Recent developments in pharmacotherapy for hypertriglyceridemia: what’s the current state of the art?

ABSTRACT

Introduction: Hypertriglyceridemia is associated with both the development of cardiovascular disease (CVD) when mild-to-moderate and high risk of pancreatitis when more severe. The residual CVD risk after low-density lipoprotein cholesterol (LDL-C) lowering is, in part, attributed to high triglyceride (TG) levels. Therefore, there appears to be a need for effective TG-lowering agents.

Areas covered: This review presents the most recent advances in hypertriglyceridemia treatment; specifically, it discusses the results of clinical trials and critically comments on apolipoprotein C-III inhibitors, angiopoietin-like 3 inhibitors, alipogene tiparvovec, pradigastat, pemafibrate and novel formulations of omega-3 fatty acids.

Expert opinion: In the era of extreme lowering of LDL-C levels with several agents, there seems to be space for novel therapeutic options to combat parameters responsible for residual CVD risk, among which are elevated TGs. Furthermore, a significant number of individuals have very high TG levels and encounter the risk of acute pancreatitis. The most recently developed TG-lowering drugs appear to have a role in both conditions; the choice is mainly based on baseline TG levels. Dyslipidemia guidelines are likely to change in the near future to include some of these agents. Of course, long-term data regarding their safety and efficacy in terms of CVD outcomes and pancreatitis are warranted.

KEYWORDS:

• Angiopoietin-like 3 inhibitors
• docosahexaenoic acid
• eicosapentaenoic acid
• pemafibrate
• pradigastat
• tiparvovec
• triglycerides
• volanesorsen

Article highlights

• Modest hypertriglyceridemia (TG 200–499 mg/dL; 2.26–5.63 mmol/L) has been associated with increased risk of CVD, whilst severe hypertriglyceridemia (TG > 500 mg/dL; 5.65 mmol/L) significantly increases risk of acute pancreatitis. Development of new agents to effectively reduce TG levels is imperative.

• Volanesorsen, a pharmacologic apoC-III inhibitor, has been highly efficacious in reducing TG levels in patients with severe hypertriglyceridemia and has been approved for the management of FCS. Its associated thrombocytopenia represents a major limitation in its use.

• Targeting ANGPTL3, which is an LPL inhibitor, through ASO diminishing its hepatic expression or mAb (evinacumab), has been proven efficacious in reducing TGs and other atherogenic lipoproteins in patients with hypertriglyceridemia and HoFH. Whether this benefit translates to CVD risk reduction needs to be evaluated in clinical trials.

• Omega-3 FAs are indicated for prevention of acute pancreatitis in patients with severe hypertriglyceridemia. Their previously disputed role on CVD prevention will be reconsidered in the light of favorable outcomes with the use of icosapent ethyl, while hard outcomes data for the novel omega-3 carboxylic acid are currently awaited.

• Pemafibrate, a newly developed fibrate with high potency and selectivity against PPARα, exhibits similar lipid-lowering effect as fenofibrate and is safe and well-tolerated. Its role in reducing CV outcomes in patients with type 2 diabetes and mixed dyslipidemia is evaluated in an ongoing clinical trial.

• Acyl-coA: DGAT-1 is an enzyme required for TG synthesis from absorbed dietary fat. Pradigastat, an inhibitor of this enzyme, was highly efficacious in reducing postprandial lipemia having been promising for the management of FCS. However, its development was suspended due to severe gastrointestinal side effects.

• Tiparvovec is an AVV-1-based gene therapy promoting synthesis and secretion on biologically active LPL. Despite its significant TG-lowering effect its development was suspended due to non-sustainable lipid-lowering benefits in correlation with the development anti-AVV-1 antibodies and due to its potential tumorigenic effect.

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

One author declares an employee relationship with Omthera Pharmaceuticals, the developer of Epanova acquired by AstraZeneca. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This manuscript has not been funded.