Genetic studies have established angiopoietin-related protein 4 (ANGPTL4) as a key regulator of triglyceride metabolism and a promising target to reduce atherosclerotic cardiovascular disease (ASCVD) risk beyond traditional risk factors. Human ANGPTL4 loss-of-function shows no adverse consequences and is associated with reduced triglycerides and remnant cholesterol, and a reduced risk of type 2 diabetes and ASCVD. Nonetheless, development of ANGPTL4 inhibitors has been delayed due to adverse findings in ANGPTL4-knockout mice fed a high saturated fat diet, including lipid accumulation in mesenteric lymph nodes, systemic inflammation, adverse clinical signs, and reduced survival. We previously reported the development and preclinical characterisation of MAR001, an ANGPTL4 inhibitory antibody. Here, we report a comprehensive safety assessment of ANGPTL4 inhibition, including novel analysis of genetic ANGPTL4 loss on mesenteric lymph node architecture in humans and two early-phase clinical trials.

One in five of the population lives with chronic pain. Psychological interventions for pain reveal core principles that can be used to create opportunities for chronic pain self-management in primary practice, across health-care settings, and at home. We highlight the different types of chronic pain and illustrate the psychoneurobiological mechanisms involved. We review core principles for psychological pain management, evaluate the evidence, and illustrate the underlying neurobiology involved. We provide practical advice for how to facilitate pain self-management in clinical practice. Finally, we discuss scientific caveats and practical obstacles to improvement, suggesting possible pathways to implementation.