Opinion
VIEWPOINT
Treatment of Cholesterol in 2017
Harlan M. Krumholz, Clinicians and patients may find recent studies rel-
MD, SM evant to decisions about lipid-lowering therapy to be per-
Section of Cardiovascular plexing. There are now, for the first time, 3 evidence-
Medicine, Department
based options to modify atherosclerotic cardiovascular
of Internal Medicine,
Yale School of Medicine; disease risk via lipid-lowering medications. With new in-
and The Center for formation emerging, recent guidelines aging, and deci-
Outcomes Research sions needing to be made, this is an opportune time to
and Evaluation,
YaleNew Haven
review lipid-lowering therapy in the age of increasing
Health, New Haven, evidence-based choice. The focus in this Viewpoint is on
Connecticut. typical patients, not those with extreme phenotypes.
When the American College of Cardiology/Ameri-
can Heart Association (ACC/AHA) published the Guide-
line on the Treatment of Blood Cholesterol to Reduce
Viewpoint page 419
Atherosclerotic Cardiovascular Risk in Adults1 in 2013,
only the use of statins, among lipid-lowering medica-
tions, was strongly supported by evidence of improved
patient outcomes. The guidelines emphasis on statins for
secondary prevention and for individuals at higher risk of
disease was reinforced by a recent report that estimated
the treatment of 10 000 patients for 5 years would cause
1 case of rhabdomyolysis, 5 cases of myopathy, 75 new
cases of diabetes, and 7 hemorrhagic strokes while avert-
ing about 1000 events among those with preexisting dis-
ease, and 500 among those with elevated risk but with-
out preexisting disease.2 Despite this evidence, uptake of
statins remains suboptimal in the United States and else-
where and offers an opportunity for improvement. More-
over, despite the available research, evidence is lacking
about the comparative effectiveness and safety of par-
ticular statins for specific individuals.3
The groundbreaking pivot of the ACC/AHA Guide-
line from targets to the use of evidence-based treat-
ments based on risk was not a repudiation of the lipid
hypothesis, but rather an effort to align recommenda-
tions with evidence. The trials had tested the effect of
specific drug regimens on risk, not a strategy of treat-
ing to a target-level agnostic to drug. Moreover, the trial
evidence proved that not all drugs that favorably modify
lipid levels improve patient outcomes, perhaps be-
cause of their negative pleiotropic effects.
More evidence-based options have emerged for sec-
ondaryprevention.TheImprovedReductionofOutcomes:
VytorinEfficacyInternationalTrial(IMPROVE-IT)4 reported
that adding ezetimibe to effective statin therapy in stable
patientswhoexperiencedanacutecoronarysyndromere-
duced low-density lipoprotein cholesterol (LDL-C) from
Corresponding
Author: Harlan M. 70 mg/dL to 54 mg/dL (to convert LDL-C from mg/dL to
Krumholz, MD, SM, mmol/L, multiply by 0.0259), and reduced risk of athero-
Section of sclerotic cardiovascular disease outcome at 7 years from
Cardiovascular
Medicine, Department
34.7% to 32.7%. The Further Cardiovascular Outcomes
of Internal Medicine, Research with PCSK9 Inhibition in Subjects with Elevated
Yale School of Risk (FOURIER) trial5 reported that the addition of evo-
Medicine, 1 Church St,
locumab, a proprotein convertase subtilisinkexin type 9
Ste 200, New Haven,
CT 06510 (harlan (PCSK9) inhibitor, to effective statin therapy reduced
.krumholz@yale.edu). LDL-C from 92 mg/dL to 30 mg/dL and decreased the
jama.com
2017 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ on 08/07/2017
composite cardiovascular outcome over 2.2 years from
11.3% to 9.8%, a 15% relative reduction. Of note, both
drugs were only tested in high-risk individuals.
There are some caveats to the new evidence. Al-
though no significant safety signals emerged with either
drug,someconsiderthebenefitstoberelativelysmall.The
USFoodandDrugAdministrationdeterminedin2016that
the IMPROVE-IT trial was insufficient to expand the label
for ezetimibe to include reducing the risk of myocardial in-
farction and stroke. Ezetimibe, nevertheless, is now avail-
able as a generic and is inexpensive. But evolocumab is
costly, and its value is under debate. Also, evolocumab was
not tested against a statin-plus-ezetimibe combination,
which might currently be the appropriate comparator. For
most patients, both drugs will be second-line and third-
line options. Meanwhile, physicians await evidence re-
garding other alternatives, such as alirocumab, anacetra-
pib, icosapent ethyl, and RNA interference agents, to see
if they will join the evidence-based outcomes options.
New evidence has suggested that niacin is not effec-
tive. The Heart Protection Study 2Treatment of HDL to
Reduce the Incidence of Vascular Events (HPS2-THRIVE)
trial6 reported that among 25 673 high-risk individuals
with established atherosclerotic cardiovascular disease,
adding extended-release niacin in combination with la-
ropiprant (used to mitigate the discomfort of niacin-
generated flushing) to effective statin-based LDL-C
lowering treatment failed to realize any clinical benefit.
The niacin combination increased the risk of adverse
events, reduced quality-of-lifeadjusted survival, and in-
creased costs.6
Lipid-lowering therapy for primary prevention, that
is, for patients with no previous cardiovascular event, can
be a complex decision. Risk assessment is a linchpin that
guides decision making for primary prevention. Individu-
als with the highest risk have the most to gain. Mean-
while, there are debates about which risk calculator is best
for which patients. Studies show some differences, but,
from the patients perspective, the differences among
them likely seem small and only important when guide-
lines suggest there is a specific artificial threshold above
which treatment is recommended. What is increasingly
clear is that nearly half of individuals without prior dis-
ease who are identified as being at high risk of disease by
conventional risk scores may be reclassified as having
muchlowerriskintheabsenceofcoronaryarterycalcium.7
In addition, shared decision making is particularly im-
portant when the risks and costs of an intervention are
immediate and the benefits are in the future. Moreover,
patients vary considerably in their views about what
amount of benefit from a prevention drug is meaningful
enough to merit taking a pill every day. Nevertheless, de-
spite the importance of shared decision making, as noted
in the ACC/AHA guideline, few effective tools exist. In par-
ticular, there remains a need for better point-of-care
(Reprinted) JAMA August 1, 2017 Volume 318, Number 5 417
 Opinion Viewpoint

be right based on their preferences. The key is that clinicians do not

Figure. Lipid-Lowering Therapy to Reduce Risk of Atherosclerotic
Cardiovascular Disease (ASCVD) dictate treatments but help inform choices. Different people may
choose differently, and all be correct for what is important to them.
1 Determine patients ASCVD risk. If the patient does not have Sofirst,orientthepatienttoASCVDrisksanddetermineriskbased
clinical ASCVD, use an ASCVD risk calculator and/or measure on prior ASCVD events, risk calculator, or coronary calcium score. Pro-
coronary artery calcium score.
mote a healthful lifestyle for everyone, with attention to smoking ces-
2 Encourage a healthful lifestyle (smoking cessation; healthful diet;
regular physical activity; optimal weight).
sation, healthful diet, regular physical activity, and optimal weight.
Then, discuss benefits, risks, and costs of evidence-based lipid-
3 Discuss benefits, risks, and costs of lipid-lowering medication
to reduce patients ASCVD risk. As ASCVD risk increases, lowering therapy, helping patients understand what they stand to gain
benefit of evidence-based lipid-lowering treatment increases. and what it will take to get there. For people at highest risk, including
those who have already experienced an ASCVD event, treatment with
4 If patient favors treatment with lipid-lowering medication,
use drugs supported by evidence. high-dosage, high-intensity statins (eg, atorvastatin 80 mg/d) can best
reduce risk with minimal adverse effects and cost. For lower-risk in-
20 Prevention 10 Prevention
dividuals, treatment with statins provides a smaller benefit,
(Presence of clinical ASCVD) Begin low- or moderate-
Begin high-intensity statin intensity statin therapy
but many will find the benefits to outweigh risks. In this case, it is pru-
therapy (eg, atorvastatin 40 mg/d (eg, pravastatin 20 mg/d dent to begin with a lower dosage of statins (eg, atorvastatin 20 mg /d)
or 80 mg/d). or 40 mg/d or atorvastatin and intensify depending on the patients preference for greater risk
10 mg/d or 20 mg/d).
For patients who desire additional reduction. For those who have experienced an event and desire even
ASCVD risk reduction, discuss Intensify treatment according
benefits, risks, and costs of adding to patient preference for more risk reduction, nonstatin treatment may be considered using
evidence-based nonstatin greater ASCVD risk reduction. ezetimibe first, and then, possibly, evolocumab. For those who have
treatment. Consider add-on a mild or moderate intolerance to statins, another statin may be tried
treatment with ezetimibe first
before considering evolocumab. before progressing to the evidence-based nonstatin therapies. For
those with a severe reaction, the use of evidence-based nonstatins
For mild to moderate intolerance to statin therapy, consider switching
to another statin before considering nonstatin treatment. would be preferred. In all cases, the use of medications without out-
Discuss lipid-level testing with patient to assess treatment adherence. comes evidence should be avoided, especially those with safety con-
cerns. Physicians can consider lipid-level testing as a tool to evaluate
5 Regularly reassess patient goals for ASCVD risk reduction, tolerance to adherence, in partnership with patients. Finally, best practice should
medication, and treatment plan. involve regular reassessment of the patients preference, medica-
tion approach, and tolerance to the medication.
The overarching goal is to derive maximum benefit from clini-
algorithms that individualize estimates of risks and benefits and that cal care while maintaining alignment with each patients prefer-
could be presented in a way that would enable patients to partici- ences and goals. The strongest treatment recommendations should
pate actively in the decision if that were their choice. be where the risk is highest, the evidence is robust, and the cost is
So how should clinicians address cholesterol in 2017 (Figure). Ex- affordable. The use of statins for higher-risk patients and the judi-
cept for extreme phenotypes, the decision is about risk reduction, not cious use of other evidence-based options, partnership in decision
cholesterol levels. The evidence-based lipid-lowering drugs seem to making with patients, and wise reliance on healthful lifestyles pro-
lower risk even if a patients initial LDL is low; they are risk-reduction vide the best hope of success in preventing the morbidity and mor-
medications. Two people may choose different strategies and both tality caused by cardiovascular disease.

ARTICLE INFORMATION
Published Online: July 24, 2017.
doi:10.1001/jama.2017.6753
Conflict of Interest Disclosures: The author has
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
reported that he received research grants from
Medtronic, Johnson & Johnson (Janssen), the US
Food and Drug Administration, all through Yale;
works under contract with the Centers for Medicare
& Medicaid Services; chairs a cardiac scientific
advisory board for UnitedHealth; is a participant and
participant representative of the IBM Watson Health
Life Sciences Board; is a member of the Advisory
Board for Element Science and the Physician
Advisory Board for Aetna; and is the founder of
Hugo, a personal health information platform.
Additional Contributions: The author thanks
Suveen Angraal, MBBS, Maria Johnson, MBA, and
Erica Spatz, MD, Yale School of Medicine; Marilyn
Mann, JD; Khurram Nasir, MD, Baptist Health South
Florida, Miami; and Karol Watson, MD, PhD,
Department of Medicine/Cardiology, Barbra
Streisand Womens Heart Health Program, David
Geffen School of Medicine at UCLA, for their
thoughtful review of this work, for which they were
not remunerated.
REFERENCES
1. Stone NJ, Robinson JG, Lichtenstein AH, et al;
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. J Am Coll Cardiol. 2014;63(25 pt B):
2889-2934.
2. Collins R, Reith C, Emberson J, et al.
Interpretation of the evidence for the efficacy and
safety of statin therapy. Lancet. 2016;388(10059):
2532-2561.
3. Green JB, Ross JS, Jackevicius CA, Shah ND,
Krumholz HM. When choosing statin therapy. JAMA
Intern Med. 2013;173(3):229-232.
4. Cannon CP, Blazing MA, Giugliano RP, et al;
IMPROVE-IT Investigators. Ezetimibe added to
statin therapy after acute coronary syndromes.
N Engl J Med. 2015;372(25):2387-2397.
5. Sabatine MS, Giugliano RP, Wiviott SD, et al;
Open-Label Study of Long-Term Evaluation against
LDL Cholesterol (OSLER) Investigators. Efficacy and
safety of evolocumab in reducing lipids and
cardiovascular events. N Engl J Med. 2015;372(16):
1500-1509.
6. Landray MJ, Haynes R, Hopewell JC, et al;
HPS2-THRIVE Collaborative Group. Effects of
extended-release niacin with laropiprant in
high-risk patients. N Engl J Med. 2014;371(3):
203-212.
7. Nasir K, Bittencourt MS, Blaha MJ, et al.
Implications of coronary artery calcium testing
among statin candidates according to American
College of Cardiology/American Heart Association
Cholesterol Management Guidelines. J Am Coll
Cardiol. 2015;66(15):1657-1668.

418 JAMA August 1, 2017 Volume 318, Number 5 (Reprinted) jama.com

2017 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ on 08/07/2017