Metabolic Communication by SGLT2 Inhibition.

BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood. METHODS: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or are secondary to improvement by SGLT2i, we performed an in-depth proteomics, phosphoproteomics, and metabolomics analysis by integrating signatures from multiple metabolic organs and body fluids after 1 week of SGLT2i treatment of nondiabetic as well as diabetic mice with early and uncomplicated hyperglycemia. RESULTS: Kidneys of nondiabetic mice reacted most strongly to SGLT2i in terms of proteomic reconfiguration, including evidence for less early proximal tubule glucotoxicity and a broad downregulation of the apical uptake transport machinery (including sodium, glucose, urate, purine bases, and amino acids), supported by mouse and human SGLT2 interactome studies. SGLT2i affected heart and liver signaling, but more reactive organs included the white adipose tissue, showing more lipolysis, and, particularly, the gut microbiome, with a lower relative abundance of bacteria taxa capable of fermenting phenylalanine and tryptophan to cardiovascular uremic toxins, resulting in lower plasma levels of these compounds (including p-cresol sulfate). SGLT2i was detectable in murine stool samples and its addition to human stool microbiota fermentation recapitulated some murine microbiome findings, suggesting direct inhibition of fermentation of aromatic amino acids and tryptophan. In mice lacking SGLT2 and in patients with decompensated heart failure or diabetes, the SGLT2i likewise reduced circulating p-cresol sulfate, and p-cresol impaired contractility and rhythm in human induced pluripotent stem cell-derived engineered heart tissue. CONCLUSIONS: SGLT2i reduced microbiome formation of uremic toxins such as p-cresol sulfate and thereby their body exposure and need for renal detoxification, which, combined with direct kidney effects of SGLT2i, including less proximal tubule glucotoxicity and a broad downregulation of apical transporters (including sodium, amino acid, and urate uptake), provides a metabolic foundation for kidney and cardiovascular protection.

Effects of semaglutide, empagliflozin and their combination on renal diffusion-weighted MRI and total kidney volume in patients with type 2 diabetes: a post hoc analysis from a 32 week randomised trial.

AIMS/HYPOTHESIS: The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV). METHODS: This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the 'semaglutide' group), or the combination of semaglutide and empagliflozin (referred to as the 'combination-therapy' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico-medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI. RESULTS: Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: -0.20×10-3 mm2/s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10-3 mm2/s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10-3 mm2/s [95%CI -0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of -0.13×10-3 mm2/s (95% CI -0.22, -0.04; p=0.01). Compared with placebo, TKV decreased by -3% (95% CI -5%, -0.3%; p=0.04), -3% (95% CI -5%, -0.4%; p=0.02) and -5% (95% CI -8%, -2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA1c. CONCLUSIONS/INTERPRETATION: In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin significantly reduced cortical ADC compared with placebo, indicating microstructural changes in the kidneys. These changes were not associated with changes in GFR, albuminuria or inflammation. Further, we found a decrease in TKV in all active treatment groups, which was possibly mediated by a reduction in hyperfiltration. Our findings suggest that DWI-MRI may serve as a promising tool for investigating the underlying mechanisms of medical interventions in individuals with type 2 diabetes but may reflect effects not related to fibrosis. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2019-000781-38.

Separate and combined effects of empagliflozin and semaglutide on vascular function: A 32-week randomized trial.

AIM: Despite the increasing use of combination treatment with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, data are limited on the effects of combination treatment on markers of cardiovascular disease. This study aimed to investigate the effect of empagliflozin, semaglutide, and their combination on vascular function. MATERIALS AND METHODS: In total, 120 patients with type 2 diabetes were randomized into four groups (n = 30 in each) for 32 weeks: placebo, semaglutide, empagliflozin, and their combination. The study had two co-primary outcomes: change in arterial stiffness and kidney oxygenation. This paper reports on arterial stiffness assessed as carotid-femoral pulse wave velocity. Secondary outcomes included 24-h blood pressure (BP), 24-h central BP, urinary albumin to creatinine ratio and glycaemic control assessed by both continuous glucose monitoring and glycated haemoglobin. RESULTS: The carotid-femoral pulse wave velocity did not change significantly in any of the groups compared with placebo. Twenty-four-hour systolic BP was reduced by 10 mmHg (95% CI 6-14), p < .001 in the combination group, significantly superior to both placebo and monotherapy (p < .05). Combination treatment increased glycaemic time in range from 72% at baseline to 91% at week 32, p < .001, without increasing time below range. The urinary albumin to creatinine ratio decreased by 36% (95% CI 4-57), p = .03 in the combination group compared with placebo. CONCLUSIONS: Empagliflozin, semaglutide, or their combination did not reduce arterial stiffness. Combination treatment showed a substantial and clinically important reduction in 24-h systolic BP compared with either treatment alone. Combination treatment increased glycaemic time in range without increasing the risk of hypoglycaemia.

One size does not fit all: universal cuff overestimates oscillometric blood pressure in persons with large arm circumference.

OBJECTIVE: Some brachial cuffs for oscillometric blood pressure (BP) measurement are claimed to cover a wide range of upper-arm circumferences; however, their validation is rarely conducted. Our aim was to compare oscillometric BP measurements obtained with a universal cuff with those obtained with an appropriately sized cuff. METHODS: We utilised the Microlife B6 Connect monitor, conducting oscillometric BP measurements in a random sequence with both a universal cuff (recommended for arm circumferences from 22 to 42 cm) and an appropriately sized cuff (medium for circumference 22-32 cm and large for 32-42 cm). We included 91 individuals with an arm circumference of 22-32 cm and 64 individuals with an arm circumference of 32-42 cm. RESULTS: For arm circumferences > 32 cm, systolic and diastolic BP measured with the universal cuff was higher than that measured with the large cuff (systolic 6.4 mmHg, 95% confidence interval [CI]). 3.9-8.8, diastolic 2.4 mmHg, 95%CI, 1.2-3.7, p < 0.001 for both). Overestimation of BP with the universal cuff was statistically significant after correcting for the sequence of measurements. No statistical difference was found between the universal cuff and medium cuff for circumferences in the 22-32 cm range. The bladder size in the universal cuff matched the dimensions of the medium-sized cuff; however, the cuff was larger. CONCLUSION: Overestimation of BP measured with a universal cuff in persons with large arm circumferences is clinically important. It poses the risk of unnecessary initiation or intensification of antihypertensive medication in persons using the universal cuff.

What is the context?Clinical guidelines recommend individualisation of the size of the cuff used for blood pressure measurement according to the circumference of the upper arm.Many blood pressure monitors are sold with a single "universal" cuff claimed to cover a wide range of upper arm sizes.We compared blood pressure obtained with the Microlife B6 Connect monitor and a "universal" cuff with the results obtained with individual sized cuffs (medium size for arm circumference between 22 and 32 cm and large size for arm circumference between 32 and 42 cm).What is new?In persons with large upper arm circumference is the systolic blood pressure 6.4 mmHg higher and the diastolic blood pressure 2.4 mmHg higher with the universal cuff than with the individual-sized large cuff.What is the impact?The universal cuff overestimates blood pressure in persons with large arm circumference.

Separate and combined effects of semaglutide and empagliflozin on kidney oxygenation and perfusion in people with type 2 diabetes: a randomised trial.

AIMS/HYPOTHESIS: Glucagon-like peptide-1 receptor agonists (GLP-1ras) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) have shown kidney-protective effects. Improved kidney oxygenation and haemodynamic changes are suggested mechanisms; however, human data are scarce. We therefore investigated whether semaglutide (GLP-1ra), empagliflozin (SGLT2i) or their combination improve kidney oxygenation and perfusion. METHODS: The trial was undertaken at Aarhus University Hospital, Denmark. A total of 120 people with type 2 diabetes (HbA1c ≥48 mmol/mol [6.5%]) and at high risk of CVD (age ≥50 years) were randomised into four parallel groups (n=30 in each group) for 32 weeks: 1.0 mg semaglutide (open label); 10 mg empagliflozin (blinded to participants, caregivers, examiners and outcome assessors); their combination (1.0 mg semaglutide open label plus 10 mg empagliflozin blinded to participants, caregivers, examiners and outcome assessors); and placebo tablet (blinded to participants, caregivers, examiners and outcome assessors). Sequentially numbered, sealed envelopes containing computer-generated randomisation codes, provided by Glostrup Pharmacy, Glostrup, Denmark, determined the intervention. The two co-primary outcomes were change in kidney oxygenation and change in arterial stiffness. This paper reports on kidney oxygenation, for which 80 individuals as prespecified, 20 in each group, underwent MRI. We primarily hypothesised that kidney oxygenation would be improved in the active treatment groups compared with placebo after 32 weeks. Secondary outcomes included changes in kidney perfusion, erythropoietin, haematocrit, urine albumin/creatinine ratio (UACR) and GFR (measured using technetium-99m) compared with baseline and between treatment groups at week 32. RESULTS: Our model estimated a common baseline R2* value across all four groups in the cortex and the medulla. At baseline, the value was 24.5 (95% CI 23.9, 24.9) Hz in the medulla. After 32 weeks, the R2* values in the medulla were estimated to be 25.4 (95% CI 24.7, 26.2) Hz in the empagliflozin group and 24.5 (95% CI 23.9, 25.1) Hz in the placebo group (p=0.016) (higher R2* corresponds to a lower oxygenation). Semaglutide decreased perfusion in both the cortex and the medulla. Empagliflozin increased erythropoietin and haematocrit. All three active treatments decreased GFR but not UACR. Ten serious adverse events were reported, among them two occurrences of semaglutide-associated obstipation. CONCLUSIONS/INTERPRETATION: Our hypothesis, that semaglutide, empagliflozin or their combination improve kidney oxygenation, was rejected. On the contrary, empagliflozin induced a reduction in medullary kidney oxygenation. Semaglutide substantially reduced kidney perfusion without affecting oxygenation. TRIAL REGISTRATION: Clinicaltrialsregister.eu EudraCT 2019-000781-38 FUNDING: Novo Nordisk Foundation, Central Denmark Region Research Fund and Danish Medical Associations Research Foundation.

Evaluation of renal oxygenation by BOLD-MRI in high-risk patients with type 2 diabetes and matched controls.

BACKGROUND: Diabetic kidney disease (DKD) accounts for ∼50% of end-stage kidney disease. Renal hypoxia is suggested as a main driver in the pathophysiology underlying chronic DKD. Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) has made noninvasive investigations of renal oxygenation in humans possible. Whether diabetes per se contributes to measurable changes in renal oxygenation by BOLD-MRI remains to be elucidated. We investigated whether renal oxygenation measured with BOLD-MRI differs between people with type 2 diabetes (T2DM) with normal to moderate chronic kidney disease (CKD) (Stages 1-3A) and matched controls. The repeatability of the BOLD-MRI method was also assessed. METHODS: In this matched cross-sectional study, 20 people with T2DM (age 69.2 ± 4.7 years, duration of diabetes 10.5 ± 6.7 years, male 55.6%) and 20 matched nondiabetic controls (mean age 68.8 ± 5.4 years, male 55.%) underwent BOLD-MRI analysed with the 12-layer concentric object method (TLCO). To investigate the repeatability, seven in the T2DM group and nine in the control group were scanned twice. RESULTS: A significant reduction in renal oxygenation from the cortex to medulla was found in both groups (P < .01) but no intergroup difference was detected [0.71/s (95% confidence interval -0.28-1.7), P = .16]. The median intraindividual coefficient of variation (CV) varied from 1.2% to 7.0%. CONCLUSION: T2DM patients with normal to moderate CKD do not seem to have lower renal oxygenation when measured with BOLD-MRI and TLCO. BOLD-MRI has a low intraindividual CV and seems like a reliable method for investigation of renal oxygenation in T2DM.

Low physical activity is associated with impaired endothelial function in patients with type 2 diabetes and controls after 5 years of follow-up.

BACKGROUND: The long-term association between physical activity and endothelial function has not previously been investigated in patients with type 2 diabetes. Therefore, we aimed to evaluate the relationship between physical activity and endothelial function, assessed by peripheral arterial tonometry, in patients with type 2 diabetes and non-diabetic controls after 5 years of follow-up. METHODS: We included 51 patients with newly diagnosed type 2 diabetes and 53 sex- and age matched controls. Participants underwent baseline clinical characterization including objective measurement of physical activity level using accelerometery. After 5 years of follow-up, participants were re-examined, and endothelial function was assessed as natural logarithm of reactive hyperemia index (lnRHI). RESULTS: Physical activity at baseline was associated with lnRHI after 5 years of follow-up in both patients with type 2 diabetes and controls. An increase of 1 standard deviation (SD) in daytime physical activity corresponded to a 6.7 % increase in RHI (95 % confidence interval: 1.1;12.5 %, p = 0.02). We found no difference in lnRHI between patients with diabetes and controls (0.67 ± 0.29 vs. 0.73 ± 0.31, p = 0.28). CONCLUSIONS: Daytime physical activity is associated with endothelial function after 5 years of follow-up in patients with type 2 diabetes and controls.

Effect of 12 weeks continuous positive airway pressure on day and night arterial stiffness and blood pressure in patients with type 2 diabetes and obstructive sleep apnea: A randomized controlled trial.

The objective of this study was to evaluate the effect of continuous positive airway pressure treatment on pulse wave velocity and blood pressure in patients with type 2 diabetes and obstructive sleep apnea. A randomized controlled study was performed, including 72 patients with type 2 diabetes and newly diagnosed obstructive sleep apnea recruited from outpatient clinics at three Danish hospitals. The patients were randomized to continuous positive airway pressure for 12 weeks or no continuous positive airway pressure. Office measurements were performed at baseline, 4 weeks and 12 weeks. At baseline and 12 weeks, a 24-hr measurement of pulse wave velocity and blood pressure was performed. No significant change was observed in the primary outcome variable of carotid-femoral pulse wave velocity measured with SphygmoCor. With the Mobil-O-Graph, changes in office pulse wave velocity between the groups were significant: 0.3 m/s; 95% confidence interval, 0.1-0.6; p = .02. The group receiving continuous positive airway pressure had a larger decrease in pulse wave velocity than controls but none of the changes within the groups were significant. No significant change in ambulatory blood pressure was observed in any of the two groups after 12 weeks. In conclusion, continuous positive airway pressure treatment for 12 weeks does not significantly reduce pulse wave velocity or blood pressure in patients with type 2 diabetes and obstructive sleep apnea.

Aortic Calcification Affects Noninvasive Estimates of Central Blood Pressure in Patients with Severe Chronic Kidney Disease.

BACKGROUND: Central blood pressure (BP) assessed noninvasively considerably underestimates true invasively measured aortic BP in chronic kidney disease (CKD) patients. The difference between the estimated and the true aortic BP increases with decreasing estimated glomerular filtration rates (eGFR). The present study investigated whether aortic calcification affects noninvasive estimates of central BP. METHODS: Twenty-four patients with CKD stage 4-5 undergoing coronary angiography and an aortic computed tomography scan were included (63% males, age [mean ± SD ] 53 ± 11 years, and eGFR 9 ± 5 mL/min/1.73 m2). Invasive aortic BP was measured through the angiography catheter, while non-invasive central BP was obtained using radial artery tonometry with a SphygmoCor® device. The Agatston calcium score (CS) in the aorta was quantified on CT scans using the CS on CT scans. RESULTS: The invasive aortic systolic BP (SBP) was 152 ± 23 mm Hg, while the estimated central SBP was 133 ± 20 mm Hg. Ten patients had a CS of 0 in the aorta, while 14 patients had a CS >0 in the aorta. The estimated central SBP was lower than the invasive aortic SBP in patients with aortic calcification compared to patients without (mean difference 8 mm Hg, 95% CI 0.3-16; p = 0.04). The brachial SBP was lower than the aortic SBP in patients with aortic calcification compared to patients without (mean difference 10 mm Hg, 95% CI 2-19; p = 0.02). CONCLUSION: In patients with advanced CKD the presence of aortic calcification is associated with a higher difference between invasively measured central aortic BP and non-invasive estimates of central BP as compared to patients without calcifications.

Impaired aortic distensibility and elevated central blood pressure in Turner Syndrome: a cardiovascular magnetic resonance study.

BACKGROUND: Women with Turner Syndrome have an increased risk for aortic dissection. Arterial stiffening is a risk factor for aortic dilatation and dissection. Here we investigate if arterial stiffening can be observed in Turner Syndrome patients and is an initial step in the development of aortic dilatation and subsequent dissection. METHODS: Fifty-seven women with Turner Syndrome (48 years [29-66]) and thirty-six age- and sex-matched controls (49 years [26-68]) were included. Distensibility, blood pressure, carotid-femoral pulse wave velocity (PWV), the augmentation index (Aix) and central blood pressure were determined using cardiovascular magnetic resonance, a 24-h blood pressure measurement and applanation tonometry. Aortic distensibility was determined at three locations: ascending aorta, transverse aortic arch, and descending aorta. RESULTS: Mean aortic distensibility in the descending aorta was significantly lower in Turner Syndrome compared to healthy controls (P = 0.02), however, this was due to a much lower distensibility among Turner Syndrome with coarctation, while Turner Syndrome without coarctation had similar distensibility as controls. Both the mean heart rate adjusted Aix (31.4% vs. 24.4%; P = 0.02) and central diastolic blood pressure (78.8 mmHg vs. 73.7 mmHg; P = 0.02) were higher in Turner Syndrome compared to controls, and these indices correlated significantly with ambulatory night-time diastolic blood pressure. The presence of aortic coarctation (r = - 0.44, P = 0.005) and a higher central systolic blood pressure (r = - 0.34, P = 0.03), age and presence of diabetes were inversely correlated with aortic distensibility in TS. CONCLUSION: Aortic wall function in the descending aorta is impaired in Turner Syndrome with lower distensibility among those with coarctation of the aorta, and among all Turner Syndrome higher Aix, and elevated central diastolic blood pressure when compared to sex- and age-matched controls. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( #NCT01678274 ) on September 3, 2012.

Estimated aortic blood pressure based on radial artery tonometry underestimates directly measured aortic blood pressure in patients with advancing chronic kidney disease staging and increasing arterial stiffness.

Central blood pressure (BP) can be assessed noninvasively based on radial tonometry and may potentially be a better predictor of clinical outcome than brachial BP. However, the validity of noninvasively obtained estimates has never been examined in patients with chronic kidney disease (CKD). Here we compared invasive aortic systolic BP (SBP) with estimated central SBP obtained by radial artery tonometry and examined the influence of renal function and arterial stiffness on this relationship. We evaluated 83 patients with stage 3 to 5 CKD (mean estimated glomerular filtration rate [eGFR] 30 ml/min/1.73 m(2)) and 41 controls without renal disease undergoing scheduled coronary angiography. BP in the ascending aorta was measured through the angiography catheter and simultaneously estimated using radial tonometry. The mean difference between estimated central and aortic SBP was -13.2 (95% confidence interval -14.9 to -11.4) mm Hg. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (cf-PWV) and was significantly increased in CKD patients compared with (versus) control patients (mean 10.7 vs. 9.3 m/s). The difference in BP significantly increased 1.0 mm Hg for every 10 ml/min decrease in eGFR and by 1.6 mm Hg per 1 m/s increase in cfPWV. Using multivariate regression analysis including both eGFR and cfPWV, the difference between estimated central and invasive aortic SBP was significantly increased by 0.7 mm Hg. For the entire cohort brachial SBP significantly better reflected invasive SBP than estimated SBP. Thus, tonometry-based estimates of central BP progressively underestimate invasive central SBP with decreasing renal function and increasing arterial stiffness in CKD patients.

Should There be Concern About Autoimmune Diabetes in Adults? Current Evidence and Controversies.

Autoimmune diabetes has a heterogeneous phenotype. Although often considered a condition starting in childhood, a substantial proportion of type 1 diabetes presents in adult life. This holds important implications for our understanding of the factors that modify the rate of progression through the disease prodrome to clinical diabetes and for our management of the disease. When autoimmune diabetes develops in adulthood, insulin treatment is often not required at the time of diagnosis, and this autoimmune non-insulin requiring diabetes is generally termed latent autoimmune diabetes in adults (LADA). Patients with LADA are generally leaner, younger at diabetes onset; have a greater reduction in C-peptide; and have a greater likelihood of insulin treatment as compared with patients with type 2 diabetes. The LADA subset of patients with adult-onset autoimmune diabetes has highlighted many shortcomings in the classification of diabetes and invokes the case for more personalized data analysis in line with the move towards precision medicine. Perhaps most importantly, the issues highlight our persistent failure to engage with the heterogeneity within the most common form of autoimmune diabetes, that is adult-onset type 1 diabetes, both insulin-dependent and initially non-insulin requiring (LADA). This review discusses characteristics of autoimmune diabetes and specifically aims to illustrate the heterogeneity of the disease.

Morning blood pressure surge and target organ damage in newly diagnosed type 2 diabetic patients: a cross sectional study.

BACKGROUND: Type 2 diabetic patients display significantly higher incidence of cardiovascular (CV) events including stroke compared to non-diabetics. Morning blood pressure surge (MBPS) and blunted systolic night-day (SND) ratio have been associated with CV events in hypertensive patients. No studies have evaluated MBPS in newly diagnosed diabetic patients or studied the association with vascular target organ damage at this early time point of the diabetes disease. METHODS: Ambulatory blood pressure monitoring was performed in 100 patients with newly diagnosed type 2 diabetes and 100 age and sex matched controls. MBPS and SND-ratio were calculated. Markers of early vascular target organ damage included pulse wave velocity (PWV), white matter lesions (WML) on brain MRI, and urine albumin/creatinine ratio (UAE). RESULTS: No significant differences in MBPS were found between diabetic patients and controls. Neither MBPS or SND-ratio were associated with PWV, UAE or WML in the diabetic group independently of age, gender and 24-h systolic blood pressure. 40.2 % of diabetic patients and 25.8 % of controls were classified as non-dippers (p = 0.03). CONCLUSION: MBPS and SND-ratio are not associated with subclinical markers of vascular target organ damage in our study sample of newly diagnosed type 2 diabetic patients.

Feasibility of Arteriograph 24 for evaluation of 24-hour pulse wave velocity and central blood pressure in patients with type 2 diabetes and non-diabetic controls.

The objective of this study was to assess the feasibility of the Arteriograph 24 device to measure 24-hour PWV and central systolic blood pressure (cSBP) in patients with type 2 diabetes (T2DM) and non-diabetic controls and compare daytime and nighttime characteristics in the two groups. Twenty-four-hour PWV and cSBP was measured in 58 patients with T2DM (mean age: 66 ±â€…9 years, 50% women, mean duration of T2DM: 7.8 ±â€…1.5 years) and 62 age- and sex-matched controls. Seventy percent of participants (71% T2DM patients and 69% controls) had sufficient readings to generate an acceptable 24-hour report (≥14 day and ≥7 night readings). Lower nocturnal than daytime PWV and cSBP were observed in both groups. Nocturnal PWV and cSBP dipping were attenuated in T2DM patients compared to controls (PWV: -0.3 ±â€…0.9 vs. -0.7 ±â€…0.9 m/s, P  = 0.04, cSBP: -8 ±â€…14 vs. -18 ±â€…18 mmHg, P  < 0.01). No group differences in PWV or cSBP were observed during daytime (T2D vs. controls, PWV: 9.2 ±â€…1.1 vs. 9.2 ±â€…1.3 m/s, P  = 0.99, cSBP: 133 ±â€…19 vs. 137 ±â€…25 mmHg, P  = 0.42) or nighttime (PWV: 8.9 ±â€…1.3 vs. 8.4 ±â€…1.3 m/s, P  = 0.14, cSBP 124 ±â€…20 vs. 118 ±â€…27 mmHg, P  = 0.26). The study findings indicate that the nocturnal dipping of PWV and cSBP is attenuated in T2DM patients. The significant number of missing measurements raises concerns regarding the clinical utility of the Arteriograph 24 device.

Invasively Measured Aortic Systolic Blood Pressure and Office Systolic Blood Pressure in Cardiovascular Risk Assessment in CKD.

Introduction: Central aortic blood pressure (BP) could be a better risk predictor than brachial BP. This study examined whether invasively measured aortic systolic BP improved outcome prediction beyond risk prediction by conventional cuff-based office systolic BP in patients with and without chronic kidney disease (CKD). Methods: In a prospective, longitudinal cohort study, aortic and office systolic BPs were registered in patients undergoing elective coronary angiography (CAG). CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m2. Multivariable Cox models were used to determine the association with incident myocardial infarction (MI), stroke, and death. Results: Aortic and office systolic BPs were available in 39,866 patients (mean age: 64 years; 58% males; 64% with hypertension) out of which 6605 (17%) had CKD. During a median follow-up of 7.2 years (interquartile range: 4.6-10.1 years), 1367 strokes (CKD: 353), 1858 MIs (CKD: 446), and 7551 deaths (CKD: 2515) occurred. CKD increased the risk of stroke, MI, and death significantly. Office and aortic systolic BP were both associated with stroke in non-CKD patients (adjusted hazard ratios with 95% confidence interval per 10 mm Hg: 1.08 [1.05-1.12] and 1.06 [1.03-1.09], respectively) and with MI in patients with CKD (adjusted hazard ratios: 1.08 [1.03-1.13] and 1.08 [1.04-1.12], respectively). There was no significant difference between prediction of outcome with office or aortic systolic BP when adjusted models were compared with C-statistics. Conclusion: Regardless of CKD status, invasively measured central aortic systolic BP does not improve the ability to predict outcome compared with brachial office BP measurement.

The effects of semaglutide, empagliflozin and their combination on the kidney sodium signal from magnetic resonance imaging: A prespecified, secondary analysis from a randomized, clinical trial.

AIMS: To evaluate the effect of treatment with semaglutide and empagliflozin on the cortico-medullary sodium gradient (MCR; medulla/cortex ratio), urine sodium/creatinine ratio (UNACR), and estimated plasma volume (ePV) and to compare the MCR between persons with and without type 2 diabetes. METHODS: Using the 23Na magnetic resonance imaging (23Na-MRI) technique, we investigated the effects of 32 weeks of treatment with semaglutide, empagliflozin or their combination on MCR in 65 participants with type 2 diabetes and high risk of cardiovascular disease. The participants were recruited from a randomized, controlled interventional trial and further characterized by UNACR and ePV. In addition, in a cross-sectional design, we compared MCR by 23Na-MRI in 12 persons with type 2 diabetes and 17 matched controls. Data from the interventional trial were analyzed using a single, multivariate linear mixed model strategy for repeated measurements. Data from the cross-sectional study were analyzed by fitting a linear regression model adjusted for age and sex. RESULTS: Compared to placebo, semaglutide, but not empagliflozin, significantly decreased the MCR (-9 %, 95%CI (-18, -0.06)%, p = 0.035 and -0.05 %, 95%CI(-0.15, 0.05)%, p = 0.319, respectively). The UNACR decreased in the semaglutide group(-35 %, 95 % CI(-52, -14) %, p = 0.003) but not in the empagliflozin group (7 %, 95 % CI(-21, 44)%, p = 0.657), whereas the ePV decreased in the combination group. The MCR was not different between persons with and without type 2 diabetes. CONCLUSION: 23Na magnetic resonance imaging can identify drug induced changes in the MCR in persons with type 2 diabetes, and 32 weeks of semaglutide decreases the MCR in such persons. There is no difference in the MCR between persons with and without type 2 diabetes. TRIAL NUMBER AND REGISTRY: EUDRACT 2019-000781-38, clinicaltrialsregister.eu.

Plasma levels of the arterial wall protein fibulin-1 are associated with carotid-femoral pulse wave velocity: a cross-sectional study.

BACKGROUND: The arterial system in diabetic patients is characterized by generalized non-atherosclerotic alterations in the vascular extracellular matrix causing increased arterial stiffness compared with subjects without diabetes. The underlying pathophysiology remains elusive. The elastin-associated extracellular matrix protein, fibulin-1, was recently found in higher concentrations in the arterial wall and in plasma in patients with long duration type 2 diabetes. Furthermore, plasma fibulin-1 independently predicted total mortality and was associated with pulse pressure, an indirect measure of arterial stiffness. Whether plasma fibulin-1 is associated with arterial stiffness at earlier phases of type 2 diabetes has not been determined. METHODS: In this cross-sectional study, we examined 90 patients with recently diagnosed type 2 diabetes (< 5 years) and 90 gender- and age-matched controls. Plasma fibulin-1 was measured immunochemically. Arterial stiffness was assessed by carotid-femoral Pulse Wave Velocity (PWV). Differences in means were assessed by t-tests. Associations were assessed by multivariate regression analyses. RESULTS: Plasma fibulin-1 levels were lower in the diabetic group compared with the control group, 93 ± 28 vs 106 ± 30 µg/mL, p = 0.005. In unadjusted analysis of the total study sample, plasma fibulin-1 was not associated with PWV, p = 0.46. However, with adjustment for the confounders age, gender, mean blood pressure, heart rate, body mass index, diabetes and glomerular filtration rate, a 10 µg/mL increase in plasma fibulin was associated with 0.09 ± 0.04 m/s increase in PWV, p < 0.05. In subgroup analysis, plasma fibulin-1 was associated with PWV in the diabetes group, (0.16 ± 0.07 m/s increase in PWV per 10 µg/mL increase in plasma fibulin-1, p<0.05), but not controls, ß = 0.021 ± 0.057 m/s per 10 µg/mL, p = 0.70. The association remained significant in the diabetes group after adjustment for covariates, p < 0.05. CONCLUSIONS: Plasma fibulin-1 is independently associated with PWV. Yet, as the plasma level of fibulin-1 was lower in patients with recently diagnosed type 2 diabetes than in healthy controls, plasma fibulin-1 levels are not a simple marker of the degree of arterial stiffening. Further studies are needed to determine the exact role of fibulin-1 in arterial stiffness and cardiovascular risk in patients with type 2 diabetes.