Non-HDL cholesterol series: PCSK9 inhibitor new season!

After a long and restless fight with “the evil” low-density lipoprotein (LDL) cholesterol, cardiologists discovered that the residual cardiovascular risk is still high, despite the achievement of dramatically decreased target levels of the LDL fraction of cholesterol with the statin, the beloved and multipotent drug. That is why the most recent European cardiovascular guidelines recommend targeting non-high-density lipoprotein (HDL) cholesterol levels, especially in patients with diabetes mellitus (DM) or high triglyceride (TG) levels for evaluation and reduction in cardiovascular risk. Since the non-LDL part of non-HDL cholesterol consists of TG-rich lipoproteins that correlate with TG levels and contribute to the atherogenic risk, it seems intuitive that lowering TG levels will decrease the non-HDL cholesterol in patients with on-target LDL levels, thus decreasing the cardiovascular risk. Even genetic testing concluded that low TG and LDL levels lead to a lower risk of cardiovascular outcomes. Furthermore, individuals with elevated plasma TG levels overproduce very LDL 1 (VLDL1) and have reduced lipolysis rates. The VLDL1 remodeling gives rise to remnants within the VLDL size range that are enriched in apolipoprotein E and such circulating remnants can be removed from the bloodstream by several mechanisms, primarily based in the liver. VLDL1 and VLDL2 are targeted by cholesteryl ester transfer protein, which exchanges core cholesteryl ester for TG in both VLDL1 and VLDL2. The following hydrolysis of TG by the hepatic lipase then shrinks the LDL particles to preferentially form small, dense LDL-III in moderate hypertriglyceridemia, or even smaller LDL-IV in severe hypertriglyceridemia. Such small dense LDL exhibit an attenuated binding affinity for the LDL receptor, resulting in prolonged plasma residence. The complexity of this interactive process is best translated in terms of high-risk by the atherogenic dyslipidemia, a key feature of metabolic syndrome and type 2 DM, a lipid phenotype originating in increased levels of large VLDL1 and small dense LDL, keeping in mind that when small dense LDL is abundant, apolipoprotein B (ApoB) is elevated more than LDL. So far, the medication that proved efficacy in lowering TG levels were the statins (by 10–20% from baseline values), ezetimibe (by 8% compared to placebo) and fibrates (up to a 50% reduction, depending on the baseline TG level) . Recently, the REDUCE-IT trial brought back into the spotlight fish oil, by proving that icosapent ethyl, a highly purified form of the omega-3 fatty acid eicosapentaenoic acid (EPA), in a higher than previously used dose (4 g/d), significantly reduces TG levels and cardiovascular risk when used in patients already on statin therapy. In this issue, Vallejo-Vaz et al. publish pooled data from 10 Phase 3 ODYSSEY clinical trials, assessing the impact of baseline TG on the non-HDL-cholesterol (HDL-C) goal attainment with alirocumab (a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor) versus control (placebo or ezetimibe). A total of 4983 patients from 10 trials were grouped into four pools according to their alirocumab dose, and on the control and statin therapy. The goals of LDL cholesterol (LDL-C) and non-HDL-C by which the patients were chosen in this analysis were less tight than the 2019 European Society of Cardiology lipidlowering guidelines recommend – in patients with moderate or high cardiovascular risk, a non-HDL-C <3.36 mmol/L (130 mg/dL) in the study versus non-HDL-C <2.6 mmol/L (100 mg/dL) in the guidelines, with a LDL-C <2.59 mmol/L (100 mg/dL) in the study versus LDL-C <1.8 mmol/L (<70 mg/dL) in the guidelines, while, in patients with a very high cardiovascular risk, a non-HDL-C <2.59 mmol/L (100 mg/dL) in the