Dyslipidemia

By Craig J. Beavers, Pharm.D., BCCP, BCPS, CACP; and

Michael S. Kelly, Pharm.D., BCACP, CDE, CLS
Reviewed by Dave L. Dixon, Pharm.D., FCCP, FACC, FNLA, BCPS, BCACP, CDE, CLS; Andrew P. Clark, Pharm.D., BCPS, CDE, CPP; Sally Earl,
Pharm.D., BCPS; and Garcia Simon-Clarke, Pharm.D., MS, BCPS, BCGP, BCNP

LEARNING OBJECTIVES

1. Assess ASCVD risk based on recommendations from the 2018 ACC/AHA cholesterol guidelines.
2. Design an appropriate treatment plan for dyslipidemia according to patients’ individual risk factors and comorbidities
using 2018 cholesterol guidelines.
3. Develop a treatment plan for patients with statin intolerance.
4. Using current evidence, evaluate the appropriate use of non-statin agents and emerging lipid-lowering therapies.

INTRODUCTION
ABBREVIATIONS IN THIS CHAPTER
Despite improvements in prevention and treatment, cardiovascular
ACS Acute coronary syndrome
disease (CVD) remains the No. 1 cause of death in the United States
ApoB Apolipoprotein B
and worldwide (Benjamin 2018). Among the diseases that help cause
ApoC-III
Apolipoprotein C-III
CVD mortality, coronary heart disease (CHD) and ischemic stroke are
ART Antiretroviral therapy
the top contributors. Atherosclerosis develops over decades and is
ASCVD Atherosclerotic cardiovascular
disease caused by atherogenic lipid particles entering arterial walls. After a
series of oxidation and inflammation processes, a lipid-rich plaque
CHD Coronary heart disease
is formed. Plaques characterized by thin fibrous caps are likely to
CKD Chronic kidney disease
rupture, leading to thrombosis and arterial ischemia. Plaques that do
CV Cardiovascular
not rupture may inhibit adequate blood flow or embolize, also lead-
CVD Cardiovascular disease
ing to ischemia. Epidemiologic evidence supports the relationship
DM Diabetes mellitus
between elevated atherogenic lipid particles and the risk of athero-
ECDP Expert consensus decision
pathway sclerotic cardiovascular disease (ASCVD) (Jacobson 2015a).
In addition to lifestyle management, lipid-lowering drugs remain
FH Familial hypercholesterolemia
a cornerstone in preventing initial and secondary ASCVD events.
HeFH Heterozygous familial
hypercholesterolemia Statins remain the first-line agents, given their ability to lower the risk
HoFH Homozygous familial of major CV events and mortality. The four statin benefit groups were
hypercholesterolemia created in the 2013 American College of Cardiology/American Heart
HTG Hypertriglyceridemia Association (ACC/AHA) (Table 1). Since then, there have been major
Lp(a) Lipoprotein(a) advances made in the treatment of dyslipidemia. In November 2018,
PCSK9 Proprotein convertase subtilisin/ new ACC/AHA cholesterol guidelines were released.
kexin type 9
PLWHA People living with HIV/AIDS REVIEW OF CURRENT GUIDELINES
RCT Randomized controlled trial FOR DYSLIPIDEMIA MANAGEMENT
SAMS Statin-associated muscle
2018 Guideline on the Management
symptoms
of Blood Cholesterol
Table of other common abbreviations. Updated recommendations for reducing ASCVD risk were released fol-
lowing the 2013 ACC/AHA guidelines, including the 2014 NLA, 2016
and 2017 EDCP, and NLA recommendations for PSCK9 inhibitors. In
each update, atherogenic targets (either LDL-C or non-HDL-C) were

PSAP 2019 BOOK 1 • Cardiology 31 Dyslipidemia

 Table 1. Statin Benefit Groups and Statin Intensities from the 2013 ACC/AHA Guideline

Statin Benefit Group Suggested Statin Intensity

Moderate intensity if age > 75 or patient is

Clinical ASCVD High
not a candidate for high-intensity statin

Moderate intensity if not a candidate for

Baseline LDL ≥ 190 mg/dL High
high-intensity statin

Diabetes age 40–75 Moderate High intensity if 10-yr ASCVD risk ≥ 7.5%

10-yr ASCVD risk ≥ 7.5% age 40–75 Moderate- to high-intensity

Statin Intensity (by dose)

Low-Intensity Statins Moderate-Intensity Statins High-Intensity Statins

(< 30% expected LDL-C reduction) (30%–49% expected LDL-C reduction) (≥ 50% expected LDL-C reduction)

Simvastatin 10 mg Atorvastatin 10–20 mg Atorvastatin 40–80 mg

Pravastatin 10–20 mg Rosuvastatin 5–10 mg Rosuvastatin 20–40 mg
Lovastatin 20 mg Simvastatin 20–40 mg
Fluvastatin 20–40 mg Pravastatin 40–80 mg
Pitavastatin 1 mg Lovastatin 40 mg
Fluvastatin 40 mg BID
Fluvastatin XL 80 mg
Pitavastatin 2–4 mg

ASCVD = atherosclerotic cardiovascular disease; BID = twice daily; XL = extended release.

Information from: Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to
reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association
task force on practice guidelines. J Am Coll Cardiol 2014;63:2889-934.

recommended to assess whether additional lipid-lowering

therapies should be added to maximum statin therapy. Most
BASELINE KNOWLEDGE STATEMENTS
recently, the 2018 Guideline on the Management of Blood Cho-
Readers of this chapter are presumed to be familiar lesterol (Grundy 2018) provided additional recommendations
with the following: for each of the 4 statin benefit groups, as well as recommen-
• Fundamental knowledge of lipid-lowering drugs’ dations for special populations not included in the 2013 ACC/
mechanism of action, lipid-lowering efficacy, and AHA guidelines. Notably, the 2018 guidelines were endorsed
safety by multiple partnering organizations, including the Ameri-
• Awareness of the four statin benefit groups identi- can Pharmacist Association, American Diabetes Association,
fied by the 2013 ACC/AHA guideline and recom- and NLA. Several recommendations from the 2013 ACC/AHA
mendations for statin intensity
remain in the 2018 guideline, including importance of lifestyle
• Therapeutic lifestyle recommendations to reduce therapies, the use of fixed-dose statins in the four statin ben-
the risk of cardiovascular disease
efit groups, and monitoring LDL-C response to assess percent
Table of common laboratory reference values LDL-C reduction as a measure of statin efficacy (table 1). New in
the 2018 guidelines are LDL-C thresholds for when to consider
ADDITIONAL READINGS adding non-statins, recommendations for use of non-statin
agents, and additional risk factors to consider when determin-
The following free resources have additional back- ing patients’ ASCVD risk and lipid-lowering treatment.
ground information on this topic:
Fixed-Dose Statin Therapy
• NCEP ATP III.
• 2013 AHA/ACC Guideline of Lifestyle Management Introduced in 2013 and continued in the 2018 guideline is the
to Reduce Cardiovascular Risk. recommendation for use of fixed doses of statin, based on
• Goldberg AC, Hopkins PN, Toth PP, et al. Familial the percent LDL-C reduction with specific statin doses used
hypercholesterolemia: screening, diagnosis, and in RCTs. Of note, individual response to statin therapy is
management of pediatric and adult patients. J Clin acknowledged to be variable. A post hoc analysis of JUPITER
Lipidol 2011;5:133-40. (Justification for the Use of Statins in Prevention: An Inter-
vention Trial Evaluating Rosuvastatin), which randomized

PSAP 2019 BOOK 1 • Cardiology 32 Dyslipidemia

primary prevention patients to high-intensity rosuvastatin LDL-C Thresholds and Use of Non-statins
20 mg daily or placebo, found that in patients randomized to in Secondary ASCVD Prevention
rosuvastatin 20 mg daily, only 46.3% had an LDL-C reduction In patients with ASCVD, high-intensity statins are able to
of at least 50% from baseline (Ridker 2016). Further analy- reduce LDL-C by 50% or more remain the preferred treatment.
sis revealed higher rates of major CV events in statin-treated Those with ASCVD who cannot tolerate a high-intensity statin
patients with less than a 50% LDL-C reduction than in those may receive moderate-intensity statin with a goal to achieve
with a 50% or greater LDL-C reduction from baseline. Com- 30 to 49% LDL-C reduction. Following data from RCT demon-
pared with placebo, patients with an LDL-C reduction of less strating that additional LDL-C lowering with non-statins fur-
than 50% had a smaller relative risk reduction (HR 0.61; 95% ther reduced risk among patients with ASCVD, achieved LDL-C
CI, 0.44–0.83) than did those with an LDL-C reduction of 50% on maximally tolerated statins is now a consideration for addi-
or greater (HR 0.42; 95% CI, 0.30–0.60). Although this was a tion of non-statin therapies. In patients with ASCVD receiving
secondary analysis of an RCT, it supports recommendations maximally tolerated statin therapy, an LDL-C of 70 mg/dL or
that percent LDL reduction is important in reducing ASCVD higher is the recommended threshold for considering addi-
risk. Even with fixed-dose statins, LDL-C should be monitored tion of non-statin therapies. Lipid-lowering agents to consider
at baseline and 4–12 weeks after initiating therapy to moni- adding include ezetimibe or a PCSK9-I, with ezetimibe being
tor percent LDL-C reduction. Because individuals may have the preferred over PCSK9-I as the initial non-statin agent due
a less-than-anticipated LDL-C reduction, clinicians must to its generic availability and documented safety and tolera-
assess additional factors such as nonadherence to statin bility. Addition of PCSK9-I is reserved for patients considered
therapy and lifestyle recommendations, which may affect “very high-risk” due to multiple major ASCVD events or high-
LDL-lowering ability. risk conditions (Figure 1) with elevated LDL-C or non-HDL-C

Clinical ASCVD

Receiving high-intensity or
maximally tolerated statin

LDL-C ≥70
Ezetimibe
Very high-risk ASCVD mg/dL
(≥2 major ASCVD events or major ASCVD event + high risk condition)
Major ASCVD events
• ACS within previous 12 months
• Previous MI or ischemic stroke
• Symptomatic PAD, previous peripheral revascularization/
amputation, or claudication with ABI <0.85

High-Risk Conditions Very high-risk ASCVDa

• Prior revascularization (CABG; PCI) outside of ASCVD event
• Diabetes mellitus LDL-C ≥70 mg/dL PCSK9-I
• Hypertension oror
• Current smoking Non-HDL-C ≥100 mg/dL
• eGFR 15-59 ml/min/1.73m2
• LDL-C ≥100 mg/dLa
• Age ≥65 years
• HeFH
• CHF

Figure 1. 2018 ACC/AHA cholesterol guidelines for patients with clinical ASCVD.
a
Maximally tolerated statin with ezetimibe
ABI= ankle-brachial Index; ACS= Acute Coronary Syndrome; ASCVD= atherosclerotic cardiovascular disease; CABG= coronary artery
bypass grafting; CHF= congestive heart failure; HeFH= Heterozygous Familial Hypercholesterolemia; HDL-C= high-density
lipoprotein cholesterol; LDL-C= low-density lipoprotein cholesterol; MI= myocardial infarction; PAD= peripheral arterial disease;
PCI= percutaneous coronary intervention; PCSK9-I= proprotein convertase subtilisin/kexin type 9 inhibitor.
Information from: Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/
PCNA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol 2018:Nov 10 [Epub ahead of print].

PSAP 2019 BOOK 1 • Cardiology 33 Dyslipidemia

while receiving maximally tolerated LDL-C lowering therapy, than 50%, or those with an LDL-C of 100 mg/dL or higher. If
defined as maximally tolerated statin with ezetimibe. While additional lipid-lowering therapy is pursued, guidelines now
PCSK9-I provide LDL-C reductions of 40-60%, uncertainties favor use of ezetimibe over PCSK9-I, despite greater LDL-C
regarding their long-term safety and perceived inconvenience efficacy with the later. Whether severe hypercholesterol-
of subcutaneous administration limit their use in patients emia is due to genetic familial hypercholesterolemia or not,
with ASCVD. The 2018 guidelines also include a value state- further LDL-C lowering is still beneficial in reducing ASCVD
ment which classifies PCSK9-I as having “low cost value” due risk. Following treatment with maximally tolerated statin and
to current cost of therapy. Manufacturers of both PCSK9-I ezetimibe, specific thresholds for consideration of PCSK9-I
announced plans in mid-late 2018 to significantly reduce the are dependent on patient age, baseline LDL-C, and achieved
costs of each PCSK9-I by 60% or more, which may improve the LDL-C (Figure 2). Evidence supporting the use of ezetimibe
calculated value. over PCSK9-I is based on secondary prevention RCT. Cur-
rently, there are no RCT demonstrating reduced ASCVD
LDL-C Thresholds and Use of Non-statins in events with either PCSK9-I or ezetimibe for primary preven-
Primary ASCVD Prevention tion. Additional cost considerations are expected to limit
Addition of non-statins to maximally tolerated statin therapy access to PCSK9-I for primary prevention patients. The 2018
is also recommended in select primary prevention groups; cholesterol guidelines point out inconsistent cost-effective-
notably patients with baseline LDL-C of 190 mg/dL or greater ness data of ASCVD risk prevention with PCSK9-I, thus limit-
(severe hypercholesterolemia) and patients with diabetes ing their use to patients with elevated LDL-C while receiving
mellitus. Patients with severe hypercholesterolemia should maximally tolerated statin therapy with ezetimibe. In patients
ideally be treated with a high-intensity statin, and maximally who cannot access or are not candidates for PCSK9-I, bile
tolerated statin at minimum (figure 2). Following maximally acid sequestrants may be considered in patients with TG of
tolerated statin therapy, consideration of non-statins may be 300 mg/dL or lower, despite no RCT demonstrating reduced
warranted for those whose percent LDL-C reduction is less ASCVD events when combined with statins.

Severe Hypercholesterolemia

Age 20-75 with baseline LDL-C ≥190 mg/dL

High-intensity statin
(or maximally tolerated statin)

LDL-C responsea:
<50% reduction from baseline
and/or Age 40-75
Age 20-75 with Age 30-75
achieved LDL-C ≥100 mg/dL with baseline
LDL-C ≥190 mg/dL with HeFH or
LDL-C ≥220 mg/dL

LDL-C <50%
reduction from Ezetimibe LDL-C ≥100 mg/dLb LDL-C ≥130 mg/dLb
baselineb

Bile acid
PCSK9-I
sequestrantc

Figure 2. 2018 ACC/AHA cholesterol guidelines for patients with severe hypercholesterolemia.
a
While receiving maximally tolerated statin.
b
While receiving maximally tolerated statin and ezetimibe.
c
If fasting triglycerides ≤300 mg/dL.
LDL-C = low-density lipoprotein cholesterol; PCSK9-I = proprotein convertase subtilisin/kexin type 9 inhibitor.
Information from: Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/
PCNA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol 2018:Nov 10 [Epub ahead of print].

PSAP 2019 BOOK 1 • Cardiology 34 Dyslipidemia

Patients with Diabetes Mellitus New in the 2018 cholesterol guidelines are recommen-
Similar to the 2013 ACC/AHA guidelines, moderate-inten- dations for patients with DM, but outside of the traditional
sity statin is recommended in patients age 40 to 75 years age range (40 to 75 years). In patients above 75 years, initi-
with diabetes mellitus (DM) and LDL-C of 70 to 189 mg/dL. ating or continuing statin treatment may be appropriate in
Additionally, use of the PCE is recommended to further iden- select individuals, following a patient-clinician discussion
tify those at high ASCVD risk. In the 2013 ACC/AHA guide- of consideration of potential benefits of ASCVD risk reduc-
lines, high-intensity statin was a consideration for patients tion and adverse effects. A recent retrospective cohort study
with DM and a 10-year ASCVD risk of 7.5% or higher. The found that in patients with DM, statin use was associated
most recent 2018 guidelines depart from absolute 10-year with reduced risk of ASCVD events (HR=0.76; 95% CI, 0.65–
risk ASCVD estimates to guide initial statin intensity, but 0.89) and all-cause mortality (HR=0.84; 95% CI, 0.75–0.94)
instead offer recommendations to consider additional risk in patients aged 75–84 years (Ramos 2018). No significant
factors (Figure 3). Noting that ASCVD risk increases with ASCVD or mortality reduction was noted for patients without
age and other risk factors, high-intensity statin therapy is DM in this age range, or patients 85 years and older with DM.
now recommended in patients with DM with diabetes-spe- In patients aged 20–39 years, 10-year ASCVD risk is likely
cific risk enhancers (Box 1) or with increased age; notably low and no RCT have evaluated statin therapy in patients with
men above 50 years and women above 60 years (Grundy DM younger than age 40. Although the PCE cannot estimate
2018). Although no LDL-C threshold is recommended when 10-year ASCVD risk in this younger cohort, it may be used to
considering the addition of non-statin agents, achieving a calculate lifetime risk. As these younger patients age, their
50% or more LDL-C reduction is advised. In patients with DM ASCVD risk is likely to increase and thus moderate-intensity
and elevated 10-year ASCVD risk (20% or higher) who fail to statin therapy may be considered in those aged 20–39 years
achieve a 50% LDL-C reduction with moderate or high-inten- with diabetes-specific risk factors, including microvascular
sity statins, addition of ezetimibe may be considered to fur- complications and long-duration of DM.
ther reduce LDL-C.

Diabetes Mellitus

Age 20-39 years with diabetes- Age 40-75 years

Age >75 years
specific risk enhancersa LDL-C 70-189 mg/dL

10-year yes
Moderate-intensity statin Currently taking
ASCVD risk
statin
assessment
Reasonable to
continue
no considering
Multiple ASCVD
High-intensity statin to reduce risk factors benefit vs risks
LDL-C by ≥50% or Consider statin if
age 50-75 years benefit vs risks

10-year ASCVD ≥20% and

<50% LDL-C reductionb

Ezetimibe

Figure 3. 2018 ACC/AHA cholesterol guidelines for patients with diabetes mellitus.
a
Diabetes-specific risk enhancers are listed in Box 1.
b
While receiving maximally tolerated statin.
ASCVD = atherosclerotic cardiovascular disease; LDL-C= low-density lipoprotein cholesterol.
Information from: Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/
PCNA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol 2018:Nov 10 [Epub ahead of print].

PSAP 2019 BOOK 1 • Cardiology 35 Dyslipidemia

 calculation of 10-year ASCVD risk with the PCE, as well as
Box 1. Risk-Enhancing Factors from
assessing for other ASCVD risk-enhancing factors (see Box 1).
2018 ACC/AHA Cholesterol Guidelines
New in 2018 guidelines are four ASCVD risk categories (low,
Diabetes-specific risk enhancing factors borderline, intermediate, high) based on calculated 10-year
• Long duration of diabetes mellitus (DM) ASCVD risk score. For each ASCVD risk group, a patient-cli-
○○ ≥10 years for type 2 DM; ≥20 years for type 1 DM
nician discussion about the patient’s risk is recommended.
• Microvascular complications
○○ Nephropathy (eGFR <60 ml/min/1.73m2 or As recommended in previous cholesterol guidelines, the
albuminuriaa) patient-clinician risk discussion should include potential ben-
○○ Neuropathy efits, risks of adverse effects, drug-drug interactions, lifestyle
○○ Retinopathy therapies, as well as evaluating the presence of risk-enhanc-
• ABI <0.9 ing factors. Additional risk assessment using coronary artery
Risk-enhancing factors to guide clinician-patient discus-
sion in non-DM patients calcium scoring is now recommended for borderline and inter-
• Family history of premature ASCVD mediate risk patients when ASCVD risk is uncertain.
• Metabolic syndrome Recommended statin intensity varies by risk. Those at
• CKD (eGFR 15-59 ml/min/1.73m ± albuminuria ) not
2 a
highest risk (10-year ASCVD 20% or higher) are recommended
treated by HD or kidney transplant to receive high-intensity statin to achieve 50% or greater
• Primary hypercholesterolemia LDL-C lowering; moderate-intensity statins preferred in bor-
○○ LDL-C 160-189 mg/dL or non-HDL-C
190-219 mg/dL derline and intermediate risk groups. The HOPE-3 trial evalu-
• Chronic inflammatory disorders ated moderate-intensity statin (rosuvastatin 10 mg daily) over
○○ HIV/AIDS, RA, psoriasis 5.6 years in an “intermediate risk” primary prevention popula-
• History of premature menopause (before age 40 years) tion to evaluate a primary composite end point of CV death
pre-eclampsia
and non-fatal MI or stroke (Yusuf 2016). Notably, this trial
• High-risk race/ethnicities (South Asian ancestry) included representation from several diverse ethnic groups,
Lipid/biomarkers
including Hispanic and Chinese patients. Compared to pla-
• Persistently elevated TG (≥175 mg/dL)
• hs-CRP ≥2 mg/L cebo, rosuvastatin lowered LDL-C by 26.5% from baseline and
• Lp(a) >50 mg/dL or >125 nmol/L was associated with a 24% reduction in the primary end point.
• apoB ≥130 mg/dL Although no LDL-C threshold for addition of non-statins is
• ABI <0.9 recommended by the 2018 cholesterol guidelines, addition of
a
Albuminuria defined as urine albumin-to-creatinine ratio ≥ ezetimibe or BAS may be recommended in patients with sta-
30 mcg/mg. tin intolerance, or those who wish to avoid statin therapy.
ABI= ankle-brachial index; apoB= apolipoprotein B; ASCVD
= atherosclerotic cardiovascular disease; CKD = chronic kid-
ney disease; eGFR= estimated glomerular filtration rate; HD Pooled Cohort Equation: Design and Limitations
= hemodialysis; HIV/AIDS= human immunodeficiency virus/ The pooled cohort equation (PCE), was developed by the
acquired immunodeficiency syndrome; hs-CRP = high-sensi-
tivity CRP; Lp(a) = lipoprotein(a); RA= rheumatoid arthritis; TG= ACC/AHA Work Group from several large cohort studies that
triglycerides. evaluated ASCVD events (fatal and nonfatal MI or stroke).
Information from: Grundy SM, Stone NJ, Bailey AL, et al. 2018 The PCE allows calculation of 10-year ASCVD risk in patients
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/
aged 40-79 years, but also lifetime ASCVD risk in patients age
NLA/PCNA Guideline on the Management of Blood Choles-
terol. J Am Coll Cardiol 2018:Nov 10 [Epub ahead of print]. 40-59 years. Initially, the PCE was recommended to estimate
the 10-year ASCVD risk to guide statin therapy for primary
prevention in patients without diabetes and a baseline LDL of
Risk Stratifying Using Additional Risk Factors 70–189 mg/dL. The PCE can also be used to guide initial sta-
and the Pooled Cohort Equation tin intensity in statin benefit group 3 (patients 40–75 years of
In patients without ASCVD, DM, and baseline LDL-C below 190 age with diabetes). The PCE includes options of race (white,
mg/dL, the decision to initiate statin therapy for primary pre- African American, or other) to stratify risk as well as presence
vention is multi-factorial. Across all age ranges, assessment of diabetes to further estimate the ASCVD risk in patients with
of ASCVD risk and reinforcement of healthy lifestyle is pro- diabetes.
moted. In the younger population, age 20 to 39 years, assess- Although the PCE was developed from data representing
ing lifetime ASCVD risk with the PCE can be useful to educate racially and geographically diverse U.S. populations, some
on lifestyle modifications which may lower their risk; how- have questioned its ability to accurately assess risk on the
ever, statin therapy is recommended in patients with FH, con- basis of race/ethnicity, sex, and age. The ACC risk estimator
sistently elevated LDL-C 160 mg/dL or higher, or family history acknowledges that the PCE may underestimate the 10-year
of premature ASCVD. and lifetime risks in certain race/ethnicity groups such as
Determining which patients aged 40–75 years should American Indians, Asian Americans from south Asia ances-
receive statin therapy is outlined in figure 4 and requires try, and Hispanics from Puerto Rico. In addition, using race/

PSAP 2019 BOOK 1 • Cardiology 36 Dyslipidemia

ethnicity groups such as Mexican Americans and Asian consider when considering one’s ASCVD risk. Both the 2013
Americans of East Asia ancestry in the equation may result in ACC/AHA guidelines and the 2014 NLA Part 1 recommenda-
overestimation of ASCVD risk (Grundy 2018). However, the cal- tions both list CAC as an additional factor to consider when
culated risk should still be used to discuss lifestyle changes deciding on statin initiation. In each aforementioned guide-
to reduce ASCVD risk. Age is perhaps one of the biggest influ- line, a CAC score of 300 Agatston units or higher was con-
ences on estimated 10-year ASCVD risk using the PCE. Using sidered a risk factor, similar to elevated hs-CRP. The 2018
national mean values for risk factors, the estimated 10-year guidelines recommend use of CAC to further risk stratify
ASCVD risk increases dramatically after age 60 in each sex- patients aged 40 to 75 years defined intermediate ASCVD risk,
race population. Race may also place some at higher ASCVD based on 10-year ASCVD risk calculated by the PCE (Figure 4).
risk. An analysis of the PCE found a higher 10-year ASCVD In the event that the CAC score is zero, statin therapy may
risk score among African American men 40–55 years of age be withheld, and recommendations to re-assess risk in 5 to
with identical mean risk factor values (blood pressure, TC, 10 years. In an analysis of the multi-ethnic study of athero-
HDL) regardless of blood pressure treatment, diabetes mel- sclerosis (MESA) cohort, CAC scores were assessed against
litus (DM), or smoking status (Fox 2016). In addition, given ASCVD events over a 11-year period in patients free of CHD at
that the PCE includes estimates of stroke risk, more women baseline (Budoff 2018). Patients with a CAC of zero had low
may reach thresholds for starting statin therapy for primary 10-year ASCVD event rates (1.3% to 5.6%), with higher ASCVD
prevention than with the Framingham risk calculator used in event rates associated with age. Those with CAC scores 300
the National Cholesterol Education Program Adult Treatment Agatston units and above had the highest ASVD event rates,
Panel III guideline (Karmali 2014). suggesting that elevated CAC is strongly associated with
increased 10-year ASCVD risk. Recommendations from the
Coronary Artery Calcium Scoring 2018 cholesterol guidelines state that patients with a CAC
Assessing coronary artery calcium (CAC) was recommended score of zero, but with diabetes, family history of premature
in previous dyslipidemia guidelines as an additional factor to ASCVD, current smoking, or inflammatory disorders may be

Figure 4. 2018 ACC/AHA cholesterol guidelines for patients without diabetes mellitus.
a
Risk enhancing factors listed in Box 1.
ASCVD = atherosclerotic cardiovascular disease; CAC= coronary artery calcium; LDL-C= low-density lipoprotein cholesterol.
Information from: Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/
PCNA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol 2018:Nov 10 [Epub ahead of print].

PSAP 2019 BOOK 1 • Cardiology 37 Dyslipidemia

exceptions and benefit from statin therapy. In patients with points on the basis of the presence of each risk factor. Event
CAC score greater than zero, statin therapy would be favored. rates for the composite outcome of CV death, MI, or ischemic
stroke over 7 years were significantly lower in patients con-
sidered at high risk (three or more TRS 2°P risk factors) and
NEW EVIDENCE FOR NON-STATIN
intermediate risk (two TRS 2°P risk factors) who received sim-
THERAPIES IN PREVENTING ASCVD
vastatin/ezetimibe than in placebo. Hazard ratios for the com-
Ezetimibe posite CV outcome were 0.81 (95% CI, 0.73–0.90) for patients
Ezetimibe, when added to statins, reduces the LDL-C by 20%– at high risk, with a reported absolute risk reduction of 6.3%.
25%. The IMPROVE-IT study showed additional ASCVD risk No significant risk reduction was reported for patients at low
reduction when ezetimibe 10 mg was added to moderate-in- risk (less than TRS 2°P risk factors). As might be expected,
tensity statin monotherapy. In this trial, over 18,000 patients the patient population in the high-risk group was older and
hospitalized with an acute coronary syndrome (ACS) event included a more patients with comorbidities (DM, heart fail-
within the previous 10 days were randomized to receive sim- ure, ASCVD) than did the intermediate- and low-risk groups.
vastatin 40 mg and placebo daily or simvastatin 40 mg and However, more patients in the high-risk group were receiving
ezetimibe 10 mg daily (Cannon 2015). The mean LDL-C in both statins and aspirin before the index ACS event.
study groups was 93.8 mg/dL at baseline, with over one-third A subgroup analysis from IMPROVE-IT of patients strati-
of patients in each group receiving statin therapy before the fied by diabetes status at baseline found that ezetimibe/sim-
index ACS event. After a median follow-up of 6 years, the vastatin had a greater absolute risk reduction in patients with
median time-weighted average LDL-C fell to 53.7 mg/dL in the DM (5.5%) than in patients without DM (0.7%) (p=0.02) (Giug-
simvastatin/ezetimibe group and to 69.5 mg/dL in the sim- liano 2018). Patients without DM but with a thrombolysis
vastatin/placebo group. The primary composite end point in myocardial infarction (TIMI) risk score of 3 or higher had
of CV death, nonfatal MI or stroke, hospitalization for unsta- greater benefit with ezetimibe/simvastatin than with statin
ble angina, or coronary revascularization was significantly monotherapy (HR 0.82; 95% CI, 0.68–0.98). The absolute risk
reduced by year 7 in patients receiving the simvastatin/eze- reduction in patients without DM and with TIMI risk scores of
timibe combination compared with those receiving simvas- 2 or lower was not significantly different between the study
tatin/placebo, with a reported hazard ratio of 0.936 (95% CI, groups (HR 0.91; 95% CI, 0.78–1.07).
0.89–0.99; p=0.016). Among the individual CV end points of
the primary outcome, significant reductions in nonfatal MI PCSK9 Inhibitor Efficacy and Safety
(HR 0.87; 95% CI, 0.80–0.95) and ischemic stroke (HR 0.79; The PCSK9 inhibitors lower LDL-C by up to 70% when added
95% CI, 0.67–0.94) were reported. Subgroup analysis found to statin therapy. In the United States, alirocumab and evo-
two populations – patients with DM (HR 0.86; 95% CI, 0.78– locumab are the currently available drugs in this class.
0.94) and patients 75 and older (HR 0.80; 95% CI, 0.70–0.90) Alirocumab is indicated for use as an adjunct to lifestyle mod-
– in which simvastatin/ezetimibe seemed to be of greater ifications and maximally tolerated statin therapy in patients
benefit. Despite showing significant, though modest, ASCVD with heterozygous familial hypercholesterolemia (HeFH) or
risk reduction when added to statin therapy, ezetimibe did clinical ASCVD who require additional LDL-C lowering. Evo-
not receive an extended indication for CV reduction. The rela- locumab has several indications, including adjunct therapy
tive risk reduction of 6% over a 7-year treatment is a criticism to LDL-C-lowering therapies in patients with HoFH, as mono-
of this study, despite its relatively positive number needed therapy or in combination with other lipid-lowering agents in
to treat (NNT) of 50. Furthermore, this study began before patients with primary hyperlipidemia (including HeFH), and to
the 2013 ACC/AHA guideline and used moderate-intensity reduce the risk of CV events in patients with ASCVD.
statins in a patient population that would have been rec-
ommended to receive high-intensity therapy. However, this Evolocumab
study followed lipid recommendations at the time to treat The Further Cardiovascular Outcomes Research with PCSK9
patients with ASCVD with statin therapy to an LDL-C of less Inhibition in Subjects with Elevated Risk (FOURIER) study
than 70 mg/dL. was published in 2017 (Sabatine 2017). Over 27,000 patients
A recent post hoc analysis of IMPROVE-IT evaluated the with clinical ASCVD and an LDL-C of 70 mg/dL or greater (or a
Thrombolysis in Myocardial Infarction Risk Score for Second- non-HDL of 100 mg/dL or greater) while taking moderate-in-
ary Prevention (TRS 2°P) risk stratification tool to assess char- tensity statin therapy (with or without ezetimibe) were ran-
acteristics of patients post-ACS who might benefit the most domized to subcutaneous injections of evolocumab 140 mg
from adding ezetimibe to statin therapy (Bohula 2017). The every 2 weeks or placebo. The median LDL at baseline was 92
TRS 2°P stratification tool assesses nine risk factors (CHF, mg/dL among both study groups. After 48 weeks, LDL-C was
hypertension, age 75 or older, DM, prior stroke, prior coro- significantly reduced to a median value of 30 mg/dL in the
nary artery bypass grafting, peripheral arterial disease, eGFR evolocumab group, a mean absolute reduction of 56 mg/dL.
less than 60 mL/minute/1.73 m2, and smoking) and assigns In addition, treatment with evolocumab reduced the LDL-C to

PSAP 2019 BOOK 1 • Cardiology 38 Dyslipidemia

less than 40 mg/dL in two-thirds of participants, which had analysis showed consistent results across age and sex, though
previously been suggested by the 2013 ACC/AHA guideline as patients with a baseline LDL-C above 100 mg/dL had greater
a threshold to lower the statin dose. Significant reductions benefit. Safety analysis showed no significant difference in
in non-HDL-C (52%) and ApoB (49%) were also reported in the reported adverse effects, new-onset diabetes, or neurocogni-
study group that received evolocumab compared with pla- tive dysfunction (Schwartz 2018).
cebo. After a median follow-up of only 26 months, event rates
for the primary composite end point of CV death, nonfatal MI PCSK9 Inhibitor Safety
or stroke, coronary revascularization, or hospitalization for Given the relative newness of PCSK9 inhibitors and their abil-
unstable angina were 9.8% with evolocumab compared with ity to dramatically lower LDL-C, the safety of these agents is
11.3% with placebo (HR 0.85; 95% CI, 0.79–0.92). In addition, of great concern. The FOURIER trial reported similar rates of
the evolocumab group had a significantly reduced risk of key adverse events between evolocumab and placebo, but a mod-
secondary outcomes, including MI, total stroke, and coronary estly higher incidence of injection-site reactions with evolo-
revascularization; however, the incident rates of CV death cumab. The incidence of new-onset diabetes, which has been
were similar between the study groups. Subgroup analysis associated with statin therapy, was numerically higher in
showed similar benefits of evolocumab across age, sex, and the evolocumab group (8.1%) than in placebo (7.7%) but was
baseline LDL-C. These new RCT data were one of the major not statistically significant (Sabatine 2017). Because evolo-
changes in the 2017 ACC ECDP focused update, considering cumab is a monoclonal antibody, concern exists that patients
that both LDL-C and non-HDL-C were used as inclusion crite- may develop neutralizing antibodies, thus lowering the effec-
ria and that significant reductions in ASCVD end points were tiveness of the treatment. This did not occur in FOURIER,
associated with evolocumab without a greater risk of adverse where LDL-C reductions were maintained throughout the fol-
effects during the study. low-up. Adverse effects of cognitive dysfunction have been
A secondary analysis of FOURIER evaluated the efficacy and reported with statin use, which is thought to be a result of low
safety of evolocumab achieved with evolocumab treatment LDL-C. Although FOURIER was relatively short, low neurocog-
across several LDL-C ranges (Giugliano 2017b). After 4 weeks of nitive event rates were reported in both study groups.
treatment, 10% of patients achieved an LDL-C less than 20 mg/ To address concerns regarding cognitive dysfunction
dL, 31% achieved 20–49 mg/dL, 13% achieved 50–69 mg/dL, related to evolocumab and/or achieving low LDL values, a sub-
29% had 70–99 mg/dL, and 17% had LDL-C 100 mg/dL or higher. group of FOURIER participants (n=1204) also participated in
Event rates of the primary outcome over 3 years were lower in the concurrent Evaluating PCSK9 Binding Antibody Influence
those who achieved the lowest LDL-C (10.3%) and increased on Cognitive Health in High Cardiovascular Risk Subjects
with each achieved LDL-C range; the highest event rates were (EBBINGHAUS) trial (Giugliano 2017a). This trial prospectively
in those with the highest LDL-C (15.5%). evaluated FOURIER subjects’ cognitive function with the Cam-
bridge Neuropsychological Test Automated Battery (CANTAB),
Alirocumab
specifically the CANTAB’s spatial working memory strategy
The ODYSSEY-OUTCOMES trial evaluated alirocumab or pla- index of executive function component. Scores of this com-
cebo in over 18,000 patients at 1–12 months after an ACS event, ponent were 4–28, with lower scores indicating more efficient
with LDL-C 70 mg/dL and higher or non-HDL-C 100 mg/dL and use of strategy and planning. Subjects in EBBINGHAUS were
higher while receiving a high-intensity statin or a maximally tol- evaluated with the CANTAB at baseline, at week 24, yearly,
erated statin. Baseline median LDL-C concentrations were 87 and at the end of the trial. At baseline, each group had a mean
mg/dL in both study groups and were significantly lowered by score of 17.8 and over a median 19-month follow-up; no signif-
54.7% after 48 months with alirocumab compared with placebo. icant changes were noted between the groups for the spatial
Alirocumab treatment could be interrupted to achieve a target working memory strategy index of executive function. Several
LDL-C of 15–50 mg/dL. After a median follow-up of 2.8 years, secondary end points assessing working memory, episodic
treatment with alirocumab was associated with a 15% reduc- memory, and psychomotor speed scores also indicated no
tion in the primary composite end point of CV death, nonfatal significant differences between patients treated with evolo-
MI or ischemic stroke, or unstable angina requiring hospital- cumab or placebo. Post-study exploratory analysis reported
ization compared with placebo (95% CI, 0.78–0.93; p=0.0003). no association of cognitive effects by treatment LDL-C value.
In addition, similar to results from FOURIER, the individual Given the relatively short study duration, follow-up data on
secondary CV end points of nonfatal MI, ischemic stroke, and patients in the FOURIER trial will be necessary to determine
unstable angina requiring hospitalization were all statistically the long-term safety and efficacy of evolocumab.
lower in the alirocumab group. Unlike in FOURIER, alirocumab The secondary analysis from FOURIER not only examined
was associated with a 15% reduced risk of all-cause mortality ASCVD risk by achieved LDL, but also assessed adverse events
compared with placebo (95% CI, 0.73–0.98; p=0.026), but was across the five LDL-C categories (Giugliano 2017b). Rates of
not a primary end point of the trial and is potentially influenced patients discontinuing study drug were relatively low (4% or
by the slightly longer follow-up period. Available subgroup less) across all LDL-C groups. Among 10 prespecified safety

PSAP 2019 BOOK 1 • Cardiology 39 Dyslipidemia

 Patient Care Scenario
A 57-year-old Hispanic man is referred to your lipid clinic his BP is 136/78 mm Hg, heart rate 88 bpm, and BMI is
for assessment of ASCVD risk. He has a medical history 27.5 kg/m2. His most recent fasting lipid panel is as fol-
of hypertension, chronic kidney disease stage 3, major lows: TC 209 mg/dL, TG 286 mg/dL, HDL-C 38 mg/dL, and
depressive disorder, and chronic back pain. The patient LDL-C 181 mg/dL. His most recent eGFR calculated to be
also has a history of hypertriglyceridemia (HTG), but 58 mL/min/1.73m2. His calculated 10-year ASCVD risk is 11.3%.
no history of pancreatitis and no family history of pre- According to the 2018 ACC/AHA cholesterol guidelines,
mature ASCVD. The patient denies use of tobacco or which of the following is the most appropriate recommenda-
alcohol. He reports full adherence to the following medi- tion for initial lipid-lowering therapy to lower his ASCVD risk?
cations: chlorthalidone 25 mg/day, amlodipine 5 mg/day, A. Rosuvastatin 20 mg
fluoxetine 20 mg/day, tramadol 50 mg every 6 hours as
B. Atorvastatin 10 mg
needed for pain. The patient meets monthly with a regis-
C. Fenofibrate 135 mg daily.
tered dietitian for dietary planning and exercises for up to
30 minutes most days, as tolerated by back pain. Today D. Ezetimibe 10 mg daily.

ANSWER
Based on the lipid panel and calculated 10-year ASCVD 20% or higher. Answer C is not appropriate as this therapy
risk score, this patient is considered to be “intermediate should be reserved in patients with severe hypertriglycer-
risk”. Moderate-intensity statin therapy to reduce LDL-C idemia (TG ≥500 mg/dL). Answer D may be considered
30 to 49% is recommended due to the presence of CKD, a if the patient cannot tolerate the recommended statin
risk-enhancing factor. High-intensity statin would be rec- intensity and does not achieve the recommended LDL-C
ommended for patients with a 10-year ASCVD risk score of reduction.

1. S tone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic
cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guide-
lines. J Am Coll Cardiol 2014;63:2889-934.
2. G rundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE,
Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ,
Smith Jr SC, Sperling L, Virani SS, Yeboah J, 2018.

outcomes – including neurocognitive effects, new-onset DM, these adverse events result in the need to reduce the statin
hemorrhagic stroke, and non-CV death – differences were not dose or discontinue therapy, it is commonly labeled intoler-
significant between the LDL-C groups over a median follow-up ance. However, the term statin intolerance is overly simplistic,
of 2.2 years. According to this analysis and to the data from and consensus is lacking on its definition (Rosenson 2017a).
long-term PCSK9 inhibitor trials, available PCSK9 inhibitors The 2013 ACC/AHA guideline does not define statin intoler-
appear to be safe even if the LDL-C falls below 20 mg/dL. ance but mentions the need to adjust therapy for patients who
Safety data from ODYSSEY-OUTCOMES reported similar do not reach therapeutic goals or who cannot tolerate therapy
adverse event rates between alirocumab and placebo. Serious (Stone 2014). In contrast, several other societies have tried to
adverse effects occurred in 23.3% and 24.9% of patients random- define this phenomenon (Box 2). Statin intolerance is “a syn-
ized to alirocumab and placebo, respectively (Schwartz 2018). drome that has been verified, confirmed, and documented that
Individual adverse event rates were similar between groups, but leads to suboptimal statin dosing, reductions in statin com-
higher rates of injection-site reactions were reported with aliro- pliance, reduction in patient quality of life and function, statin
cumab (HR 1.82; 95% CI, 1.54–2.17) (Schwartz 2018). cessation, and/or suboptimal LDL lowering” (Rosenson 2017a).
One of the most common symptoms of statin intolerance is
statin-associated muscle symptoms (SAMS). Like with intol-
DEFINING AND MANAGING STATIN erance, consensus is lacking on how to define various SAMS
INTOLERANCE (Box 3). However, each organization recognizes that SAMS
Data analyses suggest that 10%–25% of patients who meet can occur without CK elevations (Thompson 2016). To fur-
the criteria for statin therapy cannot tolerate the appropriate ther complicate the issue, because of the lack of consensus
intensity of a particular statin or any statin therapy because or diagnostic test, providers often rely on subjective reports
of the adverse drug events associated with therapy (Thomp- from the patient, which could be true SAMS or musculoskel-
son 2016). Globally, statin-associated adverse effects are etal problems attributable to other causes (Rosenson 2017).
described as any effect thought to be contributed by the statin The common symptoms consistent with SAMS are myal-
on an organ system or process (Thompson 2016). Statin ther- gias, cramps, or muscle weakness (Rosenson 2014). Typi-
apy has been associated with adverse events affecting the cally, myalgias are bilateral and include large muscle groups
skeletal muscle, metabolic, and neurologic systems. When such as the thigh, buttocks, back, or shoulder girdle, whereas

PSAP 2019 BOOK 1 • Cardiology 40 Dyslipidemia

 Box 2. Guideline Definitions of Statin Intolerance
2013 ACC/AHA Cholesterol Guideline
• Not defined
2014 NLA Expert Consensus
• Characterized by the inability to tolerate at least two statins: one statin at the lowest starting daily doses AND another statin at
any daily dose, because of either objectionable symptoms (real or perceived) or abnormal laboratory determinations, which are
temporally related to statin treatment and reversible on statin discontinuation but reproducible by rechallenge, with other known
determinants excluded
• The lowest starting statin daily dose is defined as the lowest approved dose
2015 International Lipid Expert Panel
• The inability to tolerate at least two different statins: one statin at the lowest starting average daily dose and the other statin at
any dose
• Intolerance associated with confirmed, intolerable statin-related adverse effect(s) or significant biomarker abnormalities
• Symptoms of biomarker change resolution or significant improvement upon dose decrease or discontinuation
• Symptoms of biomarker changes not attributable to established predispositions such as drug-drug interactions and recognized
conditions increasing the risk of statin intolerance
2016 Canadian Consensus Working Group
• A clinical syndrome characterized by:
○○ Significant symptoms and/or biomarker abnormalities that prevent long-term use of, and adherence to, indicated use
of statins
○○ Documented by challenge/dechallenge/rechallenge, when appropriate, using at least two statins, including atorvasta-
tin and rosuvastatin
○○ Not because of drug-drug interactions or untreated risk factors for intolerance
○○ And leading to failure to maintain therapeutic goals as defined by national guidelines

Rosenson RS, Baker S, Banach M, et al. Optimizing cholesterol treatment in patients with muscle complaints. J Am Coll Cardiol
2017a;70:1290-301.

Box 3. Definitions of SAMSa cramps are often unilateral and occur in smaller muscles
2002 ACC/AHA Advisory on Statins (Bruckert 2005). A temporal relationship is usually present
• Myopathy: Any muscle symptoms (SAMS) with the symptoms, given that they often occur in the first 2
• Myalgia: SAMS CK = NL weeks after starting therapy or increasing the dose (Thomp-
• Myositis: SAMS CK > ULN son 2016). Symptoms typically improve within 1–2 weeks of
• Rhabdomyolysis: CK > 10 x ULN statin discontinuation (Rosenson 2014).
2013 Canadian Work Group
• Myopathy: Any muscle symptoms (SAMS) Many risk factors for SAMS have been identified, includ-
• Symptomatic myalgia: ing increased serum statin concentrations or reduced muscle
○○ Myalgia CK ≤ ULN mass. Additional risk factors include advanced age, female
○○ Myositis CK > ULN sex, physical disability, lower BMI, hypothyroidism, vitamin
○○ Rhabdomyolysis CK > 10 x ULN
D deficiency, high-intensity statins, use of muscle toxic com-
2014 NLA Muscle Safety Task Force
pounds (e.g., steroids), and drugs that can inhibit CYP3A4 for
• Myalgia: Aching, stiffness, cramps
• Myopathy: Weakness certain statins (Thompson 2016).
• Myositis: Inflammation Given these factors, determining the true incidence of
• Myonecrosis: CK 3 x ULN SAMS is challenging. Pooled data analyses of 56,000 patients
○○ Mild: CK > 3, < 10 x ULN
from 42 large-scale RCTs showed a 13% rate of reported mus-
○○ Moderate: CK > 10, < 50 x ULN
○○ Severe: CK > 50 x ULN cle symptoms, which was consistent with the placebo group
○○ Rhabdomyolysis: CK > ULN and SCr > 0.5 mg/dL (Stulc 2015). In contrast, in the Goal Achievement After Utiliz-
baseline ing an Anti-PCSK9 Antibody in Statin Intolerance 3 (GAUSS-3)
2018 ACC/AHA Cholesterol Guidelines trial at 12 weeks, 42.6% of patients receiving atorvastatin 20
• Myalgias: CK = NL mg daily had intolerable SAMS compared with 26.5% receiv-
• Myositis/myopathy: CK > ULN with concerning symp- ing placebo (Nissen 2016). Of note, the highly publicized
toms or objective weakness
nature of SAMS could have elevated the rates of documented
• Rhabdomyolysis: CK >10x ULN + renal injury
intolerance in both arms of the GAUSS trial because of the
a
Note: Normal CK range is 38–174 units/L for men and 96–140 “nocebo effect” (Thompson 2016). To better explain the true
units/L for women.
occurrence of SAMS, the NLA has developed a SAMS-Clinical
UNL = upper normal limits; SAMS = statin-associated muscle
symptoms. Index (SAMS-CI) score that helps determine the likelihood of
SAMS (Figure 5). This scoring system focuses on the timing,

PSAP 2019 BOOK 1 • Cardiology 41 Dyslipidemia

 Figure 5. Statin-Associated Muscle Symptom Clinical Index. The Index provides a scoring system to evaluate statin-
associated muscle symptoms on the basis of location, pattern, timing of onset/offset of symptoms, timing of recurrence
based on rechallenge, and previous symptoms with statin exposure. A total score is used to assess the likelihood of
patient’s symptoms from statin use. A score of 2–6 is unlikely, 7–8 is possible, and 9–11 is probable.
Adapted with permission from: Rosenson RS, Miller K, Bayliss M, et al. The Statin Myalgia Clinical Index (SMCI): revision for clinical
use, content validation, and inter-rater reliability. Cardiovasc Drug Ther 2017;31:179-86.

PSAP 2019 BOOK 1 • Cardiology 42 Dyslipidemia

 Figure 6. Clinical approach to patients with statin-associated muscle symptoms.
Reprinted with permission from: Rosenson RS, Baker S, Banach M, et al. Optimizing cholesterol treatment in patients with muscle
complaints. J Am Coll Cardiol 2017;70:1290-301.

location, and response when rechallenged to another statin Despite the limited data, many experts recommend treatment
regimen to truly define intolerance. This score has further with vitamin D supplementation if deficiency is documented,
been validated with a predictive value of 91% for a SAMS-CI given the low risk, potential benefits, and low cost of vitamin
score of 4 or lower that a patient was unlikely to have a statin D (Thompson 2016). In addition, providers should continu-
myalgia (Rosenson 2017b). ally assure patients about the safety of statin therapy despite
If a patient has subjective concerns for SAMS after start- having a SAMS.
ing a statin, the first step in treatment is to discontinue the Once a statin is discontinued, the patient’s symptoms
offending agent (Figure 6) (Rosenson 2014). Per the 2018 should be reassessed in 2–3 weeks. If the symptoms persist,
cholesterol guidelines, it is a Class 1, Level of Evidence A other reasons for myalgia should be explored. If the symp-
recommendation that the patient should have symptoms toms resolve, the statin, either the same agent at a lower
evaluated, using a tool such as the SAMS-CI score and mea- dose/intensity or a different agent at the same or lower dose/
surement of CK levels, be assessed for myalgia risk factors, intensity, should be reinstated per the updated 2018 guide-
and profile reviewed for drug-drug interactions that could lines (Grundy 2018). When prescribing an alternative sta-
contribute to SAMS (Grundy 2018, Rosenson 2017a). As noted tin compared with the initial agent, an agent with a different
earlier, vitamin D deficiency has been implicated in SAMS, pharmacokinetic profile should be chosen.
though some of these data were not blinded or did not use a The usefulness of coenzyme Q10 remains questionable.
standardized mean to assess intolerance. Limited data sug- Statins have been theorized to lead to the depletion of coen-
gest that patients who receive vitamin D supplementation zyme Q10, and replacing it may prevent or limit SAMS. How-
are more likely to remain adherent to statin therapy with no ever, a randomized, double-blind, crossover trial comparing
muscle concerns after 24 months of treatment (Wu 2018). simvastatin 20 mg/daily with 600 mg/daily of coenzyme Q10

PSAP 2019 BOOK 1 • Cardiology 43 Dyslipidemia

versus placebo showed no change in muscle strength, as patients dichotomously into younger old (age 65–75) and
measured by oxygen uptake, and no difference in reported very old or very elderly (≥75 years) (Schwartz 2015). The risk
muscle pain (Taylor 2015). Given the lack of positive out- of ASCVD increases by 10%–15% with each decade of age
comes in this trial and in subsequent meta-analyses, coen- (Mortensen 2018). An estimated 30.6% of male patients and
zyme Q10 cannot routinely be recommended and the 2018 21.7% of female patients older than 80 have CHD, compared
guidelines provide a Class III recommendation of no benefit with 19.7% of male and 11.0% of female patients age 60–79
for this use (Grundy 2018, Rosenson 2017a). years (Benjamin 2018). Furthermore, it is unclear on the basis
Providers can also consider alternative dosing regimens. of epidemiologic data whether LDL contributes the same
Statins with longer half-lives such as rosuvastatin and ator- ASCVD risk in older adults as in younger patients or whether
vastatin can be dosed every other day or less often, which it could potentially be protective (Ruscica 2018). Data from
leads to reduced exposure to therapy (Rosenson 2014). This RCTs for primary prevention in older adults are lacking, with
approach effectively reduces LDL, with rosuvastatin achiev- most statin trials limiting or excluding this group (Mortensen
ing a 26% LDL reduction at a dose of about 10 mg twice 2018).
weekly (Gadarla 2008). Supplementation with non-statin ther- In the Prospective Study of Pravastatin in the Elderly at
apy such as a PCSK9 inhibitor or ezetimibe can be consid- Risk (PROSPER), patients 70 and older were randomized to
ered if the patient is placed on a secondary regimen with less pravastatin 40 mg or placebo (Shepherd 2002). Patients were
intensity. However, the long-term outcomes with this combi- followed for 3.2 years to evaluate the primary end points of
nation have not been explained. Patients who cannot take a CHD death, nonfatal MI, and fatal or nonfatal stroke. Patients
statin after two or more attempts can be deemed intolerant. who received treatment had a 15% reduction in end points
Once intolerant, non-statin agents with ASCVD risk reduction (HR 0.85; 95% CI, 0.74–0.97; NNT 48). However, the popula-
should be considered (Grundy 2018, Rosenson 2017a). tion was not strictly a primary prevention cohort in the study,
with ~44% having vascular disease at baseline. A subgroup
STATINS AND DM RISK analysis of the patients who did not have vascular disease
Another common patient concern is the potential increased had no reduction in CHD or stroke during follow-up (Shepherd
risk of developing type 2 DM. An exact mechanism for an 2002). Thus, the study’s mixed primary and secondary pre-
increased DM risk has not clearly been defined. However, vention patient population is a limitation. Beyond the PROS-
there appear to be several risk factors for developing DM PER trial, a Cholesterol Treatment Trialists meta-analysis of
with statin therapy, including statin dose, history of meta- a cohort of very elderly patients from primary prevention tri-
bolic syndrome, female sex, increased age, and Asian eth- als showed, with respect to vascular events, an absolute risk
nicity (Thompson 2016). Two meta-analyses have provided reduction of 0.6% per year per 38.7-mg/dL reduction in LDL
clarity on the risk-benefit of statin therapy on DM risk. One concentrations in patients older than 75 (Cholesterol Treat-
meta-analysis reviewed 20 statin trials, both randomized con- ment Trialists 2010). This translates to a NNT of 167.
trolled and genetic studies, of around 130,000 patients who This dearth of data creates an evidence gap that has led
were followed for an average of 4.2 years (Swerdlow 2015). A to a lack of consensus regarding guideline recommendations
total of 3858 statin-treated and 3481 placebo-treated patients for this high-risk subpopulation. Despite the lack of data, the
developed new-onset DM (OR 1.12; 95% CI, 1.06–1.18). Another 2018 cholesterol guidelines recommend moderate-intensity
analysis explored the relationship between high- and moder- statin therapy for adults older than 75 years of age who have
ate-intensity statin therapy (Preiss 2011). In this analysis, the an LDL-C level of 70 to 189mg/dL (Grundy 2018). When consid-
five RCTs that were included showed that new DM occurred ering outcomes in the very elderly patient population, provid-
in 4.4% in the high-intensity group versus 4.0% in the moder- ers must realize that the treatment will more effectively reduce
ate-intensity group (OR 1.12; 95% CI, 1.04–1.22). The authors nonfatal ASCVD events than mortality (Mortensen 2018). This
determined that intense statin therapy would prevent 3.2 must be weighed with the consideration of frailty, multiple
ASCVD events for each new DM case. Overall, patients can comorbidities, and polypharmacy, which may increase the
be informed that the small increase in risk is exceeded by the risk of statin-associated adverse effects (Rosenson 2017).
ASCVD benefit reduction; as such, adherence to statin ther- It is critical to have a shared decision-making conversation
apy, heart healthy diet, and regular, moderate-intensity exer- with the patient regarding benefit-risk and desired outcomes
cise should be emphasized (Grundy 2018). and to limit exposure to statin-associated adverse events if
treatment is pursed. The 2018 cholesterol guidelines state
it may be reasonable to stop statins therapy with functional
SELECT SPECIAL POPULATIONS
decline, frailty, multi-morbidity, and when life-expectancy is
Primary Prevention in the Very Elderly reduced. Furthermore, the guidelines recommend patient
The older adult population is rapidly growing worldwide. In who are aged 76-80, who have an LDL-C of 70-189mg/dL, can
general, the term elderly includes patients older than 65. How- use a CAC score of zero to avoid statin therapy (Grundy 2018).
ever, many organizations and research studies have classified

PSAP 2019 BOOK 1 • Cardiology 44 Dyslipidemia

 The ongoing STAREE (Statins for Reducing Events in the Given the limited data supporting any agent that targets
Elderly; NCT02099123) trial is currently recruiting 18,000 both TG and ASCVD risk reduction, most experts and soci-
patients age 70 and older to determine the efficacy and safety eties currently do not recommend starting drug therapy for
of statins in primary prevention. The trial, whose primary this reason (Miller 2011). Often, patients with a TG of 200–499
objective is to determine whether treatment with atorvastatin mg/dL have other indications for ASCVD reduction with statin
40 mg daily compared with placebo will prolong overall sur- therapy, and a high-intensity statin alone provides upward to
vival or disability-free survival among healthy older adults, is a 30%–40% reduction in TG (Kelly 2017).
estimated to be completed in 2022. Beyond statin therapy, other lipid-lowering agents such as
fibrates, omega-3 fatty acids, and niacin can be added to reach
Hypertriglyceridemia non-HDL goals, given limited positive data regarding their
The prevalence of hypertriglyceridemia (HTG) is about 25% impact on ASCVD risk. When deciding among agents, several
in the United States (Rosinger 2016). Epidemiologic data and factors can be considered. For example, fenofibrate may be
meta-analyses provide a link between elevated TG and the risk preferred to add to statin therapy because of its daily admin-
of ASCVD (Miller 2011). However, no pathophysiologic mecha- istration, favorable adverse effect profile, and generic avail-
nism for the direct role of TG in this increased risk is known. ability (Kelly 2017). Of note, fenofibrate appears to reduce the
Often, HTG occurs in patients with metabolic syndrome, DM, or risk of myalgia when co-administered with a statin compared
obesity (Jacobson 2015b). Various CV and endocrinology soci- with the fibrate gemfibrozil. However, proper dosing should
eties recognize the linked ASCVD risk with TG and define vari- still be used for both agents, given the limited potential for
ous thresholds for HTG. Most experts, including the 2014 NLA interaction. A preplanned subgroup analysis for the ACCORD-
expert panel and the 2018 cholesterol guidelines, recommend Lipid trial of patients with type 2 DM with a TG of 204 mg/dL
treating patients only when fasting TG concentrations are 500 or greater and an HDL of 34 mg/dL or less suggested a rel-
mg/dL or greater (Jacobson 2015a; Grundy 2018). However, this ative risk reduction of major adverse cardiac events by 27%
treatment threshold is meant to reduce the risk of acute pancre- (HR 0.73; 95% CI, 0.56–0.95) at 5 years (ACCORD Study Group
atitis and is not specifically meant to reduce ASCVD risk. When 2010). The benefit of fibrates for ASCVD risk reduction may be
concentrations are 200–499 mg/dL, experts focus treatment more pronounced if a patient is not receiving statin therapy,
on ASCVD risk reduction with the traditional targets of LDL and/ according to historical data (Kelly 2017).
or non-HDL, such as statins (Jacobson 2015a, Grundy 2018). The lack of ASCVD risk reduction with niacin in combina-
Patients with HTG should be educated regarding changes tion with a statin in both the AIM-HIGH and the HPS2-THRIVE
in lifestyle, including diet and exercise. The 2011 AHA con- trials has raised questions about the benefit of this combi-
sensus document, the 2014 NLA expert panel, and the 2018 nation (HPS2-THRIVE Collaborative Group 2014; AIM-HIGH
cholesterol guidelines recommend interventions such as 2011). Omega-3 fatty acids appeal to patients because of their
eliminating trans-fatty acids, increasing fiber, reducing simple availability as a dietary supplement; however, some patients
carbohydrates, reducing or limiting alcohol consumption, and find the multiple-daily dosing a challenge. Moreover, the evi-
attaining a weight loss of 5%–10% (Jacobson 2015b; Miller dence supporting reduced ASCVD risk is limited to clinical
2011). Patients with a TG of 500 mg/dL or greater need more trials of specific populations, such as those with advanced
aggressive treatment with these measures. Optimizing these heart failure or patients in Japan. In contrast, a large-scale
factors can reduce TG concentrations by 20%–50% (Miller placebo-controlled trial randomized 15,480 patients with dia-
2011). Furthermore, non-dietary, secondary causes of HTG betes and no ASCVD to 1 g of omega-3 fatty acids or placebo
such as hypothyroidism, drugs, renal disease, and diabetes (ASCEND Study Collaborative Group 2018). After a mean fol-
should be investigated and appropriately managed (Jacobson low-up of 7.4 years, serious vascular events occurred in 8.9%
2015b, Grundy 2018). of patients in the treatment group and in 9.5% of the pla-
Pharmacologic therapy has two distinct indications for cebo (p=0.55). These results agree with a meta-analysis of
treating HTG: prevention of pancreatitis and theoretic lower- 10 large RCTs including 77,917 patients at high ASCVD risk
ing of ASCVD risk. For pancreatitis, therapy is often initiated that explored the outcomes of fatal CHD, nonfatal MI, stroke,
only at persistent concentrations above 500 mg/dL (Jacob- major vascular events, and all-cause mortality with omega-3
son 2015a, Jacobson 2015b). The logic behind this threshold fatty acid products (Aung 2018), specifically eicosapentae-
is the potential for non-fasting TG to be above 1600 mg/dL, noic acid at doses of 226–1800 mg/day. Supplementation
and the risk of pancreatitis is minimal below around 750 mg/ with these agents was not associated with death from CHD
dL. When treating pancreatitis, the goal is to lower the TG to (p=0.05), nonfatal MI (p=0.43), any CHD events (p=0.12), or
below 500 mg/dL; however, clinical trial data are limited to major vascular events (p=0.10) in the overall population or
support outcomes for this recommendation (Lederle 2012). subgroup. The results raise questions regarding dosing and
For a TG concentration of 500 mg/dL or greater for pancre- whether omega-3 alone or in combination with omega-6 is
atitis, first-line therapy includes fibrates, omega-3 fatty acids, better. Large trials with prescription omega-3 combination
and niacin (Jacobson 2015b, Grundy 2018). products in conjunction with statins are lacking (Kelly 2017).

PSAP 2019 BOOK 1 • Cardiology 45 Dyslipidemia

The highly anticipated Reduction of Cardiovascular Events Should the patient’s risk remain elevated after these steps,
with Icosapent Ethyl-Intervention Trial (REDUCE-IT) resulted the first line treatment would be moderate or intensive sta-
in 25% relative risk reduction in major adverse cardiac events tin therapy (Grundy 2018, Jacobson 2015a). Of note, the use
(17.2% in treatment versus 22.0% in placebo, p<0.001) when a of CAC can also be used to further elucidate risk in these
2 grams twice daily of icosapent ethyl was given to patients patients before starting statin therapy (Grundy 2018). Cur-
at risk for ASCVD events and were treated with statins (Bhatt rently, treatment goals and monitoring follow those for other
2018). These results indicate that the dose and type of omega patients at high risk of ASCVD; however, this recommenda-
fatty acid could be the key to benefit; however, the mechanis- tion is extrapolated, given the lack of specific data in this pop-
tic benefit is not completely clear since TG were only reduced ulation. Although statins are the treatment of choice, use of
by 18.3% in the treatment arm (Bhatt 2018). Experts suspect a optimal-dosed statins in the PLWHA population is limited
combination of TG lowering, antiplatelet effects, and anti-in- (Chastain 2017). One of the barriers to appropriate use are the
flammatory effects maybe have contributed to the results. many and varied drug-drug interactions between statins and
ART. The protease inhibitors are the most common class of
People Living with HIV/AIDS agents that lead to drug interactions because of the inhibition
The life span of people living with HIV/AIDS (PLWHA) has or induction of CYP3A4, P-glycoprotein, and organic anion–
increased because of research about the virus and the devel- transporting polypeptide (Wiggins 2017). Although protease
opment of antiretroviral therapy (ART). Before the advent inhibitors are the most common, classes such as nonnu-
of ART, a PLWHA average life span was 40 years, which has cleoside reverse-transcriptase inhibitors also have interac-
increased to an average of 50 years post-ART (Chastain tions. Providers should be aware of the various effects on
2017). Declining HIV-associated deaths/complications have statin therapy with ART. Often, these interactions lead to the
led to an increased occurrence of CVD in PLWHA. The diag- need for statin dose reductions in order to minimize the risk
nosis of HIV is independently associated with an increased of statin-associated adverse events. Providers should also
risk of CVD because of inflammation as well as activation avoid ART with a high likelihood of interactions with statins,
and dysfunction of the immune system. In fact, CVD morbid- and the patient’s HIV provider should be consulted.
ity and mortality is 1.5–2 times greater in PLWHA than those If patients need additional agents beyond statin therapy,
without HIV (Maggi 2017). Compounding this risk is the dys- fibrates, ezetimibe, niacin, and omega-3 fatty acids can be
lipidemia and metabolic syndrome related to the use of ART, used (Jacobson 2015b). If fibrates are used, the fenofibrate
which commonly occurs with the protease inhibitors (Jacob- agents should be used instead of gemfibrozil because of
son 2015b). The true impact of ART on ASCVD risk is poorly the risk of drug-drug interactions (Wiggins 2017). The lim-
defined and varies with each agent. A single-center retro- ited interaction profile with ezetimibe makes it an optimal
spective analysis of ritonavir-boosted protease inhibitor reg- adjunctive therapy for additional LDL reduction. Despite
imens in PLWHA and heart failure found a 2-fold increase in these recommendations, clinical trials have not shown pos-
ASCVD mortality (Alvi 2018). An estimated 80% of patients itive outcomes in this population. No published studies cur-
with HIV have dyslipidemia, of whom only about 10% receive rently explore the use of PCSK9 inhibitors specifically in the
statin therapy (Chastain 2017). HIV population, but providers can extrapolate similar LDL and
Despite this increased risk of ASCVD, the ideal treatment ASCVD risk reductions.
of these patients has been poorly defined because of lim-
ited trials with major CV event outcomes. Specifically, with Pregnancy
respect to dyslipidemia, trials have relied on the use of sur- Pregnant women with dyslipidemia are a unique population
rogate end points such as LDL reduction or carotid or fem- requiring careful clinical consideration (Wild 2015). Although
oral intima-medial thickness (Chastain 2017). Trials with some cholesterol is derived from fetal development, other
lipid-lowering agents in PLWHA have shown percent reduc- sources include maternal circulation and synthesis from
tions in LDL and non-HDL similar to those in patients with- the placenta and yolk sac. Overproduction or high concen-
out HIV infection (Wiggins 2017). The 2014 NLA’s expert trations of cholesterol from the maternal source can lead
consensus recommends that HIV, on or off treatment, be to increased fatty streaks in the fetus’s vascular walls (Wild
considered a major risk factor for ASCVD and recommends 2016). Evidence suggests these atherosclerotic changes lead
that the patient receive statin therapy (Jacobson 2015a). to epigenetic changes that increase the child’s risk of future
In addition, the 2018 cholesterol guidelines recommend ASCVD. The comorbidities of metabolic syndrome and FH in
screening for ASCVD via risk factor assessment and fast- the mother pose increased risk to the fetus of these changes.
ing lipid profile early and regularly in these patients (Grundy Beyond LDL and ASCVD, TG often increases during preg-
2018). When considering ASCVD prevention among PLWHA, nancy (Jacobson 2015b).
the main management strategies are to ensure the patient Unfortunately, given that clinical ASCVD events occur on
is receiving ART and to control modifiable risk factors average 10 years later in women than in men, disparities exist
(Wiggins 2015). regarding the appropriate time to screen and treat women

PSAP 2019 BOOK 1 • Cardiology 46 Dyslipidemia

 Table 2. Select Agents in Development to Treat Hyperlipidemia

Effect on Lipid Values

Lipid-Lowering Agent TC (%) HDL (%) LDL (%) TG (%) Lp(a) (%)

Inclisiran ↓ 17.6–33.2 ↑ 4.4–10.3 ↓ 27.9–52.6 ↓ 1.1–14.2 ↓ 14.3–25.6

Bempedoic acid ↓ 11.5–17.1 ↑ 0.9–7.2 ↓ 17.9–26.6 ↓ 12.5–14.5 0.0

Volanesorsen ↓ 1.2–11.1 ↑ 31.1–33.9 ↑ 48.3–118.3 ↓ 31.3–70.3 NR

Pemafibrate ↓ 5.3–7.0 ↑ 11.9–21.0 ↑ 0.0–8.9 ↓ 30.9–51.5 NR

Lp(a) = lipoprotein(a); NR = not reported.

(Wild 2016). Many women have undiagnosed dyslipidemia Despite the available evidence-based therapies, many
before pregnancy. Recommendations are lacking from the patients do not meet treatment goals and remain at high
American Academy of Pediatrics (AAP)/American College of residual ASCVD risk. Patients may not achieve these goals
Obstetricians and Gynecologists (ACOG) guidelines and the because of a history of FH or because they do not tolerate
2013 ACC/AHA cholesterol guideline regarding lipid screen- high-dose statins as the result of perceived adverse events
ing recommendations for women of childbearing age. The or nonadherence. This section briefly summarizes select
AAP/ACOG guidelines suggest that lipid assessment should agents being developed (Table 2).
occur annually for all age groups (Jacobson 2015b). The NLA Inclisiran is a chemically synthesized small interfering
expert consensus suggests women should be screened for RNA (siRNA) molecule that is designed to produce sustained
dyslipidemia before pregnancy as part of routine obstetric hepatocyte-specific, PCSK9-specific RNA silencing (Ray
laboratory panels (Jacobson 2015b). 2017). Using siRNA molecules, the translation of their com-
Pregnant women with dyslipidemia should be educated on plementary target messenger RNA can selectively and cat-
proper diet, exercise, and other lifestyle changes. Exercise alytically be silenced, which produces silencing complexes
routines and intensity should be determined in consultation – in this case PCSK9 (Fitzgerald 2017). The downstream
with the patient’s obstetrician (Jacobson 2015b). Given the effect is a reduction in LDL by preventing PCSK9 synthe-
risk of fetal abnormalities, most cholesterol-lowering drugs sis resulting in decreased destruction of the LDL-R. This is
should be discontinued 1-2 months before getting pregnant in contrast to the monoclonal antibodies, which inhibit the
or as soon as pregnancy is discovered (Wild 2016, Grundy ability of PCSK9 to bind to the LDL-R but have no effect on
2018). The only agents with the historic FDA pregnancy cat- PCSK9 synthesis. The phase II, multicenter, double-blind, pla-
egory B are bile acid sequestrants and omega-3 fatty acids cebo-controlled, ORION-1 trial randomized 501 patients with
(Lloyd-Jones 2017; Wild 2016). Of note, a meta-analysis of an average age of 63 to six different inclisiran regimens for
various clinical trials that included pregnant women had no dose-finding purposes (Ray 2017). In the study, around 69%
increased risk of statin-associated fetal abnormalities; how- of patients had ASCVD, 24% had DM, and around 5% had FH.
ever, the trial investigators could not conclude safety in this Most patients, 73%, were receiving statin therapy, and 31%
population (Karalis 2016). Currently, statins are FDA preg- were receiving ezetimibe. Patients were given either a single
nancy category X (Jacobson 2015b). If bile acid sequestrants dose of 200, 300, or 500 mg of inclisiran or placebo on day
and omega-3 fatty acids do not control the patient’s dyslip- 1 or two doses of 100, 200, or 300 mg on days 1 and 90 or
idemia, LDL apheresis can be considered (Wild 2016). This placebo. The primary end point of LDL reduction at 180 days
recommendation may apply more toward women with FH. was a reduction of 27.9%–41.9% in the single-dose inclisiran
Furthermore, patients with HoFH can be administered mipo- arm and of 35.5%–52.6% in the two-dose arm (p<0.0001 for
mersen when needed, given that it is FDA pregnancy risk all comparisons vs. placebo). The most effective dose regi-
category B (Jacobson 2015b). When a patient presents with men for reductions was the two-dose 300-mg regimen. The
an elevated TG, treatment should consist of diet/lifestyle LDL reduction was sustained at 240 days. Injection-site reac-
changes and omega-3 fatty acids. In select patients at higher tions were most common with respect to safety. Further data
risk, fenofibrate and gemfibrozil, which are FDA pregnancy analyses from the other ORION trials will better describe the
risk category C, can be considered in the second trimester potential safety and efficacy of inclisiran.
(Jacobson 2015b). Pemafibrate is a selective peroxisome proliferator–acti-
vated receptor-α (PPARα) modulator. Pemafibrate works
EMERGING THERAPIES like a fenofibrate but is over 5000-fold more selective for the
PPARα than fenofibrate (Fruchart 2017). Because PPARα is a

PSAP 2019 BOOK 1 • Cardiology 47 Dyslipidemia

specific transcription factor for HDL synthesis, very low-den- bempedoic acid is realized, it could provide an alternative for
sity lipoprotein hydrolysis, and expression of apolipopro- patients intolerant of statin therapy.
teins (Fruchart 2017), it may be added for patients who are
still not meeting their non-HDL goals despite maximal toler- CONCLUSION
ate statin therapy, given its ability to reduce TG while increas- The four statin benefit groups created by the 2013 ACC/AHA
ing HDL. In a phase III, randomized, double-blind clinical trial guideline serve as a well-intended starting point for iden-
of 225 patients who had high TG concentrations (150 mg/dL tifying patients most likely to benefit from statin therapy to
or greater and less than 500 mg/dL) and low HDL (less than reduce ASCVD risk. New RCT evidence since the 2013 ACC/
50 mg/dL in men or less than 55 mg/dL in women), patients AHA guideline has demonstrated ASCVD-lowering effects of
were randomized to either pemafibrate 0.2 mg or 0.4 mg daily
or fenofibrate 106.6 mg/day (Ishibashi 2018). Of note, all the
patients were enrolled from Japan, and statin therapy was Practice Points
not used in the study. Compared with fenofibrate, pemafi-
• Alirocumab, evolocumab, and ezetimibe have demon-
brate was associated with a least squares mean difference strated further ASCVD risk reduction when added to statin
in TG of 6.5% in the 0.2-mg group and of 6.3% in the 0.4-mg therapy in patients with clinical ASCVD.
group compared with fenofibrate. Pemafibrate caused no • Ezetimibe and PCSK9 inhibitors may be added to statin
increase in adverse events compared with fenofibrate. The therapy if both patient and prescriber agree that the addi-
positive results should be taken with caution, given the lack tional ASCVD-lowering benefits outweigh the potential
adverse effects of non-statin agents.
of statin treatment in each arm. The Pemafibrate to Reduce
• Ezetimibe is the preferred initial non-statin due to generic
Cardiovascular Outcomes by Reducing Triglycerides in Dia- availability and demonstrated safety and tolerability.
betic Patients (PROMINENT) will be a major outcomes trial Current costs of PCSK9 inhibitors may limit their use due
that recruits 10,000 patients with type 2 DM and elevated TG perceived lack of cost-effectiveness.
and low HDL concentrations to determine whether pemafi- • In addition to considering the percent LDL-C reduction
achieved with statin therapy, LDL-C thresholds may be
brate improves the hard outcomes of death, nonfatal MI, non-
considered to help guide the decision to add non-statin
fatal stroke, or hospitalization for unstable angina. Results of
agents, with more aggressive thresholds (LDL above
this trial should provide better guidance on using pemafibrate 70 mg/dL or non-HDL above 100 mg/dL) in patients with
(Fruchart 2017). clinical ASCVD at high risk and less strict thresholds (LDL
Volanesorsen is an antisense oligonucleotide that inhibits above 100 mg/dL) in patients without clinical ASCVD but at
the production of apolipoprotein C-III (ApoC-III) by knocking high risk.
• Available data on the safety of PCSK9 inhibitor therapy do
out the messenger RNA (Gaudet 2015). In a phase II, random-
not suggest any serious adverse effects associated with
ized, double-blind, placebo-controlled, dose-ranging study, treatment or with very-low LDL-C values achieved during
57 patients either with an untreated fasting TG of 350–2000 therapy.
mg/dL or receiving fenofibrate treatment with TG concen- • Patients can be classified as statin intolerant once the
trations of 225–2000 mg/dL were assigned to 100 mg, 200 offending agent is removed for 2 weeks and symptoms
mg, or 300 mg subcutaneously daily of volanesorsen for 13 return after a rechallenge with a different statin or a lower
dose of the original statin.
weeks (Gaudet 2015). The trial’s primary outcome was per-
• If a patient is truly intolerant of statin therapy, adding any
cent change in ApoC-III concentrations. Baseline TG concen- non-statin agent can be considered, with preference given
trations in each cohort were 581 mg/dL (±291 mg/dL) in the to agents with proven ASCVD risk reduction.
non–fenofibrate-treated arm and 376 mg/dL (±188 mg/dL) in • Data are limited to guide whether patients older than 75
the fenofibrate-treated arm. Administration of volanesorsen benefit from statin therapy in primary prevention. Thus,
any decision to initiate therapy should be made with
led to an ApoC-III reduction of around 40%–71% and TG reduc-
risk-benefit and goals of therapy in mind.
tions of 31%–71%, depending on the dose and treatment
• Patients with TG concentrations of 150–499 mg/dL should
group. No safety concerns were identified. The trial was lim- initially be treated with statin therapy.
ited by its low sample size, short duration, and lack of major • PLWHA are at an increased risk of ASCVD through both the
adverse cardiac event end points. virus itself and the antiviral treatment.
Bempedoic acid is a synthetic molecule that is converted • Many of the HIV drugs, especially the protease inhibitors,
interact with statin therapy. Statins should be selected
to a coenzyme A derivative that inhibits ATP citrate lyase
carefully to limit the risk of adverse events.
(Saeed 2018). This enzyme is a key substrate for cholesterol • Pregnant women should avoid many of the common drugs
and fatty acid synthesis in the liver. The benefit of this mecha- used to manage dyslipidemia; use of bile acid sequestrants
nism is that it provides potent LDL reduction with a theorized and omega-3 fatty acids is preferred.
limited risk of muscle-related adverse effects. Administration • The development pipeline for dyslipidemia is focused on
novel agents that are designed to target non-HDL. These
of this agent in phase II trials has reduced LDL by around 30%
studies should help determine whether targeting non-HDL
(Saeed 2018) with no increased reported events of SAMS. provides further ASCVD risk reduction.
Phase III clinical trials are almost complete. If the promise of

PSAP 2019 BOOK 1 • Cardiology 48 Dyslipidemia

select non-statin agents in patients with ASCVD taking max- Bruckert E, Hayem G, Dejarger S, et al. Mild to moderate mus-
imally tolerated statin therapy. Primary prevention patients cular symptoms with high-dosage of statin therapy in
with LDL-C values above recommended thresholds may also hyperlipidemic patients – the PRIMO study. Cardiovasc
Drug Ther 2005;19:403-14.
be considered for additional non-statin lipid-lowering agents.
A new risk assessment approach is recommended for pri- Budoff MJ, Young R, Burke G, et al. Ten-year association of
mary prevention patients without diabetes and baseline LDL-C coronary artery calcium with atherosclerotic cardiovascu-
below 190 mg/dL. Patient-clinician discussion about benefits lar disease (ASCVD) events: the multi-ethnic study of ath-
erosclerosis (MESA). Eur Heart J 2018;39(25):2401-24018.
of statin therapy, potential adverse effects, and patient spe-
cific risk-enhancing factors is recommended to personalize Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added
ASCVD risk reduction. New lipid-lowering agents are being to statin therapy after acute coronary syndromes. N Engl J
developed that may provide additional choices for treating the Med 2015;372:2387-97.
residual ASCVD risk in patients with an elevated non-HDL-C. Chastain DB, Stover KR, Riche D. Evidence-based review of
Identifying other ASCVD risk factors and assessing patients’ statin use in patients with HIV on antiretroviral therapy.
adherence to lifestyle and medication therapies are critical J Clin Transl Endocrinol 2017;8:6-14.
to preventing ASCVD. Weighing the potential ASCVD benefit
Cholesterol Treatment Trialists C, Baigent C, Blackwell L, et
against the potential risk of adverse effects is key in deter- al. Efficacy and safety of more intensive lowering of LDL
mining which patients will most likely benefit from additional cholesterol: a meta-analysis of data from 170,000 partici-
therapy, as well as the appropriateness of non-statin agents. pants in 26 randomized trials. Lancet 2010;376:1670-81.

Fitzgerald K, White S, Borodovsky A, et al. A highly dura-

REFERENCES ble RNAi therapeutic inhibitor of PCSK9. N Engl J Med
ACCORD Study Group, Ginsberg NH, Elam MB, et al. Effects 2017;376:41-51.
of combination lipid therapy in type 2 diabetes mellitus.
N Engl J Med 2010;362:1563-74. Fox ER, Samdarshi TE, Musani SK, et al. Development and
validation of risk prediction models for cardiovascular
AIM-HIGH Investigators, Boden WE, Probstfield JL, events in black adults. JAMA 2016;1:15-25.
et al. Niacin in patients with low HDL cholesterol
levels receiving intensive statin therapy. N Engl J Med Fruchart JC. Pemafibrate (K-877), a novel selective peroxi-
2011;365:2255-67. some proliferator-activated receptor alpha modulator for
management of atherogenic dyslipidaemia. Cardiovasc
Alvi RM, Neilan AM, Tarig N, et al. Protease inhibitors and Diabetol 2017;16:124.
cardiovascular outcomes in patients with HIV and heart
failure. J Am Coll Cardiol 2018;72:518-30. Gadarla M, Kearns AK, Thompson PD. Efficacy of rosuvasta-
tin (5 mg and 10 mg) twice a week in patients intolerant to
ASCEND Study Collaborative Group. Effects of n-3 fatty daily statins. Am J Cardiol 2008;101:1747-8.
acid supplements in diabetes mellitus. N Engl J Med
2018;379:1540-1550. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibi-
tion of apolipoprotein C-III in patients with hypertriglyceri-
Aung T, Halsey J, Kromhourt D, et al. Associations of demia. N Engl J Med 2015;373:438-47.
omega-3 fatty acid supplement use with cardiovascular
disease risks: meta-analysis of 10 trials involving 77,917 Giugliano RP, Cannon CP, Blazing MA, et al. Benefit of add-
individuals. JAMA Cardiol 2018;3:225-33. ing ezetimibe to statin therapy on cardiovascular out-
comes and safety in patients with versus without
Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease diabetes mellitus: results from IMPROVE-IT. Circulation
and stroke statistics-2018 update: a report from the Ameri- 2018;137:1571-82.
can Heart Association. Circulation 2018;137:e67-e492.
Giugliano RP, Mach F, Zavitz K, et al. Cognitive func-
Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduc- tion in a randomized trial of evolocumab. N Engl J Med
tion with icosapent ethyl for hypertriglyceridemia. N Engl 2017a;377:633-43.
J Med 2018; DOI:10.1056/NEJMoa1812792.
Giugliano RP, Pedersen TR, Park J, et al. Clinical efficacy
Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Statin use and safety of achieving very low LDL-cholesterol con-
for the primary prevention of cardiovascular disease in centrations with the PCSK9 inhibitor evolocumab: a pre-
adults: US Preventive Services Task Force recommenda- specified secondary analysis of the FOURIER trial. Lancet
tion statement. JAMA 2016;316:1997-2007. 2017b;390:1962-71.

Bohula EA, Morrow DA, Giugliano RP, et al. Atherothrombotic Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/
risk stratification and ezetimibe for secondary prevention. AACVPR/AAPA/ACPM/ADA/AGS/APhA/ASPC/NLA/
J Am Coll Cardiol 2017;69:911-21. PCNA Guideline on the management of blood cholesterol:
A report of the American College of Cardiology/Ameri-
can Heart Association Task Force on Clinical Practice

PSAP 2019 BOOK 1 • Cardiology 49 Dyslipidemia

 Guidelines. J Am Coll Cardiol 2018;25709; DOI: 10.1016/j. patients: the GLAGOV randomized clinical trial. JAMA
jacc2018.11.003. 2016;316:2373-84.

HPS2-THRIVE Collaborative Group, Landray MJ, Haynes R, Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tol-
et al. Effects of extended-release niacin with laropiprant in erability of evolocumab versus ezetimibe in patients with
high-risk patients. N Engl J Med 2014;371:203-12. muscle-related statin intolerance: the GAUSS-3 random-
ized clinical trial. JAMA 2016;315:1580-90.
Ishibashi S, Hidenori A, Yokote K, et al. Efficacy and safety
of pemafibrate (K-877), a selective peroxisome prolifera- Pasternak RC, Smith SC Jr, Bairey-Merz CN, et al. ACC/AHA/
tor-activated receptor-alpha modulator, in patients with NHLBI clinical advisory on the use and safety of statins.
dyslipidemia: results from a 24-week randomized, dou- J Am Coll Cardiol 2002;40:567-72.
ble-blind, active-controlled phase III trial. J Clin Lipid
2018;12:173-84. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident dia-
betes with intensive-dose compared with moderate-dose
Jacobson TA, Ito MK, Maki KC, et al. National Lipid Associa- statin therapy: a meta-analysis. JAMA 2011;305:2556-64.
tion recommendations for patient-centered management
of dyslipidemia: part 1. J Clin Lipidol 2015a;9:129-69. Ramos R, Comas-Cufi M, Marti-Lluch R, et al. Statins for pri-
mary prevention of cardiovascular events and mortality in
Jacobson TA, Maki KC, Orringer C, et al. National Lipid Asso- old and very old adults with and without type 2 diabetes:
ciation recommendations for patient-centered manage- retrospective cohort study. BMJ 2018;362:1-12.
ment of dyslipidemia: part 2. J Clin Lipidol 2015b;9(6
suppl):S1-122. Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients
at high cardiovascular risk with elevated LDL cholesterol.
Karalis DG, Hill AN, Clifton S, et al. The risks of statin N Engl J Med 2017;376:1430-40.
use in pregnancy: a systematic review. J Clin Lipidol
2016;10:1081-90. Ridker PM, Mora S, Rose L, et al. Percent reduction in
LDL cholesterol following high-intensity statin therapy:
Karmali KN, Goff DC, Ning H, et al. A systematic examina- potential implications for guidelines and for the pre-
tion of the 2013 ACC/AHA pooled cohort risk assessment scription of emerging lipid-lowering agents. Eur Heart J
tool for atherosclerotic cardiovascular disease. J Am Coll 2016;37:1373-9.
Cardiol 2014;64:959-68.
Rosenson RS, Baker S, Banach M, et al. Optimizing choles-
Kelly MS, Beavers CJ, Bucheit JD, et al. Pharmacologic terol treatment in patients with muscle complaints. J Am
approaches for the management of patients with moder- Coll Cardiol 2017a;70:1290-301.
ately elevated triglycerides. J Clin Lipidol 2017;11:872-9.
Rosenson RS, Baker SK, Jacobson TA, et al. The National
Lederle FA, Bloomfield HE. Drug treatment of asymptomatic Lipid Association’s muscle safety expert panel. An assess-
hypertriglyceridemia to prevent pancreatitis: where is the ment by the statin muscle safety task force: 2014 update.
evidence? Ann Intern Med 2012;157:662-4. J Clin Lipidol 2014;8(suppl):S58-71.

Maggi P, DiBiagio A, Rusconi S, et al. Cardiovascular risk and Rosenson RS, Miller K, Bayliss M, et al. The Statin Myalgia
dyslipidemia among person living with HIV: a review. BMC Clinical Index (SMCI): revision for clinical use, content val-
Infect Dis 2017;17:551-68. idation, and inter-rater reliability. Cardiovasc Drug Ther
2017b;31:179-86.
Mancini GB, Baker S, Bergeron J, et al. Diagnosis, prevention,
and management of statin adverse effects and intoler- Rosinger A, Carroll MD, Lacher D, et al. Trends in total cho-
ance: Canadian Consensus Working Group update (2016). lesterol, triglycerides, and low-density lipoprotein in US
Can J Cardiol 2016;32(suppl):S35-65. adults, 1999-2014. JAMA Cardiol 2017;2:339-41.

Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and car- Ruscica M, Macchi C, Pavanello C, et al. Appropriateness
diovascular disease: a scientific statement from the Amer- of statin prescription in the elderly. Eur J Intern Med
ican Heart Association. Circulation 2011;123:2292-333. 2018;50:33-40.

Mortensen MB, Falk E. Primary prevention with statins in the Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and
elderly. J Am Coll Cardiol 2018;21:85-94. clinical outcomes in patients with cardiovascular disease.
N Engl J Med 2017;376:1713-22.
National Clinical Guideline Centre (UK). Lipid Modification:
Cardiovascular Risk Assessment and the Modification of Saeed A, Ballantyne CM. Bempedoic acid (ETC-1002): a cur-
Blood Lipids for the Primary and Secondary Prevention rent review. Cardiol Clin 2018;36:257-64.
of Cardiovascular Disease. London: National Institute for
Health and Care Excellence (NICE), July 2014. Schwartz GC, Szarek M, Bhatt DL, et al. ODYSSEY
OUTCOMES Trial. Topline results alirocumab in patient
Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab after acute coronary syndrome. Presented at: American
on progression of coronary disease in statin-treated College of Cardiology Scientific Sessions; March 2018;
Orlando, FL.

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Schwartz JB. Primary prevention: do the very elderly Thompson PD, Panza G, Zaleski A, et al. Statin-associated
require a different approach? Trends Cardiovasc Med side effects. J Am Coll Cardiol 2016;67:2395-410.
2015;25:228-39.
Wiggins BS, Lamprecht DG, Page RL, et al. Recommenda-
Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in tions for managing drug-drug interactions with statins and
elderly individuals at risk of vascular disease (PROSPER): HIV medications. Am J Cardiovasc Drug 2017;17:375-89.
a randomised controlled trial. Lancet 2002;360:1623-30.
Wild R, Weedin EA, Gill EA. Women’s health considerations
Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/ for lipid management. Endocrinol Metab Clin North Am
AHA guideline on the treatment of blood cholesterol to 2016;45:65-85.
reduce atherosclerotic cardiovascular risk in adults: a
report of the American College of Cardiology/American Wild R, Weedin EA, Wilson D. Dyslipidemia in pregnancy.
Heart Association task force on practice guidelines. J Am Cardiol Clin 2015;33:209-15.
Coll Cardiol 2014;63:2889-934. Wu Z, Camargo CA Jr, Khaw KT, et al. Effects of vitamin D
Stulc T, Ceska R, Gotto AM Jr, et al. Statin intolerance: the supplementation on adherence to and persistence with
clinician’s perspective. Curr Atheroscler Rep 2015;17:69. long-term statin therapy: secondary analysis from the ran-
domized, double-blind, placebo-controlled ViDA study.
Swerdlow DI, Preiss D, Kuchenbaecker KB, et al. Atherosclerosis 2018;273:59-66.
H MG-coenzyme A reductase inhibition, type 2 diabetes,
and bodyweight: evidence from genetic analysis and ran- Yusuf S, Bosch J, Dagenais G, et al. Cholesterol lowering in
domized trials. Lancet 2015;385:351-61. intermediate-risk persons without cardiovascular disease.
N Engl J Med 2016;374:2021-31.
Taylor BA, Lorson L, White CM, et al. A randomized trial of
coenzyme Q10 in patients with confirmed statin myopathy.
Atherosclerosis 2015;238:329-35.

PSAP 2019 BOOK 1 • Cardiology 51 Dyslipidemia

Self-Assessment Questions
Questions 16–18 pertain to the following case. 19. Based on the 2018 ACC/AHA cholesterol guidelines,
T.H., a 63-year-old African American man with a medical his- which one of the following is best to recommend given
tory of hypertension, dyslipidemia, type 2 diabetes, myo- A.V.’s most recent lipid results?
cardial infarction, and obesity, presents for dyslipidemia
A. No change necessary.
management. His home drugs include: metformin ER 500 mg
B. Rechallenge with rosuvastatin 40 mg daily.
– 2 tablets twice daily, linagliptin 5 mg daily, lisinopril 40 mg
C. Add ezetimibe 10 mg daily.
daily, chlorthalidone 12.5 mg daily, atorvastatin 80 mg daily,
D. Add colesevelam 3.75 g daily
metoprolol succinate 50 mg daily, and aspirin 81 mg daily.
T.H.’s most recent lipid panel shows TC 214 mg/dL; TG 186 20. According to the 2018 ACC/AHA cholesterol guidelines,
mg/dL; HDL-C 41 mg/dL; and LDL-C 106 mg/dL; all other lab which one of the following is the best time to add a
results are within normal limits. PCSK9 inhibitor to A.V.’s regimen?

16. According to the 2018 ACC/AHA cholesterol guidelines, A. After an ASCVD event while taking maximally
which of the following patient factors, in addition to his- tolerated statin
tory of ASCVD, most places T.H. at “very-high” risk? B. LDL-C ≥70 mg/dL while taking maximally tolerated
statin
A. Type 2 diabetes mellitus
C. If non-HDL-C ≥100 mg/dL while taking maximally
B. Age
tolerated statin and ezetimibe
C. Race
D. If LDL-C ≥100 mg/dL while taking maximally
D. LDL-C >80 mg/dL on high-intensity statin
tolerated statin and ezetimibe
17. T.H. is adherent to his current statin therapy. On the basis
of the 2018 cholesterol guidelines, which one of the fol- Questions 21 and 22 pertain to the following case.
lowing is the best threshold to consider additional lipid
R.T., a 63 year-old non-Hispanic white woman (weight 184
lowering agents for T.H.?
lb), is a new patient referred to your compressive cardiovas-
A. LDL-C ≥70 mg/dL cular assessment clinic. Her medical history includes type
B. Non-HDL-C ≥100 mg/dL 2 diabetes mellitus (diagnosed in 2016), hypertension (diag-
C. LDL-C ≥100 mg/dL nosed in 2012), and CKD3 with albuminuria (diagnosed in
D. Non-HDL-C ≥130 mg/dL 2018); she also is a former smoker (quit in 2010). R.T.’s home
drugs include lisinopril/HCTZ 20/12.5 mg twice daily, aspirin
18. According to the 2018 ACC/AHA cholesterol guidelines,
81 mg daily, metformin 1000 mg twice daily, dulaglutide 0.75
which of the following non-statin agents is best to rec-
mg weekly, and glipizide XL 5 mg daily. A baseline lipid panel
ommend to add to T.H.’s current therapy?
returns at TC 183 mg/dL; TG 123 mg/dL; HDL-C 41 mg/dL; and
A. Alirocumab 75 mg every 2 weeks LDL-C 115 mg/dL. Renal function test results include eGFR of
B. Ezetimibe 10 mg daily 53 mL/min/1.73m2 and urine albumin-to-creatinine ratio of
C. Colesevelam 1.875 g twice daily 74 mcg/mg. R.T.’s BP today is 132/74 mm Hg and pulse 76
D. Fenofibrate 145 mg daily beats/minute. Her calculated 10-year ASCVD risk is 13.2%.
21. Which one of the following diabetes-specific risk
Questions 19 and 20 pertain to the following case.
enhancers would most favor initiating high-intensity sta-
A.V. is a 48-year-old non-Hispanic man who presents for fol-
tin therapy in R.T.?
low up of elevated LDL-C. He was referred to you for lipid
management after a baseline LDL-C of 236 mg/dL and pos- A. Diagnosis of type 2 diabetes mellitus within last 5
itive family history of premature ASCVD. A.V. is initiated on years
rosuvastatin 40 mg, but shortly afterward complains of myal- B. Presence of albuminuria
gias. These symptoms resolved once the rosuvastatin dose C. Baseline LDL-C above 100 mg/dL
was reduced to 20 mg daily. After 6 weeks of recommended D. Former smoker
lifestyle therapies and rosuvastatin 20 mg daily, A.V.’s lipid
panel shows TC 204 mg/dL TG 156 mg/dL; HDL-C 43 mg/dL
and LDL-C 128 mg/dL. All other labs are within normal limits.

PSAP 2019 BOOK 1 • Cardiology 52 Dyslipidemia

22. After initiating high-intensity statin therapy, which one of Questions 25 and 26 pertain to the following case.

the following is the best primary target for R.T. according D.D. is a 50-year-old white man (height 68 in, weight 91 kg
to the 2018 ACC/AHA guidelines? [200 lb]) who presents to your lipid clinic for evaluation. His
medical history is significant for gout, HIV infection, type 2
A. LDL-C reduction of 30% from baseline
diabetes mellitus, and hypertension. For these, he takes allo-
B. LDL-C reduction of at least 50% from baseline
purinol 300 mg daily, lisinopril 10 mg daily, metformin 500 mg
C. LDL-C of <70 mg/dL
twice daily, rosuvastatin 20 mg daily, and the combination
D. LDL-C of <100 mg/dL
efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil
23. A primary care physician contacts you regarding a fumarate 300 mg daily. D.D. is a smoker who drinks 1 or 2 gin
patient with history of ischemic stroke and recent ACS. and tonics a day. His blood pressure is 120/79 mm Hg. His
The patient’s most recent lipid panel showed a direct lipid panel results are TC 170 mg/dL, HDL 30 mg/dL, LDL 80
LDL-C of 22 mg/dL while taking rosuvastatin 40 mg daily mg/dL, and TG 650 mg/dL. D.D.’s A1C is 6.5%; his renal and
and evolocumab 140 mg every 2 weeks. The physician hepatic function are within normal limits.
asks if any changes should be made to this patient’s lip-
25. Which one of following best evaluates the factors that
id-lowering regimen in the setting of the low LDL-C value.
could be contributing to D.D.’s HTG?
Which one of the following is the best response to this
physician regarding current dyslipidemia treatment and A. Smoking, history of HIV, amlodipine use, weight, and
LDL value? poorly controlled diabetes
B. History of hypertension, allopurinol use, alcohol use,
A. Patients who achieved very-low LDL in the FOURIER
and weight
trial had no increased risk of adverse effects, so
C. Smoking, history of HIV, alcohol use, and weight
continue current therapy.
D. History of HIV, amlodipine use, alcohol use, and
B. Patients who achieved a very-low LDL in
male sex
the FOURIER trial had an increased risk of
neurocognitive effects, so discontinue evolocumab. 26. In addition to nonpharmacologic recommendations,
C. The 2018 cholesterol guideline recommends which one of the following is best to recommend for D.D.?
lowering the statin dose when LDL-C falls below A. Fenofibrate 145 mg daily
40 mg/dL, so lower the rosuvastatin dose to B. Omega-3 fatty acids 1 g daily
20 mg daily. C. Niacin extended release 500 mg daily at bedtime
D. In the FOURIER trial, evolocumab was used to D. Evolocumab 420 mg subcutaneously monthly
target an LDL value of 25–50 mg/dL, so lower the
evolocumab dose to 70 mg twice weekly.
Questions 27 and 28 pertain to the following case.
24. A 62-year-old non-Hispanic white man has a medical his- H.M. is a 47-year-old man with a medical history of HIV infec-
tory of hypertension, which is controlled with amlodip- tion. He is being taken to the cardiac catheterization labora-
ine 5 mg daily and irbesartan 150 mg daily. Based on tory for an anterior wall MI. H.M. has no history of angina or
his recent lipid panel (TC 186 mg/dL; TG 189 mg/dL; ischemic heart disease. His only other significant medical his-
HDL-C 34 mg/dL; LDL-C 113 mg/dL), the patient’s 10-year tory is hypertension, for which he takes hydrochlorothiazide
ASCVD risk was calculated to be 13.3%. To further assess 25 mg daily. He denies smoking or drug use. The patient’s
ASCVD risk, his primary care physician ordered an apoB antiretroviral therapy (ART) includes darunavir 800 mg daily,
lab, which came resulted as 88 mg/dL. Which of the fol- ritonavir 100 mg daily, and tenofovir disoproxil fumarate/
lowing would most favor initiating statin therapy in this emtricitabine 300 mg/200 mg daily. His lipid panel shows TC
patient? 188 mg/dL, LDL 123 mg/dL, HDL 29 mg/dL, and TG 182 mg/dL.
A. Serum triglycerides 189 mg/dL 27. Which one of the following would be the best statin regi-
B. apoB 88 mg/dL men to recommend for H.M.?
C. LDL-C 113 mg/dL
A. Rosuvastatin 10 mg daily
D. HDL-C 34 mg/dL
B. Simvastatin 40 mg daily
C. Atorvastatin 80 mg daily
D. Atorvastatin 20 mg daily

PSAP 2019 BOOK 1 • Cardiology 53 Dyslipidemia

28. Two weeks after being discharged from the hospital, C. A 76-year-old woman who has no history of ASCVD
H.M. (weight 71 kg) returns to his cardiologist’s office but with an ASCVD pooled cohort risk score of 15.4%
with “the feeling he is getting charley horses in his thigh,” who is not receiving statin therapy.
which he finds upsetting because he cannot do his nor- D. A 65-year-old stroke survivor with an LDL of
mal activities. H.M.’s discharge regimen includes rosu- 71 mg/dL and a non-HDL to 120 mg/L while taking
vastatin 10 mg daily, clopidogrel 75 mg daily, aspirin 81 atorvastatin 80 mg daily.
mg daily, lisinopril 10 mg daily, carvedilol 3.25 mg twice
30. A 29-year-old woman takes rosuvastatin 20 mg orally
daily, and nitroglycerin 0.4 mcg as needed for chest
daily, ezetimibe orally 10 mg daily, and evolocumab 420
pain. He has a panel of labels collected with results that
mcg subcutaneously monthly for homozygous familial
include CK 100 IU/L, 25-hydroxy vitamin D 35 ng/mL, thy-
hypercholesterolemia (HoFH) for historically extremely
roid-stimulating hormone 2.2 mIU/L, and SCr 1.05 mg/
difficult-to-control LDL. Her LDL today is 169 mg/dL. She
dL. Which one of the following is best to recommend for
just tested positive for pregnancy. Which one of the fol-
H.M.?
lowing is best to recommend regarding this patient’s
A. Continue statin therapy because his CK is within perinatal pregnancy care?
normal limits.
A. Do not change her drug therapy; continue to monitor
B. Initiate vitamin D 1000 units daily in addition to
LDL every 3 months.
statin therapy.
B. Discontinue rosuvastatin; continue ezetimibe and
C. Hold statin therapy for 2 weeks; then decrease
evolocumab.
rosuvastatin to 5 mg daily if symptoms resolve.
C. Discontinue rosuvastatin, ezetimibe, and
D. Hold statin therapy for 2 weeks; then change therapy
evolocumab; initiate colesevelam.
to simvastatin 10 mg daily if symptoms resolve.
D. Discontinue rosuvastatin, ezetimibe, and
29. Which one of the following patients is most likely to ben- evolocumab; initiate colesevelam and mipomersen.
efit from enrolling in a clinical trial studying inclisiran?
A. A 17-year-old with heterozygous familial
hypercholesterolemia (HeFH) whose LDL has been
120 mg/dL while taking rosuvastatin 20 mg daily and
ezetimibe 10 mg daily.
B. A 50-year-old man who has had an MI in the past
year and has an LDL of 150 mg/dL while taking
atorvastatin 80 mg and ezetimibe 10 mg daily after
3 months.

PSAP 2019 BOOK 1 • Cardiology 54 Dyslipidemia