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The primary therapeutic goal for treating dyslipidemia PCSK9 inhibitors should be introduced into the treatment.
is lowering LDL cholesterol. However, there is clear eviden- ESC/EAS guidelines further state that PCSK9 inhibitors may
ce today that lowering lipoprotein(a), as a new therapeutic also be considered for primary cardiovascular prevention in
target, significantly contributes to reducing cardiovascular very high-risk patients who do not achieve target LDL cho-
(CV) risk 8-10 . Despite achieving target LDL cholesterol levels, lesterol levels on the maximum tolerable dose of statin in
there is evidence that CVD still occurs, highlighting the combination with ezetimibe (Table 1, Image 1).
need to focus on residual cardiovascular (CV) risk 11, 12 . In re-
cent years, there has been increasing evidence suggesting The following text provides an overview of existing the-
that the duration of exposure to elevated LDL cholesterol rapeutic options for lowering lipid levels, new agents, as
determines the risk for atherosclerotic CVD and its compli- well as future perspectives in the treatment of dyslipide-
cations, perhaps even more so than the actual level of LDL mias (Table 2, Image 2).
cholesterol. Therefore, greater and earlier reduction of LDL
cholesterol provides better CVD prevention. Such findings
emphasize the urgency of identifying and treating high LDL Statins
cholesterol early. Based on the accumulation of evidence, Statins are medications used for lowering cholesterol in
guidelines, and clinical trial practices have evolved towar- both primary and secondary prevention of cardiovascular
ds achieving stricter LDL cholesterol targets, especially in disease (CVD) over the past four decades. The benefit of
patients at high risk . Recent studies on the use of combi- statin use in lowering LDL cholesterol and preventing CVD
9
nation therapy, with significant lowering of LDL cholesterol, has been demonstrated in a large number of randomized
have not shown a threshold for clinical benefit and have al- clinical trials, and a meta-analysis involving 170,000 patients
leviated many safety concerns, thus reinforcing the concept indicated that reducing LDL cholesterol by just 1 mmol/L re-
of “lower is better“ 13, 14 . duces the risk of major adverse cardiovascular events by as

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Recent successes in trials with non-statin lipid-lowering much as 22% .
agents in reducing cardiovascular events have shown that Statins are competitive inhibitors of 3-hydroxy-3-methyl-
lowering LDL cholesterol through different mechanisms, glutaryl coenzyme A (HMG-CoA) reductase. By inhibiting the
including increased expression of LDL receptors or decre- enzyme that regulates the synthesis of cholesterol, statins
ased cholesterol absorption, significantly reduces cardio- reduce intracellular cholesterol synthesis, leading to increa-
vascular events . Therefore, the focus has expanded from sed expression of low-density lipoprotein receptors (LDL-R).
15
“high-intensity statin therapy“ to “high-intensity therapy“ for There are several types of statins available on the market,
lowering LDL cholesterol. This understanding, along with including atorvastatin, simvastatin, rosuvastatin, fluvasta-
the often observed significant residual risk for CVD, even in tin, pitavastatin, lovastatin, and pravastatin.
individuals treated with statins, has accelerated the search
for therapies that reduce highly atherogenic lipoproteins The efficacy of statins depends on the dosage used in
containing Apo B (primarily LDL). everyday clinical practice. Low or moderate-intensity statins
reduce LDL cholesterol by 30% and triglycerides by 20%,
Exactly, this review article aimes to highlight contem- while high-intensity statins reduce LDL cholesterol levels by
porary therapeutic approaches in the treatment of dyslipi- more than 50% and triglyceride levels by up to 40%. Statins
demias, with a focus on new agents and the perspective of can raise HDL cholesterol levels by up to 10%, depending
future treatment of these disorders. on the dosage . Studies show that statins do not affect on
13
Lp(a) levels 9, 16, 17 . In vitro and in vivo studies have shown that
besides modifying lipid levels in the blood, statins have ple-
Therapeutic approaches to the iotropic effects such as improving endothelial dysfunction,
treatment of dyslipidemia antioxidant properties, inhibition of inflammatory respon-
se, and stabilization of atherosclerotic plaque . However,
16
The latest joint recommendations from the European
Society of Cardiology (ESC) and the European Atherosclero- in a certain number of patients, despite statin therapy, lipid
9, 17
sis Society (EAS) for the treatment of dyslipidemias recom- parameter levels remain above target values .
mend firstly stratifying cardiovascular risk and then, based A major problem in clinical practice is the potential “in-
on the level of risk, further treatment with statins, ezeti- tolerance“ to statins, predominantly characterized by the
mibe, and proprotein convertase subtilisin/kexin type-9 presence of muscle pain, leading to inadequate dosing of
(PCSK9) inhibitors . In the guidelines, high-intensity statins statins or discontinuation of this type of therapy. However,
9
are recommended as the first-line therapy in the primary a meta-analysis covering 176 studies and a total of 4.1 mi-
and secondary prevention of patients with hypercholeste- llion patients showed that about 9% of patients do not to-
rolemia. If target LDL cholesterol levels are not achieved lerate statins. The most significant adverse effects of statin
based on the level of cardiovascular risk, adding ezetimibe therapy are myopathy (11 per 100,000 patients/year), rhab-
is recommended. For patients who do not achieve the the- domyolysis (3 per 100,000 patients/year), elevation of liver
rapeutic goal of this combined therapy (statin + ezetimibe), enzymes, and hyperglycemia .
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REVIEW PAPER Galenika Medical Journal, 2024; 3(9):26-34. 27