Hyperlipidemia: Drugs for Cardiovascular

Risk Reduction in Adults

ALLEN R. LAST, MD, MPH, Medical College of Wisconsin Fox Valley Family Medicine Residency Program, Appleton, Wisconsin
JONATHAN D. FERENCE, PharmD, Wilkes University Nesbitt School of Pharmacy, Wilkes-Barre, Pennsylvania
ELIZABETH ROLLMANN MENZEL, MD, Medical College of Wisconsin Fox Valley Family Medicine Residency Program,
Appleton, Wisconsin
Suscríbete
Guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) and the U.K.
National Institute for Health and Care Excellence (NICE) indicate that lipid-lowering drugs have benefit for pri-
mary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD) events. The evidence is stron-
gest for statins. ACC/AHA, NICE, and U.S. Preventive Services Task Force (USPSTF) guidelines recommend statin
therapy based on patients’ risk of an ASCVD event, rather than treating to specific lipid levels. For patients with no
previous ASCVD event, risk calculators should be used to determine the 10-year risk of ASCVD. The ACC/AHA
guideline recommends starting moderate- to high-intensity statins if the risk is 7.5% or greater, whereas the NICE
and USPSTF guidelines recommend statins if the risk is 10% or greater. Patients with known ASCVD should receive
high-intensity statins unless they fall into special categories (e.g., older age) or do not tolerate high-intensity statins,
in which case moderate-intensity statins are appropriate. Liver transaminase levels should be checked before starting
statins; guidelines vary on if and when to recheck them in the absence of symptoms. Lipid levels should be rechecked
one to three months after starting statins, although guidelines differ on subsequent checks. Other lipid-lowering
drugs (e.g., bile acid sequestrants, ezetimibe) can be considered if patients do not tolerate statins. Niacin should not
be used. Some evidence supports adding ezetimibe to statin therapy in patients with acute coronary syndrome or
chronic kidney disease. The role of proprotein convertase subtilisin/kexin type 9 inhibitors is unclear, but initial
studies suggest a decrease in the rate of acute ASCVD events in patients with hypercholesterolemia. (Am Fam Physi-
cian. 2017;95(2):78-87. Copyright © 2017 American Academy of Family Physicians.)

T
More online he American College of Cardi- lipoprotein cholesterol levels because studies
at http://www. ology (ACC) and the American to date have focused on treatment intensity
aafp.org/afp.
Heart Association (AHA) jointly rather than cholesterol levels (Table 1).1-4 As a
See related editorial on
▲

issued a new guideline in 2013 on result of this shift, the ACC/AHA and NICE
page 66 and related U.S.
Preventive Services Task
the treatment of blood cholesterol to reduce guidelines recommend a different inten-
Force recommendation atherosclerotic cardiovascular risk in adults.1 sity of statin therapy based on ASCVD risk
statement at http://www. This guideline presented significant changes (Table 2).1 The USPSTF recommends using
aafp.org/afp/2017/0115/ to previous recommendations on the man- low- to moderate-intensity statins only in
od1.html.
agement of hyperlipidemia for primary and patients with a combination of at least one
CME This clinical content
secondary prevention of atherosclerotic ASCVD risk factor and a 10-year ASCVD
conforms to AAFP criteria
for continuing medical
cardiovascular disease (ASCVD), which risk of at least 10%.3 The NICE guideline also
education (CME). See includes acute coronary syndrome, stable or uses a 10-year ASCVD risk of 10% or greater
CME Quiz Questions on unstable angina, coronary or other arterial as the trigger for statin therapy, whereas
page 75. revascularization, stroke, transient ischemic the ACC/AHA guideline recommends a
Author disclosure: No rel- attack, and peripheral arterial disease pre- threshold of 7.5% or greater (Table 1).1-4 The
evant financial affiliations. sumed to be of atherosclerotic origin. ACC/AHA also recommends that patients
Recommendations and guidelines from the with a 10-year risk between 5.0% and 7.5%
ACC/AHA, U.K. National Institute for Health be considered for statin therapy. Recommen-
and Care Excellence (NICE), and U.S. Pre- dations for statin initiation based on these
ventive Services Task Force (USPSTF) have guidelines are shown in Figure 1.1-3
eliminated goals for low-density lipoprotein Although the ACC/AHA and NICE guide-
cholesterol (LDL-C) and non–high-density lines do not recommend treating to lipid

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 Suscríbete
Hyperlipidemia
Table 1. Key Recommendations for the Management of Lipid Levels and Cardiac Risk

Indicator ACC/AHA 2013 guideline 1 NICE 2014 guideline 2 USPSTF 2016 recommendation3

Risk calculator Use Pooled Cohort Use QRISK2 because it includes Use Pooled Cohort Equations*
Equations* (http://www. kidney function as part of its
cvriskcalculator.com) calculation4 (http://www.qrisk.org)
Threshold for Initiate therapy if patient has Initiate therapy if patient has Initiate therapy if one or more ASCVD risk
initiating statin 10-year ASCVD risk ≥ 7.5% 10-year ASCVD risk ≥ 10% factors† and 10-year ASCVD risk ≥ 10%
therapy Consider therapy if patient Consider therapy if one or more ASCVD
has 10-year ASCVD risk 5% risk factors† and 10-year ASCVD risk
to 7.5% < 10%
Patients with clinical If 75 years or younger, use Atorvastatin (Lipitor), 80 mg No recommendation
ASCVD high-intensity statin
If older than 75 years, use
moderate-intensity statin
Patients with If 40 to 75 years of age with Atorvastatin, 20 mg, in patients with: If 40 to 75 years of age with:
diabetes mellitus diabetes and LDL-C of 70 Type 1 diabetes and age older No history of CVD, one or more
to 189 mg per dL (1.81 to than 40 years ASCVD risk factors† (e.g., diabetes),
4.90 mmol per L), use a and 10-year ASCVD risk ≥ 10%,
Type 1 diabetes for > 10 years
moderate-intensity statin initiate low- to moderate-intensity
(unless 10-year ASCVD risk Nephropathy or other ASCVD risk
statin
≥ 7.5%, in which case use a factors
No history of CVD, one or more
high-intensity statin) Type 2 diabetes and 10-year
ASCVD risk factors,† and 10-year
ASCVD risk ≥ 10%
ASCVD risk < 10%, consider low- to
moderate-intensity statin
Patients with chronic No specific recommendation Atorvastatin, 20 mg No recommendation
kidney disease
stage 3b or worse
Patients without Moderate-intensity statin if Atorvastatin, 20 mg, if 10-year If 40 to 75 years of age with:
diabetes or 40 to 75 years of age and ASCVD risk ≥ 10% No history of CVD, one or more
chronic kidney LDL-C is 70 to 189 mg per ASCVD risk factors,† and 10-year
disease dL and 10-year ASCVD risk ASCVD risk ≥ 10%, initiate low- to
≥ 7.5% moderate-intensity statin
No history of CVD, one or more
ASCVD risk factors,† and 10-year
ASCVD risk < 10%, consider low- to
moderate-intensity statin
Patients with LDL-C High-intensity statin No specific recommendation No recommendation
≥ 190 mg per dL
(4.92 mmol per L)
Patients older than No specific recommendation Consider atorvastatin, 20 mg Insufficient evidence for primary
85 years prevention recommendation in
patients 76 years and older
Liver enzyme testing Measure at baseline; after Measure at baseline, within three No recommendation
with alanine that, measure only if months of starting statin, and at
transaminase clinically indicated† 12 months; after that, measure
only if clinically indicated‡
Follow-up lipid Measure lipid panel at baseline, Measure lipid panel at baseline and No recommendation
testing after four to 12 weeks to non–HDL-C after three months; if
discuss adherence and < 40% decrease in non–HDL-C,
lifestyle changes, and then at consider titrating therapy; consider
three- to 12-month intervals annual non–HDL-C testing

ACC/AHA = American College of Cardiology/American Heart Association; ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular
disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; NICE = National Institute for Health and Care
Excellence; USPSTF = U.S. Preventive Services Task Force.
*—The Pooled Cohort Equations risk calculator was developed using data from black and non-Hispanic white patients. The calculator may under-
estimate the risk for patients from certain racial or ethnic groups, including Native Americans, some Asian Americans (e.g., of south Asian descent),
and some Hispanics (e.g., Puerto Ricans), and may overestimate risk for others, such as some Asian Americans (e.g., east Asian descent) and some
Hispanics (e.g., Mexican Americans). In spite of these shortcomings, the ACC/AHA still recommends using the Pooled Cohort Equations for all patients
regardless of ethnicity because it is more reliable than other risk calculators.
†—ASCVD risk factors include dyslipidemia (LDL-C > 130 mg per dL [3.37 mmol per L] or HDL-C < 40 mg per dL [1.04 mmol per L]), diabetes, hyper-
tension, or smoking.
‡—Indications include unusual fatigue or weakness, loss of appetite, abdominal pain, dark colored urine, or yellowing of the skin or sclera.
Information from references 1 through 4.
 Suscríbete
Hyperlipidemia
WHAT IS NEW ON THIS TOPIC: HYPERLIPIDEMIA

A Cochrane review found that for every 1,000 persons treated with a statin for
five years, 18 avoid myocardial infarction, angina, or stroke (number needed
to treat = 56). This review focused on studies that included fewer than 10%
goals, the ACC/AHA guideline recommends of participants with known cardiovascular disease.
checking lipid levels four to 12 weeks after A meta-analysis of 13 trials involving more than 90,000 patients found that
initiation of statins to determine a patient’s statin use increases the overall absolute risk of developing diabetes mellitus
by 0.39% (number needed to harm = 255) over four years.
adherence and every three to 12 months
In early 2016, the U.S. Food and Drug Administration withdrew approvals
thereafter as clinically indicated. The NICE for extended-release niacin and delayed-release fenofibric acid (fibrate) in
guideline recommends checking lipid levels combination with statins based on lack of cardiovascular benefit.
three months after starting statins, but not
routinely after that. Liver transaminase lev-
els should be checked before starting statins. However, mentions a 0.1% risk of diabetes and some studies have
guidelines vary on if and when to recheck them in the found higher rates associated with statin use, a 2010
absence of symptoms. Both guidelines emphasize that meta-analysis of 13 trials involving 91,140 patients found
shared decision making is essential to any treatment plan an overall absolute risk of diabetes of 0.39% (number
(Figure 2).1,2,5 needed to harm = 255) over four years.12

Risk Calculators AAFP Endorsement

After reviewing validated risk-prediction tools, the ACC/ The American Academy of Family Physicians (AAFP)
AHA panel determined that none was sufficiently accu- endorses the ACC/AHA guideline with qualifications13:
rate for calculating the 10-year risk of an ASCVD event The Pooled Cohort Equations risk calculator has not been
and subsequently developed the new Pooled Cohort validated and may overestimate risk. Using a cutoff of
Equations risk calculator that is available at http://www. 7.5% for the 10-year risk of an ASCVD event rather than
cvriskcalculator.com. Concerns have been raised that the 10% significantly increases the number of individuals
new calculator may overestimate risk by as much as 75% taking statins. Many of the ACC/AHA recommendations
to 150%,6 but it is nonetheless more accurate for deter- were based on expert opinion, and several members on
mining risk than the previously recommended Fram- the guideline panel had conflicts of interest. The AAFP
ingham risk calculator.7,8 The NICE guideline, however, has not commented on the NICE or USPSTF guidelines.
recommends using the QRISK2 calculator,
which is available at http://www.qrisk.org/.4
Clinicians should use the Pooled Cohort Table 2. High-, Moderate-, and Low-Intensity Statin
Equations risk calculator, the QRISK2 cal- Therapy Recommended by the ACC/AHA Guideline
culator, or both to determine a patient’s risk.
High-intensity statin Moderate-intensity statin Low-intensity
Questions About the Guideline therapy* therapy* statin therapy*
Questions about the ACC/AHA guideline
Atorvastatin (Lipitor), Atorvastatin, 10 mg Lovastatin, 20 mg
have focused on bias in the development. 40 to 80 mg Fluvastatin, 40 mg twice daily Pravastatin, 10 to
Nearly every panelist for the 2004 ACC/ Rosuvastatin Lovastatin, 40 mg 20 mg
AHA guidelines, developed in collaboration (Crestor), 20 mg
Pravastatin (Pravachol), 40 mg
with the National Heart, Lung, and Blood Rosuvastatin, 10 mg
Institute,9 had industry ties. The ACC/AHA Simvastatin (Zocor), 20 to 40 mg
committee made efforts to exclude industry
influence for the 2013 guideline, but seven of NOTE: See Figure 1 to determine which patients are candidates for low-, medium-, or
high-intensity statins.
the 15 panelists still had ties to industry.10
Additionally, there is concern that current ACC/AHA = American College of Cardiology/American Heart Association.

guidelines underestimate the risks associ- *—Dosages used in randomized controlled trials reviewed by the expert panel that
created the guideline. Alternative dosages are sometimes used in clinical practice, but
ated with statins. Major risks from statin they have not been evaluated in clinical trials and are not specifically recommended
use include myopathy (incidence of 0.5 per in the ACC/AHA guideline.
1,000 more than in the general population Adapted from Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline
over five years) and rhabdomyolysis (inci- on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in
adults: a report of the American College of Cardiology/American Heart Association
dence of 0.1 per 1,000 more than in the gen- Task Force on Practice Guidelines [published corrections appear in J Am Coll Cardiol.
eral population over five years).11 There is 2015;66(24):2812, and J Am Coll Cardiol. 2014;63(25 pt B):3024-3025]. J Am Coll Car-
also a small increase in the risk of diabetes diol. 2014;63(25 pt B):2902.
mellitus. Although the ACC/AHA guideline

80  American Family Physician www.aafp.org/afp Volume 95, Number 2 ◆ January 15, 2017
 Suscríbete
Hyperlipidemia
Initiating Statin Therapy
Recommend heart-healthy lifestyle to prevent ASCVD

Clinical ASCVD?

Yes No

LDL-C ≥ 190 mg per dL (4.92 mmol per L)?

Yes No

High-intensity statin (moderate intensity Diabetes mellitus?

if not a candidate for high intensity
[e.g., age > 75 years, intolerance])

Yes No

Age 40 to 75 years and LDL-C 70 to Age 40 to 75 years and LDL-C

189 mg per dL (1.81 to 4.90 mmol per L)? 70 to 189 mg per dL?

Yes No Yes No

Use Pooled Cohort Equations Age < 40 years or Primary prevention Age < 40 years or > 75 years
or QRISK2 to estimate > 75 years or LDL-C Estimate 10-year ASCVD and LDL-C < 190 mg per dL
10-year ASCVD risk < 70 mg per dL risk with Pooled Cohort
Equations or QRISK2
Go to A
10-year ASCVD risk ≥ 10%?*

< 5% 10-year 5% to < 10% ≥ 10% 10-year

Yes No
ASCVD risk 10-year ASCVD risk*
Recommend moderate- Consider low- ASCVD risk*
or high-intensity statin† or moderate-
(moderate intensity if intensity statin† A Consider additional factors
not a candidate for high (e.g., family history, LDL-C Consider low- or Recommend
intensity [e.g., age > 75 ≥ 160 mg per dL [4.14 mmol moderate- moderate- or
years, intolerance]) per L], high-sensitivity intensity statin† high-intensity
C-reactive protein ≥ 2 mg statin†
per L [19.05 nmol per L],
coronary artery calcium
score ≥ 300, ankle-brachial
index < 0.9, or lifetime risk)

Shared decision making (Figure 2)

*—ACC/AHA recommends initiating statin therapy for a 10-year risk ≥ 7.5%. NICE and USPSTF recommend a threshold of ≥ 10%.
†—USPSTF recommends low- or moderate-intensity statin only if one or more ASCVD risk factors and 10-year risk ≥ 10%.

Figure 1. Recommended approach to the initiation of statin therapy. (ACC/AHA = American College of Cardiology/
American Heart Association; ASCVD = atherosclerotic cardiovascular disease; LDL-C = low-density lipoprotein choles-
terol; NICE = National Institute of Health and Care Excellence; USPSTF = U.S. Preventive Services Task Force.)
Information from references 1 through 3.

Primary Prevention of ASCVD augment the benefits of therapeutic lifestyle modifica-

The foundation of primary prevention of ASCVD is tion, medications developed for the treatment of lipid
therapeutic lifestyle modifications, which were reviewed disorders are sometimes used for primary prevention.
in a previous issue of American Family Physician.14 To eTable A summarizes the contraindications, adverse

January 15, 2017 ◆ Volume 95, Number 2 www.aafp.org/afp American Family Physician 81
 Suscríbete
Hyperlipidemia
Monitoring Therapeutic Response and Adherence
to Statin Therapy
Shared decision making for statin therapy*
effects, effectiveness, and administration
considerations for these medications. A Heart-healthy lifestyle
Risk factor modification
STATINS
Monitor adherence to plan
Statins have been shown to reduce the risk of
ASCVD events when used for primary pre-
Plan includes statin?
vention, regardless of baseline risk. However,
the magnitude of benefit becomes greater as
the baseline risk of cardiovascular disease Yes No
increases. For example, the five-year num-
Fasting lipid levels 4 to 12 weeks Return to A
bers needed to treat (NNT) for the preven- after statin initiation show
tion of one ASCVD event are 160, 108, 80, anticipated response†?
54, and 40 for baseline 10-year ASCVD risks
of 5%, 7.5%, 10%, 15%, and 20%, respec-
Yes No
tively.15 Similarly, when used for primary
prevention, statins reduce overall mortality Reinforce adherence Intolerance to
Consider rechecking lipid recommended
rates in patients with a baseline ASCVD risk
levels in 3 to 12 months dosage?
of 10% or greater (five-year NNT = 250 to
500), but may not benefit those at lower risk
(i.e., less than 10%). Yes No
Individuals with diabetes are at an Consider alternative statin or Reinforce adherence
increased lifetime risk of ASCVD events, alternative dosing schedule, Exclude secondary causes
and a high level of evidence supports the use such as every other day or
Consider increasing statin intensity
once-weekly dosing
of statin thrapy for the primary prevention
Consider nonstatin therapy
of major ASCVD events in these patients (ezetimibe [Zetia], bile acid
B Follow-up lipid levels
40 to 75 years of age.1 For individuals with sequestrant, proprotein
in 4 to 12 weeks show
diabetes who fall outside of this age range, convertase subtilisin/kexin
anticipated response†?
type 9 inhibitors)
statin therapy should be considered on an
individual basis after considering risk reduc-
Yes No
tion benefits, the potential for adverse effects
and drug-drug interactions, and patient Reinforce adherence Reinforce adherence
preferences. Consider rechecking lipid Consider increasing statin
A 2013 Cochrane review of 56,934 patients levels in 3 to 12 months intensity or adding
nonstatin therapy
found that for every 1,000 persons treated
with a statin for five years, 18 would avoid a
major ASCVD event (i.e., myocardial infarc- Return to B
tion [MI], angina, or stroke; NNT = 56).11
*—Shared decision making should include: benefits of ASCVD risk reduction (multi-
Although the review focused on studies that ply 10-year ASCVD risk by anticipated risk reduction for recommended statin: 30%
included fewer than 10% of participants with for moderate intensity, 45% for high intensity); risks of statins (e.g., diabetes melli-
known ASCVD, the inclusion of individu- tus: absolute risk = 0.39% [number needed to harm = 255] over 4 years; myopathy:
approximately 0.5 excess cases per 1,000 over 5 years; rhabdomyolysis: approximately
als with known cardiovascular disease may 0.1 excess cases per 1,000 over 5 years); medication interactions; patient preferences;
have overestimated the benefit of statins. A and other risk factors (e.g., family history, LDL-C > 160 mg per dL [4.14 mmol per L],
separate review indicated that statins are lifetime ASCVD risk, coronary artery calcium score, ankle-brachial index, high-sensitivity
C-reactive protein).
cost-effective for primary prevention.16 †—Anticipated response: high intensity: LDL-C reduction of at least 50% from base-
The Cholesterol Treatment Trialists’ Col- line (untreated); moderate intensity: LDL-C reduction of 30% to 49% from baseline
laboration provided further evidence in (untreated).
support of statin use for primary preven-
tion of ASCVD events. The meta-analyses Figure 2. Approach to monitoring the therapeutic response and
of 27 studies (n = 174,149), using individual adherence to statins. (ASCVD = atherosclerotic cardiovascular disease;
participant data from the majority of statin LDL-C = low-density lipoprotein cholesterol.)
trials, demonstrated a reduction in major Information from references 1, 2, and 5.

82  American Family Physician www.aafp.org/afp Volume 95, Number 2 ◆ January 15, 2017
 Suscríbete
Hyperlipidemia

ASCVD events (e.g., nonfatal MI, fatal coronary events, guideline until more evidence emerges. The consensus
coronary revascularization, stroke) associated with statement recommends that nonstatin therapy should
statin use in low-risk individuals (five-year risk less than be considered in at-risk individuals who do not achieve
10%). The authors found that for each reduction of 39 the expected statin response (e.g., 50% or greater LDL-C
mg per dL (1.01 mmol per L) in LDL-C, there were 11 reduction with high-intensity statin therapy or 30% to
fewer major vascular events per 1,000 persons treated for 49% LDL-C reduction with moderate-intensity statin
five years.17 However, statin therapy for primary preven- therapy) or who cannot tolerate the recommended statin
tion was not associated with reduced rates of vascular dose. Nonstatin therapies should not, however, be con-
death in patients with a five-year risk less than 10%. A sidered as alternatives to evidence-based statin therapy
secondary analysis evaluating all-cause mortality did unless intolerance has been systematically determined.
not find a benefit from statin therapy in low-risk groups A decision support tool to assist clinicians in this process
(i.e., 10-year risk less than 10%).18 is available at http://www.acc.org/StatinIntoleranceApp.
Another recent trial comparing moderate-intensity If nonstatins are used because of documented statin
statin therapy with placebo in patients at an intermedi- intolerance or a failure to achieve an expected response
ate risk of cardiovascular disease (i.e., approximately 1% with statins, the ECDP recommends ezetimibe as first-
annual cardiovascular event risk) also demonstrated a line therapy or bile acid sequestrants as second-line ther-
reduction in MI (NNT = 250), stroke (NNT = 200), coro- apy (e.g., if a patient cannot tolerate ezetimibe and the
nary heart disease (NNT = 200), and cardiovascular- triglyceride level is less than 300 mg per dL [3.4 mmol
related hospitalization (NNT = 72) after a median of per L]) for primary prevention in patients with or with-
5.6 years in patients receiving statins.19 Statin therapy out diabetes, a 10-year ASCVD risk of 10% or greater,
was associated with an increased risk of cataract surgery and a baseline LDL-C level of 70 to 189 mg per dL (1.81
(number needed to harm = 142) and muscle pain or weak- to 4.90 mmol per L).5 These recommendations also apply
ness (number needed to harm = 91), and as with the Cho- to patients without ASCVD and a baseline LDL-C level
lesterol Treatment Trialists’ Collaboration, there were no of 190 mg per dL (4.92 mmol per L) or greater. However,
differences in cardiovascular or all-cause mortality. in these patients, it is reasonable to consider a proprotein
Based on study findings, statin therapy may be rec- convertase subtilisin/kexin type 9 (PCSK9) inhibitor in
ommended for primary prevention of cardiovascular combination with maximally tolerated statin therapy
events in patients with or without diabetes and a 10-year before a bile acid sequestrant because PCSK9 inhibitors
ASCVD risk of at least 7.5% according to the ACC/AHA are more effective at lowering LDL-C levels. The ECDP
guideline, or at least 10% according to the NICE and recommends that complex cases be referred to lipid
USPSTF guidelines (Figure 1).1-3 subspecialists.
As a new class of medications, PCSK9 inhibitors are
NONSTATINS showing early promise for the prevention of ASCVD.
There is no convincing evidence that routine use of non- PCSK9 is a natural protein that binds to and destroys
statin lipid-lowering medications (i.e., ezetimibe [Zetia], LDL receptors in the liver, thereby preventing them from
niacin, fibrates, and omega-3 fatty acids) are useful in the removing LDL-C from the circulation. The PCSK9 inhibi-
primary prevention of ASCVD.20 The addition of niacin tors block this protein, allowing the receptors to con-
demonstrated significant harm in a recent randomized tinue clearing LDL-C. A 2015 meta-analysis of 24 trials
controlled trial, and its use is no longer recommended.21 involving adults with hypercholesterolemia (individual
In early 2016, the U.S. Food and Drug Administration trials consisted of mixed populations of primary and sec-
withdrew approvals for extended-release niacin and ondary prevention) found significant reductions in MI
delayed-release fenofibric acid (fibrate) in combination (NNT = 136 to 1,442) and all-cause mortality (NNT = 246
with statins based on the lack of cardiovascular benefit to 1,354) in patients who received PCSK9 inhibitors com-
reported in trials.22 bined with maximally tolerated statin therapy compared
In 2016, the ACC issued an Expert Consensus Decision with patients who received placebo or ezetimibe.23
Pathway (ECDP) on the role of nonstatin therapies in the The studies in the meta-analysis were limited by their
management of ASCVD risk.5 The ECDP did not involve short duration of follow-up (two months to two years),23
formal systematic reviews, grading of the evidence, or and the use of these medications is limited by high cost
synthesis of the evidence. Rather, as expert opinion, its and the need for administration by injection. Although
goal was to provide practical advice for clinicians and promising, more data are needed on the long-term safety,
patients in situations not covered by the 2013 ACC/AHA effectiveness, and cost-effectiveness of PCSK9 inhibitors

January 15, 2017 ◆ Volume 95, Number 2 www.aafp.org/afp American Family Physician 83
 Suscríbete
Hyperlipidemia
BEST PRACTICES IN CARDIOLOGY – RECOMMEN­
DATIONS FROM THE CHOOSING WISELY CAMPAIGN

Sponsoring
Recommendation organization
before they can be recommended for the primary preven-
Do not routinely prescribe lipid- American Medical
tion of ASCVD events in patients other than those with
lowering medications in individuals Directors Association
extreme LDL-C elevations (i.e., 190 mg per dL or greater). with a limited life expectancy.

Secondary Prevention of ASCVD Source: For more information on the Choosing Wisely Campaign,
see http://www.choosingwisely.org. For supporting citations and to
STATINS
search Choosing Wisely recommendations relevant to primary care,
Statins are recommended for secondary prevention in see http://www.aafp.org/afp/recommendations/search.htm.
almost all patients with established ASCVD.1,2 Statins
benefit patients with established ASCVD indepen-
dently of sex or baseline cholesterol levels.24,25 In adults (cardiovascular death, MI, or nonfatal stroke; 32.7% vs.
with a history of ASCVD, statins decrease the five-year 34.7%; NNT = 50 for six years). Most of the benefit came
risk of death (NNT = 61), MI (NNT = 47), and stroke from a reduction in nonfatal MIs (NNT = 58 over six
(NNT = 189).26-28 A 2015 meta-analysis of 27 secondary- years). All-cause mortality, cardiovascular death, and
prevention studies comparing statins (or more intensive discontinuation of medication because of adverse events
statin therapy) with a control group (or less intensive did not differ between groups. It is important to note
statin therapy) demonstrated similar reductions in major that the comparison group received less than the recom-
vascular events in men (NNT = 91 for five years) and in mended dose of a statin (i.e., moderate-intensity rather
women (NNT = 143 for five years) for each 39-mg-per-dL than high-intensity). The most conservative conclusion
reduction in LDL-C levels.25 that can be drawn from this trial is that a moderate-
The effectiveness of statin therapy for reducing cardio- intensity statin plus ezetimibe may serve as an alterna-
vascular risk does not appear to differ among statins and tive in patients with acute coronary syndrome who do
should be considered a class effect.29 The comparative not tolerate high-intensity statin therapy.
effectiveness likely relates more to the intensity of dosing The ACC’s ECDP acknowledges a gap in evidence
than to the specific agent used. from randomized controlled trials demonstrating ben-
If high-intensity statins are indicated (Table 11-4) but efit when adding nonstatins to statin therapy in patients
the patient cannot tolerate this level of statins, moderate- with stable clinical ASCVD (i.e., an ASCVD event more
intensity statin therapy is the preferred approach. Simi- than three months prior) who have not achieved an
larly, moderate-intensity statins can be used in patients expected response to a statin. Ezetimibe (first line), a
with established ASCVD who have a risk factor for statin- bile acid sequestrant (second line, if intolerant to ezeti-
induced adverse effects, such as advanced age, frailty or mibe and triglyceride level is less than 300 mg per dL), or
small body frame, hypothyroidism, surgery (i.e., during a PCSK9 inhibitor (added to maximally tolerated statin
the perioperative period), or alcohol abuse.30 In cases of and either ezetimibe or bile acid sequestrant) may be
true statin intolerance (i.e., intolerance to two or three reasonable if patients and clinicians agree after engaging
statins with at least one at the lowest dose), nonstatin in shared decision making.5 The discussion should
therapies may be considered. address the potential for further ASCVD risk reduction
that can be expected from adding a nonstatin, the poten-
NONSTATINS tial for adverse events or drug-drug interactions, and
To date, there are no convincing clinical data showing patient preferences. However, intensifying lifestyle modi-
that niacin, fibrates, or omega-3 fatty acids, either as fications and addressing other major ASCVD risk factors
monotherapy or in addition to high-intensity statins, should be considered before adding nonstatin therapy.
provide additional benefit for secondary prevention In patients with documented statin intolerance, the
of ASCVD events with an acceptable margin of safety ECDP recommends referral to a lipid subspecialist. Ezet-
beyond that of high-intensity statins.1,31-40 imibe, a bile acid sequestrant, or both are recommended
However, there is some initial evidence that ezeti- in these patients. A PCSK9 may be considered only if use
mibe may have a role in secondary prevention of of these medications does not produce a greater than
ASCVD. The IMPROVE-IT trial randomized patients 50% reduction in LDL-C levels.
who experienced a recent acute coronary syndrome
event to ezetimibe plus moderate-intensity simvastatin Statins for Specific Vascular Conditions
(Vytorin; 40 mg daily) or to placebo plus simvastatin ACUTE CORONARY SYNDROME
(Zocor; 40 mg daily).31 Combination therapy produced High-intensity statin therapy is recommended for
a 2% absolute risk reduction of the composite outcome acute coronary syndrome. A systematic review of

84  American Family Physician www.aafp.org/afp Volume 95, Number 2 ◆ January 15, 2017
 Suscríbete
Hyperlipidemia
SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References Comments

Patients with a high risk of ASCVD (a 10-year risk of at least 7.5% or B 1, 3, 11, 17, Inconsistent results from
10%, depending on the guideline) should receive statin therapy for 18 meta-analyses regarding
primary prevention. benefit in low-risk patients
Statin therapy should be prescribed for secondary prevention in patients A 1, 2, 24-28 Recommendation from
with known ASCVD, unless contraindicated. consensus guidelines and
meta-analyses
Niacin, fibrates, and omega-3 fatty acids should not be routinely prescribed A 1, 20, 32-40 Consistent results in meta-
for primary or secondary prevention of ASCVD. Although these agents analyses and systematic
lower cholesterol levels, they do not affect patient-oriented outcomes. review
A moderate-intensity statin plus ezetimibe should be considered as B 31 One randomized
an alternative in patients with acute coronary syndrome who do not controlled trial with high
tolerate high-intensity statin therapy. discontinuation rates

ASCVD = atherosclerotic cardiovascular disease.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented
evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.

three randomized trials comparing high-intensity vs. included patients with a mean age of 73.0 ± 2.9 years who
moderate-intensity statins in patients with acute coro- did not have clinical ASCVD, statin use was associated
nary syndrome demonstrated reductions in all-cause with a reduced risk of MI (NNT = 45 to 171) and stroke
mortality (NNT = 85; 95% confidence interval [CI], 55 (NNT = 97 to 511).45 There was no difference, however,
to 236) and cardiovascular mortality (NNT = 109; 95% in all-cause mortality.
CI, 69 to 469) with high-intensity statin therapy.27 An earlier meta-analysis found that in patients 62 to
85 years of age with ASCVD, statin use reduced the risk
CEREBROVASCULAR DISEASE of death (NNT = 28; 95% CI, 15 to 56), nonfatal MI
Statin use lowers the risk of stroke, even in moderate-risk (NNT = 38; 95% CI, 16 to 118), and stroke (NNT = 58;
individuals (five-year ASCVD risk of 10% or less), with 95% CI, 27 to 177) over five years.46
an NNT of 90 over five years, independent of age, sex, Frail patients may be more likely to have adverse
LDL-C levels, or previous diagnosis of vascular disease.17 effects with statin therapy. Despite this, frail older adults
There was concern that statins might increase the risk of still benefit; just one year of statin therapy has been
hemorrhagic stroke and offset the benefits, but a meta- demonstrated to lower mortality rates (adjusted haz-
analysis of 31 trials did not demonstrate an association ard ratio = 0.67; 95% CI, 0.53 to 0.84) and slow physical
between statin use and hemorrhagic stroke risk.41 functional decline.47
The NICE guideline recommends treating older
PERIPHERAL ARTERIAL DISEASE AND AORTIC ANEURYSM patients up to 84 years of age the same as adults of any
A Cochrane review found that statin use among patients age, and that moderate-intensity statins should be con-
with peripheral arterial disease nearly doubled total sidered for the prevention of nonfatal MI in patients
walking distance, from an average of 175 to 327 m (574 to older than 85 years.2 The USPSTF guideline concludes
1,073 ft); it also increased pain-free walking distances there is insufficient evidence to balance the risks and
from 148 to 238 m (486 to 781 ft).42 A 2014 meta-analysis benefits of primary prevention with statins in persons 76
revealed that in patients with peripheral arterial dis- years and older.3 The ACC/AHA guideline does not have
ease, statin use reduced all-cause mortality (NNT = 12; recommendations for patients older than 75 years unless
95% CI, 9 to 23).43 they have clinical ASCVD, recommending moderate-
Similarly, statin use in patients with an abdominal intensity rather than high-intensity statins in those
aortic aneurysm repair lowers mortality rates (NNT = 12 patients.1 Shared decision making is especially impor-
for five years; 95% CI, 8 to 25).44 There is not, however, tant in frail older adults because the risk of adverse
an effect on the rate of aneurysm expansion in patients effects increases in this population while life expectancy
who have not undergone repair. is diminished, which may offset the potential benefits.

Statin Therapy in Specific Populations CHRONIC KIDNEY DISEASE

OLDER ADULTS In patients with chronic kidney disease who do not
Few clinical trials have evaluated the use of statins in require dialysis, statin therapy reduces the risk of major
older patients. In a 2013 meta-analysis of eight trials that cardiovascular events (NNT = 16 to 25), all-cause

January 15, 2017 ◆ Volume 95, Number 2 www.aafp.org/afp American Family Physician 85
 Suscríbete
Hyperlipidemia

mortality (NNT = 36 to 124), and cardiovascular mor-

REFERENCES
tality (NNT = 56 to 116).48 However, statin use may not
1. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline
reduce all-cause or cardiovascular mortality in patients
on the treatment of blood cholesterol to reduce atherosclerotic cardio-
on dialysis.49 vascular risk in adults:​a report of the American College of Cardiology/
For patients with chronic kidney disease, there is American Heart Association Task Force on Practice Guidelines [pub-
lished corrections appear in J Am Coll Cardiol. 2015;​66(24):​2812, and J
evidence to support the addition of ezetimibe to statin
Am Coll Cardiol. 2014;​63(25 pt B):​3024-3025]. J Am Coll Cardiol. 2014;​
therapy. The SHARP trial found reductions in ischemic 63(25 pt B):​2889-2934.
strokes (NNT = 112) and coronary revascularization 2. National Institute for Health and Care Excellence. Cardiovascular dis-
(NNT = 84) with ezetimibe/simvastatin compared with ease:​risk assessment and reduction, including lipid modification. NICE
clinical guideline CG181. July 2014. http://www.nice.org.uk/guidance/
placebo over five years in patients with chronic kidney dis- cg181. Accessed October 30, 2015.
ease.50 Moderate- to high-intensity statin therapy should 3. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Statin use for
be recommended for primary prevention in patients with the primary prevention of cardiovascular disease in adults: US Pre-
stage 3b or more severe chronic kidney disease. ventive Services Task Force recommendation statement. JAMA.
2016;316(19):1997-2007.
PREGNANCY 4. Hippisley-Cox J, Coupland C, Vinogradova Y, et al. Predicting cardiovas-
cular risk in England and Wales:​prospective derivation and validation of
Because of the risks of fetal harm, women taking statins QRISK2. BMJ. 2008;​336(7659):​1475-1482.
should be advised to discontinue treatment imme- 5. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2016 ACC Expert
Consensus Decision Pathyway on the role of non-statin therapies for
diately if they become pregnant, and they should be LDL-cholesterol lowering in the management of atherosclerotic cardio-
counseled on intensive lifestyle modifications.5 Bile acid vascular disease risk:​a report of the American College of Cardiology
sequestrants may be appropriate in the interim. Statin Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol.
2016;​6 8(1):​92-125.
therapy may be resumed after completion of breastfeed-
6. Ridker PM, Cook NR. Statins:​new American guidelines for prevention
ing. Women who plan to become pregnant should dis- of cardiovascular disease. Lancet. 2013;​382(9907):​1762-1765.
continue statin use at least one to three months before 7. Pursnani A, Massaro JM, D’Agostino RB Sr, O’Donnell CJ, Hoffmann U.
attempting to conceive. Guideline-based statin eligibility, coronary artery calcification, and car-
diovascular events. JAMA. 2015;​314(2):​134-141.
This article updates previous articles on this topic by Last, et al.,51 and 8. Johnson KM, Dowe DA. Accuracy of statin assignment using the 2013
Safeer and Lacivita.52 AHA/ACC Cholesterol Guideline versus the 2001 NCEP ATP III guide-
line:​correlation with atherosclerotic plaque imaging. J Am Coll Cardiol.
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using the key terms lipid, cholesterol, prevention, pharmacotherapy,
treatment, ASCVD and subtypes CHD, stroke, PAD, as well as for the spe- 9. Grundy SM, Cleeman JI, Merz CN, et al.;​National Heart, Lung, and Blood
cific treatments considered (e.g., statins, fibrates). The search included Institute;​American College of Cardiology Foundation;​American Heart
Association. Implications of recent clinical trials for the National Choles-
meta-analyses, randomized controlled trials, clinical trials, and reviews.
terol Education Program Adult Treatment Panel III guidelines [published
The following databases and summaries were also used: Cochrane Data-
correction appears in Circulation. 2004;​110(6):​763]. Circulation. 2004;​
base of Systematic Reviews, BMJ Clinical Evidence, National Guideline
110(2):​227-239.
Clearinghouse, and Essential Evidence Plus. Search dates: July 2015
10. Ioannidis JP. More than a billion people taking statins? Potential implica-
through October 2016.
tions of the new cardiovascular guidelines. JAMA. 2014;​311(5):​463-464.
11. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary preven-
tion of cardiovascular disease. Cochrane Database Syst Rev. 2013;​(1):​
The Authors CD004816.
ALLEN R. LAST, MD, MPH, is an associate professor in the Department 12. Sattar N, Preiss D, Murray HM, et al. Statins and the incident risk of dia-
of Family and Community Medicine and program director of the Medi- betes:​a collaborative meta-analyis of randomised statin trials. Lancet.
cal College of Wisconsin Fox Valley Family Medicine Residency Program, 2010;​375(9716):​735-742.
Appleton. 13. American Academy of Family Physicians. Clinical practice guideline.

Treatment of blood cholesterol to reduce atherosclerotic cardiovascular
JONATHAN D. FERENCE, PharmD, is an associate professor, director of the risk in adults. June 2014. http://www.aafp.org/patient-care/clinical-
Pharmcy Care Lab, and assistant dean of assessment and alumni affairs at recommendations/all/cholesterol.html. Accessed March 3, 2016.
the Wilkes University Nesbitt School of Pharmacy, Wilkes-Barre, Pa. At the 14. Kelly RB. Diet and exercise in the management of hyperlipidemia. Am
time the article was submitted, Dr. Ference was a community preceptor Fam Physician. 2010;​81(9):​1097-1102.
for the Wright Center for Graduate Medical Education–Family Medicine 15. DynaMed. Statins for primary and secondary prevention of cardio-

Residency Program, Kingston, Pa. vascular disease. June 8, 2016. https://www.dynamed.com/topics/
dmp~AN~T115052 [login required]. Accessed October 19, 2016.
ELIZABETH ROLLMANN MENZEL, MD, is an assistant professor in the
Department of Family and Community Medicine at the Medical College of 16. Pandya A, Sy S, Cho S, Weinstein MC, Gaziano TA. Cost-effectiveness
Wisconsin Fox Valley Family Medicine Residency Program. of 10-year risk thresholds for initiation of statin therapy for primary
prevention of cardiovascular disease [published correction appears in
Address correspondence to Allen R. Last, MD, MPH, Medical College of JAMA. 2015;​314(15):​1647]. JAMA. 2015;​314(2):​142-150.
Wisconsin, 229 S. Morrison St., Appleton, WI 54911 (e-mail: alast@mcw. 17. Mihaylova B, Emberson J, Blackwell L, et al.;​Cholesterol Treatment
edu). Reprints are not available from the authors. Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol

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 Suscríbete
Hyperlipidemia

with statin therapy in people at low risk of vascular disease:​meta- 36. Boden WE, Probstfield JL, Anderson T, et al.;​AIM-HIGH Investigators.
analysis of individual data from 27 randomised trials. Lancet. 2012;​ Niacin in patients with low HDL cholesterol levels receiving intensive
380(9841):​581-590. statin therapy [published correction appears in N Engl J Med. 2012;​
18. Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at 367(2)189]. N Engl J Med. 2011;​365(24):​2255-2267.
low risk of cardiovascular disease take a statin? [published correction 37. Kwak SM, Myung SK, Lee YJ, Seo HG;​Korean Meta-analysis Study
appears in BMJ. 2014;​348:​g3329]. BMJ. 2013;​347:​f6123. Group. Efficacy of omega-3 fatty acid supplements (eicosapentae-
19. Yusuf S, Bosch J, Dagenais BG, et al.;​HOPE-3 Investigators. Cholesterol noic acid and docosahexaenoic acid) in the secondary prevention of
lowering in intermediate-risk persons without cardiovascular disease. cardiovascular disease:​a meta-analysis of randomized, double-blind,
N Engl J Med. 2016;​374(21):​2021-2031. placebo-controlled trials. Arch Intern Med. 2012;​172(9):​686-694.
20. Sando KR, Knight M. Nonstatin therapies for management of dyslipid- 38. Yokoyama M, Origasa H, Matsuzaki M, et al.;​Japan EPA lipid inter-
emia:​a review. Clin Ther. 2015;​37(10):​2153-2179. vention study (JELIS) Investigators. Effects of eicosapentaenoic acid
on major coronary events in hypercholesterolaemic patients (JELIS):​a
21. Landray MJ, Haynes R, Hopewell JC, et al.;​HPS2-THRIVE Collaborative
randomised open-label, blinded endpoint analysis [published correc-
Group. Effects of extended-release niacin with laropiprant in high-risk
tion appears in Lancet. 2007;​370(9583):​220]. Lancet. 2007;​369(9567):​
patients. N Engl J Med. 2014;​371(3):​203-212.
1090-1098.
22. U.S. Food and Drug Administration. Withdrawal of approval of indi-
39. Duggal JK, Singh M, Attri N, et al. Effect of niacin therapy on cardio-
cations related to the coadministration with statins in applications for
vascular outcomes in patients with coronary artery disease. J Cardiovasc
niacin extended-release tablets and fenofibric acid delayed-release
Pharmacol Ther. 2010;​15(2):​158-166.
capsules. Federal Register. April 18, 2016. https://www.federalregister.
gov/articles/2016/04/18/2016-08887/abbvie-inc-et-al-withdrawal-of- 4 0. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden
approval-of-indications-related-to-the-coadministration-with-statins. death by n-3 polyunsaturated fatty acids after myocardial infarction:​
Accessed October 17, 2016. time-course analysis of the results of the Gruppo Italiano per lo Studio
della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circu-
23. Navarese EP, Kołodziejczak M, Schulze V, et al. Effects of proprotein
lation. 2002;​105(16):​1897-1903.
convertase subtilisin/kexin type 9 antibodies in adults with hypercho-
lesterolemia:​a systematic review and meta-analysis. Ann Intern Med. 41. McKinney JS, Kostis WJ. Statin therapy and the risk of intracerebral
2015;​163(1):​4 0-51. hemorrhage:​ a meta-analysis of 31 randomized controlled trials. Stroke.
2012;​43(8):​2149-2156.
24. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on
coronary events after myocardial infarction in patients with average 42. Aung PP, Maxwell HG, Jepson RG, Price JF, Leng GC. Lipid-lowering for
cholesterol levels. Cholesterol and Recurrent Events Trial investigators. peripheral arterial disease of the lower limb. Cochrane Database Syst
N Engl J Med. 1996;​335(14):​1001-1009. Rev. 2007;​(4):​CD000123.
25. Fulcher J, O’Connell R, Voysey M, et al.;​Cholesterol Treatment Trialists’ 43. Antoniou GA, Fisher RK, Georgiadis GS, Antoniou SA, Torella F. Statin
(CTT) Collaboration. Efficacy and safety of LDL-lowering therapy among therapy in lower limb peripheral arterial disease:​systematic review and
men and women:​meta-analysis of individual data from 174,000 partici- meta-analysis. Vascul Pharmacol. 2014;​63(2):​79-87.
pants in 27 randomised trials. Lancet. 2015;​385(9976):​1397-1405. 4 4. Twine CP, Williams IM. Systematic review and meta-analysis of the

26. Gutierrez J, Ramirez G, Rundek T, Sacco RL. Statin therapy in the preven- effects of statin therapy on abdominal aortic aneurysms. Br J Surg.
tion of recurrent cardiovascular events:​a sex-based meta-analysis. Arch 2011;​98(3):​346-353.
Intern Med. 2012;​172(12):​9 09-919. 45. Savarese G, Gotto AM Jr, Paolillo S, et al. Benefits of statins in elderly
27. Mills EJ, O’Regan C, Eyawo O, et al. Intensive statin therapy compared subjects without established cardiovascular disease:​a meta-analysis
with moderate dosing for prevention of cardiovascular events:​a meta- [published correction appears in J Am Coll Cardiol. 2014;​63(11):​1122].
analysis of >40 000 patients. Eur Heart J. 2011;​32(11):​1409-1415. J Am Coll Cardiol. 2013;​62(22):​2090-2099.
28. Wilt TJ, Bloomfield HE, MacDonald R, et al. Effectiveness of statin
4 6. Afilalo J, Duque G, Steele R, Jukema JW, de Craen AJ, Eisenberg MJ.
therapy in adults with coronary heart disease. Arch Intern Med. 2004;​ Statins for secondary prevention in elderly patients:​a hierarchical bayes-
164(13):​1427-1436. ian meta-analysis. J Am Coll Cardiol. 2008;​51(1):​37-45.
29. Zhou Z, Rahme E, Pilote L. Are statins created equal? Evidence from 47. Galindo-Ocaña J, Bernabeu-Wittel M, Formiga F, et al.;​PROFUND Proj-
randomized trials of pravastatin, simvastatin, and atorvastatin for car- ect researchers. Effects of renin-angiotensin blockers/inhibitors and
diovascular disease prevention. Am Heart J. 2006;​151(2):​273-281. statins on mortality and functional impairment in polypathological
30. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, patients. Eur J Intern Med. 2012;​23(2):​179-184.
Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of 4 8. Palmer SC, Navaneethan SD, Craig JC, et al. HMG CoA reductase inhibi-
statins. Circulation. 2002;​106(8):​1024-1028. tors (statins) for people with chronic kidney disease not requiring dialy-
31. Cannon CP, Blazing MA, Giugliano RP, et al.;​IMPROVE-IT Investiga- sis. Cochrane Database Syst Rev. 2014;​( 5):​CD007784.
tors. Ezetimibe added to statin therapy after acute coronary syndromes. 49. Palmer SC, Navaneethan SD, Craig JC, et al. HMG CoA reductase inhibi-
N Engl J Med. 2015;​372(25):​2387-2397. tors (statins) for dialysis patients. Cochrane Database Syst Rev. 2013;​( 9):​
32. Sharma M, Ansari MT, Abou-Setta AM, et al. Systematic review:​com- CD004289.
parative effectiveness and harms of combination therapy and mono- 50. Baigent C, Landray MJ, Reith C, et al.;​SHARP Investigators. The effects
therapy for dyslipidemia. Ann Intern Med. 2009;​151(9):​622-630. of lowering LDL cholesterol with simvastatin plus ezetimibe in patients
33. Studer M, Briel M, Leimenstoll B, Glass TR, Bucher HC. Effect of differ- with chronic kidney disease (Study of Heart and Renal Protection):​a ran-
ent antilipidemic agents and diets on mortality:​a systematic review. domised placebo-controlled trial. Lancet. 2011;​377(9784):​2181-2192.
Arch Intern Med. 2005;​165(7):​725-730. 51. Last AR, Ference JD, Falleroni J. Pharmacologic treatment of hyperlipid-
34. Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular out- emia [published correction appears in Am Fam Physician. 2012;​86(10):​
comes:​a systematic review and meta-analysis. Lancet. 2010;​375(9729):​ 889]. Am Fam Physician. 2011;​8 4(5):​551-558.
1875-1884. 52. Safeer RS, Lacivita CL. Choosing drug therapy for patients with hyper-
35. Keene D, Price C, Shun-Shin MJ, Francis DP. Effect on cardiovascular risk lipidemia. Am Fam Physician. 2000;​61(11):​3371-3382.
of high density lipoprotein targeted drug treatments niacin, fibrates,
and CETP inhibitors:​meta-analysis of randomised controlled trials
including 117,411 patients. BMJ. 2014;​349:​g4379.

January 15, 2017 ◆ Volume 95, Number 2 www.aafp.org/afp American Family Physician 87
 Hyperlipidemia
87A  American Suscríbete
noncommercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests.
Downloaded

eTable A. Medications to Treat Lipid Disorders and Reduce Cardiovascular Risk

Familyfrom

Medication Contraindications Adverse effects Effectiveness Administration

Physician

StatinsA1,A2 Active liver disease and Generally better tolerated than other agents Primary prevention: NNT = 56 for Most statins are taken once daily at
the American Family Physician website at www.aafp.org/afp.

Atorvastatin (Lipitor) pregnancy Myopathies occur in < 1% of patients; increased five years to prevent one major bedtime
incidence when used with fibrates atherosclerotic cardiovascular disease
Fluvastatin
event
Lovastatin Rhabdomyolysis occurs in < 0.2% of patients
Secondary prevention: NNT = 61 for five
Pitavastatin (Livalo) Liver function test results greater than three
years to prevent one death
times the upper limit of normal occur in < 2%
Pravastatin (Pravachol)
of patients
Rosuvastatin (Crestor)
NNH = 255 for four years to cause one case of
Simvastatin (Zocor) diabetes mellitus

Ezetimibe (Zetia) A3,A4 No serious safety Well tolerated as monotherapy; adverse effects Primary prevention: lacks clinical outcome Taken once daily
Ezetimibe/simvastatin (Vytorin) concerns with ezetimibe similar to placebo data No known effect on absorption of other
monotherapy, but it Arthralgias and myalgias are more common Secondary prevention: NNT = 58 for six medications
should be avoided in those when combined with a statin years to prevent one nonfatal myocardial Ezetimibe may increase concentrations
with active liver disease infarction when combined with a
www.aafp.org/afp

of cyclosporine (Sandimmune); closely

when combined with a moderate-intensity statin monitor cyclosporine concentrations in
statin (e.g., Vytorin)
Monotherapy reduces LDL-C by 18% patients taking both medications
Copyright © 2017 American Academy of Family

Bile acid sequestrantsA5 Complete biliary or bowel Constipation, nausea, and bloating are common, Primary or secondary prevention: no effect Many drug interactions; separate from
Cholestyramine (Questran) obstruction leading to poor adherence in most patients on all-cause mortality warfarin (Coumadin), digoxin, and
May increase triglyceride level; use with caution Reduces LDL-C by 15% to 30% amiodarone by at least two hours
Colesevelam (Welchol)
when triglyceride level > 200 mg per dL
Colestipol (Colestid)
(2.3 mmol per L)

PCSK9 inhibitorsA6-A8 Serious hypersensitivity to No difference in serious adverse events when Associated with reduced risk of Alirocumab: 75 mg subcutaneously
Alirocumab (Praluent) any component of the compared with placebo mortality (NNT = 246 to 1,354), once every two weeks (150 mg
formulation Injection site reaction occurs in 6% to 7% myocardial infarction (NNT = 136 to subcutaneously once every two weeks if
Evolocumab (Repatha)
1,442), and lipid profile compared LDL-C response is inadequate)
with no PCSK9 therapy in adults with Evolocumab: 140 mg subcutaneously
hypercholesterolemia once every two weeks or 420 mg
subcutaneously once monthly
Volume
Physicians.

FibratesA5,A9,A10 Severe hepatic or renal Gastrointestinal upset, rash, and abdominal pain Primary or secondary prevention: no effect Gemfibrozil: twice daily before meals
Gemfibrozil (Lopid) disease are common on all-cause mortality Micronized fenofibrate tablets and
95, Number

Multiple prescription Decreased renal function and myopathies are Lowers LDL-C and triglycerides by 5% to capsules should be taken with food
rare 20% and 20% to 50%, respectively
For the private,

preparations of fenofibrate
are available Increases risk of gallstones in 1% to 2% Increases HDL-C by 10% to 35%
continues
◆ 2 January 15, 2017

HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; NNH = number needed to harm; NNT = number needed to treat; OTC = over-the-counter; PCSK9 = proprotein convertase subtilisin/
kexin type 9.
*—Combination niacin/laropiprant was withdrawn from the market by the manufacturer based on results of HPS2-THRIVE trial. A12
†—Adult dosing: Lovaza 4 g (4 capsules) once daily or 2 g (2 capsules) twice daily; Vascepa 2 g (2 capsules) twice daily with or following meals.
 Hyperlipidemia
87B  American Suscríbete

eTable A. Medications to Treat Lipid Disorders and Reduce Cardiovascular Risk (continued)
noncommercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests.

Medication Contraindications Adverse effects Effectiveness Administration

Downloaded

Nicotinic acid (niacin) A5,A10-A12

Severe peptic ulcer disease, Flushing is common; may be reduced with aspirin Primary or secondary prevention: no effect Taken twice daily with food
Familyfrom

Multiple OTC preparations chronic liver disease, and pretreatment on all-cause mortality OTC preparations may be less effective but
severe gout Discontinuation is common (one in 20 patients) Improves cholesterol levels when have fewer adverse effects
Multiple controlled-release
Physician

prescription products May increase uric acid and glucose levels combined with statins
the American Family Physician website at www.aafp.org/afp.

Increased risk of serious adverse events with Primarily increases HDL-C by 15% to 35%
niacin/laropiprant* vs. placebo:
Bleeding (NNH = 71)
Infection (NNH = 71)
New-onset diabetes mellitus (NNH = 71)
Gastrointestinal event (NNH = 100)
Musculoskeletal event (NNH = 142)
Dermatologic event (NNH = 333)

Omega-3 fatty acidsA13,A14 Use with caution in patients Dyspepsia, burping, and fishy taste more Primary and secondary prevention: no Two to four prescription capsules
Multiple OTC preparations with fish allergy common effect on all-cause mortality taken once or twice daily based on
preparation†
Lovaza
OTC preparations may require multiple
Vascepa
www.aafp.org/afp

capsules to achieve doses used in clinical

trials
Copyright © 2017 American Academy of Family

HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; NNH = number needed to harm; NNT = number needed to treat; OTC = over-the-counter; PCSK9 = proprotein convertase subtilisin/
kexin type 9.
*—Combination niacin/laropiprant was withdrawn from the market by the manufacturer based on results of HPS2-THRIVE trial. A12
†—Adult dosing: Lovaza 4 g (4 capsules) once daily or 2 g (2 capsules) twice daily; Vascepa 2 g (2 capsules) twice daily with or following meals.
Adapted with permission from Last AR, Ference JD, Falleroni J. Pharmacologic treatment of hyperlipidemia [published correction appears in Am Fam Physician. 2012;86(10):889]. Am Fam Physician. 2011;84(5):554-555, with
additional information from:
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