Review Article

ISSN: 2574 -1241 DOI: 10.26717/BJSTR.2022.43.006869

Pathophysiology and Management of Dyslipidaemia

Gudisa Bereda*
Department of Pharmacy, Negelle Health Science College, Ethiopia
*Corresponding author: Gudisa Bereda, Department of Pharmacy, Negelle Health Science College, Guji, Ethiopia

ARTICLE INFO ABSTRACT

Received: April 01, 2022 Dyslipidaemia is a circumstance described by accelerated total cholesterol,
or triglycerides, a low-high-density lipoprotein (HDL) or a combination of these
Published: April 12, 2022 abnormalities. Dyslipidemia is associated with atherosclerosis in the process of
causing cardiovascular disease. Cholesterol accumulated due to dyslipidemia is
oxidized and accelerates the description of intercellular adhesion molecule-1 and
Citation: Gudisa Bereda. Pathophysiolo- endothelial selectin (E-selectin) for monocyte adhesion, thereupon resulting in
gy and Management of Dyslipidaemia. Bi- monocyte influx and cytokine production. The therapeutic approach and therapeutic
omed J Sci & Tech Res 43(2)-2022. BJSTR. objectives depending on the risk of developing atherosclerotic cardiovascular disease,
MS.ID.006869. and the criteria are more restricted for those at high risk. It intended to decrease
cardiovascular disease risk in the future; thus, management criteria will depend
Abbreviations: ADA: American Diabetes
initially on low-density lipoprotein values. Statins prevent the reductase of 3-hydroxy-
Association; BAS: Bile Acid Sequestrant;
3-methylglutaryl-coenzyme-A, which is the rate limiting step in the hepatic cholesterol
CVD: Cardiovascular Disease; FFA: Free
secretion or an enzyme that limits endogenous cholesterol secretion with reduced
Fatty Acids; GI: Gastrointestinal; HDL-C:
intracellular cholesterol content and accelerated low-density lipoprotein clearance.
High-Density Lipoprotein Cholesterol;
Statins remain the 1st line therapy in the treatment of dyslipidemia. American diabetes
HMG-CoA: 3-Hydroxy-3-Methylglutar-
association recommends that statins should be used, irrespective of baseline lipid
yl-Coenzyme-A Reductase Inhibitors;
levels, in diabetic patients with cardiovascular disease or who are over the age of 40
IL: Interleukin; LDL-C: Low-Density Li-
and have one or further cardiovascular disease risk factor involving family history of
poprotein Cholesterol; Lp(a): Lipopro-
cardiovascular disease, hypertension, smoking, dyslipidemia, or albuminuria.
tein(a); PCSK9: Proprotein Convertase
Subtilisin/Kexin Type 9; ROS: Reactive Keywords: Dyslipidemia; Pathophysiology; Management
Oxygen Species; TG: Triglyceride; TNF-α:
Tumour Necrosis Factor-α

Introduction
because significant enzymes and lipid metabolism pathways
Dyslipidemia can result from an intrinsic, extrinsic, or a
are affected [4]. Dyslipidemia is a collection of metabolically
combination of genetic predisposition and external factors. Initial
interrelated plasma lipid and lipoprotein abnormality including
dyslipidemias are a heterogeneous group of diseases of genetic,
low High-Density Lipoprotein Cholesterol (HDL-C), High Low-
mono, or polygenic etiology, whereas secondary ones sequence
Density Lipoprotein Cholesterol (LDL-C), Total Cholesterol (TC)
from the association of risk factors with external factors or other
and triglyceride (TG) levels. In DM patients, the most frequent
pathologies. Dyslipidemias can alter the values of Total Cholesterol
patterns of dyslipidemia were hypertriglyceridemia, declined HDL
(TC), TG, Low-Density Lipoprotein (LDL) cholesterol, or High-
cholesterol levels, and accelerated levels of LDL particles and it
Density Lipoprotein (HDL) cholesterol and occur from childhood
increases the risk of CVD among DM patients [5-7]. People with
to adolescence alone or in association and persist during adult life
dyslipidemia are two-times escalated risk of CVD as compared to
[1-3]. Dyslipidemia is more frequent in diabetes mellitus patients
those with normal lipid levels [8].

Copyright@ Gudisa Bereda | Biomed J Sci & Tech Res | BJSTR. MS.ID.006869. 34369
Volume 43- Issue 2 DOI: 10.26717/BJSTR.2022.43.006869

Pathophysiology Diagnostic Procedure

Dyslipidemia is associated with atherosclerosis in the Screening can be at fast or postprandial (higher TG in the
procedure of causing cardiovascular disease. Cholesterol latter) but must be verified in two fasting samples (12-h minimum
accumulated due to dyslipidemia is oxidized and accelerates the fast) if altered, 2–3 weeks apart. The percentage between these
description of intercellular adhesion molecule (ICAM)-1 and two values will be used for diagnostic and therapeutic purposes.
endothelial selectin (E-selectin) for monocyte adhesion, thereupon The postprandial sample notifies the determination of non-
sequencing in monocyte influx and cytokine generation. The HDL cholesterol by subtracting HDL from the TC. Inflammation
monocytes differentiate into macrophages and synthesis Monocyte secondary to severe infections can cause importantly accelerated
Chemoattractant Protein (MCP)-1 to more promote the influx of TG, for which lipid profile screening should not be performed in 3
monocytes. Furthermore, monocytes synthesis cytokines, such weeks after infections. A fasting lipoprotein profile that involves
as interleukin (IL)-6, and increases the oxidation of cholesterol total cholesterol, LDL, HDL, and Triglycerides should be measured
through the release of oxidizing substances. Macrophages absorb [21,22] (Table 1).
oxidized cholesterol and become foam cells, which are deposited Table 1: Classification of total LDL, HDL, cholesterol and
on the walls of the blood vessels. This procedure sequences triglycerides.
in the formation of plaque and causes atherosclerosis. In this
Total cholesterol
manner, dyslipidemia accelerates the risk of atherosclerosis
<200mg/dL Desirable
and cardiovascular disease [9-14]. Atherosclerotic lesions are
200-239mg/dL Borderline high
considered to arise from transport and retention of plasma LDL
≥/240mg/dL High
through the endothelial cell layer into the extracellular matrix of
LDL cholesterol
the subendothelial space. Once in the artery wall, LDL is chemically
revised through oxidation and nonenzymatic glycation, mildly <100mg/dL Optimal

oxidized LDL then recruits monocytes into the artery wall. 100-129mg/dL Near or above optimal
130-159mg/dL Borderline high
These monocytes then become transformed into macrophages
160-189mg/dL High
that increase LDL oxidation. Repeated damage and repair within
≥/ 190md/dL Very high
an atherosclerotic plaque finally lead to a fibrous cap protecting
HDL cholesterol
the underlying core of lipids, collagen, calcium, and inflammatory
<40mg/dL Low
cells such as T lymphocytes. Maintenance of the fibrous plaque
≥/60mg/dL High
is critical to inhibit plaque rupture and subsequent coronary
thrombosis [15,16]. Oxidative stress represents one of the basic Triglycerides

pathogenetic procedures of atherosclerosis, as the escalated <150mg/dL Low

generation of Reactive Oxygen Species (ROS) is closely related 150-199mg/dL Borderline high
to endothelial dysfunction and the promotion of the vascular 200-299mg/dL High
inflammatory response. Common situations that are also respected ≥/500mg/dL Very high
as cardiovascular risk factors that predispose to atherosclerosis,
Treatment
such as hypercholesterolemia, hypertension, diabetes, and smoking,
are associated with accelerated generation of ROS. Atherosclerosis The therapeutic approach and therapeutic objectives depending
is also recognized as an inflammatory disorder of the medium on the risk of developing atherosclerotic CVD, and the criteria
and large arteries. Cytokines have a paramount influence on the are further restricted for those at high risk. It aimed to decrease
pathogenesis of this disease as they are included in all stages of CVD risk in the future; thus, management procedures will depend
atherosclerosis. Tumour necrosis factor-α (TNF-α), interleukin initially on LDL values [23].
(IL)-1, and IL-6 are pro-atherogenic cytokines generated by Lifestyle Modifications
macrophages, lymphocytes, natural killer cells, and vascular smooth
muscle cells. TNF-α and IL-1 promote the description of cytokines, The management basis is focused on diet and at least 30–60
adhesion molecules, and the migration and mitogenesis of vascular min of physical activity. Tobacco smoke exposure (passive or active)
smooth muscle and endothelial cells on the vascular wall during the should be avoided and age-appropriate sleeping habits should be
atherosclerotic procedure [17-20]. adopted. Restricted total fats, saturated fats, cholesterol intake,

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Volume 43- Issue 2 DOI: 10.26717/BJSTR.2022.43.006869

modest accelerate in polyunsaturated fat, accelerated soluble fiber Nicotinic Acid

intake and weight reduction (initial goal of 10%) if needed [24-27].
Nicotinic acid (eg, extended-release niacin, immediate-release
The recommended diet is depending on escalated consumption
niacin) prevents the lipolysis of adipocytes, which sequences in
of fruit, vegetables, and whole grains compared to the average
reduced FFA levels, decreased VLDL secretion, and a slight accelerate
of ingested fat (lipids by 25%–30%; carbohydrates by 55%, and
in HDL generation rate and reduced catabolism of HDL. These alter
proteins by 15%–20% of the total calories) [28].
by niacin subsequently lead to 15%–35% lower TG levels and
Pharmacological Therapy 10%–25% higher HDL-C concentrations [41-43]. Niacin is recently
the frequent potent medicine in increasing HDL cholesterol. Niacin
Pharmacotherapy should be thought-out comprehending to
also has moderate effect in lowering LDL-cholesterol, triglycerides
CVD risk stratification. The decision to commence pharmacological
and lipoprotein (a) [44]. Adverse drug reactions: Cutaneous
treatment depends on age, severity, and the availability of other
flushing; itching (aspirin 325 mg shortly before niacin ingestion);
individual or familial CVD risk factors [29,30]. The intentions of
GI intolerance; hyperglycaemia; hhyperuricemia and hepatotoxicity
management are to lower total and LDL cholesterol in order to
[45,46].
decrease the risk of first or recurrent events such as myocardial
infarction, angina, heart failure, ischemic stroke, or other forms of Bile Acid Sequestrants
peripheral arterial disease such as carotid stenosis or abdominal
Bile acid scavengers (e.g., Cholestyramine resin, colesevelam,
aortic aneurysm [31-33]. Pharmacological management perhaps
colestipol HCl) bind to bile acids, decreasing their absorption, and
instituted ad initium in high-risk individuals with LDL of ≥130 mg/
enhancing their hepatic secretion, thus reducing the cholesterol
dl and age of >10 years. In the case of pharmacological therapy
content of the hepatocytes [47]. Bile Acid Sequestrants (BAS)
indication, the patient should be referred for hospital consultation
bind to bile acids in the intestinal lumen, thereupon interrupting
[34].
the enterohepatic circulation of bile acids. As a sequence, the liver
3-Hydroxy-3-Methylglutaryl-Coenzyme-A Reductase accelerates the generation of bile acids, which leads to reduce in
Inhibitors (Statins) cholesterol pool. BAS lower plasma total and LDL-cholesterol while
increasing HDL-cholesterol and apoA1. The cholesterol-lowering
Statins prevent the reductase of 3-hydroxy-3-methylglutaryl-
effect of BAS perhaps accompanied by accelerates in triglycerides
coenzyme-A (HMG-CoA), which is the rate limiting step in the
[48-50].
hepatic cholesterol secretion or an enzyme that limits endogenous
cholesterol synthesis with reduced intracellular cholesterol Adverse Drug Reactions: Constipation; bloating; epigastric
content and accelerated LDL clearance [35,36]. Statins remain the fullness; nausea, and flatulence are most frequently observed
1stline therapy in the treatment of dyslipidemia. ADA recommends and injured absorption of fat soluble vitamins, digoxin, warfarin,
that statins should be used, irrespective of baseline lipid levels, thiazides, b-blockers, thyroxine and phenobarbital [51]. The
in diabetic patients with CVD or who are over the age of 40 and following are recommended for patients receiving BASs accelerate
have one or further CVD risk factor involving family history of fluid uptake; modify the diet to enhance bulk, and use stool
CVD, hypertension, smoking, dyslipidemia, or albuminuria. Statin softeners [52].
treatment is also recommended for diabetic patients under
Cholesterol Absorption Inhibitors: Cholesterol absorption
the age of 40 with multiple CVD risk factors or LDL > 100 mg/
inhibitors (e.g., ezetimibe) are a class of hypocholesterolemic
dl (82.6mmol/l) despite lifestyle intervention [37]. Statins are
medicine that prevents intestinal cholesterol absorption from plant
most effective at lowering LDL and, to a lesser extent, also lower
sterols. They can be used from ten years of age as monotherapy
triglycerides and raise HDL. Furthermore, statins have anti-
or in association with statins, useful in children/adolescents with
inflammatory and anti-thrombotic properties and the capability
familial hypercholesterolemia or high-risk factors for immature
to stabilize atherosclerotic plaques [38]. The most frequently
CVD, who do not reach therapeutic objectives with the optimized
used are rosuvastatin or pravastatin (over 8 years old), and other
statin dose. They do not change TG, vitamin A, and D, fat, or bile acids
statins (atorvastatin, simvastatin, or lovastatin) are recommended
absorption [53,54]. Ezetimibe decreases the cholesterol content
above 10 years old [39]. Adverse drug reactions: Constipation
of both fasting and postprandial triglyceride-rich lipoproteins,
less than10%; increased serum aminotransferase levels (initially
thereupon lowering the concentrations of atherogenic remnant
alanine aminotransferase); increased creatine kinase levels;
particles [55].
myopathy [40].

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Volume 43- Issue 2 DOI: 10.26717/BJSTR.2022.43.006869

Fibrates 3) Escalated removal of LDL particles

Fibrates (eg, Bezafibrate, fenofibrate (micronized/microcoated/ 4) Decrement in neutral lipid, and

nano crystals), gemfibrozil) action is linked to the initiation of
5) Accelerate in HDL generation and stimulation of reverse
transcription of genes included in peroxisomal-oxidation; this
cholesterol transport [57].
procedure is mediated by specific transcription factors called
peroxisome proliferator activated receptors (PPARs) [56]. Fibrates are the most potent medicines for lowering triglycerides.
They also lower LDL and raise HDL. They are preferentially used
The mechanisms of action of fibrates can be divided into 5
in hypertriglyceridemia, but their use in under eighteen years
groups:
old is not yet confirmed, thus only revealed in children with
1) Initiation of lipoprotein lipolysis hypertriglyceridemia of >500 mg/dl or at risk of pancreatitis, who
are unresponsive to dietary measure [58]. Adverse drug reactions:
2) Initiation of hepatic fatty acid (FA) intake and decrement of
Gastrointestinal complaints; rash; dizziness; transient increases in
hepatic TG generation
transaminase levels and alkaline phosphatase [59] (Table 2).

Table 2: Effects of drug therapy on lipids and lipoproteins.

Medications Class Mechanism of action Effects on lipids Effects on lipoproteins

Decrease LDL and VLDL Decrease cholesterol and Decrease LDL, increase HDL
Niacin Nicotinic acid
synthesis decrease triglycerides and decrease VLDL
Increase LDL catabolism;
Cholestyramine resin, Decrease LDL and increase
Bile acid sequestrants decrease cholesterol Decrease cholesterol
colesevelam, colestipol HCl VLDL
absorption;
Lovastatin, rosuvastatin, Decrease LDL synthesis and
HMG-CoA or statin Decrease cholesterol Decrease LDL
atorvastatin, simvastatin increase LDL catabolism
Blocks cholesterol
Cholesterol absorption
Ezetimibe absorption across the Decrease cholesterol Decrease LDL
inhibitors
intestinal border
Increase VLDL clearance
Bezafibrate, fenofibrate, Decrease triglycerides and Decrease LDL, increase HDL
Fibrates and decrease VLDL
gemfibrozil decrease cholesterol and decrease VLDL
synthesis
decrease the hepatic Decrease hepatic secretion
Omega-3-fatty acids Fish oil supplementation Decrease TG
synthesis of TG of VLDL

Omega-3-Fatty Acids or Fish Oil Supplementation with hypocholesterolemia and decreased risk of CVD [61].

Omega-3 fatty acids lower triglycerides but have little effect on Combinations
LDL and HDL. Additionally to hypotriglyceridemic consequences,
Techniques for combination therapies with statins to reach
omega-3 fatty acids perhaps ameliorate inflammation, attenuate
even lower cholesterol levels have been reviewed. Combinations
endothelial function and decrease thrombus formation. Omega-3
can be made with ezetimibe, which prevents the intestinal
fatty acids, which reduce the hepatic secretion and accumulation
cholesterol absorption by interaction with Niemann-Pick C1 like 1
of TG, have been indicated to decrease plasma TG by 25%–30% by
protein (NPC1L1), which sequences in an additional 20% lowering
effectively decreasing the hepatic synthesis of VLDL [60].
effect on LDL-C, but without affecting TG or HDL-C concentrations.
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9 Statin plus a BAR or niacin plus a BAR provide the highest reduction
Inhibitor) in total and LDL cholesterol. The concomitant use of fibrates and
statins increased adverse muscle effects. Combination therapy of
PCSK9 inhibitor (eg, Alirocumab; Evolocumab) prevent the
fibrates with statins in patients with diabetes and the characteristic
lysosomal breakdown of LDL receptors, consequently accelerating
dyslipidemia with high TG and low HDL-C occasionally have
their cell surface description. PCSK9 is a protein initially described
beneficial consequences. Thereupon, fenofibrate perhaps used
in liver, intestine and kidney. It binds to LDL receptors and promotes
to manage residual dyslipidemia in diabetic patients on top of
their breakdown, consequently decreasing the removal of LDL
statin therapy. Regimens aimed to accelerate HDL levels should
from plasma. While gain-of-function mutations of PCSK9 cause
involve either gemfibrozil or niacin, with statins combined with
hypercholesterolemia, loss-of-function mutations are associated
either of these medicines perhaps sequence in a higher incidence

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Volume 43- Issue 2 DOI: 10.26717/BJSTR.2022.43.006869

of hepatotoxicity or myositis. Omega-3 fatty acids have also been 3. Kim HL, Chung J, Kim KJ, Kim HJ, Seo WW, et al. (2022) Lifestyle
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