Scientific Sessions 2011
ORLANDO, Fla. — Using HDL as both a target for treatment and a predictor for CVD has received a great deal of attention, several speakers said here. Questions remain, however, about its potential place for
use in clinical practice.
One important issue discussed by Frank Sacks, MD,
of the Harvard School of Public Health in Boston, was the “HDL
paradox.” Basic science has identified the predictive functions of HDL and epidemiological studies firmly
characterize HDL as a “powerful risk factor,” he said. Even so,
several trials indicate that lowering HDL with various medications did not
significantly reduce risk for CVD.
Questions persist about whether HDL is beneficial or
harmful. Alan M. Fogelman, MD, of the David Geffen School of Medicine at
University of California, Los Angeles, said, the answer is complicated by the
complex nature of HDL. For example, HDL is able to change in the setting of
inflammation, converting from anti-inflammatory to pro-inflammatory depending
on a patient’s state. Because inflammation may play a role in the
development of atherosclerosis, this mutability could affect a patient’s
risk for CHD, Fogelman explained. Nevertheless, he noted that only
“multiple clinical trials will answer the question of whether HDL is
‘good’ or ‘bad.’”
Considering HDL cholesterol might be even more difficult in
patients with diabetes, as low HDL may not only be a consequence but a cause of
the disease as well, according to Arnold von Eckardstein, MD, of the
University of Zurich, Switzerland. Data from the PROCAM study, for instance,
show that participants in the lowest tertile for HDL had a twofold higher risk for
developing diabetes compared with those in higher HDL tertiles, he said.
Additionally, other trials suggest that HDL can protect beta cells and that
dysfunctional HDL metabolism may contribute to the development of type 2
diabetes. Consequently, von Eckardstein said, HDL may be an appropriate
therapeutic target for preventing both diabetes and CVD.
In terms of treatment, many researchers have focused
their efforts on developing cholesteryl ester transfer protein (CETP)
inhibitors, such as torcetrapib (Pfizer), to raise HDL. Although the
Investigation of Lipid Level Management to Understand its Impact in
Atherosclerotic Events (ILLUMINATE) trial associated torcetrapib with
significant toxicity, which halted its development, researchers determined the
adverse events were unrelated to CETP inhibition, according to H. Bryan
Brewer, Jr., MD, of Washington Cardiovascular Associates and MedStar
Research Institute. Now, studies are suggesting that second-generation CETP
inhibitors, including anacetrapib (Merck) and dalcetrapib (Hoffman-La Roche),
are safe and effective for lowering LDL and raising HDL, Brewer said.
Recently, the concept of raising HDL to lower CVD risk
has taken several hits, Daniel J. Rader, MD, of the University of
Pennsylvania, said. For example, some genetic studies show that certain variants that
raise HDL do not seem to protect against CHD. Similarly, trials indicating no
connection between reduced risk for CVD and interventions for raising HDL also
serve to debunk this simple “HDL hypothesis.”
Nevertheless, Rader pointed out that HDL still plays a
role in reverse cholesterol transport and cholesterol efflux, both of which
contribute to prevention of CHD. Instead of discarding HDL altogether, maybe a
shift in focus is needed, he said.
“There are quite a few novel approaches to explore,
such as targeting and regulating macrophage cholesterol efflux pathways and
conducting a genome-wide association study to look for variants relating to
HDL,” Rader said. “It is time to abandon the HDL hypothesis and time
to move toward an HDL efflux hypothesis that promotes cholesterol efflux and
macrophage reverse cholesterol transport to reduce CV events.” –
by Melissa Foster
For more information:
- Braun L. HDL-based therapy: The new frontier in atheroprevention.
Presented at: American Heart Association Scientific Sessions 2011; Nov. 12-16,
2011; Orlando, Fla.
Disclosure: Dr. Brewer has received honoraria
from or has been a speaker, consultant or advisory board member for Abbott,
Lilly, Merck, Roche and Sanofi-Aventis. Dr. Fogelman has received grant support
from HL-30568, and is an officer and has ownership interest in Bruin Pharma.
Dr. Rader has ownership interest in VascularStrategies and Aegerion and has
been a consultant, speaker or advisory board member for AstraZeneca, Eli Lilly,
Merck, Novartis, Pfizer, Roche and Sanofi-Aventis. Dr. Sacks has received grant
support from R3i Foundation, has been an expert witness for Abbott and a
consultant or advisory board member for Amgen, Eli Lilly, Merck and Roche. Dr.
von Eckardstein reports no relevant financial disclosures.