Recent advances in dyslipidemia

Recent Advances in
Dyslipidemia
Dr. Shakeeb Dhorajiwala

Outline
Introduction- Brief summary of existing drugs
Need for novel therapy
• Drugs:
1. MOA
2. Dosage form and strengths
3. Pk. and Pd. profile
4. Drug interactions
5. ADRs
6. Clinical trials
Dyslipidemia Management Guidelines
Conclusion
217-09-2020

Abbreviations
• LOC: Loss of consciousness
• AHA: American Heart Association
• HP: Health Practitioner
• LDL-Ch.: Low-density lipoprotein-Cholesterol
• ASCVD: Atherosclerotic cardio-vascular disease
• PCSK9: Protein convertase subtilisin/kexin9
• HoFH: Homozygous Familial Hypercholesterolemia
• CAD: Coronary artery disease
• MTP: Microsomal triglyceride transport protein
• NICE: National Institute of Healthcare excellence
317-09-2020

Introduction
• Dyslipidemia is defined as a disorder of lipoprotein metabolism manifested by:
 elevated fasting level of total cholesterol (TC), LDL cholesterol (LDL-C), and
triglycerides (TG),
decreased levels of HDL cholesterol (HDL-C).
• Previous class of drugs:
1. Statins
2. Fibrates
3. Resins
4. Niacin
5. Sterol absorption inhibitors
17-09-2020 4

Need for novel treatment modality
• ASCVD, CAD equivalents like DM, cerebro-vascular disease and pancreatitis are
life-threatening sequalae which ensues if dyslipidemia is left untreated.
• Statins efficiently block hepatic cholesterol synthesis and lower LDL-C sufficiently
up to 50% from the baseline [1]
• corner stone of the medical treatment of dyslipidemia.
• reduce ASCVD risk by 15% to 37%, but residual 60% to 80% risk still remains
[1] and
• caused major vascular event in about 20% of patients with coronary heart
disease despite optimal statin treatment [1].
• Furthermore, a subset of patients are intolerant to high dose statin therapy due
to adverse effects including myotoxicity or hepatotoxicity.
Ahn CH, Choi SH. New Drugs for Treating Dyslipidemia: Beyond Statins. Diabetes Metab J 2015;39:87-94 517-09-2020

• Familial hypercholesterolemiagenetic disorder caused by a
mutation in:
• LDL receptor gene,
• ApoB gene
• PCSK9 gene
• Prevalence:
• 1 in 300-500 -heterozygous
• 1 in a mn.- homozygous form [1].
• High dose statins are the first choice of treatment for these patients,
but even with maximal intensity of statin treatment only 20% of
patients with familial hypercholesterolemia achieve optimal LDL-C
goal [1].
Ahn CH, Choi SH. New Drugs for Treating Dyslipidemia: Beyond Statins. Diabetes Metab J 2015;39:87-94
617-09-2020

• Bile acid-binding resins, fibrates, niacin, and ezetimibe are approved
non-statin agents for treating dyslipidemia [1].
• Each class of non-statin drugs show meaningful improvement in lipid
profiles.
• However, none of these agents show additional risk reduction of
ASCVD when combined with statins.
• Only ezetimibe showed significant decrease of cardiovascular events
from the recent randomized clinical trial: IMPROVE-IT.
• Due to the lack of functional LDLr in patients with HoFH and due to
the variable LDLr activity in patients with severe HeFH, different
hypolipidemic regimens, even at maximal doses, produce insufficient
reductions in LDL-C level.
Ahn CH, Choi SH. New Drugs for Treating Dyslipidemia: Beyond Statins. Diabetes Metab J 2015;39:87-94 717-09-2020

• These factors necessitate research for the development of new
additional effective therapies with favorable s/e profile that would
improve our ability to achieve LDL-C goals and decrease CVD risk.
• Newer modalities available are:
I. PCSK9 inhibitor: Alirocumab and Evolocumab
II. MTP inhibitor: Lomitapide
III. Antisense oligonucleotide against ApoB: Mipomersen
IV. Apolipoprotein A1 (ApoA1) mimetics:D-4f
V. Thyromimetic: Sobetirome
VI. Drugs in pipeline: i.FXR modulators: INT 767 ii. CETP inh.:
Torcetrapib and anacetrapib iii. AMP kinase activators iv.
Cyclodextrins
817-09-2020

Laboratory tests
• Elevations in total cholesterol, LDL, triglycerides, apolipoprotein B,
and high sensitivity C-reactive protein (hsCRP).
• Low HDL
• Other diagnostic tests:
• Lipoprotein (a), and small, dense LDL (pattern B), HDL
subclassification, apolipoprotein E isoforms,
• apolipoprotein A-1, fibrinogen, folate, lipoprotein-associated
phospholipase A2.
1217-09-2020

I.PCSK9 inhibitors:
1317-09-2020

I.PCSK9 inhibitors
• Most significant advancement in clinical cardiology and lipidology this
decade is the emergence and availability of PCSK9 monoclonal Ab
therapies.
• PCSK9, a 692-amino acid mature serine protease ,
• expressed in the liver, intestines and kidneys.
• forms a complex with the LDLR-LDL-P extracellular domain undergo clathrin
mediated endocytosis,
• acts as a “chaperone” protein resulting in lysosomal degradation of the entire
complex, including the LDLR decreased LDLR recycling fewer liver cell
surface LDLRs to process LDL increased circulating plasma LDL particles. [2]
2. Nathan D. Wong1, Paul D. Rosenblit2, Robert S. Greenfield. Advances in dyslipidemia management for prevention of atherosclerosis:
PCSK9 monoclonal antibody therapy and beyond. Cardiovasc Diagn Ther 2017;7(Suppl 1):S11-S20
1417-09-2020

3.1 Pharmacological Profile: MOA
1517-09-2020

I.a Alirocumab-Brief Introduction
• First member of it’s class to receive approval.
• FDA approved on July 2015.
• Second line treatment in management of cholesterol not controlled
by statins/diet.
• IgG1 isotype human monoclonal Ab.
• Primary indications:
 Primary hyperlipidemias
1. Heterozygous familial hypercholesterolemia (HFH)
2. Clinical atherosclerotic cardio and cerebrovascular disease(CACVD)
1617-09-2020

2. 1 Alirocumab- Dosage and administration
• Dosing Information:
• Recommended starting dose is 75 mg S.C. every 2 weeks check for
response (lipid profile) if still uncontrolled consider up-titrating
maximum to a dose of 150 mg S.C. every 2 weeks.
• Titration of dose ( ) is base on Sr. LDL-Ch. levels repeated at every 4-
8 weeks if needed.
• In c/o missed dose, take it at the earliest within a window of 7 days
and then continue taking the medicine as per schedule.
• However if > 7 days have lapsed skip and resume taking the next
dose as scheduled.
1717-09-2020

2.2 Dosage form and strength
Syringe(75 mg/ml) Syringe (150 mg/ml)
Available as prefilled pen and syringe in two strengths ie 75mg/ml and 150 mg/ml.
1817-09-2020

2.3 Prefilled pen device
75 mg/ml 150 mg/ml
1917-09-2020

2.4 Sites of subcutaneous injection
Special points of observation:
• Don’t try to remove air bubbles
• Inject with a quick dart- like motion.
• Do not rub after injections
• Each time inject on a different site and
keep on rotating the sites.
• In c/o same site don’t inject on the
same spot.
• DO NOT USE the preparation if it turns
yellow or has particulate matter.
• DO NOT SHAKE
Leave 2’’ area around the navel
2017-09-2020

2.5 Pharmacokinetic and Pharmacodynamic Profile
Absorption:
• tmax (median):3-7
days independent of
the site of
administration.
• BA of alirocumab
:85%
• Steady state
reached after 2 to 3
doses with an
accumulation ratio of
about 2-fold.
Distribution:
• Vd= 0.04-0.05 L:
Distributed primarily
in blood.
Metabolism:
• Degraded to
peptides and amino
acids.
• Microsomal enzymes
and Transporters: No
interaction
Elimination:
• Two elimination
phases. At low
concentrations,
predominately
through saturable
binding to target
(PCSK9)
• At higher
concentrations
largely through a
non-saturable
proteolytic pathway.
• t1/2(median) at
steady state :17 to
20 days.
2117-09-2020

Renal Impairment :
• Monoclonal
antibodies not
eliminated via renal
pathways, so renal
function is not
expected to impact
the
pharmacokinetics of
alirocumab.
• No data available in
severe renal
impairment cases.
Hepatic Impairment :
• Single 75 mg SC
dose alirocumab
pharmacokinetic
profiles in subjects
with mild and
moderate hepatic
impairment were
similar to those with
normal hepatic
function.
• No data available in
severe hepatic
impairment cases.
Drug-Drug
Interactions
• Median apparent
t1/2 of alirocumab is
reduced to 12 days
when administered
with a statin;
however, this
difference is not
clinically meaningful
and does not impact
dosing
recommendations.
2217-09-2020

Clinical trials of Alirocumab3
17-09-2020 3.Kampangkaewa J, Picketta,S, Nambi V. Advances in the management of dyslipidemia.co-cardiology.;2017 Volume 32:2-4 23

I.b Evolocumab: Brief Introduction
• FDA approval: 2015
• IgG2 isotype of human monoclonal Ab.
• Primary indication:
• As an adjunct to diet
• Alone or in combination of other lipid lowering measures like statins, sterol
absorption inhibitors in:
• Heterozygous familial hypercholesterolemia
• Homozygous familial hypercholesterolemia (more severe and may even
need LDL apheresis)
2417-09-2020

2.1 Evolocumab: Dosage and Administration
• Dosing information:
• Subcutaneous injections
• Adults with established cardiovascular disease or primary hyperlipidemia
(including heterozygous familial hypercholesterolemia): 140 mg every 2
weeks or 420 mg once monthly in abdomen, thigh, or upper arm.
• HoFH: 420 mg once monthly administered in any of 2 ways:
• over 9 minutes by using the single-use on-body infusor with prefilled cartridge, or
• giving 3 injections consecutively within 30 minutes using the single-use prefilled
autoinjector or single-use prefilled syringe.
• In HoFH cases, measure LDL-C levels 4 to 8 weeks after starting Evolocumab,
since response depends on the degree of LDL-receptor function.
2517-09-2020

What to do if I miss a dose?:
• Instruct the patient to administer evolocumab within 7 days from the
missed dose and resume original schedule.
• If an every-2-week dose is not administered within 7 days wait until
the next dose on the original schedule.
• If a once-monthly dose is not administered within 7
daysadminister the dose and start a new schedule based on this
date.
2617-09-2020

2.2 Dosage form and strength
• Single use prefilled syringe (140 mg/ml)
• Single use prefilled auto-injector (140 mg/ml)
• Single use on-body infusor with prefilled cartridge (420 mg/3.5ml)
2717-09-2020

2.3 Pharmacodynamics of Evolocumab
• After single SC administration of 140 mg or 420 mg of evolocumab,
maximum suppression of circulating unbound PCSK9 occurred by 4
hours.
• Unbound PCSK9 concentrations returned toward baseline when
evolocumab concentrations decreased below the limit of
quantitation.
2817-09-2020

2.4 Pharmacokinetic Profile of Evolocumab
• Exhibits non-linear kinetics after binding to the enzyme.
• At 140 mg dose in healthy volunteers :
• Cmax :18.6 +7.3 μg/mL
• AUClast: 188 +98.6 μgx day/mL.
• Cmin 7.21 +6.6 μg/mL
• At 420 mg dose:
• Cmax 59.0 +17.2μg/mL
• AUClast :924 +346 μgxday/mL.
• Cmin :11.2 +10.8μg/mL,
• After a single 420 mg intravenous dose:
• systemic clearance: 12+2 mL/hr.
• Serum trough concentrations approached steady state by 12 weeks of dosing.
2917-09-2020

2.4 ADME of Evolocumab
Absorption:
• After single subcutaneous
dose of 140 mg or 420 mg
evolocumab administered
to healthy adults:
• Tmax(median) :3 to 4 days,
• Bioavailability :72%.
Distribution:
• After a single 420 mg
intravenous dose:
• At steady-state: Vd :3.3 +0.5
L.
Metabolism and Elimination :
• Two elimination phases
were observed.
• At low concentrations:
• elimination is
predominately through
saturable binding to target
(PCSK9)
• At higher concentrations :
• largely through a non-
saturable proteolytic
pathway.
• t1/2: 11 to 17 days.
3017-09-2020

Clinical trials of Evolocumab
17-09-2020 31

I.c Inclisiran: MOA
• Alternative to use of monoclonal Ab.
• 20-30 nucleotide small interfering
RNA (siRNA) molecule.
• Critical regulator of expression and
function of human genome
(somatic+germ cell-line).
• siRNA interferes with the expression
of speciﬁc genes  forms RISC
degradation of mRNA post-
transcription prevent
translationProtects genome from
invasive nucleic acids.
• Evades interferon response mounted
against long ds-RNA molecules.
17-09-2020 32

Inclisiran
• Inclisiran is a long-acting, synthetic siRNA
• Tissue specificity:
• conjugated to triantennary N-acetylgalactosamine carbohydrates.
• These carbohydrates bind to abundant liver-expressed asialoglycoprotein
receptors  uptake of inclisiran speciﬁcally into the hepatocytes.
• Proposed dosing regimen (Orion 11 trial):
• 300 mg SC dose on day 1, day 90 then 6 monthly.
17-09-2020 33

Clinical trials of Inclisiran
17-09-2020 34
Other pivotal clinical trials:
ORION-5 trial- with 60 patients with homozygous FH in Europe, Middle East, and North
America.
ORION-9 trial with approximately 400 patients with heterozygous familial
hypercholesterolemia (FH) in North America, Europe, Israel, and South Africa.
ORION-10 trial with approximately 1500 ASCVD patients in North America
ORION-11 trial is one of the four phase 3 pivotal trials with inclisiran.

How is it different from monoclonal Ab?
• Infrequent administration: twice a year vs. 12–26 injections per year for
Ab.
• Anti-PCSK9 monoclonal antibodies act at a plasma level, whereas inclisiran
acts at the intracellular level of hepatocytes.
• Relatively benign side effect proﬁle(ORION-1 trial).
• There were only rare symptoms of immune activation, such as ﬂu-like
symptoms.
17-09-2020 35

Somethings not so good about this class
3.1 Warnings and Precautions:
• Allergic reactions: Hypersensitivity
(pruritis, eczema, urticaria,
redness)  hypersensitivity
vasculitis. May be severe enough to
require hospital admission.
Adverse drug reactions:
• Nasopharyngitis- Most common
• Injection site reactions
• Influenza, Sinusitis, Cough,
Bronchitis
• UTI
• Neurocognitive symptoms:
• Musculoskeletal symptoms
• Liver insults: enzymes > 3x upper
limit of normal.
The most common ADR leading to treatment discontinuation is allergic reactions
and elevated liver enzymes.
3617-09-2020

II.Microsomal triglyceride
transport protein (MTP) inhibitors
3717-09-2020

II.a. Lomitapide: MOA
Decreased plasma LDL
Decreased VLDL and chylomicrons
VLDL synthesis inhibited
Tg transfer to ApoB100 inhibited
MTP(ER) inhibition
17-09-2020 38

Dosage and administration
• Dosage form: orange/white hard gelatin capsule
• Available in strengths of 5,10 and 20 mg.
• ROA: oral
• Dosing schedule:
• One capsule daily
• Preferably in evening 2 hours before meal.
17-09-2020 39

Pk profile: ADME
Absorption:
• PO single 60-mg
dose
• tmax : 6 hours
• The absolute BA :7%.
• Pk is approximately
dose-proportional
for oral single doses
from 10-100 mg.
Distribution:
• Vd at steady state:
• 985-1292 liters.
• 99.8% plasma-
protein bound.
Metabolism:
• Extensive liver
metabolism  oxidation,
oxidative N-dealkylation,
glucuronide conjugation,
and piperidine ring
opening.
• Lomitapide M1 and M3
(Cyp3A4 metabolism),
• M1 moiety piperidine ring
• M3 rest of the lomitapide
molecule in vitro.
• CYPs 1A2, 2B6, 2C8, and
2C19 may metabolize
lomitapide to a small
extent to M1.
• Metabolites are inactive
in-vitro.
Excretion:
• Urine:59.5%(M1- major
metabolite)
• Feces:33.4(majorly
Lopitamide)
• t1/2 : 39.7 hours
17-09-2020 40

Drug interactions
17-09-2020 41
• Strong Cyp3A4 inhibitors: drug level by 27 fold.
• Concurrent use is contraindicated (CI).
• Moderate CYP3A4:Better avoid concurrent use.
• Even grapefruit juice better be avoided
• Weak CYP3A4 inh.:
• Raise drug level by two fold. So accordingly dose adjustment to half the maximum(<
30 mg) dose needed should be given or better concurrent use be avoided.
• Warfarin: plasma concentrations of both R(+) /S(-)-forms ̴30% and
increased the INR 22%.Regular INR monitoring and dose adjustment
required.
• Raises levels of Simvastatin/ lovastatin and substrates for P-gp. Dose has to
adjusted accordingly

Adverse Drug Reaction
• Hepatic steatosis
• In chronic bowel or pancreatic pts. predisposed to malabsorption at
increased risk for nutritional deficiencies.
• GIT s/e: Very severe to the extent of causing disease itself.
• Under an FDA REMS due to its concerning side-effect profile
17-09-2020 42

III. Antisense oligonucleotide
against ApoB
17-09-2020 43

III.a Mipomersen- MOA
• FDA approval: 2013
Mipomersen, a synthetic 20
nucleotide antisense
oligonucleotidebind to ApoB
mRNA via complementary
sequence interactions [1].
• Hybridization of mipomersen to
the target ApoB mRNA creates a
substrate for RNase H1the
decrease of the ApoB mRNA
level and the production of ApoB
protein.
17-09-2020
Ahn CH, Choi SH. New Drugs for Treating Dyslipidemia: Beyond Statins. Diabetes Metab J 2015;39:87-94
44

Dosage and administration
4517-09-2020
• Dosing information:
• ROA: SC only
• Vials: Single use- 200 mg/1 ml
• Prefilled syringe 200mg/ml: For single use only

Dosing schedule
• 200 mg weekly SC only and preferably on same day every week.
• In case of missed dose:
• To be taken within next 3 days or else skip the dose and continue the rest as
per schedule.
• Due to its inherent property of affecting liver, LFT is adviced at
intervals of 3 monthly-1st year every 6 months till Sr. Transaminase<
2x ULN.
• Rotation of injection site is recommended and inflamed, tender site
should be avoided.
17-09-2020 46

Pk profile:ADME
Absorption:
• Tmax:3 to 4
hours.
• Relative BA: 54%
to 78%.
Distribution:
• high plasma
protein binding
(≥ 90%) at
clinically relevant
concentrations
(1-8 µg/mL).
• distribution t1/2 :
2 to 5 hours.
• With once weekly
dosing, plasma
trough levels
increase over
time and
approach steady
state, typically
within 6 months.
Metabolism:
• No CYP450
metabolism
• metabolism: in
tissues by
endonucleases
shorter
oligonucleotides
 substrates for
additional
metabolism by
exonucleases.
Excretion:
• Metabolism in
tissues and
excretion,
primarily in urine.
• < 4% with
metabolites in
urine within the
24 hours post
dose.
• Elimination t1/2: 1
to 2 months.
17-09-2020 47

Adverse drug reactions
• Flu like symptoms within 2 days of
starting treatment (30% cases).
• Steato- hepatitis:
• Sr. Transaminase raised to >3-5 ULN.
• In such cases treatment is differed
and resumed when level falls<2x ULN.
• Cautious use with other liver harming
drugs like: Tetracycline,
Paracetamol,Methotrexate etc
• Injection site reactions-84% cases
17-09-2020 48

IV. Apolipoprotein A1 mimetics
4917-09-2020

IV. Apolipoprotein A1 mimetics
• A peptide called D-4F
• The high serum level of HDL-C is a well-known protective factor of ASCVD.
• ApoA1 is the major apolipoprotein component of mature HDL.
• ApoA1 takes cholesterol from macrophages in atherosclerotic lesions via ATP-
binding cassette A1 (ABCA1)reverse cholesterol transport.
• The central role of ApoA1 in comprising HDL-C makes it as an attractive target for
modifying ASCVD risk.
• ApoA1 mimetics are a class of drugs which mimics the effect of ApoA1 and HDL-C
to reverse the progression of atherosclerosis.
• MOA :
• increased cholesterol efflux from macrophages via ABCA1,
• increased transport of cholesterol to the liver via SR-B1,
• decreased monocyte chemotaxis and adhesion, and binding of oxidized lipids.
5017-09-2020

V. Sobetirome and Eprotirome
• Excess thyroid hormone reduces serum cholesterol and body fat.
• Thyroid receptor β  cholesterol reducing propensity.
• MOA:
• Thyromimetics binds selectively to TRβ1 expressed in liver and impairs
cholesterol synthesis.
• Converts stubborn white fat to calorigenic brown fat which.
• Limitations: similar receptors present in heart, bones and muscles
have undesirable effects.
• Therefore development of the molecule halted in PIb.
5217-09-2020

AHA Ch. Management guide for HP
• Latest guidelines on management of uncontrolled blood cholesterol
(Ch.) Updated in 2018.
• consistent, clear, and evidence-based guidance for treating patients at
risk for atherosclerotic cardiovascular disease (ASCVD).
• Guideline emphasizes on:
• the lifetime risk of unmanaged high cholesterol
• importance of primary and secondary prevention strategies to reduce a
patient’s risk of future ASCVD.
5417-09-2020

The clinical diagnosis of atherosclerotic
cardiovascular disease (ASCVD) includes:
1. Acute coronary syndrome (ACS)
2. Myocardial infarction, also known as a heart attack
3. Stable or unstable angina or other arterial revascularization
4. Stroke and transient ischemic attack
5. Peripheral artery disease, including aortic aneurysm, all of
atherosclerotic origin.
5517-09-2020

10 Take-Home messages to reduce risk of ASCVD through
cholesterol management
1. Emphasize heart- healthy lifestyle in all individuals.
2. Use high intensity/ maximally tolerated statin therapy in patients with
clinical ASCVD to reduce LDL-Ch.
3. Consider adding non-statins with statin in patients with very high risk ASCVD
taking LDL-Ch. Level of 70 mg/dl as cut off.
4. Start high-intensity statin therapy in patients with severe Primary
Hypercholesterolemia (LDL-Ch.>190 mg/dl)without assessing 10-years
ASCVD risk.
5. Start moderate intensity statin therapy in patients in age group 40-75 years
with DM and LDL-Ch.>70 mg/dl without assessing 10 years ASCVD risk.
5817-09-2020

6. In adults of 40-75 years being evaluated for primary ASCVD prevention, its better to have clinician-
patient risk discussion before starting statin therapy.
7.40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL (≥1.8 mmol/L), at a
10-year ASCVD risk of ≥7.5%, start a moderate-intensity statin if a discussion of treatment options
favors statin therapy.
8. 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate
risk), risk-enhancing factors favor initiation of statin therapy.
9. In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL- 189
mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy
is uncertain, consider measuring CAC.
10. Assess adherence and percentage response to LDL-C–lowering medications and lifestyle changes
with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated
every 3 to 12 months as needed.
5917-09-2020

Changes in Guidelines and implications:
• In 2014 the American Heart Association (AHA) and the American College of
Cardiology published revised guidelines on the treatment of blood cholesterol to
reduce atherosclerotic risk in adults.
• This report supersedes the National Cholesterol Education Program Adult
Treatment Panel III (ATP III) published more than a decade ago.
• The 2014 guidelines did not find sufficient evidence to recommend specific
targets for any lipid, but rather, it identifies four groups of patients who qualify
for treatment with statins. The other substantive change is the method used for
risk assessment resulting in identifying significantly more patients who would
qualify for therapy
• Changes in the NCEP guidelines have increased the number of persons eligible
for therapeutic life style changes (TLC) or lipid-lowering therapy by millions.
• Based on estimates from the AHA, 42.8% American adults over age 20 years
have total cholesterol levels of 200 mg/dL (5.17 mmol/L) or higher.
17-09-2020 61

• More than half of individuals at borderline-high risk remain unaware
that they have hypercholesterolemia and fewer than half of highest
risk persons (those with symptomatic CHD) are receiving lipid-
lowering treatment.
• About one third of treated patients are achieving their LDL goal;
fewer than 20% of CHD patients are at their LDL goal.
• Patients who are at risk but who have not yet experienced their first
cardiovascular or cerebrovascular event (eg, myocardial infarction
[MI]) are termed primary prevention, whereas those with manifest
vascular disease are termed secondary intervention.
17-09-2020 62

Conclusion
Research in galore in this field of treating atherogenic dyslipidemia is being
undertaken with many promising results coming out to be applied in real
clinical settings.
The PCSK9 inhibitors facilitates the uptake of LDL-C by enhancing LDLR
recycling. It showed favorable effects for additional lowering of LDL-C when
adding on to statin and nice safety profile with consistent long-term
efficacy in large phase III trials.
Lomitapide, the MTP inhibitor, and mipomersen, the antisense
oligonucleotides against ApoB, have shown their efficacy in lowering LDL-C
in recent phase III trials and were already approved for treating patients
with homozygous familial hypercholesterolemia.
• These two drugs still have a major safety concern in the form of increased hepatic fat
accumulation as a result of TG trapped in liver due to inhibited hepatic VLDL
secretion.
• The long term safety profiles need evaluation.
6317-09-2020

The ApoA1 mimetic is the most experimental class of drugs.
• It has been shown to alter or reverse the natural course of atherosclerosis
despite the range of LDL-C level in preclinical studies.
• However, their efficacy seems to be modest and the results are not consistent
from previous studies. It awaits further validation through various human
studies.
The new classes of drugs beyond statin could enlighten the
improvement for anti-atherosclerosis therapy.
Clinicians should keep their eyes on the results of upcoming studies
using new class of drugs to find the best and the optimal treatment
modality for patients with dyslipidemia.
6417-09-2020

Recent advances in dyslipidemia

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