Metabolic disorders such as obesity, diabetes, dyslipidemia, and hypertension are increasingly recognized as systemic diseases that extend their pathological impact far beyond energy imbalance [...]

Although the beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibition in heart failure (HF) have been well established, it is unknown whether SGLT2 inhibition confers benefit in carriers of rare variants in cardiomyopathy-associated genes. Here we evaluated whole-exome sequencing data from the randomized DECLARE-TIMI 58 trial, in which adults with type 2 diabetes and increased cardiovascular risk were randomized to dapagliflozin or placebo treatment. Pathogenic or likely pathogenic variants (P/LP) in high-confidence cardiomyopathy genes were identified, and treatment effects on hospitalization for HF (HHF) were compared between carriers of such variants and noncarriers. Among 12,685 patients for whom sequence data were obtained, 121 carried a cardiomyopathy variant (76 dilated cardiomyopathy, 25 hypertrophic cardiomyopathy and 25 arrhythmogenic cardiomyopathy). Over a median follow-up of 4.2 years, dapagliflozin lowered the risk of HHF more strongly in carriers (hazard ratio 0.18, 95% confidence interval 0.04-0.86) than in noncarriers (hazard ratio 0.70, 95% confidence interval 0.57-0.86; P interaction 0.03). Absolute risk reduction was 13.0% in carriers and 1.0% in noncarriers (P interaction 0.03). Most carriers (82%) had no prior HF, and in carriers without prior HF, treatment with dapagliflozin reduced the absolute risk of HHF by 12.8%, compared with a reduction of 0.6% in noncarriers (P interaction 0.01). The findings from this cohort of older and high-risk patients raise the possibility that SGLT2 inhibitor treatment should be started early to prevent HF in individuals who carry P/LP cardiomyopathy variants. These results need to be confirmed in a prospective, dedicated trial of preventive HF treatments in carriers of P/LP cardiomyopathy-associated variants.

AIMS:To assess the impact of Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an enzymatic deficiency prevalent in individuals of African or Asian descent, on Hemoglobin A1c (HbA1c) levels, diabetes medication purchases, and the cumulative incidence of diabetes related complications. METHODS:A large cohort study was conducted within a national health organization, comparing 3,913 G6PD-deficient patients to a matched control group without G6PD deficiency over two decades. The main measures and outcomes were the HbA1c levels, patterns of diabetes medication purchases, and the incidence of severe diabetes-related complications. RESULTS:HbA1c levels significantly underestimated blood glucose concentrations in G6PD-deficient individuals. Individuals with diabetes and G6PD deficiency had lower rates of treatment with most diabetes medications, notably GLP-1 receptor agonists and SGLT2 inhibitors. Severe diabetes-related complications were more frequent among G6PD-deficient patients, with adjusted hazards ratios [95% confidence intervals] of 1.44 [1.16-1.81] for severe kidney insufficiency, 1.75 [1.23-2.49] for myocardial infarction, and 1.27 [1.02-1.58] for neuropathy. CONCLUSIONS:This research highlights serious gaps in the management of G6PD-deficient patients with diabetes, who suffer from insufficient medication management and higher rates of complications. These findings underscore the need to account for G6PD deficiency in diabetes treatment to ensure equitable and effective healthcare for this vulnerable population.

BACKGROUND:Galectin-3 (Gal-3) is a circulating biomarker of fibrosis, with higher levels being associated with an increased risk of progression of heart failure and kidney disease. Patients with type 2 diabetes mellitus (T2DM) are at increased risk of both. METHODS:DECLARE-TIMI 58 was a randomized, placebo-controlled trial of dapagliflozin in patients with T2DM with or at high risk for atherosclerotic cardiovascular disease and creatinine clearance ≥60 mL/min. In a nested biomarker substudy, Gal-3 was measured at baseline and in adjusted analyses associated with the prespecified kidney-specific composite endpoint [Kidney-EP; sustained ≥40% decrease in estimated glomerular filtration rate (eGFR) to <60 mL/min, new end-stage kidney disease or adjudicated kidney-related death]. RESULTS:Among 14 530 pts, median Gal-3 was 14.9 ng/mL [interquartile range (IQR), 11.9, 18.4]. Gal-3 was weakly associated with urine albumin creatinine ratio (r = 0.098, P < 0.0001) and eGFR (r = -0.27, P < 0.001) at baseline and independently associated with the Kidney-EP:adj hazard ratio (HR) 1.15 [95% confidence interval (CI) 1.03, 1.28] per 1-SD log (Gal-3), P = 0.013. Dapagliflozin significantly reduced the relative risk of the Kidney-EP across quartiles of baseline Gal-3 [overall HR 0.45 (95% CI 0.23, 0.85), P < 0.0001; P interaction = 0.87]. A greater risk difference was observed with dapagliflozin in patients with higher Gal-3, in whom a higher absolute risk at baseline was observed [absolute risk reduction (ARR) Q4 1.9 (95% CI 0.6, 3.2) vs. Q1 0.6% (-0.1, 1.3), ARR P trend 0.048]. CONCLUSIONS:Plasma Gal-3 is independently associated with the progression of kidney dysfunction in patients with T2DM and normal kidney function. There was a gradient of greater absolute benefit for reducing kidney disease progression in patients treated with dapagliflozin and with higher Gal-3 concentrations at baseline, in whom a higher absolute risk was observed. REGISTRATION:clinicaltrials.gov (NCT01730534).

AIMS:To evaluate GDM screening compliance and prevalence, and the association between gestational glucose intolerance and 5-year postpartum diabetes mellitus (DM). MATERIALS AND METHODS:We used population-based data from three Israeli health maintenance organisations (HMOs), covering 75% of all births in 2016. GDM screening followed a two-step approach: a 50-g 1-h oral glucose challenge test (OGCT), followed by a 100-g 3-h oral glucose tolerance test (OGTT) using Carpenter-Coustan criteria. Data included age, socioeconomic status (SES), results of OGCT and OGTT tests, child birth weight, and gestational age. The dataset was linked to the Israeli National Diabetes Registry to identify postpartum DM. Logistic regression models estimated odds ratios (ORs) for GDM and postpartum DM, adjusting for maternal age, SES, ethnicity, and glucose tolerance status. RESULTS:Among 128,454 women, 10% were unscreened. Of those screened, 23,451 underwent the full OGTT. GDM prevalence was 4.3%. Postpartum DM incidence was 8.6% in women with GDM, 3.1% with unknown GDM status, and 2.1% with impaired glucose tolerance (IGT) (defined as one abnormal value on the OGTT). Compared with normoglycemia, adjusted ORs for the 5-year postpartum DM were 25.48 (95% CI: 21.80-29.79) for GDM, 10.04 (95% CI: 8.59-11.74) for unknown GDM status, 6.48 (95% CI: 5.07-8.28) for IGT, and 2.17 (95% CI: 1.63-2.88) for abnormal OGCT with normal OGTT. Older age, lower SES, and Arab or Bedouin ethnicity were linked to higher GDM and postpartum DM. CONCLUSIONS:Gestational glucose intolerance and screening gaps were strong predictors of postpartum DM. Age, SES, and ethnicity highlight the need for targeted efforts to reduce health disparities.

Introduction: Semaglutide (SEMA) has shown potential benefits in metabolic dysfunction-associated steatotic liver disease (MASLD). This large real-world study aimed to evaluate the effects of SEMA on MASLD patients’ clinical outcomes and liver-related complications. Results: Following propensity score matching based on 34 variables (demographics, comorbidities, laboratory tests, and medication history), SEMA-treated (n = 19,112) patients were compared with non-SEMA (n = 19,112) cases. Both cohorts were well-balanced, except for higher BMI in the SEMA group (36.60 ± 6.25 vs. 34.89 ± 6.84 kg/m2). After one year, the SEMA group demonstrated ~one BMI point reduction but maintained significantly higher BMI (35.51 ± 6.34 vs. 34.11 ± 6.64, p < 0.001). LDL, triglycerides, and HbA1c levels significantly improved with SEMA, as evidenced by decreased rates of poor metabolic markers (31.13% vs. 34.32%, p < 0.001). The SEMA-treated patients demonstrated significantly higher survival, lower cardiovascular risk, and reduced progression to advanced liver disease compared to controls. Discussion: In this large real-world cohort, SEMA use in MASLD patients was associated with significantly improved 1-year survival, cardiovascular, and liver-related outcomes. These benefits appear to result primarily from metabolic improvements and anti-inflammatory effects. Materials and Methods: Data were sourced from TriNetX, a global health research platform with de-identified electronic medical records spanning 135 million patients across 112 healthcare organizations worldwide. We included MASLD adults diagnosed according to ICD9 criteria. Assessed outcomes included survival, biochemical, hematologic, AFP, metabolic and cardiovascular parameters, advanced liver disease (ALD), synthetic function, and metabolic markers. Conclusions: Semaglutide may serve as an effective therapeutic strategy to improve outcomes in MASLD.

Aims To evaluate the quality of inpatient care for patients with diabetic foot ulcers (DFU) and examine the relationship between managerial awareness of quality indicators and the actual care provided, as documented in the electronic medical records (EMRs). Methods A peer-reviewed audit of inpatient DFU care based on interviews with hospital and department management, yielding a comprehensive management score for each hospital; review of electronic medical records (EMR); and patient interviews. Data regarding facilities and personnel were collected as well. Results Data was collected from 26 hospitals, 199 EMR and 86 patient interviews. Larger hospital size was correlated with higher comprehensive management scores (p = 0.008). Moreover, large hospitals were more likely to have dedicated DFU cohorts thus simplifying provision of multidisciplinary state-of-the-art care (p = 0.034). Committed managers were more likely to dedicate surgical sessions to DFU patients, mean (±SD) comprehensive management score of 95.9 ± 3.4 in hospitals with dedicated session vs. 79.7 ± 9.6 in those without (p < 0.001). Hospitals with committed management had better documentation and more prevalent use of correct diagnostic codes (r = 0.542), while higher dedication of head nurses of the DFU departments was significantly correlated with higher scores in inpatient care and patient education (r = 0.509, 0.826 respectively). Overall, patient communication and shared decision-making scored relatively low with only 78.8 % of the patients interviewed noting satisfaction. Conclusions Large hospitals were more likely to deliver high-quality multidisciplinary care, pivotal to the care of DFU patients. Dedicated management teams strongly impact better delivery of care. Better communication and shared decision-making should be reinforced.

Background Genetic variants in cardiomyopathy genes are associated with risk of atrial fibrillation (AF), although data on clinical outcomes for AF patients with such variants remain sparse. Objectives We aimed to study the prognostic implication of rare cardiomyopathy-associated pathogenic variants (CMP-PLP) in AF patients from large, well-phenotyped clinical trials. Methods CMP-PLP carriers were identified using exome sequencing in 5 multinational trials from the Thrombolysis in Myocardial Infarction study group (ENGAGE AF, FOURIER, SAVOR, PEGASUS, and DECLARE), with replication in the EAST-AFNET-4 trial. Associations with centrally adjudicated outcomes were assessed using logistic and Cox regression, among patients with AF. Results In 17,190 patients with a history of AF, we identified 421 (2.4%) CMP-PLP carriers. CMP-PLP variants were associated with a history of heart failure (HF) (OR: 1.66; P < 0.0001), most notably for dilated cardiomyopathy-associated variants. CMP-PLP variants were also associated with incident HF hospitalizations (HR: 1.75; 95% CI: 1.34-2.29; P < 0.0001), most notably for hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy variants. CMP-PLP variants were nominally associated with increased risk of cardiovascular death (HR: 1.46; 95% CI: 1.06-2.02; P = 0.02), driven mainly by dilated cardiomyopathy-associated variants. In contrast, CMP-PLP variants were not associated with prevalent (OR: 0.99; P = 0.96) or incident (HR: 0.95; P = 0.84) ischemic stroke, although anticoagulation use was high. In replication, among 1,479 EAST-AFNET-4 participants, CMP-PLP variants were also associated with prevalent HF and incident HF hospitalizations. Conclusions In patients with AF, rare cardiomyopathy gene variants are associated with increased risks of HF hospitalizations and cardiovascular death, but not stroke. These results, collected from large well-phenotyped clinical trials, demonstrate important prognostic implications for cardiomyopathy-associated genetic variants in AF patients. (c) 2025 Published by Elsevier on behalf of the American College of Cardiology Foundation.

Background and Aims: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown promise in metabolic dysfunction-associated steatotic liver disease (MASLD). This large real-world study aimed to evaluate the effects of SGLT2 inhibitors on MASLD patients’ clinical outcomes and liver-related complications over extended follow-up. Patients and Method: Data were sourced from TriNetX, a global health research platform with de-identified electronic medical records spanning 135 million patients across 112 healthcare organizations worldwide. We included MASLD adults diagnosed according to ICD9/10 criteria. Following propensity score matching based on 34 variables (demographics, comorbidities, laboratory tests and medication history), SGLT2 inhibitor-treated (n = 19,922) patients were compared with non-SGLT2 inhibitor (n = 19,922) cases. Exclusion criteria included baseline improved alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels > 4 upper normal limit (UNL), baseline advanced liver disease, liver transplant and cancer, past anticoagulation and non-MASLD etiologies. Assessed outcomes included survival, biochemical, hematologic, AFP, metabolic and cardiovascular parameters, progression to advanced liver disease (ALD), synthetic function, and metabolic markers over 1, 5, and 10 years. Results: Following matching, both cohorts were well-balanced across baseline characteristics. After one year, the SGLT2 inhibitor group demonstrated significantly reduced BMI (33.2 ± 6.2 vs. 34.1 ± 6.5 kg/m2, p < 0.001), improved ALT (40.3 ± 31.5 vs. 48.3 ± 41.2 U/L, p < 0.001), and better glycemic control (HbA1c 7.35 ± 1.51% vs. 7.93 ± 1.72%, p < 0.001). The SGLT2 inhibitor group showed higher 10-year survival rates (95.00% vs. 88.69%, p < 0.001), fewer cardiovascular events (10.19% vs. 11.80%, p < 0.001), and markedly reduced progression to advanced liver disease (6.90% vs. 14.15%, p < 0.001). These benefits were consistent across clinical, laboratory, and medication-defined ALD categories. Notably, rates of hepatic decompensation events were significantly lower with SGLT2 inhibitor therapy. Conclusions: In this large real-world cohort, SGLT2 inhibitor use in MASLD patients was associated with significantly improved long-term survival, cardiovascular, and liver-related outcomes over 10 years of follow-up. These benefits likely result from combined metabolic improvements, anti-inflammatory effects, and direct hepatoprotective mechanisms. SGLT2 inhibitors represent a promising therapeutic strategy for improving outcomes in MASLD.

Importance:Elevated lipoprotein(a) (Lp[a]) is a putative causal risk factor for atherosclerotic cardiovascular disease (ASCVD). There are conflicting data as to whether Lp(a) may increase cardiovascular risk only in the presence of concomitant inflammation. Objective:To investigate whether Lp(a) is associated with cardiovascular risk independent of high-sensitivity C-reactive protein (hs-CRP) in both primary and secondary prevention populations. Design, Setting, and Participants:This cohort study uses data from 3 distinct cohorts, 1 population-based cohort and 2 randomized clinical trials. Participants included individuals from the UK Biobank (data from 2006-2010) without prevalent ASCVD, participants in the FOURIER (TIMI 59) trial (data from 2013-2017) who had baseline Lp(a) and hs-CRP data, and participants in the SAVOR-TIMI 53 trial (data from 2010-2013) who had prevalent ASCVD and baseline values for Lp(a) and hs-CRP. The data analysis took place from November 2022 to November 2023. Exposure:Baseline plasma Lp(a), considered either as a continuous variable or dichotomized at 125 nmol/L. Main Outcomes and Measures:Risk of major adverse cardiovascular events (MACE) (composite of cardiovascular death, myocardial infarction [MI], or ischemic stroke), the individual MACE components, and peripheral artery disease (PAD). Results:Among 357 220 individuals in the UK Biobank without prevalent ASCVD, 232 699 (65%) had low hs-CRP (<2 mg/L), and 124 521 (35%) had high hs-CRP (≥2 mg/L) values. In a Cox proportional hazard model adjusted for ASCVD risk factors, higher Lp(a) was associated with increased cardiovascular risk regardless of baseline hs-CRP value for MACE (hs-CRP ≥2 mg/L: hazard ratio [HR] per 50-nmol/L higher Lp[a], 1.05; 95% CI, 1.04-1.07; P < .001; for hs-CRP <2 mg/L: HR, 1.05; 95% CI, 1.04-1.07; P < .001; P = .80 for interaction), as well as MI, ischemic stroke, and PAD individually. Among 34 020 individuals in the FOURIER and SAVOR trials with baseline cardiometabolic disease, there were 17 643 (52%) with low and 16 377 (48%) with high baseline hs-CRP values. In Cox proportional hazard models using aggregated data from FOURIER and SAVOR, higher baseline Lp(a) was associated with increased cardiovascular risk regardless of baseline hs-CRP for MACE (hs-CRP ≥2 mg/L: HR per 50-nmol/L higher Lp[a], 1.02; 95% CI, 1.00-1.05; P = .04; hs-CRP <2 mg/L: HR, 1.05; 95% CI, 1.02-1.08; P < .001; P = .16 for interaction), MI, and PAD. Conclusions and Relevance:In this study, higher levels of Lp(a) were associated with MACE, MI, and PAD in both primary and secondary prevention populations regardless of baseline hs-CRP value.

Aims: To examine the efficacy and safety of Curalin, as a supplement to anti-diabetic drugs (ADD). Methods: 135 patients were enrolled in the study. Among them, 109, ages 18-85 years, with HA1c 7.5-10 % under treatment with ADD were randomized 1:1 to receive Curalin supplement or placebo. The primary efficacy endpoint was the change in HbA1c after 3 months. The secondary endpoint was a decrease in HbA1c by more than 0.5 % and by more than 1 %. The exploratory endpoints included the Diabetes Treatment Satisfaction Questionnaire (DTSQ), clinical and laboratory results. Results: After 3 months, the mean reduction in HbA1c was 1.30 % (SD = 0.79) in the Curalin group compared to 0.10 % (SD = 0.70) in the placebo group (P < 0.0001). A decrease in HbA1c of >= 0.5 % was observed in 90.0 % of Curalin patients versus 19.0 % of placebo patients (P < 0.0001). HbA1c reduction of >= 1 % occurred in 64.0 % of Curalin patients and 11.9 % of placebo patients (P < 0.0001). Curalin patients reported higher satisfaction (DTSQ) with no severe adverse events. Conclusions: Curalin treatment significantly reduced HbA1c over a period of 3 months and was well-tolerated.

AIMS:To describe the development and report the first-stage validation of a digital version of the digit symbol substitution test (DSST), for assessment of cognitive function in older people with diabetes. MATERIALS AND METHODS:A multidisciplinary team of experts was convened to conceptualize and build a digital version of the DSST and develop a machine-learning (ML) algorithm to analyse the inputs. One hundred individuals with type 2 diabetes (aged ≥ 60 years) were invited to participate in a one-time meeting in which both the digital and the pencil-and-paper (P&P) versions of the DSST were administered. Information pertaining to demographics, laboratory measurements, and diabetes indices was collected. The correlation between the digital and P&P versions of the test was determined. Additionally, as part of the validation process, the performance of the digital version in people with and without known risk factors for cognitive impairment was analysed. RESULTS:The ML model yielded an overall accuracy of 89.1%. A strong correlation was found between the P&P and digital versions (r = 0.76, p < 0.001) of the DSST, as well as between the ML model and the manual reading of the digital DSST (r = 0.99, p < 0.001). CONCLUSIONS:This study describes the development of and provides first-stage validation data for a newly developed digital cognitive assessment tool that may be used for screening and surveillance of cognitive function in older people with diabetes. More studies are needed to further validate this tool, especially when self-administered and in different clinical settings.