Vol 1, No 1 (2022)

The causal role of low-density lipoprotein cholesterol LDL-C in atherosclerotic-related cardiovascular disease (ASCVD) has been undoubtedly established over the last decades, and lowering plasma LDL-C levels represents the main approach to reduce the risk of cardiovascular (CV) events. A large number of observations has definitely proven that the protective effect is independent of the drug used to lower LDL-C, with a continuous linear reduction of CV risk with further LDL-C reductions. Although high-intensity statin therapy may significantly reduce CV event incidence, frequently statins are insufficient to achieve the large reductions recommended by current guidelines for high and very high risk patients.
Several non-statin drugs, having mechanisms of action complementary to that of statins, are now available, and include ezetimibe, monoclonal antibodies targeting PCSK9, and, more recently, inclisiran, bempedoic acid, and evinacumab. Combining these drugs based on the recommendations by current and future guidelines should be considered for optimal risk reduction, although several gaps in clinical practice remain to be filled.

Ezetimibe is an intestinal cholesterol/sterol inhibitor. It is generally well-tolerated, and except for coadministration with cyclosporin (which increases concentration of both ezetimibe and cyclosporin), has limited drug interactions. Clinical trial data suggests that ezetimibe 10 mg orally once a day reduces low density lipoprotein cholesterol (LDL-C) levels about 15-25% as monotherapy or when added to statins, depending on the patient and individual clinical trial. Ezetimibe also reduces lipoprotein remnants. Due to its additive effects to statins, international lipid guidelines recommend ezetimibe as an option for patients who do not achieve LDL-C treatment goals with statins alone. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial demonstrated that when added to statin therapy, ezetimibe incrementally lowered LDL-C levels and modestly improved cardiovascular outcomes. Ezetimibe is formulated as monotherapy, or as a fixed-dose combination with statins or bempedoic acid. Finally, ezetimibe is the only pharmacotherapy approved for treatment of beta-sitosterolemia, which is a rare autsomal recessive disorder resulting in enhanced intestinal cholesterol absorption, increased circulating sterols, and tendinous and cutaneous xanthomas, arthritis or arthralgia, and premature cardiovascular disease.

The causal role of cholesterol in atherosclerosis was established more than 100 years ago. Along with the fact that the higher the cholesterol, the greater the risk of atherosclerotic cardiovascular diseases (ASCVD), many randomized controlled trials (RCT) have shown that lowering LDL cholesterol (LDL-C) is associated with a lower incidence of ASCVD. This impact of lipid-lowering therapies on cardiovascular risk is independent of the drug used, as shown by several meta-analyses and Mendelian randomization studies. Therefore, the concept of using “high-intensity statins” should be changed to “high-intensity lipid-lowering therapies” that go beyond the use of statins.
Recent RCTs using non-statin lipid-lowering therapies has provided scientific evidence that the lower the LDL-C, the better in terms of cardiovascular events. Based on these observations, current guidelines recommend achieving very low LDL-C levels in patients with high and very-high cardiovascular risk.
To achieve these demanding goals, the physician must use the full spectrum of lipid-lowering therapies, beyond high-intensity, high-dose statins. Oral combination therapies and, when necessary, subcutaneous treatments become the new standard of care for hypercholesterolemia.
However, the number of patients achieving LDL-C goals is unacceptably low. This is due in part to insufficient prescription and insufficient treatment. To improve the efficacy of therapy, several strategies have been proposed, step by step, planning therapy and maximizing treatment, based on the needs of the patient.
A wider use of lipid-lowering

Low density lipoprotein-cholesterol (LDL-C) is the main etiologic factor for the development and progression of atherosclerotic cardiovascular disease (ASCVD) and LDL-C reduction is a central tenet of ASCVD treatment and prevention. Moreover, ASCVD risk reduction is proportional to the magnitude of LDL-C lowering. Recent European guidelines have recommended a goal of <55 mg/dL (<1.4 mmol/L) for patients at very-high cardiovascular risk, while the U.S. guideline considers an LDL-C ≥70 mg/dL (≤1.8 mmol/L) as a threshold to intensify therapy with the addition of a non-statin therapy to statins. To reach these lower LDL-C goals of <55 mg/dL or <70 mg/dL, combination therapy is necessary in the majority of these patients. Drug combinations, and in particular single-pill combinations, may substantially increase adherence to therapy. Adherence is essential for achieving a clinical benefit and, as many patients discontinue medications, the long-term adherence to lipid-lowering therapy represents a major issue in ASCVD prevention. Secondary prevention or high-risk primary prevention patients, such as those with familial hypercholesterolemia in whom maximally-tolerated statin doses alone would not be anticipated to sufficiently lower LDL-C, would benefit from combination therapy. In current clinical practice, statins with ezetimibe, statins plus PCSK9 inhibitors (with or without ezetimibe), and, most recently statins or ezetimibe with bempedoic acid are the most commonly used combination therapies for LDL-C-lowering. This review outlines the importance of using combination therapy for the achievement of LDL-C treatment