Practice Update: Diabetes

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Dr Libby is Mallinckrodt
Professor of Medicine
at Harvard Medical
School in Boston,
Massachusetts.
The last decade witnessed intense
interest in raising high-density lipo-
protein (HDL) as a strategy for
reducing cardiovascular risk. A wealth of
observational epidemiologic evidence fed
this enthusiasm. Yet, numerous attempts
to raise HDL have failed to reduce car-
diovascular events. Most recently, the
ACCELERATE trial showed the futility of
evacetrapib, a cholesteryl ester transfer
protein inhibitor, to improve cardiac out-
comes in a large-scale investigation.1 This
failure occurred despite the apparent
beneficial effects of plasma from eva-
cetrapib-treated patients on cholesterol
efflux in vitro and raising the subclass of
HDL (pre-beta1) deemed to be important
in reverse cholesterol transport.2 Moreover,
human genetic studies have failed consist-
ently to support a protective effect against
cardiovascular events of lifelong exposure
to higher levels of HDL.3,4
In stark contrast to this disappointment,
the human genetic studies sporting a
causal role for triglyceride-rich lipopro-
teins at the genes that encode proteins
that regulate their levels continue to accu-
mulate at an accelerating pace.4 We have
previously reviewed some of these stud-
ies for PracticeUpdate, including recent
evidence supporting a causal role for
angiopoietin-like factor 3 (ANGPTL3) in
cardiovascular events.5
Triglycerides tend to vary inversely with
HDL. Convinced by the weight of the
observational evidence, researchers have
traditionally adjusted triglycerides for HDL,
a statistical maneuver that markedly atten-
uates the relationship of triglycerides with
cardiovascular events. But what if we bet
on the wrong member of this dyad, and
rather than adjusting triglycerides for HDL,
should have done the contrary? Indeed, I
have argued that the data drive us ineluc-
tably to this conclusion.6
Therefore, rather than attempting to raise
HDL, should we target triglycerides or the
various factors that determine triglyceride
concentrations, shown by recent human
genetic studies to contribute to cardiovas-
cular events? A pair of papers in the New
England Journal of Medicine provide strong
support for this contention.7,8 Both studies
found that interruption of ANGPTL3, by
either a monoclonal antibody strategy or by
administration of an antisense oligonucleo-
tide, could alleviate atherogenesis in mice.
One study reinforced the human genetic
case for a causal role by probing large
human populations for variants that impair
the function of ANGPTL3.7 They found that
participants who had genetic variants that
limited function of ANGPTL3 had reduced
plasma triglycerides compared with con-
trols. In a small number of humans treated
with a monoclonal antibody that neutralizes
ANGPTL3, the authors found a dose-de-
pendent decrease in circulating triglyceride
levels by up to 75%, which endured for
almost 1 month. The second paper used an
oligonucleotide approach and documented
not only decreases in the plasma levels of
ANGPTL3, but in tandem, considerable
reductions in triglycerides (to about 1/3 to
almost 2/3 below baseline levels).8
Together, these studies reinforce the cau-
sality of determinants of triglyceride-rich
lipoproteins as contributors to human
atherosclerotic risk, provide support for
therapeutic targeting of ANGPTL3 experi-
mentally in mice, and illustrate the feasibility
of two distinct mechanisms for targeting
ANGPTL3 in humans. The monoclonal anti-
bodies strategy joins a number of other
approaches that use biological agents to
treat cardiovascular risk factors. While ear-
lier generation antisense oligonucleotides
provoked unacceptably high adverse reac-
tions, such as flulike syndromes and not
infrequent serious injection site reactions,
later generation antisense oligonucleo-
tides have improved characteristics and use
hepatocyte targeting strategies that permit
achieving biological effects (on proteins that
are manufactured in the liver) at much lower
doses than previously employed.
A new era in lipidology appears on the
horizon. Refocusing on triglyceride-rich
lipoproteins as a therapeutic target and
applying newer biological strategies offer
us new tools for managing residual risk in
individuals who have high triglyceride con-
centrations, despite all current therapies,
including those that lower LDL effectively.
In the current era of epidemic obesity
and diabetes, dyslipidemia characterized
by high triglycerides and low HDL repre-
sents an increasing challenge for clinicians.
The shifting attention to triglycerides from
HDL may provide us with a new avenue to
address this category of residual risk in our
contemporary patient population.
Disclosures: Dr Libby has served as an
unpaid consultant to Ionis and Regeneron.
References
1. Lincoff AM, Nicholls SJ, Riesmeyer JS, et al.
Evacetrapib and cardiovascular outcomes
in high-risk vascular disease. N Engl J Med
2017;376(20):1933-1942.
2. Nicholls SJ, Ruotolo G, Brewer HB, et al.
Cholesterol efflux capacity and pre-beta-1 HDL
concentrations are increased in dyslipidemic
patients treated with evacetrapib. J Am Coll
Cardiol 2015;66(20):2201-2210.
3. Musunuru K, Kathiresan S. Surprises from genetic
analyses of lipid risk factors for atherosclerosis.
Circ Res 2016;118(4):579-585.
4. Khera AV, Kathiresan S. Genetics of coronary
artery disease: discovery, biology and clinical
translation. Nat Rev Genet 2017;18(6):331-344.
5. Libby P. ANGPTL3 deficiency and protection
against CAD. PracticeUpdate 2017.
6. Libby P. Triglycerides on the rise: should
we swap seats on the seesaw? Eur Heart J
2015;36(13):774-776.
7. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic
and pharmacologic inactivation of ANGPTL3 and
cardiovascular disease. N Engl J Med 2017 May
24. doi: 10.1056/NEJMoa1612790. [Epub ahead of
print]
8. Graham MJ, Lee RG, Brandt TA, et al.
Cardiovascular and metabolic effects of
ANGPTL3 antisense oligonucleotides. N Engl J
Med 2017 May 24. doi: 10.1056/NEJMoa1701329.
[Epub ahead of print]
Dr Peter Libby
on New Territory
in Targeting
Triglycerides
By Peter Libby MD
MY PERSPECTIVE 21
VOL. 1 • NO. 2 • 2017