Daniel H. van Raalte

Background and Aims: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce cardiovascular disease (CVD) in type 2 diabetes (T2D) and have anti-inflammatory effects in experimental studies, but their mechanism of action in humans remains unclear. This study characterized the cardiovascular–haematopoietic axis in individuals with T2D receiving semaglutide, as a potential mediator of GLP-1RA cardioprotective properties. Methods: In 16 individuals with T2D [63.2 ± 6.1 years, 37.5% female, weight 82.3 ± 15.3 kg, body mass index (BMI) 28.33 ± 3.5 kg/m2, LDL cholesterol 2.2 ± 0.9 mmol/L, glycated haemoglobin (HbA1c) 78.1 ± 13.1 mmol/mol, high-sensitivity C-reactive protein (hsCRP) 1.9 (1.2, 5.8) mg/L], blood and sternal bone marrow aspirates (subset, n = 14) were collected at baseline and after 6 months of semaglutide ≤2.0 mg weekly. Circulating monocytes and haematopoietic precursors were quantified by flow cytometry, plasma cytokines using an nELISA™ assay (Nomic Bio) and inflammatory macrophages in coronary arteries, bone marrow, and spleen by gallium-68–labelled DOTA-(Tyr3)-octreotate (68Ga-DOTATATE) positron emission tomography-computed tomography scans. Results: After 6 months of semaglutide, significant reductions in HbA1c (−21.1 mmol/mol, P < .0001), weight (−6.7 kg, P < .001), BMI (−2.5 kg/m2, P < .001), and hsCRP (−1.0 mg/L, P = .005) were observed. Circulating CD16+ monocytes were markedly lower (−18.8%, P = .034), with increased bone marrow retention correlating with weight loss, alongside reductions in interleukin-1 receptor antagonist, leptin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), C-C motif chemokine ligand 2, C-C motif chemokine ligand 11, and C-X-C motif chemokine ligand 13. Gallium-68–labelled DOTA-(Tyr3)-octreotate PET-CT showed lower bone marrow uptake (−17.5%, P = .037), but not in spleen or coronary arteries. Conclusions: Semaglutide in T2D potentially reduces circulating inflammatory monocytes, increases bone marrow retention, and lowers markers of endothelial inflammation, with no reduction in coronary artery inflammatory macrophages. Semaglutide is associated with lower bone marrow 68Ga-DOTATATE uptake, which may relate to anti-inflammatory effects relevant to CVD risk.

Even though insulin therapy is the cornerstone of diabetes mellitus management, multiple daily injections are associated with poor adherence. Once-weekly basal insulin therapy has emerged as a novel therapeutic approach and is being evaluated in multiple ongoing clinical trials. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of once-weekly insulin efsitora therapy compared with once-daily basal insulin therapy in patients with type 1 or type 2 diabetes mellitus. Primary endpoints include glycemic control, assessed via HbA1c reduction, and hypoglycemia, classified as level 1 (54-69 mg/dL), level 2 (<54 mg/dl), or level 3 (any hypoglycemic episode characterized by altered mental and/or physical functioning requiring assistance). We have performed a systematic review and meta-analysis through an extensive literature search of major databases including Scopus, PubMed/Medline, and Cochrane databases, and have only included randomized controlled trials. We have included 5 randomized controlled trials comprising a total of 2,562 patients: 1,358 (53%) in the insulin efsitora arm and 1,204 (47%) in the insulin degludec arm. Our data show that insulin efsitora therapy achieved a similar HbA1c reduction overall (estimated treatment difference (ETD) 0.08%, 95% CI -0.01 to 0.17; I² = 42.6%), in patients with type 1 diabetes mellitus (ETD 0.10%, 95% CI -0.64-0.85; I² =24.0%) and in patients with type 2 diabetes mellitus (ETD 0.05%, 95% CI -0.25 – 0.26; I² = 38.1%) compared with insulin degludec therapy. Moreover, no statistically significant differences were identified in overall hypoglycemic events, level 2 or 3 hypoglycemic episodes, or nocturnal hypoglycemia, irrespective of diabetes mellitus subtype. Our meta-analysis shows no statistically significant difference between once-weekly insulin efsitora therapy and insulin degludec therapy in terms of glycemic control and hypoglycemic events.

BACKGROUND: Youth with type 2 diabetes (T2D) and severe obesity face high risk of diabetic kidney disease, which metabolic bariatric surgery (MBS) can mitigate. This study explores structural and molecular changes in kidneys after vertical sleeve gastrectomy (VSG), a form of MBS. METHODS: We performed paired analyses, including metabolic profiling, kidney volume assessment, histological evaluation, and single-cell RNA sequencing (scRNA-seq), on kidney biopsies from 5 youth with T2D and obesity pre- and 12 months post-VSG in the IMPROVE-T2D (Impact of Metabolic surgery on Pancreatic, Renal and cardiOVascular hEalth in youth with T2D) cohort. Circulating proteomics with kidney transcriptomics were linked using data from an independent cohort of youth with obesity, with or without T2D, undergoing MBS in Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS, n = 64). RESULTS: After VSG, participants lost weight and had improvements in insulin sensitivity and metabolic parameters. Kidney changes included reduced renal hyperfiltration, total kidney volume, mesangial matrix area, and microalbuminuria. scRNA-seq in proximal tubule (PT) and thick ascending limb cells indicated repression of glycolysis, gluconeogenesis, and tricarboxylic acid (TCA) cycle genes, with upregulation of AMP-activated protein kinase (AMPK) and forkhead box O3 (FOXO3). Decreased metabolic signaling aligned with reduced ribosomal phosphorylated S6K (pS6K), suggesting attenuated mTORC1 activity. Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation in PT was diminished, correlating with lower circulating ligands from Teen-LABS proteomic data. CONCLUSION: MBS/VSG prompts kidney molecular adaptations, providing potential targets for nonsurgical interventions against obesity- and diabetes-associated kidney disease. FUNDING: University of Washington with the American Diabetes Association, University of Michigan with Chan Zuckerberg Initiative, and Breakthrough T1D.

Background: The OMED2 ( Optimization of Medication in Elderly with Diabetes ) study addresses the effect and implementation of integrating a deprescribing programme (DPP) in general practice. The aim of the DPP is to reduce glucose-lowering medication (SU/insulin) in overtreated older patients. The protocol for this study has been published previously. This statistical analysis plan (SAP) contains a more elaborate outline of the (statistical) methods we plan to use for data analysis. Methods: The OMED2 study is a randomized mixed-methods study with a 2-year follow-up period that compares the effect of the implementation of a DPP in general practice to regular care (control). In this SAP, we report on the (statistical) approaches that we plan to use to address the study objectives. The main objective of the OMED2 study is to examine the effect of the implementation of the DPP on diabetes complications, whereby the total number of diabetes complications related to undertreatment and overtreatment will be summed. Generalized linear mixed models with a Poisson distribution and the DPP as the main determinant will be used to test whether the total number of diabetes complications occurring from the start of the 2-year follow-up until the end of follow-up differs between intervention and control. The incident rate of the number of diabetes complications will be calculated to correct for possible differences in follow-up duration. The model will also include a random effect variable to allow for possible clustering effects by general practice. We will perform intention-to-treat analyses, which include all patients eligible for deprescribing, as well as per protocol analyses, which omit patients who were not deprescribed in the intervention arm. Additionally, approaches to study the implementation of the DPP and the cost-effectiveness of the implementation are outlined in the SAP. Trial registration: ISRCTN Registry ISRCTN50008265. Registered on 1 November 2024.

Background: Chronic diseases may injure the pancreas and result in a reduction in pancreas volume (PV), which may adversely impact its critical role in endocrine and exocrine function. Less is known about whether individuals with smaller PV face higher risks of adverse clinical outcomes. Methods: We estimated baseline age‐adjusted predicted PV (pPV) from abdominal magnetic resonance imaging in 36 592 UK Biobank participants. Since the initial magnetic resonance imaging occurred 9.0 (interquartile range, 7.5–10.1) years after baseline, we fit a linear regression equation that included age for the outcome of PV slope in 451 participants with repeat magnetic resonance imaging 2.8 (interquartile range, 2.2–4.8) years after the initial scan. Using these data, we calculated baseline age‐adjusted pPV slope by adding or subtracting the annual change to the initial PV measurement assuming linear change in PV over time. Multivariable‐adjusted proportional hazards models tested associations of pPV with incident chronic kidney disease, cardiovascular disease (CVD; myocardial infarction, heart failure, or stroke), and death. Results: Participants (52.2% women) were 55±8 years old and had a pPV of 63.3±15.3 mL. During median follow‐up of 13.9 years, there were 757 incident chronic kidney disease, 1392 CVD, and 702 death events. In final adjusted models, participants in the first pPV quartile had a 1.67‐fold (95% CI, 1.34–2.07) and 1.28‐fold (95% CI, 1.10–1.49) increased risk of incident CVD and death compared with the fourth quartile, respectively. pPV had nonlinear associations with incident CVD and death (each P <0.001). pPV was not associated with incident chronic kidney disease. Conclusions: Lower pPV is associated with increased risk of incident CVD and death but not incident chronic kidney disease. Future studies should investigate the pathophysiologic mechanisms driving these associations.

Purpose: Women are generally protected against insulin resistance and related comorbidities when compared with men, potentially due to the role of sex hormones. While epidemiological and animal studies suggest that sex hormones may impact insulin sensitivity, studies in humans on the effects of estradiol and testosterone treatment on insulin sensitivity assessed by gold-standard measures remain limited. The molecular mechanisms involved are also not well understood. Therefore, we aimed to investigate changes in insulin sensitivity and associated change in plasma proteome following 3 months of sex hormone therapy. Methods: This prospective, observational study included 29 individuals initiating feminizing (estradiol with GnRH analogue; n = 16) or masculinizing (testosterone; n = 13) therapy. Measurements at baseline and after 3 months included insulin sensitivity, assessed via hyperinsulinemic-euglycemic clamp (M-value: adjusted for lean body mass and M/I ratio: M-value adjusted for plasma insulin concentrations), along with plasma proteomics. Results: During feminizing hormone therapy, insulin sensitivity increased (M-value: + 23.3%, M/I ratio: + 20.2%; P < .05), whereas during masculinizing hormone therapy, no changes were observed. Of the differentially expressed plasma proteins (49 during feminizing and 356 during masculinizing hormone therapy), 16 correlated with changes in insulin sensitivity. Several were involved in immunoregulation and inflammation (vascular endothelial growth factor D, 5′-nucleotidase), iron homeostasis and erythropoiesis (hepcidin, transferrin receptor protein 1:cytoplasmic domain), and oxidative stress (superoxide dismutase 3). Conclusion: Feminizing hormone therapy, characterized by high serum estradiol and low serum testosterone concentrations, enhanced insulin sensitivity. These findings highlight the impact of sex hormones on insulin sensitivity and may inform sex-specific precision medicine.

Aims/hypothesis: Sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiorenal risk in type 2 diabetes. However, the effect of combining these drugs remains uncertain. This systematic review aimed to evaluate the potential effectiveness and safety of combination therapy compared with monotherapy in individuals with type 2 diabetes. Method: We systematically searched PubMed and Embase from inception to 1 May 2025 for cohort studies comparing the effect of combination therapy with SGLT2 inhibitor or GLP-1 RA monotherapy on (cardiovascular) mortality and cardiovascular or kidney endpoints in individuals with type 2 diabetes. Studies enrolling individuals with type 1 diabetes or a maximum follow-up of less than 1 year were excluded. The primary outcome was a composite of major adverse cardiovascular events (MACE). Secondary outcomes included all-cause mortality, cardiovascular mortality, hospitalisation for heart failure, a kidney composite endpoint and serious adverse events. Risk of bias was assessed with ROBINS-I. Risk ratios (RRs) and 95% CIs were pooled in random effects meta-analyses. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Results: We included 18 cohort studies (1,164,774 participants). In cohort studies, combination therapy was associated with a lower risk of MACE (RR 0.56 [95% CI 0.43, 0.71]; low certainty of evidence) and the kidney composite endpoint (RR 0.48 [95% CI 0.32, 0.73]; very low certainty of evidence) relative to SGLT2 inhibitor or GLP-1 RA monotherapy. Combination therapy was also associated with a lower risk of all-cause mortality (RR 0.50 [95% CI 0.40, 0.63]; low certainty of evidence), cardiovascular mortality (RR 0.26 [95% CI 0.16, 0.43]; low certainty of evidence) and hospitalisation for heart failure (RR 0.67 [95% CI 0.64, 0.71]; moderate certainty of evidence). Although safety data could not be pooled due to lack of events, no differences were observed in the risk of severe hypoglycaemia, diabetic ketoacidosis, genitourinary infections and gastrointestinal side effects. No data were reported on the risk of serious adverse events or major adverse limb events. Conclusions/interpretation: Observational studies suggest that combining an SGLT2 inhibitor and a GLP-1 RA in type 2 diabetes may lower the risk of MACE, all-cause and cardiovascular mortality, hospitalisation for heart failure and kidney composite endpoints compared with monotherapy with either drug. Of course, residual confounding cannot be overcome but results support the need for future randomised trials of combined vs monotherapy. Registration: PROSPERO registration no. CRD42024532383 Graphical