Circulation

PERSPECTIVE

The New 2018 Cholesterol Guidelines

Filling Gaps and Expanding Opportunities

T
he long-anticipated release of the 2018 American College of Cardiology/ Amit Khera, MD, MSc
American Heart Association cholesterol guidelines is now at hand and likely
to be met with broad interest by clinicians in multiple specialties.1
The last update to the American College of Cardiology/American Heart Associa-
tion cholesterol guidelines in 2013 takes a much narrower approach to evidence
assessment than prior guidelines, focusing predominantly on evidence from high-
quality randomized clinical trials.2 This resulted in the elimination of low-density
lipoprotein cholesterol (LDL-C) treatment goals from the document, which had
been a mainstay in prior guidelines and clinical practice. The writing group created
a simplified algorithm of 4 groups who were most likely to benefit from moderate-
or high-intensity statin therapy (Table). This approach greatly expanded the num-
ber of individuals eligible for statins in the population. In addition to eliminating
LDL-C treatment goals, the old guideline recommended minimal use of nonstatin
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therapies. However, there was no clinical trial evidence to support a strategy of tar-
geting specific LDL-C numbers, and at that time, there were sparse data support-
ing the addition of nonstatin therapies to statins to further lower atherosclerotic
cardiovascular disease (ASCVD) events.

NONSTATIN AGENTS
Since publication of the old guidelines, a new class of nonstatin drugs has be-
come available, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors,
with evidence now from 2 large randomized clinical end-point trials of secondary
prevention patients. Furthermore, long-awaited clinical trial results validated the
utility of ezetimibe for ASCVD event reduction when added to statins in patients
with recent acute coronary syndromes. These agents now clearly have a role in
the management of dyslipidemia and ASCVD risk, but there have been different
interpretations of how to incorporate them into clinical practice.
The new guidelines represent a comeback of sorts for both LDL-C thresholds and
nonstatin therapies. The authors recommend additional nonstatin therapy predomi-
nantly for those at higher risk with explicit LDL-C thresholds at which to consider these
therapies (Table). For the very high-risk patient with ASCVD and LDL-C ≥70 mg/dL
despite maximal statin therapy, ezetimibe is the preferred initial agent (Class IIa; Level
of Evidence B), and PCSK9 inhibitors (Class IIa; Level of Evidence A) are a reasonable The opinions expressed in this article are
not necessarily those of the editors or
option only if the patient is already prescribed statin and ezetimibe (Class I; Level of of the American Heart Association.
Evidence B). The requirement for ezetimibe first was based on generic availability, tol-
Key Words: cholesterol ◼ guidelines
erability, safety, and lower cost and appreciating that a significant proportion of indi- as topic
viduals would achieve an LDL-C <70 mg with this strategy. However, if ASCVD event
© 2018 American Heart Association, Inc.
reduction is proportional to the absolute change in LDL-C, PCSK9 inhibitors would be
more effective at event reduction than ezetimibe in these higher-risk groups. https://www.ahajournals.org/journal/circ

Circulation. 2019;139:2805–2808. DOI: 10.1161/CIRCULATIONAHA.118.038629 June 18/25, 2019 2805

 Khera
Table.  Key Comparisons of 2013 and 2018 American College of Cardiology/American Heart Association Cholesterol Guidelines
FRAME OF REFERENCE
2013 Cholesterol Guidelines
Statin treatment groups (1) Clinical ASCVD, (2) diabetes mellitus with LDL-C
≥70 mg/dL, (3) 40–75 y of age with LDL-C 70–189
mg/dL and 10-y ASCVD risk ≥7.5%, and (4) severe
hypercholesterolemia (LDL-C ≥190 mg/dL)
Secondary prevention LDL-C threshold No thresholds
Nonstatin agents* Individuals at higher ASCVD risk with less-than-
anticipated response to statin (Class IIb; Level of Evidence
E) or statin candidates who are completely statin
intolerant (Class IIa; Level of Evidence B); recommend
nonstatins with proven ASCVD benefit in RCTs
Value statement None
Risk assessment Pooled Cohort Equations (Class I; Level of Evidence B)
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Additional risk factors Can be considered if treatment decision uncertain:
primary LDL–C ≥160 mg/dL, family history of
premature ASCVD, hs-CRP ≥2 mg/L, CAC score
≥300 Agatston units or ≥75th percentile for age/sex/
ethnicity, ABI <0.9, or high lifetime risk of ASCVD
(Class IIb; Level of Evidence C)
CAC testing In select individuals when statin decision uncertain,
upgrade risk if CAC ≥300 or >75th percentile for age/
sex/ethnicity (Class IIb; Level of Evidence C)
Fasting lipid measurements Fasting preferred
Children and young adults No specific statements
Racial/ethnic considerations Pooled Cohort Equations with separate calculator for
blacks
ABI indicates ankle-brachial index; apo B, apolipoprotein B; ASCVD atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CKD, chronic kidney
disease; CVD, cardiovascular disease; FH, familial hypercholesterolemia; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; Lp(a),
lipoprotein(a); PCSK9, proprotein convertase subtilisin/kexin type 9; and RCT, randomized clinical trial.
*Groups that include Class of Recommendation IIa or higher.
2806 June 18/25, 2019 Circulation. 2019;139:2805–2808. DOI: 10.1161/CIRCULATIONAHA.118.038629
The New 2018 Cholesterol Guidelines
2018 Cholesterol Guidelines
Unchanged
LDL-C ≥70 mg/dL as threshold for nonstatin drug
consideration
ASCVD on maximal statin therapy:
Ezetimibe for clinical ASCVD and LDL-C ≥70 (Class IIb; Level
of Evidence C); ezetimibe and PCSK9 inhibitor as add-on
therapy for very high-risk ASCVD and LDL-C ≥70 mg/dL
(Class IIa)
Ezetimibe should be initiated first, then PCSK9 inhibitor
(Class I; Level of Evidence B-NR)
LDL-C ≥190 mg/dL on maximal statin therapy:
Ezetimibe if LDL-C <50% reduced on statin or remains ≥100
mg/dL (Class IIa)
Bile acid sequestrant if LDL-C <50% reduced on statin and
ezetimibe (Class IIb; Level of Evidence B-R)
PCSK9 inhibitor after statin and ezetimibe if LDL-C still ≥100
mg/dL (Class IIb; Level of Evidence B-R) or if LDL-C still ≥130
mg/dL and baseline LDL-C ≥220 mg/dL (Class IIb; Level of
Evidence C-LD)
PCSK9 inhibitor low value based on mid-2018 list prices
(Level of Evidence B-NR)
PCSK9 inhibitor uncertain value in primary prevention
patients with FH (Level of Evidence: B-NR)
Pooled Cohort Equations and categorization as low risk
(<5%), borderline risk (5%–<7.5%), intermediate risk
(7.5%–<20%), and high risk (≥20%) (Class I; Level of
Evidence B-NR)
In intermediate-risk adults, risk-enhancing factors favor
statin initiation/intensification: same as 2013 guidelines
(except CAC) and include metabolic syndrome, CKD,
chronic inflammatory conditions, premature menopause and
preeclampsia, high-risk race/ethnicity, persistent triglycerides
≥175 mg/dL, elevated Lp(a) or apo B (Class IIa; Level of
Evidence B-R)
Reasonable in intermediate-risk or selected borderline-risk
adults with uncertainty about statins (Class IIa; Level of
Evidence B)
CAC=0, reasonable to withhold statins and reassess
CAC 1–99 and age ≥55 y, reasonable to initiate statins
CAC ≥100 or ≥75th percentile, reasonable to initiate statins
Fasting or nonfasting appropriate unless known triglycerides
≥400 mg/dL (Class I; Level of Evidence B-NR)
Age ≥10 y with persistent LDL-C ≥190 mg/dL or ≥160 with
likely FH, statins reasonable (Class IIa; Level of Evidence B-R)
Lipid testing ≥2 y if family history of early CVD or significant
hypercholesterolemia (Class IIa; Level of Evidence B-NR)
Reasonable for clinicians to review racial/ethnic features that
can influence ASCVD risk for treatment decisions (Class IIa;
Level of Evidence B-NR)
Table delineating specific issues to consider for Asian,
Hispanic/Latino, and black Americans in evaluation, risk
decisions, and treatment
 Khera
Thus, another important consideration in these non-
statin recommendations was value. The new guidelines
included an explicit value statement about PCSK9 in-
hibitors, stating that at mid-2018 list prices, they have
a low value (>$150 000 per quality-adjusted life-year).
Given the various drug options, availability of generic
therapies, sizeable costs of newer treatments, and un-
fettered rise in healthcare costs, the new inclusion of
value considerations is a positive step forward in guide-
line development. However, a challenge in embedding
the calculations in treatment algorithms is that value
changes with pricing. Indeed, the price point of both
PCSK9 inhibitors is coming down,3,4 although not yet
to the level where they would be considered high value
(<$50 000).
SHARED DECISION MAKING
One misconception about the old guidelines was the
notion that they delineated groups in whom statins
should be prescribed. In fact, the guidelines identified
those who were most likely to benefit from statins and
called for a clinician-patient discussion in a process of
shared decision making to determine statin prescrip-
tion. The new guidelines greatly expand on and en-
hance the emphasis on shared decision making.
The foundation of shared decision making is an as-
sessment of ASCVD risk. The Pooled Cohort Equations
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were unveiled with the old guidelines and were among
the most controversial elements because these equa-
tions were found to overestimate ASCVD risk in several
analyses. The new guideline writers acknowledged that
the Pooled Cohort Equations are tailored to populations
and may be imprecise for certain individuals. Thus, they
provided additional elements to consider, called risk-en-
hancing factors, and favor the use of statins when there
is uncertainty in risk discussions. Furthermore, the new
guidelines delineate categories of 10-year ASCVD risk
as low risk (<5%), borderline risk (5%–<7.5%), inter-
mediate risk (7.5%–<20%), and high risk (≥20%) and
recommend applying the aforementioned risk-enhanc-
ing factors in considerations for the intermediate-risk
group.
Coronary artery calcium (CAC) scanning is one of the
most powerful emerging risk assessment tools, with a
wealth of data supporting its ability to enhance ASCVD
risk estimation. Since the publication of the old guide-
lines, several studies have expanded our understanding
of the potential application of CAC scanning, including
the “derisking” ability of a CAC score of zero.5 There-
fore, the new guidelines provide a detailed algorithm
for application of CAC testing and elevate the strength
of recommendation (Class IIa; Level of Evidence B;
Table). Here, in predominantly intermediate-risk indi-
viduals (7.5%–<20% 10-year risk) for whom there is
uncertainty about statin initiation, a lower threshold of
Circulation. 2019;139:2805–2808. DOI: 10.1161/CIRCULATIONAHA.118.038629
The New 2018 Cholesterol Guidelines
≥100 Agatston units (or ≥75th percentile) favors statin
FRAME OF REFERENCE
initiation. If the CAC score is zero in these individuals
and there are no higher-risk conditions, statin therapy
can be deferred. This last point highlights the core of
a shared decision-making conversation in which a pa-
tient’s aversion to statins is balanced against a small
number of ASCVD events that could have been avoided
with statin use.
FOCUS ON POPULATION SUBGROUPS
The new guidelines provide greater guidance and at-
tention to cholesterol considerations in various popula-
tion subgroups. Appreciating that atherosclerosis is a
lifelong process and the potential to modify the natural
history of the disease by starting early, the guidelines
include specific recommendations for children (age,
0–19 years). These entail the importance of risk factor
assessment, early lifestyle interventions, and identifica-
tion of inherited dyslipidemias, including familial hyper-
cholesterolemia. Furthermore, lifetime risk assessment
is recommended for young adults (age, 20–39 years)
who generally have low short-term ASCVD risk but in
whom lifestyle interventions are foundational aspects
of ASCVD prevention. For young adults with severe
dyslipidemia (LDL-C ≥190 mg/dL), early statin use is also
warranted.
A major advance of the old guidelines was incorpo-
rating strategies to address the increased ASCVD risk
in blacks, including a separate Pooled Cohort Equation
for blacks and the inclusion of stroke in the ASCVD end
point. The new guidelines fill in gaps for other racial
and ethnic groups, highlighting higher ASCVD risk in
South Asians and the potential for underestimation
of risk with the Pooled Cohort Equations derived for
whites, whereas there is potential for overestimation
of risk for East Asians. In addition, the guidelines ac-
knowledge the heterogeneity of ASCVD risk within ra-
cial/ethnic groups such as Hispanics in whom country
of origin, socioeconomic status, and acculturation may
significantly influence risk estimates.
CONCLUSIONS
Guidelines are not static documents but rather iterative
pieces that morph, grow, and build on one another. The
new 2018 American College of Cardiology/American
Heart Association cholesterol guidelines expand on the
sturdy framework of the old guidelines to provide a more
complete picture, one that takes into account the rapidly
evolving landscape of the cholesterol field. Ultimately,
the value of a guideline is determined by how effectively
it is implemented into practice and by how much mor-
bidity and mortality are avoided through its application.
Therefore, the work is just beginning to translate the
June 18/25, 2019 2807
 Khera The New 2018 Cholesterol Guidelines

message of this guideline to a language that resonates AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood
FRAME OF REFERENCE

Cholesterol: A Report of the American College of Cardiology/American

with patients, providers, and public health officials.
ARTICLE INFORMATION
Correspondence
Amit Khera, MD, MSc, Division of Cardiology, UT Southwestern Medical Cen-
ter, 5323 Harry Hines Blvd, Dallas, TX 75390–8830. Email amit.khera@utsouth-
western.edu
Affiliation
Department of Internal Medicine and Division of Cardiology, University of Texas
Southwestern Medical Center, Dallas.
Disclosures
None.
REFERENCES
1. Grundy 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 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/
Downloaded from http://ahajournals.org by on June 17, 2019
Heart Association Task Force on Clinical Practice Guidelines. Circulation.
2018;138:e1082–e1143. doi: 10.1161/CIR.0000000000000625
2. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB,
Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P,
Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW, Eddleman KM,
Jarrett NM, LaBresh K, Nevo L, Wnek J, Anderson JL, Halperin JL, Albert
NM, Bozkurt B, Brindis RG, Curtis LH, DeMets D, Hochman JS, Kovacs RJ,
Ohman EM, Pressler SJ, Sellke FW, Shen WK, Smith SC Jr, Tomaselli GF;
American College of Cardiology/American Heart Association Task Force
on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of
blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a
report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines. Circulation. 2014;129(suppl 2):S1–S45.
doi: 10.1161/01.cir.0000437738.63853.7a
3. Dhruva SS, Ross JS, Desai NR. Alirocumab’s price reduction: implica-
tions of a paradigm shift toward cost-effective pricing. Circulation.
2018;138:1502–1504. doi: 10.1161/CIRCULATIONAHA.118.036069
4. Thomas K. Amgen slashes the price of a promising cholesterol drug. New
York Times. October 25, 2018. https://www.nytimes.com/2018/10/25/
health/amgen-repatha-cholesterol-drug.html. Accessed October 27, 2018.
5. Nasir K, Bittencourt MS, Blaha MJ, Blankstein R, Agatson AS, Rivera JJ,
Miedema MD, Miemdema MD, Sibley CT, Shaw LJ, Blumenthal RS, Budoff
MJ, Krumholz HM. Implications of coronary artery calcium testing among
statin candidates according to American College of Cardiology/American
Heart Association cholesterol management guidelines: MESA (Multi-Eth-
nic Study of Atherosclerosis). J Am Coll Cardiol. 2015;66:1657–1668. doi:
10.1016/j.jacc.2015.07.066

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