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492 New Lipid Lowering Therapies

PCSK9(9). While Monoclonal antibodies to PCSK9 ers of clinical glycaemia control(10).
requires the drug to be administered fortnightly, the The familial chylomicronaemia syndrome (FCS) is
RNAi to PCSK9 only requires to be administer every an inherited disorder of lipoprotein lipase deficiency
6m after a loading dose of 1 and 3 months(7). An characterised by elevated chylomicrons concentra-
extensive clinical trial programme is under way for tion and a high risk for pancreatitis. Current therapy
this drug also.
for FCS is ineffective and use of Apo C3 inhibition
reduced triglyceride from 1406 to 2083mg /dl and
New HDL raising therapies Apo C3 level fell by 71 to 90%. The concept that re-
There is a large interest in HDL-C as a cardioprotec- duction of Apo C3 liberates the lipoprotein lipase in-
tive and athero protective fraction with an extensive dependent pathway is more likely for the reduction
development programme targeting raising the con- of TG levels(11).
centration of this lipoprotein fraction. Some progress
has been made in investigation of use of cholesteryl Another target for reduction of elevated TG level is
ester transfer protein (CETP) inhibitors. These agents angiopoetin like 3 proteins, the absence of which
inhibit transfer of cholesteryl ester and triglycerides causes familial hypobetalipoproteinaemia charac-
between lipoproteins. Development of three of the terised by low levels of all lipoproteins except lipo-
CETP inhibitors torcetrapib,dalcetrapib and evace- protein(a).A second generation antisense molecule
trapib have all been halted for various reasons such to ANGPTL3 results in favourable cardio metabolic
as off target side effect and lack of effectiveness(8). effects. The trial in humans has shown inhibition
of ANGPTL3 lowered TG levels, LDL and VLDL as
Other drugs include artificially reconstituted r/HDL well as Apo C3. An antibody based as well as an
that is administered as infusion and Apo A1 mimetics. antisense molecule are in development, and there
Direct up regulation of Apolipoprotein A1 synthesis may be differences between the two molecules in
using small proteins is another concept that may lead effectiveness and dosing regimen. There is evidence
to success in this area. RVX208 a novel epigenetic that by inhibiting ANGPTL3 in plasma by blocking its
approach directed to raise HDL –C concentration by synthesis in liver reduces plasma concentration of
regulation of gene transcription. Apo A1 mimetics are atherogenic Apo B containing lipoproteins (10). The
small amphipathic helical peptides that have the bio- drug may also benefit people with fatty liver. Because
logical functions of Apo A1 and these activate all the Antisense oligonucleotide acts on the liver, the doses
steps involved in reverse cholesterol transport that used can be smaller
includes ABCA1 mediated cholesterol efflux(9).
Lipoprotein(a) Lp(a) is a modified LDL molecule, and
on a molar basis Lp(a) is more atherogenic than LDL
New TG lowering therapies
-C as it in addition to LDL pathway, additionally apo
There is an explosion of interest in new drugs to tar- (a) component also exerts an adverse outcome. Ionis
get raised TG for both CVD reduction s well as reduc- -Apo(a) –Lrx has the potential to lower Lp(a) by 92.4%
tion in pancreatitis a very important complication of and is a new therapeutic paradigm(12)
very high TG concentration.
Statins have had an enormous impact on CVD pre-
Apolipoprotein CIII (ApoC3) is an important regula- vention worldwide. Clinical trials with LLT have shown
tor of triglyceride concentration with elevated levels the important principle that ‘even lower is even better’
contributing to higher CVD risk. Conversely loss of The need for more effective and better tolerated LLT
function mutation of Apo C3 attenuates the level continues along with the quest for alternate targets
of this lipoprotein and therefore reducing CV event for arresting atherosclerosis. Some of these newer
rates in this population. The expression of Apo C3 therapies are likely to complement existing therapies
is regulated by insulin through the insulin response like statin, fibric acid derivatives in achieving cardio-
element encoded in the Apo C3 gene Plasma con- vascular outcomes far superior to the existing well
centration of Apo C3 is associated with a degree of established benefits.
insulin resistance. Apo C3 inhibition is likely to en-
hance insulin sensitivity and therefore giving a hope References
that these drugs may be particularly of use in dia- 1. Kruth HS. Subendothelial accumulation of unesterified cholesterol: an
betics. Selective antisense inhibition of Apo C3 syn- early event in the atherosclerotic lesion development. Atherosclero-
thesis is another new concept that has established sis. 1985;57:337-341.
safety and a dose dependent lowering of TG levels. 2. Ridker PM, Genest J, Boekholdt SM, Libby P, Gotto AM, Nordestgaard
Volanesorsen is an antisense molecule to Apo C3 BG, Mora S, MacFadyen JG, Glynn RJ, Kastelein JJ; JUPITER Trial Study
and has been shown to substantially improve mark- Group.. HDL cholesterol and residual risk of first cardiovascular events

GCDC 2017