Publications by Year: 2026

Orforglipron (LY3502970) is a novel, orally available, nonpeptide glucagon-like peptide-1 receptor agonist (GLP-1 RA) designed to replicate the efficacy of injectable GLP-1 RAs for glycemic control and weight reduction while improving convenience and adherence. Preclinical studies have demonstrated potent receptor engagement, favorable pharmacokinetics, and central nervous system activity. Phase 1-3 clinical trials have shown significant reductions in glycated hemoglobin (HbA1c), fasting and postprandial glucose, body weight, and cardiovascular risk biomarkers, with an acceptable safety profile. This comprehensive review integrates pharmacological, clinical, and mechanistic evidence, critically evaluates the data, identifies knowledge gaps, and outlines future directions for orforglipron in the treatment of type 2 diabetes and obesity.

Vitamin D, a fat-soluble secosteroid traditionally recognized for skeletal health, exerts pleiotropic effects on cardiovascular physiology and disease. Circulating 25-hydroxyvitamin D [25(OH)D], the principal biomarker of vitamin D status, is frequently suboptimal worldwide, particularly in older adults, individuals with darker skin pigmentation, and populations at higher latitudes. Observational studies consistently associate low 25(OH)D concentrations with increased risk of hypertension, atherosclerosis, myocardial infarction, heart failure, arrhythmias, stroke, and cardiovascular mortality. Mechanistic investigations have revealed that vitamin D modulates cardiomyocyte calcium handling, endothelial function, vascular smooth muscle proliferation, inflammation, oxidative stress, and renin-angiotensin-aldosterone system activity, establishing biologically plausible links to cardiovascular outcomes. Despite these associations, large randomized trials of vitamin D supplementation have failed to demonstrate reductions in major cardiovascular events, likely due to heterogeneity in baseline status, dosing regimens, intervention timing, genetic variability, and underlying comorbidities. Vitamin D may function more effectively as a biomarker of cardiovascular risk rather than a universal therapeutic agent, with deficiency reflecting systemic vulnerability rather than acting as a dominant causal factor. Emerging evidence supports precision approaches targeting individuals with severe deficiency, high renin activity, early endothelial dysfunction, or specific genetic profiles, potentially in combination with lifestyle or pharmacologic interventions. Future research should focus on defining optimal dosing strategies, intervention timing, and mechanistic biomarkers to identify subpopulations most likely to benefit, integrating vitamin D therapy into multifaceted cardiovascular prevention frameworks. This systematic review synthesizes molecular, observational, and clinical trial evidence, critically evaluating the current understanding of vitamin D in cardiovascular medicine and highlighting opportunities for targeted, personalized interventions. Vitamin D represents a complex, context-dependent modulator of cardiovascular health, offering both prognostic insight and potential therapeutic value when appropriately applied.

BACKGROUND: Dysregulation of lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs) is linked to endothelial dysfunction and impaired tissue repair. Nevertheless, the organ-specific modulation of lysolecithin remodeling in T2DM remains unexplored. Here, we investigate the LPC/PC remodeling dynamics in a T2DM model and propose a novel therapeutic approach using an orally bioavailable peptide (SP6) derived from Spirulina platensis.

METHODS: LPC/PC levels were analyzed by UHPLC-HRMS. Membrane fluidity, VEGF/API5, LPCAT1, VE-cadherin, and GLUT1 were evaluated by merocyanine assay, qPCR, immunoblotting, and immunofluorescence. In vivo, T2DM was induced by a high-fat diet and streptozotocin, and SP6 was orally administered. Tissue lipidomics, GLUTs expression, and insulin secretion were assessed, with the latter also spatially characterized in pancreatic tissue by MALDI-MS imaging.

RESULTS: High glucose induced LPC/PC imbalance, enhanced membrane fluidity, impaired VEGF/API5 expression, and hindered wound healing and VE-cadherin localization via LPCAT1 downregulation and subsequent impact on GLUT1 translocation. In vivo analysis of diabetic mice revealed a multi-organ influence of SP6 preserving LPCAT1 mRNA levels in pancreas, liver, skeletal muscle, and adipose tissue and a specific pattern of lysolecithin remodeling, with selective modulation of LPC 16:0, 18:0, and 20:4 in plasma. Finally, its effects in T2DM are mediated by preserving insulin secretion and glycemic control through increased ATP production.

CONCLUSION: These findings reveal tissue-specific lysolecithin reprogramming in T2DM development and identify LPCAT1-mediated lysolecithin remodeling as a mechanism involved in T2DM-related endothelial and metabolic dysfunction. SP6 modulates lipid metabolism, vascular integrity, and glucose regulation at the transcript level, suggesting its potential as a new preventive treatment for T2DM and its complications.