascular risk factors or a clinical history suggesting familial hyperlipidemia.
density lipoprotein choles-
terol: enhanced vasorelax-
Although guideline groups disagree on which cholesterol levels to measure, they all agree on
ation and increased measuring HDL-C and either total cholesterol or LDL-C. Nonfasting lipid measurements may
endothelial nitric oxide be used, as they have little effect on triglyceride levels and calculation of LDL-C levels.
synthase expression. Am
Heart J. 2002;144:165-
172. [PMID: 12094204]
23. Gordon DJ, Probstfield JL,
Garrison RJ, et al. High-
CLINICAL BOTTOM LINE
density lipoprotein choles-
terol and cardiovascular
disease. Four prospective
American studies.
Circulation. 1989;79:8-
15. [PMID: 2642759]

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 Clinical Evaluation 24. Hewing B, Moore KJ,
Fisher EA. HDL and cardi-
ovascular risk: time to call
How should clinicians interpret lipid prompt consideration of moderate- the plumber? Circ Res.
2012;111:1117-1120.
screening results when evaluating intensity statin therapy. [PMID: 23065341]
overall cardiovascular risk? 25. Boden WE, Probstfield JL,
What should clinicians look for in the Anderson T, et al.; AIM-
When diagnosing dyslipidemia, clinicians HIGH Investigators.
history and physical examination? Niacin in patients with
should estimate a patient’s cardiovas- low HDL cholesterol levels
The history and physical examination receiving intensive statin
cular risk. Calculation of risk using spe- therapy. N Engl J Med.
should focus on evaluating traditional 2011;365:2255-2267.
cific equations is more accurate than
risk factors and ASCVD risk enhancers, [PMID: 22085343]
using lipid levels alone or simply count- 26. Schwartz GG, Olsson AG,
detecting secondary causes of dyslipi- Abt M, et al.; dal-
ing risk factors. In 2013, the ACC/AHA OUTCOMES Investigators.
demia, and identifying persons at risk Effects of dalcetrapib in
jointly analyzed data from 5 community- patients with a recent
for adverse effects from therapy. acute coronary syndrome.
based cohorts and generated the Pooled Traditional risk factors include older N Engl J Med.
2012;367:2089-2099.
Cohort Equations (PCE) score, which is age, male sex, tobacco smoking, hy- [PMID: 23126252]
now the standard of care for risk estima- perlipidemia, hypertension, and dia-
27. Sniderman AD,
Thanassoulis G, Glavinovic
tion in the United States (21). The score betes. Secondary causes of dyslipidemia
T, et al. Apolipoprotein B
particles and cardiovascu-
includes age, sex, race (Black, White, or include hypothyroidism, obstructive liver lar disease: a narrative
review. JAMA Cardiol.
other), systolic blood pressure, hyper- disease, nephrotic syndrome, renal fail- 2019;4:1287-1295.
[PMID: 31642874]
tension treatment status, diabetes sta- ure, uncontrolled diabetes, and tobacco 28. Austin MA, Sandholzer C,
tus, smoking status, and total and HDL or alcohol use. The history should also
Selby JV, et al.
Lipoprotein(a) in women
cholesterol levels. The equations are sex- include a detailed reconciliation of all twins: heritability and
relationship to apolipo-
and race-specific, taking into account the medications because some may affect protein(a) phenotypes.
Am J Hum Genet.
different baseline ASCVD risk among dif- lipid levels (Box: Drugs That Can Cause 1992;51:829-840.
[PMID: 1415225]
ferent sex and race groups (21), although Dyslipidemia). The physical examination 29. Vasan RS, van den Heuvel
some experts have recently called for should include measuring body mass
E. Differences in estimates
for 10-year risk of cardio-
race to be eliminated from the PCE (29). index (BMI) and blood pressure, examin- vascular disease in Black
versus White individuals
An electronic tool that calculates ASCVD ing peripheral pulses to assess for signs with identical risk factor
profiles using pooled
risk using the PCE is available (https:// of peripheral artery disease, and check- cohort equations: an in
silico cohort study. Lancet
tools.acc.org/ascvd-risk-estimator-plus/# ing carotids and other vessels for bruits. Digit Health. 2022;4:e55-
!/calculate/estimate). Some experts Clinicians should also assess for potential e63. [PMID: 34952676]
30. Selvarajah S, Kaur G,
believe that cardiovascular risk scores to signs of familial hyperlipidemias, includ- Haniff J, et al.
Comparison of the
predict CVD lack validation in popula- ing presence of corneal arcus in patients Framingham Risk Score,
SCORE and WHO/ISH car-
tions outside the United States (30); the younger than 45 years, xanthelasmas, diovascular risk prediction
models in an Asian popu-
ESC recommends use of an alternative and tendon xanthomas. Liver and thy- lation. Int J Cardiol.
risk estimation tool, SCORE2, which was roid examination may also identify 2014;176:211-218.
[PMID: 25070380]
developed based on community surveil- secondary causes of dyslipidemia. An 31. Curry SJ, Krist AH, Owens
DK, et al.; US Preventive
lance data from several European coun- enlarged or tender thyroid may indi- Services Task Force. Risk
assessment for cardiovas-
tries (5). In addition to the PCE, the 2018 cate existing thyroiditis, which should cular disease with nontra-
ditional risk factors: US
ACC/AHA guidelines recommend using prompt assessment for hypothyroid- Preventive Services Task
other ASCVD risk enhancers not incorpo- ism, and hepatomegaly could suggest Force recommendation
statement. JAMA.
rated in the PCE to adjust risk estimation underlying liver disease. Finally, when 2018;320:272-280.
[PMID: 29998297]
in patients with intermediate risk (5% to considering initiation of statin therapy, 32. U.S. Food and Drug
Administration. FDA Drug
7.5%, or 7.5% to 20% 10-year risk) based clinicians should perform and docu- Safety Communication:
Important safety label
on the PCE (see the Box: ASCVD Risk ment a comprehensive evaluation of changes to cholesterol-
Enhancers). Presence of any of those musculoskeletal symptoms because lowering statin drugs. 28
February 2012. Accessed
additional risk enhancers in persons these are common at baseline and can at www.fda.gov/drugs/
drug-safety-and-
aged 40 to 75 years with intermediate help identify persons at risk for statin- availability/fda-drug-
safety-communication-
ASCVD risk based on the PCE should associated muscle symptoms. important-safety-label-
changes-cholesterol-
lowering-statin-drugs on
7 April 2023.

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 found insufficient evidence to assess
Drugs That Can Cause the balance of benefits and harms of
Dyslipidemia
adding a calcium score to traditional
• Corticosteroids
• Androgenic steroids risk assessment in asymptomatic adults
33. Gencer B, Kronenberg F, • Progestogens for primary prevention (31). Although
Stroes ES, et al.
Lipoprotein(a): the reven-
• Thiazide diuretics routine monitoring of liver function dur-
ant. Eur Heart J. • b-Blockers
2017;38:1553-1560. • Retinoic acid derivatives ing statin therapy is no longer recom-
[PMID: 28329241] • Oral estrogens mended (2), the U.S. Food and Drug
34. Navarese EP,
Kolodziejczak M, Schulze
V, et al. Effects of propro-
Administration (FDA) suggests baseline
tein convertase subtilisin/ measurement of liver aminotransferase
kexin type 9 antibodies in
adults with hypercholes-
What test results should clinicians levels before statin initiation, both for
terolemia: a systematic
review and meta-analysis. obtain before starting therapy? future comparison and to identify per-
Ann Intern Med.
2015;163:40-51. [PMID: Before developing a treatment plan, sons at theoretical risk for drug-related
25915661]
the clinician should consider potential injury (32).
35. Tsimikas S, Karwatowska-
Prokopczuk E, Gouni-
Berthold I, et al.; AKCEA-
secondary causes of dyslipidemia. It is
APO(a)-LRx Study important to address secondary causes When should clinicians consider
Investigators. Lipoprotein
(a) reduction in persons before drug therapy is started because specialized lipid tests or referral to a
with cardiovascular dis- specialist?
ease. N Engl J Med. treatment of the secondary cause may
2020;382:244-255.
render lipid-lowering therapy unneces- Clinicians should consider an apolipo-
[PMID: 31893580]
36. Moyer VA; U.S. Preventive sary. If history and physical examination protein evaluation and referral to a
Services Task Force.
Screening for and man- findings suggest a secondary cause of lipid specialist if they suspect familial
agement of obesity in
dyslipidemia, appropriate laboratory test- hypercholesterolemia, which can lead
adults: U.S. Preventive
Services Task Force recom-
ing (such as thyroid function tests or kid- to premature ASCVD. An LDL-C level
mendation statement.
Ann Intern Med.
ney function tests) should be ordered to above 250 mg/dL (or >190 mg/dL in
2012;157:373-378.
persons with a first-degree relative with
[PMID: 22733087] diagnose it. If a drug is suspected to be
37. Estruch R, Ros E, Salas- similar levels) and/or a history of prema-
Salvadó J, et al.; the cause of the lipid abnormality, clini-
PREDIMED Study ture ASCVD should prompt consideration
Investigators. Primary pre- cians should consider the benefits versus
vention of cardiovascular of familial hypercholesterolemia and sub-
the risks before discontinuing therapy.
disease with a
Mediterranean diet sup- sequent screening of all first-degree fam-
plemented with extra-vir- The absolute benefit of beginning med- ily members. Similarly, triglyceride levels
gin olive oil or nuts. N
Engl J Med. 2018;378: ical therapy depends on the patient’s persistently above 500 mg/dL may also
e34. [PMID: 29897866]
38. de Lorgeril M, Salen P, CVD risk. Besides a baseline lipid panel, warrant evaluation for other familial
Martin JL, et al.
Mediterranean diet, tradi-
additional laboratory studies, including hyperlipidemias. Measurement of apoli-
tional risk factors, and the kidney function tests and measurement poprotein A-I and B levels and Lp(a) mea-
rate of cardiovascular
complications after myo- of Lp(a) and high-sensitivity C-reactive surement may help to provide a more
cardial infarction: final
report of the Lyon Diet protein, can help with risk stratification detailed characterization of the lipid disor-
Heart Study. Circulation.
1999;99:779-785. [PMID: at baseline (see the Box: ASCVD Risk der or serve as additional risk markers
9989963]
39. Dujovne CA, Ettinger MP,
Enhancers). In addition, the 2018 ACC/ for future atherothrombotic events (33).
McNeer JF, et al.; AHA guidelines recommend consider- Proprotein convertase subtilisin/kexin
Ezetimibe Study Group.
Efficacy and safety of a ing calcium scoring for persons at bor- type 9 (PCSK9) inhibitors are effective in
potent new selective cho-
lesterol absorption inhibi- derline to moderate risk in whom the decreasing Lp(a) levels but have not
tor, ezetimibe, in patients
with primary hypercholes-
decision to start treatment is uncertain. been studied for isolated Lp(a) elevation
terolemia. Am J Cardiol. A calcium score of zero may be an argu- (34). Antisense oligonucleotides against
2002;90:1092-1097.
[PMID: 12423709] ment against statin therapy in those apolipoprotein(a) are the subject of
40. Bailen Almorox R. [Effect
of a monoclonal antibody populations (2). In contrast, the USPSTF ongoing study (35).
to PCSK9 on LDL choles-
terol]. Rev Clin Esp.
2012;212:408-409.
[PMID: 22937541]
41. Stein EA, Mellis S,
Yancopoulos GD, et al.
Effect of a monoclonal
antibody to PCSK9 on LDL
cholesterol. N Engl J Med.
2012;366:1108-1118.
[PMID: 22435370]

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 Clinical Evaluation... Formal cardiovascular risk estimation is recommended as part of
routine screening for dyslipidemias, which includes assessment of traditional risk factors,
including age, sex, active smoking, hypertension, diabetes, total cholesterol level, and
HDL-C level. Further assessment of ASCVD risk enhancers and calcium score is helpful
in guiding treatment decisions for patients at intermediate risk according to traditional
risk factors. History and physical examination should focus on identifying cardiovascular
risk factors and potential secondary causes of dyslipidemia. Specialized testing and spe-
cialty referral may be useful when familial hypercholesterolemia is suspected. 42. Blom DJ, Hala T,
Bolognese M, et al.;
DESCARTES Investigators.
A 52-week placebo-con-
CLINICAL BOTTOM LINE trolled trial of evolocumab
in hyperlipidemia. N Engl
J Med. 2014;370:1809-
1819. [PMID: 24678979]
43. Ray KK, Bays HE,
Catapano AL, et al.; CLEAR
Harmony Trial. Safety and
Treatment efficacy of bempedoic
acid to reduce LDL choles-
What should clinicians advise patients exercise regularly to maintain a healthy terol. N Engl J Med.
2019;380:1022-1032.
with dyslipidemia about lifestyle body weight and reduce lipid levels, [PMID: 30865796]
44. Ray KK, Wright RS,
changes? regardless of whether they receive medi- Kallend D, et al.; ORION-
10 and ORION-11
All guideline organizations recommend cal therapy for dyslipidemia (36). Obesity Investigators. Two phase
that all persons follow a healthy lifestyle increases incidence of insulin resistance,
3 trials of inclisiran in
patients with elevated LDL
regardless of age or ASCVD risk. The diabetes, and hypertension and is associ- cholesterol. N Engl J
Med. 2020;382:1507-
2019 ACC/AHA guideline on primary 1519. [PMID: 32187462]
ated with increased circulating inflamma-
prevention emphasizes a diet rich in fruits, 45. Cannon CP, Blazing MA,

vegetables, legumes, nuts, whole grains, tory markers, thereby increasing risk for Giugliano RP, et al.;
IMPROVE-IT Investigators.
and fish; replacing saturated fats with multiple cardiovascular disorders, includ- Ezetimibe added to statin
therapy after acute coro-
monounsaturated (for example, olive oil ing ASCVD (4). Patients with a BMI of nary syndromes. N Engl J
Med. 2015;372:2387-
and canola oil) and polyunsaturated fats; 25 kg/m2 or higher should be encour- 2397. [PMID: 26039521]
46. Schwartz GG, Steg PG,
strictly avoiding trans fats; and reducing aged to reduce their caloric intake and Szarek M, et al.; ODYSSEY
intake of cholesterol, sodium, processed OUTCOMES Committees
lose weight. High-intensity (≥14 sessions and Investigators.
meats, refined carbohydrates, and sweet- in 6 months) comprehensive weight loss Alirocumab and cardiovas-
cular outcomes after acute
ened beverages (2). A diet low in red interventions provided by a trained inter- coronary syndrome. N
Engl J Med.
meat and animal fat seems to substan-
ventionist offer the best weight loss out- 2018;379:2097-2107.
tially reduce risk independent of se- [PMID: 30403574]
comes (4). All adults should perform at 47. Bhatt DL, Steg PG, Miller
rum lipid levels (36). M, et al.; REDUCE-IT
least 150 minutes of moderate-intensity Investigators.
Cardiovascular risk reduc-
The PREDIMED trial randomly assigned or 75 minutes of vigorous-intensity aero- tion with icosapent ethyl
7447 participants to a Mediterranean bic physical activity per week. Studies of for hypertriglyceridemia.
N Engl J Med.
diet with either extra virgin olive oil or weight loss with or without exercise sug- 2019;380:11-22. [PMID:
30415628]
nuts or a control diet (advice to reduce
gest that exercise can optimize lipid 48. Wiggins BS, Saseen JJ,
dietary fat). After a median follow-up of Page RL 2nd, et al.;

4.8 years, there were reductions of 31% levels (38). Although the AHA does American Heart
Association Clinical
and 28% in the olive oil and nuts groups, not make specific recommendations Pharmacology Committee
of the Council on Clinical
respectively, compared with the control on muscle-strengthening nonaerobic Cardiology; Council on
Hypertension; Council on
group in the primary end point of myo- exercise, the 2021 ESC guidelines on Quality of Care and
Outcomes Research; and
cardial infarction, stroke, or cardiovascu- primary prevention recommend resist- Council on Functional
lar mortality (37). ance exercise in addition to aerobic Genomics and
Translational Biology.

All patients with dyslipidemia should activity on 2 or more days per week to Recommendations for
management of clinically
quit smoking and control other comor- reduce all-cause mortality. significant drug-drug
interactions with statins
bid conditions that increase ASCVD and select agents used in
patients with cardiovascu-
risk, including diabetes and hyperten- When should clinicians recommend lar disease: a scientific
sion. Patients with dyslipidemia and a drug therapy? statement from the
American Heart
normal BMI (18.5 to 24.9 kg/m2) should Most guidelines, including the 2018 Association. Circulation.
2016;134:e468-e495.
be encouraged to eat healthily and ACC/AHA guidelines, emphasize adjusting [PMID: 27754879]

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Figure. When to initiate treatment for dyslipidemia.
Age 0–19 y: Statin
therapy only if
diagnosis of familial
hypercholesterolemia
ASCVD = atherosclerotic cardiovascular disease; CAC = coronary artery calcium; LDL-C = low-density lipoprotein cholesterol.
49. Newman CB, Preiss D,
Tobert JA, et al.; American
Heart Association Clinical
Lipidology, Lipoprotein,
Metabolism and
Thrombosis Committee, a
Joint Committee of the
Council on
Atherosclerosis,
Thrombosis and Vascular
Biology and Council on
Lifestyle and
Cardiometabolic Health;
Council on Cardiovascular
Disease in the Young;
Council on Clinical
Cardiology; and Stroke
Council. Statin safety and
associated adverse events:
a scientific statement
from the American Heart
Association. Arterioscler
Thromb Vasc Biol.
2019;39:e38-e81. [PMID:
30580575]
© 2023 American College of Physicians
LDL-C level >190 mg/dL: No risk
assessment; start high-intensity
statin therapy
Diabetes and age 40–75 y: Start
Assess ASCVD risk and moderate-intensity statin therapy
emphasize healthy lifestyle and perform risk assessment to
consider high-intensity statin therapy
Age >75 y: Clinical assessment, risk
discussion
Age 20–39 y: Consider Age 40–75 y and LDL-C
statin therapy if LDL-C level of 70–189 mg/dL:
level >160 mg/dL and Estimate 10-y ASCVD
family history of risk using Pooled Cohort
premature ASCVD Equations
Low risk (<5%): Emphasize lifestyle
Borderline risk (5%–7.5%): Moderate-intensity statin
therapy may be considered if ASCVD risk enhancers
are present
Intermediate risk (7.5%–20%): If ≥1 ASCVD risk
enhancer present, initiate moderate-intensity statin
therapy to reduce LDL-C level by 20%–49%;
if uncertain, consider obtaining CAC score
High risk (>20%): Initiate high-intensity statin
therapy to reduce LDL-C level by >50%
LDL-C treatment goals according to cardio- For persons aged 40 to 75 years with
vascular risk. an LDL-C level of 70 to 189 mg/dL, the
ACC/AHA recommends that clinicians
For some patient groups, the ACC/AHA calculate ASCVD risk to determine
recommends medication regardless of whether to start statin therapy. For
risk estimates (Figure). These patients persons at high risk (>20% 10-year
fall into 3 categories: those with definite ASCVD risk based on the PCE), high-
familial hypercholesterolemia independ- intensity statin therapy is recommended.
ent of LDL-C level and age group, those For persons at intermediate risk (>7.5%
with primary elevation of LDL-C level to but <20%), a risk discussion and shared
190 mg/dL or higher, and those aged decision making with the patient are
40 to 75 years with diabetes of either recommended. The discussion should
type. Lipid-lowering therapy (Table) should incorporate the presence of ASCVD risk
also be offered to all patients with enhancers; the patient’s lifestyle and
established ASCVD who need second- potential to intensify lifestyle interventions;
ary prevention. the potential for adverse events from
ITC8 In the Clinic Annals of Internal Medicine
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Table. Drug Treatments for Lipid Disorders
Class Mechanism of Action Drugs and Doses Benefits Adverse Effects Notes

Statins (HMG-CoA Partially inhibit HMG- Atorvastatin: 10–80 mg/d Safety and efficacy well Abnormal liver function test Choice of drug for elevated
reductases) CoA reductase (the Fluvastatin: 20–40 mg studied in many trials: results (relatively uncom- LDL-C based on efficacy
rate-limiting step of every night or 80 mg LDL-C–lowering ranges mon) and safety
cholesterol synthesis), XL every night from 22% to 63% Myositis/myalgias (use with Each statin is metabolized
which induces LDL re- Lovastatin: 10–40 mg depending on the drug fibrates increases risk) differently, allowing sub-
ceptor formation and with evening meal or Rosuvastatin should not be stitution if adverse effects
removal of LDL-C 10–60 mg XL every given with warfarin or occur
from the blood night gemfibrozil Sometimes used in combi-
Pravastatin: 10–80 mg at nation with bile acid
bedtime sequestrants to synergisti-
Rosuvastatin: 5–40 mg/d cally reduce LDL-C
Simvastatin: 5–80 mg If combined with a fibrate,
with evening meal monitor for aminotransfer-
Pitavastatin: 2–4 mg/d ase elevations
Do not use in pregnant or
nursing women
Contraindicated in active
liver disease
Bile acid sequestrants Interrupt bile acid Colestipol: 2 scoops 2 or Not absorbed Unpleasant taste/texture First-line drug to lower cho-
reabsorption requir- 3 times per day Long-term safety estab- Bloating lesterol in children and in
ing bile acid synthesis Colesevelam hydrochlor- lished Heartburn women with childbearing
from cholesterol ide: three 625-mg tab- LDL-C lowering of 10%– Constipation potential
lets 2 times per day 15% Drug interaction (decreased Second-line drug with sta-
(3.8 g total) by administrating drugs tins to synergistically
1 h before or 4 h after induce LDL-C receptors
meals) Do not use if triglyceride
Increase in triglyceride level levels >300 mg/dL or in
gastrointestinal motility
disorder
Fibrates Reduce VLDL synthesis Gemfibrozil: 600 mg Best drugs for reducing tri- Nausea Do not reliably reduce (and
and lipoprotein lipase 2 times per day glyceride levels (by Rash can increase) LDL-C level
Fenofibrate: 45–145 mg/d, ≥50% in many patients) Use with caution if renal Use cautiously with statins
depending on brand Increase HDL-C level by insufficiency or gallblad- due to the possibility of
15% der disease myositis/myalgia
Use with repaglinide may
cause severe hypoglycemia
Ezetimibe Selectively inhibits 10 mg once per day Reduces LDL-C level by Well tolerated, but contrain- Can use with statins for fur-
intestinal absorption 18%, triglyceride level by dicated in patients with ther reductions in LDL-C
of cholesterol and 8%, and apoB level by liver disease or elevated and triglyceride levels and
related phytosterols 16% liver enzyme levels to increase HDL-C level
Do not combine with resins,
fibrates, or cyclosporine
Niacin Largely unknown; 500–750 mg to 1–2 g Lowers LDL-C and triglyc- Flushing of the skin Extended-release prepara-
reduces hepatic pro- extended-release every eride levels by 10%–30% Nausea tions limit flushing and
duction of B-contain- night Most effective in increas- Glucose intolerance liver function test abnor-
ing lipoproteins ing HDL-C level (25%– Gout malities
Increases HDL-C level 35%) Liver function test abnor- Long-acting over-the-coun-
malities ter niacin preparations are
Elevated uric acid level not recommended
May increase homocysteine because they increase
level incidence of hepatotoxic-
ity
Primarily used for patients
with hypertriglyceridemia
Do not use in pregnant or
nursing women
Omega-3 fatty acids Polyunsaturated fatty Lovaza: 4 g/d Effective in controlling tri- Dyspepsia Can increase LDL-C level in
acids inhibit hepatic Omtryg: 4.8 g/d glyceride levels up to Nausea some patients with
triglyceride synthesis Vascazen: 4 g/d 45% May increase bleeding time increased triglyceride
and augment chylo- Epanova: 2–4 g/d Increases HDL-C level by Use cautiously in patients levels
micron triglyceride Vascepa (icosapent): 2 g 13% receiving anticoagulant
clearance secondary every 12 h with food Used as an adjunct to diet therapy
to increased activity when triglyceride level is
of lipoprotein lipase ≥500 mg/dL

Continued on following page

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 Table—Continued
Class
PCSK9 inhibitors
Microsomal triglyceride
transport protein
inhibitor
apoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; HMG-
CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; Lp(a) =
lipoprotein (a); PCSK9 = proprotein convertase subtilisin/kexin type 9; ULN = upper limit of normal; VLDL = very-low-density lipoprotein;
XL = extended release.
50. Finegold JA, Manisty CH,
Goldacre B, et al. What
proportion of sympto-
matic side effects in
patients taking statins are
genuinely caused by the
drug? Systematic review
of randomized placebo-
controlled trials to aid
individual patient choice.
Eur J Prev Cardiol.
2014;21:464-474. [PMID:
24623264]
51. McKenney JM, Davidson
MH, Jacobson TA, et al.;
National Lipid Association
Statin Safety Assessment
Task Force. Final conclu-
sions and recommenda-
tions of the National Lipid
Association Statin Safety
Assessment Task Force.
Am J Cardiol.
2006;97:89C-94C. [PMID:
16581336]
52. Landray MJ, Haynes R,
Hopewell JC, et al.; HPS2-
THRIVE Collaborative
Group. Effects of
extended-release niacin
with laropiprant in high-
risk patients. N Engl J
Med. 2014;371:203-212.
[PMID: 25014686]
53. U.S. Food and Drug
Administration. FDA
requests removal of
strongest warning against
using cholesterol-
lowering statins during
pregnancy; still advises
most pregnant patients
should stop taking statins.
20 July 2021. Accessed at
www.fda.gov/drugs/drug-
safety-and-availability/fda-
requests-removal-
strongest-warning-
against-using-cholesterol-
lowering-statins-during-
pregnancy on 7 April
2023.
© 2023 American College of Physicians
Mechanism of Action Drugs and Doses Benefits Adverse Effects Notes
Inhibit PCSK9, there- Evolocumab: 140 mg/mL Used as an adjunct to diet Mild or moderate hepatic Requires prior authorization
fore preventing lyso- subcutaneously every and maximally tolerated impairment Decreases Lp(a) levels by
somal destruction 2 wk statin therapy for treat- Mild or moderate renal about 20%, but not
and promoting cell Alirocumab: 75–150 mg/ ment of adults with het- impairment approved for this
membrane recycling mL subcutaneously erozygous familial Severe impairment has not indication
of LDL receptors every 2 wk hypercholesterolemia or been studied
clinical ASCVD, who
require additional lower-
ing of LDL-C level
– Lomitapide: 5–60 mg/d Indicated for use as an – Available only through re-
adjunct to other lipid- strictive-access programs
lowering agents and LDL due to potential risk for
apheresis to reduce LDL- hepatotoxicity
C level in persons with Administer with daily sup-
homozygous familial plements that contain vita-
hypercholesterolemia min E (400 IU), linoleic
acid (200 mg), and a-lino-
lenic acid (210 mg)
statin therapy and drug–drug interac- A meta-analysis of statin RCTs performed
tions; and, if the decision is still uncer- by the USPSTF showed that statin therapy
tain, obtaining a coronary artery calcium was associated with decreased risk for all-
score. If the discussion favors initiation cause mortality (18 trials; risk ratio, 0.92
of statin therapy, moderate-intensity ther- [95% CI, 0.87 to 0.98]), fatal or nonfatal
apy is recommended. For persons at bor- stroke (15 trials; risk ratio, 0.78 [CI, 0.68 to
derline risk (5% to 7.5%), a similar shared 0.90]), and fatal or nonfatal myocardial in-
decision-making discussion to start ther- farction (12 trials; risk ratio, 0.67 [CI, 0.60
apy may be considered, although to 0.75]) (9).
the benefit of treatment in that group
is less certain and this is a class IIb Other options may be available when
statins are not tolerated, in combina-
recommendation.
tion with statins when additional medi-
The USPSTF uses a similar approach of cation is needed, or to treat particular
tiered risk, although thresholds for dyslipidemia conditions (Table). For
treatment may vary slightly. The USPSTF example, ezetimibe decreases LDL-C
recommends moderate-intensity statin level by targeting the Niemann–Pick C1-
use for persons aged 40 to 75 years Like 1 protein; however, no RCT has
whose 10-year ASCVD risk, estimated evaluated whether it alone can decrease
by the PCE, is at least 10% and selective cardiovascular events (39), a finding also
statin use for those with 10-year ASCVD noted with PCSK9 inhibitors (40–42). Bile
risk of 7.5% to 10%.
acid sequestrants reduce LDL-C level by
What options are available for drug about 15% to 30%, but their use is lim-
therapy? ited by their gastrointestinal adverse
All guidelines agree that statins are the effects (for example, constipation) and
first-line therapy for dyslipidemia once the potential to cause severe hypertri-
a decision to start a cholesterol-lower- glyceridemia in people with a triglycer-
ing medication has been made. Statins ide level above 300 mg/dL. Lomitapide,
not only decrease LDL-C levels but also a microsomal triglyceride transfer pro-
decrease cardiovascular events in patients tein inhibitor, is an LDL-C–lowering medi-
with preexisting ASCVD and those at high cation that has been developed and
risk for ASCVD. studied in persons with homozygous
ITC10 In the Clinic Annals of Internal Medicine
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familial hypercholesterolemia. Finally,
although newer FDA-approved medica-
tions have shown significant effects in
LDL-C lowering, including bempedoic
acid (an ATP citrate lyase inhibitor) (43)
and inclisiran (a small interfering ribonu-
cleic acid against PCSK9) (44), none
have been shown to decrease cardiovas-
cular events.
For triglyceride lowering, the 2018 ACC/
AHA guidelines recommend addressing
reversible causes of high triglyceride lev-
els, including obesity, diabetes, chronic
liver or kidney disease, nephrotic syn-
drome, hypothyroidism, and medications.
If severe hypertriglyceridemia (fasting
triglyceride level >500 mg/dL) persists,
specific triglyceride-lowering therapy
with omega-3 fatty acids, niacin, or
fibrate therapy is reasonable (2).
What are the therapeutic goals of
treatment?
The primary goal of therapy is to
decrease risk for cardiovascular events.
The relationship between dyslipidemia
and ASCVD may be mediated in part
through inflammation, which is a known
risk factor for ASCVD. Because statins
also have potent anti-inflammatory effects
beyond their lipid-lowering effects, the
2013 ACC/AHA guidelines advocated for
fixed-dose (low- vs. moderate- vs. high-in-
tensity) statin therapy based on individual
risk rather than to target LDL-C levels (21).
However, in 2018, the ACC/AHA guide-
lines went back to recommending tar-
get LDL-C reductions in addition to
fixed-dose statin therapy. The ACC/
AHA set a goal of an LDL-C reduction
of at least 50% for patients at high risk
for ASCVD and at least 30% for patients
at intermediate risk (2). The 2018 re-
vised guidelines also set numerical LDL-
C goals for patients with clinical ASCVD
(LDL-C reduction ≥50% and LDL-C level
<70 mg/dL) and those with severe
hypercholesterolemia, defined as an
LDL-C level above 190 mg/dL (LDL-C
reduction of ≥50% and LDL-C level
Annals of Internal Medicine
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<100 mg/dL). The ESC guidelines rec-
ommend an even stricter goal of an
LDL-C level below 55 mg/dL for patients
with clinical ASCVD or those at very
high risk for ASCVD (10-year ASCVD
risk ≥10% based on the SCORE calcula-
tor or history of ASCVD or severe chronic
kidney disease or diabetes with target
organ damage) and recommend con-
sidering an LDL-C level below 40 mg/dL
in patients with a second ASCVD event
within 2 years despite maximally tolerated
statin therapy (3).
When is combination drug therapy
warranted?
The 2018 ACC/AHA guidelines recom-
mend adding other cholesterol-lowering
medications when guideline-recom-
mended LDL-C goals are not achieved
despite recommended fixed-dose statin
therapy (2). Ezetimibe and potentially
PCSK9 inhibitors may be added in
persons with either clinical ASCVD or
severe hypercholesterolemia (LDL-C
level >190 mg/dL) who are unable to
achieve the recommended LDL-C tar-
get (<70 mg/dL for clinical ASCVD
and <100 mg/dL for severe hypercho-
lesterolemia) with high-dose statins
alone.
IMPROVE-IT recruited 18 144 patients
who were hospitalized for an acute cor-
onary syndrome and had an LDL-C
level below 125 mg/dL. Adding ezeti-
mibe to existing statin therapy resulted
in a small improvement in a combined
cardiovascular end point (hazard ratio,
0.93 [CI, 0.89 to 0.99]) (45). The FOURIER
trial and the ODYSSEY OUTCOMES trial
showed that adding a PCSK9 inhibitor to 54. Goldberg AC, Hopkins
PN, Toth PP, et al.;
existing moderate- or high-dose statin National Lipid Association
therapy improved a combined cardio- Expert Panel on Familial
Hypercholesterolemia.
vascular outcome (hazard ratios, 0.85 Familial hypercholestero-
lemia: screening, diagno-
[CI, 0.79 to 0.92] and 0.85 [CI, 0.78 to sis and management of
pediatric and adult
0.93], respectively) (18, 46). patients: clinical guidance
from the National Lipid
Despite inconsistency among study Association Expert Panel
on Familial
findings and the lack of guideline rec- Hypercholesterolemia. J
Clin Lipidol. 2011;5:S1-8.
ommendations to add icosapent ethyl [PMID: 21600525]
In the Clinic ITC11 © 2023 American College of Physicians

Medications That Interact With Statins
• Amiodarone
• Amlodipine
• Conivaptan
• Colchicine
• Cyclosporine/tacrolimus/
everolimus/sirolimus
• Digoxin
• Diltiazem
• Dronedarone
• Fenofibrate
• Gemfibrozil
• Ranolazine
• Ticagrelor
• Verapamil
• Warfarin
(an omega-3 fatty acid) to statins for
patients with ASCVD or diabetes and
elevated triglyceride levels, the FDA has
approved an indication for icosapent
ethyl for persons who meet the REDUCE-
IT enrollment criteria. The REDUCE-IT trial
enrolled patients with a history of ASCVD
or diabetes and other risk factors and ele-
vated triglyceride levels (135 to 499 mg/
dL) who were taking statin therapy (47).
Although it found reduced risk for future
ASCVD events with the addition of icosa-
pent ethyl compared with placebo, the
study has been criticized for its use of
mineral oil placebo (3). In contrast, the
STRENGTH trial, which compared high-
dose combination omega-3 fatty acids
versus corn oil, showed no benefit in
ASCVD event reduction (3).
When prescribing combination ther-
apy, clinicians need to be vigilant for
drug interactions. Fibrates should be
used with caution when combined with
statins, particularly gemfibrozil, because
they compete with the statin for metab-
olism via the cytochrome P450 system.
This interaction can cause or exacerbate
myalgia and may in rare cases induce
rhabdomyolysis. Several other medica-
tions are known to interact with statins
(see the Box: Medications That Interact
With Statins). Clinicians should refer to
the 2016 AHA scientific statement on
statin interactions for detailed guidance
on how to address interactions with spe-
cific agents (48).
© 2023 American College of Physicians ITC12 In the Clinic
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How should therapy be monitored?
Most dyslipidemia interventions require
at least 6 months to reduce risk for CVD
events, and treatment is usually lifelong.
Regular follow-up is important and
should include a lipid profile 4 to 12
weeks after initiation of any new lipid-
lowering agent (2). During all follow-up
visits, the clinician should discuss adher-
ence, identify adverse effects, and en-
courage lifestyle changes. Statin-
induced hepatotoxicity seems to be
much less common than previously
believed. According to a recent AHA
systematic review, about 1% of patients
develop an asymptomatic dose-related
increase in aminotransferase levels to
more than 3 times the upper limit of
normal (ULN), but only 0.001% develop
clinically apparent hepatotoxicity, and
monitoring of aminotransferase levels is
not useful for preventing hepatotoxicity
(49), so the ACC/AHA guideline on
treatment of dyslipidemia does not
recommend monitoring liver function
test results in patients treated with sta-
tins (2). In 2012, the FDA concluded that
serious liver injury with statins is rare
and unpredictable and therefore stated
that routine periodic measurement of liver
enzymes does not seem to be effective in
detecting or preventing liver dysfunction.
However, when statin therapy is begun,
liver function (aminotransferase levels)
should be measured at baseline for inter-
pretation of future test results. Risk for
serious liver injury is small with moder-
ate-dose statins, but patients with amino-
transferase levels greater than 3 times
the ULN should be reevaluated for
whether the benefits of continuing statin
therapy outweigh the harms of discontin-
uing treatment or whether treatment can
be adjusted (50, 51).
What are adverse effects of drug
therapy?
The most common adverse effects of sta-
tins are myalgias; however, the frequency
of serious events is low. The incidence
Annals of Internal Medicine
of myopathy, defined as unexplained
muscle pain or weakness accompanied
by creatine kinase elevations more than
10 times the ULN (including rhabdomyol-
ysis) due to statins, is 1 case per 10 000
patients per year at maximal recom-
mended doses (51). An additional
known adverse effect of statins is that
they modestly increase risk for new-
onset diabetes via mechanisms that are
not understood. The hazard ratio is
approximately 1.1 for moderate-inten-
sity statin therapy and 1.2 for high-inten-
sity therapy at 5 years and is largely
confined to patients with many preexist-
ing risk factors for diabetes. It is impor-
tant to note that statins are known to
decrease ASCVD in patients with and
without diabetes and therefore the
increase in diabetes risk should not pre-
vent clinicians from prescribing statins in
patients deemed to have an indication for
them.
The intestinal cholesterol absorption–
blocking drugs and the bile acid–bind-
ing resins tend to cause abdominal
bloating and constipation but are other-
wise generally well tolerated. The pri-
mary adverse effect of PCSK9 inhibitors
is injection site reaction. Fibrates can
cause nausea and rash and must be
used cautiously with statins because the
combination tends to increase the inci-
dence of myalgia, myopathy, and rhab-
domyolysis. Niacin, which is still pres-
cribed by some clinicians even though it
is not recommended for routine treat-
ment of dyslipidemia, is the least well-
tolerated lipid-lowering agent. It can
cause flushing, nausea, headache, glu-
cose intolerance, and gout. Furthermore,
the HPS2-THRIVE trial revealed rare but
serious adverse effects of niacin (gastroin-
testinal events, musculoskeletal events,
skin events, infection, and bleeding) (52).
Some of these can be minimized with
proper drug administration. To minimize
flushing, a non–enteric-coated aspirin can
be taken 1 hour before the evening dose
along with a low-fat snack.
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In the JUPITER RCT of nearly 18 000
patients (16), 16% of patients receiv-
ing high-intensity statin therapy (rosu-
vastatin, 20 mg/d) developed muscle
pain compared with 15.4% of patients
receiving placebo (P = 0.34); 2.4% of
patients receiving statins versus 2.1%
receiving placebo developed a hepatic
disorder, defined as an elevation in ala-
nine aminotransferase level to more than
3 times the ULN (P = 0.13); and 3% in the
statin group versus 2.4% in the placebo
group developed new-onset diabetes
(P = 0.01).
Clinicians should be vigilant for adverse
effects when prescribing drugs for dys-
lipidemia. Because metabolism of the
various statins differs, it may be reasona-
ble to substitute one statin for another if
adverse effects occur, as recommended
in the AHA scientific statement on
adverse effects of statins (49).
When should clinicians consult a lipid
specialist?
Clinicians should consider consulting a
lipid specialist for patients with rare or
treatment-resistant lipid disorders.
Patients in this category may include
those with familial hypercholestero-
lemia, type 3 hyperlipoproteinemia,
very-low-HDL-C syndromes (HDL-C level
<20 mg/dL), and resistant hypertri-
glyceridemia (triglyceride level >1000
mg/dL). Also, patients at high risk for a
vascular event, such as those with vascular
disease before age 45 years and those
with evidence of disease progression de-
spite treatment, are candidates for referral
to a lipid specialist. If lipid levels do not
decrease as expected with statins, ad-
herence issues and lifestyle modifica-
tions should be addressed and referral
to a lipid specialist should be consid-
ered (2). Also, persons with a history of
transplant of any organ and rare syn-
dromes, such as sitosterolemia, should
be referred to a lipid specialist.
In the Clinic ITC13 © 2023 American College of Physicians
 Are there special considerations for
pregnant patients?
Treating dyslipidemias during preg-
nancy is challenging because most lipid-
lowering medications have not been suffi-
ciently tested in this population to deter-
mine the risk for unwanted effects for
the fetus. Statins were contraindicated
in pregnancy until recently. In 2021,
after reviewing additional data from
human studies, the FDA found that exist-
ing data do not support a drug-associ-
ated risk for major birth defects after
adjustment for confounders. As a result,
the FDA removed the contraindication
for statins in pregnancy but continues
to advise against statin therapy in
most pregnant women and recom-
mends against statins during breast-
feeding (53). Most other cholesterol-
lowering therapies either have been
associated with teratogenicity or have
not been sufficiently tested during preg-
nancy and are therefore not indicated in
pregnant women. The only exception is
bile acid sequestrants, which are not
systemically absorbed and thus are
believed to pose no risk (54).

Treatment... Treatment of dyslipidemia should always include modification of diet and

exercise to optimize lipid levels, smoking cessation, blood pressure control, and diabe-
tes control. Clinicians should base drug therapy decisions on the individual patient’s risk
for cardiovascular events. Statins are the first-line treatment for dyslipidemia. The most
recent ACC/AHA guidelines recommend LDL-C targets of less than 70 mg/dL during
treatment for secondary prevention, and combination therapy may be needed to
achieve those targets.

CLINICAL BOTTOM LINE

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In the Clinic Patient Information

Tool Kit
https://medlineplus.gov/cholesterol.html
https://medlineplus.gov/languages/
cholesterol.html
Information and handouts on cholesterol
management in English and other languages
from the National Institutes of Health’s
MedlinePlus.
Dyslipidemia
www.nhlbi.nih.gov/health/high-blood-
triglycerides
Information on high blood triglyceride levels
from the National Heart, Lung, and Blood
Institute.
www.lipid.org/patient-tear-sheets
Information and tear sheets on dyslipidemia
and other lipid disorders from the National
Lipid Association.
www.cdc.gov/cholesterol/materials_for_
patients.htm
Patient education resources on cholesterol
from the Centers for Disease Control and
Prevention.
Information for Health Professionals
www.ahajournals.org/doi/10.1161/
CIR.0000000000000625
2018 guideline on the management of blood
cholesterol from the American Heart

In the Clinic
Association, American College of Cardiology,
American Association of Cardiovascular and
Pulmonary Rehabilitation, American
Academy of Physician Associates,
Association of Black Cardiologists, American
College of Preventive Medicine, American
Diabetes Association, American Geriatrics
Society, American Pharmacists Association,
American Society for Preventive Cardiology,
National Lipid Association, and Preventive
Cardiovascular Nurses Association.
https://academic.oup.com/eurheartj/article/
41/1/111/5556353
2019 guidelines for management of dyslipide-
mia from the European Society of Cardiology
and the European Atherosclerosis Society.
www.ahajournals.org/doi/10.1161/
CIR.0000000000000677
2019 guideline on primary prevention of cardio-
vascular disease from the American College of
Cardiology and the American Heart Association.
https://academic.oup.com/eurheartj/article/
42/34/3227/6358713
2021 guidelines on cardiovascular disease pre-
vention in clinical practice from the
European Society of Cardiology.

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 In the Clinic
WHAT YOU SHOULD KNOW Annals of Internal Medicine
ABOUT DYSLIPIDEMIA
What Is Dyslipidemia?
• Lipids are fatty substances in your blood. These
substances are called cholesterol and triglycer-
ides. 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 cause inflammation or build up and clog the
blood vessels in your heart. This can cause heart
attack, stroke, and other diseases.

What Are the Risk Factors for

Dyslipidemia?
You may be at higher risk for dyslipidemia or heart
disease if you:
• Are older
• Have a family history of dyslipidemia
• Smoke
• Eat an unhealthy diet
• Do not exercise
• Have high blood pressure, obesity, diabetes, kid-
ney disease, or thyroid disease
How Is Dyslipidemia Diagnosed?
• Your doctor will ask you questions about your
current health and health history.
• You may also get a physical examination.
• Your health care provider will give you a blood
Sometimes lifestyle changes aren't enough.
Several medicines are available that help lower
the fat levels in your blood. Many people are
prescribed medications called statins. You and
your doctor should work together to decide
what medicine is right for you.
Should I Be Screened for
Dyslipidemia?
• In general, people between the ages of 40 and
75 years should be screened regularly.
• If your levels are high, your doctor might suggest
screening more often.
• You may be screened at a younger age if you
have certain risk factors or a family history of dys-

Patient Information
test to check fat levels in your blood. lipidemia.

How Is Dyslipidemia Treated? Questions for My Doctor

Your doctor will work with you to create a plan for
your treatment. One part of your treatment will
include making healthy changes, such as:
• Eating a heart-healthy diet that is low in fat and
cholesterol
• Getting regular exercise
• Quitting smoking
• Losing weight if needed
• Do I need to be screened for dyslipidemia?
• What is the healthiest diet for me to eat?
• Are there foods that I should not eat?
• What is the best form of exercise for me?
• What is the best medicine for me?
• Does the medicine have side effects?
• Will this medicine interact with my other medicines?

For More Information

National Heart, Lung, and Blood Institute
www.nhlbi.nih.gov/resources/heart-smart-basics-what-know-keep-
yours-healthy
MedlinePlus
https://medlineplus.gov/ency/article/000403.htm

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Appendix Table. Dyslipidemia Screening Guideline Recommendations
Question American College of Cardiology/
American Heart Association
When Class I recommendation for
screening of persons aged 40–
75 y
Class IIa recommendation for
screening of persons aged 20–
39 y
How often Every 4–6 y
Fasting or nonfasting Either, but a repeated fasting
lipid profile should be obtained
if nonfasting triglyceride level
exceeds 400 mg/dL
What lipids to measure Routine lipid profile is recom-
mended for screening
Relative indication to measure
apoB in persons with hypertri-
glyceridemia
Relative indication to measure
Lp(a) in persons with family
history of premature ASCVD
apoB = apolipoprotein B; ASCVD = atherosclerotic cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density
lipoprotein cholesterol; Lp(a) = lipoprotein (a).
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European Society of Cardiology
Lipid screening should be con-
sidered for men aged >40 y
and women aged >50 y or post-
menopausal women
No recommendation for other
age groups
No recommendation
Either, but caution is recom-
mended in interpretation of
LDL-C levels in nonfasting lipid
profiles in persons with diabe-
tes, metabolic syndrome, or
hypertriglyceridemia
Class I indication to measure rou-
tine lipid profile
Class I indication to measure
apoB, particularly in persons
with hypertriglyceridemia, dia-
betes, metabolic syndrome, or
very low LDL-C levels
Class IIa indication to measure
Lp(a) at least once in each
adult’s lifetime
In the Clinic
U.S. Preventive Services Task Force
Screening recommended for all
persons aged 40–75 y
No recommendation for other
age groups
Reasonable to measure lipids
every 5 y
Either
2022 guideline recommends
estimating individual risk using
the pooled cohort equation,
which requires measurement of
total cholesterol and HDL-C lev-
els
A direct recommendation for lip-
ids to be tested is not provided
in this guideline
© 2023 American College of Physicians