Targeting apoC-III and ANGPTL3 in the treatment of hypertriglyceridemia

ABSTRACT

Introduction

The prevalence of hypertriglyceridemia (HTG) is increasing. Elevated triglyceride (TG) levels are associated with an increased cardiovascular disease (CVD) risk. Moreover, severe HTG results in an elevated risk of pancreatitis, especially in severe HTG with an up to 350-fold increased risk. Both problems emphasize the clinical need for effective TG lowering.

Areas covered

The purpose of this review is to discuss the currently available therapies and to elaborate the most promising novel therapeutics for TG lowering.

Expert opinion

Conventional lipid lowering strategies do not efficiently lower plasma TG levels, leaving a residual CVD and pancreatitis risk. Both apolipoprotein C-III (apoC-III) and angiopoietin-like 3 (ANGPTL3) are important regulators in TG-rich lipoprotein (TRL) metabolism. Several novel agents targeting these linchpins have ended phase II/III trials. Volanesorsen targeting apoC-III has shown reductions in plasma TG levels up to 90%. Multiple ANGPLT3 inhibitors (evinacumab, IONIS-ANGPTL3-L_Rx, ARO-ANG3) effectuate TG reductions up to 70% with concomitant potent reduction in all other apoB containing lipoprotein fractions. We expect these therapeutics to become players in the treatment for (especially) severe HTG in the near future.

KEYWORDS:

• ANGPTL3
• apoC-III
• CVD risk
• evinacumab
• hypertriglyceridemia
• pancreatitis
• triglycerides

Article highlights

• Hypertriglyceridemia has a high burden in the modern Western world due to the pandemic of obesity and diabetes

• Hypertriglyceridemia is associated with an increased CVD and pancreatitis risk

• Current pharmacological strategies are not sufficient for TG lowering, especially in moderate to severe HTG patients

• Volanesorsen, an antisense oligonucleotide (ASO) targeting apoC-III, potently lowers TG levels up to 90%

• Evinacumab (monoclonal antibody) and IONIS-ANGPTL3-L_Rx (ASO) effectively lower TG levels up to 70% with concomitant lowering of all other atherogenic apoB containing lipoprotein fractions

• These and more novel therapeutics will be the cornerstone of future HTG treatment, especially in severe HTG patients.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.