R3i Editorials

R3i editorials, created by members of the R3i board, focus on addressing the persistent challenges of residual cardiovascular risk. These editorials serve to educate healthcare professionals about emerging insights and therapeutic strategies related to lipid-related risk factors, such as triglyceride-rich lipoproteins and lipoprotein(a).

July 2025
New approaches to triglyceride-lowering: back to the future with ANGPTL4?
Prof. Peter Libby, Prof. Michel Hermans, Prof. Pierre Amarenco

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality world-wide (1). Moreover, with escalating obesity, particularly among younger individuals (2), ASCVD will continue to be a global challenge.  Advances in the management of low-density lipoprotein cholesterol have been welcome; yet, even with best evidence-based treatment, high-risk individuals have a persistent residual cardiovascular risk. Crucial drivers of this risk are elevated concentrations of triglyceride-rich lipoproteins and remnant cholesterol (3). Mechanistic and genetic studies have identified key targets in the regulation of triglyceride-rich lipoprotein metabolism that offer promising approaches to address atherogenic dyslipidemia and the associated residual risk (3). 

Angiopoietin-like protein 4 (ANGPTL4) is one target that attracted early interest. Predominantly expressed in adipose tissue and the liver, ANGPTL4 plays a crucial role in regulating lipid metabolism, via its inhibitory effect on lipoprotein lipase, and may also enhance the clearance of triglyceride-rich lipoproteins from circulation (4).  Genetic studies support the potential of this target, showing that carriers of loss-of-function mutations in ANGPTL4 have lower levels of triglycerides, remnant cholesterol and apolipoprotein B and a reduced risk of ASCVD (5-7). Despite this, enthusiasm for ANGPTL4 inhibition as a therapeutic approach has waned with evidence that Angptl4 knockout mice fed a high-saturated-fat diet exhibited lipid accumulation in mesenteric lymph nodes and systemic inflammation, as well as reduced survival (8,9). 

Against this background, early results with a novel ANGPLT4 monoclonal antibody promote a reassessment of the utility of this therapeutic target. First presented as a late breaker at the recent European Atherosclerosis Society Annual Congress in Glasgow and now published in The Lancet (10), first in-human data with MAR001 allay prior safety concerns with ANGPTL4 inhibition. 

Briefly, this latest report discusses findings from early studies of single dosing with MAR001 in healthy adults (15 mg, 50 mg, 150 mg, or 450 mg), as well as multiple dosing (150 mg, 300 mg, or 450 mg every 2 weeks) in adults with hypertriglyceridemia (≥1.7 mmol/L and ≤5.6 mmol/L at screening) and evidence of metabolic dysfunction (type 2 diabetes, or HOMA-IR >2.2 and abdominal obesity). The primary objective of the study was evaluation of the safety of MAR001. After 12 weeks, there was no adverse safety signal with MAR001 treatment, including the absence of changes in mesenteric lymph node size or inflammation. Moreover, at the highest dose regimen, MAR001 more than halved triglycerides and remnant cholesterol (with reductions of  52.7% and 52.5%, respectively). These findings provide a rationale for further clinical development of this new treatment. 

Together with preclinical findings (11), these results align with the effects of ANGPTL4 inhibition based on human genetics and support further development of MAR001 as a promising option for management of elevated triglycerides and remnant cholesterol in patients with atherogenic dyslipidemia. After a faltering start, we look forward to further insights into the therapeutic potential of ANGPTL4 inhibition in addressing residual cardiovascular risk associated with this common dyslipidemia.

References

    1. Vaduganathan M, Mensah GA, Turco JV, et al. The global burden of cardiovascular diseases and risk: a compass for future health. JACC 2022; 80: 2361–71.
    2. GBD 2021 Adolescent BMI Collaborators. Global, regional, and national prevalence of child and adolescent overweight and obesity, 1990–2021, with forecasts to 2050: a forecasting study for the Global Burden of Disease Study 2021. Lancet 2025;405:785-812.
    3. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021; 42:4791-806.
    4. Kersten S. Role and mechanism of the action of angiopoietin-like protein ANGPTL4 in plasma lipid metabolism. J lipid Res 2021;62: 100150.
    5. Landfors F, Henneman P, Chorell E, et al. Drug-target Mendelian randomization analysis supports lowering plasma ANGPTL3, ANGPTL4, and APOC3 levels as strategies for reducing cardiovascular disease risk. Eur Hear J Open 2024;4:oeae035.
    6. Dewey FE, Gusarova V, O’Dushlaine C, et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. New Engl J Medicine. 2016;374:1123–33.
    7. Gagnon E, Bourgault J, Gobeil É, et al. Impact of loss-of-function in angiopoietin-like 4 on the human phenome. Atherosclerosis 2024;393:117558.
    8. Lichtenstein L, Mattijssen F, de Wit NJ, et al. Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages. Cell Metab 2010;12:580–92.
    9. Desai U, Lee E-C, Chung K, et al. Lipid-lowering effects of anti-angiopoietin-like 4 antibody recapitulate the lipid phenotype found in angiopoietin-like 4 knockout mice. Proc Natl Acad Sci USA. 2007;104:11766–71.
    10. Cummings BB, Joing MP,  Bouchard PR, et al. Safety and efficacy of a novel ANGPTL4 inhibitory antibody for lipid lowering: results from phase 1 and phase 1b/2a clinical studies. Lancet 2025; doi: 10.1016/S0140-6736(25)00825-6. 
    11. Cummings  BB , Bouchard  PR , Milton MN, et al. An ANGPTL4 inhibitory antibody safely improves lipid profiles in non-human primates. BioMedicine 2025; doi: 10.1016/j.ebiom.2025.105748.