Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality among individuals with type 2 diabetes mellitus (T2DM), imposing a substantial burden on healthcare systems. This systematic review and network meta-analysis evaluated the comparative efficacy of antidiabetic medications and combination therapies in reducing cardiovascular outcomes in patients with T2DM. PubMed (Medline), Embase, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to December 30, 2024, for randomized controlled trials (RCTs) assessing cardiovascular outcomes in adults with T2DM treated with metformin, sulfonylureas, thiazolidinediones (TZDs), dipeptidyl peptidase‑4 (DPP‑4) inhibitors, glucagon‑like peptide‑1 (GLP‑1) receptor agonists, sodium-glucose cotransporter‑2 (SGLT2) inhibitors, or insulin. Outcomes included cardiovascular mortality, myocardial infarction (MI), stroke, heart failure, hospitalization for cardiovascular events, and unstable angina. Risk of bias was assessed using the Cochrane RoB 2.0 tool, and analyses were conducted with a random-effects model in Stata (version 18). From 10,514 records, 133 RCTs involving 289,558 participants (mean age: 64.7 years) were included. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly reduced cardiovascular mortality (RR = 0.85, 95% CI: 0.75-0.98; high-certainty evidence) and stroke (RR = 0.83, 95% CI: 0.74-0.93; high-certainty evidence). SGLT2 inhibitors significantly reduced heart failure (RR = 0.64, 95% CI: 0.53-0.77; high-certainty evidence) and hospitalization for cardiovascular events (RR = 0.72, 95% CI: 0.68-0.77; high-certainty evidence). An indirect comparison suggested lower cardiovascular mortality with DPP-4 inhibitors versus GLP-1 receptor agonists, although this finding should be interpreted cautiously due to network imbalance. GLP-1 RAs and SGLT2 inhibitors are associated with significant reductions in specific cardiovascular outcomes in patients with T2DM, particularly in reducing cardiovascular mortality, stroke, heart failure, and hospitalization. Treatment decisions should integrate patient-specific risk profiles and cost-effectiveness to optimize outcomes.
Diabetes mellitus is a chronic metabolic disorder associated with a two- to four-fold higher risk of cardiovascular morbidity and mortality compared with individuals without diabetes due to complex interactions between metabolic, inflammatory, and vascular pathways. Despite extensive research, uncertainties remain regarding the integrated effects of emerging therapies and persistent cardiovascular risk in diabetic populations. This systematic literature review aimed to evaluate the cardiovascular implications of diabetes mellitus by synthesizing evidence on epidemiology, mechanisms, and clinical outcomes. A structured search was conducted across PubMed, Scopus, Web of Science, and Cochrane Library for studies published between 2015 and 2025, using predefined Boolean search terms, including MeSH terms in PubMed, to identify randomized controlled trials and observational studies reporting cardiovascular outcomes; no review protocol was registered prospectively. Eleven studies were included in the final review after searches were conducted for studies published between 2015 and 2025. Data were extracted and synthesized narratively because clinical and methodological heterogeneity, including differences in populations, interventions, outcomes, study designs, and follow-up durations, precluded formal meta-analysis, and I² assessment. The findings indicate that diabetes significantly increases the risk of major adverse cardiovascular events, heart failure, and mortality, driven by hyperglycemia-induced endothelial dysfunction, inflammation, and atherosclerosis. Pharmacological therapies such as SGLT2 inhibitors, GLP-1 receptor agonists, and mineralocorticoid receptor antagonists demonstrated significant reductions in cardiovascular and renal outcomes, while lifestyle interventions contributed to risk reduction. Persistent residual risk highlights incomplete therapeutic control. These findings emphasize the need for integrated and individualized management strategies. This review reinforces the importance of combining pharmacological and lifestyle interventions to effectively reduce cardiovascular complications in diabetes.
Cardiovascular-kidney-metabolic (CKM) syndrome is recognized as a progressive pathophysiological continuum linking metabolic dysfunction, dysfunctional adiposity, chronic kidney disease, and cardiovascular injury. The atherogenic index of plasma (AIP) reflects lipid-related atherogenic burden, whereas novel adiposity indices, including body roundness index (BRI), weight-adjusted waist index (WWI), and a body shape index (ABSI), capture body-shape-related adiposity burden. However, the associations of AIP and AIP-based adiposity composite indices with mortality outcomes across the CKM spectrum remain unclear. This study aimed to evaluate the associations of AIP and integrative AIP-based composite indices, including AIP-BRI, AIP-WWI, and AIP-ABSI, with all-cause and cardiovascular mortality among individuals across CKM stages. We conducted a retrospective cohort analysis using prospectively collected data from 22,587 US adults in the National Health and Nutrition Examination Survey (NHANES) 1999-2018. Following the 2023 American Heart Association (AHA) Presidential Advisory, participants were classified into a hierarchical staging framework (Stages 0-4) to reflect the CKM disease continuum. Primary outcomes were all-cause and cardiovascular mortality, identified through linkage to the National Death Index. Integrative AIP-based composite indices were constructed by directly multiplying AIP by each adiposity index, including BRI, WWI, and ABSI, yielding AIP-BRI, AIP-WWI, and AIP-ABSI, respectively. These indices were evaluated as integrated exposure variables reflecting the combined burden of atherogenic dyslipidemia and adiposity-related body shape. All analyses incorporated complex survey weights to ensure national representativeness. Survey-weighted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Model 2 adjusted for demographic and socioeconomic characteristics, lifestyle factors, blood pressure, and total cholesterol. Nonlinear associations were examined using restricted cubic splines (RCS). Incremental prognostic value was assessed using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). During follow-up, non-survivors exhibited significantly higher baseline integrative composites than survivors (P < 0.001). In the fully adjusted model (Model 2), which adjusted for demographic and socioeconomic characteristics, lifestyle factors, blood pressure, and total cholesterol, each standard deviation increase in the integrative composites was independently associated with a higher risk of all-cause mortality: AIP-BRI (HR, 1.09; 95% CI, 1.05-1.14), AIP-WWI (HR, 1.07; 95% CI, 1.02-1.11), and AIP-ABSI (HR, 1.07; 95% CI, 1.02-1.11). These point estimates were numerically slightly higher than that of stand-alone AIP (HR, 1.06; 95% CI, 1.01-1.10), but the differences should be interpreted cautiously. For cardiovascular mortality, the corresponding HRs were 1.17 (95% CI, 1.09-1.27) for AIP-BRI, 1.11 (95% CI, 1.03-1.21) for AIP-WWI, and 1.11 (95% CI, 1.02-1.20) for AIP-ABSI, compared with 1.10 (95% CI, 1.02-1.20) for AIP. RCS analyses revealed J-shaped associations, with a clinical risk threshold for AIP-BRI at 1.57. Subgroup analyses indicated that these associations were most evident in participants aged < 50 years. Adding BRI to AIP assessment yielded a statistically significant but modest NRI of 3.10% for cardiovascular mortality. Across the CKM spectrum, higher AIP-based adiposity composite indices, particularly AIP-BRI, were associated with increased risks of all-cause and cardiovascular mortality, especially among younger individuals. However, their incremental predictive improvement was modest, suggesting that these indices may serve as supplementary exploratory markers rather than stand-alone tools for CKM risk stratification.
Social network size influences survival through health behaviors and psychosocial support, while cardiovascular health (CVH) predicts all-cause mortality. However, their combined effect remains unclear. We investigated the independent and joint associations of CVH and network size with all-cause mortality in a Korean cohort. We analyzed 11,312 participants aged 30-79 years from the Cardiovascular and Metabolic Diseases Etiology Research Center cohort (2013-2018). CVH scores based on Life's Essential 8 were categorized into tertiles. Network size was classified as small (0-1), medium (2-3), or large (≥4 close contacts). Mortality data through 2024 were obtained from national death records. Multivariable Cox models estimated hazard ratios (HRs) after adjustment for demographic, socioeconomic, and clinical covariates. During 100,739 person-years of follow-up (mean 8.9 years), 397 deaths occurred. Compared with lower tertile CVH group, hazard of mortality was lower in middle (HR: 0.84, 95% CI: 0.66-1.06) and upper tertile CVH group (HR: 0.61, 95% CI 0.45-0.82). Medium (HR: 0.70, 95% CI: 0.55-0.90) and large (HR: 0.69, 95% CI: 0.51-0.92) network size was also associated with lower hazard of mortality compared with small network size. Participants with both upper tertile CVH and large network size had the lowest hazard of mortality (HR: 0.36, 95% CI: 0.22-0.58). No significant interaction was observed (p = 0.41). Higher CVH and larger networks were independently associated with lower all-cause mortality in middle-aged Korean adults. Public health strategies that combine lifestyle promotion with social engagement may help reduce premature death. This Korean prospective cohort study investigated the independent and joint associations of cardiovascular health (CVH) and network size with all-cause mortality. Higher cardiovascular health and larger social network size were independently associated with reduced all-cause mortality. Individuals who maintained both optimal cardiovascular health and wide social networks experienced greater longevity. Our current analysis results underscore the prognostic importance of cardiovascular health and social connectedness as key determinants of longevity, and support the rationale for public health strategies that address both lifestyle and social factors simultaneously. These findings underscore the growing significance of social relationships in cardiovascular health and mortality, highlighting social support and behavioral influence as key mechanisms linking social networks to health outcomes.
Irisin is a metabolism-related myokine associated with lipid metabolism and insulin resistance. However, its changes during glucagon-like peptide-1 (GLP-1) receptor agonist therapy remain unclear. This exploratory analysis of a multicenter trial included 189 adults with T2DM inadequately controlled with metformin and/or insulin secretagogue. The participants received the GLP-1 receptor agonist exenatide as an add-on therapy for 16 weeks. Serum irisin and glycolipid metabolism were evaluated. Comparison was performed between two subgroups of the participants stratified by a median change from baseline in serum irisin level. Associations between change in irisin level and changes in metabolic parameters were assessed using Pearson or Spearman correlation analysis and multivariable linear regression analysis. After the 16-week exenatide treatment, serum irisin level significantly declined from baseline (3.22 ± 0.53 ng/mL vs. 3.35 ± 0.64 ng/mL, P = 0.031). Change in irisin level was positively associated with change in high-density lipoprotein cholesterol (HDL-C) level (r = 0.154, P = 0.035), and negatively associated with changes in triglyceride (TG) level (r = -0.159, P = 0.029) and TG/HDL-C ratio (r = -0.172, P = 0.018). These associations for TG level and TG/HDL-C ratio remained significant after multivariable adjustment. No significant association was observed between change in irisin level and glycemic control parameters. Serum irisin level declines during the exenatide treatment in patients with T2DM, and this reduction is associated with change in lipid metabolism but not glycemic control, suggesting a potential link between dynamic change of irisin and lipid metabolism during the exenatide treatment.
Obesity, diabetes, and cardiovascular disease often co-exist in people with chronic kidney disease, placing them at high risk for adverse health outcomes. Availability of highly effective medications that span cardiovascular-kidney-metabolic (CKM) conditions, but limited uptake in real world settings, calls for a new transformative practice paradigm. We sought to identify key gaps, barriers, and facilitators to implementing a standardized CKM-focused comprehensive medication management (CMM) intervention, including needs/solutions among various care team members involved in CKM care in diverse health systems across the United States. This was a qualitative study guided by the Consolidated Framework for Implementation Research (CFIR) deployed in five health care systems across the United States. Clinical pharmacists, pharmacist administrators, primary care and specialty (nephrology, cardiology, endocrinology) physicians, and advanced practice professionals were interviewed using open-ended questions that were informed by results from three mainly quantitative online surveys. A total of 26 interviews were conducted with 42 participants. Practitioners and administrators reported many similar challenges to successfully implement CMM for people with CKM including lack of standardized CMM practice and workflow across the health system, electronic medical record integrated tools to identify and track patients with CKM, automatic pharmacist referrals, broad clinical practice agreements, and holistic CKM performance metrics, as well as pharmacist time constraints and limited reimbursement. Participants also highlighted CMM-CKM practice facilitators including recognition across most health care professionals that CKM should be a system priority, requiring strong supportive professional relationships among physician and/or administrator champions, and tools, knowledge, and resources that could be shared with others. Successful implementation of a transformative, holistic CMM-CKM interprofessional team-practice will require a tailored implementation strategy for each health system including consolidated tools such as a CMM-CKM Change Package, integrated with coaching, field experts, and peer-to-peer learning.
Background/Objectives: Cardiovascular risk remains substantial after myocardial infarction (MI) despite established clinical risk markers. Erythrocyte and platelet indices are routinely available, but their long-term prognostic relevance remains insufficiently studied. Methods: This retrospective cohort study was based on the Styrian Registry on Genuine Myocardial Infarction (STRONG-MI) and included patients with MI undergoing invasive coronary angiography in Styria, Austria, between January 2007 and March 2016. Multivariable Cox regression models were used to assess the associations of admission and discharge erythrocyte and platelet indices with 3-point major adverse cardiovascular events (MACE) during follow-up extending to 175 months. Results: Among 10,920 patients, admission hemoglobin showed a U-shaped association with MACE. Median hemoglobin decreased from admission to discharge (14.2 g/dL vs. 13.1 g/dL) and the lowest discharge tertile showed the highest association with MACE compared with the middle tertile (AHR 1.27, 95% CI 1.18-1.38). Lower mean corpuscular hemoglobin concentration (MCHC) was independently linked to adverse outcomes at both admission and discharge (AHR 1.17, 95% CI 1.08-1.27, and 1.14, 95% CI 1.05-1.23, respectively). Higher platelet count and mean platelet volume (MPV) were also associated with increased risk, particularly at discharge (AHR 1.15, 95% CI 1.06-1.24, and 1.19, 95% CI 1.10-1.29, respectively). Conclusions: Routine erythrocyte and platelet indices were independently associated with long-term cardiovascular outcomes after invasively treated MI and reflect residual biological risk after discharge.
While nutrient-stimulated hormone (NuSH) therapies (e.g., glucagon-like pepide-1 receptor agonists and dual/triple agonists) have transformed the landscape of obesity pharmacotherapy, the next generation of medications may target body composition optimization or other cardiovascular benefits. This review examines novel obesity mechanisms outside of the NuSH class. Unique mechanisms for obesity treatment include peripherally restricted cannabinoid-1 receptor antagonism, myostatin/activin inhibitors, selective androgen receptor modulators, melanocortin-4 receptor agonism, mitochondrial modulation, thyroid receptor agonists, and fibroblast growth factor analogues. By targeting fat distribution, muscle preservation, inflammatory/oxidative stress pathways, lipid metabolism, and energy expenditure, these agents may improve both the magnitude and quality of weight loss. Early evidence suggests complementary roles alongside NuSH-based therapies for induction, augmentation, and maintenance strategies. Several non-NuSH agents have demonstrated potential in preclinical and early clinical studies to optimize body composition, but additional studies are required to prove large-scale, long-term safety and efficacy.
Cardiovascular-kidney-metabolic (CKM) syndrome refers to the co-occurrence of obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease. However, it is underdiagnosed due to silent clinical nature of the early stages of its components and subsequent siloed medical care. Electrocardiography (ECG) is an inexpensive and widely available diagnostic tool but its utility in automated detection of CKM syndrome has not been previously explored. To develop and evaluate deep learning models for predicting CKM syndrome using scanned limb and augmented limb leads ECGs images in people with diabetes. Clinical data of adults with type 1 or type 2 diabetes enrolled in the prospective Silesia Diabetes-Heart Project were analyzed. CKM syndrome was defined by the presence of either CKD [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 and/or urine albumin to creatinine ratio (UACR) ≥ 30 mg/g) or established CVD. High-resolution scanned ECG tracings were processed into lead-specific inputs to train ResNet-50-based convolutional neural network (CNN) models, including single- and dual-channel variants. Class imbalance was addressed using resampling strategies, and model performance was evaluated using standard classification metrics, including area under the receiver operating characteristic curve (AUROC), with confidence intervals estimated by bootstrap resampling. Among 2779 participants, 492 (17.7%) met criteria for CKM syndrome. The best-performing individual model was a dual-channel ResNet-50 with soft voting ensemble, achieving an AUROC of 0.8199 (95% CI 0.7549-0.8795), F1-score of 0.7213 (95% CI 0.6404-0.7957), accuracy of 0.7385, and balanced precision and recall. Ensemble models consistently outperformed individual architectures, particularly in handling class imbalance and improving generalization. Deep learning applied to scanned ECG image data predicts CKM syndrome in individuals with diabetes with reasonable accuracy. This approach holds promise as a low-cost, scalable risk stratification tool and which could augment clinical decision-making in settings particularly with limited access to advanced diagnostics. Trial registration The study is registered at ClinicalTrials.gov (NCT05626413).
Cardiovascular-kidney-metabolic (CKM) syndrome, newly introduced by the American Heart Association, aims to promote the integrated management of metabolic dysfunction, chronic kidney disease, and cardiovascular disease (CVD). The C-reactive protein-triglyceride-glucose index (CTI), a novel composite biomarker that captures both systemic inflammation and insulin resistance, has emerged as a promising metric in cardiometabolic research. However, current evidence regarding its clinical utility remains limited. To date, no studies have systematically examined the association between CTI and CVD risk, particularly across CKM syndrome stages 0 to 3. The China Health and Retirement Longitudinal Study (CHARLS), initiated in 2011, is a large-scale, nationally representative, multicenter prospective cohort study. In accordance with predefined inclusion and exclusion criteria, a total of 6,859 participants were included in the final analysis. To assess the association between CTI and CVD risk, Cox proportional hazards models, receiver operating characteristic (ROC) curve analysis, restricted cubic spline modeling, and stratified subgroup analyses were conducted. During the 10-year follow-up period, 1391 incident CVD events were recorded. In the fully adjusted model, a significant positive association was observed between CTI and CVD risk, with each one-standard deviation increases in CTI corresponding to a 7% higher risk of CVD. Receiver operating characteristic (ROC) curve analysis demonstrated that the CTI improved the discriminatory power of the baseline model for predicting CVD. Restricted cubic spline modeling revealed a nonlinear, S-shaped relationship between CTI and CVD risk. Moreover, analyses stratified across most CKM syndrome stages consistently revealed a positive correlation between CTI and CVD risk. Our findings suggest a positive, S-shaped association between CTI and CVD risk in individuals with CKM syndrome stages 0-3. Enhancing the assessment of CTI could provide a more accessible and efficient screening tool for the prevention and management of CVD in this population.
The relationship between the mean platelet volume-to-lymphocyte ratio (MPVLR), a composite indicator of the body's inflammatory response and immune function, and the prognosis of cancer patients is unclear. A total of adult cancer patients with complete information between 1999 and 2018 were included in this study. The Cox proportional hazards model was used to investigate the association between MPVLR levels and all-cause and cardiovascular disease (CVD) mortality in adult cancer patients. The probability of all-cause and CVD mortality in cancer patients with different MPVLR levels was compared by plotting Kaplan-Meier survival curves. Restricted cubic spline analysis, threshold effect analysis, and subgroup analysis were also used. This study ultimately included a total of 3997 adult cancer patients, with a median age of 69 years. During a median follow-up period of 7.08 years, a total of 1379 (34.50%) all-cause deaths and 299 (7.48%) deaths from CVD occurred. According to the Cox proportional hazards model analysis, MPVLR was associated with all-cause mortality rate (hazard ratio [95% confidence interval]: 1.13 [1.11-1.16], P < .001) and a CVD mortality rate (hazard ratio [95% confidence interval]: 1.16 [1.11-1.20], P < .001), which were significantly associated with an increased risk of mortality. Kaplan-Meier survival curve analyses showed that the prognosis of the high-level MPVLR group was significantly worse than that of the low-level group. This association persisted in subgroup analyses based on age, sex, race, marital status, education level, ratio of family income to poverty, body mass index, smoking status, drinking status, hypertension, and diabetes. Restricted cubic spline analysis models showed a nonlinear association between MPVLR and all-cause or CVD mortality in adult cancer patients. Higher MPVLR levels were significantly associated with an increased risk of all-cause and CVD mortality in adult cancer patients. There was a nonlinear relationship between MPVLR and all-cause or CVD mortality in adult cancer patients.
Individuals living with type 1 diabetes (T1D) are at increased risk for cardiovascular (CV) and renal complications, yet therapeutic strategies specifically targeting cardiorenal risk reduction in this population remain limited. The role of glucagon-like peptide-1 (GLP-1)-based therapies in T1D remains unclear. We conducted a review of published studies examining the CV, clinical, and renal effects of GLP-1-based therapies in people with T1D, while also evaluating safety outcomes and future research priorities. Three observational real-world studies evaluating GLP-1-based therapies in adults with T1D were identified. Overall, these studies demonstrated clinically meaningful reductions in all-cause mortality, hospitalisation, heart failure, and composite CV outcomes. Renal benefits were also observed, including lower risks of early estimated glomerular filtration rate decline and end-stage kidney disease. Importantly, no consistent increase in diabetic ketoacidosis or severe hypoglycemia was identified, supporting a generally reassuring safety profile. These findings challenge the traditional view of GLP-1 receptor agonists as therapies of predominantly glycemic relevance in T1D and support their potential role in cardiorenal risk reduction. Nevertheless, the currently available evidence is entirely observational and warrants confirmation through prospective randomised studies specifically designed for T1D populations. Current real-world evidence suggests that GLP-1-based therapies in T1D may provide clinically meaningful CV and renal benefits with a reassuring safety profile; however, adequately powered randomised trials are needed to confirm these findings.
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Nutritional overflow and a positive energy balance are hallmarks of metabolic diseases including obesity and type 2 diabetes. Brown and beige adipocytes maintain systemic metabolic homeostasis by clearing and oxidizing energy-rich nutrients during thermogenic activation. Myoglobin (MB) is classically regarded as a muscle-associated oxygen-binding protein; however it is also expressed in brown and beige adipocytes, where it contributes to intracellular lipid handling and oxidative metabolism. Here, we report that loss of MB exclusively in adipose tissue (AT) lowers whole-body energy expenditure, impairs thermoregulation, and increases susceptibility to diet-induced obesity. AT-specific MB knockout (ATMBKO) mice exhibit elevated circulating triglycerides (TG) and fatty acids, indicating defective lipid clearance and utilization. Omics analyses reveal coordinated downregulation of oxidative phosphorylation, fatty acid metabolism, and myogenic programs. Conversely, restoration of MB in MB knockout (MBKO) mice improves metabolism in vivo. MB expression determines the capacity for mitochondrial fatty acid oxidation in brown adipocytes, whereas MB overexpression in primary human white adipocytes enhances thermogenic activity, confirming functional relevance of MB in human AT. Together, these findings establish MB as a key determinant of thermogenic lipid metabolism and energy expenditure in vivo and increasing adipocyte MB expression could increase energy expenditure and complement obesity treatment strategies.
Do women with exercise-induced functional hypothalamic amenorrhea (Ex-FHA) have an increased risk of subclinical atherosclerosis, as measured by carotid intima-media thickness (cIMT)? Women with Ex-FHA appear to show greater cIMT than non-exercising control women (nonEx-control). Long-term cardiovascular risk is a major concern in women with functional hypothalamic amenorrhea who exercise regularly. Although hypoestrogenic women with Ex-FHA consistently exhibit markers of risk, such as endothelial dysfunction, evidence of atherosclerosis is lacking. From 2019 to 2025, we conducted a cross-sectional comparative study of five groups of premenopausal adult women (N = 50). According to our calculations, this sample size allowed us to detect a minimum difference of 0.019 mm in common cIMT between any pair of groups, setting α to 0.05 and power (1-β) to 0.80. We included three groups of women with different mechanisms of ovulatory dysfunction: women with Ex-FHA, women with classic PCOS, and women with non-hyperandrogenic PCOS. Healthy exercising (Ex-control) and nonEx-control served as control groups. Smokers were excluded. All women received a comprehensive cardiometabolic phenotyping including anthropometrics, circulating sex steroids, carbohydrate metabolism and lipid profiles, office and 24-h ambulatory blood pressure monitoring, and cardioautonomic function studies. Ultrasound measurement of mean cIMT served as a marker of subclinical carotid atherosclerosis. Women with Ex-FHA were the only subgroup of study participants showing higher cIMT values than nonEx-controls [cIMT: 0.514 ± 0.057 vs 0.411 ± 0.054 mm, respectively; mean difference: 0.103 (95% CI: 0.031; 0.175); P = 0.002]. This difference remained after adjusting for BMI. Regarding carbohydrate and lipid metabolism, women with Ex-FHA showed a higher insulin sensitivity index than both subgroups of women with PCOS. Individuals with Ex-FHA had higher concentrations of HDL-cholesterol, HDL-triglycerides, and large- and medium-HDL particles than both subgroups of women with PCOS, Ex-controls, and nonEx-controls. Women with Ex-FHA presented with a lower resting heart rate than participants with classic PCOS, Ex-controls, and nonEx-controls. They also showed a lower diastolic blood pressure response to standing than nonEx-controls. The limited sample size of our study population precluded us from identifying the main determinants of subclinical atherosclerosis in each subgroup of women. The cross-sectional observational design of this study does not allow causal inference regarding associations between independent variables and cIMT. Lastly, multiple comparisons may have led to spurious associations in some cases, despite having implemented rigorous adjustments for multiplicity whenever possible. While data on robust endpoints of women with Ex-FHA are lacking, this novel finding on subclinical carotid atherosclerosis may enhance scientific understanding of their cardiovascular risk profile. Still, larger confirmatory studies are needed with the aim of establishing cIMT as an early marker of atherosclerosis in Ex-FHA and, secondly, clarifying which intrinsic risk factors underlie this association. This research was funded by Instituto de Salud Carlos III grants PI1801122 and PI2100116, and co-funded by the European Union. The authors declare not to have any conflicts of interest. ClinicalTrials.gov ID: NCT03841981.
Friedreich ataxia is a multi-system neurodegenerative disorder with frequent cardiac and metabolic involvement. Omaveloxolone, the first approved therapy for Friedreich ataxia, improves neurological outcomes through nuclear factor erythroid 2-related factor 2 activation and exerts measurable systemic effects. However, its effects on lipid metabolism have not been systematically assessed. The present study aimed to systematically evaluate the longitudinal effects of omaveloxolone on serum lipid parameters in a real-world cohort of patients with Friedreich ataxia over a 12-month observation period. We conducted a retrospective, single-center, real-world observational study in adults with genetically confirmed Friedreich ataxia newly treated with omaveloxolone (150 mg/day). Serum lipid parameters, including total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, very low-density-lipoprotein cholesterol, triglycerides, C-reactive protein, apolipoprotein A-I, and apolipoprotein B (ApoB), were measured at baseline and after 1, 2, 3, 6, and 12 months. Longitudinal changes were analyzed using frequentist and Bayesian linear mixed-effects models. A total of 17 patients were included in the analysis (13 male [76%]; mean age 36.1 years [range 20-55]; mean disease duration 17.4 years [range 6-33 years]). Total cholesterol increased shortly after treatment initiation and remained elevated throughout the follow-up period, driven almost entirely by a sustained rise in low-density lipoprotein-cholesterol (+ 35-50 mg/dL) and ApoB (+ 20-25 mg/dL) levels, whereas high-density lipoprotein-cholesterol, apolipoprotein A-I, very low-density-lipoprotein cholesterol, and triglyceride levels remained stable. Low-density lipoprotein-cholesterol and ApoB levels were strongly correlated at all timepoints (r = 0.83-0.95). The total cholesterol/high-density lipoprotein-cholesterol ratio increased by approximately one unit and persisted throughout the follow-up period. In this real-world Friedreich ataxia cohort, omaveloxolone treatment was associated with a sustained shift toward a more atherogenic lipid profile, driven almost entirely by increased low-density lipoprotein-cholesterol and ApoB levels. This pattern is consistent with impaired hepatic clearance of ApoB-containing particles rather than increased production, supporting routine lipid monitoring and further evaluation of long-term cardiovascular risk.
The Mediterranean diet (MedDiet) has emerged as a promising dietary strategy for the prevention and management of type 2 diabetes mellitus (T2DM). This narrative review provides a comprehensive synthesis linking the biological pathways of the MedDiet with established clinical evidence. Adherence to this traditional dietary pattern-characterized by a high intake of fiber, complex carbohydrates, antioxidants, and healthy fats-has demonstrated significant benefits in terms of glycemic control, enhanced insulin sensitivity, and overall metabolic health. Mechanistically, the review explains how the MedDiet improves health by modulating key physiological processes, including anti-inflammatory and antioxidant pathways, the regulation of branched-chain amino acid metabolism, the enhancement of short-chain fatty acid production via gut microbiota modulation, and upregulated incretin effects. Importantly, this review explains how the MedDiet complements modern medications, including glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. By integrating molecular mechanisms with human clinical outcomes, this narrative review addresses multiple aspects of the MedDiet in both the prevention and management of T2DM including glycemic control, weight management, and cardiovascular risk reduction, rendering it a valuable dietary strategy for both the prevention and treatment of this chronic condition.
Diabetes pharmacology has historically been dominated by a glucose-centric framework in which therapeutic efficacy is defined primarily by reduction in blood glucose and glycated haemoglobin (HbA1c). Although this paradigm transformed diabetes from a fatal disease into a chronic manageable condition, persistent cardiovascular, renal, inflammatory, and metabolic complications have exposed the limitations of viewing diabetes principally as a hyperglycaemic disorder. This perspective examines the progressive conceptual transition occurring across modern diabetes therapeutics, beginning with the exhaustion of the traditional glucose-centred model and extending through the emergence of incretin-based therapies, organ-protective pharmacology, immunological intervention, regenerative endocrinology, bioengineering, and AI-enabled closed-loop systems. Drawing on these developments, it argues that contemporary therapeutic advances progressively derive their efficacy from coordinated modulation of interconnected physiological networks rather than solely glucose-lowering effect. On this basis, the article proposes biological systems redesign as a unifying conceptual model for the future of diabetes therapeutics, in which treatment is directed toward the restoration of integrated metabolic and organ-level homeostasis, the preservation of system resilience, and the interception of disease progression across multiple biological scales.
Primary aldosteronism (PA) results from excessive aldosterone production by one or both adrenal glands and is an important cause of hypertension, leading to increased cardiovascular and renal morbidities. PA is primarily caused by a spectrum of somatic or germline mutations in aldosterone-driver genes and superimposed aberrant adrenal expression of various G-protein-coupled receptors and their ligands, leading to dysregulated aldosterone production. PA remains underdiagnosed, and simplified testing by measuring renin and aldosterone is recommended in all people with hypertension to maximize the diagnosis of PA. Some individuals with PA may also have co-secretion of cortisol, which contributes to cardiometabolic morbidities. Adrenal vein sampling, emerging functional imaging and novel biomarkers can identify whether a unilateral source of PA can be treated with surgical adrenalectomy. However, the majority of patients with PA have bilateral disease, warranting medical therapy with dietary sodium restriction and mineralocorticoid receptor antagonists, and aldosterone synthase inhibitors in the near future. Medical therapy objectives are to normalize blood pressure and serum potassium; a rise in renin can serve as a biomarker of adequate therapy and reduced risk for adverse cardio-renal outcomes. Patients with PA should be monitored longitudinally for disease progression or recurrence, to manage potential adverse effects of treatment, and to optimize therapy of cardiovascular and other co-morbidities.