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PubMed2026

Protective association of the ELMO1 rs741301 variant against diabetes mellitus and diabetic nephropathy: a systematic meta-analysis of case-control studies.

CONTEXT: Diabetes mellitus (DM), an endocrine disorder, is characterised by persistently elevated blood glucose levels due to inadequate insulin production. Diabetic nephropathy (DN), is a critical complication associated with DM, often leading to end-stage renal failure and increased mortality. OBJECTIVE: This meta-analysis aimed to evaluate the association between the ELMO1 rs741301 polymorphism and susceptibility to DN among individuals with diabetes. METHOD: A systematic literature search was conducted for studies published between 2014 and 2024 using Embase, Google Scholar, and PubMed. Eligible case-control studies investigating the association between ELMO1 rs741301 and DN among individuals with DM were selected according to predefined inclusion criteria. Nine case-control studies comprising 880 individuals with DM and 1008 individuals with DN were included in the meta-analysis. RESULTS: The pooled analysis demonstrated a significant protective association between the ELMO1 rs741301 polymorphism and DN under the allelic model (OR = 0.77, 95% CI: 0.67-0.88), recessive model (OR = 0.74, 95% CI: 0.61-0.90), and dominant model (OR = 0.68, 95% CI: 0.53-0.88). In contrast, no statistically significant association was observed under the over-dominant model. CONCLUSION: The findings suggest that the ELMO1 rs741301 polymorphism may be associated with a reduced susceptibility to DN among individuals with DM. These findings provide evidence for a potential genetic contribution of ELMO1 to DN susceptibility and may help improve understanding of the genetic factors underlying diabetic complications. Further well-designed studies in diverse populations are warranted to validate this association.

Humans↗

PubMed2026

Optimal dose and exercise modality to improve HbA1c in older adults with type 2 diabetes mellitus: a systematic review with pairwise, network, and dose-response meta-analyses.

We aimed to compare exercise modalities and evaluate dose-response relationships with glycemic control including continuous aerobic exercise (CAE), resistance training (RT), combined exercise (CE), mind-body exercise (MBE), and high-intensity interval training (HIIT) in older adults with type 2 diabetes mellitus (T2DM). Three databases were searched for randomized controlled trials of exercise interventions in older adults with T2DM reporting glycated hemoglobin (HbA1c). Pairwise, Bayesian network, and dose-response meta-analyses were conducted. Compared with control, HIIT demonstrated the largest estimated reduction (MD = -0.95%; 95% CrI -1.45, -0.49), followed by CE (MD = -0.59%; 95% CrI -0.93, -0.25), CAE (MD = -0.46%; 95% CrI -0.69, -0.24), MBE (MD = -0.42%; 95% CrI -0.76, -0.10), and RT (MD = -0.29%; 95% CrI -0.51, -0.08). Dose-response network meta-analyses suggested a non-linear association between overall exercise dose and HbA1c reduction, with maximal estimated benefits at approximately 704 METs-min/week with the 95% CrI excluding zero between 241 and 920 METs-min/week. HIIT demonstrated the steepest estimated dose-response relationship, but with wider credible intervals. Other exercise modalities showed more gradual dose-response patterns across their estimated effective ranges. Our findings suggest that exercise prescription for older adults with T2DM should be individualized according to exercise modality, dose, and health status.

Humans↗

PubMed2026

Mobile health apps improve Health-Related Quality of Life in Type 2 Diabetes Mellitus by enhancing medication adherence: A multicentre randomised controlled trial with mediation analysis.

AIMS: This study evaluated whether a gamified mHealth application (CareAide®) improves Health-Related Quality of Life (HRQoL) in Type 2 Diabetes Mellitus (T2DM) and whether this effect is mediated by medication adherence. METHODS: Prespecified secondary analysis of the T2DM cohort from a 6-month multicentre RCT (NCT06068309; N = 663; three Malaysian hospitals). Participants were randomised 1:1 to standard care or CareAide®. Adherence (MMAS-8), EQ-5D-5L utility (Malaysian value set), and AQoL-6D were assessed at baseline and 6 months. Simple mediation analysis (PROCESS Model 4; 5000 bootstraps) adjusted for baseline HRQoL. RESULTS: CareAide® significantly predicted higher MMAS-8 scores (mean difference +1.756; d = 1.638; p < 0.001). Higher MMAS-8 scores significantly predicted improved AQoL-6D utility (b = 0.024; p < 0.001). The direct effect on AQoL-6D was non-significant (p = 0.248). Bootstrapped indirect effect confirmed full mediation via AQoL-6D (0.042; 95% CI [0.024, 0.060]). A sensitivity analysis adjusting for baseline HbA1c confirmed full mediation (indirect = 0.034; 95% CI [0.015, 0.052]; n = 563). EQ-5D-5L utility showed a significant direct between-group difference at 6 months (p = 0.012) but did not operate as a mediation outcome. CONCLUSIONS: Medication adherence fully mediates the AQoL-6D HRQoL benefit of a gamified mHealth intervention in T2DM, as confirmed by both the primary and HbA1c-adjusted sensitivity analyses. These findings support integration of behaviourally informed digital adjuncts into routine primary diabetes care.

Humans↗

PubMed2026

Plasma proteome profiling identifies XPNPEP3 as a novel biomarker associated with metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus.

OBJECTIVE: To identify plasma protein differences between type 2 diabetes mellitus (T2DM) patients with and without metabolic dysfunction-associated steatotic liver disease (MASLD), and to evaluate the diagnostic potential of X-prolyl aminopeptidase 3 (XPNPEP3) for identifying MASLD in T2DM patients. METHODS: Twenty T2DM inpatients were categorized into groups with and without MASLD and their plasma samples were analyzed using data-independent acquisition mass spectrometry, followed by bioinformatics analysis to identify differentially expressed proteins. The cohort was then expanded to 84 patients, and plasma XPNPEP3 levels were validated by enzyme-linked immunosorbent assay. Correlation between XPNPEP3 and clinical indicators were evaluated, and diagnostic performance was determined via receiver operating characteristic (ROC) analysis. Immunohistochemistry was employed to compare hepatic XPNPEP3 expression between the two groups. RESULTS: Proteomic analysis identified 176 differentially expressed proteins, with XPNPEP3 exhibiting the most significant down-regulation by fold change. In the validation cohort, plasma XPNPEP3 was significantly lower in T2DM+MASLD versus T2DM alone. XPNPEP3 levels were negatively correlated with diabetes duration, liver function markers, and triglyceride levels, and was identified as an independent factor inversely associated with MASLD in T2DM.ROC analysis demonstrated strong diagnostic performance for XPNPEP3, further enhanced when combined with BMI and diabetes duration.  Immunohistochemistry confirmed reduced hepatic XPNPEP3 expression in T2DM+MASLD patients. CONCLUSIONS: Lower plasma XPNPEP3 is independently associated with MASLD in T2DM patients and demonstrates strong diagnostic potential, positioning XPNPEP3 as a promising biomarker for diagnosing MASLD in T2DM patients and a novel target for non-invasive diagnostic tool development.

Humans↗

PubMed2026

Metformin Adherence and Risk of Polyneuropathy in Type 2 Diabetes Mellitus: An International Matched Cohort Study with Independent Validation.

BACKGROUND: Metformin is a popular first-line glucose-lowering medication for type 2 diabetes mellitus (T2DM). Although metformin reduces the risks of various complications of diabetes, its potential to cause polyneuropathy by depleting vitamin B12 levels is concerning. This study investigated whether the adherence or discontinuation of metformin after adding-on a second-line antiglycemic agent increases the risk of polyneuropathy in patients with T2DM. METHODS: Data from TriNetX were obtained, and patients with T2DM who were receiving second-line antiglycemic agents were divided into metformin-adherent and metformin-nonadherent groups based on prescription claims data. Neuropathy incidence was evaluated using diagnostic claims and nerve conduction examinations. For independent confirmation and external validation of the primary findings, we used data from the National Health Insurance Research Database (NHIRD) of Taiwan. RESULTS: After matching, 58,027 patients were included in each group. Compared with metformin adherent patients, metformin nonadherent patients had a higher risk of polyneuropathy (adjusted hazard ratios [aHR] 1.26; 95% confidence interval [CI] 1.23-1.29; P < 0.001). Risks of diabetic foot ulcer, amputation, neuropathy-related medication use, and bone fracture were also higher among nonadherent patients. Sensitivity analyses confirmed the robustness of findings. In the validation NHIRD cohort (31,384 matched pairs), metformin nonadherence remained associated with increased polyneuropathy risk (aHR 1.25; 95% CI 1.10-1.42; P < 0.001). CONCLUSIONS: Metformin adherence in patients with T2DM who require second-line treatment may reduce the risk of polyneuropathy; vitamin B supplementation may enhance this benefit.

Humans↗

PubMed2026

Efficacy of dapagliflozin on hepatic steatosis and fibrosis in patients with type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease: a pre-specified single-arm analysis from a randomized controlled trial.

AIM: To evaluate the association of dapagliflozin therapy with changes in hepatic steatosis and non-invasive fibrosis surrogate markers in patients with type 2 diabetes mellitus (T2DM) and Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) over 12 months. METHODS: This is a pre-specified single-arm analysis from a randomised, open-label, parallel-group trial. Of 54 participants randomised to dapagliflozin 10 mg daily, 50 (92.6%) completed the 12-month follow-up and were included in the per-protocol analysis. Assessments at baseline, 3, 6, and 12 months included transient elastography (CAP and LSM), ultrasonography, and biochemical tests. Primary endpoints were changes in hepatic steatosis (CAP) and non-invasive fibrosis surrogates (LSM). RESULTS: Significant reductions were observed in hepatic steatosis (CAP: 316.7 to 245.7 dB/m; mean change - 71.02 dB/m, 95% CI: -63.4 to - 78.6; p < 0.001) and in liver stiffness as a non-invasive fibrosis surrogate (LSM: 8.59 to 7.28 kPa; mean change - 1.31 kPa, 95% CI: -0.92 to - 1.70; p < 0.001). Improvements were also observed in glycaemic control, body weight, lipid profile, liver enzymes, ultrasonographic steatosis grading, and serum fibrosis markers. Genitourinary infections were the most frequently reported adverse events (32%); no serious adverse events were recorded. CONCLUSIONS: Dapagliflozin was associated with significant improvements in hepatic steatosis, non-invasive fibrosis surrogate markers, metabolic parameters, and liver function in T2DM patients with MASLD over 12 months. These findings provide region-specific evidence for an Indian population and support further controlled investigation. However, these findings should be interpreted in light of the pre-specified single-arm design of this analysis, the open-label methodology, relatively small sample size, and the absence of liver biopsy confirmation.

Humans↗

PubMed2026

Digital health interventions for diabetes management in the eastern mediterranean region: A systematic review of types and effectiveness.

AIM: The aim of this study was to systematically review and evaluate the types and effectiveness of digital health interventions used for diabetes management in the Eastern Mediterranean Region (EMRO). METHODS: This systematic review, conducted according to PRISMA guidelines, searched PubMed, Web of Science, and Scopus up to May 2025 to identify studies on digital interventions for diabetes management in EMRO countries. Methodological quality of the included studies was evaluated using the EPHPP tool, and findings were categorized by intervention type, outcome measures, and intervention effectiveness. RESULTS: A total of 46 studies were included, mainly from Iran and Saudi Arabia. Phone calls and SMS were the most common digital tools. Digital interventions significantly improved HbA1c, fasting blood sugar, and several behavioral outcomes such as physical activity, medication adherence, and self-efficacy, while effects on psychological outcomes were mixed. CONCLUSION: Digital health interventions, especially phone calls and SMS, effectively improve glycemic control and self-care behaviors, though their impact on psychological outcomes remains inconsistent.

Humans↗

PubMed2026

Apoptosis protein markers in comorbid type 2 diabetes mellitus and depression; relationships with cognitive performance, incident dementia, and white matter hyperintensities.

Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) are reciprocal risk factors, and both elevate dementia risk. Dysregulation of programmed cell death is implicated in T2DM, MDD, and neurodegeneration, but proteomic markers of apoptosis have yet to be studied as dementia predictors in people with T2DM and/or MDD. This study examines apoptosis markers in comorbid T2DM and MDD, and their associations with cognitive, dementia, and neuroimaging outcomes. The retrospective sample (n = 15,765) consisted of UK Biobank participants (MDD only n = 1230; T2DM only n = 3644; comorbid T2DM + MDD n = 721). Individuals with T2DM + MDD comorbidity had poorer cognitive performance, and a higher 15-year dementia incidence (HR = 4.44, 95% CI = [3.23,6.11]). Among 60 apoptosis-related proteins identified by Kyoto Encyclopedia of Genes and Genomes pathway enrichment, 41 were significantly up-regulated in comorbid T2DM + MDD relative to controls, and 4 were higher in the comorbid group than both T2DM alone and MDD alone. Tumor necrosis factor ligand superfamily member 10 (TNFSF10), growth arrest and DNA damage-inducible protein GADD45 beta, tumor necrosis factor ligand superfamily member 6, and RAC-gamma serine/threonine-protein kinase were associated with dementia risk. Nine proteins (e.g. apoptosis-inducing factor 1, mitochondrial, caspase-2, mitogen-activated protein kinase kinase kinase 5, TNFSF10), were associated with white matter hyperintensity volumes in comorbid T2DM + MDD after FDR correction, but none were associated with cognitive performance, atrophy, or white matter microstructural changes. These findings identify peripheral apoptosis markers that were further elevated in comorbid T2DM + MDD compared to either alone, pointing to an important pathophysiological element underlying adverse outcomes in the context of mood and metabolic comorbidity.

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PubMed2025

Treatment preference for once-weekly versus once-daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND/OBJECTIVE: Although once-weekly and once-daily DPP-4 inhibitors have gained widespread market recognition, patient preference differences remain a key focus. This meta-analysis compares treatment preferences for once-weekly versus once-daily DPP-4 inhibitors in T2DM, offering evidence to guide clinical decisions and healthcare policies. METHODS: PubMed, OVID, EBSCO, Web of Science, CNKI, Wanfang, and clinical trial registries were searched up to June 30, 2025. After screening literature against predefined criteria, a systematic review was conducted to compare the effects of once-weekly and once-daily DPP-4 inhibitors on the treatment preferences of patients with T2DM. RESULTS: 8 RCTs with 1,575 participants were analyzed. No significant difference in medication adherence and DTSQ total score between the once-weekly and once-daily groups (p > 0.05). HbA1c percentage (MD = -0.21, 95% CI [-0.42, -0.01], p < 0.05) decreased significantly with once-weekly dosing, while GA and FPG showed no change (p > 0.05), this suggests greater improvement in HbA1c percentage levels following a switch to once-weekly DPP-4 inhibitors. Once-weekly DPP-4 inhibitors showed higher musculoskeletal/connective tissue disorder risk (RR = 2.63; 95% CI [1.18, 5.83]), but no significant differences in other adverse events (p > 0.05). No significant differences in treatment burden between both groups (p > 0.05). CONCLUSION: No statistically significant association between treatment preferences for once-weekly versus once-daily DPP-4 inhibitors among T2DM patients and medication adherence, treatment satisfaction, glycemic level changes, safety, or treatment burden for these two dosing regimens. Further research is needed to elucidate the influence of physician prescribing behavior on these preferences.

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PubMed2026

Genetic determinants of gestational diabetes mellitus in thai pregnant women: role of GCKR, CDKAL1, TCF7L2, NEDD1, and CMIP variants.

BACKGROUND: Gestational diabetes mellitus (GDM) has a high global prevalence and arises from complex interactions between genetic predisposition and environmental factors. GDM is associated with metabolic disturbances and chronic low-grade inflammation, both of which contribute to its pathogenesis. This study aimed to investigate the association between GDM and 135 single-nucleotide polymorphisms (SNPs) across 20 genes related to metabolic traits. METHODS: In this case-control study, 152 pregnant women with GDM and 684 pregnant women with normal glucose tolerance (NGT) who underwent antenatal examination at Siriraj Hospital, Bangkok, were enrolled. Clinical data and blood samples were collected from all participants. Genomic DNA was isolated and subjected to whole-genome sequencing using the DNBSEQ-T7RS high-throughput sequencing platform. Genotype analyses were performed using R software, and haplotype analyses were conducted using the online SNPStats software. RESULTS: After adjusting for maternal age and pre-pregnancy body mass index, polymorphisms in TCF7L2 (rs34872471, rs7901695, rs4506565, rs7903146, rs12243326, and rs12255372), NEDD1 (rs10431408, rs11830756, rs249579, rs249585, and rs4762339), CMIP (rs2306115 and rs201681534), CDKAL1 (rs4710942), GCKR (rs2293572 and rs2293571), and GCK (rs5883890) were significantly associated with the risk of GDM. Haplotype analysis demonstrated that the TCF7L2 rs12243326-rs12255372 CA haplotype was associated with a decreased risk of GDM (OR = 0.44, 95% CI: 0.23-0.81), while the NEDD1 rs249579-rs249585-rs4762339 GGT haplotype was associated with an increased risk of GDM (OR = 1.40, 95% CI: 1.08-1.82). CONCLUSIONS: These findings suggest that genetic variations in TCF7L2, NEDD1, CMIP, CDKAL1, GCK, and GCKR contribute to GDM susceptibility in the Thai population.

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PubMed2026

Externally validated risk prediction models for gestational diabetes mellitus: A systematic review and meta-analysis.

INTRODUCTION: Risk prediction models for gestational diabetes mellitus (GDM) offer potential for early identification and targeted prevention. External validation is crucial to assess model performance across diverse populations. Despite the availability of numerous GDM prediction models, limited evidence exists on their external validation frequency, methodological quality, and clinical applicability. This systematic review evaluated externally validated GDM prediction models, focusing on methodological rigor, reporting standards, and clinical relevance to inform future research and implementation. MATERIAL AND METHODS: Databases including Ovid MEDLINE, Embase, Scopus, Emcare, and CINAHL were searched up to May 1, 2025. Studies reporting external validation of GDM risk prediction models were included. Two reviewers independently screened studies. Data were extracted using the CHARMS framework, and risk of bias and applicability were assessed using PROBAST+AI. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420251125758). RESULTS: Twenty-six studies validated 33 models, with validation sample sizes ranging from 50 to 75 161. Over half used the IADPSG criteria to define GDM. Discrimination metrics were commonly reported, but calibration, overall performance, and clinical utility were often lacking. Meta-analysis was feasible for only four models: Teede et al., Nanda et al., Naylor et al., and Van Leeuwen et al., each showing fair discrimination. The Teede et al. model was the most widely validated, with 11 external validations across six continents and a pooled AUC of 0.72 (95% CI: 0.67-0.76). Despite fewer validations, the Nanda et al. model achieved the highest pooled discrimination (5 validations; pooled AUC 0.77, 95% CI: 0.74-0.80). The Naylor et al. and van Leeuwen et al. models also underwent meta-analysis, as sufficient external validation studies were available to support comparative performance assessment. Notably, 69.23% of studies had a high risk of bias. CONCLUSIONS: While many models showed acceptable predictive performance, most validations were methodologically weak. Future studies should follow best-practice guidelines and promote scalable validation strategies, such as algorithm sharing, to enhance clinical utility.

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PubMed2026

Comparative evaluation of oxidative stress biomarkers F2-isoprostanes and 8-OHdG in Parkinson's disease and Type 2 Diabetes Mellitus: a systematic review and meta-analysis of human studies.

BACKGROUND: Oxidative stress is central to type 2 diabetes mellitus (T2DM) and Parkinson's disease (PD). However, the utility of biomarkers for lipid peroxidation (F2-isoprostanes) and DNA damage (8-OHdG) in the comorbidity of PD and T2DM remains unclear. METHODS: We conducted a systematic review and meta-analysis of 54 unique studies of human subjects aged ≥ 50 years (n = 7,521: 3,522 with T2DM, 722 with PD, and 3,277 controls), measuring biomarkers in serum, plasma, or leukocytes. Mixed-effects models quantified standardized differences (Hedges' g) across subgroups. RESULTS: In T2DM, F2-isoprostanes (g = 1.60, 95% CI: 0.95-2.25) and 8-OHdG (g = 2.64, 95% CI: 2.13-3.14) were markedly elevated (p < 0.001). Stronger effects were observed in younger cohorts and serum/plasma samples, with complications like nephropathy exhibiting extreme oxidative stress (g = 5.24). In PD, 8-OHdG was moderately elevated (g = 0.78, 95% CI: 0.18-1.39; p = 0.011), particularly in randomized controlled trials and plasma samples, whereas F2-isoprostanes were not significantly elevated (g = 0.47, 95% CI: -0.43-1.38). High heterogeneity in T2DM (I2 > 90%) reflected methodological variability. CONCLUSION: Distinct profiles - both markers elevated in T2DM but only 8-OHdG in PD - underscore 8-OHdG's potential in PD-T2DM comorbidity. Future research should focus on standardized assays, multi-compartmental or multi-modal sampling, and longitudinal studies to clarify mechanisms and therapeutic targets.

Humans↗

PubMed2026

Acute Stevia Consumption does not Alter Endocrine Responses in Individuals with Normal Weight, Overweight, and Type 2 Diabetes Mellitus.

BACKGROUND: Stevia is a plant-based non-nutritive sweetener. Acute effects of stevia ingestion on glycemia and hormonal responses have not been fully investigated. OBJECTIVE: This objective of this study was to evaluate the acute effects of beverages containing stevia alone and in combination with glucose on glycemic, hormonal, and appetite responses. METHODS: This study evaluated three cohorts of n=23 individuals with either normal weight (NW), overweight (OW), or type 2 diabetes mellitus (T2DM) for which each individual completed four test conditions in a randomized sequence crossover study design. The four test conditions were beverages containing stevia (75.6 mg steviol equivalents), water, glucose (30 g), and stevia+glucose (30 g glucose+75.6 mg steviol equivalents). Blood samples were collected before and for 180 min after beverage consumption. Assessments included net area under the curve (niAUC) and incremental maximal concentration values for plasma glucose, insulin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1, glucagon, and PYY. Appetite was assessed with visual-analog scale questions and energy consumption during an ad libitum meal. RESULTS: Responses to the stevia beverage did not differ significantly from those for water alone, and stevia + glucose did not differ significantly from glucose alone for any of the three groups. CONCLUSION: Acute stevia consumption did not materially alter responses for glycemia or hormones involved in glucose and appetite regulation, appetite ratings, or energy intake at a subsequent meal. Clinical Trial Registry number and website where it was obtained: Clinical Trials.gov Identifier: NCT05287906. Study Details | NCT05287906 | A Trial to Assess Steviol Glycosides on Acute Appetite Hormone Release | ClinicalTrials.gov.

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PubMed2026

The Association Between NT-Pro BNP, Nephropathy and Endothelial Dysfunction in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-Pro BNP) is an established biomarker of heart failure and has been recommended for cardiovascular risk stratification in type 2 diabetes mellitus (T2DM). However, its relationship with diabetic nephropathy and endothelial dysfunction across varying stages of kidney impairment remains unclear. This study examined the associations of NT-Pro BNP, renal impairment, albuminuria and endothelial dysfunction in patients with T2DM without overt heart failure. METHODS: A comparative cross-sectional study was conducted among 192 adults with T2DM. Participants were stratified by KDIGO eGFR groups (≥ 90, 60-89, 30-59 mL/min/1.73m2). NT-Pro BNP was considered abnormal at a cut-off of ≥ 125 pg/mL. Albuminuria was categorized using the urinary albumin-to-creatinine ratio (uACR). Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD). Logistic regression analysis was performed to identify independent factors of elevated NT-Pro BNP, with p-values < 0.05 considered statistically significant. RESULTS: NT-Pro BNP levels were significantly higher in the lower eGFR groups compared with normal eGFR (204.3 vs. 96.8 vs. 62.2 pg/mL, p < 0001). A weak but significant positive correlation was observed between NT-Pro BNP and uACR (r = 0.31, p < 0.001). However, no significant association was found between NT-Pro BNP and FMD (p = 0.388). Following multivariable adjustments, older age (adjusted OR 1.14, 95% CI: 1.06-1.23, p < 0.001), higher systolic blood pressure (adjusted OR 1.05, 95% CI: 1.02-1.08, p = 0.010), lower eGFR (adjusted OR 0.97, 95% CI: 0.95-0.99, p = 0.003) and beta-blocker use (adjusted OR 4.65, 95% CI: 1.61-13.45, p < 0.001) were independently associated with elevated NT-Pro BNP. CONCLUSION: In patients with T2DM without overt heart failure, elevated NT-Pro BNP showed a statistically significant association with lower eGFR and higher albuminuria. Moderate to severe albuminuria becomes an independent factor for elevated NT-Pro BNP after adjustment excluding eGFR. The lack of association with endothelial dysfunction suggests that NT-Pro BNP may reflect different pathophysiological pathways. NT-Pro BNP may serve as a useful biomarker for early cardiovascular risk stratification and identification of individuals at risk of pre-heart failure in diabetic kidney disease.

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PubMed2026

Impact of Albuminuria-Lowering Treatments on Cardiovascular Predictive Ceramides in Diabetes: Post Hoc Analysis of the ROTATE Trials.

AIM: Cardiovascular disease (CVD) is the leading cause of mortality in individuals with diabetes. Diabetic kidney disease, closely related to CVD risk, is prevalent in up to 40% of this population. Emerging evidence suggests ceramide lipids as accurate biomarkers for CVD. We assessed the effect of four albuminuria-lowering drugs on CVD-related ceramides in diabetes by post hoc analysis of the ROTATE trials. MATERIALS AND METHODS: Twenty six adults with type 1 (T1D) as well as 37 with type 2 diabetes (T2D) with a urine albumin-creatinine ratio (UACR) of 30-500 mg/g participated in a 4-week 4-time randomized crossover study with periods of telmisartan, empagliflozin, linagliptin and baricitinib treatment, each separated by a 4-week washout period. Blood samples were collected at the beginning and end of each period and ceramide lipids (Cer16, Cer18, Cer20, Cer22, Cer24 and Cer24:1) were measured. The effect of each treatment was evaluated using linear mixed-effect models. RESULTS: At baseline, individuals with T2D had greater levels of Cer22 and Cer24 compared to the individuals with T1D. Among the treatments, linagliptin was the only drug that demonstrated a reduction of Cer22, Cer24 and Cer24:1 from baseline by 22.6% (95% CI: -33.58; -9.79, p = 0.001), 25.7% (95% CI: -38.94; -9.69, p = 0.003) and 19.6% (95% CI: -31.34; -5.95, p = 0.007), respectively. No changes in the ceramides were observed for the other drugs. CONCLUSION: Our exploratory findings suggest that certain albuminuria-lowering drugs may affect ceramide levels as a secondary effect. However, further mechanistic investigations are needed.

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PubMed2026

Clopidogrel vs Aspirin According to Diabetes Mellitus: A Prespecified Analysis of the SMART-CHOICE 3 Trial.

BACKGROUND: Recent trials support the superior efficacy of clopidogrel compared to aspirin monotherapy after completion of dual antiplatelet therapy (DAPT) in patients who have undergone percutaneous coronary intervention (PCI). However, limited evidence is available in patients with diabetes mellitus (DM). OBJECTIVES: This study sought to evaluate the comparative efficacy and safety of clopidogrel vs aspirin monotherapy according to the presence of DM. METHODS: This was a prespecified analysis of the SMART-CHOICE 3 trial, which was a multicenter, open-label, randomized controlled trial comparing clopidogrel vs aspirin monotherapy in patients with complex coronary lesions or high-risk clinical characteristics. From August 2020 to July 2023, a total of 5,506 patients who underwent PCI and standard DAPT duration and had complex coronary lesions, DM, or previous myocardial infarction, were randomized to clopidogrel or aspirin monotherapy groups. The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), which was defined as a composite of death from any cause, myocardial infarction, or stroke. RESULTS: Of 5,506 patients, 2,089 had DM (1,039 in the clopidogrel group and 1,050 in the aspirin group). At a median follow-up of 2.3 years (IQR: 1.6-3.0 years), DM patients had a higher risk of MACCE compared to non-DM patients (6.8% vs 4.7%; HR: 1.44, 95% CI: 1.10-1.87; P = 0.008). Clopidogrel showed a significantly lower risk of MACCE than aspirin in DM patients (4.5% vs 9.1%; HR: 0.57, 95% CI: 0.38-0.86; P = 0.008). There was no significant interaction between DM and antiplatelet monotherapy regarding MACCE (P for interaction = 0.124). The risk of bleeding was comparable between the 2 groups in DM patients (2.9% vs 2.9%; HR: 1.06, 95% CI: 0.57-1.95; P = 0.855). CONCLUSIONS: Among DM patients who completed the standard duration of DAPT after PCI, clopidogrel monotherapy was associated with a lower risk of a composite of death from any cause, myocardial infarction, and stroke compared with aspirin monotherapy, without increased rates of bleeding. There was no significant interaction between DM and antiplatelet monotherapy with respect to MACCE. (SMART-CHOICE 3 [SMart Angioplasty Research Team: CHoice of Optimal Anti-Thrombotic Strategy in Patients Undergoing Implantation of Coronary Drug-Eluting Stents 3]; NCT04418479).

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PubMed2026

Baseline Computed Tomography Coronary Angiography and Polygenic Risk Profiles in Adults With Type 2 Diabetes: A Cross-Sectional Analysis From the VOLTAIRE Study.

AIMS: To characterise baseline clinical, anatomical, and genetic cardiovascular risk profiles in participants enrolled in the VOLTAIRE (Evaluation of Polygenic Scores and CT Imaging in Risk Factor Modification in Patients with Type 2 Diabetes) study and examine concordance across these domains. METHODS: This analysis included adults with T2D who completed baseline computed tomography coronary angiography (CTCA) and polygenic risk score (PRS) assessment prior to randomisation in the VOLTAIRE study. Coronary atherosclerosis was evaluated using coronary artery calcium (CAC) score and CTCA-derived stenosis severity. Clinical risk was assessed using the New Zealand Society for the Study of Diabetes 5-year cardiovascular risk calculator. Polygenic risk for coronary artery disease was assessed using a genome-wide PRS and categorised into tertiles. RESULTS: Among 126 participants with T2D (mean age 57.5 ± 8.7 years; 62.7% male), coronary atherosclerotic burden was highly heterogeneous: 34.9% had CAC = 0, whereas 19.8% had CAC ≥ 400. Moderate-to-severe coronary stenosis (≥ 50%) was present in 40.5% of participants overall, including 20.4% of those classified as low clinical risk. PRS distribution was variable (low 37.3%, intermediate 35.7%, high 27.0%). Overlap between anatomical, genetic, and clinical domains was limited, with only 8.7% of participants classified as high risk across all three. CONCLUSIONS: Substantial heterogeneity and limited overlap exist between anatomical, genetic, and clinical cardiovascular risk measures in T2D. These findings support a multimodal approach to risk assessment integrating imaging and genetic profiling. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov; ID: NCT07091162.

Aged↗

PubMed2026

The association between prenatal PM2.5 constituent exposure and gestational diabetes mellitus: Exploratory analysis of the potential modifying role of thyroid hormones.

The associations of PM2.5 constituents with blood glucose and GDM remain unclear, and the interplay between PM2.5 exposure and thyroid hormone levels in relation to GDM has not been well characterized. This retrospective cohort study included 1314 pregnant women with data collected through multiple methods. A generalized linear model analyzed PM2.5-glucose links, logistic regression assessed pollutant-GDM associations, and stratified analyses explored these relationships at different thyroid hormone levels. In the study population, first-trimester exposure to SO42- and BC correlated positively with FBG, as did PM2.5 and its components in the second trimester. First-trimester SO4²⁻ exposure (OR=1.26, 95% CI: 1.06, 1.51) and second-trimester exposures to PM2.5 (OR=1.67, 95% CI: 1.19, 2.35), NO3⁻ (OR=1.34, 95% CI: 1.06, 1.68), and NH4⁺ (OR=1.33, 95% CI: 1.06, 1.65) were associated with increased GDM risk. Stratified analyses showed that second-trimester BC and OM were positively correlated with FBG in the high-TSH and low-FT4 strata, respectively. In addition, first-trimester exposure to SO42- (high TSH: OR = 1.42, 95% CI: 1.10, 1.84; low FT4: OR = 1.35, 95% CI: 1.05, 1.74) and to PM2.5 (high TSH: OR = 1.93, 95% CI: 1.14, 3.27; low FT4: OR = 1.82, 95% CI: 1.46, 2.25) in the second trimester were associated with higher odds of GDM. These findings show that PM2.5 exposure was associated with glucose dysregulation and GDM in pregnant women differently by trimester and component. Across the separate TSH- and FT4-stratified analyses, women in the high-TSH and low-FT4 strata, respectively, appeared to show greater susceptibility to air pollution-related GDM. These subgroup findings should therefore be interpreted as exploratory and require validation in future studies.

Effect modification↗