Opinion

VIEWPOINT

William H. Shrank, MD,

MSHS
CVS Health,
Woonsocket, Rhode
Island.
Jane F. Barlow, MD,
MPH
CVS Health,
Woonsocket,
Rhode Island.
Troyen A. Brennan,
MD, JD
CVS Health,
Woonsocket,
Rhode Island.

Corresponding
Author: William H.
Shrank, MD, MSHS,
1 CVS Dr, Woonsocket,
RI 02895 (william
.shrank@cvshealth
.com).

New Therapies in the Treatment

of High Cholesterol
An Argument to Return
to Goal-Based Lipid Guidelines
this challenge in 2013, when little clinical evidence was
available for this new class of medications.
One problem is that the recent ACC/AHA guidelines abandoned the longstanding principle that clinicians should treat patients to a specific LDL-C target.
Prior to the release of the new guidelines, this groups
earlier guidelines had always centered on stratifying
patients by their cardiovascular risk, assigning an LDL-C
target, and titrating medication use to reach that target. The newest set of guidelines noted that the trials
on which those guidelines were based were not
designed to test a treat-to-target approach. 5 The
authors modified the guidelines and now suggest that
once patients are stratified based on risk, the most
effective therapy should be initiated. For patients at
high risk of a cardiovascular event, high-dose, highpotency statin medications are recommended, indicating that more aggressive management of cholesterol is
appropriatelower LDL-C is better. Moreover, a microsimulation model suggested that applying the arteriosclerotic cardiovascular
disease risk threshold (7.5% risk) used
As clinicians and payers prepare
in the current guidelines has an acceptfor the likely entry of PCSK-9 inhibitors
able cost-effectiveness profile when
to the market, there is a need
used to guide statin therapy and dose.6
How can these guidelines be interto achieve consensus around
preted now that the treatment options
management strategies for patients
to address hyperlipidemia are increaswith hyperlipidemia.
ing? The guidelines were established
when statins were the primary treatcost and relatively large eligible population, up to 3 mil- ment for hyperlipidemia. The results of the recently publion infected individuals.3 Unlike new therapies for hepa- lished Improved Reduction of Outcomes: Vytorin Effititis C, which represent a cure for most patients, PCSK-9 cacy International Trial (IMPROVE-IT) study were not yet
inhibitors will be used long-termgenerally for the re- available, demonstrating improved clinical outcomes in
mainder of the lives of treated patients. As a result, most hyperlipidemic patients treated with ezetimibe.7 No evipayers, both government and commercial, should be- dence was yet available on the efficacy of PCSK-9 inhibigin to consider thoughtful ways to rationalize the use of tors. In the absence of other therapeutic options, initiating higher-dose therapy and selecting more potent
these medications.
The best approach will be to promote use of low- statins for patients at high risk of cardiovascular events
cost statin medications rather than PCSK-9 inhibitors, but did not represent a very challenging clinical scenario;
this approach will be complicated by recent changes in high-potency statins are available as generic products,
recommendations for treating hyperlipidemia. In par- limiting the financial effects on patients and payers. The
ticular, the release of the American College of Cardiol- dilemma presented by the introduction of the PCSK-9
ogy and American Heart Association (ACC/AHA) choles- inhibitors reinforces the need to update guidelines on a
terol management guidelines in 2013 fundamentally regular basis, or at least offer clarification when new data
altered the way cholesterol-lowering medications are emerge.
Now, a richer set of therapeutic options are availprescribed4 and inadvertently limited the ability of payers to employ typical utilization management tools. The able to clinicians treating hyperlipidemia, and the most
authors of the guidelines may not have contemplated recent set of guidelines do not provide clarity on how to
On July 25, the US Food and Drug Administration
(FDA) approved alirocumab (Praluent), the first in a
new class, the proprotein convertase subtilisin/kexin
type 9 (PCSK-9) inhibitors. Approval of a second medication in the class is expected shortly. The injected
medications are used to treat patients with hyperlipidemia, and early results suggest these drugs have a powerful effect on levels of low-density lipoprotein cholesterol (LDL-C), likely more potent than statins.1 Although
evidence continues to accumulate, the class appears to
represent an important new development in hyperlipidemia management.
This class also poses a new challenge for health care
payers. It is an expensive specialty medication that targets a very common condition; more than 73 million
adults (32%) in the United States have elevated LDL-C.2
As a reference, when sofosbuvir, which is used to treat
hepatitis C, was approved and marketed over a year ago,
it shocked the health care system because of the high

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1443

Opinion Viewpoint

choose. In particular, the guidelines do not recommend titration of

therapy based on LDL-C control. Will clinicians interpret the guidelines to indicate that the highest-risk patients should be prescribed
PCSK-9 inhibitors? Perhaps most concerning from a social cost point
of view, will relatively low-risk patients be considered for PCSK-9 inhibitors? The cost implications for payers and society could be extraordinary; if used broadly, PCSK-9 inhibitors would likely be the
most costly class of medications marketed thus far.
The FDA advisory panels noted the lack of outcomes data and
the need for more broad evaluation to assess potential adverse effects of the PCSK-9 inhibitors; the panels suggested that use for those
who do not have a diagnosis of familial hypercholesterolemia should
be limited. However, there is likely to be substantial enthusiasm about
this class of drugs in the marketplace.
When faced with expensive new therapies, payers generally
apply utilization management criteria to be sure that the treatments are used in those who are eligible and for indication and
patients for which the evidence about benefit is clear. Traditional
utilization management techniques, such as step therapy and prior
authorization, require patients to first try a lower-cost, evidencebased therapy, and if clinical goals are not met, therapy can be
escalated to a more intensive and costly therapy. However, some
may argue that such a strategy cannot be supported when the
guidelines do not endorse treating to specific targets and titrating
therapy based on their effects.
This may mean that reasonable utilization management can
occur only with a return to reliance on lipid goals. Although studies
in the literature may not have been designed to test the approach
of treating to specific cholesterol targets, ample evidence supports
the clinical utility of reaching specific cholesterol targets. The European Atherosclerosis Society consensus statement on treating
familial hypercholesterolemia (August 2013),8 the American Asso-

and Stroke Statistics Subcommittee. Heart disease

and stroke statistics2015 update. Circulation.
2015;131(4):e29-e322.

ARTICLE INFORMATION
Published Online: August 10, 2015.
doi:10.1001/jama.2015.10017.
Conflict of Interest Disclosures: All authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest. The
authors are all employed by CVS Health, which
dispenses cholesterol-lowering medications and
provides point-of-service cholesterol testing. No
other disclosures were reported.

1444

ciation of Clinical Endocrinologists (AACE) Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis (March
and April 2012),9 and the National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia (September 2014) all maintain specific LDL-C targets in the management of
hyperlipidemia. The commonly referenced AACE guidelines are
similar to the previous ACC/AHA guidelines, the Third Report of the
National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
(ATP III), affirming the utility of these thresholds. Use of such lipid
goals could facilitate the cost-effective use of PCSK-9 inhibitors,
although given the cost of the drugs, lack of evidence of effect on
hard outcomes such as stroke and myocardial infarction, clinical
trials that compare treating to a specific cholesterol target with
PCSK-9 inhibitors vs more traditional statins, may be necessary.
As clinicians and payers prepare for the entry of PCSK-9 inhibitors to the market, there is a need to achieve consensus around management strategies for patients with hyperlipidemia. The differences in costs between newer and older therapies are substantial
(Praluent is priced at $14 600 a year). The comparative clinical outcomes are not yet clear. Large-scale clinical trials currently under way
will provide greater insight into the long-term clinical outcomes and
population health effects of different management strategies. The
guidelines will likely change.
In the meantime, a rational, step-wise approach that again utilizes specific LDL-C target levels would help. In the absence of such
an approach, clinicians will be forced to simultaneously consider multiple competing priorities in clinical decision-making: efficacy, safety,
evidence quality, as well as responsible stewardship of limited health
care budgets. Clear guidelines and targets would be attractive to support rational clinical decision making, particularly as increasing evidence emerges about the optimal role of PCSK-9 inhibitors.

3. Brennan T, Shrank W. New expensive treatments

for hepatitis C infection. JAMA. 2014;312(6):593-594.

REFERENCES

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et al. Effects of proprotein convertase
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