Viewpoints
Nonstatin Therapy for Dyslipidemia
Current and Future Directions
Haitham M. Ahmed, Steven E. Nissen
H MG Co-A (β-hydroxy β-methylglutaryl-coenzyme A)
reductase inhibitors (statins) were introduced in 1987
and have revolutionized the prevention and treatment of car-
diovascular disease (CVD). However, for the next 37 years,
the treatment of dyslipidemia stagnated with no truly pivotal
new therapies introduced until 2015 when the first PCSK9
(proprotein convertase subtilisin kexin 9) inhibitor was ap-
proved by the Food and Drug Administration. PCSK9 inhibi-
tors are undoubtedly the most effective lipid-lowering therapy
ever developed and have been demonstrated to prevent coro-
nary artery plaque progression and cardiovascular events in
well-controlled randomized trials. Despite that, they remain
drastically underutilized in clinical practice. In this article,
we discuss the barriers that have led to underutilization and
propose ways to avoid such pitfalls with other emerging lipid
therapies, such as antisense oligonucleotide inhibitors and
small interfering RNA addressing novel targets.
PCSK9 Inhibitors
Monoclonal antibodies targeting the PCSK9 protein in the liver
reduce LDL-C (low-density lipoprotein cholesterol) receptor
Downloaded from http://ahajournals.org by on March 3, 2024
degradation, thereby increasing receptor activity which lowers
circulating LDL-C.1,2 Clinical trials have shown that these drugs
can reduce LDL-C by 60% to 70% in patients with familial hy-
percholesterolemia and CVD. This large reduction in LDL-C
was initially shown to slow atherosclerotic plaque progression
and enhance atheroma regression in the GLAGOV Trial (Global
Assessment of Plaque Regression With a PCSK9 Antibody as
Measured by Intravascular Ultrasound).3 Subsequently, cardio-
vascular outcomes trials in >46 000 subjects have demonstrated
that PCSK9 inhibitors can reduce major adverse cardiovascular
events (MACE) even when LDL-C is already well controlled.4,5
Most importantly, these outcomes were achieved safely with no
significant increase in adverse events for subjects taking these
drugs as compared with placebo.
Barriers to Adoption
With such significant LDL-C and MACE reduction, one
would expect this class of medications to achieve rapid and
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Department of Cardiovascular Medicine, Cleveland
Clinic, OH.
Correspondence to Steven E. Nissen, MD, Department of
Cardiovascular Medicine Cleveland Clinic Foundation 9500 Euclid Ave
Desk J2-230 Cleveland, OH 44195. Email nissens@ccf.org
(Circ Res. 2018;123:1036-1038.
DOI: 10.1161/CIRCRESAHA.118.313829.)
© 2018 American Heart Association, Inc.
Circulation Research is available at https://www.ahajournals.org/
journal/res
DOI: 10.1161/CIRCRESAHA.118.313829
1036
widespread acceptance for the prevention of CVD. Yet, that
has not been the case. Despite the impressive results in clini-
cal trials, PCSK9 inhibitors are grossly underutilized. Recent
data shows that a shocking <0.5% of eligible patients (based
on the American College of Cardiology Expert Consensus
Decision Pathway) are actually prescribed PCSK9 inhibitors.6
This drastic underutilization is a consequence of critical flaws
in trial design, marketing, and drug pricing, all of which have
significantly undermined the success of these drugs.
How Did We Get Here?
The FOURIER Trial (Further Cardiovascular Outcomes
Research With PCSK9 Inhibition in Subjects With Elevated
Risk) was the first large cardiovascular outcomes trial of
PCSK9 inhibitors in patients with known CVD.4 This trial
enrolled 27 564 subjects with established CVD from 49 coun-
tries. Subjects were randomized to evolocumab versus pla-
cebo and followed for the primary outcome of MACE which
included CVD death, myocardial infarction, stroke, hospi-
talization for unstable angina, or coronary revascularization.
After 48 weeks, evolocumab reduced the median LDL-C from
92 to 30 mg/dL, an astonishingly low value. Moreover, evo-
locumab reduced MACE from 11.3% to 9.8%. Results were
consistent across all major subgroups, including those with
the lowest baseline LDL-C levels. In fact, a linear relation-
ship was observed between LDL-C and MACE with events
reduced with progressively lower LDL-C levels.
By every measure, the results in FOURIER were impres-
sive. However, critical errors undermined the impact of the
trial. First, the study was stopped prematurely before real-
izing the drug’s full potential. As is commonly the case in
lipid trials, the magnitude of risk reduction increases over
time. Since all subjects were already on background statin
therapy with well-controlled LDL-C, a lag of ≈1 year oc-
curred before separation in the event curves. There was a
12% risk reduction in the first year, which increased to 19%
the following year. Shortly after year 2, the trial reached the
requisite number of prespecified events. This was unfortu-
nate since the Kaplan-Meier curves were beginning to sepa-
rate markedly just as the trial concluded. It is, therefore, not
surprising that no significant reduction in cardiovascular or
all-cause death was observed.
Another major issue for both PCSK9 inhibitors was
their initially high price of >$13 000 per year. A contro-
versial analysis before completion of the outcome trials
suggested that PCSK9 inhibitor use in patients with CVD
was not cost-effective, and concluded that a price reduc-
tion to $4536 was needed to meet quality-adjusted life-year
thresholds.7 After FOURIER results were released, an up-
dated analysis argued the price would have to be reduced
even further.8 Armed with these analyses, pharmacy benefits

Nonstandard Abbreviations and Acronyms
CVD cardiovascular disease
LDL-C low-density lipoprotein cholesterol
Lp(a) lipoprotein (a)
MACE major adverse cardiovascular events
PCSK9 proprotein convertase subtilisin kexin 9
managers began to systematically deny coverage to patients
with some reports showing up to a 90% denial rate by insur-
ance providers.9 In the end, < 0.5% of eligible patients were
able to access the drug.6
After FOURIER completed, the ODYSSEY Outcomes
Trial (Evaluation of Cardiovascular Outcomes After an Acute
Coronary Syndrome During Treatment With Alirocumab), the
second large PCSK9 inhibitor outcomes trial reported results.
In ODYSSEY, 18 924 patients with prior CVD and LDL-C
≥70 mg/dL were randomized to low-dose alirocumab (75 mg)
versus placebo with a target LDL-C of 25 to 50 mg/dL.5 Per
the protocol, there was an option to increase the dose to 150
mg if target LDL-C was not achieved. The trial was continued
for 2.8 years (6 months longer than FOURIER), but LDL-C
only decreased from a median of 101 to 66 mg/dL on study
drug, representing a much lower efficacy than observed in
FOURIER. The primary end point of MACE was reduced
from 11.1% to 9.5%. This 1.6% absolute risk reduction was
positive but still troubling because it was nearly identical to
that in FOURIER, despite subjects being on drug for 6 months
Downloaded from http://ahajournals.org by on March 3, 2024
longer and starting out with a higher median LDL-C.
The likely reason for alirocumab falling short of expec-
tations was the trial design. Per the ODYSSEY Outcomes
protocol, patients who had LDL-C levels below target ranges
were switched to placebo, which resulted in a considerable
number of patients in the alirocumab arm removed from study
drug, diluting the effect size.5 Simply put, the purpose of the
drug is to reduce LDL-C. If the drug worked well, patients
were actually removed from the therapy. Consequently, only
patients with LDL-C >100 mg/dL were found to have con-
sistent benefit in the trial. However, these patients were the
only ones who actually stayed on drug. Notably, because all
patients remained on drug in FOURIER, similar efficacy was
observed regardless of baseline LDL-C with a similar reduc-
tion in MACE across all LDL-C subgroups, including those
with the lowest baseline LDL-C levels.4
Finally, in ODYSSEY Outcomes the results of individ-
ual endpoints are difficult to interpret.5 For example, results
showed that the drug reduced myocardial infarction and all-
cause death, but not CVD death, which does not seem bio-
logically plausible. Moreover, the outcome for all-cause death
was not significant using prespecified hierarchical testing but
was still reported as a major result. These discrepancies in
observed outcomes, the manner in which outcomes were de-
scribed, the narrowing of subgroups shown to benefit, the high
drug price, and the modest absolute risk reduction relative to
its price have all undermined the case for this class of drugs.
As a result, two of the most powerful lipid-lowering medica-
tions in history sit idly on the shelf with few patients actually
benefiting from them.
Ahmed and Nissen  Nonstatin Therapy  1037
Additional Lipoprotein Targets
With regards to other lipoprotein targets, Lp(a) (lipoprotein
[a]) is a lipoprotein comprised of apo(a) and apoB proteins
covalently linked by a disulfide bond.10 Lp(a) is thought to me-
diate cardiovascular risk through inflammatory, atherogenic,
and thrombotic mechanisms. It has been shown to indepen-
dently predict CVD risk in >120 000 participants from the
Emerging Risk Factors Collaboration.11
Unfortunately, despite its independent risk prediction,
there are no therapies specifically indicated for Lp(a) re-
duction. High doses of niacin can reduce Lp(a) by ≈20%
but has not been shown to reduce CVD events in clinical
trials.12 Conversely, statins reduce CVD events, but they
do not reduce and, in fact, may even raise Lp(a) levels.10
Interestingly, PCSK9 inhibitors are unique in that they do
both—reduce CVD events and also lower Lp(a) by ≈22%.1
However, a specific trial investigating PCSK9 inhibitor
therapy in patients with elevated Lp(a) is not available.
Antisense oligonucleotide inhibitors of Lp(a) have also
shown great promise in their ability to lower Lp(a) by as
much as 78% in phase I clinical trials.13 A multinational
phase II trial has now completed enrollment. We anxiously
await those results and look forward to a phase III trial if the
drug continues to show promise.
Hypertriglyceridemia represents an additional lipid fron-
tier with a history of inconsistent results in clinical trials
to date. Data from our lipid center shows that patients with
extreme hypertriglyceridemia, particularly familial chylo-
micronemia syndrome, have a much higher prevalence than
previously reported and a ≈50% CVD event rate by age 60.14
That rivals the high rates observed for familial hypercholes-
terolemia. Moreover, patients with familial chylomicrone-
mia are, by definition, refractory to lipid-lowering therapies.
No therapies have been shown to adequately treat their tri-
glycerides and reduce CVD risk, so novel approaches are
desperately needed for that population as well. Volanesorsen
is a promising antisense oligonucleotide inhibitor of
ApoCIII and has been shown to reduce triglyceride levels
by up to 71% in phase II trials.15 We await results from the
phase III APPROACH FCS study (A Randomized, Double-
Blind, Placebo-Controlled, Phase 3 Study of ISIS 304801
Administered Subcutaneously to Patients With Familial
Chylomicronemia Syndrome), as well as the AKCEA-
APOCIII-LRx phase IIb study for the treatment of CVD driv-
en by hypertriglyceridemia. We look forward to other novel
approaches, such as using small interfering RNA to reduce
ApoCIII mRNA and triglycerides.
Finally, fish oil supplements containing eicosapentaenoic
acid/docosahexaenoic acid have long been known to reduce
triglycerides, but it remains unclear whether that translates
to lower CVD events. Two ongoing trials, REDUCE-IT and
STRENGTH (Outcomes Study to Assess Statin Residual
Risk Reduction With EpaNova in High CV Risk Patients
With Hypertriglyceridemia), are aimed at answering that
question. REDUCE-IT (Reduction of Cardiovascular Events
With EPA-Intervention Trial) is a phase III randomized con-
trolled trial evaluating icosapent ethyl versus placebo in pa-
tients with residual hypertriglyceridemia on statin therapy
and at high risk for CVD. It has completed enrollment of
 1038  Circulation Research  October 12, 2018
8175 subjects with results expected to be reported in the next
year. STRENGTH is a larger multicenter, randomized con-
trolled trial evaluating Epanova versus corn oil in hypertri-
glyceridemic patients at high risk for CVD and on statins.
A total of 13 086 subjects have been enrolled and are now
being followed for a total of 3 to 5 years for the primary
outcome of MACE. The results of these trials will help de-
finitively inform whether fish oil supplements should play
any role in CVD risk reduction.
Lessons Moving Forward
With emerging lipoprotein targets, such as ApoA and ApoCIII,
and with the advent of novel strategies for silencing gene ex-
pression, such as antisense oligonucleotide inhibitors and
small interfering RNA, it is more important than ever to learn
from the PCSK9 inhibitor trials. We propose the following key
points that industry and trialists should consider to facilitate
successful bench to bedside delivery:
1. We must size clinical trials correctly. Studies that are
too small will be underpowered, and those that are too
large (eg. FOURIER) will be too expensive, resulting in
higher drug costs.
2. There is no substitute for good trial design. Even the
most powerful lipid-lowering drugs can appear less ef-
fective if trial participants do not receive the drug (eg,
ODYSSEY Outcomes).
3. Cardiovascular outcomes studies must be continued for
adequate durations. In an era when most cardiovascular
patients are already on statins, it is increasingly difficult
Downloaded from http://ahajournals.org by on March 3, 2024
to show rapid separation in event curves. Despite the
pressures to cut costs, sometimes ending a trial just a
few months early can lead to unsatisfactory results and
undermine confidence in the therapy.
4. The drug has to be priced wisely. Overpricing can be
fatal to the drug’s long-term success. For example, even
if the price of PCSK9 inhibitors is reduced, it remains
unclear how long it will take for these drugs to recover
from initial disappointment. With multiple competing
lipid-lowering therapies on the horizon, pricing remains
a critical consideration.
For the sake of our patients, we must learn from our mistakes.
Often the patients that need advanced lipid-lowering therapies
are desperate. They may have uncontrolled LDL-C despite
maximum statin therapy; they may have had multiple CVD
events already; or as in the case of familial chylomicronemia,
they may have no available therapies at all. With these new
therapies coming soon, we need to adopt strategies that allow
many more patients to benefit from these innovations.
Disclosures
H.M. Ahmed has received grant funding from Akcea Therapeutics.
S.E. Nissen has received research support from Amgen, Astra Zeneca,
Novo Nordisk, Pfizer, Novartis, Esperion, and Eli Lilly but does not
accept any honoraria or other personal income from for-profit entities.
References
1. Blom DJ, Hala T, Bolognese M, et al; DESCARTES Investigators.
A 52-week placebo-controlled trial of evolocumab in hyperlipidemia.
N Engl J Med. 2014;370:1809–1819. doi: 10.1056/NEJMoa1316222
2. Robinson JG, Farnier M, Krempf M, et al; ODYSSEY LONG TERM
Investigators. Efficacy and safety of alirocumab in reducing lipids
and cardiovascular events. N Engl J Med. 2015;372:1489–1499. doi:
10.1056/NEJMoa1501031
3. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progres-
sion of coronary disease in statin-treated patients: the GLAGOV randomized
clinical trial. JAMA. 2016;316:2373–2384. doi: 10.1001/jama.2016.16951
4. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD,
Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen
TR; FOURIER Steering Committee and Investigators. Evolocumab and
clinical outcomes in patients with cardiovascular disease. N Engl J Med.
2017;376:1713–1722. doi: 10.1056/NEJMoa1615664
5. Steg PG. Evaluation of cardiovascular outcomes after an acute coronary
syndrome during treatment with alirocumab – ODYSSEY OUTCOMES.
Paper Presented at: American College of Cardiology Scientific Session;
March 10, 2018; Orlando, FL.
6. Karalis DG, Mallya UG, Ghannam AF, Elassal J, Gupta R, Boklage SH.
Prescribing patterns of proprotein convertase subtilisin-kexin type 9 in-
hibitors in eligible patients with clinical atherosclerotic cardiovascular
disease or heterozygous familial hypercholesterolemia. Am J Cardiol.
2018;121:1155–1161. doi: 10.1016/j.amjcard.2018.02.002
7. Kazi DS, Moran AE, Coxson PG, Penko J, Ollendorf DA, Pearson SD,
Tice JA, Guzman D, Bibbins-Domingo K. Cost-effectiveness of PCSK9
inhibitor therapy in patients with heterozygous familial hypercholester-
olemia or atherosclerotic cardiovascular disease. JAMA. 2016;316:743–
753. doi: 10.1001/jama.2016.11004
8. Kazi DS, Penko J, Coxson PG, Moran AE, Ollendorf DA, Tice
JA, Bibbins-Domingo K. Updated cost-effectiveness analysis of
PCSK9 inhibitors based on the results of the FOURIER trial. JAMA.
2017;318:748–750. doi: 10.1001/jama.2017.9924
9. Baum SJ, Toth PP, Underberg JA, Jellinger P, Ross J, Wilemon K.
PCSK9 inhibitor access barriers-issues and recommendations: improv-
ing the access process for patients, clinicians and payers. Clin Cardiol.
2017;40:243–254. doi: 10.1002/clc.22713
10. Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, con-
troversies, and emerging therapies. J Am Coll Cardiol. 2017;69:692–
711. doi: 10.1016/j.jacc.2016.11.042
11. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson
A, Wood AM, Lewington S, Sattar N, Packard CJ, Collins R, Thompson
SG, Danesh J, et al; Emerging Risk Factors Collaboration. Major lipids,
apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993–
2000. doi: 10.1001/jama.2009.1619
12. Guyton JR, Blazing MA, Hagar J, Kashyap ML, Knopp RH, McKenney
JM, Nash DT, Nash SD. Extended-release niacin vs gemfibrozil for the
treatment of low levels of high-density lipoprotein cholesterol. Niaspan-
Gemfibrozil Study Group. Arch Intern Med. 2000;160:1177–1184.
13. Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ, Baker BF,
Burkey JL, Yang Q, Marcovina SM, Geary RS, Crooke RM, Witztum
JL. Antisense therapy targeting apolipoprotein(a): a randomised, double-
blind, placebo-controlled phase 1 study. Lancet. 2015;386:1472–1483.
doi: 10.1016/S0140-6736(15)61252-1
14. Shah NP, Cho L, Ahmed HM. Familial chylomicronemia syndrome:
clinical characteristics and long-term cardiovascular outcomes. JACC.
2018;72:1177–1179.
15. Gaudet D, Alexander VJ, Baker BF, Brisson D, Tremblay K, Singleton W,
Geary RS, Hughes SG, Viney NJ, Graham MJ, Crooke RM, Witztum JL,
Brunzell JD, Kastelein JJ. Antisense inhibition of apolipoprotein C-III in
patients with hypertriglyceridemia. N Engl J Med. 2015;373:438–447.
doi: 10.1056/NEJMoa1400283
Key Words: cardiovascular disease ◼ cholesterol ◼ dyslipidemia ◼ patients
◼ proprotein convertase subtilisin kexin 9, human