Opinion
EDITORIAL
A New Personalized, Patient-Centric, and Cost-Conscious
Guideline for Contemporary Cholesterol Management
Eric Peterson, MD, MPH; Philip Greenland, MD
Elevated serum cholesterol is one of the world’s most
common and modifiable risk factors for cardiovascular dis-
ease (CVD). In the 5 years since the release of the 2013
American Heart Association/American College of Cardiology
(AHA/ACC) guideline for lipid
Related article
management, 1 there have
been multiple advances in
lipid biology, epidemiology, and therapeutic clinical trials. This
wealth of new evidence led the AHA/ACC to release a major
revision of the lipid practice recommendations in 2018.2 Over-
all, the new guidelines are more evidence based and person-
alized than in the past but also more complex. The full
content of the new lipid guidelines is contained in a well-
referenced 65-page document and summarized in 10 suc-
cinct top messages highlighted in this issue of JAMA.3
As with prior versions, the 2018 cholesterol guideline rec-
ommends statins as the bedrock therapy for all patients with
clinical CVD. However, the guideline also proposes that clini-
cians should further identify patients with CVD who have very
high-risk for future events based on recent CVD events, poly-
vascular disease, and other high-risk CVD risk factors, de-
fined as age ≥65 years, heterozygous familial hypercholester-
olemia, history of coronary artery bypass graft surgery or
percutaneous coronary intervention outside of the major
ASCVD event(s), diabetes, hypertension, chronic kidney dis-
ease (estimated glomerular filtration rate of 15-59 mL/min/
1.73 m2), current smoking, persistently elevated low-density
lipoprotein cholesterol (LDL-C; ≥100 mg/dL [≥2.6 mmol/L]) de-
spite maximally tolerated statin therapy and ezetimibe, and
history of congestive heart failure. Individuals at high risk are
recommended to be treated to a target LDL-C goal of less than
70 mg/dL. For those in whom this goal is not achieved with
high-dose statins, the guideline recommends the addition of
nonstatin therapy (either ezetimibe or a proprotein conver-
tase subtilisin/kexin type 9 [PCSK9] inhibitor). In choosing be-
tween these nonstatin options, the guideline favors ezeti-
mibe (a generic medication) as next-in-line therapy because
PCSK9 inhibitors were deemed to have “low economic value
based on their 2018 prices.”2
The stratification of patients with known CVD and more
aggressive treatment for those at very high risk are needed
changes in the guidelines. These changes emphasize the im-
portance of achieving target lipid goals, integrate the value of
combination statin-nonstatin therapies for those at highest risk,
and are consistent with a wealth of clinical trial data. The guide-
line writers also explicitly considered value in their new treat-
ment recommendation, one of the first times this has been done
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in guideline statements, and increasingly important as US
health care costs continue their inexorable rise. Even though
2 recent trials have now demonstrated that PCSK9 therapy
added to high-dose statins is safe and effective to reduce ma-
jor cardiovascular events,4,5 the drugs were initially priced very
high, reducing their cost-effectiveness estimates (>$100 000
per quality-adjusted life-year). Some may argue that guide-
line writers should not explicitly consider cost in treatment
decisions, but this seems unavoidable from a societal view-
point. Furthermore, the decision by the AHA/ACC guideline
writers to consider cost likely put needed pressure on the drug-
makers to lower drug prices. The challenge for incorporating
cost-effectiveness into the guideline is that prices can change
quickly. Even before the release of the 2018 guideline, the costs
of PCSK9 inhibitors were reduced by more than 50%, making
prior cost-effectiveness estimates and the nonstatins treat-
ment algorithms dated.
For primary prevention, the 2018 guideline suggests that
treatment recommendations should be based on a patient’s over-
all CVD risk profile, estimated using the 10-year Pooled Cohort
Equations CV Risk Calculator.2 The current guideline further per-
sonalized these CVD risk estimates for those with inflamma-
tory illnesses, preeclampsia, early menopause, and South Asian
ethnicity. The guideline also stresses that patients should play
a central role in the decision-making process. For patients who
remain unsure whether to initiate therapy after clinical risk as-
sessment, the guideline suggests that coronary artery calcium
scores could be useful.6 A high calcium score can encourage pa-
tients to consider therapy, whereas the absence of coronary cal-
cium predicts lower risk of CVD and may lead to a decision for
lifestyle modification rather than drug therapy. Additionally, the
2018 guideline clarifies that it is important to monitor re-
sponse to drug therapy between 4 and 12 weeks after starting
therapy and annually thereafter to ensure adherence.
Overall, the 2018 guideline addresses a diverse spectrum
of clinical factors and selective imaging to inform CVD risk as-
sessment. This strategy will lead to more precise patient esti-
mates. Yet applying the maze of branching guideline algo-
rithms will be more challenging for clinicians to implement.
In the past, clinicians could use simple heuristic cutoffs (based
on LDL-C levels, 10-year risk estimates, or both) to determine
which patients needed lipid treatment. Now clinicians also
must consider multiple subgroups based on cholesterol lev-
els, age, presence or absence of CVD, diabetes, other tradi-
tional and nontraditional CVD clinical risk factors, and per-
haps even imaging studies to determine whether and what
treatment to recommend.
(Reprinted) JAMA Published online February 4, 2019 E1
 Opinion Editorial

The 2018 guideline also places considerable emphasis on
engaging patients in the process. Incorporation of an individu-
al’s values in treatment decisions is not only the right thing to
do but can also increase the likelihood of adherence to the se-
lected strategy. The challenge for shared decision making, how-
ever, is how to convey therapeutic risks and benefits in a man-
ner that is accurate, objective, and understandable to a patient.
The choice of risk estimate, time horizon, and visual display
can have significant influence on patients’ impressions of their
disease risk and their willingness to consider treatment.7
Moving forward, several remaining gaps in evidence need
to be filled. Among individuals aged 20 to 40 years, the 2018
guideline recommends starting statin therapy only in those
with LDL-C greater than 160 mg/dL and a family history of pre-
mature atherosclerosis or have high lifetime estimated CVD
risk. Epidemiological studies demonstrate clearly that the num-
ber of years of exposure to elevated serum LDL-C is predic-
tive of risk of CVD.8 Thus, many young people with elevated
LDL-C levels (eg, 140-160 mg/dL) have a high lifetime risk of
CVD and should be considered for statin therapy. Similarly, in-
dividuals older than 75 years have been historically under-
studied, and the guideline is appropriately cautious in treat-
ment recommendations pending upcoming clinical trials
directed specifically at elderly persons. Moreover, the guide-
line mostly focuses on therapies that lower LDL-C. However,
immediately after the release of the guideline, the results of
the REDUCE-IT trial raised the hope that lowering other lipid
components including triglycerides may improve down-
stream outcomes in select populations.9
In conclusion, the 2018 lipid guideline represents a sig-
nificant and positive step forward for cardiovascular disease
prevention. While no guideline is perfect, if the algorithms
in these new guidelines were followed, thousands if not
millions of people worldwide each year would be able to
avoid CVD events. However, the uptake and translation of
guidelines into practice has been historically poor. Even in
the United States, which spends more on health care than
any other country, more than half of all residents did not
meet the 2013 less stringent lipid management guidelines
recommendations.10 Moving forward, the United States will
need to do better to improve individual and population
health. Ideally, the increased use of electronic medical rec-
ords, computer-aided clinical decision support, and team-
based care models could assist in the appropriate applica-
tion of these algorithms for management of cholesterol
levels in community practice.

ARTICLE INFORMATION
Author Affiliations: Duke University Medical
Center, Durham, North Carolina (Peterson);
Associate Editor, JAMA (Peterson); Department of
Preventive Medicine, Northwestern University
Feinberg School of Medicine, Chicago, Illinois
(Greenland); Senior Editor, JAMA (Greenland).
Corresponding Author: Eric Peterson, MD, MPH,
Duke University Medical Center, PO Box 17969,
Durham, NC 27715 (eric.peterson@duke.edu).
Published Online: February 4, 2019.
doi:10.1001/jama.2019.0045
Conflict of Interest Disclosures: Dr Peterson
reported receiving grants and/or fees for consulting
from Abiomed, Amgen, Bayer, Genentech, Merck,
Novartis, Sanofi, Regeneron, Livongo, AstraZeneca,
Janssen, Merck, and the Society of Thoracic
Surgeons. No other disclosures were reported.
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