Page 457 - fbkCardioDiabetes_2017

New Armamentarium In Combined Dyslipidemia 433
Management - Current Evidences

placebo arm). Injection-site reactions occurred in 5% LOMITAPIDE
of the patients receiving inclisiran. 7
Lomitapide is an MTP inhibitor. MTP is crucial for
VLDL synthesis in the liver. MTP facilitates the trans-
ANGPTL3 Antagonistic Agents: fer of lipids to Apo B-100, playing an important role
An association was found between loss-of-function in assembling and synthesis of VLDL, and ultimately
genetic variants in the gene encoding angiopoie- LDL. MTP also participates in the association of TG
tin-like 3 (ANGPTL3) and low levels of LDL, HDL, and with Apo B-48 in chylomicrons. Lomitapide binds to
triglycerides. 16 MTP and inhibits its function, therefore reducing both
chylomicrons and VLDL, and consequently decreas-
In a study loss-of-function variants in ANGPTL3 were ing plasma levels of LDL, TG, and Lp(a). Lomitapide
associated with decreased plasma triglycerides, LDL, lowers plasma LDL levels by up to 51%. 3
HDL and reduced risk of CVD. In this study, ANGPTL3
monoclonal antibody injection resulted in a lipopro- There are no clinical outcome trials published yet.
tein profile similar to that found in people who have However since preventing VLDL formation is highly
loss of function variants. cytotoxic for the liver, the FDA has mandated that
16
patients should be monitored for liver toxicity.
Similarly in another study targeting ANGPTL3 in the
liver with the use of antisense oligonucleotides also Cholesterylester Transfer Protein (CETP): Cholestery-
leads to reduction in triglycerides and other plasma lester transfer protein (CETP) normally works to
lipoproteins. 16 facilitate the transfer of cholesteryl esters and tri-
glycerides from HDL to lipoproteins. CETP inhibition
A meta-analysis of all five studies showed an odds increases HDL and decreases LDL and lipoprotein(a)
ratio for coronary artery disease of 0.61 (95% con- levels. Early studies of CETP inhibitors have failed
3
fidence interval, 0.45 to 0.81) among patients with to show any clinical benefit, while one study of the
loss-of-function variants in ANGPTL3. Progressive CETP inhibitor anacetrapib is currently ongoing. 3
reductions in ANGPTL3 levels achieved with the use
of either single ascending doses of a monoclonal ANTISENSE TARGETING PCSK9: Several PCSK9
antibody targeting ANGPTL32 or multiple ascend- orally effective antibodies are also in development
ing doses of an antisense oligonucleotide targeting i.e. Adnectin (BMS-962476).
ANGPTL33 led to similar maximum reductions in lev-
els of triglyceride (76% and 63%, respectively), LDL CONCLUSION:
cholesterol (23% and 33%), and HDL cholesterol (18% Although statins are used for dyslipidemia manage-
and 27%). 16 ment since more than 30 years, they fail to achive

Antagonism of ANGPTL3 was associated with de- target lipid levels in some patients. Recently new
creased levels of LDL, HDL, TGs and decreased risk drugs are coming including PCSK9 inhibitors (aliro-
of atherosclerotic CVD. cumab and evolocumab) for patients who fail to re-
spond to conventional lipid lowering therapies. These
Orphan Drugs: These lipid lowering drugs are used drugs also have shown promising results in familial
to treat HoFH in combination with a low-fat diet and hypercholesterolemia. Mipomersen and Lomitapide
other lipid- lowering therapies. Currently, two drugs are also approved for familial hypercholesterolemia.
are approved- mipomersen and lomitapide.
Inclisiran, ANGPTL3 antagonistic agents and anti-
MIPOMERSEN sense targeting PCSK9 are under development.
Mipomersen is an apo B-100 antisense, a synthetic These newer agents in our armamentarium would
strand of nucleic acid that enters hepatocyte nuclei hopefully reduce dyslipidemia and cardiovascular
to form an antisense-Apo B-100 mRNA complex. This burden.
complex can be recognized and cleaved by RNase
H or interfere with translation to reduce synthesis of TAKE HOME MASSAGE:
Apo B-100. Since Apo B- 100 is the major apolipopro- New approaches that increase lipoprotein lipase ac-
tein of LDL and VLDL, a reduction of Apo B-100 ex- tivity, including PCSK9 inhibitors, ANGPTL3 inhibi-
pression decreases the synthesis of both VLDL and tors, mipomersen and lomitapide represent a fresh
LDL, and subsequently total plasma cholesterol and frontier in the treatment of dyslipidemia not ade-
LDL. Weekly subcutaneous injections of mipomersen quately managed with conventional drugs.
200 mg for 26 weeks reduce LDL by up to 36%. No
changes were observed in HDL-cholesterol. 3

Cardio Diabetes Medicine