Aims

The use of pharmacotherapies with weight loss properties for the management of obesity and chronic disease are now routinely prescribed. We investigated the evidence from randomised-controlled trials for the effects on lean body mass of glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) in humans.

Materials and Methods

PubMed, MEDLINE, the Cochrane Library and CINAHL were searched from inception to October 2022. The primary outcome was change in body composition focused on measures of lean body mass (LBM).

Results

Thirty-six studies in population groups with obesity (n = 8), type 2 diabetes mellitus (n = 20), type 1 diabetes mellitus (n = 5) and polycystic ovary syndrome (n = 3) receiving a GLP-1RA or SGLT2i therapy versus placebo or active comparator satisfied our inclusion criteria, including 21 for GLP-1RA and 15 for SGLT2i. Meta-analysis showed an overall loss of LBM in the direction of the intervention groups prescribed GLP-1RA (MD: −1.51 kg [95% CI: −2.00 to −1.01]) and SGLT2i (MD: −1.04 kg [95% CI: −1.45 to −0.64]) with sub-group analysis showing largely consistent results when stratified by type of body composition outcome, type of body composition measurement technique and disease status. Results were not modified by sex. Further meta-analysis found that lean mass accounted for 28% (95% CI: 22%–34%) of overall weight loss induced by GLP-1RA and SGLT2i.

Conclusions

GLP-1RA and SGLT2i are associated with a loss of LBM that appears congruent with overall weight loss. Monitoring of body composition and provision of combined therapy to preserve lean mass during weight loss should be considered.

Introduction

Administration of a somatostatin receptor 2 antagonist (SSTR2a) increases glucagon responsiveness to hypoglycaemia in insulin-treated type 2 diabetes (T2D), but the durability of this effect and the impact of repeated SSTR2a dosing on overall glycaemia in T2D are unclear. This study evaluated the effects of daily SSTR2a administration on glucagon counterregulation and overall glycaemia in a male rat model of T2D.

Methods

T2D was induced in male Sprague–Dawley rats using high-fat feeding and streptozotocin (35 mg/kg) (day 0). After a 7-day insulin maintenance period, T2D and control rats were administered a single dose of SSTR2a (ZT-01, 3 mg/kg) or vehicle (n = 7–8 per group) prior to a hypoglycaemic challenge with an insulin overdose (day 8). After a one-week washout period, T2D and control rats were administered drug or vehicle for 8 days, with a second hypoglycaemic challenge performed on the last day.

Results

Glucagon counterregulation to both hypoglycaemic exposures increased with SSTR2a in T2D and controls (all p < 0.05). Dosed without hypoglycaemia, SSTR2a induced a transient rise in glucagon, c-peptide, and glucose levels in both healthy and T2D rats, but food intake and body weight were unaffected. T2D rats on SSTR2a (days 8–22) had reduced daily insulin needs without significantly affecting blood glucose levels.

Conclusion

In this male rat model of T2D, repeat dosing of SSTR2a increases glucagon counterregulation without worsening glycemia.

Background

Endoscopic sleeve gastroplasty (ESG), a natural orifice transluminal endoscopic procedure, is increasingly integrated into multidisciplinary obesity care. We performed a systematic review and meta-analysis to quantify the durability of ESG-associated weight loss and metabolic outcomes across short- and long-term follow-up.

Methods

Databases were searched from inception to September 2, 2025 (PROSPERO: CRD420251139333). Peer-reviewed studies reporting ESG outcomes were included; primary outcomes were % total body weight loss (%TBWL), % excess body weight loss (%EBWL), and BMI reduction, stratified by follow-up (≤ 6 months vs. ≥ 1 year). Random-effects models were used; heterogeneity (I
²), publication bias (Egger’s test), GRADE assessment, sensitivity analyses, and meta-regression for baseline BMI were performed.

Results

Thirty-three studies (8880 patients; 31 cohorts, 2 RCTs) were included. %TBWL increased from 8.66% (1 month) to 16.13% (6 months) and was 17.88% at 1 year. Long-term pooled %TBWL declined modestly over time (17.88% at 1 year to 15.67% at 3 years). Remission rates were 62% for type 2 diabetes, 43% for hypertension, and 43% for dyslipidaemia. Weight regain occurred in 6%. Baseline BMI predicted higher %TBWL but lower %EBWL.

Conclusion

ESG is associated with clinically meaningful weight loss maintained beyond 6 months with modest attenuation over longer follow-up, alongside favourable metabolic remission rates and low reported weight regain.

Aims

To evaluate the association between diabetic corneal neuropathy and diabetic foot risk by examining corneal nerve features, clinical characteristics, and tear mediators in patients with different diabetic foot risk categories.

Methods

In this cross-sectional study, 710 participants underwent diabetic foot examination, in vivo confocal microscopy scans, ocular surface assessments, and tear mediators measurements. Ordinal regression analysis was applied to determine the associations between foot risk categories and corneal nerve metrics. ROC curve analysis assessed the ability of corneal nerve parameters to identify high-risk diabetic foot.

Results

All diabetic foot risk categories exhibited significantly impaired corneal nerve fibre length, density, fractal dimension, and more swollen width compared with controls (all p < 0.001). These patients also demonstrated significantly shorter tear break-up time, more severe ocular symptoms, elevated tear MMP-9, and reduced tear Substance P levels (all p < 0.05). Patients with high-risk diabetic foot showed significantly more pronounced corneal nerve alterations than those in low and moderate-risk groups (all p < 0.05). The more severe diabetic foot risk category was significantly associated with reduced nerve fibre length, density, fractal dimension, and increased width (all p < 0.05). A predictive model incorporating corneal nerve fibre length, width, and serum creatinine achieved an AUC of 0.80 for identifying high-risk diabetic foot. A CNFL < 5.7 mm/mm² was associated with 4.37-fold higher odds of having a high-risk diabetic foot.

Conclusion

Corneal nerve impairment is evident even in low-risk diabetic foot patients and is associated with foot risk severity. Corneal nerve metrics may serve as early indicators for identifying high-risk diabetic foot.

Hyperglycaemia first diagnosed in pregnancy (HIP) is the most common medical condition affecting pregnancy, affecting up to 40% of pregnancies in some countries. The global incidence of HIP is increasing owing to rising rates of overweight and obesity, advanced maternal age, and early screening for HIP. Current guidelines recommend self-monitoring of blood glucose (SMBG) via frequent capillary finger-prick testing, which can be painful and inconvenient, contributing to poor adherence, psychological distress, and suboptimal glycaemic control. Continuous glucose monitoring (CGM) offers an alternative approach, providing real-time, automated glucose readings without the need for repeated invasive testing. This review evaluates the current evidence on the clinical benefits of CGM in HIP, including its effects on glycaemic control, maternal and neonatal outcomes, and patients’ quality of life. Although existing studies are limited by small sample sizes and methodological variability, findings suggest that CGM might improve adherence, patient satisfaction, glycaemic control, and neonatal birth weight compared with SMBG. However, the lack of large-scale randomised trials has hindered widespread adoption and reimbursement of CGM for HIP. There is a clear need for more patient-centred glucose monitoring strategies and further research to confirm the long-term benefits of CGM in HIP management and to identify the patient populations most likely to benefit from CGM use. Addressing these gaps is essential to optimising care and improving outcomes for the growing population affected by HIP.

Importance

Clinical guidelines for type 2 diabetes (T2D) provide population-level recommendations, but real-world treatment patterns evolve dynamically and vary across patients. Understanding longitudinal prescribing trajectories may reveal heterogeneity in care not captured by cross-sectional analyses.

Objective

To identify and characterise real-world T2D prescribing trajectories using nationwide electronic health record (EHR) data.

Design, Setting and Participants

This retrospective cohort study used de-identified EHR data from the TriNetX Research Network. Adults newly diagnosed with T2D who initiated their first glucose-lowering medication in the first half of 2019 were followed from 2019 through 2024.

Exposures

Longitudinal glucose-lowering prescribing trajectories derived from prescription orders across nine drug classes (metformin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 RAs (GLP-1 RAs), dual glucose-dependent insulinotropic polypeptide/GLP-1 RAs (GIP/GLP-1 RAs), insulin and other antidiabetic agents), encoded in 12 semiannual intervals and identified using hierarchical agglomerative clustering.

Main Outcomes and Measures

Prescribing trajectory cluster membership; adjusted longitudinal changes in body mass index (BMI) and haemoglobin A1c (HbA1c); and associations between cluster membership and patient characteristics assessed using multivariable logistic regression.

Results

Among 9327 patients, 30 distinct prescribing trajectory clusters were identified and grouped into monotherapy, dual therapy, complex therapy, variant therapy and GLP-1 RA-based trajectories. Treatment intensification patterns, BMI and HbA1c trajectories and demographic composition varied substantially across clusters. Within GLP-1 RA–based trajectories (11 clusters), substantial within-group reductions in BMI and HbA1c were observed; these clusters generally comprised patients with higher baseline BMI and most commonly involved transitions following metformin. GLP-1 RA prescribing was more frequent among younger patients and those with higher baseline BMI. In early GLP-1 RA transition trajectories, Asian and Hispanic patients had lower odds of cluster membership compared with non-Hispanic White patients (Asian: odds ratio [OR] 0.40; 95% CI 0.23–0.63; Hispanic: OR 0.57; 95% CI 0.40–0.79).

Conclusions and Relevance

Data-driven clustering of longitudinal EHR medication data identifies substantial heterogeneity in real-world T2D treatment trajectories. Differences in the timing and adoption of newer therapies were observed across demographic groups, underscoring the value of longitudinal approaches for evaluating real-world diabetes care patterns.

Purpose

HDM1002 is a potent, orally active, and highly selective small-molecule full agonist of the glucagon-like peptide-1 receptor (GLP-1R), independently developed by Hangzhou Sino-American Huadong Pharmaceutical Co. Ltd. Our aim was to evaluate the pharmacokinetics, relative bioavailability, and food effects of two tablet strengths (100 and 200 mg) of HDM1002 in Chinese health volunteers (HVs).

Methods

This single-centre, randomised, open-label, single-dose, two-formulation, three-period, double-crossover phase I study enrolled 33 HVs. All subjects received each of the following three treatments in different periods: (A) two 100-mg tablets under fasting conditions; (B) a single 200-mg tablet under fasting conditions; and (C) a single 200-mg tablet following a high-fat meal. A washout period of 7 days was implemented. The plasma concentrations of HDM1002 were measured using HPLC-MS/MS method, and PK parameters were determined by non-compartmental analysis.

Results

Under fasting conditions, the 90% confidence intervals (CI) for the geometric mean ratios (two 100-mg tablets vs. one 200-mg tablet) of C
_max, AUC_0-t, AUC_0-∞ were 106.87% (91.42%, 124.92%), 99.64% (95.32%, 104.15%), and 99.55% (95.20%, 104.09%), respectively, all within the 80.00%–125.00% bioequivalence range. For the food effect on the 200-mg tablet, the 90% CI of C
_max (fed vs. fasted) was 87.53% (76.88%, 99.66%), with its lower limit slightly below 80.00%; AUC_0-t and AUC_0-∞ were 105.90% (99.80%, 112.37%) and 106.01% (99.92%, 112.47%), both within the range. And there were no serious adverse events (AEs) occurred.

Conclusion

HDM1002 was well-tolerated and safe. The two tablet strengths (100 and 200 mg) were bioequivalent under fasting conditions. A high-fat meal modestly reduced the C
_max of the 200-mg tablet but did not significantly affect its overall exposure (AUC).

Trial Registration:
ClinicalTrials.gov identifier: ChiCTR2500111569

Aims

The escalating global prevalence of childhood and adolescent overweight and obesity constitutes a pressing public health issue. This network meta-analysis aimed to compare the efficacy and safety of pharmacologic interventions as adjuncts to lifestyle therapy in this population.

Materials and Methods

Randomized controlled trials (RCTs) were sourced from systematic searches of PubMed, Embase (using the OVID platform), the Cochrane Library (CENTRAL), the WHO International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov from database inception to July 28, 2025. A frequentist network meta-analysis was performed using a random-effects model. We used the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach to evaluate the overall certainty of evidence and categorized the interventions.

Results

A total of 41 RCTs (N = 3923) were included. Compared with lifestyle modification alone, semaglutide produced the largest reduction in the 95th BMI percentile (MD −20.40%, 95% CI −24.22 to −16.58), with an additional 500 and 399 patients per 1000 person-years achieving ≥ 5% and ≥ 10% BMI reduction, respectively. Phentermine-topiramate showed the next largest reduction (MD −18.35%, 95% CI −22.26 to −14.45), corresponding to 554 and 734 additional responders per 1000 person-years. Liraglutide and exenatide also significantly reduced the 95th BMI percentile compared with lifestyle modification alone, although the reductions were smaller than those achieved with semaglutide and phentermine-topiramate.

Conclusions

Both semaglutide and phentermine-topiramate were closely linked to weight management, and phentermine-topiramate, with its favourable tolerability, may serve as the optimal adjunct to lifestyle interventions.

Objective

Soluble receptor for advanced glycation end-products (sRAGE) and soluble Toll-like receptor 4 (sTLR4) are circulating pattern recognition receptor isoforms implicated in inflammatory regulation in type 2 diabetes mellitus (T2DM). This study examined the effects of supervised aerobic exercise training (AET) on circulating sRAGE, sTLR4, and related skeletal muscle inflammatory signalling outcomes in adults with T2DM.

Methods

Thirty-three sedentary adults with T2DM were randomized to AET (n = 20; age: 54.5 ± 9.3 years; BMI: 34.6 ± 1.3 kg/m²; HbA1c: 7.5% ± 1.1%) or standard of care control (CON; n = 13; age: 59.6 ± 9.3 years; BMI: 32.6 ± 1.6 kg/m²; HbA1c: 6.9% ± 0.9%). Participants in AET completed 12 weeks of supervised aerobic exercise (60 min/day, 5 days/week) at ~70% VO2peak. Pre—and post-intervention assessments included oral glucose tolerance testing, DXA-derived body composition, VO2peak testing, and an acute aerobic exercise trial with blood and skeletal muscle sampling. Circulating sRAGE, sTLR4, hsCRP, and skeletal muscle protein expression of RAGE, TLR2/4, ADAM10, MMP2/9, and TIMP1/3 were quantified.

Results

AET increased circulating sRAGE concentrations across the intervention period, whereas sTLR4 was unchanged. AET improved cardiorespiratory fitness, reduced body fat percentage and fat mass, lowered fructosamine concentrations, and increased the Matsuda Index. In skeletal muscle, significant alterations were observed in selected TIMP:MMP and TIMP:ADAM10 ratios, although no changes were detected in ADAM10 activity or skeletal muscle RAGE protein expression. Exploratory analyses demonstrated associations between changes in circulating sRAGE and aerobic fitness.

Conclusions

AET increased circulating sRAGE and improved select metabolic health outcomes in adults with T2DM. These findings are consistent with the concept that chronic exercise training may favourably influence inflammatory regulation in metabolic disease. However, the tissue-specific mechanisms contributing to exercise-induced changes in circulating sRAGE remain incompletely understood and warrant further investigation.

Aim

Evaluate ecnoglutide (XW003) effects on rosuvastatin and digoxin pharmacokinetics (PKs) in healthy adults.

Methods

This was an open-label, single-sequence crossover Phase 1 study. Eligible participants received rosuvastatin (10 mg, single dose) and digoxin (0.25 mg, single dose) in two periods: Once before subcutaneous treatment with ecnoglutide and once during steady-state subcutaneous ecnoglutide (1.2 mg). Coadministration effect was assessed via PK parameters of both drugs.

Results

A total of 28 volunteers received at least one dose of study drug. Co-administration of ecnoglutide did not affect rosuvastatin and digoxin to a clinically relevant degree. For the area under the concentration-time curve from time zero to infinity, the geometric mean (GM) ratio (with ecnoglutide vs. alone) [90% confidence interval (CI)] was 106% (94%, 120%) for rosuvastatin and 84% (76%, 94%) for digoxin. Additionally, the maximum plasma concentration (C
_max) of digoxin decreased from 1.39 to 1.31 ng/mL but remained within the therapeutic window. The most common adverse events (AEs) were weight loss and gastrointestinal AEs, which are pharmacologically associated with glucagon-like peptide-1 (GLP-1). No serious AEs were reported. Notably, ecnoglutide treatment led to substantial body weight reduction, with a mean decrease of 11.2% across the 14-week intervention.

Conclusion

Based on the PK and safety evaluations, ecnoglutide does not cause clinically significant PK interactions with rosuvastatin or digoxin. Consequently, no dose adjustments for rosuvastatin or digoxin are required when ecnoglutide is co-administered. However, close clinical and plasma monitoring is advised during the coadministration of digoxin, especially in patients with renal impairment.

Gestational diabetes mellitus (GDM) represents far more than a transient glycaemic disorder: it is a sentinel metabolic event that unveils pre-existing defects in β-cell function and insulin action, with profound implications for both maternal and offspring cardiometabolic health across the lifespan. The physiological insulin resistance of pregnancy, driven by placental hormones and maternal immune modulation, intensifies progressively, resulting in a 60%–65% reduction in insulin sensitivity by the third trimester. This metabolic challenge necessitates a compensatory 200%–250% increase in insulin secretion to maintain euglycaemia. When pancreatic β-cells fail to meet this demand, maternal hyperglycaemia develops, triggering foetal hyperinsulinemia and establishing an intrauterine environment that promotes accelerated foetal growth, adipogenesis and adverse metabolic programming.

The intergenerational consequences of GDM extend beyond the perinatal period. Landmark studies in Pima Indians demonstrate that intrauterine exposure to maternal diabetes confers an elevated risk of childhood obesity and early-onset type 2 diabetes in offspring, independent of shared genetic susceptibility, thereby perpetuating a transgenerational cycle of metabolic disease, potentially mediated in part by epigenetic mechanisms.

Diagnostic strategies for GDM vary internationally, with the one-step 75-g OGTT (IADPSG/ADA criteria) and the two-step Carpenter–Coustan approach yielding comparable maternal and neonatal outcomes.

In GDM, management typically starts with individualized medical nutrition therapy and physical activity, with insulin as the preferred pharmacological treatment when glycaemic targets are not achieved. Metformin and glyburide, despite their convenience and oral administration, remain controversial due to placental transfer and still limited long-term safety data in offspring.

Given its increasing prevalence and long-term implications, GDM is both a clinical and public health concern. Early recognition and evidence-based management provide an opportunity to interrupt the intergenerational transmission of metabolic risk and preserve long-term cardiometabolic health.

ABSTRACT

Aims

There is uncertainty whether traditional glycemic metrics remain associated with long-term outcomes among patients with type 2 diabetes who achieve recommended continuous glucose monitoring (CGM) targets. This study was aimed to investigate the association of glycated albumin (GA) and ratio of glucose management indicator to GA (GMI/GA) with risks of all-cause mortality in type 2 diabetes achieving CGM targets.

Materials and Methods

A total of 3482 patients with type 2 diabetes who met CGM targets, defined as time in range (TIR) >70%, time below range (TBR_<3.9) <4%, and time above range (TAR_>10.0) <25%, were included in the cohort study. Cox proportional hazards models and restricted cubic spline were used to evaluate associations of GA and GMI/GA with mortality.

Results

During a median follow-up of 11.0 years, 514 patients (14.8%) died. GA exhibited significant linear positive association with risks of all-cause mortality, and the highest GA quartile had 34% increased risk (HR = 1.34, 95% CI 1.01–1.78). Conversely, GMI/GA ratio showed significant non-linear association (p for nonlinearity = 0.042). Compared with the reference third quartile (0.36–0.40), participants in the lowest quartile (<0.30) had 40% higher risk of all-cause mortality (HR = 1.40, 95% CI 1.10–1.80).

Conclusion

Among patients achieving CGM targets, elevated GA and lower GMI/GA were associated with higher risks of all-cause mortality. These findings suggest that traditional glycemic metrics may complement CGM metrics in the assessment of long-term risks.

Background

In the SELECT trial, semaglutide reduced major adverse cardiovascular outcomes (MACE) in individuals with overweight or obesity and established cardiovascular disease (CVD) but without diabetes. However, real-world cardiovascular event rates in comparable populations remain uncharacterised. We therefore aimed to (1) assess real-world cardiovascular outcomes in a SELECT-like cohort with obesity, (2) compare them to the general population and a broader population of individuals with obesity and (3) evaluate the cardiovascular preventive potential of semaglutide in this SELECT-like cohort with obesity.

Methods

We used healthcare registries and electronic health records from three Swedish regions (2013–2023), covering ~40% of the national population, to identify individuals aged ≥ 45 years with obesity (body mass index [BMI] ≥ 30 kg/m²) and established CVD but without diabetes, in alignment with the SELECT trial criteria. Cardiovascular outcomes in this SELECT-like obesity cohort were compared with matched individuals from the general population as well as with a broader population of individuals with obesity, irrespective of CVD status or other comorbid conditions. To estimate the number needed to treat (NNT), the relative treatment effect of semaglutide observed in the SELECT trial was applied to the absolute risks identified in the SELECT-like obesity cohort.

Results

The SELECT-like obesity cohort (n = 9652) had a mean (SD) age of 68.4 (11.3) years, a mean BMI of 33.1 kg/m² (SD 3.5) and 57.9% were men. Most had a history of myocardial infarction (48.1%) or stroke (41.7%). Over a mean (SD) follow-up of 5.4 (3.2) years, MACE occurred in 21.7%. Compared with the SELECT trial, this real-world population had a higher mean age, had a higher proportion of females, and more often had a prior stroke. Applying the estimated effect of semaglutide from the SELECT trial, the NNT to prevent one MACE was 35 (95% CI, 24–66). Compared with the General population cohort (n = 48 260), the SELECT-like obesity cohort had a higher burden of cardiovascular and obesity-related comorbidities and an increased risk of adverse cardiovascular outcomes, including MACE (HR 2.3 [2.2–2.4]) and heart failure (HR 2.7 [2.5–2.9]).

Conclusion

In a real-world setting, despite the use of extensive preventive medications, individuals with obesity and CVD had a higher risk of adverse cardiovascular outcomes and mortality compared with the SELECT trial as well as the general population. These findings highlight the substantial disease burden and the need for improved secondary CVD prevention strategies.