Aims: Proteinuria is a risk factor for end-stage kidney disease (ESKD) and cardiovascular disease (CVD) in patients with diabetes. However, the clinical implications of fluctuating proteinuria are unclear. We investigated the proteinuria burden and the risks of clinical outcomes in patients with diabetes using the Korean National Health Insurance Service database.
Materials and methods: This retrospective cohort study included patients with diabetes who participated in a national health screening between 2015 and 2016, with records of three previous health screenings. Each end-point was followed until 31 December 2022. The proteinuria burden (range: 0-4) was defined as the cumulative number of positive urine protein dipstick tests at each health screening. The outcomes included ESKD, CVD and all-cause mortality.
Results: Among 1 264 699 patients, 86.3%, 9.4%, 2.5%, 1.2% and 0.6% had proteinuria burdens of 0 to 4, respectively. The proteinuria burden and risks of clinical outcomes had dose-dependent associations; compared to proteinuria burden 0, the adjusted hazard ratio (95% confidence interval) of proteinuria burdens 1, 2, 3 and 4, respectively, were as follows: ESKD, 3.539 (3.326-3.766), 9.373 (8.816-9.965), 14.539 (13.652-15.484) and 19.704 (18.412-21.087); CVD, 1.247 (1.214-1.280), 1.530 (1.465-1.599), 1.815 (1.713-1.923) and 2.032 (1.883-2.192); and all-cause mortality, 1.335 (1.302-1.369), 1.703 (1.635-1.774), 1.959 (1.855-2.068) and 2.092 (1.945-2.250). Within the same proteinuria burdens, late-positive proteinuria was associated with worse outcomes than early-positive proteinuria.
Conclusions: The proteinuria burden was dose-dependently associated with clinical outcomes in patients with diabetes. Even a single positive dipstick test requires active management.
Objective: This study seeks to analyse the effect of the change and accumulation of residual cholesterol (RC) on the risk of diabetes.
Methods: The analysis included 5124 participants from the China Health and Retirement Longitudinal Study (CHARLS) and 2704 participants from the English Longitudinal Study of Ageing (ELSA), all of whom underwent two repeated RC measurements. Changes in the RC were assessed through K-means clustering analysis, and the cumulative RC was determined using the formula: by (RCfirst + RCsecond)/2 × (time interval between first and second assessments). We employed Cox proportional hazards regression models to analyse the effect of the changes and accumulation of RC on the development of diabetes.
Results: Individuals with consistently elevated RC levels (class 4) demonstrated a 1.98-fold increase in diabetes risk 95% confidence interval (CI: 1.38-2.84) in the CHARLS study and a 2.73-fold increase (95% CI: 1.69-4.38) in the ELSA study, compared with those with consistently low RC levels (class 1). Similarly, the risk of diabetes increased by 1.62 (95% CI: 1.21-2.18) times in CHARLS and 2.98 (95% CI: 1.81-4.88) folds in ELSA for participants with highest levels of cumulative RC relative to those with lowest levels of cumulative RC. Elevated cumulative RC remains a substantial risk factor for diabetes, irrespective of the cumulative LDL-C level.
Conclusions: Long-term exposure to high RC levels links to an elevated risk of diabetes. Therefore, maintaining optimal RC levels and continuously monitoring them may contribute to reducing the incidence of diabetes.
Aims: To evaluate the safety and effectiveness of iGlarLixi in people with type 2 diabetes mellitus (T2DM) in clinical practice in Mexico.
Materials and methods: This was a prospective, observational, multicentre study in adults with T2DM who were prescribed iGlarLixi in routine clinical practice in Mexico. The participants were followed for 24 ± 1 months. The primary endpoint included the incidence proportion, incidence rate of adverse drug reactions (ADRs), serious ADRs and the severity of suspected ADRs possibly related to iGlarLixi throughout the study.
Results: The study included 330 participants (mean ± SD age: 57.8 ± 11.9 years, weight: 77.1 ± 17.7 kg, duration of diabetes: 14.1 ± 9.9 years, and female: 55.5%). During the 24-month study, 59 participants (17.9%; 95% confidence interval [CI]: 13.9-22.4) reported 95 ADRs, with a mean of 0.164 events per participant-year. The most commonly reported ADRs were gastrointestinal disorders (11.2%), with nausea being the most frequent (7.3%). HbA1c decreased from 9.5% at baseline to 7.3% at the end of the study. Additionally, 51.7%, 64.6% and 86.3% of participants achieved the glycaemic target of HbA1c < 7%, FPG < 110 mg/dL and PPG < 180 mg/dL, respectively, at the end of the study. A significant decrease (p < 0.0001) in 7-point self-monitoring plasma or capillary blood glucose was observed from baseline to 3, 6, 12 and 24 months post iGlarLixi initiation.
Conclusions: iGlarLixi demonstrated a consistent safety profile aligned with findings from previous randomised controlled trials. The most common ADRs were gastrointestinal disorders that were generally tolerable. Over 50% of participants treated with iGlarLixi achieved their glycaemic targets.
Aims: To compare the risk of new-onset hyperglycaemia between inpatients treated versus non-treated with systemic glucocorticoids and identify factors associated with glucocorticoid-induced hyperglycaemia (GIH).
Materials and methods: We conducted a cohort study using electronic healthcare records of adults admitted to the Oxford University Hospitals between 2013 and 2023. We excluded patients with diabetes or prescribed systemic glucocorticoids before admission. The outcome was new-onset hyperglycaemia defined as a new glucose-lowering therapy, coded diagnosis of diabetes or random blood glucose ≥11.1 mmol/L. We used Poisson regression to estimate the incidence rate ratio (IRR) of new-onset hyperglycaemia during periods of exposure versus non-exposure to systemic glucocorticoids, adjusting for confounders. We used Poisson regression models to identify potential risk factors for GIH.
Results: Of 451 606 included patients, 17 258 (3.8%) received systemic glucocorticoids during admission. Totally 316 (1.8%) of patients exposed to systemic glucocorticoids developed new-onset hyperglycaemia versus 3430 (0.8%) non-exposed to systemic glucocorticoids. The multivariable-adjusted IRR (95% CI) for new-onset hyperglycaemia among exposed versus non-exposed was 2.15 (1.18-3.12). Covariates associated with GIH were: age (relative risk, 95% CI) 1.02 (1.01-1.03) per year, ethnicity (1.72 [1.04-2.86] Asian vs. White, 1.26 [1.05-2.70] other vs. White), weight 1.01 (1.01-1.03) per kg, indication (2.15 [1.21-3.52] autoimmune/inflammatory/infection vs. malignant, 2.11 [1.18-4.20] other vs. malignant) and cumulative glucocorticoid dose (1.23 [1.04-1.42], for 51-205 mg vs. >0-50 mg and 2.53 [1.89-3.40] for > 205 mg vs. >0-50 mg).
Conclusions: Treatment with systemic glucocorticoids versus no glucocorticoid treatment during hospitalisation more than doubles the risk of new-onset hyperglycaemia. Higher age, weight, cumulative glucocorticoid dose, non-White ethnicity and autoimmune/inflammatory conditions were independently associated with a higher risk of GIH.
Aims: This study aims to compare adverse drug reaction patterns of liraglutide, semaglutide and tirzepatide-glucagon-like peptide-1 receptor agonists (GLP-1 RAs) approved for anti-obesity medications-to evaluate their real-world safety.
Materials and methods: This disproportionality analysis utilized a case-control design with VigiBase. The study focused on reports of adverse events associated with liraglutide, semaglutide and tirzepatide, selected based on warnings in the US Food and Drug Administration approval labels for each drug. Data were restructured using unique identifiers to differentiate individuals affected by adverse drug reactions. Multivariable logistic regression models estimated adjusted reporting odds ratios (aRORs) with 95% confidence intervals (CIs) to assess the association between various adverse events and GLP-1 RAs, adjusting for age, sex, region, reporter qualification, reporting year and concomitant medication. The information component (IC) was analysed, and signals of adverse drug reactions were considered significant only when both aROR and IC were statistically significant.
Results: Our analysis of targeted adverse drug reactions included 24 725 individuals using liraglutide, 21 454 using semaglutide and 11 538 using tirzepatide. Tirzepatide had fewer reports of adverse drug reactions compared with the other two drugs, and its pharmacovigilance association strength was the lowest. Semaglutide, however, was significantly associated with several unusual adverse events, including suicidal ideation and behaviour (IC, 1.53 [IC025, 1.28]; aROR, 2.52 [95% CI, 2.18-2.93]), hair loss (IC, 0.78 [IC025, 0.63]; aROR, 1.42 [95% CI, 1.30-1.55]) and vision loss (IC, 1.27 [IC025, 1.13]; aROR, 1.80 [95% CI, 1.66-1.97]).
Conclusions: Our findings emphasize the need for cautious prescribing and further research to ensure the safe use of these medications.
Background: Emerging evidence has linked metabolic dysfunction-associated steatotic liver disease (MASLD) with accelerated cognitive decline and dementia. We aimed to investigate the associations of MASLD with volumes of total brain tissue and subcortical grey matter, and white matter microstructures in the UK Biobank.
Methods: This cross-sectional study included 29,195 individuals (aged 45-82 years) from the UK Biobank who undertook a magnetic resonance imaging (MRI) sub-study between 2014 and 2022. The brain MRI covers three modalities (T1, T2 FLAIR, and diffusion). Volumes of grey matter, subcortical grey matter structures, and regional cortex were derived from T1-weighted images. Fractional anisotropy (FA) and mean diffusivity (MD) were derived from diffusion tensor imaging (DTI) to assess global and tract-specific microstructure. MASLD was defined as the MRI-derived proton density fat fraction (MRI-PDFF) ≥5% and the presence of at least one cardiometabolic criterion. Data were analysed using multiple linear regression models.
Results: MASLD was significantly associated with smaller volumes of total grey matter and subcortical grey matter (p < 0.05) and reduced Alzheimer's disease (AD)-signature cortical thickness (multivariable-adjusted β = -0.04; 95% confidence interval [CI]: -0.07, -0.01). Having MASLD was associated with higher total white matter hyperintensity (WMH) volume (multivariable-adjusted β = 0.12; 95% CI: 0.10, 0.15). For white matter microstructure, MASLD was associated with increased global FA (multivariable-adjusted β = 0.05; 95% CI: 0.03, 0.08) and reduced global MD (multivariable-adjusted β = -0.04; 95% CI: -0.07, -0.01).
Conclusions: Brain morphology associated with MASLD is characterized by smaller subcortical grey matter volume and higher coherence but lower magnitudes of white matter microstructure.
Aims: [D3,G40,K41.C16 diacid]exendin-4 (acyl-ExD3) and [F1,G40,K41.C16 diacid]exendin-4 (acyl-ExF1) are oppositely biased glucagon-like peptide-1 (GLP-1) receptor agonists that preferentially promote β-arrestin recruitment or G protein-induced signalling, respectively. The latter is more favourable in glycaemic control and induces a steeper reduction in body weight in diet-induced obese mice. Here, we compared the effects of G protein-biased agonist acyl-ExF1 to those of β-arrestin-biased agonist acyl-ExD3 on lipid metabolism in hyperlipidaemic mice.
Materials and methods: APOE*3-Leiden.CETP mice were treated with saline, acyl-ExD3 or acyl-ExF1 via intraperitoneal injections for 6 weeks or intracerebroventricular infusion for 18 days. Body weight and composition were monitored at regular intervals, as were plasma glucose, triglyceride and cholesterol levels. At endpoint, mice were injected with very low-density lipoprotein (VLDL)-like particles containing glycerol tri[3H]oleate to study triglyceride-derived fatty acid uptake by peripheral tissues including brown and white adipose tissue (BAT and WAT).
Results: Upon peripheral treatment, body weight gain was prevented and plasma glucose levels were reduced by acyl-ExF1, but circulating lipids were not affected by either acyl-ExF1 or acyl-ExD3. In contrast, central administration of either agonist strongly reduced plasma triglyceride and cholesterol levels, but did not affect glucose levels. Acyl-ExD3 and acyl-ExF1 increased [3H]oleate uptake by adipose tissue, reaching statistical significance for the uptake by BAT and WAT, respectively, compared to vehicle treatment.
Conclusion: The oppositely biased GLP-1 receptor agonists acyl-ExD3 and acyl-ExF1 do not differentially affect lipid metabolism in APOE*3-Leiden.CETP mice, while effects on glucose homeostasis and prevention of body weight gain are more pronounced upon peripheral acyl-ExF1 treatment.
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