To characterize the cardiometabolic profiles of oral and subcutaneous glucagon-like peptide-1 (GLP-1) receptor mono-agonists in adults with overweight or obesity, with or without type 2 diabetes (T2D), using network meta-analysis (NMA).
PubMed, Embase and CENTRAL were searched (January 2014–November 2025) for randomized controlled trials (RCTs) evaluating GLP-1 receptor mono-agonists (semaglutide, liraglutide and orforglipron) in adults with overweight or obesity. The primary outcome was the cardiometabolic efficacy index (CEI), a ranking-based composite (0 to 1) summarizing performance across seven cardiometabolic endpoints: total body weight loss percentage, triglycerides, HDL cholesterol-C, LDL-C, waist circumference, HbA1c and systolic blood pressure. Secondary outcomes included treatment effects for each individual CEI component.
Nineteen RCTs (N = 13 117) were analysed. Semaglutide 7.2 mg achieved the highest CEI (0.86), followed by orforglipron 36 mg (bioequivalent to Foundayo 17.2 mg tablet) (0.68) and semaglutide 2.4 mg (0.66), all exhibiting placebo-adjusted weight reductions ≥ 10%. CEI rankings were generally consistent across T2D and non-T2D subgroups. Among oral formulations in non-T2D adults, OFG 36 mg showed a CEI comparable to oral semaglutide 25 mg (0.67 vs 0.63).
Higher-dose GLP-1 receptor mono-agonists, particularly semaglutide 7.2 mg and orforglipron 36 mg (Foundayo 17.2 mg tablet), demonstrated the most consistent multidimensional cardiometabolic improvements, although domain-specific differences were observed across agents.
]]>Cardiovascular diseases (CVD) are the leading cause of death worldwide, with excess visceral adipose tissue (VAT) being identified as an independent indicator of poor cardiovascular outcomes. We examined the association between three indices of VAT, namely, metabolic score for visceral fat (METS-VF), visceral adiposity index (VAI), and lipid accumulation product (LAP), and the development of CVD in a large cohort of middle-aged Korean adults.
The study recruited 8192 participants without CVD at baseline from the Korean Genome and Epidemiology Study. METS-VF, VAI, and LAP were calculated using established formulas based on anthropometric and metabolic parameters. Incident CVD was defined based on self-reported physician diagnoses confirmed by trained interviewers. Multivariable Cox proportional hazard regression analyses were performed to estimate the hazard ratio (HR) with a 95% confidence interval (CI) for incident CVD. Heagerty’s integrated areas under the receiver operating characteristic curves (iAUC) were used to compare the discriminatory performance of three indices.
The adjusted HRs (95% CIs) for incident CVD in the highest tertile compared with the lowest tertile were 1.62 (1.29–2.03), 1.38 (1.08–1.77), and 1.66 (1.32–2.09) for METS-VF, VAI, and LAP, respectively. METS-VF showed statistically higher discriminatory performance than VAI and LAP for incident CVD (p < 0.001), although the overall discriminative ability of indices was modest.
METS-VF, VAI, and LAP were independently associated with an increased risk of CVD events. Among these indices, METS-VF demonstrated relatively better discriminatory performance, suggesting its potential role as a complementary tool for cardiovascular risk stratification.
]]>Type 1 diabetes (T1D) is a complex autoimmune disorder heavily influenced by heritable traits. However, the interplay between modifiable lifestyle factors and genetic susceptibility remains insufficiently characterised. This study sought to elucidate how genetic background and lifestyle determinants jointly affect T1D liability.
Utilising the UK Biobank cohort, we performed both cross-sectional and longitudinal assessments. A polygenic risk score (PRS) was computed to quantify genetic predisposition to T1D across 403,778 subjects. Concurrently, a composite lifestyle index was generated based on six domains: adiposity, smoking status, alcohol intake, physical exertion, diet quality, and sleep duration. We evaluated cross-sectional relationships using multivariable logistic regression and assessed longitudinal outcomes using Cox proportional hazard models.
In a 15-year longitudinal study (median follow-up: 12.3 years) of 402,005 participants, 1474 cases of T1D were identified. Stratified by genetic risk, participants in the intermediate (hazard ratio [HR] = 1.17; 95% CI: 1.00–1.37) and highest (HR = 2.89; 95% CI: 2.46–3.39) risk groups demonstrated significantly elevated risks of incident T1D compared to the lowest risk group, independent of lifestyle factors. Conversely, when categorised by lifestyle patterns, both intermediate (HR = 0.61; 95% CI: 0.52–0.71) and healthy (HR = 0.43; 95% CI: 0.37–0.52) lifestyle groups exhibited substantially reduced risks of T1D compared to the unhealthy lifestyle group, irrespective of genetic predisposition. A significant interaction between genetic risk and lifestyle on the risk of T1D was found in both cross-sectional and longitudinal analyses (p < 0.001).
The data reveal a robust inverse relationship between adherence to a healthy lifestyle and T1D incidence across all genetic strata, even among those with elevated hereditary risk. These results underscore the critical role of lifestyle modification in mitigating T1D susceptibility, distinct from genetic inheritance.
]]>South Asians exhibit an unfavourable metabolic phenotype characterized by visceral obesity, insulin resistance and dyslipidemia. While various hormones play a critical role in regulating postprandial energy metabolism, it remains unclear whether they respond differently to food intake. We aimed to compare the meal-induced excursion of incretin hormones (GLP-1 and GIP) and glucagon between South Asians and Europids.
Forty nine young, lean South Asian (n = 24), and Europid (n = 25) males and females underwent an extended (up to 240 min) mixed meal tolerance test (MMTT). At seven time points circulating incretins (active and total GLP-1 and GIP), glucagon, and parameters related to glucose (i.e., glucose, insulin) and lipid metabolism were measured.
In response to the MMTT, Europids generally exhibited a single peak in glucose levels at t = 30 min, while South Asians tended to display a biphasic glucose response, with peaks at t = 30 and t = 90 min. Among South Asian males, this was accompanied by an increased insulin response, characterized by elevated levels at the corresponding glucose peaks. South Asian females, however, demonstrated a marked drop in circulating glucagon at t = 90 min, and biphasic excursions of total and active GLP-1 and GIP (t = 30 and t = 120 min). Postprandial lipid excursions did not differ between ethnicities.
In contrast to a monophasic glucose response to the MMTT of Europids, South Asians tended to exhibit a biphasic glucose response, with sex-specific hormonal patterns, suggesting altered incretin and insulin dynamics despite similar postprandial lipid excursions.
ClinicalTrials.gov (NCT05829018; registration date: 25-04-2023)
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]]>Diabetes-associated cognitive decline (DACD) is gradually gaining attention as a major complication of diabetes. However, to date, the specific molecular mechanisms underlying DACD have not been thoroughly characterized.
Db/db and streptozotocin (STZ) treated high-fat diet (HFD)-induced mice were established. Different behavioural assessments were performed, followed by evaluation of mitochondrial homeostasis, including mitochondrial morphology and function. Mitochondrial dynamics proteins, synaptic-related proteins and O-GlcNAc cycling enzymes were examined. Thereafter, OGT-interacting proteins were identified using co-immunoprecipitation mass spectrometry. Additionally, mouse hippocampal neuronal cells were treated with OGT siRNA and subsequent changes were measured. Mice were stereotaxically injected with adeno-associated viruses to overexpress OGT specifically in the hippocampus, and relevant in vivo experiments were performed. Finally, mice received semaglutide for 16 weeks and subsequent changes were assessed.
Decreased OGT expression disrupted mitochondrial homeostasis and led to neuronal injury and cognitive impairment in diabetic mice. In addition, hippocampus-specific OGT overexpression improved DACD. Mechanistically, OGT deficiency resulted in a reduced mitochondrial membrane potential, promoting mitochondrial fission and impairing mitochondrial function by modulating DRP1 function. Furthermore, our results showed that semaglutide alleviated DACD through the OGT/DRP1 pathway.
OGT deficiency-mediated mitochondrial homeostasis imbalance contributes to the occurrence of DACD, and semaglutide with an OGT protective effect may be a potential therapeutic approach for DACD.
]]>Sodium-glucose cotransporter 2 inhibitors (SGLT2is) improve glycaemic control and cardiorenal outcomes in Type 2 diabetes, particularly in patients at elevated cardiovascular and kidney risk, yet discontinuation following infections appears common. Guidelines do not generally recommend stopping treatment after a urinary tract infection (UTI) or genital tract infection (GTI). We investigated the impact of these infections on SGLT2i discontinuation.
We conducted a population-based matched cohort study of new SGLT2i users with Type 2 diabetes in Denmark during 2016–2021. All SGLT2i users with an incident UTI or GTI episode within the first year after treatment initiation were matched 1:3 to users without a UTI/GTI by sex, age, treatment duration and calendar year. Discontinuation was defined as not filling a new prescription within 60 days after previous medication supply ended.
Among 68 277 SGLT2i initiators, 5892 (8.6%) experienced UTI and 1389 (2%) experienced GTI during the following year. Among users with versus without UTI, discontinuation was 21.9% versus 14.3% on the date of the first expected SGLT2i refill (excess risk among users with UTI: 7.6% [95% CI 6.4%, 8.8%]), increasing to 39.5% versus 28.6% after 1 year. Among users with versus without GTI, discontinuation was 17.9% versus 15.6% (excess risk: 2.2% [95% CI −0.1%, 4.5%]) on the date of the first expected refill, rising to 43.6% versus 30.3% after 1 year.
Patients with Type 2 diabetes who initiate SGLT2i and experience a UTI or GTI within the following year have an elevated frequency of subsequent SGLT2i discontinuation.
]]>Sodium–glucose cotransporter 2 inhibitors (SGLT2i) slow kidney disease progression, but their cardiorenal outcomes in type 2 diabetes mellitus (T2DM) with nephrotic-range proteinuria, an extremely high-risk phenotype, are uncertain.
We conducted a retrospective cohort study in the TriNetX network using a new-user, active-comparator target trial emulation design. Adults with T2DM and nephrotic-range proteinuria, defined as UPCR > 3500 mg/g or UACR > 1967 mg/g, who initiated SGLT2i or dipeptidyl peptidase-4 inhibitors (DPP4i) were included. Propensity score matching (1:1) balanced covariates. The primary outcome was major adverse kidney events (MAKE); secondary outcomes were end-stage kidney disease (ESKD) on dialysis, all-cause mortality, cardiovascular events and safety endpoints.
After matching, 1051 participants were included per group (mean UPCR 5181–5416 mg/g). SGLT2i users had a lower risk of MAKE than DPP4i users (30.0% vs. 41.2%; HR 0.75, 95% CI 0.65–0.86), lower risk of ESKD (HR 0.73, 95% CI 0.62–0.85) and all-cause mortality (HR 0.71, 95% CI 0.55–0.91). Risks of cardiovascular events and safety outcomes, including genital infection, ketoacidosis, hypoglycaemia and urinary tract infection, showed no clear differences between groups.
Among adults with T2DM and nephrotic-range proteinuria, SGLT2i versus DPP4i was associated with lower long-term risks of ESKD and all-cause mortality and no clear differences in cardiovascular or safety outcomes were observed. These real-world observational findings support a potential kidney-protective role of SGLT2i in this very high-risk group and complement existing randomized trial data, but dedicated randomized trials in patients with nephrotic-range proteinuria remain necessary.
]]>Semaglutide is a GLP-1 receptor agonist for the treatment of type 2 diabetes and obesity. Its clinical effects are well established, but the underlying mechanisms remain unclear. This study aims to use computational modelling to generate hypotheses about semaglutide’s long-term metabolic (body weight, net energy intake, blood glucose, insulin, insulin sensitivity, glucotoxicity, leptin, leptin sensitivity, lipotoxicity, GLP-1 and βcell function) and neural (AgRP, POMC, and dopamine neural activity) effects.
The SemaGBA computational model was developed in Julia using a system dynamics approach, integrating 14 metabolic and neural variables. First, a version without neural variables was constructed and validated against clinical data for blood glucose and weight loss. Subsequently, the model was extended with neural variables. To represent distinct population groups, baseline variable profiles were defined, capturing the typical physiological characteristics for people with type 2 diabetes, obesity, and a healthy condition. Simulations were performed for semaglutide treatment in groups with prediabetes induced by chronic overeating, type 2 diabetes, and obesity over periods ranging from 30 weeks to 5 years.
The reduced model accurately reproduced clinical outcomes. It predicts glucose reductions of 38.0 mg/dL (data: 41.0 mg/dL) and weight loss of 3.2 kg (data: 3.8 kg) for diabetes (0.5 mg semaglutide), and 15.1% weight loss (data: 14.9%–17.1%) for obesity (2.4 mg semaglutide). Simulations showed semaglutide’s interconnected mechanisms, including reduced lipotoxicity and glucotoxicity, enhanced β-cell function, and glucose-dependent insulin secretion. Intervention during prediabetes prevented progression to diabetes by preserving β-cell function and maintaining glucose in the pre-diabetic range. Neural variables illustrated the potential contribution of AgRP, POMC, and dopamine neuron activity to reduced net energy intake.
The SemaGBA model demonstrates how semaglutide achieves glucose control and weight loss through integrated metabolic and neural pathways. Validation is limited by data availability, but the framework provides hypotheses for future research into semaglutide’s neural effects.
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