👤 Gabriel A Marx

The incretin hormone glucagon-like peptide-1 (GLP-1) exerts potent effects on glucose metabolism, prompting the development of therapeutic strategies that enhance activity of the GLP-1 receptor (GLP-1R) pathway. Inhibitors of dipeptidyl peptidase 4 (DPP-4) prolong the half-life of endogenous GLP-1 and typically achieve reductions in HbA1c of 0.5%-0.8%. However, large-scale cardiovascular (CV) outcomes trials (CVOTs) with DPP-4 inhibitors demonstrated CV safety but did not show a reduction in CV events. A second incretin-based therapeutic approach was the development of GLP-1R agonists (GLP-1RAs). Various GLP-1RAs, including liraglutide, semaglutide, and dulaglutide, demonstrated a reduction in CV outcomes in large CVOTs. Initially, these medications were only available as injectable agents for subcutaneous administration, but recent technological advancements have enabled the development of orally available GLP-1RAs. A third incretin-based approach is tirzepatide, a dual agonist of GLP-1R and glucose-dependent insulinotropic polypeptide receptor (GIPR), which achieves greater HbA1c reduction and weight loss compared with GLP-1RAs alone. Ongoing large-scale CVOTs will determine its effects on hard cardiovascular endpoints. This Review summarizes the effects of GLP-1 and GLP-1RAs in the CV system as well as clinical data of GLP-1RAs in individuals with CV disease or high CV risk. Show less

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality in individuals with diabetes, partly driven by dyslipidemia. While low-density lipoprotein cholesterol (LDL-C) reduction is the primary target of lipid management, many patients with diabetes exhibit mixed dyslipidemia characterised by elevated triglycerides and increased concentrations of atherogenic remnant lipoproteins, which are more comprehensively captured by non-high-density lipoprotein cholesterol (non-HDL-C). Current guidelines from international societies, including the American Diabetes Association (ADA), the American Association of Clinical Endocrinology (AACE), and the European Society of Cardiology (ESC), recommend LDL-C and non-HDL-C targets based on individual cardiovascular risk profiles. Despite clear therapeutic algorithms, lipid target attainment remains suboptimal in routine clinical practice, necessitating more intensive and individualised treatment strategies. Lipid-lowering therapies, including statins, ezetimibe, bempedoic acid and PCSK9 inhibitors, effectively reduce LDL-C and non-HDL-C, significantly lowering cardiovascular risk. Triglyceride-lowering therapies, including omega-3 fatty acids and fibrates, have demonstrated substantial reductions in triglyceride levels, but their impact on cardiovascular outcomes remains uncertain. Given the heterogeneity of dyslipidemia in diabetes, non-HDL-C and apolipoprotein B (apoB) have emerged as superior markers for assessing atherogenic burden. While LDL-C reduction remains central, additional efforts are needed to optimise the management of residual atherogenic lipoprotein particles in diabetes. Future research should focus on refining risk stratification, improving lipid target attainment, and integrating novel lipid-modifying agents to enhance cardiovascular outcomes in this high-risk population. Show less

Alzheimer disease neuropathologic change (ADNC) is the most common pathology underlying cognitive impairment and dementia in the aging population, but there is significant variation in outcome between affected individuals. Moreover, other common neurodegenerative processes are often concurrent and may significantly worsen cognition, but the degree to which these processes interact and affect the We performed a cross-sectional cohort study of 586 participants from the National Alzheimer’s Coordinating Center (NACC) database, who were ≥ 65 years of age and displayed high-level ADNC at autopsy, and who had available longitudinal cognitive data and Clinical Dementia Rating (CDR) performed within the final 24 months of life. This cohort was subdivided into “resilient” individuals/those with minimal progression of cognitive decline (MinP; Individuals with rapid progression were more likely to have at least one These data suggest that resilience and progression in ADNC are impacted by AD-relevant genetics and the severity of late-stage ADNC (even within the narrow range of values compatible with high-level ADNC), additional pathologic features, and potentially the clinical management of underlying systemic disorders. The online version contains supplementary material available at 10.1186/s13195-025-01904-6. Show less

Migration of CD4-positive lymphocytes into the vessel wall is a critical step in atherogenesis. Recent data suggest that CD4-positive lymphocytes express the nuclear transcription factors Liver-X-Receptor (LXR) alpha and beta with an effect of LXR activators on TH1-cytokine release from these cells. However, the role of LXR in lymphocyte migration remains currently unexplored. Therefore, the present study investigated whether LXR activation might modulate chemokine-induced migration of these cells. Stimulation of CD4-positive lymphocytes with SDF-1 leads to a 2.5 +/- 0.8-fold increase in cell migration (P < 0.05; n = 12). Pretreatment of cells with the LXR activator T0901317 reduces this effect in a concentration-dependent manner to a maximal 0.9 +/- 0.4-fold induction at 1 micromol/L T0901317 (P < 0.05 compared to SDF-1-treated cells; n = 12). Similar results were obtained with the LXR activator GW3965. The effect of LXR activators on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced PI-3 kinase activity as determined by PI-3 kinase activity assays. Downstream, T0901317 inhibited activation of the small GTPase Rac and phosphorylation of the myosin light chain (MLC). Moreover, LXR activator treatment reduced f-actin formation as well as ICAM3 translocation to the uropod of the cell, thus interfering with two important steps in T cell migration. Transfection of CD4-positive lymphocytes with LXRalpha/beta siRNA abolished T0901317 inhibitory effect on MLC phosphorylation and ICAM3 translocation. LXR activation by T0901317 or GW3965 inhibits chemokine-induced migration of CD4-positive lymphocytes. Given the crucial importance of chemokine-induced T cell migration in early atherogenesis, LXR activators may be promising tools to modulate this effect. Show less