Diabetes, Obesity & Metabolism最新文献

Aims: To evaluate the efficacy and safety of adding a fourth oral antidiabetic drug versus metformin uptitration in patients with type 2 diabetes inadequately controlled with oral triple therapy.

Materials and methods: In this 24-week, randomized, open-label trial, adults with type 2 diabetes having glycated haemoglobin (HbA_1C) 7.0-9.0% despite oral triple therapy with metformin plus a thiazolidinedione (TZD), sodium-glucose cotransporter 2 inhibitor (SGLT2i), or dipeptidyl peptidase 4 inhibitor (DPP-4i) were randomized to an oral quadruple add-on group or a metformin uptitration group. The quadruple group received the class not previously used (TZD, SGLT2i, or DPP-4i), whereas the metformin uptitration group increased the metformin dose by up to 500 mg per day. The primary endpoint was the change in HbA_1C at week 24. Secondary endpoints included fasting glucose, metabolic parameters, and safety.

Results: Hundred and ninety-three were evaluable: 48 in the metformin uptitration group and 145 in the quadruple group. Compared to baseline, HbA_1C at week 24 decreased by 0.70% (interquartile range [IQR] 0.40%, 1.10%) with quadruple therapy and 0.40% (IQR 0.10%, 0.80%) with metformin uptitration (p = 0.002). The rate achieving HbA_1C ≤7.0% was higher in the quadruple group (69.7% vs. 47.9%, p = 0.006). Insulin resistance improved only in the quadruple group and was accompanied by reduced albuminuria. Adverse events were mild and comparable between groups.

Conclusions: Oral quadruple therapy achieved greater glycaemic and metabolic improvement without compromising safety, compared with metformin uptitration, supporting its role as an intensification strategy.

Introduction: With new advancements in obesity medicine, clarity on goals and expectations for successful disease management is limited. This post hoc analysis assessed application of proposed treat-to-target (TtT) thresholds for obesity to the outcome measures of SURMOUNT-5, which randomised participants with obesity to tirzepatide or semaglutide.

Methods: The proportion of participants in each treatment group reaching proposed TtT thresholds for waist to height ratio (WHtR) <0.53, body mass index (BMI) <27 kg/m², or a combination was evaluated. The associations between the thresholds and achieving low disease activity to remission (meeting goals for at least four of five defined cardiometabolic risk parameters) and normalisation or improvement in SF-36v2 physical component score (PCS) from baseline to week 72 were explored.

Results: About 23.1%-33.9% of participants treated with tirzepatide and 14.2%-20.7% treated with semaglutide reached the TtT thresholds, with greater weight reduction than the overall population. About 77% of participants who reached WHtR <0.53 achieved low disease activity to remission, with an odds ratio of 2.31 (p < 0.001) compared to those who did not reach this target. The BMI threshold was not statistically associated with the assessed outcomes for SF-36v2 PCS.

Conclusion: In this post hoc analysis of SURMOUNT-5, most participants who reached the proposed TtT thresholds achieved the goal of low disease activity to remission defined by cardiometabolic risk parameters. These data suggest that TtT thresholds in obesity medicine may clarify goals in shared decision-making and improve clinical outcomes.

Aims: Little is known about how the alignment between daily behaviours, such as physical activity and eating, and chronotype relates to glucose metabolism. We investigated whether alignment of physical activity and meal timing with chronotype was associated with glycaemic parameters and with prediabetes or type 2 diabetes (T2DM).

Materials and methods: In a cross-sectional analysis of 1384 participants from The Maastricht Study, we examined associations between behaviour-chronotype alignment and glucose metabolism. Physical activity timing was assessed by accelerometry and defined as the daypart with the highest step count. Meal timing, from a chrono-nutrition questionnaire, was defined as the daypart with the most eating occasions. Chronotype was estimated using the midpoint of sleep on free days corrected for sleep debt. Alignment reflected concordance between behaviour timing and chronotype. Confounder-adjusted logistic and linear regression models estimated associations with (pre)diabetes and with log-transformed fasting plasma glucose (FPG), 2-h post-load glucose (2hPLG), and haemoglobin A1c (HbA1c).

Results: Weekday alignment of physical activity timing with chronotype was associated with lower HbA1c (β per 20% more aligned weekdays: -0.48%, 95% CI -0.95, -0.02). Weekday meal timing alignment was associated with lower odds of prediabetes or T2DM (OR aligned vs. misaligned: 0.62, 95% CI 0.43-0.89). No significant associations were observed for weekend alignment, for FPG or 2hPLG, or for interactions between activity and meal timing alignment.

Conclusions: Weekday, but not weekend, alignment of physical activity and meal timing with chronotype was modestly associated with more favourable glucose metabolism. These findings suggest a potential role of behaviour-chronotype alignment in metabolic health, warranting confirmation in prospective and intervention studies.

Aims: The 1 mg dexamethasone suppression test (DST) shows variable results in obesity, yet the impact of extreme obesity (body mass index [BMI] ≥50 kg/m²) on hypothalamic-pituitary-adrenal axis function remains poorly characterized. This study evaluated post-dexamethasone cortisol levels across distinct BMI categories and their associations with metabolic parameters.

Materials and methods: This retrospective study included 352 adults with obesity (BMI ≥30 kg/m²) who underwent 1 mg overnight DST between February 2019 and August 2023. Patients were stratified into three groups: BMI 30.0-39.9 kg/m² (n = 64), BMI 40.0-49.9 kg/m² (n = 202), and BMI ≥50.0 kg/m² (n = 86). Clinical, anthropometric, and laboratory parameters were compared between groups.

Results: The cohort had a median age of 41 years and comprised 284 females (80.7%). Post-dexamethasone cortisol levels showed modest differences across BMI categories (median 0.79, 0.77, and 0.88 μg/dL, respectively; p = 0.038). Inadequate cortisol suppression after the 1 mg dexamethasone test was rare, occurring in four patients (1.1%) overall: 0/64 (0%) in BMI 30.0-39.9 kg/m², 2/202 (1.0%) in BMI 40.0-49.9 kg/m², and 2/86 (2.3%) in BMI ≥50.0 kg/m²; continuous BMI was not associated with post-dexamethasone cortisol levels. Patients with super obesity demonstrated higher rates of hypertension (36% vs. 18.7-22.2%, p = 0.021) and diabetes (30.2% vs. 16.8-18.7%, p = 0.033).

Conclusions: These findings emphasize that elevated post-dexamethasone cortisol levels in patients with obesity should not be attributed to body weight alone but warrant appropriate evaluation for true hypercortisolism, with clinical interpretation guided by metabolic phenotype rather than BMI.

Aims: To assess the prevalence and risk factors of increased residual gastric content (RGC) under fasting conditions in patients with type 2 diabetes mellitus (T2DM) treated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs), providing evidence for peri-procedural medication management.

Materials and methods: This single-centre prospective cohort study enrolled inpatients with T2DM at the Endocrinology Department of Ningbo No.2 Hospital between April and December 2024. Patients aged 18-80 years with BMI <40 kg/m² were categorized as GLP-1 RA users or non-users. Those with conditions known to affect gastric motility were excluded. After a standard overnight fast, bedside gastric ultrasonography was performed. The primary outcome was the prevalence of increased RGC, defined as solid content or clear fluid volume >1.5 mL/kg. Secondary analyses explored associated risk factors.

Results: Of 390 patients included (237 [60.8%] male), 224 (57.4%) were GLP-1 RA users. After propensity score matching, the prevalence of increased RGC remained significantly higher in GLP-1 RA users compared with non-users (53.3% vs. 32.1%; p < 0.001). In multivariate logistic regression adjusted by inverse probability of treatment weighting (IPTW), GLP-1 RA use was robustly associated with increased RGC (OR 2.52; 95% CI 1.84-3.45). Notably, diabetic retinopathy (OR 1.84; 95% CI 1.14-2.99) and diabetic kidney disease (OR 1.67; 95% CI 1.17-2.39) emerged as independent risk factors, identifying a high-risk microvascular phenotype. Furthermore, among GLP-1 RA users, each additional day since the last GLP-1 RA dose reduced the odds of increased RGC by 23% (adjusted OR 0.77; 95% CI 0.65-0.90).

Conclusions: GLP-1 RA therapy is a potent, independent driver of significant gastric retention in patients with T2DM, persisting despite standard fasting. Crucially, the presence of diabetic retinopathy or nephropathy identifies a "double-hit" high-risk phenotype, where pharmacological delay interacts with microvascular burden. These findings suggest that current fasting protocols may be insufficient for these patients, necessitating individualized preoperative assessment based on microvascular status and dosing timing.

Aims: As type 2 diabetes (T2D) continues to rise globally and remains a major driver of cardiovascular disease, its remission has emerged as a therapeutic target. Current evidence supports bariatric surgery and low-calorie diets with meal replacements. No clinical trial to date has evaluated plant-based dietary alternatives as an intensive lifestyle intervention (ILI) strategy, despite the emphasis on plant-based diets in current clinical practice guidelines for diabetes and cardiovascular disease. The REmission of diabetes using a PlAnt-based weight loss InteRvention (REPAIR) trial will assess whether a 52-week plant-based ILI targeting ≥15% weight loss is effective for diabetes remission in a multi-ethnic Canadian population.

Materials and methods: The REPAIR trial is a prospective, randomised, 2-arm, open-label, blinded-endpoint efficacy trial. Participants will include 160 adults with early T2D (<6 years) and living with obesity. They will be randomised to standard of care or a 2-phase ILI targeting ≥15% weight loss consisting of a 12-week weight loss phase on a plant-based total diet meal replacement, followed by a 40-week weight loss maintenance phase on a plant-based dietary pattern combined with a 16-week structured exercise program, and a 52-week (19-session) sustainable behaviour change curriculum. The primary outcome is diabetes remission (HbA1c <6.5% without glucose-lowering medication for ≥3 months) and the key secondary outcome is the proportion achieving ≥15% weight loss at 52 weeks.

Conclusions: This trial will provide high-quality clinical evidence on the use of plant-based ILIs to address the epidemics of obesity and diabetes to inform public health policies and programs in Canada and beyond.

Aim: Coronary artery calcium (CAC) scoring is observed to improve risk stratification for major adverse cardiovascular events (MACE). Semaglutide, a recently introduced anti-obesity drug, is very effective, but wider use is limited due to high costs. Hence, this study investigated the cost-effectiveness (CEA) of semaglutide across CAC groups.

Materials and methods: CAC scores for 38 058 CLARIFY registry participants meeting SELECT criteria were included. They were stratified into four CAC groups: 0, 1-99, 100-399, ≥400. To determine MACE (composite of myocardial infarction, heart failure, stroke or all-cause mortality) risk across CAC groups, hazard ratios (HR) were estimated from multi-variable adjusted Cox proportional hazard models. Next, lifetime-horizon Markov models were created to simulate semaglutide therapy and the potential clinical benefit (reported as number needed to treat [NNT]) and CEA (estimated with incremental cost-effectiveness ratio [ICER]) were examined for CAC groups. Multiple scenarios to mimic real-world experience were fitted for robust sensitivity analyses.

Results: Compared to CAC = 0, MACE risk was higher for CAC ≥400 (HR: 1.97 [95% CI: 1.66-2.35]), heart failure (HR: 1.76 [95% CI: 1.36-2.28]), mortality (HR: 1.62 [95% CI: 1.21-2.17]). Modelling 3.3 years of semaglutide use resulted in potential MACE NNT values of 151 (95% CI: 108-302) and 34 (95% CI: 25-69) for CAC = 0 and CAC ≥400. Markov modelled ICER for semaglutide use reduced across CAC groups ($625 863/QALY [CAC = 0] vs. $168 666/QALY [CAC ≥400]).

Conclusions: CAC scores have potential use as a tool to estimate potential clinical benefit and cost for lifetime semaglutide therapy among obese individuals.

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.