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Treatment of Cholesterol in 2017
Treatment of Cholesterol in 2017
VIEWPOINT
Treatment of Cholesterol in 2017
Harlan M. Krumholz, Clinicians and patients may find recent studies rel- composite cardiovascular outcome over 2.2 years from
MD, SM evant to decisions about lipid-lowering therapy to be per- 11.3% to 9.8%, a 15% relative reduction. Of note, both
Section of Cardiovascular plexing. There are now, for the first time, 3 evidence- drugs were only tested in high-risk individuals.
Medicine, Department
based options to modify atherosclerotic cardiovascular There are some caveats to the new evidence. Al-
of Internal Medicine,
Yale School of Medicine; disease risk via lipid-lowering medications. With new in- though no significant safety signals emerged with either
and The Center for formation emerging, recent guidelines aging, and deci- drug,someconsiderthebenefitstoberelativelysmall.The
Outcomes Research sions needing to be made, this is an opportune time to USFoodandDrugAdministrationdeterminedin2016that
and Evaluation,
YaleNew Haven
review lipid-lowering therapy in the age of increasing the IMPROVE-IT trial was insufficient to expand the label
Health, New Haven, evidence-based choice. The focus in this Viewpoint is on for ezetimibe to include reducing the risk of myocardial in-
Connecticut. typical patients, not those with extreme phenotypes. farction and stroke. Ezetimibe, nevertheless, is now avail-
When the American College of Cardiology/Ameri- able as a generic and is inexpensive. But evolocumab is
can Heart Association (ACC/AHA) published the Guide- costly, and its value is under debate. Also, evolocumab was
line on the Treatment of Blood Cholesterol to Reduce not tested against a statin-plus-ezetimibe combination,
Viewpoint page 419
Atherosclerotic Cardiovascular Risk in Adults1 in 2013, which might currently be the appropriate comparator. For
only the use of statins, among lipid-lowering medica- most patients, both drugs will be second-line and third-
tions, was strongly supported by evidence of improved line options. Meanwhile, physicians await evidence re-
patient outcomes. The guidelines emphasis on statins for garding other alternatives, such as alirocumab, anacetra-
secondary prevention and for individuals at higher risk of pib, icosapent ethyl, and RNA interference agents, to see
disease was reinforced by a recent report that estimated if they will join the evidence-based outcomes options.
the treatment of 10 000 patients for 5 years would cause New evidence has suggested that niacin is not effec-
1 case of rhabdomyolysis, 5 cases of myopathy, 75 new tive. The Heart Protection Study 2Treatment of HDL to
cases of diabetes, and 7 hemorrhagic strokes while avert- Reduce the Incidence of Vascular Events (HPS2-THRIVE)
ing about 1000 events among those with preexisting dis- trial6 reported that among 25 673 high-risk individuals
ease, and 500 among those with elevated risk but with- with established atherosclerotic cardiovascular disease,
out preexisting disease.2 Despite this evidence, uptake of adding extended-release niacin in combination with la-
statins remains suboptimal in the United States and else- ropiprant (used to mitigate the discomfort of niacin-
where and offers an opportunity for improvement. More- generated flushing) to effective statin-based LDL-C
over, despite the available research, evidence is lacking lowering treatment failed to realize any clinical benefit.
about the comparative effectiveness and safety of par- The niacin combination increased the risk of adverse
ticular statins for specific individuals.3 events, reduced quality-of-lifeadjusted survival, and in-
The groundbreaking pivot of the ACC/AHA Guide- creased costs.6
line from targets to the use of evidence-based treat- Lipid-lowering therapy for primary prevention, that
ments based on risk was not a repudiation of the lipid is, for patients with no previous cardiovascular event, can
hypothesis, but rather an effort to align recommenda- be a complex decision. Risk assessment is a linchpin that
tions with evidence. The trials had tested the effect of guides decision making for primary prevention. Individu-
specific drug regimens on risk, not a strategy of treat- als with the highest risk have the most to gain. Mean-
ing to a target-level agnostic to drug. Moreover, the trial while, there are debates about which risk calculator is best
evidence proved that not all drugs that favorably modify for which patients. Studies show some differences, but,
lipid levels improve patient outcomes, perhaps be- from the patients perspective, the differences among
cause of their negative pleiotropic effects. them likely seem small and only important when guide-
More evidence-based options have emerged for sec- lines suggest there is a specific artificial threshold above
ondaryprevention.TheImprovedReductionofOutcomes: which treatment is recommended. What is increasingly
VytorinEfficacyInternationalTrial(IMPROVE-IT)4 reported clear is that nearly half of individuals without prior dis-
that adding ezetimibe to effective statin therapy in stable ease who are identified as being at high risk of disease by
patientswhoexperiencedanacutecoronarysyndromere- conventional risk scores may be reclassified as having
duced low-density lipoprotein cholesterol (LDL-C) from muchlowerriskintheabsenceofcoronaryarterycalcium.7
Corresponding
Author: Harlan M. 70 mg/dL to 54 mg/dL (to convert LDL-C from mg/dL to In addition, shared decision making is particularly im-
Krumholz, MD, SM, mmol/L, multiply by 0.0259), and reduced risk of athero- portant when the risks and costs of an intervention are
Section of sclerotic cardiovascular disease outcome at 7 years from immediate and the benefits are in the future. Moreover,
Cardiovascular
Medicine, Department
34.7% to 32.7%. The Further Cardiovascular Outcomes patients vary considerably in their views about what
of Internal Medicine, Research with PCSK9 Inhibition in Subjects with Elevated amount of benefit from a prevention drug is meaningful
Yale School of Risk (FOURIER) trial5 reported that the addition of evo- enough to merit taking a pill every day. Nevertheless, de-
Medicine, 1 Church St,
locumab, a proprotein convertase subtilisinkexin type 9 spite the importance of shared decision making, as noted
Ste 200, New Haven,
CT 06510 (harlan (PCSK9) inhibitor, to effective statin therapy reduced in the ACC/AHA guideline, few effective tools exist. In par-
.krumholz@yale.edu). LDL-C from 92 mg/dL to 30 mg/dL and decreased the ticular, there remains a need for better point-of-care
ARTICLE INFORMATION Department of Medicine/Cardiology, Barbra 4. Cannon CP, Blazing MA, Giugliano RP, et al;
Published Online: July 24, 2017. Streisand Womens Heart Health Program, David IMPROVE-IT Investigators. Ezetimibe added to
doi:10.1001/jama.2017.6753 Geffen School of Medicine at UCLA, for their statin therapy after acute coronary syndromes.
thoughtful review of this work, for which they were N Engl J Med. 2015;372(25):2387-2397.
Conflict of Interest Disclosures: The author has not remunerated.
completed and submitted the ICMJE Form for 5. Sabatine MS, Giugliano RP, Wiviott SD, et al;
Disclosure of Potential Conflicts of Interest and Open-Label Study of Long-Term Evaluation against
REFERENCES LDL Cholesterol (OSLER) Investigators. Efficacy and
reported that he received research grants from
Medtronic, Johnson & Johnson (Janssen), the US 1. Stone NJ, Robinson JG, Lichtenstein AH, et al; safety of evolocumab in reducing lipids and
Food and Drug Administration, all through Yale; American College of Cardiology/American Heart cardiovascular events. N Engl J Med. 2015;372(16):
works under contract with the Centers for Medicare Association Task Force on Practice Guidelines. 2013 1500-1509.
& Medicaid Services; chairs a cardiac scientific ACC/AHA guideline on the treatment of blood 6. Landray MJ, Haynes R, Hopewell JC, et al;
advisory board for UnitedHealth; is a participant and cholesterol to reduce atherosclerotic cardiovascular HPS2-THRIVE Collaborative Group. Effects of
participant representative of the IBM Watson Health risk in adults. J Am Coll Cardiol. 2014;63(25 pt B): extended-release niacin with laropiprant in
Life Sciences Board; is a member of the Advisory 2889-2934. high-risk patients. N Engl J Med. 2014;371(3):
Board for Element Science and the Physician 2. Collins R, Reith C, Emberson J, et al. 203-212.
Advisory Board for Aetna; and is the founder of Interpretation of the evidence for the efficacy and 7. Nasir K, Bittencourt MS, Blaha MJ, et al.
Hugo, a personal health information platform. safety of statin therapy. Lancet. 2016;388(10059): Implications of coronary artery calcium testing
Additional Contributions: The author thanks 2532-2561. among statin candidates according to American
Suveen Angraal, MBBS, Maria Johnson, MBA, and 3. Green JB, Ross JS, Jackevicius CA, Shah ND, College of Cardiology/American Heart Association
Erica Spatz, MD, Yale School of Medicine; Marilyn Krumholz HM. When choosing statin therapy. JAMA Cholesterol Management Guidelines. J Am Coll
Mann, JD; Khurram Nasir, MD, Baptist Health South Intern Med. 2013;173(3):229-232. Cardiol. 2015;66(15):1657-1668.
Florida, Miami; and Karol Watson, MD, PhD,