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Over the last decade, several innovative therapeutic options have been developed and marketed for the management of hypercholesterolemia. However, the impossibility of a contextual update of international guidelines and the limits imposed by national regulatory authorities do not allow the use of these treatments in many patients, in particular in those at higher cardiovascular risk. Real-world studies show that the use of lipid-lowering therapies is inadequate even among patients at higher cardiovascular risk, with only 20% achieving recommended low-density lipoprotein cholesterol (LDL-C) levels and the use of combination therapies implemented in only 24% of patients. This review aims to highlight the benefits of an approach based on combination therapy and to propose a therapeutic algorithm that includes oral combination therapy, where necessary also in triple association (statin, ezetimibe and bempedoic acid), as an initial approach based on the most favorable cost-effectiveness ratio for patients at higher cardiovascular risk and the use of injectable anti-proprotein convertase subtilisin/kexin 9 therapies if the recommended LDL-C goal is not achieved.

Background: The gap between the targets recommended by current guidelines and the lipid values observed in the real world among patients at very high or extreme cardiovascular risk has called into question the effectiveness of the stepwise lipid-lowering strategy. The BEST (Best Evidence with Ezetimibe/statin Treatment) project supported an expert panel of Italian cardiologists to investigate the different clinical-therapeutic pathways in the management of the residual lipid risk of post-acute coronary syndrome (ACS) patients at discharge and to analyze potential critical issues., Methods: Among the members of the panel, 37 cardiologists were selected to participate in a consensus process using the mini-Delphi technique. A 9-statement questionnaire, focusing on the early use of combination lipid-lowering therapies in post-ACS patients, was built up based on a previous survey that involved all members of the BEST project. For each proposed statement, participants anonymously expressed their personal level of disagreement/agreement, according to a 7-point Likert scale. The relative degree of agreement and consensus was calculated based on the median and the 25th percentile values and the interquartile range (IQR). The administration of the questionnaire was repeated twice: the second one after general discussion and analysis of the answers given in the first round in order to obtain as much consensus as possible., Results: With the exception of a single item, the responses of the participants were in agreement with a broad consensus already at the first round with a median value of 6, a 25th percentile of 5 and an IQR of 2. This trend resulted more evident at the second round (median 7, 25th percentile 6, IQR 1). In particular, there was unanimous agreement (median 7, IQR 0-1) on the statements in favor of a lipid-lowering therapy that guarantees the achievement of the targets as much and as soon as possible by the systematic early utilization of the high-dose/intensity statin + ezetimibe combination and, when needed, PCSK9 inhibitors. The percentage of the experts who changed their responses between the first and second round was 39% overall, ranging from 16% to 69%., Conclusions: According to the mini-Delphi results, there is a broad agreement and consensus to manage the lipid risk in post-ACS patients by lipid-lowering treatments that guarantee an early and "robust" lipid reduction which can be achieved only by the systematic use of combination therapies.

The last 50 years have experienced a rapid evolution in the development of lipid-lowering agents to reduce low-density lipoprotein cholesterol levels. This significant advance in medicine has not occurred without debate. Whether lowering blood cholesterol levels was beneficial has remained one of the most controversial issues during the past 50 years. The discovery of statins was the revolution that made it possible to delay and stop the progression of the atherosclerotic process resulting in improved health and longevity for millions of people. To date, statins remain the drugs of choice for the treatment of hypercholesterolemia. Despite their use, the risk of cardiovascular events persists. Therefore, the use of non-statin drugs, such as ezetimibe or PCSK9 inhibitors, in combination with statins has been shown to further reduce the risk of cardiovascular events. This review aims to summarize the advances in the field of lipid-lowering therapies over the past 50 years, focusing on advances in the development of drug therapies up to and including gene silencing or gene editing treatments that are expected in the near future.

Background: Despite the availability of effective lipid-lowering drugs, only few high-risk patients attain their LDL cholesterol (LDL-C) guideline-recommended risk-based goal because of underprescription of combination therapy. We present an 18-month experience with variation of prescription protocols after publication of the 2019 ESC/EAS guidelines for the management of dyslipidemias., Methods: Overall, 621 consecutive patients hospitalized for acute coronary syndrome at Mauriziano Hospital in Turin, Italy, between January 2020 and June 2021 were enrolled. Lipid-lowering therapy recommended at discharge was registered to evaluate how many patients received statin monotherapy, statin plus ezetimibe combination or triple therapy with high-intensity statin plus ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i). At 6-month follow-up, the reduction in LDL-C, adverse events, compliance and cardiovascular recurrences was analyzed., Results: Of 621 patients enrolled, 7 died during hospitalization. During the entire study period, 33% of patients received statin monotherapy, 50% were discharged on statin-ezetimibe combination, and PCSK9i (evolocumab) was prescribed to 17% of patients. Between April 2020 and June 2021, when new recommendations were introduced into clinical practice, 20% of patients received evolocumab, 56% combination therapy and only 24% were discharged on statin monotherapy. At the beginning of observation, evolocumab was prescribed to 3% of patients hospitalized for acute coronary syndrome, while at the end of the study period 27% of patients were discharged on PCSK9i, with an increase of the prescription rate by 759%; in the same period, prescription of statin monotherapy decreased by 75%. At 6-month follow-up, LDL-C reduction was 77% in patients treated with PCSK9i vs 48% in patients taking statin-ezetimibe combination therapy (p<0.001). All patients on evolocumab reached the guideline-directed goals and a low rate of adverse events was reported, mainly represented by local injection site reactions. Six patients experienced acute coronary syndrome recurrence; only one of them was treated with evolocumab., Conclusion: Prescription of intensive lipid-lowering therapy after acute coronary syndrome, eventually with introduction of PCSK9i during hospitalization or at discharge, leads to attainment of guideline-recommended goals for all patients, with a low incidence of adverse events and optimal compliance.

LDL-cholesterol (LDL-C) reduction after acute coronary syndromes (ACS) is associated with a significant reduction in ischemic recurrences. Accordingly, international guidelines recommend a reduction of LDL-C below 70 mg/dl in ACS patients. Such a result can be accomplished by using high intensity statins, possibly associated with ezetimibe in selected cases. This document outlines the management strategies that can be consistently implemented in clinical practice in order to achieve and maintain guideline-recommended therapeutic goals.