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Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial.
Sposito, AC, Breder, I, Soares, AAS, Kimura-Medorima, ST, Munhoz, DB, Cintra, RMR, Bonilha, I, Oliveira, DC, Breder, JC, Cavalcante, P, et al
Cardiovascular diabetology. 2021;(1):74
Abstract
BACKGROUND The glucose-lowering independent effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on arterial wall function has not yet been clarified. This study aims to assess whether SGLT2i treatment can attenuate endothelial dysfunction related to type 2 diabetes mellitus (T2D) compared with glucose-lowering equivalent therapy. METHODS In a prospective, open-label, single-center, randomized clinical trial, 98 patients with T2DM and carotid intima-media thickness above the 75th percentile were randomized 1:1 to 12 weeks of therapy with dapagliflozin or glibenclamide in addition to metformin in glucose-lowering equivalent regimens. The coprimary endpoints were 1-min flow-mediated dilation (FMD) at rest and 1-min FMD after 15 min of ischemia followed by 15 min of reperfusion time (I/R). RESULTS Ninety-seven patients (61% males, 57 ± 7 years) completed the study. The median HbA1c decreased by - 0.8 (0.7)% and -0.7 (0.95)% following dapagliflozin and glibenclamide, respectively. The first coprimary endpoint, i.e., rest FMD changed by + 3.3(8.2)% and - 1.2(7.5)% for the dapagliflozin and glibenclamide arms, respectively (p = 0.0001). Differences between study arms in the second coprimary endpoint were not significant. Plasma nitrite 1 min after rest FMD was higher for dapagliflozin [308(220) nmol/L] than for glibenclamide (258[110] nmol/L; p = 0.028). The resistive indices at 1 min [0.90 (0.11) vs. 0.93 (0.07); p = 0.03] and 5 min [0.93 (0.07) vs. 0.95 (0.05); p = 0.02] were higher for the glibenclamide group than for the dapagliflozin group. Plasma biomarkers for inflammation and oxidative stress did not differ between the treatments. CONCLUSIONS Dapagliflozin improved micro- and macrovascular endothelial function compared to glibenclamide, regardless of glycemic control in patients with T2DM and subclinical carotid atherosclerotic disease.
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Effects of indulgent food snacking, with and without exercise training, on body weight, fat mass, and cardiometabolic risk markers in overweight and obese men.
Tucker, WJ, Jarrett, CL, D'Lugos, AC, Angadi, SS, Gaesser, GA
Physiological reports. 2021;(22):e15118
Abstract
We hypothesized that exercise training would prevent gains in body weight and body fat, and worsening of cardiometabolic risk markers, during a 4-week period of indulgent food snacking in overweight/obese men. Twenty-eight physically inactive men (ages 19-47 yr) with body mass index (BMI) ≥25 kg/m2 consumed 48 donuts (2/day, 6 days/week; ~14,500 kcal total) for 4 weeks while maintaining habitual diet. Men were randomly assigned to control (n = 9), moderate-intensity continuous training (MICT; n = 9), or high-intensity interval training (HIIT; n = 10). Exercise training occurred 4 days/week, ~250 kcal/session. Controls did not increase body weight, body fat, or visceral abdominal fat. This was partially explained by a decrease in self-reported habitual energy (-239 kcal/day, p = 0.05) and carbohydrate (-47 g/day; p = 0.02) intake. Large inter-individual variability in changes in body weight, fat, and fat-free mass was evident in all groups. Fasting blood pressure, and blood concentrations of glucose, insulin, and lipids were unchanged in all groups. Glucose incremental area under the curve during an oral glucose tolerance test was reduced by 25.6% in control (p = 0.001) and 32.8% in MICT (p = 0.01) groups. Flow-mediated dilation (FMD) was not changed in any group. VO2max increased (p ≤ 0.001) in MICT (9.2%) and HIIT (12.1%) groups. We conclude that in physically inactive men with BMI ≥25 kg/m2 , consuming ~14,500 kcal as donuts over 4 weeks did not adversely affect body weight and body fat, or several markers of cardiometabolic risk. Consumption of the donuts may have prevented the expected improvement in FMD with HIIT.
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Efficacy of dulaglutide on vascular health indexes in subjects with type 2 diabetes: a randomized trial.
Tuttolomondo, A, Cirrincione, A, Casuccio, A, Del Cuore, A, Daidone, M, Di Chiara, T, Di Raimondo, D, Corte, VD, Maida, C, Simonetta, I, et al
Cardiovascular diabetology. 2021;(1):1
Abstract
BACKGROUND Recent cardiovascular outcome trials have shown significant reductions in major cardiovascular (CV) events with glucagon-like peptide (GLP)-1 receptor agonists. Additionally, adjunctive surrogates for cardiovascular risk validated by some studies include arterial stiffness and endothelial function indexes. To date, no randomized trial has addressed the possible effects of antidiabetic interventional drugs such as GLP1 agonists on endothelial and arterial stiffness indexes as surrogate markers of vascular damage. AIMS We aimed to evaluate metabolic efficacy and surrogate vascular efficacy endpoints of once-weekly dulaglutide (1.5 mg) plus traditional antidiabetic treatment compared with traditional antidiabetic treatment alone in subjects with type 2 diabetes. METHODS Men and women (aged ≥ 50 years) with established or newly detected type 2 diabetes whose HbA1c level was 9.5% or less on stable doses of up to two oral glucose- lowering drugs with or without basal insulin therapy were eligible for randomization. Subcutaneous dulaglutide was initiated at the full dose (1.5 mg/day weekly). Arterial stiffness (PWV: pulse wave velocity and augmentation index) and endothelial function (RHI: reactive hyperaemia index) were evaluated at baseline and at three-month and nine-month examination visits. At each visit (at 3 and 9 months), the subjects were also evaluated for glycaemic variables such as fasting plasma glucose (FPG) and HbA1c and lipid variables such as total cholesterol, LDL cholesterol, HDL cholesterol and triglyceride levels. RESULTS At the three-month follow-up, the subjects treated with dulaglutide showed significantly lower serum levels of FPG and HbA1c than control subjects treated with conventional therapy. At the 9-month follow-up, subjects treated with dulaglutide showed significant lower values of the mean diastolic blood pressure, BMI, total serum cholesterol, LDL cholesterol, FPG, HbA1c and PWV and higher mean RHI values than control subjects treated with conventional therapy. CONCLUSIONS Our randomized trial showed that subjects with type 2 diabetes treated with conventional therapy plus 1.5 mg/day of subcutaneous dulaglutide compared with subjects treated with conventional therapy alone showed favourable metabolic effects associated with positive effects on vascular health markers such as arterial stiffness and endothelial function markers. These findings are consistent with previous study findings indicating the strict relationship between cardiovascular risk factors such as systolic blood pressure, total serum cholesterol and LDL levels and cardiovascular events and vascular health surrogate markers.
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Acute consumption of flavanol-rich cocoa beverage improves attenuated cutaneous microvascular function in healthy young African Americans.
Kim, K, Brothers, RM
Microvascular research. 2020;:103931
Abstract
Flavanols have beneficial effects on vascular health and we have recently demonstrated that cerebral vasodilatory capacity in healthy young African Americans (AA) is improved with acute flavanol intake relative to aged-matched Caucasian Americans (CA). However, whether the positive benefits of acute flavanol consumption would also be present in the cutaneous microvascular circulation of AA remains unknown. Thus, we hypothesized that acute consumption of flavanol-rich cocoa (FC) would improve the previously reported reduced cutaneous microvascular responses to local heating in young AA. Seven AA and seven CA participated in this double-blind crossover study. Data were collected on two different days, separated by a minimum of one week. Two intradermal microdialysis membranes were inserted in the forearm and each site was randomly assigned to receive lactated Ringer's solution or NO synthase (NOS) inhibitor. Participants were randomly assigned to consume either a non-flavanol containing (NF) beverage or FC beverage. Cutaneous vascular conductance (CVC) was calculated as cutaneous blood flux/mean arterial pressure and normalized as % maximal CVC (%CVCmax). The difference in %CVCmax between the Ringer's site and NOS inhibited site was calculated to assess NO contribution (Δ %CVCmax). In the Ringer's site, acute consumption of FC beverage improved %CVCmax during 39 °C heating when compared to NF beverage in AA (NF: 36 ± 6 vs. FC: 47 ± 5%CVCmax; P < .01) while there was similar %CVCmax during 39 °C heating between beverages in CA (NF: 55 ± 4 vs. FC: 59 ± 5%CVCmax; P = .40). During 39 °C heating, NO contribution was significantly higher with FC beverage than NF beverage in AA (NF: 27 ± 5 vs. FC: 35 ± 4 Δ %CVCmax; P = .03) while there was similar NO contribution between beverages in CA (NF: 42 ± 4 vs. FC: 45 ± 4 Δ %CVCmax; P = .36). This data suggests that acute consumption of FC could be a therapeutic solution to improve an attenuated microvascular function in young AA.
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Increased fractalkine and vascular dysfunction in obesity and in type 2 diabetes. Effects of oral antidiabetic treatment.
Schinzari, F, Tesauro, M, Campia, U, Cardillo, C
Vascular pharmacology. 2020;:106676
Abstract
Activation of fractalkine and other chemokines plays an important role in atherogenesis and, in conjunction with endothelial dysfunction, promotes premature vascular damage in obesity and diabetes. We hypothesized that increased circulating fractalkine coexists with impaired vasomotor function in metabolically healthy or unhealthy obesity, and that treatment with antidiabetic drugs may impact these abnormalities in type 2 diabetes. Compared to lean subjects, in both obese groups the vasodilator responses to acetylcholine and sodium nitroprusside were impaired (both P < .001); ETA-receptor blockade resulted in greater vasodilation (both P < .001); and plasma levels of fractalkine, E-selectin and monocyte chemoattractant protein (MCP)-1 were increased (all P < .05). In diabetic patients, oral antidiabetic drugs (glyburide, metformin or pioglitazone) reduced circulating levels fractalkine and E-selectin (both P < .05), without affecting vascular responses (all P > .05). Our findings indicate that insulin resistant states are associated with elevated atherogenic chemokines and impaired vascular reactivity. Antidiabetic treatment results in lower circulating fractalkine, which may provide cardiovascular benefits.
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Dietary nitrate does not acutely enhance skeletal muscle blood flow and vasodilation in the lower limbs of older adults during single-limb exercise.
Hughes, WE, Kruse, NT, Ueda, K, Feider, AJ, Hanada, S, Bock, JM, Casey, DP
European journal of applied physiology. 2020;(6):1357-1369
Abstract
PURPOSE Blood flow (BF) and vasodilator responses to knee-extension exercise are attenuated in older adults across an exercise transient (onset, kinetics, and steady-state), and reduced nitric oxide bioavailability (NO) has been hypothesized to be a primary mechanism contributing to this attenuation. We tested the hypothesis acute dietary nitrate (NO3-) supplementation (~ 4.03 mmol NO3- and 0.29 mmol NO2-) would improve leg vasodilator responses across an exercise transient during lower limb exercise in older adults. METHODS Older (n = 10) untrained adults performed single and rhythmic knee-extension contractions at 20% and 40% work-rate maximum (WRmax) prior to and 2-h after consuming a NO3- or placebo beverage in a double-blind, randomized fashion. Femoral artery BF was measured by Doppler ultrasound. Vascular conductance was calculated using BF and mean arterial pressure. RESULTS Acute ingestion of dietary NO3- enhanced plasma [NO3-] and [NO2-] (P < 0.05). Neither dietary NO3- or placebo enhanced vasodilator responses at the onset of exercise or during steady state at 20% and 40% WRmax (P > 0.05). Leg vasodilator kinetics during rhythmic exercise remained unchanged following NO3- and placebo ingestion (P > 0.05). CONCLUSIONS The key findings of this study are that despite increasing plasma [NO3-] and [NO2-], acute dietary NO3- intake had no effect on (1) rapid hyperaemic or vasodilator responses at the onset of exercise; (2) hyperaemic and vasodilator responses during steady-state submaximal exercise; or (3) kinetics of vasodilation preceding steady-state responses. Collectively, these findings suggest that low dose dietary NO3- supplementation does not improve hyperaemic and vasodilator responses across an exercise transient in older adults.
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Acute Exenatide Therapy Attenuates Postprandial Vasodilation in Humans with Prediabetes: A Randomized Controlled Trial.
Hamidi, V, Riggs, K, Zhu, L, Bermudez Saint Andre, K, Westby, C, Coverdale, S, Dursteler, A, Wang, H, Miller Iii, C, Taegtmeyer, H, et al
Metabolic syndrome and related disorders. 2020;(5):225-233
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Abstract
Background: The state of prediabetes comprises atherosclerotic changes leading to decreased vascular function in humans. This study examined the effects on incretin mimetics on vascular physiology in the prediabetic postprandial state. Methods: Fifteen obese adults with prediabetes participated in a randomized, crossover, double-blinded trial comparing the postprandial effects of exenatide, saxagliptin, and placebo on peripheral vasodilation. All studies utilized a standardized high-fat meal. Resting and peak forearm blood flow (FBF) were measured via strain gauge venous occlusion plethysmography, and makers of vascular dysfunction were measured in plasma. Results: Exenatide attenuated resting FBF at 3 hr (P = 0.003) and 6 hr (P = 0.056) postmeal, compared to placebo. Nonsignificant reductions in resting FBF were observed between saxagliptin and placebo at the same time points. No group differences were observed for peak FBF, plasma nitrotyrosine, and plasma 8-iso-prostaglandin F2alpha. A transient increase in plasma triglyceride was abated in the exenatide group, when compared to saxagliptin and placebo groups. Only exenatide group showed no significant upsurge in plasma insulin. Plasma-free fatty acids significantly declined in all three groups, although less markedly for exenatide. Postmeal glucose increased at 2 hr with placebo and saxagliptin, but simultaneously decreased with exenatide. Conclusions: Acute treatment with exenatide blunted the postprandial vasodilatory effect of a high-fat meal in prediabetes. Exenatide's acute effects derived primarily from multiple endothelium-independent processes. Trial Registration Number: NCT02104739.
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Ubiquinol Ameliorates Endothelial Dysfunction in Subjects with Mild-to-Moderate Dyslipidemia: A Randomized Clinical Trial.
Sabbatinelli, J, Orlando, P, Galeazzi, R, Silvestri, S, Cirilli, I, Marcheggiani, F, Dludla, PV, Giuliani, A, Bonfigli, AR, Mazzanti, L, et al
Nutrients. 2020;(4)
Abstract
In this randomized, double-blind, single-center trial (ANZCTR number ACTRN12619000436178) we aimed to investigate changes in endothelium-dependent vasodilation induced by ubiquinol, the reduced form of coenzyme Q10 (CoQ10), in healthy subjects with moderate dyslipidemia. Fifty-one subjects with low-density lipoprotein (LDL) cholesterol levels of 130-200 mg/dL, not taking statins or other lipid lowering treatments, moderate (2.5%-6.0%) endothelial dysfunction as measured by flow-mediated dilation (FMD) of the brachial artery, and no clinical signs of cardiovascular disease were randomized to receive either ubiquinol (200 or 100 mg/day) or placebo for 8 weeks. The primary outcome measure was the effect of ubiquinol supplementation on FMD at the end of the study. Secondary outcomes included changes in FMD on week 4, changes in total and oxidized plasma CoQ10 on week 4 and week 8, and changes in serum nitrate and nitrite levels (NOx), and plasma LDL susceptibility to oxidation in vitro on week 8. Analysis of the data of the 48 participants who completed the study demonstrated a significantly increased FMD in both treated groups compared with the placebo group (200 mg/day, +1.28% ± 0.90%; 100 mg/day, +1.34% ± 1.44%; p < 0.001) and a marked increase in plasma CoQ10, either total (p < 0.001) and reduced (p < 0.001). Serum NOx increased significantly and dose-dependently in all treated subjects (p = 0.016), while LDL oxidation lag time improved significantly in those receiving 200 mg/day (p = 0.017). Ubiquinol significantly ameliorated dyslipidemia-related endothelial dysfunction. This effect was strongly related to increased nitric oxide bioavailability and was partly mediated by enhanced LDL antioxidant protection.
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Effects of Beetroot Powder with or without L-Arginine on Postprandial Vascular Endothelial Function: Results of a Randomized Controlled Trial with Abdominally Obese Men.
Smeets, ETHC, Mensink, RP, Hoeks, J, de Vogel-Van den Bosch, J, Hageman, RJJ, Joris, PJ
Nutrients. 2020;(11)
Abstract
BACKGROUND Through effects on nitric oxide bioavailability, vascular endothelial function is improved after the intake of a high amount of nitrate or L-arginine, but decreased after the intake of a high-fat meal. Therefore, we compared the effects of beetroot powder with or without L-arginine on postprandial brachial artery flow-mediated vasodilation (FMD) after consumption of a high-fat mixed-meal. METHODS Eighteen abdominally obese men completed this randomized, double-blinded, cross-over trial. The study consisted of five test days, each separated by a wash-out period of at least one week. Participants received in random order, a blended meal with a control or nutritional supplement consisting of beetroot powder providing 200 mg nitrate, beetroot with 0.8 g of L-arginine, beetroot with 1.5 g of L-arginine, or 3.0 g of L-arginine. Participants then fasted and 2 h postprandial FMD measurements were performed. RESULTS No significant differences between meals were observed for postprandial FMD (p = 0.45) levels. However, there was a non-significant trend towards a more beneficial postprandial FMD response with the beetroot-containing meals as compared with meals without beetroot. CONCLUSION This trial could not provide evidence for beneficial additive effects of a single dose of beetroot powder combined with L-arginine on postprandial endothelial function in abdominally obese men.
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Combination Treatment with Sodium Nitrite and Isoquercetin on Endothelial Dysfunction among Patients with CKD: A Randomized Phase 2 Pilot Trial.
Chen, J, Hamm, LL, Bundy, JD, Kumbala, DR, Bodana, S, Chandra, S, Chen, CS, Starcke, CC, Guo, Y, Schaefer, CM, et al
Clinical journal of the American Society of Nephrology : CJASN. 2020;(11):1566-1575
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Abstract
BACKGROUND AND OBJECTIVES Endothelial dysfunction is common among patients with CKD. We tested the efficacy and safety of combination treatment with sodium nitrite and isoquercetin on biomarkers of endothelial dysfunction in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This randomized, double-blind, placebo-controlled phase 2 pilot trial enrolled 70 patients with predialysis CKD. Thirty-five were randomly assigned to combination treatment with sodium nitrite (40 mg twice daily) and isoquercetin (225 mg once daily) for 12 weeks, and 35 were randomly assigned to placebo. The primary outcome was mean change in flow-mediated vasodilation over the 12-week intervention. Secondary and safety outcomes included biomarkers of endothelial dysfunction, inflammation, and oxidative stress as well as kidney function, methemoglobin, and adverse events. Intention-to-treat analysis was conducted. RESULTS Baseline characteristics, including age, sex, race, cigarette smoking, history of hypertension and diabetes, use of renin-angiotensin system blockers, BP, fasting glucose, lipid profile, kidney function, urine albumin-creatinine ratio, and endothelial biomarkers, were comparable between groups. Over the 12-week intervention, flow-mediated vasodilation increased 1.1% (95% confidence interval, -0.1 to 2.3) in the treatment group and 0.3% (95% confidence interval, -0.9 to 1.5) in the placebo group, and net change was 0.8% (95% confidence interval, -0.9 to 2.5). In addition, changes in biomarkers of endothelial dysfunction (vascular adhesion molecule-1, intercellular adhesion molecule-1, E-selectin, vWf, endostatin, and asymmetric dimethylarginine), inflammation (TNF-α, IL-6, C-reactive protein, IL-1 receptor antagonist, and monocyte chemoattractant protein-1), and oxidative stress (oxidized LDL and nitrotyrosines) were not significantly different between the two groups. Furthermore, changes in eGFR, urine albumin-creatinine ratio, methemoglobin, and adverse events were not significantly different between groups. CONCLUSIONS This randomized phase 2 pilot trial suggests that combination treatment with sodium nitrite and isoquercetin did not significantly improve flow-mediated vasodilation or other endothelial function biomarkers but also did not increase adverse events compared with placebo among patients with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER Nitrite, Isoquercetin, and Endothelial Dysfunction (NICE), NCT02552888.