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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 mm 2 /s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10 -3 mm 2 /s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10 -3 mm 2 /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 mm 2 /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 HbA 1c ., 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., (© 2024. The Author(s).)

Objective: This study aims to investigate the continuum of glucose control from normoglycemia to dysglycemia (HbA1c ≥ 5.7%/39 mmol/mol) using metrics derived from continuous glucose monitoring (CGM). In addition, we aim to develop a machine learning-based classification model to classify dysglycemia based on observed patterns. Methods: Data from five distinct studies, each featuring at least two days of CGM, were pooled. Participants included individuals classified as healthy, with prediabetes, or with type 2 diabetes mellitus (T2DM). Various CGM indices were extracted and compared across groups. The data set was split 70/30 for training and testing two classification models (XGBoost/Logistic Regression) to differentiate between prediabetes or dysglycemia and the healthy group. Results: The analysis included 836 participants (healthy: n = 282; prediabetes: n = 133; T2DM: n = 432). Across all CGM indices, a progressive shift was observed from the healthy group to those with diabetes ( P < 0.001). Statistically significant differences ( P < 0.01) were noted in mean glucose, time below range, time above 140 mg/dl, mobility, multiscale complexity index, and glycemic risk index when transitioning from health to prediabetes. The XGBoost models achieved the highest receiver operating characteristic area under the curve values on the test data set ranging from 0.91 [confidence interval (CI): 0.87-0.95] (prediabetes identification) to 0.97 [CI: 0.95-0.98] (dysglycemia identification). Conclusion: Our findings demonstrate a gradual deterioration of glucose homeostasis and increased glycemic variability across the spectrum from normo- to dysglycemia, as evidenced by CGM metrics. The performance of CGM-based indices in classifying healthy individuals and those with prediabetes and diabetes is promising.

Background and Aims: Obstructive sleep apnea (OSA) may accelerate arterial calcification, but the relation remains unexplored in diabetic kidney disease (DKD). We examined the associations between OSA, coronary calcification and large artery stiffness in patients with DKD and reduced renal function., Methods: Patients with type 2 diabetes, estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m 2 and urine albumin-creatinine ratio (UACR) > 30 mg/g were tested for OSA quantified by the apnea-hypopnea index (AHI, events/hour). Patients without OSA (AHI< 5) were compared to patients with moderate (AHI 15-29) or severe (AHI ≥30) OSA and underwent computed tomography angiography with coronary Agatston scoring (CAS) to quantify coronary calcification. Arterial stiffness was determined as carotid-femoral pulse wave velocity (PWV)., Results: Among 114 patients with acceptable AHI recordings had 43 no OSA, 33 mild OSA and 38 moderate-severe OSA. Mean age of the 74 patients completing the study was 71.5 ± 9.4 years (73% males), eGFR 32.2 ± 12.3 ml/min/1.73 m 2 and UACR 533 (192-1707) mg/g. CAS (ln-transformed) was significantly higher in patients with OSA compared to patients without (6.6 ± 1.7 vs. 5.6 ± 2.4, p = 0.04), and the same was observed for PWV (11.9 ± 2.7 vs. 10.5 ± 2.2 m/s, p = 0.02). In multivariable linear regression analyses adjusted for sex, age, body mass index, UACR, and mean arterial pressure, moderate-severe OSA remained significantly associated with PWV but not with CAS. Dominance analysis revealed OSA as the third and second most important factor relative to CAS and PWV respectively., Conclusions: In DKD patients, moderate-severe OSA is a significant predictor of arterial stiffness but is not independently associated with coronary calcification., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

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 ± 9 years, 50% women, mean duration of T2DM: 7.8 ± 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 ± 0.9 vs. -0.7 ± 0.9 m/s, P  = 0.04, cSBP: -8 ± 14 vs. -18 ± 18 mmHg, P  < 0.01). No group differences in PWV or cSBP were observed during daytime (T2D vs. controls, PWV: 9.2 ± 1.1 vs. 9.2 ± 1.3 m/s, P  = 0.99, cSBP: 133 ± 19 vs. 137 ± 25 mmHg, P  = 0.42) or nighttime (PWV: 8.9 ± 1.3 vs. 8.4 ± 1.3 m/s, P  = 0.14, cSBP 124 ± 20 vs. 118 ± 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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: Disclosures Dr Rinschen declares pending research funding from Novo Nordisk unrelated to this work. Over the past 12 months, Dr Vallon has served as a consultant for Lexicon and received speaker honoraria from AstraZeneca and grant support for investigator-initiated research from AstraZeneca, Boehringer Ingelheim, Gilead, Lexicon, Maze, Merck, and Novo-Nordisk. Dr Magnussen receives study-specific funding from the German Center for Cardiovascular Research (DZHK; Promotion of Women Scientists Programme; FKZ 81X3710112), the Deutsche Stiftung für Herzforschung, the Dr Rolf M. Schwiete Stiftung, NDD, and Loewenstein Medical unrelated to the current work. Dr Magnussen has received speaker fees from AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Bayer, Pfizer, Sanofi, Aventis, Apontis, and Abbott outside this work. Dr Dugourd and R. Fallegger report funding from Pfizer. Dr Saez-Rodriguez reports funding from GSK, Pfizer, and Sanofi and fees from Travere Therapeutics, Stadapharm, and Astex. Dr Hoxha served on advisory boards for Novartis, Morphosys AG, Sotio, and Argenx. The other authors declare no conflict of interest.

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 23 Na magnetic resonance imaging ( 23 Na-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 23 Na-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: 23 Na 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., Competing Interests: Declaration of competing interest The authors declare no conflicts of interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)