Investigated treatments for lipoprotein lipase deficiency and related metabolic disorders

ABSTRACT

Introduction: Monogenic chylomicronemia is a rare, dramatic phenotype caused by bi-allelic mutations within genes governing lipolysis, most frequently LPL, but also APOC2, APOA5, LMF1 and GPIHBP1. Features include life-threatening pancreatitis, together with failure to thrive in childhood, hepatosplenomegaly, lipemia retinalis and eruptive xanthomas. We review recent developments of new treatments for this condition.

Areas covered: Traditional therapies for severe hypertriglyceridemia are reviewed, including control of secondary causes, dietary modification, weight loss, and supplementation with omega-3 fatty acids. Current pharmacotherapies include fibrates, niacin, and statins, but these are largely ineffective. Plasmapheresis is generally not recommended as it is not a permanent solution in the absence of more specific or targeted management. Newer medications that have been evaluated in monogenic chylomicronemia include LPL gene therapy, lomitapide and mipomersen. Medications in development include volanesorsen, pradigastat, IONIS-ANGPTL3_Rx, evinacumab, and a therapeutic apolipoprotein C-II peptide.

Expert opinion: Assuming no unforeseen or off-target adverse effects, at least some of these new targeted medications may soon improve the outlook for patients with monogenic chylomicronemia. Also, because some of these therapies target specific components of the lipolytic network, it may be advantageous to know the precise molecular diagnosis in a particular patient to help guide therapy.

KEYWORDS:

• Chylomicrons
• pancreatitis
• triglycerides
• lipolysis
• next generation sequencing
• human genetics
• monoclonal antibodies
• antisense RNA
• gene therapy
• dietary treatment

Article highlights

• There are many different causes of severe hypertriglyceridemia, and genetic testing is valuable in both providing diagnostic information and guiding treatment

• Dietary modification and control of secondary factors are critical for successful control of serum triglyceride levels

• In patients with acute pancreatitis caused by hypertriglyceridemia, there is no clear evidence of improved outcomes from plasmapheresis above standard medical management of pancreatitis

• Classic therapies for hypertriglyceridemia have been inconsistent in efficacy for patients with LPL deficiency and related disorders as they rely on the patient’s intrinsic lipolytic pathway to exert effect

• Many new therapies targeting specific steps in the lipolytic pathway have been developed showing promising efficacy and side effect profile for patients with LPL deficiency and related disorders

This box summarizes key points contained in the article.

Declaration of interest

R Hegele has received honoraria for membership on advisory boards or speakers’ bureaus for Aegerion, Amgen, Ionis/Akcea, Gemphire, Merck, Pfizer, Sanofi and Valeant. 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 apart from those disclosed.

Additional information

Funding

R Hegele is supported by the Jacob J. Wolfe Distinguished Medical Research Chair, the Martha G. Blackburn Chair in Cardiovascular Research, the Edith Schulich Vinet Chair in Human Genetics, and operating grants from the Canadian Institutes for Health Research (Foundation Award), the Heart and Stroke Foundation of Ontario (T-000353) and Genome Canada through Genome Quebec (award 4530).