Individuals with elevated levels of low-density lipoprotein cholesterol (LDL-C) have an increased risk for atherosclerotic cardiovascular disease (ASCVD) [1]. For individuals with elevated LDL-C, lipid-lowering therapies (LLTs) are effective in reducing overall cardiovascular risk [2]. However, even if LDL-C treatment thresholds are achieved, a residual risk of ASCVD remains [3]. Triglyceride (TG)-rich lipoproteins (TRLs) are a heterogeneous class of lipoprotein particles that originate from the liver as very-low-density lipoproteins (VLDL) or from the intestine as chylomicrons [4]. Multiple sources of evidence, including Mendelian randomization studies, support a causal relationship between elevated TRL levels and ASCVD, independent of LDL-C levels [4,5,6,7,8].

Angiopoietin-like 3 (ANGPTL3) is an important regulator of lipoprotein metabolism, controlling plasma lipoprotein levels by inhibiting lipoprotein lipase- and endothelial lipase-mediated hydrolysis of TGs and other lipids [9]. ANGPTL3 is an attractive therapeutic target, as ANGPTL3 deficiency increases lipase activity, accelerating the turnover of TRLs [9]. The mechanism for LDL-C lowering through inhibition of ANGPTL3 appears to be independent of the low-density lipoprotein receptor (LDLR) [10]. In the absence of LDLR, endothelial lipase de-repression by ANGTPL3 inhibition leads to extensive remodeling of VLDL and the preferential removal of VLDL remnants from circulation via hepatic remnant receptors [10]. This depletes the LDL precursor pool, limits production of LDL particles, and reduces plasma LDL-C levels [10].

The ANGTPL3 monoclonal antibody inhibitor evinacumab has been shown to reduce levels of LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and apolipoprotein CIII (ApoCIII), all known contributors of risk for ASCVD [11, 12]. Previously, a phase III trial (R1500-CL-1629; NCT03399786) in patients with homozygous familial hypercholesterolemia (HoFH) [11] and a phase II trial (R1500-CL-1643; NCT03175367) in patients with refractory hypercholesterolemia [13] reported significantly reduced LDL-C levels with evinacumab. In addition, a phase II trial (R1500-HTG-1522; NCT03452228) in patients with severe hypertriglyceridemia (sHTG) showed TG reductions in the evinacumab-treated groups vs. placebo [14]. Moreover, in a mechanistic study using ApoB kinetic analysis, evinacumab was associated with an increase in the fractional catabolic rate of intermediate-density lipoprotein ApoB and LDL ApoB, indicating that evinacumab may improve hepatic clearance of TRL remnants from the circulation [15].

Therapies other than evinacumab have also been shown to reduce TRL levels. In a meta-analysis of 15,800 patients with mean baseline TG levels ≥ 177 mg/dL who were treated with statins (rosuvastatin 5 − 40 mg, atorvastatin 10 − 80 mg, and simvastatin 10 − 80 mg), mean percent reductions in TGs across all statins and doses ranged from 15.1% to 31.3% [16]. Moreover, in patients with TG levels as high as 800 mg/dL to 850 mg/dL, statins have been shown to reduce TGs by 40% to 44% in a dose-dependent manner [17]. In the PROMINENT trial comprising patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL-C levels, pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, reduced median fasting TG levels by 31.1%, VLDL cholesterol by 35.0%, remnant cholesterol by 43.6%, and ApoCIII by 27.8% from baseline to 4 months [18]. Omega-3 fatty acids such as eicosapentaenoic acid, docosahexaenoic acid, and icosapent ethyl (ethyl ester of long chain omega-3 fatty acid) can also lower TGs [19, 20]. Among statin-treated patients with hypertriglyceridemia and established cardiovascular disease (or diabetes mellitus and at least one additional risk factor) in the REDUCE-IT trial, a median reduction in TG levels of 18.3% was observed from baseline to 1-year with icosapent ethyl [19]. In the STRENGTH trial comprising statin-treated patients with high cardiovascular risk, hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels, an omega-3 carboxylic acid formulation (containing both eicosapentaenoic acid and docosahexaenoic acid) reduced TG levels by 19.0% from baseline to 1-year [20].

Although conventional therapies such as statins and omega-3 fatty acids have been shown to reduce TRLs in patients with dyslipidemia, there is still considerable risk of ASCVD events. Novel therapeutics such as ANGPTL3 inhibitors may offer additional TRL lowering and the potential to provide further cardiovascular benefit.

In this post-hoc analysis, we assessed the efficacy of evinacumab in reducing TRLs in patient cohorts from these three separate clinical trials [11, 13, 14].