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PubMed2026

Effects of Moderate-Frequency Resistance Training on Cardiometabolic Risk Factors in Adults With Overweight or Obesity: A Systematic Review and Meta-Analysis.

BACKGROUND: Resistance training (RT) effectively manages cardiometabolic risk factors in adults, but the specific effects of moderate-frequency RT (2-3 sessions/week) in adults with overweight or obesity are understudied. OBJECTIVE: This study aimed to evaluate moderate-frequency RT's effects on cardiometabolic risk factors in this population and quantify effect sizes. DATA SOURCES: PubMed, Web of Science, EMBASE, and Cochrane Library searched up to July 2025. ELIGIBILITY: English randomized controlled trials (RCTs) comparing RT (≥ 7 weeks) to nonexercise control; nonathletic adults ≥ 18 years with BMI ≥ 25 kg/m2. PARTICIPANTS: 454 participants across 12 RCTs (mean age 58.93 ± 12.87 years; mean BMI 31.2 ± 3.5 kg/m2; ~50% female). RESULTS: RT significantly reduced diastolic blood pressure (MD = -1.53 mmHg; 95% CI: -2.16 to -0.91; p < 0.01), LDL-C (MD = -0.25 mmol/L; 95% CI: -0.41 to -0.08; p < 0.01), and triglycerides (MD = -0.17 mmol/L; 95% CI: -0.30 to -0.04; p = 0.01). No significant effects on systolic blood pressure, mean arterial pressure, waist circumference, glycemic markers, total cholesterol, or HDL-C. Subgroup analyses showed larger LDL-C/triglyceride improvements with concurrent dietary control. CONCLUSION: Moderate-frequency RT inconsistently improves cardiometabolic risk factors, benefiting diastolic blood pressure, LDL-C, and triglycerides but not glycemic or other parameters. Combining with dietary control may enhance benefits, supporting RT as a complementary strategy in multimodal lifestyle interventions. TRIAL REGISTRATION PROSPERO: CRD42022343167.

Humans↗

PubMed2025

Polygenic scores capture genetic modification of the adiposity-cardiometabolic risk factor relationship.

Polygenic scores (PGSs) that can predict response to interventions can facilitate precision medicine and are detectable in observational datasets as PGS-by-exposure (PGS×E) interactions. PGSs based on interactions (iPGSs) or variance effects (vPGSs) may be more powerful than standard PGSs for detecting PGS×E, but these have yet to be systematically compared. We describe a generalized pipeline for developing and comparing these PGS types and apply it to detect genetic modification of the relationship between adiposity (measured by BMI) and a broad set of cardiometabolic risk factors. Our applied analysis in the UK Biobank identified significant PGS×BMI for 16/20 risk factors, most consistently for the iPGS approach. Many interactions replicated in All of Us (AoU); for example, we observed a 72% larger BMI-alanine aminotransferase association in the top iPGS decile in AoU. Our study provides a framework for the comparison of PGS×E strategies and informs efforts toward clinically useful response-focused PGSs.

Humans↗

PubMed2025

Proteome organ aging and cardiometabolic risk in a population at risk for heart failure.

BACKGROUND: Biological aging varies across individuals and tissues, influencing chronic diseases, including heart failure (HF). Emerging proteome techniques enable quantification of organ-specific aging acceleration (OAA), but whether OAA relates to HF severity and differs by sex remains unclear. We aim to assess the sex-related association between OAA of heart, artery and kidneys and HF severity, and to investigate relevant cardiometabolic risk factors of organ aging. METHODS: In 556 participants from the HELPFul cohort, we estimated predicted biological age for heart, artery, and kidneys using plasma proteomics and calculated OAA as the deviation from chronological age. Associations between OAA and HF stage, echocardiographic parameters, and cardiometabolic risk factors were evaluated using regression models. Composite indices, including triglyceride-glucose body mass index (TyG-BMI), c-reactive protein-triglyceride glucose index and triglyceride-to-HDL cholesterol ratio were assessed for associations with advanced OAA. RESULTS: Mean age was 63 ± 9 years; 65% were women. Patients were classified as HF stage A (35%), B (29%) and C/D (36%). Heart OAA was significantly associated with advanced HF (Stage C/D) in both sexes (OR = 1.12, 95% CI 1.03 to 1.23 in women; OR = 1.18, 95% CI 1.05 to 1.32 in men), while artery OAA was linked to HF only in women (OR = 1.10, 95% CI 1.01 to 1.18). Multi-organ aging (≥ 2 organs with advanced OAA) conferred over three-fold higher odds of being in Stage C/D. Heart OAA correlated with impaired cardiac structure and function, particularly reduced ejection fraction in men and increased left ventricular mass index in both sexes. Diabetes emerged as the most relevant factor of artery and kidney OAA. TyG-BMI was significantly associated with advanced kidney OAA, only in women (z-scored OR = 1.88, 95% CI 1.45 to 2.45). CONCLUSIONS: Proteome-derived organ aging correlates with HF severity, with possible sex-related patterns. Diabetes and higher TyG-BMI are associated with faster organ aging, which may reflect shared aging mechanisms between metabolic dysfunction and HF.

Humans↗

PubMed2026

Optimising Exercise Prescription: A Meta-Analysis Examining the Dose Response of Exercise Duration on Cardiorespiratory Fitness Following HIIT and MICT.

BACKGROUND: High-intensity interval training (HIIT) is often promoted as a time-efficient alternative to moderate-intensity continuous training (MICT) for improving cardiorespiratory fitness, yet the duration of HIIT sessions varies considerably across studies. OBJECTIVE: We aimed to characterise the dose-response relationship between exercise session duration and the improvement in cardiorespiratory fitness for HIIT and MICT. METHODS: A dose-response meta-analysis of randomised controlled trials comparing exercise duration in HIIT and MICT, following Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and registered in PROSPERO (CRD42022335590). Effect sizes were calculated using a random-effects meta-analysis. The primary outcome was maximal oxygen uptake (VO2max). Secondary outcomes included blood pressure, lipid profiles, glucose metabolism markers and body composition measures. A one-stage random-effects dose-response meta-analysis was performed to examine the relationship between exercise duration and adaptations. We searched PubMed and Google Scholar; eligibility criteria for selecting studies were randomised controlled trials in humans, published in English and exercise interventions lasting at least 4 weeks. RESULTS: We identified 69 randomised controlled trials (2387 participants). High-intensity interval training elicited greater improvements in VO2max than MICT (d = 0.38, 95% confidence interval 0.27-0.49, p < 0.001). High-intensity interval training demonstrated a non-linear dose-response relationship between exercise session duration and VO2max, with 80% of maximal effect (changes in VO2max = 3.45 mL/kg/min) achieved with only ~11 min/session (95% confidence interval 9.5-40.2). Moderate-intensity interval training showed a linear dose-response relationship between exercise session duration and VO2max, requiring ~52 min/session to achieve 80% of the maximal observed effect (95% confidence interval 30.4-55.8). The dose-response relationship was consistent across populations. High-intensity interval training and MICT had comparable effects in improving cardiometabolic risk factors. CONCLUSIONS: High-intensity interval training demonstrated a non-linear dose response, with 80% of maximal effect on VO2max in ~11 min/session, whilst MICT required four to five times longer to reach similar responses. The different types of training had comparable effects on cardiometabolic risk factors.

Journal Article↗

PubMed2026

State of Cardiovascular Disease and Stroke in Hispanic/Latino Adults in the United States: A Scientific Statement From the American Heart Association.

Cardiovascular disease became the leading cause of death among Hispanic individuals in the United States in 2022. Hispanic adults experience a disproportionate burden of cardiometabolic risk factors, including obesity, diabetes, and dyslipidemia. Hispanic populations are highly heterogeneous, with substantial variations in genetic ancestry and sociocultural influences that shape cardiovascular disease risk and outcomes. The "Hispanic paradox," describing lower cardiovascular disease mortality despite higher risk factor burden, is increasingly recognized as an oversimplification that does not apply uniformly across Hispanic heritage groups, sexes, or disease types. Disaggregated data reveal substantial differences in risk profiles and disease burden among Hispanic heritage groups, emphasizing the limitations of treating this population as a monolithic unit. Recent evidence demonstrates widening disparities in hypertension control, obesity, diabetes, and metabolic diseases among Hispanic populations, threatening this prior mortality advantage. Advancing cardiovascular and equitable health will require developing a deeper understanding of the unique drivers of cardiovascular disease within diverse Hispanic communities, addressing barriers such as language and insurance access, and implementing culturally tailored interventions and policies. This scientific statement summarizes current cardiovascular disease epidemiology in Hispanic populations, emphasizing heritage group variation and social and structural determinants of health, and presents strategies to improve prevention and healthcare delivery. Key priorities for advancing cardiovascular health in Hispanic adults include expanding disaggregated data collection, increasing representation in research, and ensuring equitable implementation of precision medicine approaches, including genomics, multi-omics, and artificial intelligence, while addressing environmental exposures, psychosocial stressors, and policy-related drivers of risk in order to achieve the American Heart Association's 2028 Impact Goals to advancing health and hope for everyone, everywhere.

AHA Scientific Statements↗

PubMed2025

Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease strongly associated with cardiometabolic risk factors. Semaglutide, a glucagon-like peptide-1 receptor agonist, improves liver histology in MASH, but the underlying signals and pathways driving semaglutide-induced MASH resolution are not well understood. Here we show that, in two preclinical MASH models, semaglutide improved histological markers of fibrosis and inflammation and reduced hepatic expression of fibrosis-related and inflammation-related gene pathways. Aptamer-based proteomic analyses of serum samples from patients with MASH in a clinical trial identified 72 proteins significantly associated with MASH resolution and semaglutide treatment, with most related to metabolism and several implicated in fibrosis and inflammation. An independent real-world cohort verified the pathophysiological relevance of this signature, showing that the same 72 proteins are differentially expressed in patients with MASH relative to healthy individuals. Taken together, these data suggest that semaglutide may revert the circulating proteome associated with MASH to the proteomic pattern observed in healthy individuals.

Humans↗

PubMed2026

Efficacy and Safety of Anti-Obesity Medications for Weight Loss Maintenance in Adults With Overweight or Obesity: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

AIMS: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of anti-obesity medications (AOMs) for long-term weight maintenance following initial weight loss in adults with overweight or obesity. METHODS: We searched PubMed, Embase, Web of Science and the Cochrane Library from inception to 31 October 2025. Eligible studies were randomised controlled trials (RCTs) comparing AOMs with placebo during the weight-maintenance phase in adults with overweight or obesity after initial weight loss achieved through lifestyle, dietary, surgical or pharmacological interventions. Outcomes included anthropometric indices, cardiometabolic measures, safety endpoints, quality of life and neuropsychiatric adverse events. Weighted mean differences (WMDs) and odds ratios (ORs), each with 95% confidence intervals (CIs), were pooled for continuous and categorical outcomes, respectively, using fixed-effect or random-effects models as appropriate. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence was evaluated using the GRADE framework. The protocol was registered with PROSPERO (CRD420261293040). RESULTS: A total of 12 RCTs comprising 4915 participants met the inclusion criteria. Compared with placebo, AOM therapy during the weight-maintenance phase was associated with prevention of weight regain and additional improvements in anthropometric and cardiometabolic outcomes. AOMs led to further reductions in body weight (BW, WMD: -8.68 kg, 95% CI: -13.25 to -4.11), waist circumference (WC, WMD: -7.16 cm, 95% CI: -10.34 to -3.98) and body mass index (BMI, WMD: -3.58 kg/m2, 95% CI: -5.69 to -1.46). Additional benefits were observed for triglycerides, total cholesterol, low-density lipoprotein cholesterol, systolic blood pressure and diastolic blood pressure. Gastrointestinal adverse events were more common with AOMs, whereas serious adverse events were not significantly increased. Neuropsychiatric adverse events were generally comparable between groups, and available quality-of-life measures favoured AOM treatment. CONCLUSIONS: AOM therapy during the weight-maintenance phase can help prevent weight regain, provide further reductions in body weight and improve cardiometabolic risk factors in adults with overweight or obesity. Gastrointestinal adverse events were more common with AOMs, whereas serious adverse events were not significantly increased. Further long-term trials are needed to clarify optimal treatment strategies and safety.

Humans↗

PubMed2026

Plasma Multiomics Links Early-Life Adversity to Disease and Cardiometabolic Health: A Population-Based Cohort Study.

BACKGROUND: Childhood adversity (CA) is associated with increased cardiovascular and cardiometabolic risk, but the molecular mechanisms remain unclear. We aimed to identify CA-related metabolomic and proteomic signatures and evaluate their roles in linking CA to incident diseases. METHODS: This prospective cohort study included 153 225 participants aged 48 to 64 years. CA was assessed using the Childhood Trauma Screener-5, capturing cumulative (0-5 domains) and individual adversity exposures. Plasma metabolomics and proteomics data were integrated to derive CA-related molecular signatures. Cox proportional hazards model was used to evaluate associations between CA, molecular signatures, and 58 incident diseases and mortality. Mediation analyses quantified the role of multiomics signatures. RESULTS: Each additional CA domain was associated with higher risk of 49 of 58 incident diseases (hazard ratios [HRs], 1.024-1.338) and a 7.3% higher all-cause mortality risk. Focusing on cardiometabolic health, the CA-related metabolic and proteomic signatures were independently associated with incident disease. Per 1-SD increase in the cumulative CA metabolic signature, the highest observed HR was 1.313 (95% CI, 1.278-1.349) for incident diabetes, and the risk for hypertension was also increased (HR, 1.136 95% CI, 1.114-1.159). Similarly, the proteomic signature was strongly associated with incident diabetes (HR, 1.645 95% CI, 1.489-1.818) and hypertension (HR, 1.223 95% CI, 1.155-1.295). The cumulative CA metabolic and proteomic signatures mediated up to 25.5% and 46.8% of the association with hypertension, respectively. CONCLUSIONS: CA is associated with a broad spectrum of diseases and mortality, with particularly strong links to cardiometabolic health. Multiomics signatures partially mediated these associations.

Humans↗

PubMed2026

The relationships between figure rating scale, anthropometric measures, and cardiometabolic outcomes: the AADM study.

INTRODUCTION: Direct measurement of anthropometrics can be impractical in research. Validated Figure Rating Scales (FRS) offer an alternative, but their validity across populations remains limited. OBJECTIVES: This study aimed to analyze the relationships between figure rating scale (FRS) and anthropometric measures (body mass index (BMI); waist circumference (WC), and waist-to-hip ratio (WHR)) and to specifically evaluate FRS at the time of enrollment and lifetime body size, an FRS-derived score as risk factors for cardiometabolic traits including type 2 diabetes (T2D). METHODS: Participants consisted of 650 adults from the America Africa Diabetes Mellitus study. Kendall's tau coefficient (τ) was used to analyze correlations between FRS at the time of enrollment, overall obesity, and abdominal obesity. Regression models were used to evaluate FRS at the time of enrollment and lifetime body size as risk factors for T2D, and related traits. RESULTS: BMI and WHR increased monotonically with increasing body size. FRS at the time of enrollment showed a stronger correlation with BMI (τ = 0.48, p < 0.0001) than with WHR (τ = 0.17, p < 0.0001) in women. Lifetime body size was significantly associated with T2D (OR = 1.044, 95% Confidence Limit: [1.006, 1.08]; both FRS at the time of enrollment and lifetime body size were associated with insulin resistance. Diastolic blood pressure was associated with FRS at the time of enrollment. CONCLUSIONS: FRS at the time of enrollment is significantly associated with BMI and WHR in this population and lifetime body size, a novel composite score, shows promising utility as a predictor of T2D.

Humans↗

PubMed2026

Exploring the role of successful exercise-induced body weight loss on cardiometabolic health in individuals with metabolic syndrome.

BACKGROUND AND AIM: High-intensity interval training (HIIT) is known to improve cardiorespiratory fitness (i.e., VO2MAX), a key marker of cardiometabolic health in individuals with metabolic syndrome (MetS). Nonetheless, body weight loss is widely recognized as a crucial factor in reducing insulin resistance and improving metabolic risk factors. Thus, we aimed to determine the importance of body weight loss following exercise training on improving MetS. METHODS AND RESULTS: Two hundred and twenty-eight adults (55.3 ± 7.9 yr) with overweight/obesity (32.5 ± 4.6 kg·m-2) and MetS were randomized to: a) standard health care non-exercise group (CONTROL group, N=58) or b) standard health care plus 16 weeks of HIIT (EXER group, N=170). MetS (MetS z-score), insulin resistance (HOMA-IR), cardiorespiratory fitness (VO2PEAK), maximal cycling power (WPEAK), and body weight/composition were assessed. After intervention, EXER group participants were divided according to their weight loss response to training: i) those achieving the weight loss predicted from estimated exercise energy expenditure (-BW group, n=78; -3.3 ± 2.2 kg); ii) those not reaching the expected weight loss (=BW group, n=38; -0.7 ± 0.5 kg); iii) and those who gained weight (+BW group, n=54; 1.1 ± 1.0 kg). VO2PEAK significantly improved regardless of body weight loss response (-BW, 0.3 ± 0.3; =BW, 0.2 ± 0.3; +BW, 0.3 ± 0.2 L·min-1; all p < 0.001) compared to CONTROL group (0.0 ± 0.3 L·min-1). However, significant improvements in MetS z-score (-0.31 ± 0.41) and HOMA-IR (-0.7 ± 1.6) were observed only in the -BW group (both p < 0.001). CONCLUSIONS: Exercise recommendations should consider that greater improvements in MetS are observed when interventions are accompanied by successful body weight loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05120778.

Humans↗

PubMed2026

The effect of dietetic counseling combined with digital tools intervention on hemodynamic markers in Greek adults: The GATEKEEPER Study.

BACKGROUND AND AIM: Hypertension is a leading cardiovascular risk factor with substantial global impact on morbidity, mortality, and healthcare costs. While lifestyle interventions remain central to management, mHealth technologies offer promising adjunctive support, though their clinical effectiveness remains uncertain. This study evaluated whether combining dietetic counseling with digital tools improves hemodynamic markers in adults aged ≥55 years with increased cardiometabolic risk. METHODS AND RESULTS: This 3-month RCT (NCT05031299) included 954 adults with at least one metabolic syndrome risk factor, allocated 1:1:1 to Standard Care (dietetic counseling), Platform (counseling plus web-based platform), or Platform + Devices (counseling plus platform plus wearables). Outcomes included anthropometrics, lifestyle characteristics, blood pressure, pulse pressure, and estimated pulse wave velocity, analyzed using linear mixed-effects models adjusted for age and sex. All groups improved over 3 months. Waist circumference decreased by -6.29, -4.92, and -4.69 cm across Standard Care, Platform, and Platform + Devices groups respectively, and systolic blood pressure declined by -4.84 to -7.15 mmHg across groups. The Platform + Devices group showed greater increases in physical activity (94.62 MET-min/week; 95% CI 66.49 to 122.76) and greater reductions in pulse pressure (-3.90 mmHg; -6.58 to -1.22) versus Standard Care. Weight loss was associated with lower odds of hypertension (OR 0.4; 95% CI 0.2-0.7), greater likelihood of hypertension reversal (OR 3.6; 1.2-10.3), and higher probability of achieving normal pulse pressure (OR 1.8; 1.1-3.1). CONCLUSIONS: Dietary lifestyle intervention improved cardiometabolic outcomes, with limited added benefit from digital tools. Weight loss was the primary driver of hemodynamic improvement.

Aged↗

PubMed2026

Integrated multi-omics analyses identify an RAS-SLC11A2-associated molecular framework linking iron metabolism with PCOS-related cardiometabolic risk.

INTRODUCTION: PCOS is a common endocrine disorder with elevated cardiometabolic risk, yet the role of the renin-angiotensin system (RAS)-iron metabolism axis in this comorbidity remains unclear. We explored its underlying mechanisms and evaluated the therapeutic potential of gentiopicroside. METHODS: Integrated multi-omics analyses combining transcriptomics, single-cell RNA sequencing, Mendelian randomization, machine learning, molecular docking, and in vitro functional assays were performed to identify shared molecular pathways and therapeutic targets across PCOS, hypertension, NAFLD, and T2DM. RESULTS: SLC11A2 was consistently dysregulated in PCOS transcriptomic datasets, and associated with iron metabolism, inflammatory response and oxidative stress pathways. Genetic analyses validated RAS-related regulation in hypertension susceptibility and revealed shared genetic architecture between PCOS and cardiometabolic traits. Network and single-cell analyses characterized SLC11A2-associated molecular patterns in disease-relevant cell types; machine learning identified disease-classifying molecular signatures. Gentiopicroside alleviated inflammatory and oxidative stress phenotypes, including reduced IL-6 expression and reactive oxygen species accumulation. CONCLUSION: This study defines an RAS-SLC11A2 molecular framework linking iron metabolism dysregulation to PCOS-related cardiometabolic risk, elucidating the mechanisms connecting ovarian dysfunction, inflammation, oxidative stress and hypertension, and supports gentiopicroside as a promising therapeutic candidate.

Humans↗

PubMed2026

Comparing genome-wide significant and chemosensory variants as instruments for dietary patterns in Mendelian randomization.

BACKGROUND: Diet is a modifiable risk factor for cardiometabolic disease, yet establishing causality remains challenging. Mendelian randomization (MR) leverages genetic variants as instrumental variables (IVs) to enable causal inference. METHOD: Using two-sample MR, we assessed the causal effects of four principal component-derived dietary patterns (DPs)-Unhealthy, Healthy, Meat-based, Pescatarian-on cardiometabolic outcomes including body mass index, coronary artery disease, blood lipids, blood pressures, type 2 diabetes, fasting glucose and insulin, and glycated haemoglobin. Two sets of IVs were employed: conventional genome-wide significant variants associated with each DP, filtered for pleiotropy and directionality; and biologically informed variants in chemosensory receptor genes, given the role of taste and smell perception in food choice. RESULTS: Using conventional IVs, the Pescatarian DP was associated with reduced fasting insulin (βIVW = -0.10 pmol/L per SD increase in the Pescatarian DP score, 95% confidence interval -0.15, -0.04; P = 1.19 × 10-3), surviving multiple sensitivity analyses. Associations between the Unhealthy DP and elevated blood pressure and glycated haemoglobin should be interpreted cautiously; one of the two filtered IVs was strongly associated with caffeine intake, limiting the attribution of these findings to the DP itself. Chemosensory Receptor IVs yielded null findings, reflecting insufficient power. CONCLUSION: Evidence for causal effects of DPs on cardiometabolic traits was limited, with the strongest support for a protective effect of the Pescatarian DP on fasting insulin. Chemosensory IVs demonstrated limited utility for DPs, likely reflecting the heterogeneous and complex sensory profiles of overall diets. Future efforts should consider guideline-based dietary indices to facilitate interpretability and translation.

Humans↗

PubMed2026

Multi-omics uncovers the pleiotropic genetic mechanisms linking MASLD and cardiometabolic syndromes.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular-kidney-metabolic (CKM) syndrome are interrelated conditions with shared pathophysiological features; however, the genetic architecture underlying their relationship has not been fully elucidated. Deciphering this shared genetic basis holds promise for advancing mechanistic insights and therapeutic discovery. METHODS: We performed an integrated genome-wide cross-trait analysis using GWAS summary statistics for MASLD and 38 CKM traits. Our analysis estimated genetic correlations, inferred causal relationships, and identified pleiotropic variants. Candidate causal genes and druggable targets were subsequently prioritized through integrating multi-omics data. RESULTS: MASLD exhibited significant genetic correlations with 16 CKM traits, especially metabolic and cardiovascular conditions. Bidirectional causal relationships were observed between MASLD and T2D, adiposity, and lipid traits. We discovered 116 pleiotropic loci, including 65 shared causal variants such as rs429358 near APOE, which exerted influence across multiple traits. Gene-based analyses prioritized 152 unique candidate pleiotropic genes, enriched in lipid and cholesterol metabolism, and highly expressed in the liver, adipose, and immune-related cell types, such as macrophages and endothelial cells. Multi-omics integration validated 131 genes using eQTL and pQTL data from multiple tissues and cohorts. Notably, FTO and APOE emerged as central pleiotropic hubs, and druggability evaluation highlighted APOE, LPL, PPARG, and GPBAR1 as established therapeutic targets for metabolic diseases. CONCLUSION: This study provides a comprehensive map of the shared genetic architecture between MASLD and CKM syndrome, reveals novel causal genes and repurposable drug targets, and offers insights into precision medicine approaches for cardiometabolic and liver diseases.

Humans↗

PubMed2026

Polyphenol-Rich Opuntia ficus-indica Cladodes: An Integrated Metabolomic, In Vivo and In Silico Study Supporting Their Hypolipidemic and Hepatoprotective Effects.

Background: Hyperlipidemia is a major risk factor for cardiometabolic disorders, including non-alcoholic fatty liver disease (NAFLD), and is closely associated with oxidative stress. Opuntia ficus-indica (OFI) cladodes are recognized as a rich source of bioactive phytochemicals; however, the molecular mechanisms underlying their metabolic benefits remain incompletely understood. Objectives: This study aimed to comprehensively evaluate the hypolipidemic and hepatoprotective potential of a polyphenol-rich O. ficus-indica cladode extract (OCE) using an integrated approach combining in vivo evaluation, untargeted metabolomics (UHPLC-Orbitrap-MS/MS), molecular docking, and ADMET prediction. Methods: Hyperlipidemic mice fed a high-fat diet (HFD) were treated with OCE, while molecular docking was performed on ten major annotated phytochemicals against twelve key proteins involved in lipid metabolism and cholesterol homeostasis, including HMGCR, FAS, PPARα, PCSK9, and NPC1L1, using simvastatin as the reference compound. Results: OCE treatment significantly improved plasma and hepatic lipid profiles, improved glucose homeostasis, and markedly reduced hepatic malondialdehyde (MDA) levels, indicating attenuation of oxidative stress. Histopathological analysis further supported a pronounced hepatoprotective effect, with a substantial reduction in hepatic steatosis. Untargeted metabolomics enabled the annotation of 102 metabolites, putatively identifying piscidic acid as the predominant phenolic constituent together with a diverse profile of flavonoids and phenolic acids. Molecular docking supported the potential contribution of these phytochemicals to the regulation of lipid metabolism through favorable interactions with multiple therapeutic targets, while ADMET prediction suggested an overall favorable pharmacokinetic and toxicity profile despite the lower intestinal permeability predicted for glycosylated derivatives. Conclusions: Overall, these findings support O. ficus-indica cladodes as a promising source of dietary bioactive compounds with potential applications in the nutritional management and prevention of hyperlipidemia and related cardiometabolic disorders.

Animals↗

PubMed2026

A polygenic risk score for peripheral artery disease and major adverse limb events.

BACKGROUND AND AIMS: Large-scale genome-wide association studies have identified common genetic variants that predict the risk of peripheral artery disease (PAD). This study assessed whether a polygenic risk score (PRS) is associated with PAD and the incidence of major adverse limb events (MALE) independent of clinical risk factors in patients with established cardiometabolic disease. METHODS: A genetic analysis was performed, pooling individual patient-level data from six TIMI trials. The association of a recently validated PAD PRS with prevalent PAD and the incidence of MALE (acute limb ischaemia, chronic limb-threatening ischaemia, major amputation, or peripheral revascularization) was assessed. RESULTS: A total of 68 816 patients were included in this analysis, with a median follow-up of 2.6 years. Of these, 5986 (8.7%) had known PAD at baseline. After adjusting for clinical risk factors, a higher PAD PRS was independently associated with a 15% greater odds of prevalent PAD (adjusted odds ratio per 1-SD: 1.15 [95% confidence interval 1.12-1.18], P < .0001), a magnitude of risk as strong as established clinical risk factors. A total of 577 patients experienced MALE during follow-up. A higher PAD PRS was associated with a 30% increased risk of MALE (adjusted hazard ratio per 1-SD: 1.30 [1.19-1.42], P < .0001). Adding the PAD PRS to clinical risk factors resulted in a statistically significant but modest improvement in discrimination (area under the curve went from 0.651 to 0.662 P < .0001). CONCLUSIONS: In a broad spectrum of patients with cardiometabolic disease, the PAD PRS is associated with an increased risk of PAD and the incidence of MALE beyond clinical risk factors; however, the improvement in discrimination was statistically significant but clinically modest.

Humans↗

PubMed2026

Proteomics of multimorbidity progression across cardiometabolic diseases and cancer in a multinational cohort.

BACKGROUND: Multimorbidity, defined here as the co-occurrence of cardiovascular disease (CVD), type 2 diabetes (T2D), and/or cancer is a major public health challenge. However, its underlying biological mechanisms remain unclear, limiting progress toward identifying shared interventional targets. METHODS: We applied large-scale plasma proteomics (SomaScan 7k; 7,289 aptamers) in 13,270 European Prospective Investigation into Cancer and Nutrition (EPIC) participants to identify protein signatures of multimorbidity. We modelled multimorbidity progression as sequential disease transitions, i.e., from the disease-free state at baseline to a first disease and from the first disease to a second disease. Using weighted multivariable Cox regression, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for risk of cancer, CVD, and T2D. Risk associations were replicated using Olink proteomics in UK Biobank (N = 44,567). RESULTS: We identified 422 aptamers associated with more than one disease (FDR-corrected P < 0.05), e.g., 265 aptamers were shared between CVD and T2D. Thirty-eight aptamers were associated with multimorbidity progression. Among these, 27 aptamers showed consistent positive associations across sequential disease transitions, including SEMA6A (disease-free to cancer HR: 1.14; 95% CI 1.05, 1.23; cancer to T2D HR: 2.61; 95% CI 1.76, 3.80). Four aptamers showed consistent inverse associations, including NLGN1 (disease-free to T2D HR: 0.72; 95% CI 0.61, 0.84; T2D to cancer HR: 0.57; 95% CI 0.43, 0.75). Nineteen of the identified proteins were also measured in UK Biobank, with broadly consistent associations. CONCLUSIONS: This study identifies candidate proteins that may indicate molecular pathways to multimorbidity of cardiometabolic diseases and cancer. Future studies should evaluate the causal roles of these proteins for targeted interventions and risk stratification.

Humans↗

PubMed2026

A GRADE-assessed systematic review and meta-analysis of randomized controlled trials evaluating the effects of olive leaf or olive pomace supplementation on cardiometabolic and anthropometric health markers.

AIMS: Cardiometabolic diseases (CMDs) are major contributors to global morbidity and mortality, and dietary bioactives such as polyphenols may modulate key risk factors. Olive by-products, particularly olive leaves (OL) and olive pomace (OP), are rich in phenolic compounds with antioxidant, anti-inflammatory, and cardiometabolic effects demonstrated across in vitro, preclinical, and clinical studies. DATA SYNTHESIS: This GRADE-assessed systematic review and meta-analysis included 30 randomized controlled trials (n = 1726) evaluating OL or OP supplementation on 21 standardized biomarkers, encompassing inflammatory markers, lipid profile, glycemic control, insulin sensitivity, anthropometric measures, and blood pressure. Meta-analyses were conducted using random-effects models, with effect sizes calculated as mean differences (or standardized mean differences for oxLDL). Between-study heterogeneity was assessed with I2 statistics, and sensitivity and subgroup analyses explored potential sources of variability. Publication bias was evaluated using Begg's test and funnel plots where appropriate. OL supplementation significantly improved lipid parameters (total cholesterol, triglycerides, LDL-C, ApoB, oxLDL) and increased ApoA1, while reducing TNF-α, systolic and diastolic blood pressure, body weight, and BMI. No significant effects were observed on glycemic markers. OP supplementation showed no consistent cardiometabolic benefits and was associated with an increase in IL-8. Certainty of evidence ranged from very low to high, with several outcomes downgraded due to imprecision, heterogeneity, or limited study numbers. CONCLUSION: These findings support the targeted use of OL as an adjunctive strategy for cardiometabolic risk management. Evidence for OP supplementation remains limited, underscoring the need for well-powered, high-quality RCTs to clarify its clinical effects.

Humans↗