Diabetes, Obesity & Metabolism最新文献

Background: Prevalence of type 2 diabetes increases with age. Both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) promote the enrollment of older patients to randomized controlled trials (RCTs) in diabetes. The objective of this study was to assess the eligibility criteria limiting the inclusion of older adults to RCTs in type 2 diabetes.

Materials and methods: This cross-sectional analysis of ClinicalTrials.gov included phase 2, 3 and 4 RCTs of drugs and biologicals, with enrollment ≥100, registered at ClinicalTrials.gov and started from 2014 through 2023.

Results: A total of 278/594 (46.8%) trials had a limit of 90 years of age or less (primary outcome). The odds of the age limits were higher in RCTs funded from non-commercial sources (adjusted odds ratio (aOR), 2.83, 95% confidence interval (CI), 1.77-4.52; p < 0.001) and phase 2 trials (aOR, 2.38; 95% CI, 1.49-3.81; p < 0.001). A total of 542/594 (91.2%) trials had other relevant exclusion criteria, mostly those concerning comorbidities common in older patients (secondary outcome). However, none of the RCTs excluded patients with frailty which is a key factor determining the prognosis of older patients with diabetes. Only two trials enrolled solely older persons.

Conclusions: Most RCTs in type 2 diabetes have the eligibility criteria limiting the enrollment of older patients. The age limits should be eliminated and patients should be excluded based on scientifically justified criteria especially those concerning comorbidities and frailty. Moreover, the benefits and harms of new drugs in older patients with multimorbidity and/or frailty should be assessed in dedicated phase 4 trials.

Aims: To compare the efficacy of adding imeglimin versus that of metformin dose escalation on glycemic control in subjects with type 2 diabetes treated with a dipeptidyl peptidase-4 inhibitor plus low-dose metformin (500-1000 mg/day).

Materials and methods: In this multicentre, open-labelled, prospective, randomized, parallel-group comparison study, the addition of imeglimin (2000 mg/day) or metformin escalation was applied for 24 weeks in eligible subjects. The primary endpoint was the mean change in glycated haemoglobin (HbA1c) over 24 weeks. As the secondary endpoints, the occurrence of adverse events, changes in metabolic parameters, biomarkers and factors associated with HbA1c improvement were analysed.

Results: Seventy-three eligible subjects were enrolled. Of them, 65 participants comprised the full analysis set. At 24 weeks, the addition of imeglimin (n = 33) resulted in greater improvement in HbA1c compared with metformin dose escalation (n = 32) (from 7.61 ± 0.48% to 6.93 ± 0.49% in imeglimin and from 7.56 ± 0.61% to 7.09 ± 0.56% in metformin escalation; change difference: -0.21% [95% confidence interval: -0.41%, -0.01%] [p = 0.038]); however, seven subjects in the imeglimin group discontinued imeglimin because of serious adverse events on gastrointestinal tract. In intra-group pre/post comparisons, imeglimin treatment significantly reduced body weight and improved liver enzyme elevation. There was a significant correlation between improvement levels of HbA1c and indicators of fatty liver disease in the imeglimin group.

Conclusions: Imeglimin in combination with a dipeptidyl peptidase-4 inhibitor and low-dose metformin improved HbA1c compared with metformin dose escalation.

Aim: We aimed to identify the characteristics of patients with diabetes who can derive cognitive benefits from intensive blood pressure (BP) treatment using machine learning methods.

Materials and methods: Using data from the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORD-MIND) study, 1349 patients with type 2 diabetes who underwent BP treatment (intensive treatment targeting a systolic BP <120 mmHg vs. standard treatment targeting <140 mmHg) were included in the machine learning analysis. Seventy-nine variables correlated with diabetes and cognitive function were used to build the causal forest and causal tree models for identifying heterogeneous BP treatment effects on cognitive decline.

Results: Our analyses identified four variables including urinary albumin-to-creatinine ratio (UACR, mg/g), Framingham 10-year cardiovascular risk score (FRS, %), triglycerides (TG, mmol/L) and diabetes duration, that categorized the participants into five subgroups with different risk benefits for cognitive decline from BP treatments. Subgroup 1 (UACR ≥65 mg/g) had an absolute risk reduction (ARR) of 15.36% (95% CI, 5.01%-25.46%) from intensive versus standard BP treatment (hazard ratio [HR], 0.36; 95% CI, 0.18-0.73). Subgroup 2 (UACR <65 mg/g, FRS ≥26%, TG <2.3 mmol/L and diabetes duration ≥9 years) had an ARR of 14.74% (95% CI, 4.56%-24.59%) from intensive versus standard BP treatment (HR, 0.34; 95% CI, 0.15-0.77). No significant benefits were found for other subgroups.

Conclusions: Patients with type 2 diabetes with high UACR, or with low UACR and low TG, but high predicted cardiovascular risk and long diabetes duration were likely to derive cognitive benefits from intensive BP treatment.

Aims: Hypothalamic endoplasmic reticulum stress (ERS) and mitochondrial dysfunction are two important mechanisms involved in the pathophysiology of obesity, which can be reversed by aerobic exercise to improve organ function. Mitofusion 2 (Mfn2), a mitochondrial membrane protein, affects both mitochondrial dynamics and ER morphology. This study explored the contribution of hypothalamic Mfn2 to exercise-induced improvements in energy homeostasis and peripheral metabolism and the underlying mechanisms involved.

Materials and methods: We determined the effects of aerobic exercise on energy metabolism and the expression of Mfn2 and α-MSH in the hypothalamus of diet-induced obesity (DIO) model mice. In addition, hypothalamic ER signalling and insulin signalling in both the hypothalamus and the liver were evaluated following 4 weeks of aerobic exercise. By using an adenovirus carrying shRNA-Mfn2, we further explored the effects of hypothalamic Mfn2 on exercise-induced improvements in energy metabolism, ER signalling and insulin signalling.

Results: Energy metabolism was obviously improved following 4 weeks of aerobic exercise in DIO model mice. However, after hypothalamic Mfn2 knockdown, the effects of exercise on food intake and peripheral metabolism were significantly suppressed. Hypothalamic ER signalling was attenuated significantly, whereas both hypothalamic and hepatic insulin signalling were obviously activated following aerobic exercise. Nevertheless, exercise-induced improvements in ER signalling and insulin signalling were attenuated significantly after Mfn2 knockdown.

Conclusion: These data indicate that aerobic exercise improves whole-body metabolism in DIO mice, probably via increased hypothalamic Mfn2, which could be further mediated by attenuated HFD-induced ER stress in the hypothalamus.

Obesity and type 2 diabetes are significant public health challenges that greatly impact global well-being. The development of effective therapeutic strategies has become more and more concentrated on the central nervous system and metabolic regulation. The primary pharmaceutical interventions for the treatment of obesity and uncontrolled hyperglycemia are now generally considered to be incretin-based anti-diabetic treatments, particularly glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptor agonists. This is a result of their substantial influence on the central nervous system and the consequent effects on energy balance and glucose regulation. It is increasingly crucial to understand the neural pathways of these pharmaceuticals. The purpose of this review is to compile and present the most recent central pathways regarding glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide and glucagon receptors, with a particular emphasis on central metabolic regulation.

Aims: This study evaluated the efficacy and safety of a combination of phentermine and delayed-release topiramate (PHEN/TPM CR) versus placebo as an adjunct to standard lifestyle recommendations in Korean adults.

Materials and methods: This 56-week, randomized, double-blind, placebo-controlled, phase 4 trial enrolled adults (age 19-70 years) with obesity (BMI ≥ 25 kg/m²) at eight sites in South Korea. After a 12-week lifestyle programme, participants were randomly assigned in a 1:1 ratio to receive PHEN/TPM CR or placebo. PHEN/TPM CR was commenced at 3.75 mg/23 mg daily for 14 days and increased to 7.5 mg/46 mg daily, and to 15 mg/92 mg if 3% weight loss was not achieved after 12 weeks. The primary outcomes were percentage change in body weight from baseline to Week 56.

Results: A total of 232 participants underwent randomization. At 56 weeks, the percentage change in body weight was -8.3% with PHEN/TPM CR and -2.3% with placebo (treatment difference -6.1%; 95% confidence interval [CI], -7.7 to -4.5, p < 0.001). Participants receiving PHEN/TPM CR were more likely to achieve ≥5% weight loss compared with those receiving placebo (68.5% vs. 25.0%, odds ratio [OR], 6.4; 95% CI, 3.5 to 11.6; p < 0.001). Dizziness, paraesthesia and dry mouth were more common in the PHEN/TPM CR group, although most adverse events were mild or moderate.

Conclusions: Administration of PHEN/TPM CR plus lifestyle intervention in Korean adults with obesity resulted in a greater reduction in body weight and adiposity than lifestyle intervention alone.

Aims: To investigate glycaemic control in Chinese adults with type 2 diabetes (T2D) initiating, or switching to insulin degludec/insulin aspart (IDegAsp), a co-formulation of basal, and bolus insulin, in a real-world setting.

Materials and methods: A 20-week, prospective, single-arm, open-label, non-interventional study was conducted in Chinese adults with T2D initiating, or switching to IDegAsp after anti-hyperglycaemic treatment with oral antidiabetic drugs (OADs), other insulins, or glucagon-like peptide-1 receptor agonists. The primary endpoint was a change in HbA_1c from baseline to end of the study; the secondary endpoints included a change in fasting plasma glucose and Diabetes Treatment Satisfaction Questionnaire (DTSQ) score.

Results: Significant reductions were observed in mean HbA_1c and fasting plasma glucose, among both the overall population (N = 878; -1.27%-points [95% CI: -1.36; -1.19]; p < 0.0001, and -1.61 mmol/L [95% CI: -1.81; -1.41]; p < 0.0001, respectively), and in subgroups switching from OADs only, or basal, or premix insulins ± OADs. The mean total DTSQ score increased from 26.4 (baseline) to 31.6 (end-of-study). No significant, or unexpected tolerability, or safety issues were observed. Significant reductions were observed in incidence rates of non-severe (rate ratio 0.37 [95% CI: 0.24; 0.59]; p < 0.0001) and nocturnal non-severe (rate ratio 0.45 [95% CI: 0.21; 0.94]; p = 0.0326) hypoglycaemic episodes.

Conclusions: In a broad, real-world Chinese population of adults with T2D, initiating or switching to IDegAsp was associated with improved glycaemic control and lower rates of hypoglycaemia. The use of IDegAsp could be an effective treatment option for those with suboptimal glycaemic control or therapeutic inertia.

Background: The co-occurrence of metabolic dysfunction and neurodegenerative diseases suggests a genetic link, yet the shared genetic architecture and causality remain unclear. We aimed to comprehensively characterise these genetic relationships.

Methods: We investigated genetic correlations among four neurodegenerative diseases and seven metabolic dysfunctions, followed by bidirectional Mendelian randomisation (MR) to assess potential causal relationships. Pleiotropy analysis (PLACO) was used to detect the pleiotropic effects of genetic variants. Significant pleiotropic loci were refined and annotated using functional mapping and annotation (FUMA) and Bayesian colocalisation analysis. We further explored mapped genes with tissue-specific expression and gene set enrichment analyses.

Results: We identified significant genetic correlations in nine out of 28 trait pairs. MR suggested causal relationships between specific trait pairs. Pleiotropy analysis revealed 25 931 significant single-nucleotide polymorphisms, with 246 pleiotropic loci identified via FUMA and 55 causal loci through Bayesian colocalisation. These loci are involved in neurotransmitter transport and immune response mechanisms, notably the missense variant rs41286192 in SLC18B1. The tissue-specific analysis highlighted the pancreas, left ventricle, amygdala, and liver as critical organs in disease progression. Drug target analysis linked 74 unique genes to existing therapeutic agents, while gene set enrichment identified 189 pathways related to lipid metabolism, cell differentiation and immune responses.

Conclusion: Our findings reveal a shared genetic basis, pleiotropic loci, and potential causal relationships between metabolic dysfunction and neurodegenerative diseases. These insights highlight the biological connections underlying their phenotypic association and offer implications for future research to reduce the risk of neurodegenerative diseases.

Aims: A novel noninvasive score, Agile-4 score, combining liver stiffness measurements, aspartate aminotransferase/alanine aminotransferase, platelet count, diabetes status and sex has been developed for the identification of cirrhosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We assessed the performance of Agile-4 for ruling-in/out liver cirrhosis in MASLD patients.

Materials and methods: We searched Medline, Cochrane library, Web of science, Scopus and Echosens website up to May 2024. Eligible studies assessed the accuracy of Agile-4 for ruling-in (≥0.565) and ruling-out (<0.251) liver cirrhosis, using biopsy as the reference standard, at predefined thresholds. We calculated pooled sensitivity and specificity estimates for both Agile-4 thresholds alongside 95% confidence intervals following bivariate random-effect models. We assessed the risk of bias using Quality Assessment of Diagnostic Accuracy Studies-2 tool.

Results: We included seven studies with 6037 participants. An Agile-4 score ≥0.565 yielded a pooled specificity of 0.93 (95% CI, 0.86-0.97). Similarly, an Agile-4 score <0.251 excluded cirrhosis with a summary sensitivity of 0.90 (0.80-0.95). Assuming a cirrhosis prevalence of 30%, the positive predictive value (PPV) for ruling-in cirrhosis was 80%, while the negative predictive value for ruling-out cirrhosis was 95%. Most studies were at high or unclear risk for bias due to concerns regarding patient selection and the blinding status of Agile-4 score interpretation in relation to biopsy results.

Conclusions: Agile-4 score performs well for ruling-in/out liver cirrhosis in MASLD patients. Owing to the relatively low PPV, sequential application of the Agile-4 after fibrosis-4 index (FIB-4) testing might further enhance its performance.