Diabetes, Obesity & Metabolism最新文献

Aims: Sotagliflozin, an inhibitor of sodium-glucose co-transporter (SGLT)-1 and 2, reduces albuminuria, slows GFR decline, and may have diuretic and osmoregulatory effects. The effect of sotagliflozin added to insulin was assessed on markers of neurohormone activation and volume homeostasis in patients with type 1 diabetes (T1D).

Materials and methods: This is a post-hoc analysis of the randomised, double-blinded, placebo-controlled inTandem3 trial, which assessed efficacy of sotagliflozin 400 mg/d versus placebo as an adjunct to insulin. The present biomarker analysis included 362 participants (26%) who had biological samples collected at baseline and week 24. Plasma renin, copeptin, serum N-terminal pro b-type natriuretic peptide (NT-proBNP), and markers of tubular injury, inflammation, haematopoiesis, and iron homeostasis were measured at baseline and following week 24 treatment; fractional excretion of lithium (FE_Li) and glucose (FE_Glucose) were calculated.

Results: Participants were 46 years of age (60% female) with a mean eGFR and median UACR of 88.4 mL/min/1.73 m² and 7.5 mg/g, respectively. Sotagliflozin increased copeptin, FE_Li, and FE_Glucose by 33%, 14%, and 60-fold, respectively (all p < 0.01), but did not change renin or NT-proBNP (both p ≥ 0.11) compared to placebo. Further, urinary kidney injury molecule-1 decreased by 19% (p = 0.03). Haemoglobin and haematocrit increased (both p < 0.01), without altering inflammatory, erythropoietic, or iron biomarkers (all p ≥ 0.11).

Conclusions: In this T1D population, sotagliflozin increased copeptin levels, FE_Li, and FE_Glucose without altering renin, reflecting adaptive mechanisms that preserve sodium and fluid balance and protect against volume depletion. Sotagliflozin also decreased markers of kidney injury and increased haematocrit.

Objective: People with chronic kidney disease (CKD) and diabetes are at high risk of cardiovascular disease (CVD). Aortic pulse wave velocity (Ao-PWV) is an independent predictor of CVD. Cardiovascular outcome trials (CVOTs) with glucagon like peptide-1 receptor agonist (GLP-1 RA) class demonstrate notable differences, with lixisenatide having neutral effects as compared to longer acting GLP-1 RA. It is unknown if shorter acting GLP-1 RA have an impact on Ao-PWV and if this may explain the discordance observed in GLP-1RA CVOTs.

Materials and methods: We studied people with type 2 diabetes and CKD in a proof-of-concept single centre, randomised, double-blind parallel-group placebo-controlled study that evaluated 24 weeks' treatment with lixisenatide as compared to placebo on the primary endpoint of Ao-PWV.

Results: In total, 101 participants (male 66%) were randomised of whom 90 were eligible for analyses (lixisenatide [n = 47] and placebo [n = 43]). Ao-PWV did not change significantly from baseline after 24 weeks of treatment with final mean (95% confidence intervals) of 9.65 (9.17, 10.13) m/s with lixisenatide and 9.96 (9.45, 10.46) m/s with placebo, p = 0.38. Similarly, no significant changes were observed in cardio-renal risk biomarkers including albuminuria and Klotho levels. HbA1c decreased with lixisenatide as compared to placebo.

Conclusions: In people with CKD and type 2 diabetes the use of short-acting GLP-1 RA lixisenatide did not significantly influence Ao-PWV. Further studies are needed to understand mechanisms that may explain discordance in CVOTs results observed with GLP-1 RA.

Clinical trial registration: ISRCTN: ISRCTN97699312; EudraCT/CTIS number: 2016-001758-17.

Background: Although semaglutide 2.4 mg has demonstrated significant weight loss efficacy in clinical trials, real-world data, particularly with regard to clinically complex and underrepresented populations, remain limited.

Objectives: The study aims to assess the real-world effectiveness and patient-reported outcomes associated with the use of semaglutide 2.4 mg in individuals with severe and complex obesity. The study also intends to characterize weight loss response in pre-defined subgroups of patients and to identify predictors of weight loss using machine learning.

Methods: SEMASEARCH is a retrospective multicentric observational cohort embedded within the French early-access program for semaglutide 2.4 mg. A total of 1100 patients with severe obesity (BMI ≥ 40 kg/m² with at least one treated obesity-related complication) were retrospectively included from 11 expert obesity centers, based on prospectively collected data at baseline, 6 months, and 12 months. Subgroups include patients with a history of bariatric surgery, binge eating disorder, hypothalamic obesity, age ≥ 60 years or altered body composition, BMI ≥ 60 kg/m², and those receiving psychotropic medications. Assessments include clinical, biological, and body composition data, as well as standardized questionnaires evaluating eating behaviour, physical activity, sleep, quality of life, digestive symptoms, and mental health.

Primary outcome: Body weight change since treatment initiation, with assessment at 6 and 12 months.

Secondary outcomes: Clinically meaningful weight loss (≥ 10%) at 12 months, metabolic improvements, patient-reported outcomes, body composition changes, and tolerance.

Expected impact: SEMASEARCH will provide real-world evidence on Semaglutide 2.4 mg use in patients living with severe and complex obesity. It will also address major knowledge gaps in specific populations underrepresented in clinical trials and generate predictive models of weight loss response.

Background and aim: Use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonists is increasing among reproductive-aged women for obesity, diabetes, polycystic ovary syndrome (PCOS), and cardiometabolic disease. However, the safety of these agents in pregnancy and lactation remains sparse, while inadvertent first-trimester exposure is becoming more common. The aim of this review is to systematically evaluate maternal, fetal, neonatal, and lactation outcomes following preconception, in-pregnancy, or postpartum exposure to GLP-1 and dual GLP-1/GIP receptor agonists.

Methods: We conducted a systematic review of PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane Library from inception to 23 September 2025. Human studies reporting exposure to GLP-1 or dual GLP-1/GIP receptor agonists during preconception, pregnancy, or lactation were included. Two reviewers independently screened studies, extracted data, and assessed risk of bias using validated tools. Given clinical heterogeneity, findings were synthesised narratively in accordance with PRISMA 2020 guidelines.

Results: Thirty-six studies met the inclusion criteria. Across large observational cohorts, periconceptional or early-pregnancy exposure to GLP-1-based therapies was not consistently associated with increased risk of major congenital malformations in adjusted analyses, fetal growth restriction, stillbirth, or neonatal mortality compared with insulin-treated or disease-matched controls. Maternal outcomes, including gestational diabetes, hypertensive disorders of pregnancy, preterm birth, and gestational weight gain, were heterogeneous without a reproducible safety signal. Indeed, in women with PCOS, GLP-1RAs seem promising in various aspects. Lactation data were sparse; one pharmacokinetic study reported no detectable semaglutide transfer into human milk.

Conclusion: Current evidence suggests that preconceptional or early-pregnancy exposure to GLP-1-based therapies is not consistently associated with increased maternal, fetal, or neonatal risk, although data on continued use throughout gestation remain limited.

Aims: Type 2 diabetes mellitus (T2DM) has been inversely associated with prostate cancer (PrCa) risk. However, it remains unclear whether a polygenic risk score (PRS) for PrCa can effectively stratify risk among men with T2DM. The primary objective of this study was to assess whether a PrCa PRS predicts PrCa risk independently of T2DM status. The secondary objective was to evaluate potential mediating factors, including insulin-like growth factor-1 (IGF-1) and sex hormones.

Materials and methods: We analysed data from over 140 000 men in the UK Biobank and Penn Medicine Biobank. A PrCa PRS was constructed using summary statistics from a large-scale genome-wide association study. Cox proportional hazards models were used to evaluate the association between PRS and incident PrCa, adjusting for relevant covariates and testing for interaction by T2DM status. Additionally, sex hormones and IGF-1 levels were analysed to explore potential mediators.

Results: T2DM was associated with a reduced incidence of PrCa. The PrCa PRS was significantly associated with PrCa risk regardless of T2DM status (p < 0.001), and men in the highest PRS category exhibited the greatest risk, especially among those without T2DM. IGF-1 levels were positively associated with PrCa risk among both diabetic and non-diabetic men, while sex hormone levels showed no significant association in men with T2DM. Adjusting for testosterone and IGF-1 did not attenuate the association between PRS and PrCa.

Conclusions: PrCa PRS effectively stratifies risk among men with and without T2DM, highlighting the independent contribution of genetic susceptibility. Lower IGF-1 levels in T2DM patients may partly mediate the reduced PrCa risk, suggesting a possible biological mechanism underlying these observations.

Background: Type 2 diabetes mellitus (T2DM) is a progressive, multi-organ disorder that often requires intensive combination therapy. This Phase III, randomised, double-blind, placebo-controlled study evaluated the efficacy and safety of two fixed-dose combinations (FDCs) of sitagliptin 100 mg with empagliflozin 10 mg (DW1026C1) or empagliflozin 25 mg (DW1026C2) as add-on therapy for patients with inadequately controlled T2DM.

Methods: Two hundred thirty adults with T2DM inadequately controlled by metformin (≥ 1000 mg/day) and sitagliptin (100 mg) were 1:1:1 randomised to receive DW1026C1 (E10 group, n = 77), DW1026C2 (E25 group, n = 76), or a placebo (n = 77). Treatment was administered for 24 weeks, followed by a 28-week extension period. The primary endpoint was the change in HbA1c from baseline to Week 24.

Results: Baseline characteristics were similar among groups. At Week 24, both active treatments demonstrated statistically significant HbA1c reductions versus the placebo. The least square mean differences [95% CI] versus the placebo were -0.54% [-0.78, -0.29] for E10 group and -0.61% [-0.85, -0.36] for E25 group (both p < 0.0001). Fasting plasma glucose (FPG), insulin resistance, body weight, systolic blood pressure, albumin-creatinine ratio and high-density lipoprotein cholesterol also improved in the active groups. Reductions in HbA1c, FPG and insulin resistance were sustained in Week 52. Safety profiles were favourable with adverse events similar in frequency and no increased hypoglycaemia risk.

Conclusion: Sitagliptin/empagliflozin FDC doses achieved improvements in glycaemic control at 24 weeks, which was maintained through 52 weeks. These benefits were accompanied by a favourable safety profile, including a very low risk of hypoglycaemia.

Trial registration: NCT07076056.

Background: Whether associations between the body roundness index (BRI) and mortality differ across population settings in metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear.

Methods: We analysed two nationally representative cohorts: NHANES (1999-2018; n = 7723; US population) and CHARLS (2011-2020; n = 6553; Chinese population). Cox proportional hazards regression with restricted cubic splines was used to assess dose-response relationships. Between-cohort heterogeneity was evaluated using I² statistics.

Results: In NHANES (mean BMI, 31.99 kg/m²; 924 deaths over median follow-up of 8.9 years), BRI demonstrated a significant linear association with all-cause mortality (hazard ratio [HR], 1.18 per SD; 95% confidence interval [CI], 1.049-1.327; p = 0.006). In CHARLS (mean BMI, 25.73 kg/m²; 110 deaths over median follow-up of 7.3 years), no significant association was observed (HR, 0.91; 95% CI, 0.749-1.101; p = 0.327). Between-cohort heterogeneity was substantial (I² = 80.7%; p = 0.023). In NHANES, the triglyceride-glucose (TyG) index was associated with 33.8% (95% CI, 18.2%-52.4%) statistical attenuation of the BRI-mortality association. The null finding in CHARLS likely reflects insufficient power (14% to detect HR = 1.18) rather than evidence against an association, highlighting the need for adequately powered studies.

Conclusions: BRI demonstrates a significant linear association with mortality in the US MASLD population. In the Chinese elderly MASLD population, statistical power was insufficient to draw definitive conclusions about BRI-mortality associations. The observed between-cohort heterogeneity likely reflects multiple factors, including differences in age structure, obesity phenotype, mortality ascertainment methods, and potentially genuine population-specific characteristics. These findings underscore the importance of population-specific validation before extrapolating Western-derived BRI thresholds to Asian populations.

Aims: The REALISED study assessed the clinical outcomes associated with oral semaglutide use in Thai patients with type 2 diabetes (T2D) in real-world clinical settings.

Materials and methods: This retrospective, multi-centre cohort study included 195 patients with T2D initiating oral semaglutide between April 2022 and December 2023. Eligible participants had no prior injectable therapy and completed at least 26 weeks of treatment. The primary endpoint was the change in HbA1c from baseline to the end-of-study (EoS, Week 26); Week 52 outcomes were exploratory. Secondary endpoints included changes in body weight and the proportion achieving HbA1c < 7%. Severe hypoglycaemia was the safety endpoint. A post hoc composite endpoint combined HbA1c < 7% with ≥ 3% weight loss. Analyses used a mixed model for repeated measures and descriptive statistics.

Results: Oral semaglutide was predominantly used as add-on therapy (190/195 [97.4%]). Mean HbA1c decreased by -0.7% (95% CI: -0.9 to -0.5; p < 0.0001), and the mean body weight decreased by -4.3 kg (95% CI: -5.5 to -3.2; p < 0.0001). At the EoS, 75.9% (117/154) achieved an HbA1c < 7%, and 57.7% (71/123) met the composite endpoint. No severe hypoglycaemia occurred. Dose escalation from 3 mg to 14 mg was observed in 53.2% by Week 26 and 70.4% by Week 52.

Conclusions: The REALISED study provides the first real-world evidence of the use of oral semaglutide in Thai patients with T2D, demonstrating significant improvements in glycaemic control and weight reduction across routine care settings.