SAT-263 - Unlocking Lipoprotein Lipase by Inhibiting the ANGPTL3 Brake

Introduction:
Familial chylomicronemia syndrome (FCS) is an autosomal recessive disorder caused by absent or severely impaired lipoprotein lipase (LPL) activity, resulting in severe and persistent hypertriglyceridemia. Classic FCS arises from biallelic pathogenic variants in the LPL gene. In contrast, heterozygous LPL deficiency, caused by a single pathogenic variant, is associated with a variable phenotype. Affected individuals may exhibit triglyceride (TG) levels ranging from mild to severe hypertriglyceridemia, particularly in the presence of exacerbating factors like diabetes mellitus, obesity, or alcohol consumption. A key component of LPL pathway is angiopoietin-like protein 3 (ANGPTL3) which is a hepatically produced protein that inhibits LPL activity. Therefore, if ANGPTL3 is inhibited, it would allow any available LPL activity promoting clearance of TG. Therefore, if ANGPTL3 is inhibited, it would allow any available LPL activity promoting clearance of TG. Such an ANGPTL3 inhibitor, like evinacumab, is approved for the treatment of severe inherited hypercholesterolemia removing a key regulatory “brake” on LPL.

Case:
A 62-year-old man with severe hypertriglyceridemia, elevated LDL-C, class I obesity, coronary artery disease (CAD), atrial fibrillation, obstructive sleep apnea, and recurrent pancreatitis presented with refractory dyslipidemia despite treatment with multiple lipid-lowering therapies and strict dietary adherence. Genetic testing revealed a complete deletion of one LPL allele's coding sequence, suggesting partial LPL activity and potential responsiveness to ANGPTL3 inhibition.

The patient was started on evinacumab and after two doses, a marked reduction in TG levels (84% reduction) was observed, with a subsequent panel confirming sustained TG lowering but elevated LDL-C. Reintroduction of alirocumab combined with evinacumab resulted in improved lipid levels: total cholesterol 129 mg/dL, TG 63 mg/dL (an 87% reduction from baseline), HDL-C 45 mg/dL, and LDL-C 72 mg/dL. Seven months of combination therapy maintained stable TG control, though LDL-C remained above treatment target for this patient.

Discussion:
FCS and related LPL deficiencies pose significant morbidity risks, including recurrent pancreatitis and increased cardiovascular risk. Targeting ANGPTL3, has shown significant TG-lowering effects, especially in individuals with residual LPL activity, highlighting the importance of genetic testing in guiding therapeutic decisions. While a sustained LDL-C increase was observed in our case, prompting reinitiated PCSK9 inhibitor therapy, clinical trial data suggest that LDL-C increase during severe hypertriglyceridemia treatment with ANGPTL3 inhibitors is expected and often transient. Intensification of statin and/or PCSK9 inhibitor therapy is recommended when LDL-C levels persist above therapeutic goals.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*