Background: We investigated the effects of insulin, glucagon‐like peptide‐1 receptor agonists ( GLP ‐1 RA ), sodium‐glucose cotransporter‐2 inhibitors ( SGLT ‐2i), and their combination on vascular and cardiac function of patients with type 2 diabetes mellitus. Methods and Results: A total of 160 patients with type 2 diabetes mellitus were randomized to insulin (n=40), liraglutide (n=40), empagliflozin (n=40), or their combination ( GLP ‐1 RA + SGLT ‐2i) (n=40) as add‐on to metformin. We measured at baseline and 4 and 12 months posttreatment: (a) perfused boundary region of the sublingual arterial microvessels (marker of endothelial glycocalyx thickness), (b) pulse wave velocity ( PWV ) and central systolic blood pressure, (c) global left ventricular longitudinal, circumferential, and radial strain, (d) myocardial work index (global work index) derived by pressure‐myocardial strain loops using speckle tracking imaging. Twelve months posttreatment, all patients improved perfused boundary region, PWV , global longitudinal strain, global circumferential strain, and global radial strain ( P <0.05). GLP ‐1 RA , SGLT ‐2i, and their combination showed a greater reduction of perfused boundary region, PWV, and central systolic blood pressure than insulin, despite a similar glycosylated hemoglobin reduction ( P <0.05). GLP ‐1 RA or GLP ‐1 RA + SGLT ‐2i provided a greater increase of global work index (12.7% and 17.4%) compared with insulin or SGLT ‐2i (3.1% and 2%). SGLT ‐2i or GLP ‐1 RA and SGLT ‐2i showed a greater decrease of PWV (10.1% and 13%) and central and brachial systolic blood pressure than insulin or GLP ‐1 RA ( PWV , 3.6% and 8.6%) ( P <0.05 for all comparisons). The dual therapy showed the greatest effect on measured markers in patients with left ventricular ejection fraction <55% ( P <0.05). Conclusions: Twelve‐month treatment with GLP ‐1 RA , SGLT ‐2i, and their combination showed a greater improvement of vascular markers and effective cardiac work than insulin treatment in type 2 diabetes mellitus. The combined therapy as second line was superior to either insulin or GLP ‐1 RA and SGLT ‐2i separately. Registration: URL : https://www.clini​caltr​ials.gov . Unique identifier: NCT 03878706.

Aims: SARS‐CoV‐2 infection may lead to endothelial and vascular dysfunction. We investigated alterations of arterial stiffness, endothelial coronary and myocardial function markers 4 months after COVID‐19 infection. Methods and results: In a case‐control prospective study, we included 70 patients 4 months after COVID‐19 infection, 70 age‐ and sex‐matched untreated hypertensive patients (positive control) and 70 healthy individuals. We measured (i) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced endothelial glycocalyx thickness), (ii) flow‐mediated dilatation (FMD), (iii) coronary flow reserve (CFR) by Doppler echocardiography, (iv) pulse wave velocity (PWV), (v) global left and right ventricular longitudinal strain (GLS), and (vi) malondialdehyde (MDA), an oxidative stress marker, thrombomodulin and von Willebrand factor as endothelial biomarkers. COVID‐19 patients had similar CFR and FMD as hypertensives (2.48 ± 0.41 vs. 2.58 ± 0.88, P = 0.562, and 5.86 ± 2.82% vs. 5.80 ± 2.07%, P = 0.872, respectively) but lower values than controls (3.42 ± 0.65, P = 0.0135, and 9.06 ± 2.11%, P = 0.002, respectively). Compared to controls, both COVID‐19 and hypertensives had greater PBR5–25 (2.07 ± 0.15 µm and 2.07 ± 0.26 µm, P = 0.8 vs. 1.89 ± 0.17 µm, P = 0.001), higher PWV (carotid–femoral PWV 12.09 ± 2.50 vs. 11.92 ± 2.94, P = 0.7 vs. 10.04 ± 1.80 m/s, P = 0.036) and impaired left and right ventricular GLS (−19.50 ± 2.56% vs. −19.23 ± 2.67%, P = 0.864 vs. −21.98 ± 1.51%, P = 0.020 and −16.99 ± 3.17% vs. −18.63 ± 3.20%, P = 0.002 vs. −20.51 ± 2.28%, P < 0.001). MDA and thrombomodulin were higher in COVID‐19 patients than both hypertensives and controls (10.67 ± 0.32 vs 1.76 ± 0.03, P = 0.003 vs. 1.01 ± 0.05 nmol/L, P = 0.001 and 3716.63 ± 188.36 vs. 3114.46 ± 179.18 pg/mL, P = 0.017 vs. 2590.02 ± 156.51 pg/mL, P < 0.001). Residual cardiovascular symptoms at 4 months were associated with oxidative stress and endothelial dysfunction markers. Conclusions: SARS‐CoV‐2 may cause endothelial and vascular dysfunction linked to impaired cardiac performance 4 months after infection.

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.

Imbalance between oxidative stress burden and antioxidant capacity is implicated in the course of atherosclerosis among type 2 diabetic patients. We addressed the effects of insulin, glucagon-like peptide-1 receptor agonists (GLP1-RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), and their combination on levels of oxidant and antioxidant biomarkers. We recruited a total of 160 type 2 diabetics, who received insulin (n = 40), liraglutide (n = 40), empagliflozin (n = 40), or their combination (GLP-1RA+SGLT-2i) (n = 40). We measured at baseline, at 4 and at 12 months of treatment: (a) Thiobarbituric Acid Reactive Substances (TBARS), (b) Malondialdehyde (MDA), (c) Reducing Power (RP), (d) 2,2¢-azino-bis-(3-ethylbenzthiazoline-6-sulphonic acid) radical (ABTS) and (e) Total Antioxidant Capacity TAC). Dual treatment resulted in significant improvement of TBARS, MDA, and ABTS at four months compared with the other groups (p < 0.05 for all comparisons). At twelve months, all participants improved TBARS, MDA, and ABTS (p < 0.05). At 12 months, GLP1-RA and GLP-1RA+SGLT2-i provided a greater reduction of TBARS (−8.76% and −9.83%) compared with insulin or SGLT2i (−0.5% and 3.22%), (p < 0.05). GLP1-RA and GLP-1RA+SGLT-2i showed a greater reduction of MDA (−30.15% and −31.44%) compared with insulin or SGLT2i (4.72% and −3.74%), (p < 0.05). SGLT2i and GLP-1RA+SGLT2-i showed increase of ABTS (12.87% and 14.13%) compared with insulin or GLP1-RA (2.44% and −3.44%), (p < 0.05). Only combined treatment resulted in increase of TAC compared with the other groups after 12 months of treatment (p < 0.05).12-month treatment with GLP1-RA and SGLT2i resulted in reduction of biomarkers responsible for oxidative modifications and increase of antioxidant biomarker, respectively. The combination treatment was superior and additive to each separate agent and also the beneficial effects appeared earlier.

Background: Hydroxytyrosol reduces low‐density lipoprotein oxidation, contributing to prevention of atherosclerosis progression.Methods: In a prospective, crossover, double‐blind, placebo‐controlled trial, 30 chronic coronary artery syndrome (CCAS) patients were randomized to 4 capsules/day, containing 412.5 mg olive oil with 2.5 mg hydroxytyrosol (OOHT) each one or placebo for 1 month and then were crossed over to the alternate treatment (placebo or OOHT). We measured (a) perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced glycocalyx thickness), (b) flow‐mediated dilation (FMD), (c) Coronary Flow Reserve (CFR) and markers of LV diastolic function by Doppler echocardiography, (d) pulse wave velocity (PWV), and (e) oxidative stress, inflammatory biomarkers and blood lipids at baseline and after treatment.Results: Treatment with OOHT improved PBR, FMD, CFR and PWV compared to baseline (1.8 ± .3 vs. 1.7 ± .4 μm, p = .040, 3.7 ± 2.1 vs. 6.5% ± 2.3%, p < .001, 2.3 ± .4 vs. 2.5 ± .4, p = .030 and 11.1 ± 1.8 vs. 11.8 ± 2.3 m/s, p = .002) while there was no effect after placebo (p = NS). No effect of OOHT treatment was observed on blood pressure. There was a parallel improvement of E' of the mitral annulus and deceleration time of the E wave of mitral inflow after OOHT (p < .05) but not after placebo. Compared to baseline, treatment with OOHT reduced malondialdehyde, a marker of lipid peroxidation, oxidized LDL, triglycerides, PCSK9 and CRP blood levels (p < .05) in contrast to placebo.Conclusions: Hydroxytyrosol‐enriched olive oil may have beneficial effects on endothelial, arterial and LV diastolic function likely by reducing oxidative and inflammatory burden in CCAS, though further studies are needed to confirm this mechanism.