Diabetes, Obesity & Metabolism最新文献

Aims: Obesity is a growing global health crisis; pharmacotherapies such as tirzepatide combined with multidisciplinary lifestyle support have shown promise but real-world evidence in digital weight-loss services (DWLSs) is limited. This retrospective study evaluated 6- and 12-month weight loss, adherence and predictors of outcomes in an Australian cohort using a tirzepatide-supported medicated DWLS.

Materials and methods: All patients initiating tirzepatide through the Juniper AU DWLS between 1 September 2024 and 23 April 2025 (n = 4309) were analysed. The study population was predominantly female (92.9%) and Caucasian (81.9%), with a mean age of 41.46 years and a mean baseline body mass index of 32.9 kg/m². Primary endpoints were programme adherence at 6 and 12 months and mean percentage weight loss among adherent patients. Adherence required ≥5 medication orders and a weight entry at 173-193 days after programme initiation (6 months), or ≥10 orders and a weight entry 355-375 days post-initiation (12 months). Full cohorts were analysed using last observation carried forward imputation.

Results: At 6 months, 31.7% met adherence criteria; mean weight loss among adherent patients was 16.9% (±8.6; 95% CI 16.6-17.2), with 98.0% achieving ≥5% weight reductions. At 12 months, 16.1% were adherent; mean weight loss was 22.7% (±7.2; 95% CI: 19.8-22.6) and 100% of patients reached the ≥5% milestone. Multivariable models identified 1-month weight loss as the strongest predictor of 6- and 12-month outcomes; sustained weekly weight tracking and health coach messaging were strongly associated with both retention and greater weight loss. Paradoxically, very frequent weight tracking in month one correlated with poorer outcomes and reduced retention. Side effects were common but mostly mild/moderate and did not correlate with weight loss or programme retention.

Conclusions: Tirzepatide plus multidisciplinary digital care yields large clinically meaningful weight loss among engaged users, but low adherence limits population-level effectiveness. Early clinical response and sustained engagement are key drivers of adherence; however, interventions are needed to manage early weight-loss expectations.

Aims: Adjunctive therapies to insulin for type 1 diabetes mellitus (T1DM), including glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is), may improve glycaemic control and reduce insulin requirements; however, safety concerns remain, particularly for diabetic ketoacidosis (DKA).

Materials and methods: PubMed, Ovid MEDLINE, Embase, Web of Science, Scopus and the Cochrane Library through 26 September 2025. Data were pooled using a random-effects model. Risk of bias analyses were performed.

Results: Ninety studies met inclusion criteria. GLP-1RAs produced modest improvements in glycaemic control, lowering glycated haemoglobin (HbA1c) (-0.56%) and increasing time-in-range (TIR), while reducing total and basal daily insulin requirements, body weight (-3.6 kg) and body mass index (BMI) (-1.05 kg/m²). Severe hypoglycaemia and DKA were rare; gastrointestinal adverse effects were the most common adverse effects; renal and cardiovascular outcomes were neutral. SGLT2is significantly improved HbA1c (-0.38%), TIR (+8.6 pp), insulin requirements (-4.7 U/day), body weight (-2.5 kg) and BMI (-0.82 kg/m²). Severe hypoglycaemia was uncommon, while DKA risk was increased (risk ratios = 2.19, 95% confidence interval 1.16-4.17), primarily in predictable clinical settings. Renal parameters remained stable or improved, and cardiovascular events were infrequent. Across drug classes, mortality and hospitalisations were rare.

Conclusions: Adjunctive GLP-1RAs and SGLT2is provide modest clinical improvements in adults with type 1 diabetes. These benefits must be balanced against class-specific safety concerns, especially the increased risk of DKA with SGLT2-based therapies. Larger, long-term trials are needed to define their optimal use in routine care.

Aims: Randomized controlled trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors have yielded inconsistent findings regarding mortality benefits. It remains unclear whether, and in which subgroups, SGLT2 inhibitors confer survival benefits in older adults with diabetic kidney disease (DKD).

Materials and methods: We emulated a target trial using a nationwide claims and health checkup database in Japan to compare all-cause mortality between SGLT2 and dipeptidyl peptidase-4 (DPP4) inhibitor initiators among 5371 adults aged ≥65 years with DKD. The primary outcome was all-cause mortality. Hazard ratios (HRs) were estimated using propensity score overlap weighting and Cox proportional hazards models in an intention-to-treat analysis. A per-protocol analysis with inverse probability of censoring weighting was conducted as sensitivity analysis. Effect modification by age, body mass index (BMI) and Charlson comorbidity index (CCI) was assessed using restricted cubic spline models.

Results: During a median follow-up of 2.23 (IQR, 1.07-3.49) years, 437 deaths occurred. SGLT2 inhibitor use was associated with significantly lower all-cause mortality than DPP4 inhibitors (HR, 0.51; 95% confidence interval, 0.38-0.70), with consistent results in the per-protocol analysis (HR, 0.50; 95% confidence interval, 0.35-0.73). Survival benefit was evident up to about 80 years of age and among individuals with BMI ≥22 kg/m², irrespective of CCI.

Conclusions: In this target trial emulation study, SGLT2 inhibitors were associated with lower mortality in older adults with DKD, particularly those under 80 years and with BMI ≥22 kg/m². These findings support personalized treatment decisions for this high-risk population in clinical practice.

Aims: This study investigated changes in how people living with obesity (PwO) perceive weight-related discussions with healthcare professionals (HCPs) in Denmark from 2022 to 2024, a period marked by shifts in obesity treatment options as well as the broader understanding of obesity.

Materials and methods: A cross-sectional online survey was conducted among adult PwO in Denmark, building on the 2022 Awareness, Care, and Treatment In Obesity maNagement-Denmark survey with a few modifications. Data were collected via representative online panels from September to October 2024. Adjusted logistic regression models were performed.

Results: A total of 1005 PwO participated in the 2024 survey, compared to 879 in the 2022 survey. The proportion of PwO discussing weight with HCPs increased significantly from 38% in 2022 to 58% in 2024. The percentage of PwO reporting positive feelings after weight consultations did not change significantly. PwO in 2024 still refrained from discussing weight due to fear of prejudice (23%), previous negative experiences (17%) and the belief that reducing weight was their own responsibility (46%). Subgroup analyses in 2024 revealed that those currently using weight loss medications reported the most positive perceptions of weight-related discussions with their HCP.

Conclusions: Overall increased engagement of PwO regarding weight-related discussions with HCPs was observed from 2022 to 2024. However, barriers persist, since some PwO avoid interactions with HCPs due to previous experiences with stigma or the fear of being judged. Continued efforts are essential to address these barriers, enhance HCP education about weight-related bias, and foster a supportive environment for PwO in healthcare settings.

Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents one of the most common chronic liver disorders worldwide, and its incidence continues to rise each year. Serine β-lactamase-like protein (LACTB) is a serine protease that plays a crucial role in lipid metabolism and hepatocellular carcinoma, but its function in MASLD remains unclear. Therefore, the study aims to elucidate the effect and mechanism of LACTB in the progression of MASLD.

Materials and methods: The expression of LACTB in liver tissues from MASLD patients and high-fat diet (HFD) fed mice was assessed. Both in vivo and in vitro models were established to examine the role and molecular mechanisms of LACTB in MASLD.

Results: LACTB protein levels were upregulated in the liver tissues from MASLD patients and HFD-fed mice. LACTB overexpression exacerbated hepatic steatosis, insulin resistance, and inflammation in HFD-fed mice. Conversely, LACTB knockdown improved these phenotypes. Mechanistically, LACTB interacted with CPT2 and promoted its ubiquitin-mediated degradation. The effect of LACTB in hepatocellular lipid metabolism was dependent on CPT2.

Conclusions: Our findings indicate that LACTB is a novel regulatory factor in MASLD by influencing the ubiquitin-mediated degradation of CPT2 to participate in disease progression. These findings may provide a novel potential therapeutic strategy for MASLD.

Aims: To investigate the association between metabolic obesity phenotypes and cognitive decline and evaluate the potential mediating role of C-reactive protein (CRP).

Methods: Longitudinal cohort study using three waves (2008-2019) of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Data were analysed from December 2024 to May 2025. Baseline sample consisted of 15 105 participants aged 35-74 years. Six phenotypes were defined by body mass index (BMI) category (normal weight, overweight, obesity) and metabolic health. Metabolic health was defined using traditional metabolic syndrome criteria and more stringent criteria: low waist-to-hip ratio (WHR), no diabetes or hypertension. Global cognition Z-scores were derived from tests of memory (immediate, delayed recall, and recognition of a word list), verbal fluency (phonemic and semantic), and Trail-Making tests (TMT-B). Mediation analysis evaluated CRP as a potential mediator.

Results: Among 12 795 participants (mean age 51.1 years; 55% women; 53% White) followed for a median of 8 years, metabolically unhealthy phenotypes-across all BMI categories-were associated with faster cognitive decline (β estimates ranged from -0.037 to -0.053; all p < 0.001), whereas metabolically healthy overweight (β = 0.016; 95% CI = -0.002, 0.034; p = 0.081) and metabolically healthy obesity (β = 0.000; 95% CI = -0.027, 0.026; p = 0.981) were not. No evidence of CRP mediation was identified. BMI was not associated with cognitive decline (β = -0.001; 95% CI = -0.002, 0.000; p = 0.170), whereas WHR was (β = -0.020, 95% CI = -0.026, -0.014, p < 0.001).

Conclusions: Metabolic dysfunction may be a stronger predictor of subsequent cognitive decline than excess body weight. Dementia prevention strategies may benefit from early identification and management of metabolic dysfunction across all weight categories.

Aims: This study aims to compare the risk of major adverse cardiovascular events (MACE) among United States individuals with type 2 diabetes (T2D) and atherosclerotic cardiovascular disease (ASCVD) treated with once-weekly semaglutide vs. dulaglutide.

Materials and methods: This was a retrospective cohort study using Optum's de-identified Clinformatics Data Mart (Optum CDM) from 1 January 2007 through 30 September 2024. New initiators of semaglutide or dulaglutide ≥18 years with both T2D and ASCVD were included. The index date was the first date of a prescription claim for semaglutide or dulaglutide within the index medication identification period (1 January 2018 through 31 March 2024). The primary outcome was 3-point MACE (stroke, myocardial infarction [MI], cardiovascular [CV]-related death). Entropy balancing was applied to balance baseline characteristics. Weighted incidence rates per 1000 person-years and doubly robust Cox proportional hazard ratios were reported.

Results: There were 75 243 enrolees included (semaglutide, 42 007; dulaglutide, 33 236). The mean age was 68.2 and 69.3 years (unweighted) in the semaglutide and dulaglutide cohorts, respectively. After balancing, standardized mean differences were <0.1 for all variables. The incidence rates of the primary outcome, 3-point MACE, were 25.7 and 33.0 in the semaglutide and dulaglutide cohorts, respectively. Compared with the dulaglutide cohort, the semaglutide cohort had a 22% lower risk of 3-point MACE (hazard ratio, 0.78 [95% CI, 0.70-0.87]; p < 0.001).

Conclusions: Among United States Medicare Optum CDM enrolees with T2D and ASCVD, semaglutide was associated with reduced risks of CV outcomes compared with dulaglutide. These results help to address an important evidence gap in selecting glucagon-like peptide-1 receptor agonists for this high-risk population.

Aims: MASLD, defined as a steatotic liver disease in the presence of one or more cardiometabolic risk factors and the absence of harmful alcohol intake, exhibits substantial heterogeneity complicating risk stratification. A prior clustering model proposed liver-specific and cardiometabolic subtypes, yet its generalizability and prognostic relevance remain unclear in the broader population. We aim to validate and replicate the prior approach in a nationally representative U.S.

Cohort:

Materials and methods: We included 3300 participants with MASLD from NHANES III. For validation, participants were assigned to previously defined clusters using published medoids. For replication, de novo clusters were derived using the Partitioning Around Medoids algorithm. Cox proportional hazards models accounting for the complex survey design of NHANES III were used to estimate hazard ratios for all-cause, cardiovascular-related, and diabetes-related mortality across clusters.

Results: Individual cluster assignments showed limited reproducibility between the validation and replication analyses, although the overall clustering pattern was preserved. Based on clinical profiles, clusters were categorized into cardiometabolic, liver-specific, and other subtypes. The cardiometabolic cluster consistently showed higher risks in both analyses, while the liver-specific cluster showed no significant associations.

Conclusions: The subtyping model demonstrated limited generalizability. Nonetheless, the consistent identification of broad cardiometabolic and liver-specific patterns suggests potential value for risk stratification, pending further validation.

Aims: Type 2 diabetes mellitus (T2DM) may lead to diabetes-associated cognitive dysfunction (DACD). We aimed to develop an amide proton transfer-weighted (APTw) magnetic resonance imaging (MRI) biomarker to assist early identification of T2DM with DACD.

Materials and methods: The study included 27 T2DM patients, comprising 19 with mild cognitive impairment (T2DM-MCI) and 8 without (T2DM-nMCI), along with 11 community-based controls without MCI (CG-nMCI). All participants completed neuropsychological tests and APTw-MRI. We measured hippocampal APTw signal intensity (SI) in both groups, analysed its correlation with cognitive scores and assessed diagnostic performance using area under the curve (AUC).

Results: In T2DM-nMCI patients, left hippocampal head APTw SI showed a positive correlation with semantic verbal fluency (SVF; r = 0.770, R² = 0.593, p = 0.025) but a negative correlation with Wechsler Memory Scale-Digit Span Test-Backward (r = -0.802, R² = 0.643, p = 0.017). In T2DM-MCI patients, left hippocampal head APTw SI positively correlated with SVF scores (r = 0.414, R² = 0.172, p = 0.044), while left tail values showed negative associations with Trail-Making Test-A (r = -0.333, R² = 0.111) and Auditory Verbal Learning Test-Huashan version-delayed recall (r = -0.376, R² = 0.141, both p ≤ 0.021). The left hippocampal body demonstrated diagnostic potential for T2DM-nMCI (AUC = 0.793, p = 0.045), while the left hippocampal head showed higher discriminative power for T2DM-MCI (AUC = 0.732, p = 0.034).

Conclusions: APTw imaging suggested a spatially evolving pattern of hippocampal damage in T2DM, where the left body may show early alterations, with the left head potentially becoming more implicated upon MCI onset. These findings provide preliminary evidence supporting the potential of APTw as an early, non-invasive biomarker for tracking neuropathological progression in DACD.

Aims: To compare the effects of dose reductions of ultra-rapid-acting insulin aspart (URA-IAsp) and rapid-acting insulin aspart (IAsp) on blood glucose concentrations during continuous moderate-intensity exercise in people with type 1 diabetes (T1D).

Materials and methods: In this double-blind, laboratory-controlled study, 43 adults with T1D completed four experimental visits in a randomised crossover design. Participants injected a 50% or 75% reduced dose of URA-IAsp or IAsp with a standardised breakfast 60 min prior to 45 min of cycling at ~61% V̇O_2peak. The same insulin type and dose were administered 4 h after the first injection, alongside an identical lunch meal. Venous blood samples were taken at 5-, 10-, and 15-min epochs, for a total of 70 timepoints, throughout the trial day until 4 h after the second injection to determine blood glucose and insulin concentrations. The primary endpoint was the four-way comparison of blood glucose change from exercise start to end.

Results: Blood glucose declined during exercise to a similar extent between 50% dose URA-IAsp (-4.0 ± 2.8 mmol L^-1) and all other conditions (all p > 0.05), yet fell more in the 50% IAsp dose (-5.1 ± 3.0 mmol L^-1) compared to the URA-IAsp (-2.8 ± 3.3 mmol L^-1) and IAsp (-3.4 ± 3.3 mmol L^-1) 75% reduced dose conditions (both p < 0.05). Differences in blood insulin concentrations between trials were only resultant of insulin doses and not insulin type from 30 min after the first insulin injection.

Conclusions: Insulin dose reductions around acute moderate-intensity exercise yield similar glucose-lowering effects with URA-IAsp and IAsp. The extent of dose reductions exerts greater influence on glycaemia than the type of fast-acting insulin.