Diabetes, Obesity & Metabolism最新文献

Aims: Conflicting data have explored the association between lipoprotein(a) [Lp(a)] and atherosclerotic cardiovascular disease (ASCVD) among individuals with different glucose metabolism statuses. We aimed to prospectively evaluate this association and to assess whether it is modified by C-reactive protein (CRP).

Materials and methods: This population-based cohort study was derived from the UK Biobank database. Lp(a) and CRP were measured between 2006 and 2010. Cox proportional hazards models and restricted cubic spline curves were employed to assess the relationship between Lp(a) levels and time to ASCVD events.

Results: A total of 307 269 participants without prevalent ASCVD were included, comprising 253 746 individuals with normal glucose regulation (NGR), 38 020 with prediabetes, and 15 503 with diabetes. The mean age was 57 years (Q1-Q3: 50-63), and 55.3% were female. Over a median follow-up of 13.2 years, 29 521 ASCVD events occurred. Higher Lp(a) levels were associated with an increased risk of ASCVD across all glucose metabolism statuses. In fully adjusted models, the hazard ratio (95% confidence interval) for ASCVD comparing participants in the top 10% of Lp(a) with those in the bottom 33% was 1.28 (1.22-1.34) among those with NGR, 1.23 (1.12-1.35) among those with prediabetes, and 1.16 (1.02-1.31) among those with diabetes. No significant interactions were observed after stratification by CRP (<2/≥2 mg/L) across glucose metabolism groups (P for interaction >0.05).

Conclusions: Elevated Lp(a) levels were associated with a higher risk of ASCVD across different glucose metabolism statuses, particularly among individuals with NGR and prediabetes, independent of baseline CRP levels.

Aims: In people with type 1 diabetes, physical activity provides important health benefits but is mainly limited by fear of hypoglycaemia. Daily step count is a simple indicator of ambulatory activity. This study examined associations between step count and health indicators.

Materials and methods: Adults from the Behaviours, Therapies, Technologies and Hypoglycaemic Risk in Type 1 Diabetes registry wore a validated pedometer (PiezoRxD®) for 7-12 days and were classified based on mean daily steps: <7000 (group 1), 7000-10 000 (group 2), and >10 000 (group 3). Between-group comparisons used analysis of variance and chi-square/Fisher's tests with Bonferroni correction. Multivariable models adjusted for potential confounders.

Results: A total of 383 participants (333 T1D, 50 latent autoimmune diabetes) were included (group 1: 163; group 2: 125; group 3: 95). Mean age was 46.7 ± 13.3 years, 63% were women, diabetes duration was 24.2 ± 15.6 years, and body mass index (BMI) 26.1 ± 4.5 kg/m². Overall, 43.6% had glycated haemoglobin (HbA1c) ≤7%. A higher proportion of participants in groups 2 and 3 had HbA1c ≤7% compared with group 1. Level 1 and 2 hypoglycaemia frequency did not differ significantly across groups. Groups 2 and 3 had lower waist circumference than group 1, and group 3 additionally had lower BMI and a lower proportion of depression/anxiety medication use.

Conclusions: Among adults living with type 1 diabetes, higher daily step counts were associated with more favourable glycaemic and anthropometric profiles, as well as lower use of depression/anxiety medication without evidence of increased hypoglycaemia. Causality cannot be inferred, and reverse causation is possible.

Aims: We investigated whether dipeptidyl peptidase-4 inhibitor (DPP-4i) use was associated with a higher risk of acute pancreatitis compared with sodium-glucose cotransporter 2 inhibitor (SGLT2i) use in antidiabetic medication-naïve individuals.

Materials and methods: In this target trial emulation study of medication-naïve individuals with diabetes from a Japanese claims database from April 2014 to August 2023, the risk of acute pancreatitis was compared between new users of DPP-4is and new users of SGLT2is. After adjusting for confounders using propensity score-based overlap weighting, we used Cox proportional hazards models for hospitalization due to acute pancreatitis to estimate the hazard ratio (HR) and 95% confidence interval (CI) within the groups in both the intention-to-treat and per-protocol analyses. We also calculated incidence rate differences (IRDs) per 1000 person-years.

Results: This study included 26 133 DPP4-i and 6497 SGLT2i users. DPP-4i use was not significantly associated with a higher risk of acute pancreatitis compared with SGLT2i use; the adjusted HRs were 0.97 (95% CI, 0.51-1.83) and 1.11 (95% CI, 0.54-2.27), with IRDs of -0.05 (95% CI, -0.97 to 0.87) and 0.15 (95% CI, -0.86 to 1.15) per 1000 person-years in the intention-to-treat and per-protocol analyses, respectively.

Conclusions: Although small differences cannot be excluded given the width of the CIs for the estimated HRs, the small IRDs observed suggest that any potential difference, if present, is likely to be clinically modest. Therefore, acute pancreatitis risk may not be a major determinant when selecting initial therapy.

Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited effective treatments. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise for metabolic and hepatic benefits. This study evaluated the therapeutic efficacy of Efsubaglutide Alfa, a novel long-acting GLP-1RA, in a mouse model of MASH.

Materials and methods: Male C57BL/6J mice with diet-induced obesity received a high-fat diet and low-dose CCl₄ injections to induce MASH. Mice were randomized to receive vehicle, obeticholic acid (OCA), semaglutide or Efsubaglutide Alfa at low, medium or high doses for 42 days. Endpoints included liver histology, collagen quantification by second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) imaging, and serum liver enzymes, lipids and metabolic parameters.

Results: By day 41, Efsubaglutide Alfa produced dose-dependent reductions in body weight, liver weight and liver-to-body weight ratio versus MASH controls (all p < 0.01). Histology showed reduced steatosis and lowered the NAFLD Activity Scores (NAS), with high-dose treatment achieving a NAS of 3.0 ± 0.47 versus 4.5 ± 0.22 in MASH controls (p < 0.01). Although Sirius Red-based fibrosis area and scoring did not show significant differences among treatment groups, SHG/TPEF imaging analysis showed lower perisinusoidal collagen metrics (%PS: 0.27%-0.30% vs. 0.40% in MASH controls, p < 0.05). Furthermore, Efsubaglutide Alfa reduced serum ALT and AST levels and improved fasting glucose and triglycerides; fasting insulin was lower in semaglutide and high-dose Efsubaglutide Alfa groups, consistent with improved glycaemic control.

Conclusions: Efsubaglutide Alfa reduced liver steatosis and improved SHG/TPEF-derived perisinusoidal collagen features, which supported further evaluation of Efsubaglutide Alfa for MASH, particularly for steatosis improvement and suggests potential effects on fibrosis-related features that warrant confirmation in longer duration studies.

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: The effective target for systolic blood pressure (SBP) control in patients with diabetes was inconsistent. We evaluated the emulated effect of maintaining SBP below clinical thresholds on the risk of cardiovascular disease (CVD) and all-cause mortality.

Materials and methods: This study included 4264 patients with type 2 diabetes from the Kailaun study. We implemented the parametric g-formula to simulate the hypothetical interventions on reducing SBP below 140, 130 and 120 mmHg over time, accounting for time-varying confounding, reporting risk ratio (RR) and number needed to treat (NNT) for 10-year risk of CVD and all-cause mortality.

Results: Maintaining SBP below 140, 130 and 120 mmHg was associated with an 18%, 24%, and 31% relative risk reduction in the risk of CVD, with the RR (95% confidence interval [CI]) of 0.82 (0.75-0.88), 0.76 (0.69-0.86), and 0.69 (0.58-0.84), and the NNT of 32, 24, and 19, respectively, compared to no intervention. However, the benefits in reducing the risk of all-cause mortality did not reach a significant level with maintaining SBP below 140 and 130 mmHg, with the RR (95% CI) of 0.98 (0.93-1.06) and 1.04 (0.95-1.12), respectively. The risk of all-cause mortality significantly increased 15% with maintaining SBP ≤120 mmHg (RR, 1.15; 95% CI, 1.02-1.32). Subgroup analyses showed that maintaining SBP ≤120 mmHg tended to bring more harms than benefits in patients aged ≥60 years or without antihypertensive agents.

Conclusion: Among Chinese patients with type 2 diabetes, maintaining SBP ≤120 mmHg may not be an optimal target, in terms of the risk-benefit association of CVD and all-cause mortality.

Aim: Eloralintide (LY3841136) is a potent, long-acting selective amylin receptor agonist currently under development for the treatment of obesity with once-weekly subcutaneous dosing.

Materials and methods: This 12-week Phase 1, randomised, placebo-controlled, participant- and investigator-blinded, multiple ascending dose study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamic profiles of eloralintide upon once-weekly subcutaneous dosing without dose escalation in participants with obesity or overweight.

Results: From 30 March 2022 to 25 January 2024, at three centres in the United States, 100 participants with a mean age of 44 years, 29% female participants, and mean body mass index of 32.6 kg/m², were randomly assigned to receive either eloralintide or placebo in 5 multiple ascending dose cohorts. At Week 12, AUC_τ,ss and C_max were dose proportional with ratios of dose-normalised geometric means of 1.1 and 1.0, respectively. The most common treatment-emergent adverse events (TEAEs) with eloralintide included decreased appetite (19% of participants), headache (12%), fatigue (11%), and COVID-19 (11%). Gastrointestinal adverse events, including diarrhoea (10% of participants), nausea (8%), and vomiting (4%), were infrequent in those receiving eloralintide. Most TEAEs were mild in severity. No deaths and one serious adverse event (in the 6 mg eloralintide cohort) unrelated to eloralintide occurred. At Week 12 with eloralintide, the least squares mean percent reduction in body weight across the dose groups ranged from 2.6% to 11.3%.

Conclusion: Eloralintide once weekly was well tolerated with minimal gastrointestinal adverse events and resulted in clinically meaningful weight loss.