Novel LDL-cholesterol lowering therapies: A step forward a personalized medicine

The Low-density lipoproteins (LDL) as well as all the ApoB-containing lipoproteins (VLDL remnants and Lp(a)) are etiological factors of atherosclerotic cardiovascular diseases (ASCVD). Several published consensuses [1], [2], [3] have reached this conclusion based on the evidence of experimental, observational, and randomized controlled interventional studies. Overall randomized controlled trials (RCTs) and Mendelian randomization studies have determined that a reduction of 1 mmol/L of LDL-C results in a short term (5 years) 22% reduction and in a lifetime reduction of 50% of the relative risk of ASCVD. The success of a pharmacological treatment in reducing ASCVD events and cardiovascular mortality in high and very high-risk patients in a setting of secondary cardiovascular prevention depends on the absolute reduction of LDL-cholesterol and more in general of ApoB plasma levels. The 2019 EAS/ESC Guidelines [4] have recommended new therapeutic goals for the target LDL-C: <70 mg/dL for the high-risk patient category, <55 mg/dL for the very high-risk category and <40 mg/dl for patients who have experienced recurrent vascular events in a recent short period of time despite the LDL-C lowering treatment. Moreover, a reduction of 50% of LDL-C is always mandatory. Since the 4S, the first pivotal trial with simvastatin, the RCTs have shown that a more intensive reduction of LDL-C - high intensity vs low intensity statins, statins vs combination therapy with ezetimibe and PCSK9 inhibitors vs combination therapy- have always added a clinical benefit without no evidence of a low threshold for LDL-C [5]. The RCTs results support the concept the lower is better and the Mendelian randomization studies that earlier is better. According to the available evidence we can safely reach levels of LDL-C between 25 and 50 mg/dL, although a single trial [6] has shown a further clinical benefit and no harms for achieved LDL-C levels of <10 mg/dl. The EAS/ESC 2019 and the ESC 2021 guidelines recommend a stepwise approach to intensify preventive treatments and achieve the LDL-C goals, but this approach has been criticized because it can favor the medical inertia and the loss of patients' compliance. Moreover, with the new LDL-C goals the use of a single drug strategy will fail to achieve the objective while a combined lipid-lowering therapy with two drugs - high intensity statin and ezetimibe- and in a near future possibly with three drugs, is an effective way to reduce LDL-C. In Europe several position papers [7], [8], [9] have in some extent corrected the guidelines stepwise approach suggesting that starting with a combination therapy is more effective in high and very high risk and in Familial Hypercholesterolemia patients. In addition, real word surveys and registries data [[10], [11]] have documented that most patients in secondary prevention are not at the LDL-C goals recommended by the recent guidelines and that the cardiovascular benefits are greater when the goals are achieved as quick as possible. A further benefit of the earlier intensive approach is represented by the effects on the atherosclerotic anatomical lesions. Recent imaging studies have shown that a rapid and aggressive reduction of LDL-C in acute coronary syndrome-ACS- patients stabilizes the atherosclerotic coronary plaques by reducing the atheroma volume, the core lipid content and by increasing the atheroma fibrous cap [[12], [13]]. In such a complex scenario characterized by a persistent gap between the guidelines and the clinical reality due to the medical inertia or the presence of true obstacles to achieve the goals such as the case of FH patients or of the statin-intolerant patients, it is necessary to build a precision-medicine based approach. In this perspective novel and innov