Diabetes, Obesity & Metabolism最新文献

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: Retrospective study evaluating real-world outcomes of hybrid closed-loop (HCL) in adults with type 1 diabetes and comorbid depression and/or anxiety disorders.

Materials and methods: Adults with type 1 diabetes and comorbid depression/anxiety disorders attending King's College Hospital diabetes centre between October 2023 and January 2025 were included. Demographic, medical and psychiatric information, acute diabetes complication rates, two-item diabetes distress scale (DDS2) scores and sensor glucometrics (time in range; TIR) were extracted from electronic health records and diabetes technology platforms.

Results: Of 1827 adults with type 1 diabetes, 226 had comorbid depressive and/or anxiety disorders [163 female/63 male; age 38 (IQR: 29.0-51.3) years, 23 (15-33.3) years diabetes duration]; 196 had depression and 119 had anxiety disorders. HCL-users (n = 108; 89 female/19 male) had lower glycated haemoglobin A_1c (HbA_1c) and higher TIR [HbA_1c 60.0 mmol/mol (7.6%) (53.0-66.0/7.0-8.2) vs. 73.0 mmol/mol (8.8%) (58.5-85.5/7.5-10.0), p < 0.001; TIR 63.5 (55.8-75.0) vs. 42.0 (23.0-55.3), p < 0.001] than non-HCL users (n = 118, 44 female/74 male) at last follow-up compared to baseline. Glycaemia improved post HCL-initiation compared to pre-HCL [HbA_1c 60.0 mmol/mol (7.6%) (53.0-66.0/7.0-8.2) vs. 67.5 mmol/mol (8.3%) (58.8-77.8/7.5-9.3), p < 0.001; TIR 63.5 (55.8-75.0) vs. 39.0 (28.0-55.8), p < 0.001]. Severe hypoglycaemia rates did not vary (p = 0.380), but fewer HCL users experienced ketoacidosis (p < 0.001). DDS2 scores were lower post-HCL (p = 0.004) but not when comparing HCL and non-HCL users (p = 0.230).

Conclusions: HCL users demonstrated improved HbA_1c and TIR, compared with non-HCL users. These real-world data support safe use of HCL in people with type 1 diabetes and depression/anxiety in a multidisciplinary setting. Qualitative studies and prospective trials are required to further evaluate the impact of HCL on biomedical and mental health outcomes.

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.

Aim: To quantify the relative importance of frequency of administration in basal insulin treatment preferences of people living with type 2 diabetes (T2D) in France and Spain, using a discrete choice experiment (DCE).

Materials and methods: A targeted literature review and qualitative patient interviews informed an attributes and levels grid consisting of six attributes (2-3 levels each). Pilot interviews were conducted to test the DCE. A quantitative DCE survey was administered to adults with T2D in France and Spain. Hierarchical Bayesian estimation was used to identify the relative importance of each attribute.

Results: The survey was completed by N = 239 participants from France (n = 166) and Spain (n = 73) across three treatment experience categories: basal insulin and injectable glucagon-like peptide-1 receptor agonists (GLP-1 RA) naïve (n = 86), basal insulin naïve but injectable GLP-1 RA experienced (n = 85), and basal insulin experienced (n = 68). Frequency of administration had a relative importance of 39%, nearly double that of the attribute with the next highest relative importance 'risk of severe hypoglycemic event (insulin experienced rates)' (21%). A preference for once weekly (OW) administration was observed relative to once daily (OD) or twice daily (BD). Reduction in the frequency of missing doses and taking doses at the prescribed time were considered the most positive impacts of OW administration. Findings were consistent across treatment experience groups.

Conclusion: This study highlights the importance of administration frequency in basal insulin treatment decisions when glycemic control is held constant. Participants indicated a preference for OW injection frequency, suggesting fewer injections may reduce the burden of insulin administration. These insights support clinical consideration of less frequent injections when making T2D treatment decisions.

Diabetic kidney disease (DKD), the leading cause of kidney failure worldwide, is associated with an increased risk of cardiovascular disease (CVD). A complex pathobiology involving hemodynamic, metabolic, and immune dysregulation promotes inflammatory and fibrotic pathways that contribute to kidney disease progression and CVD in individuals with DKD. While the standard treatment approach incorporating renin-angiotensin-aldosterone system (RAAS) blockers and sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduces the risk for kidney disease progression and CVD, the high residual risk that persists despite these treatments underscores the need for novel therapies for DKD. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), is a proven therapeutic option for DKD that targets inflammatory and fibrotic pathways involved in its progression. Furthermore, finerenone has been evaluated for DKD outcomes in phase 3 clinical trials, has a favourable side effect profile compared to steroidal MRAs, reduces the risks of major kidney and CVD outcomes in clinical trials when used with RAAS blockers, and is the only MRA specifically approved for DKD and recommended for DKD in treatment guidelines. The integration of novel biomarkers of CKD and CVD into the clinical management of DKD may improve early identification of at-risk individuals and allow for patient-specific therapeutic strategies. This review provides a brief overview of the pathogenesis of DKD and the role of mineralocorticoid receptor activation in DKD pathobiology, summarises the role of finerenone in the treatment paradigm of DKD, evaluates current and emerging biomarkers of DKD and finerenone's impact on these biomarkers, and provides forward-looking guidance on future research for biomarker-driven precision medicine in DKD.

Aims: Once-weekly insulin efsitora is a novel basal insulin designed to maintain glycaemic control with fewer injections, potentially improving adherence. Data on its efficacy and safety remain scarce. This systematic review and meta-analysis analysed randomized controlled trials (RCTs) comparing the efficacy and safety of once-weekly efsitora versus once-daily basal insulin in adults with type 2 diabetes mellitus (T2D).

Materials and methods: PubMed, Embase, and Scopus databases were searched up to July 6, 2025 to identify RCTs comparing once-weekly efsitora with once-daily basal insulin for T2D. Primary outcomes included changes in glycated haemoglobin (HbA1c), changes in fasting plasma glucose, change in total weekly insulin dose, and HbA1c target achievement. Statistical analyses were performed using Review Manager (RevMan) version 5.4, employing a random-effects model to pool mean differences (MDs) and 95% confidence intervals (CIs), with heterogeneity assessed using the I² statistic.

Results: Seven RCTs involving 4170 participants were analysed (2347 on efsitora and 1877 on once-daily insulin). At 26 weeks, HbA1c reduction was similar between groups (mean difference (MD) -0.02%; (-0.11 to 0.08; p = 0.74)). At 52 weeks, efsitora achieved statistically significant greater reduction in HbA1c (MD -0.12%; -0.20 to -0.03; p = 0.009) and was associated with a lower change in total weekly insulin dose (MD -30.55, (-46.48 to -14.52; p = 0.0002)). Time in the target glucose range showed a non-significant numerical increase (MD: 1.72 (95% CI: -0.10 to 3.53; p = 0.06)), while time above range decreased (MD: -2.13 (95% CI: -4.01 to -0.25; p = 0.03)). Hypoglycaemia, serious adverse events, injection-site reactions, and hypersensitivity events were comparable across groups, although a numerically, non-significant increase in major adverse events with efsitora was noted, with an odds ratio of 1.22 (95% CI: 0.97-1.53; p = 0.09).

Conclusions: Once-weekly insulin efsitora demonstrated comparable glycaemic efficacy and superiority in reduction of HbA1c and change in total weekly insulin dose at 52 weeks, while maintaining an acceptable safety profile. Longer-term studies and real-world data are warranted to further confirm sustained efficacy, safety, and cost-effectiveness.