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The New Brave World of Dyslipidemia : 33
Ready to Target ASCVD After Statins

Familial hypercholestolemia Evolocumab
For patients with homozygous hypercholesterolemia This has already been approved for clinical use and
(HoFH) the goals are difficult to achieve. Statins, is available commercially as 1ml pen containing 140
and non-statins drugs including ezetimibe, BAS are mg. It is given in doses of 140 mg. biweekly / 420
utilized with consideration for use of lomitapide mg. monthly sc. It was tested in the PROFICIO Global
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, mipomersen , and LDL apheresis as necessary. Programme which had 14 trials and roughly 30,000
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LDL-apheresis is also approved for heterozygous FH. patients Most of the trials have been completed and
PCSK9 inhibitors like evolocumab and alirocumab the results of FOURIER were presented in 2017. Most
may be considered if the goals of therapy have not of these trials have shown significant reduction in
been achieved on maximally tolerated statin and eze- LDL-C by 40-60% on top of statins. There is also con-
timibe in familial hypercholesterolemia.PCSK9 inibi- sistent and robust reduction in other lipoproteins. The
tors are also used in higher-risk patients with clinical Lp(a) is reduced by approximately 25%, triglyceride
ASCVD. and non HDL-C are also decreased. The HDL-C and
apo-A1 are increased.
What is PCSK9 ? Interestingly when both statins and PCSK9 MoAbs
Serum proprotein convertase subtilisin/kexin 9 are combined together they decrease LDL to super
(PCSK9) is a protein that regulates LDL-C levels in low levels as low as 25 mg/dl in substantial number
the blood by regulating LDL receptors (LDL-R). It is of cases. Two questions automatically erupts out of
secreted from the liver, goes into the blood, circulates this, first is super low LDL-C safe and is it powered
back to liver and directly binds to LDL receptors in- to produce incremental benefits on top of statins.
creasing their degradation and thereby reducing the The answer to both questions is yes because the
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rate at which LDL-C is removed from circulation and FOURIER trial has proved both safety and efficacy
thus increasing LDL-C levels in blood. Thus PCSK9 of evolucumab. We had safety data first from the
is an important regulator of LDL metabolism.PCSK9 OSLER, ODDYSEY long term trials and recently from
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is also affected by genetic mutation. There are two the FOURIER trial , the first CV outcome trial for sec-
types of mutation, loss of function mutation which ondary prevention of ASCVD. In this study LDL-C de-
results in decrease in LDL-C and provides athero- creased from median base line value 92 mg/dl to 30
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protection. The gain of function mutation causes mg/dl, i.e., approximately by 60% (P<0.001), 42% had
familial hypercholesterolemia (FH) and predisposes LDL-C <25 mg / dL. (Figure 9).Despite such low levels
to ASCVD. of LDL-C there was no evidence of muscle or liver
toxicity, diabetogenecity, neurocognitive decline. The
Both statins and ezetimibe increase secretion of dedicated sub-study, EBBINGHAUS also confirmed
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PCSK9, which could attenuate their efficacy by re- lack of neurocognitive decline with its use. The only
ducing the amount of cholesterol cleared from cir- side effect which was more common with evolocum-
culation. This explains the limitation of statin ther- ab was injection site reactions, 2.1% (evolocumab) vs
apy and may be the best explanation regarding the 1.6 % (Placebo).The study also demonstrated incredi-
classic rule of 6 observed with statin therapy. This ble safety on top of statins.
rule refers to the fact that every time the statin dose
is doubled, there is only an approximately 6% com- We had the initial efficacy data from the OSLER and
plementary decrease in LDL-C levels.Therefore the ODDYSEY long term and recently from the FOURIER
combination of PCSK9 inhibition with a statin would trial. The OSLER trial showed 53% RRR in the com-
be a sensible and logical approach and will cause a posite endpoint of death, MI, unstable angina hos-
dramatic decrease in LDL-C levels. pitalization, coronary revascularization, stroke, TIA
or CHF hospitalization (HR 0.47 95% CI 0.28-0.78
PCSK9 inhibition P=0.003) and the Post-Hoc analysis of ODYSSEY
LONG TERM showed a 48% RRR reduction in MACE
PCSK9 inhibition is now a validated therapeutic op- (HR=0.52 CI 0.31,0.90, P=0.02).This year the FOURIER
tion for modulating LDL cholesterol after the results trial showed a statistically significant 15% risk reduc-
of the FOURIER trial in 2017. Its inhibition can be tion in the primary endpoint of CV death, MI, stroke,
achieved by gene silencing, small peptides or mono- hospitalization for unstable angina and revasularisa-
clonal antibodies (MoAbs). PCSK9 MoAbs is com- tion, HR 0.85 (95% CI, 0.79-0.92 P<0.001).In the sec-
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monly used to inhibit PCSK9. Both evolocumab and ondary end point of CV death <MI, stroke there was
alirocumab have been approved for clinical use in a statistically significant reduction of 20% reduction,
2015 by EMA and US FDA. HR 0.80 (95% CI, 0.73-0.88 P<0.001). (Figure 3 a,b)

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