Effect of empagliflozin on brachial artery shear stress and endothelial function in subjects with type 2 diabetes: Results from an exploratory study

Empagliflozin reduces the risk of cardiovascular mortality in subjects with type 2 diabetes. We demonstrated that empagliflozin increases blood viscosity and carotid shear stress and decreases carotid wall thickness. Shear stress is the force acting on the endothelial surface and modulates arterial function. The current study evaluates the influence of empagliflozin on brachial artery shear stress and endothelial function compared to incretin-based therapy. The study is a nonrandomized, open, prospective cohort study including 35 subjects with type 2 diabetes administered empagliflozin or incretin-based therapy. Shear stress was calculated with a validated formula, and endothelial function was evaluated using the flow-mediated dilation technique. Both treatments resulted in comparable reductions in blood glucose and glycated haemoglobin. Brachial artery shear stress significantly increased exclusively in the empagliflozin group (61 ± 20 vs 68 ± 25 dynes/cm2, p = 0.04), whereas no significant difference was detected in the incretin-based therapy group (60 ± 20 vs 55 ± 12 dynes/cm2, p = not significant). Flow-mediated dilation significantly increased in the empagliflozin group (4.8 ± 4.5% vs 8.5 ± 5.6%, p = 0.03). Again, no change was detected in the incretin-based therapy group (5.1 ± 4.5% vs 4.7 ± 4.7%, p = not significant). The present findings demonstrate the beneficial effect of empagliflozin on shear stress and endothelial function in subjects with type 2 diabetes independent of the hypoglycaemic effect.

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Sitagliptin on carotid intima-media thickness in type 2 diabetes and hyperuricemia patients: a subgroup analysis of the PROLOGUE study

Therapeutic Advances in Chronic Disease ◽

10.1177/20406223211026993 ◽

2021 ◽

Vol 12 ◽

pp. 204062232110269

Author(s):

Yipin Zhao ◽

Huawei Wang ◽

Dazhi Ke ◽

Wei Deng ◽

Yingying Ji ◽

...

Keyword(s):

Type 2 Diabetes ◽

Carotid Artery ◽

Conventional Therapy ◽

Therapy Group ◽

Controlled Trial ◽

Intima Media Thickness ◽

Carotid Intima Media Thickness ◽

Media Thickness ◽

Significant Difference

Background and Aims: Studies have shown that dipeptidyl peptidase-4 (DDP-4) inhibitors have anti-atherosclerotic effects. However, in the PROLOGUE study, sitagliptin failed to slow the progression of carotid intima-media thickness (CIMT) relative to conventional therapy. We conducted a post hoc analysis of the PROLOGUE study and compared the effects of sitagliptin and conventional therapy on changes in CIMT in subgroups with or without hyperuricemia. Methods: The PROLOGUE study was a randomized controlled trial of 442 patients with type 2 diabetes mellitus (T2DM). Patients were randomized to receive sitagliptin added therapy or conventional therapy. Based on the serum uric acid levels of all study populations in the PROLOGUE study, we divided them into hyperuricemia subgroup ( n = 104) and non-hyperuricemia subgroup ( n = 331). The primary outcome was changed in carotid intima-media thickness (CIMT) parameters compared with baseline during the 24 months treatment period. Results: In the hyperuricemia subgroup, compared with the conventional therapy group, the changes in the mean internal carotid artery (ICA)-IMT and max ICA-IMT at 24 months were significantly lower in the sitagliptin group [−0.233 mm, 95% confidence interval (CI) (−0.419 to 0.046), p = 0.015 and −0.325 mm, 95% CI (−0.583 to −0.068), p = 0.014], although there was no significant difference in the common carotid artery CIMT. Conclusion: The results of our analysis indicated that sitagliptin attenuated the progression of CIMT than conventional therapy in T2DM and hyperuricemia patients.

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Acute Endothelial Benefits of Fat Restriction over Carbohydrate Restriction in Type 2 Diabetes Mellitus: Beyond Carbs and Fats

Nutrients ◽

10.3390/nu10121859 ◽

2018 ◽

Vol 10 (12) ◽

pp. 1859 ◽

Cited By ~ 2

Author(s):

Renate Barbosa-Yañez ◽

Ulrike Dambeck ◽

Linna Li ◽

Jürgen Machann ◽

Stefan Kabisch ◽

...

Keyword(s):

Type 2 Diabetes ◽

Adipose Tissue ◽

Endothelial Function ◽

Body Fat ◽

Protein Intake ◽

Diet Group ◽

Flow Mediated Dilation ◽

Reduced Body ◽

Diabetes Patients

Background: Cardiovascular diseases (CVD) are the major cause of mortality in type 2 diabetes patients (T2DM). The causes are embedded in a complex interplay between excess body fat, insulin resistance and serum lipid anomalies. Endothelial homeostasis is strongly affected by this pathogenic network. Even though metabolic changes and weight loss improve vascular endothelial function, the effect of different dietary approaches is still uncertain for type 2 diabetes patients. Objective: We aimed to compare the acute effects of a hypocaloric very low carbohydrate (VLC) diet versus a hypocaloric low fat (LF) diet on flow mediated dilation (FMD), intrahepatic lipid (IHL) accumulation and visceral adipose tissue as independent risk factors of CVD in T2DM patients. Design: 36 T2DM patients (age 63 ± 8 years, 60% females) were randomly assigned to the VLC diet (4–10% of total energy intake (E)) or to the LF diet (<30% E) for 3 weeks. Endothelial function was assessed by the flow mediated dilation (FMD) method. Adipose tissue depots and IHL were determined by magnetic resonance. Results: Both dietary strategies reduced body weight, body fat content and IHL. Unexpectedly, the LF group experienced significantly greater enhancement of FMD, compared to the VLC group. The FMD showed a positive correlation with protein intake and fat intake in the LF group, while it revealed a negative correlation with protein intake in the VLC diet group. Conclusions: Reduction of total and hepatic adiposity was shown to be successful using either the VLC or LF hypocaloric diets, however, improvements in FMD may be related to the interplay of fat and protein intake.

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Comparison of brachial artery flow-mediated dilation in youth with type 1 and type 2 diabetes mellitus

Journal of Diabetes Investigation ◽

10.1111/jdi.12191 ◽

2014 ◽

Vol 5 (5) ◽

pp. 615-620 ◽

Cited By ~ 6

Author(s):

Koji Ohsugi ◽

Hidenori Sugawara ◽

Kanako Ebina ◽

Kentaro Shiga ◽

Nobuyuki Kikuchi ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Brachial Artery ◽

Flow Mediated Dilation ◽

Artery Flow

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PS 17-18 DYNAMICS OF PARAMETERS OF ENDOTHELIAL FUNCTION IN PATIENTS WITH TYPE 2 DIABETES ACCORDING TO FLOW-MEDIATED DILATION DURING THE CPAP-THERAPY

Journal of Hypertension ◽

10.1097/01.hjh.0000501280.33564.8b ◽

2016 ◽

Vol 34 (Supplement 1) ◽

pp. e478-e479

Author(s):

Valentin Oleynikov ◽

Nadezhda Burko ◽

Lyudmila Salyamova ◽

Natalia Borisova

Keyword(s):

Type 2 Diabetes ◽

Endothelial Function ◽

Flow Mediated Dilation ◽

Cpap Therapy

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Effects of Dapagliflozin on Endothelial Dysfunction in Type 2 Diabetes With Established Ischemic Heart Disease (EDIFIED)

Journal of the Endocrine Society ◽

10.1210/jendso/bvz017 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 3

Author(s):

Nur Aisyah Zainordin ◽

Sharifah Faradilla Wan Muhamad Hatta ◽

Fatimah Zaherah Mohamed Shah ◽

Thuhairah Abdul Rahman ◽

Nurhuda Ismail ◽

...

Keyword(s):

Type 2 Diabetes ◽

Heart Disease ◽

Placebo Group ◽

High Risk ◽

Endothelial Function ◽

Ischemic Heart Disease ◽

Ischemic Heart ◽

Surrogate Markers ◽

Significant Difference

Abstract Objectives To evaluate the effect of the sodium-glucose cotransporter 2 inhibitor (SGLT2-I) dapagliflozin on endothelial function in patients with high-risk type 2 diabetes mellitus (T2DM). Methods This was a prospective, double-blind, randomized, placebo-controlled, clinical trial of patients with T2DM with underlying ischemic heart disease who were receiving metformin and insulin therapy (n = 81). After 12-weeks of additional therapy with either dapagliflozin (n = 40) or placebo (n = 41), systemic endothelial function was evaluated by change in flow-mediated dilation (ΔFMD), change in nitroglycerin-mediated dilation (ΔNMD) and surrogate markers including intercellular adhesion molecule 1 (ICAM-1), endothelial nitric oxide synthase (eNOS), high-sensitivity C-reactive protein (hs-CRP), and lipoprotein(a) (Lp[a]). Glycemic and lipid profiles were also measured. Results The dapagliflozin group demonstrated significant reductions of hemoglobin A1c (HbA1c) and fasting blood glucose (FBG) compared to the placebo group (ΔHbA1c –0.83 ± 1.47% vs –0.16 ± 1.25%, P = 0.042 and ΔFBG vs –0.73 ± 4.55 mmol/L vs –1.90 ± 4.40 mmol/L, P = 0.015, respectively). The placebo group showed worsening of ΔFMD while the dapagliflozin group maintained similar measurements pre- and posttherapy (P = not significant). There was a reduction in ICAM-1 levels in the dapagliflozin group (–83.9 ± 205.9 ng/mL, P < 0.02), which remained unchanged in the placebo group (–11.0 ± 169.1 ng/mL, P = 0.699). Univariate correlation analysis revealed a significant negative correlation between HbA1c and ΔFMD within the active group. Conclusion A 12-week therapy with dapagliflozin, in addition to insulin and metformin therapies, in high-risk patients resulted in significant reductions in HbA1c, FBG, and surrogate markers of the endothelial function. Although the dapagliflozin group demonstrated a significant association between reduction in HbA1c and improvement in FMD, there was no significant difference in FMD between the 2 groups.

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The OPT2MISE Study – A Review of the Major Findings and Clinical Implications

US Endocrinology ◽

10.17925/use.2015.11.02.105 ◽

2015 ◽

Vol 11 (02) ◽

pp. 105

Author(s):

Yves Reznik ◽

Michael Joubert ◽

◽

Keyword(s):

Type 2 Diabetes ◽

Glycaemic Control ◽

Therapy Group ◽

Insulin Dose ◽

Glycated Haemoglobin ◽

Target Range ◽

Insulin Regimen ◽

Pump Therapy ◽

Multiple Injections

Many patients with type 2 diabetes struggle to achieve adequate glucose control despite escalation of therapy including complex insulin regimens with multiple daily injections (MDIs). Previous randomised controlled trials failed to show a significant improvement in glycaemic control with pump therapy over multiple injections. The OPT2MISE study enrolled 495 adult patients with poorly controlled type 2 diabetes despite an intensified insulin regimen using rapid and slow-acting insulin analogues. After a 2-month run-in period, patients were randomised to switch to pump therapy or to maintain their MDI regimen. After 6 months, patients with pump therapy achieved a better glycaemic control than those who used multiple injections (glycated haemoglobin [HbA1c] difference of -0.7 %), and twice as many patients reached the target range of 8 % or less in the pump-therapy group compared with the injection group. Patients using pump therapy had a 20 % reduction of their total daily insulin dose. A moderate weight gain was observed with both treatments, and no severe hypoglycaemia nor ketoacidosis occurred in the pump therapy group. Pump therapy may now be considered as a valuable option in type 2 diabetes patients who fail to respond to an intensified insulin regimen.

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The OPT2MISE Study – A Review of the Major Findings and Clinical Implications

European Endocrinology ◽

10.17925/ee.2015.11.02.70 ◽

2015 ◽

Vol 11 (2) ◽

pp. 70 ◽

Cited By ~ 3

Author(s):

Yves Reznik ◽

Michael Joubert ◽

◽

Keyword(s):

Type 2 Diabetes ◽

Glycaemic Control ◽

Therapy Group ◽

Insulin Dose ◽

Glycated Haemoglobin ◽

Target Range ◽

Insulin Regimen ◽

Pump Therapy ◽

Multiple Injections

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Association of the polymorphism in the androgen receptor gene and endothelial function in men with type 2 diabetes

Diabetes Mellitus ◽

10.14341/dm7622 ◽

2015 ◽

Vol 18 (4) ◽

pp. 35-40 ◽

Cited By ~ 2

Author(s):

Irina Alekseevna Khripun ◽

Sergey Vladislavovich Vorobyev ◽

Michael Iosifovich Kogan

Keyword(s):

Type 2 Diabetes ◽

Lipid Metabolism ◽

Androgen Receptor ◽

Endothelial Function ◽

Flow Velocity ◽

Brachial Artery ◽

Cag Repeats ◽

Atherogenic Index ◽

Brachial Artery Diameter

In recent years, actively studied the effect of androgen deficiency on the cardiovascular system, including endothelial function. Genomic effects of testosterone caused by the length of CAG repeats polymorphism in the androgen receptor (AR) gene.Aim. To examine the association of the polymorphism in the AR gene and carbohydrate, lipid metabolism, endothelial function in men with type 2 diabetes.Materials and methods. We examined 88 men, aged 40-65 years (mean age 53±6,4years) with type 2 diabetes. All patients underwent the study of carbohydrate and lipid metabolism, the assessment of vasomotor endothelial function of the brachial artery by ultrasound sonography, were studied biochemical markers of endothelial dysfunction – ICAM-1, VCAM-1, p-selectin, e-selectin, resistin and number of CAG-repeats in the AR gene. Statistical analysis was performed using the application package SPSS 21,0 using regression analysis.Results. The number of CAG repeats had a significant positive regression to the level of total testosterone, a weak negative regression of the number of CAG repeats in the AR gene and lipid metabolism: triglycerides, LDL, atherogenic index. The assessment of the brachial artery ultrasonography revealed negative regression of the baseline brachial artery diameter and blood flow velocity in the endothelium-dependent vasodilation. The number of CAG repeats was significantly correlated with the levels of p-selectin and resistin. Thus, increasing the number of CAG repeats in the AR gene via a weakening of sensitivity to androgens leads to disruption of endothelial function in men with type 2 diabetes. Increasing the number of CAG repeats in the AR gene leads to deterioration of linear flow velocity during the test with reactive hyperemia with increasing production of p-selectin and resistin.Conclusions. The number of CAG repeats in the AR gene can be regarded as a predictor of the development and progression of cardiovascular lesions in men with type 2 diabetes.

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Examining the acute effects of retrograde versus low mean shear rate on flow-mediated dilation

Journal of Applied Physiology ◽

10.1152/japplphysiol.01065.2018 ◽

2019 ◽

Vol 126 (5) ◽

pp. 1335-1342 ◽

Cited By ~ 8

Author(s):

Joshua C. Tremblay ◽

Arman S. Grewal ◽

Kyra E. Pyke

Keyword(s):

Shear Stress ◽

Shear Rate ◽

Endothelial Function ◽

Brachial Artery ◽

Duplex Ultrasound ◽

Flow Mediated Dilation ◽

Relative Contribution ◽

Stress Components ◽

Retrograde Shear

Arterial endothelial function is acutely and chronically regulated by blood flow-associated shear stress. An acute intervention employing modest forearm cuff occlusion to simultaneously increase retrograde and decrease mean brachial artery shear rate for 30 min evokes transient impairments in flow-mediated dilation (FMD). However, the independent influence of the low mean versus the retrograde shear stress components is unclear. Healthy young adults [ n = 24 (12 women, 12 men); 22 ± 2 yr, body mass index = 25 ± 2 kg/m2 (mean ± SD)] completed three laboratory visits within 1 wk. Visits consisted of 45 min of supine rest followed by a brachial artery FMD test (duplex ultrasound) before and after a 30-min intervention: control (shear rate unchanged), cuff (mean shear rate decreased, retrograde shear rate increased), or arterial compression (mean shear rate decreased, no increase in retrograde shear rate). The mean shear rate on the compression visit was targeted to match that achieved on the cuff visit. Cuff and compression trials decreased mean shear rate to a similar extent (cuff: 43 ± 22 s−1, compression: 43 ± 21 s−1; P = 0.850) compared with control (65 ± 21 s−1; both P < 0.001), with the retrograde component elevated only in the former (cuff: −83 ± 30 s−1, compression: −7 ± 5 s−1; P < 0.001). FMD decreased by 29 ± 30% ( P < 0.001) after the cuff intervention and 32 ± 24% ( P < 0.001) after the compression trial but was unchanged on the control visit (−0.3 ± 18%; P = 0.754). This was not altered by accounting for the shear rate stimulus. An increased retrograde shear stress does not appear to be obligatory for the transient reduction in FMD achieved after a 30-min exposure to low mean shear stress. These findings provide novel mechanistic insight on the regulation of endothelial function in vivo. NEW & NOTEWORTHY Low mean and retrograde shear stress are considered atherogenic; however, their relative contribution to the acute regulation of endothelial function in humans is unclear. Matched reductions in mean shear stress (30 min), with and without increases in retrograde shear stress, elicited equivalent reductions in flow-mediated dilation in men and women. These findings afford novel insight regarding the shear stress components governing the acute (dys)regulation of conduit artery endothelial function in vivo.

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Relationship between changes in brachial artery flow-mediated dilation and basal release of nitric oxide in subjects with Type 2 diabetes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01176.2005 ◽

2006 ◽

Vol 291 (3) ◽

pp. H1193-H1199 ◽

Cited By ~ 15

Author(s):

Daniel J. Green ◽

Andrew J. Maiorana ◽

Michael E. Tschakovsky ◽

Kyra E. Pyke ◽

Cara J. Weisbrod ◽

...

Keyword(s):

Nitric Oxide ◽

Type 2 Diabetes ◽

Brachial Artery ◽

Control Period ◽

Angiotensin Ii Receptor Blocker ◽

Flow Mediated Dilation ◽

Basal Resistance ◽

Resistance Vessel ◽

Conduit Artery

Assessment of flow-mediated dilation (FMD) after forearm ischemia is widely used as a noninvasive bioassay of stimulated nitric oxide (NO)-mediated conduit artery vasodilator function in vivo. Whether this stimulated endothelial NO function reflects basal endothelial NO function is unknown. To test this hypothesis, retrospective analysis of randomized crossover studies was undertaken in 17 subjects with Type 2 diabetes; 9 subjects undertook an exercise training or control period, whereas the remaining 8 subjects were administered an angiotensin II receptor blocker or placebo. FMD was assessed by using wall tracking of high-resolution brachial artery ultrasound images in response to reactive hyperemia. Resistance vessel basal endothelium-dependent NO function was assessed by using intrabrachial administration of NG-monomethyl-l-arginine (l-NMMA) and plethysmographic assessment of forearm blood flow (FBF). FMD was higher after intervention compared with control/placebo (6.15 ± 0.53 vs. 3.81 ± 0.72%, P < 0.001). There were no significant changes in the FBF responses to l-NMMA. Regression analysis between FMD and l-NMMA responses at entry to the study revealed an insignificant correlation ( r = −0.10, P = 0.7), and improvements in FMD with the interventions were not associated with changes in the l-NMMA responses ( r = −0.04, P = 0.9). We conclude that conduit artery-stimulated endothelial NO function (FMD) does not reflect basal resistance vessel endothelial NO function in subjects with Type 2 diabetes.

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