Addressing dyslipidemic risk beyond LDL-cholesterol.

Despite the success of LDL-lowering drugs in reducing cardiovascular disease (CVD), there remains a large burden of residual disease due in part to persistent dyslipidemia characterized by elevated levels of triglyceride-rich lipoproteins (TRLs) and reduced levels of HDL. This form of dyslipidemia is increasing globally as a result of the rising prevalence of obesity and metabolic syndrome. Accumulating evidence suggests that impaired hepatic clearance of cholesterol-rich TRL remnants leads to their accumulation in arteries, promoting foam cell formation and inflammation. Low levels of HDL may associate with reduced cholesterol efflux from foam cells, aggravating atherosclerosis. While fibrates and fish oils reduce TRL, they have not been uniformly successful in reducing CVD, and there is a large unmet need for new approaches to reduce remnants and CVD. Rare genetic variants that lower triglyceride levels via activation of lipolysis and associate with reduced CVD suggest new approaches to treating dyslipidemia. Apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) have emerged as targets for inhibition by antibody, antisense, or RNAi approaches. Inhibition of either molecule lowers TRL but respectively raises or lowers HDL levels. Large clinical trials of such agents in patients with high CVD risk and elevated levels of TRL will be required to demonstrate efficacy of these approaches.

Human Angiopoietin-like Protein 3/ANGPTL3 Antibodies: Adding to the Armamentarium in the Management of Dyslipidemia.

ABSTRACT: Cardiovascular (CV) disease remains the leading cause of death in the United States. In addition to lifestyle modifications, current guidelines primarily focus on lowering low-density lipoprotein cholesterol (LDL-C) to reduce atherosclerotic CV disease risk. However, despite aggressive management, a degree of residual risk remains, suggesting that focusing on lowering LDL-C alone may be inadequate and that other lipid parameters may need to be targeted. In patients who remain at high risk despite current pharmacologic options either because of inadequate response, elevated levels of other lipoproteins, or those who have genetic variants predisposing them to atherosclerotic CV disease, additional treatment strategies continue to be sought. One such group is the homozygous familial hypercholesterolemia population, especially those patients carrying the null low-density lipoprotein receptor mutation as they often fail to derive the same benefit from traditional LDL-C lower strategies such as statins and proprotein convertase subtilisin/kexin type 9 inhibitors that work by upregulating the LDL receptor. Emerging data also suggest that patients with increased levels of triglyceride-rich lipoproteins are also at increased risk as elevated levels are proposed to have a role in various pathways promoting atherogenesis. Angiopoietin-life protein 3 (ANGLTPL3) has recently become a target of interest because of the discovery that inhibiting its action leads to reductions in lipid parameters. Although the mechanism of action of ANGLTPL3 inhibitors is independent of the LDL receptor, their ability to significantly lower triglycerides and LDL-C make them an attractive option particularly in patients with homozygous familial hypercholesterolemia and hypertriglyceridemia. The efficacy and safety of 2 ANGLTPL3 inhibitor agents have been evaluated in clinical trials. In this review, the lipid lowering, metabolic effects, and safety are reported. Ongoing trials assessing CV outcomes as well as long-term safety data are still needed to provide a more definitive role for these agents in the overall management in these populations.

Antisense oligonucleotide-mediated inhibition of angiopoietin-like protein 3 increases reverse cholesterol transport in mice.

Supported by an abundance of experimental and genetic evidence, angiopoietin-like protein 3 (ANGPTL3) has emerged as a promising therapeutic target for cardiovascular disease. ANGPTL3 is primarily produced by the liver and is a potent modulator of plasma lipids and lipoproteins. Experimental models and subjects with loss-of-function Angptl3 mutations typically present with lower levels of HDL-C than noncarriers. The effect of ANGPTL3 on HDL-C is typically attributed to its function as an inhibitor of the enzyme endothelial lipase. The ability to facilitate reverse cholesterol transport (RCT), the transport of cholesterol from peripheral tissues back to the liver, is a proposed antiatherogenic property of HDL. However, the effect of ANGPTL3 inhibition on RCT remains unclear. Here, we performed a series of dose-response and RCT studies using an Angptl3 antisense oligonucleotide (ASO) in mouse models with varying plasma lipid profiles ranging from moderately to severely hyperlipidemic. Angptl3 ASO-mediated reduction in HDL-C was limited to the model with moderate lipidemia, where the majority of plasma cholesterol was associated with HDL. Surprisingly, regardless of the effect on HDL-C, treatment with the Angptl3 ASO enhanced RCT in all models tested. The observations from the RCT assays were confirmed in HDL clearance studies, where mice treated with the Angptl3 ASO displayed increased plasma clearance and hepatic uptake of labeled HDL. The results from our studies suggest that inhibition of ANGPTL3 not only reduces levels of proatherogenic lipids but also improves HDL-mediated RCT.

Efficacy and Safety of Evinacumab for the Treatment of Hypercholesterolemia: A Meta-Analysis.

ABSTRACT: Angiopoietin-like protein 3 is essential in lipid metabolism regulation. However, the efficacy and safety of evinacumab (angiopoietin-like protein 3 inhibition drug) for hypercholesterolemia treatment is unknown. In this study, a meta-analysis of randomized controlled trials (RCTs) was conducted to assess the efficacy and safety of evinacumab. RCTs published between January 1, 2000, and November 1, 2020, were obtained from PubMed, Embase, and Cochrane Library. All RCTs evaluating the efficacy and safety of evinacumab were included without language restrictions. Our primary end points included the percent change of low-density lipoprotein cholesterol (LDL-C) from baseline and the incidence of at least one treatment emergent adverse events including nasopharyngitis, influenza-like illness, headache, dizziness, injection-site reaction, increased aspartate aminotransferase, increased alanine aminotransferase, and any other discomfort during treatments. Percentage changes of triglycerides and high-density lipoprotein cholesterol (HDL-C) from baseline indicated secondary end points. A random-effects model was used to assess pooled data if there was moderate to high heterogeneity between studies. Four studies with 5 RCTs (568 participants) were identified. Evinacumab significantly reduced LDL-C [mean difference (MD) -33.123%, 95% confidence interval (CI), -48.639% to -17.606%, P < 0.0001], triglycerides (MD -50.959%, 95% CI, -56.555% to -45.362%, P < 0.0001), and HDL-C (MD -12.773%, 95% CI, -16.359% to -9.186%, P < 0.0001) compared with placebo. The incidence of at least 1 treatment emergent adverse events was not significantly different between evinacumab and placebo groups (relative risk 1.080, 95% CI, 0.901-1.296, P = 0.405). Evinacumab decreased triglycerides, LDL-C, and HDL-C without significant adverse effects, indicating that it can be a therapeutic strategy for hypercholesterolemia.

Inhibition of angiopoietin-like 3 for the management of severe hypercholesterolemia.

PURPOSE FOR REVIEW: Despite the therapeutic advances for patients with severe hypercholesterolemia, particularly those with homozygous familial hypercholesterolemia (HoFH), most patients are unable to achieve target low-density lipoprotein cholesterol (LDL-C) levels with the current available standard lipid-lowering therapy (LLT). We review the role of angiopoietin-like 3 (ANGPTL3) inhibition as an additional therapeutic option for severe hypercholesterolemia, particularly HoFH. RECENT FINDINGS: Evinacumab is a monoclonal antibody against ANGPTL3, and reduces LDL-C independent of LDL-receptor activity. ANGPTL3 inhibitors are effective in lowering LDL-C in patients with FH, with a 50% reduction in LDL-C in those with HoFH. Longer-term efficacy and safety have been demonstrated with reductions in LDL-C maintained following 48 weeks of therapy. Gene silencing strategies directed against ANGPTL3 include antisense oligonucleotide and small-interfering ribonucleic acid (siRNA). ARO-ANG3 is a siRNA directed against ANGPTL3 messenger ribonucleic acid and is associated with up to a 42% reduction in LDL-C. SUMMARY: With the promise of these emerging novel therapeutics directed against ANGPTL3 on the horizon, achieving acceptable target LDL-C levels in HoFH without the need for lipoprotein apheresis may finally be a realistic goal and we can anticipate a decrease in cardiovascular morbidity and mortality in these difficult to treat patients.