Investigational drugs in development for hypertriglyceridemia: a coming-of-age story

ABSTRACT

Introduction: Elevated triglyceride (TG) level is a prevalent condition in the general population and in patients with cardiovascular (CV) risk even under statin therapy. Severe hypertriglyceridemia (HTG) puts patients at risk for acute pancreatitis. Several TG-lowering drugs failed in clinical trials, but subgroup analyses suggest that high-risk patients, such as those with atherogenic dyslipidemia or diabetes, benefit from TG lowering.

Areas covered: We review advances for TG-lowering drugs in clinical development. These include selective PPARα modulators, omega-3 fatty acid formulations that have been approved for severe HTG, and inhibitors of apolipoprotein C-III, angiopoietin-like-3 or microsomal transfer protein. Lessons learned from the success of the phase 3 trial REDUCE-IT with high-dose icosapent ethyl are also reviewed.

Expert opinion: We believe that TG-lowering therapies are coming of age as they will allow to treat patients with high CV risk and moderate HTG, including T2D subjects, as well as patients with severe HTG or even homozygous familial hypercholesterolemia, all of which being ‘optimally’ treated with a statin. More studies on the impact of therapy on quality of life in patients with severe HTG should be conducted with the help of patient registries.

KEYWORDS:

• Hypertriglyceridemia
• PPAR alpha agonist
• omega-3 fatty acids
• apolipoprotein C-III
• angiopoietin-like 3
• microsomal transfer protein

Article Highlights

• Elevated TG levels represent a source of residual CV risk and have been causally associated with CVD in Mendelian randomization studies.

• Several phase 3 trials of TG-lowering therapies have failed, including fenofibrate, niacin and low-dose omega-3 supplementation, but subgroup analysis suggests protection in high-risk patients with atherogenic dyslipidemia (elevated TG and low HDL-cholesterol).

• Omega-3 (OM3)-based therapies, in the form of ethyl esters (EE) or carboxylic acids (CA), are approved for severe hypertriglyceridemia (HTG), following introduction/intensification of statin therapy and lifestyle modifications as suggested by current guidelines.

• Recently, high-dose OM3-EE (icosapent ethyl) reduced CV risk by 25% in subjects with high CV risk (established CVD and elevated TG or T2D) in the REDUCE-IT trial which may be due to combined changes in lipid profile and systemic inflammation.

• Two other large-scale phase 3 trials are ongoing: PROMINENT with pemafibrate (selective PPARα agonist) in T2D patients with moderate HTG and low HDL-C and STRENGTH with OM3-CA in on-statin patients with moderate HTG and low HDL-cholesterol.

• The APOCIII antisense oligonucleotide volanesorsen has been approved in the EU for familial chylomicronemia syndrome and is under investigation for HTG, while evinacumab, a monoclonal antibody against ANGPTL3, has been granted a “breakthrough therapy designation” by FDA for homozygous familial hypercholesterolemia and is under investigation for HTG.

Declaration of interest

J-C Tardif has received grants and personal fees from Servier; grants from Amarin, grants from Ionis, grants and personal fees from Pfizer, grants and personal fees from Sanofi, grants and personal fees from DalCor, grants and personal fees from Astra Zeneca, grants from Esperion, and has a patent ‘Pharmacogenomics-guided CETP inhibition’ issued. The authors have no other 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

Notes

1. Throughout this review, we will use the terms ‘biomarker’ and ‘surrogate endpoint’ and their different types as defined by the FDA-NIH Biomarker Working Group in the Biomarkers, Endpoints, and other Tools (BEST) Resource (which can be accessed online at https://www.ncbi.nlm.nih.gov/books/NBK326791/).

2. https://www.cbc.ca/news/health/glybera-lpld-rare-drug-orphan-disease-nrc-cbc-price-1.5312177.

Additional information

Funding

This paper was not funded.