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New Trends Approved in Management
Abdulaziz Aboshahba1*, Mohamed Alassal2, Ahmed G Akoush3, Areij A Osman4, Raphael C Solomo4, Mazhar Ullah4, Ibrahim Eltaj4 and Aida Refaat5*
1Doctor of medicine in cardiovascular medicine, Cardiology department, Al Azhar university, Cairo, Egypt
of medicine, Department of Cardiac surgery, Benha University, Egypt
3 MD.NHI, Cairo, Egypt
4PAAMCC cardiac center, Arar, KSA
5Pharm D, Faculty of Pharmacy, Tanta University, Egypt
Submission: August 01, 2019; Published: August 26, 2019
*Corresponding author: Abdulaziz Aboshahba, Doctor of medicine in cardiovascular medicine, Department of Cardiology, Al Azhar university, Cairo, Egypt
How to cite this article:Abdulaziz Aboshahba, Mohamed Alassal, Heba Emad, Marwa Abdelmageed, Raphael C Solomo etc al. New Trends Approved in
Management of Dyslipidaemia. J Cardiol & Cardiovasc Ther. 2019; 14(4): 555894. DOI: 10.19080/JOCCT.2019.14.555894
Hypercholesterolemia increases the risk of atherosclerotic cardiovascular disease and is incompletely reversed by statin therapy alone in many patients. Familial hypercholesterolemia (FH) is a common genetic cause of premature cardiovascular disease (CVD). So, most of efforts and directions focused on new therapies as PCSK9 gene was identified in the past decade as a potential therapeutic target for the management of patients with hypercholesterolemia which monoclonal antibodies, Lomitapide, Mipomersen and other therapies hoping to reduce risk of hypercholesterolemia. The novel therapies are aiming for better lipid-lowering effects, fewer side effects and improved clinical outcomes.
Keywords: Total cholesterol; HDL-cholesterol; Cell membranes; Certain hormones; Heart disease; Lipid metabolism
Abbrevations: TC: Total cholesterol; LDL: Low Density Lipoprotein; HDL: High Density Lipoprotein; TG: Triglyceride; apoB: Apolipoprotein B; FH: Familial hypercholesterolemia; ADH: Autosomal dominant hypercholesterolemia; PCSK9: Proprotein convertase subtilisin/kexin type 9; LDLR: Receptor of the LDL; ARH or FH2: Autosomal recessive hypercholesterolemia; PH: Polygenic hypercholesterolemia; VLDL: Very low-density lipoprotein; ABCA1: ATP-binding cassette transporter; apo A-1: Apolipoprotein A-I; HeFH: Heterozygous state of familial hypercholesterolemia; HoFH: Homogenous state of familial hypercholesterolemia; apo E: Apolipoprotein E; FDB: Familial defective apolipoproteinB-100; LDLRAP1: Low density lipoprotein receptor adaptor protein-1; Lp a: Lipoproteins (a); TSH: Thyroid-stimulating hormone; BUN: Blood Urea Nitrogen; CYP3A4: Cytochrome P3A4; GI: Gastro-Intestinal; ALT: Alanine aminotransferase; ECG: Electrocardiography; TR: Thyroid Receptors; CETP: Cholesterylester Transfer Protein Inhibitors; ACL: ATP-Citrate Lyase Inhibitor; ASCVD: Atherosclerotic Cardiovascular Disease; CAC: Coronary Artery Calcium; CK: Creatine Kinase; mAbs: Monoclonal antibodies; PAD: Peripheral Artery Disease; MI: Myocardial Infarction.
Elevation of total cholesterol (TC) and/or low-density lipoprotein (LDL)-cholesterol or non-HDL-cholesterol in the blood, is also often referred to as dyslipidemia, to encompass it might be accompanied by a decrease in HDL-cholesterol or an increase in triglycerides the fact that.
Dyslipidemia is classified as serum TC, LDL-cholesterol, triglyceride, apolipoprotein B (apoB), or lipoprotein (a) concentrations above the 90%, or HDL-cholesterol or apolipoprotein A-I concentrations below the 10% for the general population.
That comes from animals (particularly egg yolks, meat, poultry, fish, and dairy products). The body needs this substance to build cell membranes, make certain hormones, and produce compounds that aid in fat digestion (Figure 1-3).
Too much cholesterol, however, increases a person’s risk of developing heart disease .
In a more simple and practical way, dyslipidemia can also be
a) Isolated hypercholesterolemia: mostly due to LDLcholesterol
b) Mixed or combined dyslipidemia: elevations in total or
LDL-cholesterol, and in triglycerides.
c) Isolated hypertriglyceridemia: elevation in triglycerides
d) Low HDL-cholesterol: either isolated or in association
with hypercholesterolemia or hypertriglyceridemia. Causes
of low HDL-cholesterol include abdominal obesity with
insulin resistance, hypertriglyceridemia, smoking, and
genetic diseases such as apoA-I, ABCA1 (ATP-binding cassette
transporter), or lecithin-cholesterol acyltransferase deficiency
LDLR gene is located in chromosome 19 and codifies a
membrane glycoprotein which binds to apoB and apolipoprotein
E (apoE) contained in the lipoproteins 9 and play a critical role
in regulating the amount of cholesterol in the blood 10.
Familial defective apolipoproteinB-100 (FDB)
Allow these particles to attach to specific receptors on the
surface of cells, particularly in the liver. The receptors transport
low-density lipoproteins into the cell, where they are broken
down to release cholesterol. The cholesterol is then used by the
cell, stored, or removed from the body 11.
The PCSK9 gene mutations in chromosome 1
That helps control blood cholesterol levels by breaking down
low-density lipoprotein receptors before they reach the cell
Mutations in low density lipoprotein receptor adaptor
Particularly important in the liver, that is the organ responsible
for clearing most excess cholesterol from the body 13.
a) Multiple major coronary risk factors (especially
b) Severe and poorly controlled risk factors (especially
continued cigarette smoking).
c) Multiple risk factors of metabolic syndrome:
i. Abdominal obesity (waist circumference in men more
than 40 inches [102cm] or in women more than 35inches
ii. Triglycerides 150mg/dL or more.
iii. Low HDL cholesterol (less than 40mg/dL in men or less
than 50mg/dL in women).
iv. Blood pressure 135/85mm Hg or higher.
v. Fasting glucose 110mg/dL or more.
d) Acute coronary syndrome 16.
e) Age: risk may increase as you get older. Men aged 45
years or older and women aged 55 years or older.
f) Gender: After menopause, a woman’s LDL cholesterol
level (“bad” cholesterol) goes up, as does her risk for heart
g) Family History: risk of high cholesterol may increase if a
father or brother was affected by early heart disease (before
age 55) or a mother or sister was affected by early heart
disease (before age 65).
h) Diet: The trans fats, saturated fat, sugar, and (to a lesser
extent) cholesterol in the food you eat raise total and LDL
i) Physical Activity: Increased physical activity helps to
lower LDL cholesterol and raise HDL cholesterol (the “good”
cholesterol) levels. It also helps you lose weight 17 (Figure
Cholesterol can build up in the walls of your arteries. Over time,
this build-up -- called plaque -- causes hardening of the arteries or
atherosclerosis. This causes arteries to become narrowed, which
slows the blood flow to the heart muscle. Reduced blood flow can
result in angina (chest pain) or in a heart attack if a blood vessel
gets blocked completely.
Atherosclerosis causes arteries that lead to the brain to
become narrowed and even blocked. If a vessel carrying blood to
the brain is blocked completely, you could have a stroke.
Peripheral vascular disease
In this condition, fatty deposits build up along artery walls
and affect blood circulation. This occurs mainly in arteries that
lead to the legs and feet.
Diabetes can upset the balance between HDL and LDL
cholesterol levels. People with diabetes tend to have LDL particles
that stick to arteries and damage blood vessel walls more easily.
Glucose (a type of sugar) attaches to lipoproteins (a cholesterolprotein
package that enables cholesterol to travel through blood).
Sugar coated LDL remains in the bloodstream longer and may
lead to the formation of plaque. People with diabetes tend to have
low HDL and high triglyceride (another kind of blood fat) levels.
Both of these boost the risk of heart and artery disease.
High blood pressure
When the arteries become hardened and narrowed with
cholesterol plaque and calcium, the heart has to strain much
harder to pump blood through them. As a result, blood pressure
becomes abnormally high. High blood pressure is also linked to
heart disease 17.
Lowering of low-density lipoprotein (LDL)-cholesterol leads
to reduction of cardiovascular events in moderate-to-high-risk
a. Screening in adults ages >20 years has been advocated;
however, the evidence base in adults ages 21 to 39 years is not
clear 19. Previous guidance has recommended obtaining:
i. Fasting lipid profile for all adults ages ≥20 years; this can
be repeated every 5 years.
ii. Non-fasting lipid profile, especially for total, non-highdensity
lipoprotein (HDL)-, and HDL-cholesterol, is also
iii. Screening for related cardiovascular risk factors such as
hypertension, diabetes mellitus, family history of premature
cardiovascular disease and smoking. There is no upper age
limit at which screening for hypercholesterolemia should be
b. For patients <20 years, the presence of atherosclerotic
risk factors such as hypertension, diabetes, tobacco abuse,
obesity, and premature cardiovascular disease or significant
hypercholesterolemia (total cholesterol >240mg/dL) in the
immediate family should prompt the physician to consider
a) Dietary reduction in total and saturated fat, weight loss
in overweight patients, aerobic exercise, and addition of plant
stanols/sterols to the diet leads to a decrease in low-density
lipoprotein cholesterol and an increase in high-density
b) In the US, evolocumab is approved for use in the
reduction of risk of myocardial infarction, stroke, and coronary
revascularization in adults with established cardiovascular
c) Patients should be assessed for the presence of
additional cardiovascular risk factors, such as smoking and
diabetes, and appropriate management of these risk factors
a) Signs of hypercholesterolemia, such as eyelid
xanthelasmas, arcus corneae and xanthomata.
b) Tendinous xanthomas at the Achilles, elbow and
knee tendons and over metacarpophalangeal joints are
characteristics of heterozygous and homozygous forms of
c) Palmar or cutaneous xanthomas may be present in the
homozygous form of familial hypercholesterolemia.
d) Eruptive xanthomas over the trunk, back, elbows,
buttocks, knees, hands, and feet may be present in severe
elevations of triglycerides.
e) Palmar and tuberous xanthomas are seen in patients
f) There may also be evidence of vascular disease, such as
elevated neck veins or bibasal crepitations on lung auscultation
(heart failure), hemiplegia (stroke), or diminished pulses
(peripheral arterial disease) 17.
a) Lipids are measured in the fasting state: including total
cholesterol, triglycerides, high-density lipoprotein (HDL), and
estimated low-density lipoprotein (LDL) 25,26.
b) Non-HDL-cholesterol: is a marker of cholesterol
carried by pro-atherogenic lipopoproteins: very low-density
lipoprotein and remnants, intermediate-density lipoproteins,
LDL, and lipoproteins (a) 27.
c) LDL can be accurately estimated in non-fasting states if
triglyceride levels are <400 mg/dl.
d) Extremely high lipid levels may give a lactescent (milky)
appearance to blood plasma.
e) Routine thyroid-stimulating hormone rules out most
cases of hypothyroidism.
f) These may include creatinine levels, fasting blood glucose
and glycated hemoglobin, urinalysis, ECG, echocardiogram,
cardiac stress testing, cardiac computed tomography to
measure coronary calcium scores or luminal obstruction,
cardiac catheterization, and vascular studies such as Doppler
exam or ankle-brachial indices 17.
A healthy lifestyle reduces atherosclerotic cardiovascular
disease (ASCVD) risk at all ages. In younger individuals, healthy
lifestyle can reduce development of risk factors and is the
foundation of ASCVD risk reduction. Lifestyle therapy is the
primary intervention for metabolic syndrome.
Very high-risk includes a history of multiple major ASCVD
events or 1 major ASCVD event and multiple high-risk conditions.
In very high-risk ASCVD patients, it is reasonable to add ezetimibe
to maximally tolerated statin therapy when the LDL-C level
remains ≥70mg/dL (≥1.8mmol/L). In patients at very high
risk whose LDL-C level remains ≥70 mg/dL (≥1.8mmol/L) on
maximally tolerated statin and ezetimibe therapy, adding a PCSK9
If the LDL-C level remains ≥100mg/dL (≥2.6mmol/L), adding
ezetimibe is reasonable. If the LDL-C level on statin plus ezetimibe
remains ≥100mg/dL (≥2.6mmol/L) and the patient has multiple
factors that increase subsequent risk of ASCVD events, a PCSK9
In patients with diabetes mellitus at higher risk, especially
those with multiple risk factors or those 50 to 75 years of age, it
is reasonable to use a high-intensity statin to reduce the LDL-C
level by ≥50%.
Risk discussion should include a review of major risk
factors (e.g., cigarette smoking, elevated blood pressure, LDL-C,
hemoglobin A1C [if indicated] and calculated 10-year risk of
ASCVD), the presence of risk-enhancing factors, the potential
benefits of lifestyle and statin therapies, the potential for adverse
effects and drug–drug interactions, consideration of costs of statin
therapy, patient preferences and values in shared decision making.
Risk-enhancing factors favor statin therapy. If risk status
is uncertain, consider using coronary artery calcium (CAC) to
improve specificity. If statins are indicated, reduce LDL-C levels by
≥30%, and if 10-year risk is ≥20%, reduce LDL-C levels by ≥50%.
b) Persistently elevated LDL-C levels ≥160mg/dL
c) Metabolic syndrome; chronic kidney disease; history
of preeclampsia or premature menopause (age <40 years);
chronic inflammatory disorders (rheumatoid arthritis,
psoriasis, or chronic HIV).
d) Persistent elevations of triglycerides ≥175mg/dL
(≥1.97mmol/L) and if measured in selected individuals
apolipoprotein B ≥130mg/dL, high-sensitivity C-reactive
protein ≥2.0mg/L, ankle-brachial index <0.9 and lipoprotein
(a) ≥50mg/dl or 125nmol/L, especially at higher values of
e) Risk-enhancing factors may favour statin therapy in
patients at 10-year risk of 5-7.5% (borderline risk).
If CAC is zero, treatment with statin therapy may be withheld
or delayed, except in cigarette smokers, those with diabetes
mellitus, and those with a strong family history of premature
ASCVD. A CAC score of 1 to 99 favours statin therapy, especially
in those ≥55 years of age. For any patient, if the CAC score is
≥100 Agatston units or ≥75%, statin therapy is indicated unless
otherwise deferred by the outcome of clinician-patient risk
Define responses to lifestyle and statin therapy by percentage
reductions in LDL-C levels compared with baseline. In ASCVD
patients at very high-risk, triggers for adding nonstatin drug
therapy are defined by threshold LDL-C levels ≥70mg/dL
(≥1.8mmol/L) on maximal statin therapy 35.
Statins reduce synthesis of cholesterol in the liver by
competitively inhibiting HMG-CoA reductase activity. The
reduction in intracellular cholesterol concentration induces lowdensity
lipoprotein receptor (LDLR) expression on the hepatocyte
cell surface, which results in increased LDL-C catabolism
and a decreased LDL-C synthesis and other apo B-containing
lipoproteins including TG-rich particles 36.
b) Elevated liver enzymes (rarely hepatotoxicity).
c) Muscle cell damage and death (rhabdomyolysis) result
in the release of creatine phosphokinase (CK) and myoglobin
among other intracellular molecules, while the accumulation
of myoglobin in the kidneys can lead to renal failure and death
37-42 (Table 4).
Thyroid hormones act on two main types of receptors, thyroid
receptors α and β (TRα and TRβ) [55,56]. Endogenous thyroid
hormones having Lipid-Lowering effects through TRβ; but not be
utilized due to TRα-induced cardiac, muscle and bone thyrotoxic
side effects [57,56].
Selective TRβ agonists could offer an additional approach in
HF treatment by induction hepatic bile acid production and upregulation
the expression of the HDL receptor, the receptor type
B-Class I (SR-B1), leading to increased transport of cholesterol into
HDL particles . These agents can interfere with cholesterol
metabolism, without the unwanted TRα-related side effects .
Selective TRβ agonists (GC-1 (sobetirome) and KB2115
(eprotirome)) decrease serum cholesterol levels by increasing
cholesterol utilization for synthesis of bile acids and inducing
their subsequent fecal excretion in an LDLR-independent manner
Notes: Due to the reported side effects, the future role of
thyroid mimetics will depend on their safety profile and some of
these agents may potentially find a role in HoFH treatment 
PCSK9 is a serine protease produced by hepatocytes  blocks
the LDLR recycling by mediating clathrinmediated endocytosis
and subsequently inducing the lysosomatic degradation of LDLR
[58,59] and this leads to LDL accumulation in the circulation 
and eventually promotes atherogenesis, with high PCSK9 levels
correlating to the degree of coronary artery calcification .
The strategies that target the binding include:
a) Monoclonal antibodies (mAbs) that bind to PCSK9 in the
plasma, thereby preventing it from binding to LDL-R.
b) Modified binding proteins such as adnectins, and smallmolecule
inhibitors. Notably, development of a small-molecule
inhibitor of PCSK9 .
LDL reduction: up to a 55% as monotherapy, and 75%
combined with a statin [63-68] (Figure 8) & (Table 9 & 10).
Due to the FH-related high CVD morbidity and mortality,
early prevention and effective management of these patients is
essential through organized primary care and/or Lipid Specialist
care centers. Current research further focuses on new monoclonal
antibodies/genetic targeting approaches which may offer novel
options in order to significantly lower LDL and prevent/reduce
ASCVD in FH.
Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, et al. (2019) 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 73(24): e285-350.