Atherosclerotic cardiovascular diseases (ASCVD) present a serious global public health challenge with potentially fatal consequences. However, many of these diseases can be effectively prevented by controlling and reducing the risk factors, and one of the key risk factors is LDL cholesterol (LDL-C). LDL-C value plays a central role in the development of ASCVD, which is a fact that has been confirmed in numerous scientific studies.

Rosuvastatin is one of the most potent HMG-CoA reductase inhibitors available and can reduce LDL-C levels by up to 55%. Additional beneficial effects on the cholesterol profile include an increase in HDL cholesterol (HDL-C) by around 6% and a decrease in triglyceride (TG) levels by 15% or more, as well as a reduction of cholesterol in atherosclerotic plaques (1). Rosuvastatin also has pleiotropic effects, including anti-inflammatory effects, protective effects on the endothelium, and anti-oxidant effects. Advantages of rosuvastatin in comparison with other statins include its hydrophilic nature that is connected with very low rates of myopathy and rhabdomyolysis, as well as its long-term effect that enables it to be taken at any point during the day (1, 2). In addition, only about 10% of the drug is transformed by cytochrome P450, while the remaining 90% undergoes biliary excretion, leading to very few drug interactions (2, 3).

Ezetimibe is the only drug in its class and acts by inhibiting NPC1L1, leading to a reduction in cholesterol absorption by up to 67%, resulting in a reduction of LDL-C by approximately 15-20%. Consequently, HDL-C increases by approximately 3%, without impacting TG. In addition to its anti-inflammatory effects, the combination of ezetimibe with a statin reduces high-sensitivity CRP by approximately 10% more than statin monotherapy. Ezetimibe is metabolized by glucuronidation and therefore has minimal drug interactions, just like rosuvastatin (3).

The rosuvastatin/ezetimibe combination is available in dosages of 10/10 mg, 20/10 mg, and 40/10 mg. Their complementary mechanisms of action enable the use of lower doses of individual agents for achieving the same changes in the lipid profile. When statins exhibit their lipid-lowering effects by reducing the endogenous synthesis of cholesterol in the liver, the body responds by increasing cholesterol absorption, which may reduce the effect of statins. Therefore, the addition of ezetimibe can provide an additional benefit by blocking cholesterol absorption, thereby improving the LDL-C-lowering capacity of statins (3, 4).

Statins, a class of drugs that act by inhibiting the production of cholesterol in the liver, have long been and still remain the cornerstone therapy for LDL cholesterol reduction (5, 6). Their efficacy and safety have been demonstrated in numerous studies, and each absolute reduction in LDL-C by 1 mmol/L through statin therapy reduces the risk of major cardiovascular (CV) events by an impressive 22%. Statins are the first line of defense and are often combined with dietary changes in order to achieve the recommended target values of LDL-C.

The 2019 Guidelines of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) clearly indicate the key role that LDL-C lowering plays in the prevention of cardiovascular diseases. According to the Guidelines, the LDL-C target level should be <1.8 mmol/L for high-risk patients, and <1.4 mmol/L with ≥50% reduction from baseline for very high-risk patients. A reduction in ASCVD risk is reflected in a proportional reduction of LDL-C levels (5, 6).

It should be noted that achieving target LDL-C levels is not always as simple as it might seem. Patients with acute coronary syndrome (ACS), familiar hypercholesterolemia, and other high CV risks may not necessarily reach their target values with statin therapy alone (4). This is where the importance of combining statin therapy with other cholesterol-lowering drugs, such as ezetimibe, becomes evident.

Observational studies, such as DA VINCI, demonstrate that only a minor proportion of high-risk and very high-risk patients achieve their target levels according to the 2019 Guidelines. Use of high-intensity statins and ezetimibe also remains below the desired standards, suggesting the need to reduce the gap between the recommended target LDL-C and the actual achieved values (5, 7).

Ezetimibe, an inhibitor of intestinal absorption of cholesterol, has proven to be a valuable addition to statin therapy. In a study on post-ACS patients, addition of ezetimibe to statin therapy resulted in significant reduction of LDL-C levels and a lower risk of new CV events (8). This study highlights the importance of lowering LDL-C levels using combination therapy, not only the method of reaching the values.

Despite the clear guidelines and evidence of efficacy, achieving recommended target LDL-C levels is often quite challenging in clinical practice. In this context, it is crucial to recognize that the combination of statin therapy with ezetimibe may be of vital importance, especially in patients who are most at risk (8). Research shows that the frequency of using these drugs is still inadequate and that there is a clear need to reduce the risk levels.

In a 2015 study, Cannon et al. examined the effect of adding ezetimibe to statin therapy for ACS. The study involved patients with ACS who were already on statin therapy. Ezetimibe added to statin therapy reduced LDL-C levels by an additional 21-27% vs. placebo in patients with hypercholesterolemia with or without confirmed coronary heart disease. In statin-naïve patients, the combination of ezetimibe with statins resulted in approximately 15% higher reduction in LDL-C values vs. the same statins and doses in monotherapy (8).

In other studies, this combination also significantly enhanced the reduction of LDL-C levels vs. doubling statin dosage (13-20%) and after switching from statin monotherapy to combination therapy with ezetimibe and statins (11-15%) (6). The addition of ezetimibe to statin therapy in the IMPROVE-IT study resulted in a greatly reduced risk of CV events. The results of the study demonstrated that ezetimibe added to statin therapy significantly lowered LDL-C levels, leading to lower risks of recurrent CV events. This study also confirmed the importance of controlling LDL-C levels in post-ACS patients and indicated the beneficial effects of adding ezetimibe to statin therapy (9).

A study published in 2022 provided new insights in the approach to treatment of elevated LDL-C levels. The study results suggested that the combination of ezetimibe and rosuvastatin may be more effective in reaching target LDL-C levels than using the drugs individually. This approach opens up new possibilities for the treatment of patients with dyslipidemia and indicates a need for further studies of this combination therapy (10).

Ray et al. examined combination lipid-lowering therapy as first-line strategy in high-risk patients. Published in 2022, this study examined an alternative approach to treating patients with high risk of CV disease. The results showed that a combination of lipid-lowering drugs as first-line therapy may be useful for achieving target LDL-C levels and reducing the risk of serious CV events (11).

Katzmann et al. investigated the use of fixed-dose statin/ezetimibe compared with separate pills of the drugs in very high-risk patients. This study, published in 2022, provided new insights into the practicality and effectiveness of different therapeutic approaches. The results showed that a fixed-dose combination of statin and ezetimibe may be a simpler and equally effective option in high-risk patients (12).

A prospective study evaluating malignancy in a large number of patients, randomized to either ezetimibe or placebo, was published in 2020 and examined a possible connection between the use of ezetimibe and the risk of malignancy. The results did not identify increased risk of malignant diseases connected with ezetimibe therapy, thus providing additional information on the safety of this drug in the context of lipid-lowering therapy (13).

Control of LDL-C levels plays a key role in the prevention of ASCVD, which reduces the risk of serious CV events and improves the quality of life in patients. ESC/EAS Guidelines clearly recommend target LDL-C values as the key therapeutic goal. Statins remain the cornerstone therapy, but adding ezetimibe, an inhibitor of intestinal absorption of cholesterol, can significantly improve the control of LDL-C levels, especially in high-risk patients. Despite the proven efficacy of this treatment, there are challenges in achieving the recommended target LDL-C levels in clinical practice. Observational studies indicate low rates of reaching target values, highlighting the need for better implementation of the guidelines and a better treatment approach with statins and ezetimibe. It is important to continually work on raising awareness of the importance of controlling LDL-C levels, both among patients and medical professionals, and on developing strategies for improving adherence. The statin/ezetimibe combination may be key for achieving target LDL-C levels, especially in patients with high risk of ASCVD. This will positively impact cardiac health and quality of life and will reduce the risk of mortality connected with these diseases. Ultimately, all efforts should be directed towards an integrated approach to ASCVD prevention that will combine healthy diet, exercise, and pharmacotherapy in order to achieve the goals of LDL-C control and to lessen the burden of this serious threat to public health.