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New Armamentarium In Combined Dyslipidemia 431
Management - Current Evidences

terfering RNA that silences target RNA and prevents bilized on a statin dose for 4 weeks with LDL ≥80 mg/
the synthesis of PCSK9 protein in the liver. 7 dl or individuals with 1 major or 3 minor cardiovascu-
lar risk factors who had an LDL 60-80mg/dl. Individ-
A large pooled analysis of 24 randomized phase 2 uals had at least one epicardial coronary stenosis of
and 3 trials comprising 10,159 patients concluded ≥20% on clinically indicated coronary angiogram with
49% LDL reduction by PCSK9 inhibitors and relative a target vessel suitable for imaging. There was –0.95%
risk reductions (RRR) of 55% in all-cause mortality, change in atheroma volume at 78 weeks in the evolo-
50% in cardiovascular mortality and 51% in myocardial cumab group. This study documented effectiveness
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8
infarction.
of evolocumab in reducing LDL and atheroma plaque
Two PCSK9 inhibitors alirocumab and evolucumab in coronaries.
are approved for use in familial hypercholesterolemia In March 2017, the results of FOURIER trial were
and in patients of CVD on maximum statin therapy published. This was a randomized, double-blind pla-
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who needed an additional lipid lowering drug.
cebo controlled multinational clinical trial recruiting
27,564 individuals with atherosclerotic CVD and LDL
ALIROCUMAB
≥70 mg/dl who were receiving statin therapy. Patients
Alirocumab is approved in dosage of 75 mg subcu- were randomly assigned to receive evolocumab (ei-
taneously every 2 week which can be titrated up to ther 140 mg every 2 weeks or 420 mg monthly) or
150mg every 2 weeks. matching placebo as subcutaneous injections. After
Alirocumab significantly reduces serum LDL by 62 a median follow-up of 2.2 years, LDL decreased by
% and major CVD by 48 % in a 78 week randamized 59% with median LDL of 30 mg/dl. LDL was <25mg/
placebo controlled safety trial, the ODYSSEY-LONG dl in 42% subjects on evolocumab. The primary effi-
TERM. The adverse effects were nasopharyngitis, in- cacy end point was the composite of cardiovascular
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jection site reactions, myalgia, neurocognitive events, death, myocardial infarction, stroke, hospitalization
urinary tract infection and diarrhea. for unstable angina, or coronary revascularization.
The key secondary efficacy end point was the com-
Results of the ODYSSEY OUTCOMES are awaited posite of cardiovascular death, myocardial infarction,
which is a randomized controlled trial recruiting ap- or stroke. Eevolocumab treatment significantly re-
proximately 18000 individuals, to detect a 15% hazard duced the risk of the primary end point (9.8% vs. 11.3%
reduction in MACE in individuals with a recent acute patients; hazard ratio, 0.85; 95% confidence interval
coronary syndrome (<1 year) and LDL ≥70mg/dl. 10 [CI], 0.79 to 0.92; P<0.001) and the key secondary
end point (5.9% vs. 7.4%; hazard ratio, 0.80; 95% CI,
EVOLOCUMAB 0.73 to 0.88; P<0.001). The adverse events occurred
Evolocumab decreases LDL by approximately 60% were diabetes and neurocognitive events which were
when added to statin therapy. It is approved in similar in both groups while injection-site reactions
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dosage of 140mg subcutaneously every 2 weeks or were more common with evolocumab. The FOURIER
420mg every 4 weeks. trial showed a median 30 mg/dl reduction in LDL and
significant reduction in CVD by evolocumab along
The OSLER 1 and 2 trials evaluated the safety and tol- with statin therapy in patients with established ath-
erability of evolocumab therapy and found no severe erosclerotic CVD.
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or life-threatening adverse reactions. The most side
effects reported with equal frequency in both groups Heterozygous Familial
were injection site reactions, nasopharyngitis, upper
respiratory tract infection, back pain, headache and Hypercholesterolaemia (HeFH)
arthralgia. Neurocognitive changes were more com- • Statins lower both LDL cholesterol and cardiovas-
mon with evolocumab. Evolocumab reduced LDL cular disease burden in heterozygous FH and even
by 61%, from a median of 120 mg/dl to 48 mg/dl at normalise coronary mortality if started before the
12 weeks. At 1 year the CV events were reduced to onset of cardio vascular disease (CVD). Individuals
0.95% in the evolocumab group compared to 2.18% with established CVD remain at about 4 times in-
in placebo group (hazard ratio 0.47; 95% confidence creased risk of death from coronary heart disease
interval, 0.28 to 0.78; P=0.003). 12 despite statin therapy and up to 40% of patients
with heterozygous FH fail to achieve acceptable
The GLAGOV trial used intravascular ultrasound to LDL level despite statin therapy. Both alirocumab
monitor atheroma volume in individuals on evolo- and evolocumab are effective in reduction of LDL
cumab. The GLAGOV trial recruited 968 individuals in these patients.
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with or at high risk for atherosclerosis who were sta-

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