Open Access Review

Article DOI: 10.7759/cureus.56255

An Update on Dyslipidemia Management and

Medications: A Review
Review began 02/15/2024
Ziad A. Taher 1 , Abdulrahman A. Taher 2 , Suhaib Radi 1, 3, 4
Review ended 03/08/2024
Published 03/16/2024 1. Department of Medicine, King Abdulaziz Medical City, Jeddah, SAU 2. College of Medicine, University of Jeddah,
© Copyright 2024 Jeddah, SAU 3. College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU 4. College of
Taher et al. This is an open access article Medicine, King Abdullah International Medical Research Center, Jeddah, SAU
distributed under the terms of the Creative
Commons Attribution License CC-BY 4.0.,
Corresponding author: Ziad A. Taher, [email protected]
which permits unrestricted use, distribution,
and reproduction in any medium, provided
the original author and source are credited.

Abstract
Dyslipidemia, characterized by abnormal lipid levels in the bloodstream, is a very common and
underappreciated chronic disease associated with a significant cardiovascular disease burden. The
management landscape for dyslipidemia has historically been static, with a sparse selection of therapeutic
options. This article presents a comprehensive review of contemporary approaches to dyslipidemia
management, focusing on therapeutic strategies and emerging interventions. We delineate the most current
American Heart Association/American College of Cardiology & Canadian Cardiovascular Society guidelines
and examine pivotal clinical trials that are shaping the contemporary approach to dyslipidemia
management.

Categories: Endocrinology/Diabetes/Metabolism, Cardiac/Thoracic/Vascular Surgery, Cardiology

Keywords: pcsk9 inhibitors, inclisiran, cardiovascular diseases, hypercholesterolemia, dyslipidemia

Introduction And Background

Dyslipidemia and its management were a relatively stagnant topic with few updates; however, this is no
longer the case. It is currently one of the medical areas that is changing the fastest because of new drugs and
updated recommendations from societies and communities around the world. The Food and Drug
Administration has authorized more medications in the last 10 years, and standards are being modified more
frequently than in the past [1].

In order to give current updates for clinical practice, we have reviewed the most commonly accepted papers
and the most recently published research regarding dyslipidemia.

Review
Types of lipids and clinical significance
Any sort of lipid abnormality in the blood can be referred to as dyslipidemia. As a result, the most common
conditions affecting the following lipid types will be covered in this article: (i) Low-density lipoprotein-
cholesterol (LDL-C); (ii) high-density lipoprotein-cholesterol (HDL-C); (iii) cholesterol; (iv) triglycerides.

Lipids are insoluble in plasma, for that, it is transported by proteins called lipoproteins which are divided
into four main classes as presented in Table 1.

Function Source Class

Transport dietary TAG intestine Chylomicrons

Transport of endogenously synthesized TAG liver VLDL

Transport of cholesterol to peripheral tissue Blood circulation IDL & LDL

Transport cholesterol from peripheral tissue to liver liver HDL

TABLE 1: Lipoprotein Classes and Functions

TAG: Triglyceride; VLDL: very low-density lipoprotein; IDL: intermediate lipoprotein; LDL: low-density lipoprotein; HDL: high-density lipoprotein

One of the main risk factors for heart disease is dyslipidemia. LDL-C and triglycerides are the two primary
dyslipidemia-related factors that directly affect cardiovascular health, according to the American Heart

How to cite this article

Taher Z A, Taher A A, Radi S (March 16, 2024) An Update on Dyslipidemia Management and Medications: A Review. Cureus 16(3): e56255. DOI
10.7759/cureus.56255
 Association. The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in those with elevated
LDL-C levels. Elevated levels of triglycerides are linked to a higher chance of developing cardiovascular
disease and pancreatitis [1].

LDL-C remains the targeted atherogenic lipoprotein in most guidelines. However, over the last few years, the
importance of other lipoproteins has come into play including non-HDL-C, ApoB, and lipoprotein (a) [Lp(a)]
as accurate indicators of CV mortality. These parameters offer a superior assessment of atherogenic
particles compared to LDL-C, particularly noteworthy in patients with TG > 1.5 mmol/L [2-4].

Familial hypercholesterolemia (FH)

FH is a common genetic disorder affecting children and adults, marked by elevated levels of LDL-C that
contribute to ASCVD. Early detection is crucial for effective treatment. Mutations in three genes, LDL
receptor (LDL-R), proprotein convertase subtilisin/kexin type 9 (PCSK9), and apo B, can cause FH. However,
most FH cases involve LDL-R mutations, reducing lipid uptake in the liver and increasing circulation, a
primary cause of ASCVD and mortality. There are two main types of FH: homozygous FH, rare and
associated with LDL-C level >13 mmol/l, posing a risk of death before age 20 if untreated; and heterozygous
FH, characterized by >4.9 mmol/l LDL-C level, with ASCVD development likely before the age of 60. Family
cascade screening is recommended for all family members of the affected person including children when
they reach the age of 10 years or maybe earlier at the age of 2 years [5,6].

In the treatment of FH, the objective is to reduce LDL-C levels to below 2.6 mmol/L or achieve a minimum
reduction of 50%. Typically, statins serve as the primary medication, often followed by the addition of
ezetimibe, colevabsam (a bile acid sequestrant), PCSK9 inhibitors, and lomitapide (microsomal triglyceride
transfer protein). When these treatments prove insufficient, LDL apheresis may be considered as a last resort
[7].

When to treat?
The primary approach for managing dyslipidemia has remained the consistent use of statin therapy.
Additional medications may be considered if the target levels are not achieved or if the patient cannot
tolerate statin therapy. It is crucial to highlight the following indications for therapy: (i) LDL-C ≥5 mmol/L,
OR ApoB ≥1.45 g/L, OR non-HDL-C ≥5.8 mmol/L OR confirmed familial hypercholesterolemia; (ii) Diabetic
patients older than 40 years OR those older than 30 years with a DM history of more than 15 years OR those
with microvascular complications; (iii) Chronic kidney disease with an estimated glomerular filtration rate
<60 mL/min/1.73 m2, persistent for three or more months, OR an albumin-to-creatinine ratio >3 mg/mmol
AND ≥50 years; (iv) As primary prevention for patients with a high atherosclerotic cardiovascular risk score
(initiating treatment when necessary); (v) As secondary prevention in patients with any atherosclerotic
condition, including cardiac disease, cerebrovascular disease, peripheral artery disease, and aneurysms; (vi)
A recent meta-analysis recommended maintaining lower lipid levels for elderly adults >75 who don't meet
the above indications, as it has shown to yield beneficial outcomes compared to others [8].

Treatment and management of dyslipidemia

The primary approach to treating dyslipidemia involves lowering LDL-C and increasing HDL-C levels. This is
typically achieved through lifestyle modifications, including diet, weight loss, and exercise. However, these
interventions may vary among individuals based on several factors. If LDL-C levels remain unchanged after
six months, drug therapy should be considered as part of the treatment plan.

Diet Therapy

The objective of diet therapy is to minimize cholesterol intake and typically involves three stages. Initially,
the goal is to reduce daily cholesterol intake to below 300mg/day. Subsequently, the intake is further reduced
to less than 200mg/day. Finally, cholesterol intake is restricted to 25 mg/day. Additionally, exercise plays a
crucial role not only in reducing body weight but also in increasing HDL-C levels. Individuals with
hypercholesterolemia are advised to engage in 30 to 60 minutes of moderate to vigorous aerobic exercise, at
least three days per week, which significantly contributes to preventing coronary artery disease [9].

Drug Therapy

Drug therapy is an essential adjunct to dietary modifications to lower LDL-C levels. While diet therapy
typically takes 3 to 6 months to show results, drug therapy tends to have a quicker impact. If one drug fails to
lower LDL-C, considering add-on drug therapy is advisable. However, it's important to note that many lipid-
lowering agents can have various side effects. Here's a discussion of the various classes of drugs approved for
the management of dyslipidemia:

HMG-CoA Reductase Inhibitors (Statins)

Statins, also known as HMG-CoA reductase inhibitors, are widely tolerated and commonly prescribed

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 medications. They function by inhibiting HMG-CoA reductase, a rate-limiting enzyme in cholesterol
synthesis, leading to a decrease in cholesterol levels within hepatocytes. As a compensatory response, cell
wall surface receptors increase to meet the cellular need for cholesterol, resulting in decreased blood LDL-C
levels [10]. Furthermore, a meta-analysis study revealed that in addition to reducing serum LDL-C levels, it
was linked to the regression of plaque in patients with coronary atherosclerosis, as assessed by intracoronary
ultrasound [11].

Statins can also reduce triglycerides by 10-20% and minimally increase HDL by around 5-10% [12]. Side
effects of statin therapy have been extensively studied, with the most common being myalgia occurring in
approximately 1-10% of cases. Rhabdomyolysis, a more serious side effect, is rare, occurring in less than
0.1% of cases [13]. Other reported side effects include hepatic dysfunction and renal impairment secondary
to rhabdomyolysis. Groups more prone to these side effects include the elderly, females, hypothyroid
patients, and those with multisystem diseases.

For patients unable to tolerate these side effects, switching to ezetimibe is recommended. In cases where
there is a high risk of cardiovascular complications, consideration might be given to shifting to another type
of statin therapy with dose adjustments or less frequent dosing, such as twice weekly. Statins remain a Class
I recommendation in most of the major international guidelines including the American Heart Association
and the European Society of Cardiology for patients with acute coronary syndrome [14,15].

Ezetimibe

Ezetimibe can enhance the efficacy of statin therapy for individuals at high risk of cardiovascular events,
decreasing the incidence of non-fatal heart attacks and strokes [16,17]. The 2021 CCS dyslipidemia
guidelines underscore its significance in reducing cardiovascular mortality, recommending its use as a
secondary treatment alongside statin therapy for lowering cardiovascular risk in both primary and secondary
prevention [18].

Ezetimibe operates by hindering cholesterol absorption in the intestine, likely through the inhibition of the
NPC1L1 protein. This results in a decrease in the serum levels of lipoprotein cholesterol transported to the
liver. As a compensatory mechanism, there is an increase in LDLR receptors in the liver, leading to enhanced
clearance of cholesterol from the circulation. This process results in a 20% reduction in LDL-C levels.

The efficacy of ezetimibe was demonstrated in the IMPROVE IT trial, conducted in 2015 with 18,144
participants. The trial aimed to assess the reduction in cardiovascular death, non-fatal myocardial
infarction, and unstable angina. Notably, Ezetimibe exhibited improved cardiovascular outcomes when
initiated in acute coronary syndrome patients with LDL-C levels exceeding 1.3 mmol/l [17].

Bile-Acid Sequestrants

The mechanism of bile-acid sequestrants is contingent on bile-acid levels in the liver. By reducing bile acids
after binding to resins in the small intestine and being excreted in stool, LDL receptor numbers increase.
This stimulates the production of more bile acid from circulating cholesterol, ultimately decreasing LDL-C
levels in the blood [17]. Common side effects include constipation, reflux esophagitis, and nausea.
Additionally, it can reduce the absorption of various drugs like digitalis, beta-blockers, and warfarin. Bile-
acid sequestrants typically lower LDL-C by 15-30% and increase HDL-C by 3-5%.

Niacin

Niacin, or nicotinic acid, is a water-soluble vitamin with notable effects on LDL-C, triglycerides, and HDL-C.
While it is the most effective in raising HDL-C among dyslipidemia drugs, it's not as potent as statins in
lowering LDL-C. Niacin decreases the mobilization of fatty acids from adipose tissue, leading to a drop in
triglycerides and very low-density lipoprotein cholesterol synthesis [19]. However, its use is limited due to
common side effects like flushing, pruritus, rash, nausea, and dyspepsia, causing discontinuation in 10%-
50% of patients. An extended-release form with better tolerance is Food and Drug Authority (FDA)-
approved. Despite its withdrawal for cardiovascular disease prevention, niacin is still used for other FDA-
approved indications [3,4].

Fibrates

Fibrates, another lipid-lowering agent, primarily impact triglycerides. They do not show any cardiovascular
mortality benefit but can decrease the complications related to very high levels of triglyceride like
pancreatitis [20]. Fibrates can reduce triglycerides by 50% compared to omega-3 fatty acids. To a lesser
extent, they lower LDL-C levels and increase HDL-C levels. Fibrates activate peroxisome proliferator-
activated receptors, transcribing genes involved in peroxisomal B-oxidation. Common side effects include
elevated liver enzymes and creatine phosphokinase, along with myopathy, cholelithiasis, and venous
thrombosis to a lesser extent. Certain fibrates (gemfibrozil) should not be used concurrently with statin

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 therapy, as they can inhibit statin metabolism, increasing the risk of myopathy [21,22].

Omega-3 Fatty Acids (FAs)

Similar to fibrates, omega-3 FAs primarily impact triglycerides, reducing levels by 25%-30%. They are
approved by the American Heart Association for use in hypertriglyceridemia. However, certain forms of
omega-3 FAs may increase LDL-C levels. Despite extensive clinical trials, Omega-3 FAs have failed to
demonstrate a mortality benefit in cardiovascular patients. Trials like ASCEND and STRENGTH, involving
large sample sizes, did not show cardiovascular benefits [23,24]. The STRENGTH trial was terminated early
due to the absence of cardiovascular benefits and common gastrointestinal side effects in the active
treatment group. Unfortunately, the exact mechanism of action for Omega-3 FAs in triglyceride reduction is
not well understood [25].

It's intriguing that despite the association between hypertriglyceridemia and increased ASCVD events,
omega-3 FAs and other triglyceride-lowering agents like fenofibrate have not demonstrated a decrease in
ASCVD morbidity or mortality. As a result, their approval is limited to cases of severe hypertriglyceridemia
(>500-1000) to prevent pancreatitis.

The controversy surrounding this may be attributed to the possibility that omega-3 FAs were used in less
effective doses or the use of different forms, such as eicosapentaenoic acid (EPA) and/or docosahexaenoic
acid. This highlights the importance of understanding the nuances in dosages and specific formulations
when studying the effectiveness of these agents in preventing cardiovascular events [26].

The REDUCE-IT trial focused on studying icosapent ethyl, a form of omega-3 FA, administered at a dosage of
2 g twice daily with meals. This trial spanned five years and included nearly 5000 participants. The findings
revealed that individuals in the active treatment group were 25% less likely than the comparison group to
develop unstable angina, undergo coronary revascularization, experience non-fatal myocardial infarction,
and suffer a stroke [27].

Following the positive outcomes from the REDUCE-IT trial, the FDA granted approval to EPA in December
2019 for use in patients with triglyceride levels ≥150 mg/dL, established cardiovascular disease or diabetes,
and two or more additional risk factors for cardiovascular disease. This underscores the potential of specific
formulations and dosages of omega-3 FAs in reducing cardiovascular events in high-risk individuals [28].

PCSK9 Inhibitors

The development of PCSK9 inhibitors indeed represents a revolutionary advancement in dyslipidemia

treatment. These synthesized antibodies target proprotein convertase subtilisin/kexin type 9 (PCSK9), an
enzyme responsible for breaking down LDL-C receptors in hepatocytes. Typically, PCSK9 works to enhance
the removal of LDL-R from the blood, leading to increased LDL-C levels [29].

Inhibiting this enzyme has been shown to reduce LDL-C levels by 45% to 60%, regardless of whether statin
therapy is also utilized. Notable agents in the PCSK9 inhibitor class include alirocumab and evolocumab.
The FOURIER trial, involving 27,564 participants and assessing the cardiovascular benefits of evolocumab
alongside maximally tolerated statin therapy in patients with ASCVD, concluded that while there was a
reduction in composite cardiovascular outcomes, there was no significant impact on cardiovascular and all-
cause death. This underscores the complexity of evaluating the overall mortality benefits of these innovative
treatments [30].

The ODYSSEY OUTCOME trial, conducted similarly for alirocumab, reached the same conclusion as the
FOURIER trial, demonstrating a decrease in cardiovascular morbidity but not in mortality. Both trials
provided evidence of the positive impact of PCSK9 inhibitors on composite cardiovascular outcomes [31].

As for side effects, injection-site reactions are noted as the primary adverse effect of PCSK9 inhibitors.
Remarkably, these drugs, being fully human monoclonal antibodies, rarely trigger immunologic responses
such as allergies or the formation of antidrug-neutralizing antibodies. This aspect contributes to the safety
profile of PCSK9 inhibitors in their role as innovative lipid-lowering agents [29].

Inclisiran

Inclisiran, a novel agent approved by the FDA in July 2023, is indicated for use in patients with high ASCVD
risk and elevated LDL levels while on statin therapy, as well as for patients with heterozygous FH. It operates
as a small interfering RNA that inhibits the production of the PCSK9 enzyme in hepatocytes. As previously
mentioned, PCSK9 plays a critical role in the destruction of LDL-C receptors in hepatocytes, which are
responsible for the uptake of LDL-C from the blood [32].

Notably, inclisiran was initially available in a less stable form, requiring administration through an

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 intravenous line. However, advancements have led to the development of a more stable form, allowing for
subcutaneous administration every three months, followed by subsequent doses every six months. This
marks a significant improvement in the convenience and accessibility of the treatment [33].

Insights from the ORION-10 and ORION-11 trials revealed an approximately 50% reduction in LDL-C levels
in patients with ASCVD or at high risk of ASCVD while on the maximal statin therapy dose after 90 days
[34,35].

While these results are promising in terms of LDL-C reduction, it is important to note that the studies have
not confirmed any cardiovascular morbidity or mortality benefits yet. Ongoing research and further studies
will likely provide a more comprehensive understanding of Inclisiran's impact on cardiovascular outcomes
[36].

Bempedoic Acid

Bempedoic acid, a recently developed therapeutic agent, has emerged as a promising addition to the
armamentarium for managing hypercholesterolemia. Unlike traditional statin therapy, which targets HMG-
CoA reductase, bempedoic acid acts upstream in the cholesterol biosynthesis pathway by inhibiting ATP
citrate lyase. By disrupting cholesterol production at this early stage, bempedoic acid effectively reduces
circulating levels of LDL-C, thereby mitigating the risk of atherosclerotic cardiovascular disease.

CLEAR wisdom and CLEAR harmony trials, which assessed the efficacy and safety of bempedoic acid, have
demonstrated its efficacy in LDL-C reduction as monotherapy and in combination with other lipid-lowering
agents. It showed reduction in the LDL-C level by 13.9 to 17.4 % when used with a dose of 180 mg alone.
When combined with 10 mg of ezetimibe the result was further dropped to 39%. Furthermore, bempedoic
acid exhibits a favorable safety profile, with adverse effects comparable to placebo, making it a valuable
option for patients intolerant to or inadequately controlled on statins and who cannot afford PCSK9
inhibitors. It was approved by the FDA in 2020 for use in hypercholesterolemia patients. Future research
aims to explore its long-term cardiovascular benefits and its role in combination therapy with existing
treatments, providing clinicians with additional tools for managing dyslipidemia and improving patient
outcomes [37-39].

Conclusions
Dyslipidemia is a very common and underappreciated metabolic abnormality globally, and more specifically,
locally. There have been new and rapid advancements recently with the introduction of novel drugs showing
improvement in patients’ outcomes. There are still some medications under clinical trials that might also
change the practice in dyslipidemia over the next few years.

Additional Information
Author Contributions
All authors have reviewed the final version to be published and agreed to be accountable for all aspects of the
work.

Concept and design: Ziad A. Taher, Abdulrahman A. Taher, Suhaib Radi

Acquisition, analysis, or interpretation of data: Ziad A. Taher, Abdulrahman A. Taher

Drafting of the manuscript: Ziad A. Taher, Abdulrahman A. Taher

Critical review of the manuscript for important intellectual content: Ziad A. Taher, Abdulrahman A.
Taher, Suhaib Radi

Supervision: Suhaib Radi

Disclosures
Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the
following: Payment/services info: All authors have declared that no financial support was received from
any organization for the submitted work. Financial relationships: All authors have declared that they have
no financial relationships at present or within the previous three years with any organizations that might
have an interest in the submitted work. Other relationships: All authors have declared that there are no
other relationships or activities that could appear to have influenced the submitted work.

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