CLINICAL
NEWS
American College of Cardiology Extended Learning
ACCEL interviews and topical summaries of cardiology’s
most interesting research areas
The ‘Highly Difficult Lipoprotein’
Believe it or not, optimism about HDL
A
Almost 4 decades ago, the Framingham
Study reported that high-density lipoprotein cholesterol (HDL-C) was a protective
factor against CHD1 and, about 25 years ago Badimon et al. demonstrated that intravenous infusion
of HDL-C into cholesterol-fed rabbits caused regression of atherosclerotic lesions.2
Since then there have been many attempts
to harness the potential of HDL as a therapeutic
strategy since it seems to have several protective
vascular effects:
•
promotes cholesterol efflux
•
has antioxidant properties
•
has antithrombotic properties
•
has anti-inflammatory properties
•
improves endothelial function
•
promotes endothelial repair
•
improves diabetic control.
Consequently, multiple pharmaceutical agents have
been studied with the goal of increasing HDL-C.
Niacin, the most widely used medication to raise
HDL-C, increases HDL-C by 25% or more and was
shown in multiple surrogate endpoint studies to
reduce CV risk. However, two large randomized
controlled trials of niacin, AIM-HIGH and HPS2THRIVE, have shown that despite its effects on
HDL-C, niacin does not decrease the incidence of
CV events and may have significant adverse effects.
Studies of other classes of
agents such as cholesteryl ester
transfer protein (CETP) inhibitors have also shown that even
dramatic increases in HDL-C
do not necessarily translate
to reduction in clinical events.
To listen to an
One of the latest attempts
interview with
was described by Barter and
Philip Barter, MD,
by Alfred Bove,
colleagues who reported the reMD, visit the CSWN
sults of the CHI-SQUARE study
YouTube channel by
(Can HDL Infusions Signifiscanning the code.
cantly Quicken Atherosclerosis
Regression) study, which is
the largest randomized clinical
trial to date testing the efficacy
of serial HDL infusions in
patients with a recent ACS.3
26 CardioSource WorldNews
In this case, the authors investigated the effects of
an HDL-mimetic agent on atherosclerosis by IVUS
and quantitative coronary angiography at baseline
and 3 weeks in a prospective, double-blinded, randomized trial including 507 patients from 51 centers
in the U.S., The Netherlands, Canada, and France.
Patients received 6 weekly infusions of placebo or
3, 6, or 12 mg/kg CER-001. The primary efficacy
parameter was the nominal change in total atheroma
volume. Unfortunately, CER-001 infusions did not
reduce coronary atherosclerosis as compared with
placebo, making this the fourth study to fail to show
significant improvement in atheroma volume versus
placebo after infusion of HDL in humans with coronary artery atherosclerosis.
In an accompanying comment to the CHISQUARE results, Alan Fogelman, MD, David Geffen School of Medicine at the University of California Los Angeles, offered potential expla nations
for the Barter et al. results: HDL-C may be only a
biomarker and not a causal agent; inflammation
may have rendered apolipoprotein A-I (apoA-I) ineffective; doses used may be too low or not delivered
frequently enough; HDL’s protective effect may
occur outside of the arterial circulation; or measurements used may be too crude.4
Dr. Fogelman and colleagues recently reviewed
the hypothesis that HDL is a suitable therapeutic
target despite the CHI-SQUARE results. He notes
that HDL-C “is not like other lipoproteins; it is
much more complex. It is also probably too soon
to determine if trying to harness the potential
of HDL is wishful thinking or a sound strategy.”5
Recent studies suggest, for example, that HDLC becomes modified in patients with CAD or
ACS because of oxidative processes that result in
alterations in its proteome composition (proteome
remodeling) leading to HDL dysfunction. Therefore, Dr. Fogelman wrote that it will be important
to demonstrate that novel drugs not only increase
HDL-C plasma levels but also improve HDL function in patients at high CV risk.
‘HIGHLY DIFFICULT LIPOPROTEIN’
Professor Philip Barter, MD, Director of the Centre
for Vascular Research, University of New South
Wales, Sydney, Australia, certainly concurs over the
complex nature of HDL, which he calls the “highly
difficult lipoprotein.” We noted above a number of
potential protective properties of HDL-C, including
perhaps improved diabetes control. This is based on
evidence that lipid-free and lipid-associated apoA-I
and apoA-II increase pancreatic beta cell insulin
synthesis and secretion, suggesting that interven-
tions that raise HDL-C levels may be beneficial in
type 2 diabetes.
Dr. Barter and colleagues demonstrated this in
the ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events) trial where treatment with torcetrapib
improved glycemic control in atorvastatin-treated
patients with type 2 diabetes mellitus.6 However,
whether the beneficial effect of torcetrapib on
glucose homeostasis was related to the increase
in HDL concentration or to some other off-target
activity of the drug is unclear. So, to date, there is
no clinical trial evidence that increasing the level
of HDL-C in people with diabetes translates into a
reduction in CVD risk.
In June 2015, Barter and others published (online before print) the initial results of a study using
another novel CETP inhibitor, TA-8995, in patients
with mild dyslipidemia.7 They enrolled 364 patients
and low-density lipoprotein cholesterol (LDL-C)
was reduced by about 25% to 50%, depending on
dose, and HDL-C was increased from about 75% to
179%, again depending on dosing. Dr. Barter, too,
thinks just raising HDL-C is not enough and this
new agent increases HDL-C function. He said, “It
increases the ability of HDL to promote cholesterol
efflux by about 50%.” TA-8995 was well tolerated
and clearly has beneficial effects on lipids and apolipoproteins in patients with mild dyslipidemia, but a
CVD outcomes trial is needed to determine whether
these effects translate into a reduction of CV events.
“HDL is very, very complex,” said Dr. Barter. “At
last count, there was something like 37 identifiable
subpopulations that migrate in the HDL range.”
The problem, he said, is we do not know which
functions of HDL-C are clinically important and we
Take-aways
• High-density lipoprotein cholesterol (HDL-C) is a
complex lipoprotein and while it is a promising
marker and potential therapeutic target based
on epidemiological data, randomized trials have
failed to demonstrate an advantage to raising
HDL-C on clinical outcomes.
• The concentration of HDL-C is an inverse
predictor of CVD events in people with type
2 diabetes and there is evidence that HDLs
improve diabetic control.
• Despite a number of recent disappointing
clinical trials, it may still be too soon to
determine if trying to harness the potential of
HDL-C is wishful thinking or a sound strategy.
August 2015