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.
The autonomic nervous system (ANS) is a central regulator of cardiovascular function, coordinating involuntary control of heart rate, vascular tone, and blood pressure through its sympathetic (SNS) and parasympathetic (PNS) subdivisions. The SNS mediates the "fight or flight" response via catecholamines, increasing heart rate, contractility, and vasoconstriction, whereas the PNS promotes restorative processes through acetylcholine, decreasing heart rate and enhancing vasodilation. Nitric oxide further modulates vascular tone and autonomic balance, serving as a key neuromodulator. Assessment of cardiovascular autonomic function relies on heart rate variability, baroreflex sensitivity, and other physiological tests, which provide insight into the dynamic interplay between sympathetic and parasympathetic activity. Dysregulation of the ANS contributes to cardiovascular pathologies, including cardiovascular autonomic neuropathy, hypertension, and heart failure, where sympathetic overactivity and impaired parasympathetic modulation exacerbate disease progression. Pharmacologic interventions, such as β-blockers and ivabradine, alongside non-pharmacologic approaches, including structured exercise and respiratory training, aim to restore autonomic balance and improve clinical outcomes. Understanding the exact mechanisms of autonomic neurotransmission is essential for identifying novel therapeutic targets and optimizing cardiovascular care. Future research integrating molecular, genetic, and systems-level analyses will further elucidate autonomic regulation, guiding personalized interventions to mitigate cardiovascular morbidity and mortality.
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.
Heart failure continues to impose a major global burden, with limited options for reversing progressive contractile dysfunction despite optimized pharmacologic and device therapy. In this context, the first-in-human trial of AB-1002, a cardiotropic adeno-associated viral (AAV) vector encoding a constitutively active form of protein phosphatase-1 inhibitor (I-1c) represents a major innovation. By releasing SERCA2a from phospholamban-mediated inhibition, this strategy seeks to restore calcium cycling and contractile reserve without introducing exogenous pump proteins. In an open-label phase 1 study of 11 patients with advanced nonischemic cardiomyopathy, intracoronary delivery of AB-1002 was well tolerated, with no serious vector-related adverse events and only mild transient hepatic enzyme elevations. Modest but consistent improvements were observed in LVEF, while myocardial tissue from one explanted heart confirmed successful transgene expression and phospholamban phosphorylation. These results demonstrate the feasibility and biological activity of a phosphatase-inhibition gene-therapy approach for human heart failure. The forthcoming phase 2 GenePHIT trial will determine whether these encouraging mechanistic signals can be translated into tangible clinical benefit. AB-1002 thus represents a cautiously optimistic inflection point-suggesting that, with improved vector design and rigorous evaluation, gene therapy may yet deliver on its long-sought promise of molecular restoration in the failing human heart.
Frailty and cardiometabolic disorders are highly prevalent in the aging population and frequently coexist, amplifying each other's adverse effects. Frailty, defined by decreased physiological reserves and heightened vulnerability to stressors, often occurs alongside cardiometabolic conditions such as diabetes, hypertension, and cardiovascular disease. The intersection of these conditions poses substantial clinical challenges, impacting morbidity, mortality, and quality of life. Understanding the shared pathophysiological mechanisms underlying frailty and cardiometabolic disorders is critical for guiding effective prevention and management strategies. This systematic review, registered in PROSPERO (CRD420251164236), documents current knowledge on the definitions, epidemiology, and pathophysiology of frailty in the context of cardiometabolic disorders and highlights the main clinical implications of their coexistence. Additionally, we discuss evidence-based strategies for assessment, prevention, and management, emphasizing the importance of an integrated approach to improve outcomes in older adults. These insights aim to inform both clinicians and researchers about targeted interventions that can mitigate risk, enhance resilience, and optimize patient care.
Mone, Pasquale, Klara Komici, Germano Guerra, Tommaso Dazzetti, Urna Kansakar, Gianluca Gennarelli, Antonio Rainone, et al. “Stress Hyperglycemia Ratio and Physical Frailty in HFpEF.”. Cardiovascular Diabetology, 2025. https://doi.org/10.1186/s12933-025-03020-z.
BACKGROUND: Stress hyperglycemia, reflected by the stress hyperglycemia ratio (SHR), is increasingly recognized as a marker of adverse cardiovascular outcomes in both diabetic and non-diabetic patients. Stress-induced hyperglycemia arises from acute metabolic and inflammatory stress responses and may signify impaired glycemic resilience. Heart failure with preserved ejection fraction (HFpEF) commonly coexists with metabolic abnormalities such as hyperglycemia, prediabetes, and diabetes, while physical frailty-frequent in older adults-is mechanistically linked to both dysglycemia and HFpEF. In this study, we aimed to investigate the association between SHR and physical performance in frail older adults with HFpEF.
METHODS: We conducted a prospective observational study enrolling consecutive frail adults aged > 65 years with a confirmed diagnosis of HFpEF and Montreal cognitive assessment (MoCA) score < 26. Frailty was defined by ≥ 3 of 5 Fried criteria (low physical activity, unintentional weight loss, exhaustion, weakness, and slowness). SHR was calculated as the ratio of admission plasma glucose (mmol/L) to estimated chronic glucose derived from HbA1c (%). Participants were stratified into two groups: SHR ≤ 1 and SHR > 1. Physical function was assessed by gait speed (m/s).
RESULTS: Of 295 screened individuals, 204 met inclusion criteria and completed the study. Patients with SHR > 1 demonstrated significantly reduced physical performance compared with those with SHR ≤ 1 (mean gait speed 0.65 ± 0.20 m/s vs. 0.72 ± 0.20 m/s, p = 0.0004).
CONCLUSIONS: A higher SHR was independently associated with poorer physical function in frail older adults with HFpEF. These findings suggest that stress-related dysglycemia may contribute to functional decline in this population, highlighting the potential utility of SHR as a metabolic marker of frailty severity and cardiovascular vulnerability.
Mhamedi, El Cheima, Florent Hubé, Suresh K Alahari, Francisco J Enguita, Barbara Pardini, Mark W Feinberg, Laura Poliseno, et al. “The Non-Coding RNA Journal Club: Highlights on Recent Papers-14.”. Non-Coding RNA 11, no. 6 (2025). https://doi.org/10.3390/ncrna11060075.
The field of non-coding RNA research is advancing at a breathtaking pace, continually uncovering new layers of regulatory complexity and functional diversity [...].
BACKGROUND: Statin therapy has been associated with increased risk of type 2 diabetes (T2D). We investigated the relationship between Low-Density Lipoprotein Cholesterol (LDL-C) plasma concentrations and incident T2D and evaluated the modifying effect of statin therapy in a large population-based cohort.
METHODS: Individuals free of T2D and cardiovascular disease at baseline were followed longitudinally for the development of new-onset T2D. Cox proportional hazards models were applied to evaluate the associations of LDL-C levels and statin therapy with T2D risk.
RESULTS: From a population of 202,545 individuals, we selected 13,674 participants free of T2D and cardiovascular disease (of whom 52% were on statins), who were followed for a median of 71.6 months (IQR 34.5-149.9), during which 1,819 (13%) developed incident T2D. Cox multiple regression analysis revealed a significant inverse association between LDL-C plasma levels and incident T2D (p < 0.001). When stratifying LDL-C into quartiles [i.e. low (< 84 mg/dL), medium (≥ 84 to < 107 mg/dL), high (≥ 107 to < 131 mg/dL), and very high (≥ 131 mg/dL)], we observed that patients with LDL-C < 84 mg/dL had the highest risk of developing T2D. The interaction between statin therapy and T2D incidence was significant only in the very high LDL-C group, where statin users had a greater risk than non-users (p = 0.018); in the other three LDL-C groups, statin therapy did not significantly modify the association between LDL-C and T2D risk.
CONCLUSIONS: Taken together, our findings demonstrate a strong inverse association between LDL-C and incident T2D in the general population. The increased risk of T2D at lower LDL-C levels appears to be independent of statin use, supporting the role of LDL-C as a potential biomarker of T2D susceptibility.
Wang, Brandon, Stanislovas S Jankauskas, Pasquale Mone, Fahimeh Varzideh, and Gaetano Santulli. “Immunology of Heart Failure With Preserved Ejection Fraction.”. Expert Review of Clinical Immunology, 2025. https://doi.org/10.1080/1744666X.2025.2587180.
INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by diastolic dysfunction, systemic comorbidities, and chronic low-grade inflammation. Emerging evidence suggests that immune dysregulation plays a central role in its pathophysiology. Both innate and adaptive immune responses contribute to myocardial remodeling, endothelial dysfunction, and comorbidity-driven inflammation that are hallmarks of HFpEF.
AREAS COVERED: We summarize current evidence on the contribution of immunological pathways to HFpEF, including the role of proinflammatory cytokines, immune cell infiltration (particularly macrophages, mast cells, and T cells), and immune - endothelial interactions. We also highlight findings from experimental models linking systemic metabolic inflammation to myocardial fibrosis, coronary microvascular dysfunction, and cardiomyocyte stiffness in HFpEF. Finally, we explore potential immunomodulatory therapeutic approaches currently under investigation and discuss biomarkers of immune activation with potential clinical relevance.
EXPERT OPINION: While no immunologically targeted therapy is yet approved for HFpEF, interventions that modulate inflammation - such as IL-1 blockade, mast cell stabilization, or myeloid-targeted therapies - offer promise. Future clinical trials should incorporate immune profiling to enable patient stratification and personalized treatment approaches. A deeper understanding of immune-mediated mechanisms in HFpEF will be essential to advance therapeutic innovation and improve outcomes in this challenging and growing patient population.
β-hydroxybutyrate (BHB), the predominant ketone body in human circulation, is synthesized in liver mitochondria and rises markedly during fasting, caloric restriction, ketogenic diets, and high-intensity exercise. Once considered a mere metabolic intermediate, BHB is now recognized as a potent signaling molecule that links nutrient status to gene regulation, inflammation, and cellular stress responses. In fact, beyond serving as an energy substrate, BHB functions as a versatile signaling metabolite that integrates environmental cues to epigenetic regulation, gene expression, and cellular physiology. Accumulating evidence highlights its protective and disease-modifying effects, positioning BHB as a promising therapeutic candidate for diverse conditions associated with energy deficits or metabolic imbalances. Nevertheless, the precise mechanisms underlying these benefits remain incompletely defined. This review discusses recently identified molecular pathways regulated by BHB, with a focus on its roles in cellular signaling, inflammation, transcriptional control, and post-translational protein modifications. For the first time, we also explore the translational relevance of BHB in endocrine pancreas biology, drawing mechanistic parallels with the nervous system. Although neurons and β-cells share remarkable functional similarities, the impact of BHB on β-cell survival and function remains unexplored. Clarifying these effects may uncover new strategies to harness ketosis for the treatment of diabetes.
