Hypertriglyceridaemia and elevated cardiovascular risk: will ANGPTL4 inhibition address both?

Comment to: ‘Safety and efficacy of a novel ANGPTL4 inhibitory antibody for lipid lowering: results from phase 1 and phase 1b/2a clinical studies’ by Cummings BB et al. (Lancet 2025;405:1923–1934) In the last decade, the armamentarium of therapeutic options to modify lipoprotein metabolism has substantially expanded. The discovery of novel targets involved in lipoprotein metabolism such as proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein CIII (apo CIII), lipoprotein(a), and angiopoietin-like 3 (ANGPTL3) was one prerequisite for this development. While some of these targets have been considered undruggable in the past, this has changed with the advances in the therapeutic principle of RNA interference with antisense oligonucleotides (ASOs) and small-interfering RNA (siRNA). These novel drugs have the potential to fundamentally change traditional concepts of cardiovascular prevention in the future.1 Low-density lipoprotein cholesterol (LDL-C) is the central therapeutic target in the treatment of dyslipidaemia. Combination of available LDL-C-lowering drugs with proven cardiovascular benefit enables almost all patients to achieve very low levels of LDL-C, however, there is still a so-called ‘residual risk’ of recurrent cardiovascular events, which is in part attributed to elevated triglycerides. So far, all attempts to lower triglycerides and subsequently, cardiovascular risk, have failed. Triglyceride-lowering drugs such as fibrates, omega-3 fatty acids, and novel RNA interference-based drugs are diverse in their mechanism of action.2 Notwithstanding the mechanism, the effect on the number of atherogenic particles (expressed as apolipoprotein B [apo B]) has been suggested to be the most important determinator of whether the reduction in triglycerides translates into a cardiovascular benefit, irrespective of actual triglyceride reductions.3 The latest example of triglyceride reductions without apo B-lowering is the PROMINENT trial of 10 497 patients treated with the potent, specific PPAR-α modulator pemafibrate. Despite triglyceride reductions of 26.2%, apo B increased by 4.8%, and there was no cardiovascular benefit.4 Novel RNA interference-based approaches for the reduction of triglycerides include targeting of apo CIII, ANGPTL3, and most recently, ANGPTL4.5 For all of these targets, genetic loss-of-function variants have been associated with lower cardiovascular risk. The development of drugs targeting apo CIII and ANGPTL3 is at an advanced stage. The ASO volanesorsen is approved for the treatment of the familial chylomicronaemia syndrome (FCS) in Europe, and the monoclonal antibody evinacumab is approved for the treatment of homozygous familial hypercholesterolaemia. Both conditions are very rare, and the mode of application (once per month intravenously for evinacumab) and side effects (injection site reactions and thrombocytopenia in FCS for volanesorsen) make both drugs rather unsuitable for the treatment of common conditions such as moderate hypertriglyceridaemia. Novel compounds may overcome the limitations of previous attempts. In contrast, development of ANGPTL4-targeting therapies has been delayed due to adverse effects observed in ANGPTL4-knockout mice. ANGPTL4 appears as attractive target, as ANGPTL4 loss-of-function variants are not only associated with reduced cardiovascular risk, but also reduced risk of diabetes mellitus. In the current study of Cummings et al., therapeutic targeting of ANGPTL4 with a monoclonal antibody called MAR001 is explored in humans for the first time.5 First, the authors show that in the UK Biobank and in FinnGen, carriers of different loss-of-function mutations in ANGPTL4 (homozygotes and heterozygotes) have no adverse health effects including lymphatic diseases (one concern raised in the mouse model). The analyses encompassed electronic medical health data and abdominal MRI analyses in a subset of homozygote ANGPTL4 loss-of-function carriers. The results of the first-in-human studies of targeting ANGPTL4 are presented thereafter. In a phase 1 study conducted in n = 56 healthy, obese, and individuals with moderate hypertriglyceridaemia, MAR001 was administered at doses of 15 to 450 mg and compared to placebo. In a phase 1b/2a study, n = 55 participants with metabolic dysfunction received 150 mg, 300 mg, or 450 mg of MAR001, or placebo every two weeks for 12 weeks with an additional 12-week safety follow-up. No elevation of systemic inflammatory biomarkers was noted. In MRI imaging, no signs of inflammation or changes in lymph node size were observed. MAR001 was tolerated well. At week 12, triglycerides were reduced by 52.7% compared to placebo, and remnant cholesterol by 52.5%. The authors conclude that their findings support further development of MAR001. We now have publications on reducing triglycerides by drugs directed at one of three genetically validated targets. It is unknown yet which approach will not only reduce triglycerides, but also cardiovascular risk. The effects of the different drugs on the lipid fractions differ (Figure 1). While all drugs substantially reduce triglycerides, the changes in LDL-C are negligible for apo CIII- and ANGPTL4-targeted drugs, but substantial for ANGPTL3 inhibition. High-density lipoprotein cholesterol (HDL-C) increases after apo CIII and ANGPTL4 inhibition, but decreases following ANGPTL3 inhibition. Glycated haemoglobin (HbA1c) increases after apo CIII and ANGPTL3 inhibition, but remains unchanged in participants treated with MAR001. Finally, in moderate hypertriglyceridaemia, apo B is reduced by apo CIII and ANGPTL3 inhibition.6–8 (A) Typical changes in lipid profiles in patients with mild or moderate hypertriglyceridaemia after pharmacologic inhibition of apolipoprotein C III, ANGPTL3, and ANGPTL4. (B) Key characteristics and effects of pharmacologic inhibition of apolipoprotein C III, ANGPTL3, and ANGPTL4. The current paper by Cummings and colleagues provides very important novel insights, the authors have to be congratulated for their efforts to establish safety and efficacy of an ANGPTL4-targeting strategy. Despite many important strengths, the interpretability of the data is limited by a lack of reporting effects of MAR001 on apo B. The authors report non-HDL-C and remnant cholesterol (remnant-C). However, non-HDL-C may not reflect apo B in this population. Non-HDL-C was calculated as total cholesterol minus HDL-C, and as ‘total cholesterol and LDL cholesterol concentrations remained unchanged’,5 the observed non-HDL-C reduction is due to the increase in HDL-C alone. Comparable to attempts of lowering triglycerides, attempts to increase HDL-C have failed to show a cardiovascular benefit to date. The authors also report reductions in remnant-C. There is a great heterogeneity of how remnant-C is defined. In the common definition of ‘remnant-C = total cholesterol minus LDL-C minus HDL-C’, and with replacement of the ‘LDL-C’ term with LDL-C calculated by the Friedewald formula, one gets ‘remnant-C = triglycerides in mg/dL divided by 5’, making remnant-C another expression of triglyceride concentration.9 The authors state that ‘Remnant cholesterol was calculated as triglyceride minus HDL cholesterol minus LDL cholesterol’5 which is unusual and not really substantiated in the literature. LDL-C was calculated using the Sampson equation, which is more complex than the Friedewald equation, but uses the same parameters total cholesterol, HDL-C, and triglycerides. Irrespective of which formula was used to calculate remnant-C, given the absent changes in total and LDL-C, the observed changes in remnant-C appear to be determined mainly by the changes in triglycerides and HDL-C but not the atherogenic particles that are reflected by apo B. Additionally, VLDL cholesterol changes are provided. VLDL cholesterol was calculated using the Friedewald formula,5 meaning triglycerides divided by 5. That VLDL decreases with decreasing triglycerides is therefore a mathematical necessity. It is not clear why the authors did not use the equation for VLDL provided in the same paper as the Sampson formula for LDL-C.10 Taken together, the work of Cummings et al. provides important genetic and clinical data on the safety of therapeutic ANGPTL4 inhibition in the first-in-human studies. Future studies will however be required to determine whether cardiovascular benefits can be expected from treatment with MAR001 in patients with hypertriglyceridaemia. Changes in apo B have been observed in genetic studies of ANGPTL4 and in the treatment of non-human primates with MAR001.11 Depending on the presence and magnitude of apo B changes in human following treatment with MAR001, the principle of ANGPTL4 targeting may be equally as promising as targeting apo CIII and ANGPTL3, with potentially additional metabolic advantages. The promising data by Cummings et al. certainly raise the interest in additional data from a clinical development programme. Julius L. Katzmann works as cardiologist at the Department of Cardiology at Leipzig University Hospital, Germany, since 2017. After his study at the Friedrich Schiller University in Jena, Katzmann began his clinical training in 2016 at the Heart Center Leipzig in the Department of Electrophysiology. In 2018/2019, he completed a six-months research stay at the University of Cambridge, United Kingdom, in the Cardiovascular Epidemiology Unit. Katzmann’s clinical and scientific work focusses on the epidemiology, genetics, and treatment of lipid disorders, and health services research in cardiovascular prevention. Katzmann is board member of the D•A•CH-Gesellschaft Herz-Kreislauf-Prävention and active peer reviewer for several cardiovascular journals, including the European Heart Journal, the European Journal of Preventive Cardiology, and Cardiovascular Diabetology. For his research, he was awarded with the Young Investigator Fellowship of the European Atherosclerosis Society, with the scientific award of the Josef-Freitag-Stiftung, and with the abstract award for clinical lipid research of the German Cardiac Society. Ulrich Laufs is Professor and Chief of Cardiology at Leipzig University Hospital. After completing his training at the Universities of Bochum and Hamburg, he was resident at the University of Cologne and spent two years as post-doctoral researcher at Harvard University in Boston. Before moving to Leipzig in 2017, he was Professor for Clinical and Experimental Medicine and Vice-chairman of the Department of Internal Medicine, Cardiology, Angiology and Intensive Medicine at the University of Saarland in Homburg. Laufs heads a research group focused on cellular and molecular mechanisms, and clinical studies of cardiovascular prevention with a special interest in lipid disorders. Additional research interests of the department include heart failure and cardiomyopathies, cardiac imaging, interventional cardiology and atrial fibrillation. He has > 600 publications listed medline that have been cited >40 000 times (H-index ∼100). Laufs serves on the boards of the German Society of Cardiology (DGK) and the D•A•CH-Gesellschaft Herz-Kreislauf-Prävention, the federal drug commission of German Pharmacists and in several editorial boards of cardiovascular journals, including the European Heart Journal. He is Editor of the journal Clinical Research in Cardiology and the secretary of the European Society of Atherosclerosis (EAS). His honours include the Population Sciences Award of the European Society of Cardiology, the Paul Martini Award, and the Albert Fraenkel Award of the German Cardiac Society.