Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.

Background: We investigated the effects of the combined treatment with glucagon like peptide‐1 receptor agonists (GLP‐1RA) and sodium‐glucose cotransporter‐2 inhibitors (SGLT‐2i) on NT‐proBNP (N‐terminal pro‐brain natriuretic peptide), GDF‐15 (growth differentiation factor 15), and MOTS‐c (mitochondrial‐derived peptide‐c) in patients with type 2 diabetes (T2D) and high or very high cardiovascular risk. Methods: We studied 163 consecutive patients with type 2 diabetes who were treated with insulin (n=40), liraglutide (n=41), empagliflozin (n=42), or their combination (GLP‐1RA+SGLT‐2i) (n=40) and were matched using propensity score analysis. We measured the following at baseline and 4 and 12 months of treatment: (1) NT‐proBNP, GDF‐15, and MOTS‐c; (2) 2,2′‐azino‐bis(3‐ethylbenzothiazoline‐6‐sulfonic acid), and (3) left ventricular global longitudinal strain, left atrial strain during atrial reservoir phase, and global work index using speckle‐tracking imaging. Results: At 12 months, GLP‐1RA, SGLT‐2i, and their combination showed a greater reduction of NT‐proBNP (−43.1% versus −54.2% versus −56.9% versus −14.7%) and GDF‐15 than insulin. Only treatment with SGLT‐2i and GLP‐1RA+SGLT‐2i improved MOTS‐c. GLP‐1RA, SGLT‐2i, or GLP‐1RA+SGLT‐2i provided an increase of global longitudinal strain, left atrial strain, and global work index compared with insulin. In all patients, the reduction of NT‐proBNP was associated with the improvement of global longitudinal strain, left atrial strain during atrial reservoir phase, and global work index; the decrease of GDF‐15 with the increase of ABTS and MOTS‐c; and the increase of MOTs‐c with improved global longitudinal strain and constructive myocardial work at 12 months ( P <0.05). Conclusions: Twelve‐month treatment with combination of GLP‐1RA+SGLT‐2i was associated with a greater reduction of neurohumoral markers and increase of antioxidant ability than each treatment alone and insulin. SGLT‐2i appear more effective in the improvement of neurohumoral and mitochondrial activation. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03878706.

Psoriasis predisposes to cardiovascular dysfunction. We investigated whether glycocalyx dietary supplement (GDS), which contains glycosaminoglycans and fucoidan, improves endothelial glycocalyx and arterial stiffness in psoriatic patients. Fifty participants with psoriasis under biological agents were randomly assigned to GDS (n = 25) or placebo (n = 25) for 4 months. We measured at baseline and at follow-up: (a) perfused boundary region (PBR) of the sublingual microvessels (range 4 to 25 μm), a marker of endothelium glycocalyx integrity; (b) carotid–femoral pulse wave velocity (PWV-Complior SP-ALAM) and augmentation index (AIx), markers of arterial stiffness and (c) psoriasis area and severity index (PASI) score. Both groups displayed a similar decrease in PASI at four months (p < 0.05), and no significant differences were found between groups (p > 0.05). Compared to the placebo, participants in the GDS showed a greater percentage reduction in PBR4–25 μm (−9.95% vs. −0.87%), PBR 4–9 μm (−6.50% vs. −0.82%), PBR10–19 μm (−5.12% vs. −1.60%), PBR 20–25 μm (−14.9% vs. −0.31%), PWV (−15.27% vs. −4.04%) and AIx (−35.57% vs. −21.85%) (p < 0.05). In the GDS group, the percentage reduction in PBR 4–25 μm was associated with the corresponding decrease in PWV (r = 0.411, p = 0.015) and AΙx (r = 0.481, p = 0.010) at follow-up. Four-month treatment with GDS improves glycocalyx integrity and arterial stiffness in patients with psoriasis. Clinical trial Identifier: NCT05184699.

Vascular aging is a key determinant of cardiovascular risk and is characterized by endothelial dysfunction, oxidative stress, inflammation, arterial stiffness, and alterations of the endothelial glycocalyx. In recent years, increasing scientific interest has focused on whether selected nutritional supplements can modulate these mechanisms. The objective of this narrative review is to summarize and critically evaluate the current evidence regarding the effects of selected nutritional supplements on endothelial function and vascular health, with emphasis on their proposed mechanisms of action, available preclinical and clinical evidence, and current limitations. This review examines nutritional supplements targeting nitric oxide biology (L-arginine/L-citrulline and citrulline derived from watermelon), polyphenol-rich foods and extracts (cocoa flavan-3-ols and grape polyphenols), mitochondrial redox balance (coenzyme Q10 and the mitochondria-targeted antioxidant MitoQ), endothelial glycocalyx-supporting formulations, olive-derived bioactive compounds, curcumin, and S-allyl cysteine. Across studies, improvements have been reported primarily in surrogate vascular endpoints, including flow-mediated dilation, pulse wave velocity, and blood pressure, although effect sizes vary and substantial heterogeneity exists among studies. Overall, current evidence suggests that several nutritional supplements may improve surrogate markers of vascular function; however, evidence demonstrating reductions in major cardiovascular events or cardiovascular mortality remains limited. Future research should prioritize adequately powered randomized controlled trials with longer follow-up, standardized supplement formulations, and clinically meaningful cardiovascular outcomes to more clearly define the role of nutritional supplements in cardiovascular prevention.