Cardiovasc Diabetol [JOURNAL]
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200 papers
Exerkine dysregulation links visceral adiposity to skeletal muscle impairment in end-stage heart failure with reduced ejection fraction: proteomic evidence for a cardio-adipose-muscle axis.
Załęska-Kocięcka M, Mazuruk M, Szcześniak K … +17 more , Łaba P, Kacperska M, Nogajski Ł, Nowakowski M, Mączewski M, Czerwińska H, Rosa M, Olbryś P, Mączyńska A, Kuriata J, Kołsut P, Wojdyńska Z, Michałowska I, Paterek A, Błyszczuk P, Leszek P, Mączewski M
Cardiovasc Diabetol · 2026 May · PMID 42192415 · Full text
BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is associated with profound alterations in body composition, skeletal muscle dysfunction, and impaired exercise capacity. Exerkines representing exercise-r...
BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is associated with profound alterations in body composition, skeletal muscle dysfunction, and impaired exercise capacity. Exerkines representing exercise-responsive signaling molecules released by skeletal muscle, adipose tissue, and other organs may mediate systemic metabolic communication between tissues. However, their role in advanced HFrEF and their relationship with adiposity and skeletal muscle characteristics remain poorly understood. METHODS: We studied 73 patients with end-stage HFrEF and 16 healthy controls. Body composition was assessed using computed tomography, including visceral (VAT), subcutaneous (SAT), and epicardial adipose tissue (EAT), as well as skeletal muscle quantity (psoas muscle index, PMI) and quality (psoas muscle density, PMD). Functional performance was evaluated using handgrip strength (HGT) and the 6-min walk test (6MWT). Circulating exerkines were quantified using the Olink technology. Associations between proteins and clinical variables were assessed using age- and creatinine-adjusted linear models with false discovery rate correction. RESULTS: Among patients with HFrEF, 36% were obese and 38% exhibited central obesity independent of BMI. Muscle strength and muscle quality were strongly associated with functional capacity. VAT correlated with muscle mass but not with muscle quality or performance. Compared with controls, HFrEF patients demonstrated elevated inflammatory and metabolic stress-related exerkines including CXCL8, CCL2, IL-6, TNF, IL-15, GDF15, FGF21, ANGPTL4, CTSB, DCN, and resistin. In contrast, proteins associated with muscle integrity and regenerative signaling (myostatin, BDNF, IL-7, SPARC) were significantly reduced. In HFrEF patients leptin strongly correlated with adiposity measures. Metabolic stress mediators (GDF15, IL-15, FGF21, CTSB) were inversely associated with muscle quality and functional performance, whereas myostatin positively correlated with muscle quality, strength, and exercise capacity. BDNF was inversely associated with frailty. CONCLUSIONS: Advanced HFrEF is characterized by a dysregulated exerkine network linking adiposity, skeletal muscle quality, and functional performance. Four biologically coherent axes were identified: a leptin-driven adiposity axis, a metabolic stress-muscle quality axis, a myostatin-related muscle function axis, and a neurotrophic frailty axis. These findings support the presence of a systemic cardio-adipose-muscle signaling network in end-stage HFrEF and identify candidate molecular mediators of sarcopenia and functional decline.
Associations of the combined C-reactive protein-triglyceride glucose index and frailty index in different dimensions with incident stroke among individuals with stages 0-3 cardiovascular-kidney-metabolic syndrome.
Zheng H, Zhang Y, Li L … +5 more , Zhu M, Kong W, Wang J, Liu R, Wang F
Cardiovasc Diabetol · 2026 May · PMID 42192366 · Full text
BACKGROUND: Previous studies have revealed the relationships of separated C-reactive protein-triglyceride glucose (CTI) levels and the frailty index (FI) with stroke. However, the impact of combined CTI and FI (CTI-FI) o...
BACKGROUND: Previous studies have revealed the relationships of separated C-reactive protein-triglyceride glucose (CTI) levels and the frailty index (FI) with stroke. However, the impact of combined CTI and FI (CTI-FI) on stroke incidence is unclear, especially among those with cardiovascular kidney metabolic (CKM) syndrome stages 0-3. OBJECTIVE: This research aimed to validate the associations between different CTI-FI dimensions (baseline CTI-FI, cumulative CTI-FI (cuCTI-FI), and dynamic trajectories of CTI-FI (traCTI-FI)) and stroke risk among individuals with CKM syndrome stages 0-3. METHODS: The enrolled participants and the utilized data were derived from five waves of the China Health and Retirement Longitudinal Study. K-means clustering was used to categorize participants into an appropriate number of clusters. Cox regression analysis, restricted cubic spline (RCS) curves, and Kaplan-Meier (K-M) survival curves were used to evaluate the relationships between different CTI-FI dimensions and stroke risk. Receiver operating characteristic (ROC) curves and the DeLong test were constructed to assess the performance of various dimensions of CTI-FI in predicting stroke. RESULTS: In this study, the mean age of the 5293 participants was 57.94 years, and 53.45% were female. During the nearly 9-year follow-up period, 540 (10.20%) stroke events occurred. A 61% and 41% increase in stroke risk was associated with each 1-unit increase in the baseline CTI-FI and cuCTI-FI, respectively. The RCS modeling further revealed significant positive nonlinear associations between baseline CTI-FI (P < 0.001, P = 0.049) and cuCTI (P < 0.001, P = 0.047) and stroke incidence. Compared with the lowest different dimensions CTI-FI level groups, the highest level groups had a greater stroke risk. The fully adjusted HRs (95% CIs) were as follows: baseline CTI-FI (Q4 vs. Q1), 2.36 (1.76, 3.15); cuCTI-FI (Q3 vs. Q1), 4.75 (2.73, 8.27); and traCTI-FI (Cluster 3 vs. Cluster 1), 6.24 (3.72, 10.46). In terms of predicting stroke risk, baseline CTI-FI, cuCTI-FI, and traCTI-FI performed better than CTI and FI, and cuCTI-FI and traCTI-FI performed significantly better than baseline CTI-FI (P < 0.001 and = 0.022, respectively). CONCLUSION: Persistently high CTI-FI is associated with increased stroke risk. CTI-FI, especially cuCTI-FI and traCTI-FI, are potent predictors of stroke. Long-term surveillance of CTI-FI alterations and maintenance of its low levels is clinically important for early stroke detection and prevention in patients with stages 0-3 CKM syndrome.
Effects of semaglutide on mortality, cardiovascular, and kidney outcomes across the cardio-kidney-metabolic continuum: a systematic review and meta-analysis.
Marzano F, Paolillo S, Gargiulo P … +8 more , Cotticelli C, Di Santo M, Nardi E, Abbellito GM, Liccardi L, Perrone Filardi F, Bruzzese D, Perrone Filardi P
Cardiovasc Diabetol · 2026 May · PMID 42186086 · Full text
BACKGROUND: Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated cardiometabolic benefits in randomized controlled trials (RCTs). However, its overall effects on mortality, cardiovascular (CV...
BACKGROUND: Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated cardiometabolic benefits in randomized controlled trials (RCTs). However, its overall effects on mortality, cardiovascular (CV) and kidney outcomes have not been comprehensively synthesized. This meta-analysis aimed to assess the prognostic impact of semaglutide across the cardio-kidney-metabolic continuum. METHODS: A systematic literature search was conducted to identify all eligible RCTs comparing the prognostic effects of semaglutide with placebo across diverse patient populations. Primary outcomes were all-cause and CV mortality. Secondary outcomes included major CV and kidney events, while major adverse limb events (MALE) were analyzed as an exploratory endpoint. A random-effects model was used to pool hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Eight trials encompassing 39,204 patients were included. In patients treated with semaglutide a significant reduction of all-cause (HR, 0.84; 95% CI, 0.77-0.92; p = 0.0001) and CV mortality (HR, 0.83; 95% CI, 0.72-0.95; p = 0.0078), major adverse CV events (MACE, HR, 0.82; 95% CI, 0.77-0.87; p < 0.0001), nonfatal myocardial infarction (MI, HR, 0.75; 95% CI, 0.68-0.84; p < 0.0001), worsening heart failure (HF, HR, 0.84; 95% CI, 0.73-0.98; p = 0.0245), and kidney outcomes (HR, 0.83; 95% CI, 0.73-0.95; p = 0.0080) was observed compared to placebo. No significant effects were observed for nonfatal stroke. CONCLUSIONS: Treatment with semaglutide, compared to placebo, is associated with significant lower incidence of all-cause and CV mortality, as well major CV and kidney events across the continuum of cardio-kidney-metabolic syndrome.
Shared pathophysiological mechanisms between diabetes and calcific aortic valve disease: an immunometabolic perspective.
Yue Z, SiTu Q, Bian JH … +1 more , Lu HX
Cardiovasc Diabetol · 2026 May · PMID 42185844 · Full text
This review synthesizes the immunometabolic mechanisms linking diabetes mellitus to accelerated calcific aortic valve disease (CAVD) and evaluates their therapeutic implications. Despite the absence of disease-modifying...
This review synthesizes the immunometabolic mechanisms linking diabetes mellitus to accelerated calcific aortic valve disease (CAVD) and evaluates their therapeutic implications. Despite the absence of disease-modifying pharmacotherapy for CAVD, diabetes consistently increases incident aortic stenosis risk (HR 1.3-1.7), calcification burden, and disease severity, independent of traditional cardiovascular risk factors. Epidemiological, imaging, and histological evidence demonstrate that dysglycemia promotes earlier onset, denser valvular calcium deposits, and worse post-intervention outcomes. We delineate seven interconnected and partially overlapping pathways through which diabetes remodels the aortic valve: hyperglycemia-driven valvular interstitial cell (VIC) phenotypic switching and insulin resistance; advanced glycation end-product-RAGE signaling; oxidative stress and mitochondrial dysfunction; macrophage NLRP3-IL-1β inflammasome activation; endothelial barrier compromise; BMP-Runx2-Wnt-Notch osteogenic reprogramming; and CKD-mineralocorticoid receptor cross-talk. These processes convert metabolic stress into sustained valvular inflammation, matrix remodeling, and ectopic ossification. Mechanistic and observational data provide a rationale for evaluating metformin, SGLT2 inhibitors, IL-1β/NLRP3 inhibitors, and Lp(a)-lowering strategies as candidate approaches to modulate calcification progression. Integrated metabolic-inflammatory-imaging biomarkers offer potential for risk stratification and trial enrichment. This immunometabolic framework identifies actionable nodes and underscores the urgent need for dedicated, valve-focused randomized trials in diabetic CAVD to translate mechanistic insights into clinical benefit.
Predicting cardiovascular death in overweight/obese people with prediabetes using machine learning-a proof-of-concept study.
Andersen AK, Færch K, Vistisen D … +4 more , von Scholten BJ, Jørgensen NB, Cichosz SL, Jensen MH
Cardiovasc Diabetol · 2026 May · PMID 42144637 · Full text
BACKGROUND: Individuals with prediabetes face an increased risk of cardiovascular (CV) complications, which can ultimately lead to premature mortality. However, existing risk stratification tools are not targeted for peo...
BACKGROUND: Individuals with prediabetes face an increased risk of cardiovascular (CV) complications, which can ultimately lead to premature mortality. However, existing risk stratification tools are not targeted for people with prediabetes. We aimed to develop a simple explainable model to predict if a person will develop a fatal CV outcome or not among people with prediabetes. METHODS: Participants ≥ 45 years with prediabetes (HbA1c 39-47 mmol/mol (5.7-6.4%)) and established CV disease and overweight/obesity were included. A binary logistic regression model was trained to predict CV death using stratified threefold cross-validation. The model's risk estimates were calibrated, and the predictive capability was evaluated using receiver operating characteristic (ROC) area under the curve (AUC), precision and recall. RESULTS: In total 5636 participants with 182 (3.2%) CV deaths (mean time-to-event of 2.0 years) and a mean trial duration of 3.3 years were included. Seven easily collected demographic and clinical variables were selected for the model. Discrimination (ROC AUC) was acceptable at 0.730 (95% CI 0.659-0.801). Applying our prediabetes cohort on existing benchmark models developed for major adverse cardiovascular events (MACE) in a general and type 2 diabetes population without prior CVD, demonstrated lower performance for CV death (ROC AUC: 0.630 (SCORE2) and 0.643 (SCORE2-Diabetes)) compared to our model. Lower performance was also observed for predicting MACE in our cohort (ROC AUC: 0.596 and 0.603) using the established models compared to the original populations (ROC AUC: 0.739 and 0.66-0.73). No comparative models for people with prediabetes and prior CVD exists. Thus, even with the limitations in different populations and outcome targets, this indicates that prediabetes-specific prediction models could potentially improve early prevention in this high-risk population. CONCLUSION: We have developed a prediabetes-specific proof-of-concept model that predicts whether a person is at high risk of cardiovascular death. External validation of the model is crucial before adoption to a real-world setting to clarify whether the model generalizes beyond the studied population.
Cardiovascular, limb, and kidney effects of SGLT2 inhibitors in patients with peripheral artery disease: a systematic review and meta-analysis of randomized controlled trial data.
Hu C, Ernst M, Snelling R … +7 more , Ye Q, Paneni F, Zelniker TA, Szabo GT, Pokreisz P, Kiss A, Podesser BK
Cardiovasc Diabetol · 2026 May · PMID 42144626 · Full text
BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) provide substantial cardiovascular benefits across a broad spectrum of patients at high atherosclerotic risk. However, evidence for their cardiovascular effi...
BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) provide substantial cardiovascular benefits across a broad spectrum of patients at high atherosclerotic risk. However, evidence for their cardiovascular efficacy in patients with peripheral artery disease (PAD) remains limited. Accordingly, we conducted this systematic review and meta-analysis to synthesize available evidence and clarify the cardiovascular, limb, and kidney outcomes of SGLT2i in patients with PAD. METHODS: PubMed, Embase, and the Cochrane Library were searched from inception to 20 December 2025 for studies evaluating SGLT2i therapy in patients with PAD. The primary outcome was the composite of hospitalization for heart failure (HHF) or cardiovascular death. Secondary outcomes included HHF, cardiovascular death, amputation, composite renal outcomes, all-cause mortality, and major adverse cardiovascular events (MACE). RESULTS: Five studies comprising 7,275 patients with PAD were included. Among patients with PAD, SGLT2i therapy was associated with a lower risk of the composite of HHF or cardiovascular death (HR 0.73; 95% CI 0.64 to 0.83; p < 0.001), HHF (HR 0.63; 95% CI 0.51 to 0.77; p < 0.001), cardiovascular death (HR 0.83; 95% CI 0.69 to 1.00; p = 0.045) and adverse renal outcomes (HR 0.74; 95% CI 0.55 to 0.98; p = 0.038). SGLT2i was not associated with an increased risk of amputation (HR 1.17; 95% CI 0.87 to 1.56; p = 0.293). No significant reductions were observed for all-cause mortality (HR 0.86; 95% CI 0.69 to 1.08; p = 0.192) or MACE (HR 0.89; 95% CI 0.75to 1.06; p = 0.207). There was no evidence of effect modification based on PAD status (all P >0.10). However, in exploratory subgroup analyses among patients with PAD, SGLT2i treatment for ≥ 2 years was associated with a numerically greater reduction in cardiovascular death (HR 0.73; 95% CI 0.60-0.90), whereas no clear effect was observed in trials with a duration of < 2 years (P = 0.06). CONCLUSIONS: SGLT2i-therapy is associated with a reduced risk of composite of cardiovascular and kidney outcomes in patients with PAD, without increasing the risk of amputation. These findings support a potential role of sustained long-term SGLT2i-therapy in this high-risk group.
Comparative prognostic value of TyG index and TyG-BMI for 90-day all-cause mortality in critically ill older adults with ASCVD: a machine learning analysis of the MIMIC-IV database.
Zhao S, Wang Q, Li X … +4 more , Ma S, Jiao C, Wang G, Cao H
Cardiovasc Diabetol · 2026 May · PMID 42144611 · Full text
BACKGROUND: The triglyceride-glucose (TyG) index and triglyceride-glucose-body mass index (TyG-BMI) are emerging surrogate markers of insulin resistance and metabolic risk. However, their comparative prognostic value in...
BACKGROUND: The triglyceride-glucose (TyG) index and triglyceride-glucose-body mass index (TyG-BMI) are emerging surrogate markers of insulin resistance and metabolic risk. However, their comparative prognostic value in critically ill older adults with atherosclerotic cardiovascular disease (ASCVD) remains unclear. We aimed to compare the prognostic performance of the TyG index and TyG-BMI for 90-day all-cause mortality in this high-risk population. METHODS: We conducted a retrospective cohort study of critically ill patients aged ≥ 65 years with ASCVD from the MIMIC-IV database. The TyG index and TyG-BMI were measured at intensive care unit admission, and 90-day all-cause mortality was the primary outcome. Kaplan-Meier analysis, multivariable Cox proportional hazards models, and restricted cubic splines (RCS) were used to assess associations with mortality. Five machine learning algorithms, including Extreme Gradient Boosting (XGBoost), Support Vector Machine (SVM), K-Nearest Neighbors (KNN), Decision Tree (DT), and Gaussian Naive Bayes (GNB), were adopted to construct mortality risk prediction models, with discrimination assessed by the area under the receiver operating characteristic curve (AUC) and area under the precision-recall curve (AUPRC). Additionally, the SHapley Additive exPlanations (SHAP) approach was used to identify the key predictors of mortality. RESULTS: A total of 2,368 critically ill older adults with ASCVD were included, and 18.5% died during follow-up. In multivariable Cox analysis, the TyG index was independently associated with higher 90-day mortality risk (HR 1.114, 95% CI 1.014-1.225; P = 0.025), whereas TyG-BMI was not significantly associated with mortality (P = 0.883). Kaplan-Meier analysis showed progressively worse survival across increasing TyG index quartiles. In machine learning models, the TyG index consistently outperformed TyG-BMI. XGBoost showed the best discrimination (AUPRC = 0.455; specificity = 0.912). Adding the TyG index improved AUC from 0.763 to 0.794 (P = 0.005), whereas adding TyG-BMI did not significantly improve AUC (0.783; P = 0.101). SHAP analysis identified the TyG index as the most important metabolic predictor. CONCLUSION: In elderly critically ill patients with ASCVD, the TyG index showed better prognostic performance than TyG-BMI and was an independent predictor of 90-day mortality. These findings suggest that the TyG index may be a useful and cost-effective biomarker for risk stratification in this high-risk population.
Joint association of atherogenic index of plasma (AIP) and body roundness index (BRI) with cardiometabolic multimorbidity in adults in Guangzhou, China.
Li H, Zeng C, Li Z … +8 more , Qin Y, Peng Y, Feng J, Huang J, Luo S, Yuan J, Gu J, Li Y
Cardiovasc Diabetol · 2026 May · PMID 42144608 · Full text
BACKGROUND: Cardiometabolic multimorbidity (CMM) is one of the most prevalent patterns of multimorbidity worldwide and presents a growing challenge to public health. Metabolic dysregulation and visceral adipose play cent...
BACKGROUND: Cardiometabolic multimorbidity (CMM) is one of the most prevalent patterns of multimorbidity worldwide and presents a growing challenge to public health. Metabolic dysregulation and visceral adipose play central roles in the development of CMM. The atherogenic index of plasma (AIP) has been proposed as a comprehensive indicator of lipid metabolic abnormalities, whereas the body roundness index (BRI) is a novel anthropometric measure reflecting central obesity and visceral adipose tissue (VAT). However, evidence regarding the associations of AIP and BRI with CMM remains limited, particularly in southern Chinese populations and young adults. This study examined the separate and joint associations of AIP and BRI with CMM, aiming to provide preliminary scientific evidence to identify individuals more likely to have prevalent CMM. METHODS: This cross-sectional study included 2505 adults from the 2024 Guangzhou Residents' Nutrition Survey. Multivariable logistic regression models and segmented logistic regression analyses were employed to examine the association patterns of AIP and BRI with CMM, as well as to assess potential threshold effects. For joint analysis, participants were categorized into four groups by AIP and BRI levels to evaluate the joint association and interaction between these indices and CMM. RESULTS: Among the 2505 participants, 213 (8.50%) were diagnosed with CMM. Compared with the lowest tertile, the highest tertile of AIP (OR = 4.025, 95% CI 2.591-6.455) and BRI (OR = 10.461, 95% CI 5.523-22.496) were associated with a higher likelihood of CMM. AIP was linearly associated with CMM. In contrast, BRI demonstrated a nonlinear association with CMM, with an inflection point at 4.52, below which the odds of CMM increased more rapidly. Joint analyses revealed that participants in the "high AIP+high BRI" group had the strongest association with CMM (OR = 5.081, 95% CI 3.354-7.828). Subgroup analysis revealed that the association between the "high AIP+high BRI" group and CMM was stronger in participants < 60 years. CONCLUSION: Individuals with elevated levels of AIP and BRI are more likely to have CMM. AIP is linearly associated with CMM, whereas a threshold effect is observed for BRI. The joint assessment of AIP and BRI demonstrates a stronger association with CMM compared to either indicator alone. These findings suggest that the joint assessment of AIP and BRI may be a useful tool for identifying individuals at a higher likelihood of prevalent CMM, particularly in young and middle-aged adults.
Predictive value of the combined cholesterol, high-density lipoprotein, glucose and frailty indices for cardiometabolic multimorbidity incidence: evidence from a national prospective cohort study.
Fan H, Jiang G, Cheng J … +1 more , Chen H
Cardiovasc Diabetol · 2026 May · PMID 42144600 · Full text
BACKGROUND: The cholesterol, high-density lipoprotein, and glucose (CHG) is a surrogate of insulin resistance, while frailty reflects cumulative physiological decline, yet their combined utility for cardiometabolic multi...
BACKGROUND: The cholesterol, high-density lipoprotein, and glucose (CHG) is a surrogate of insulin resistance, while frailty reflects cumulative physiological decline, yet their combined utility for cardiometabolic multimorbidity (CMM) is underexplored. We evaluated a combined CHG-frailty index (CHG-FI) for incident heart disease, stroke, diabetes, and CMM. METHODS: We conducted a retrospective cohort study of 6812 Chinese adults aged ≥ 45 years enrolled in the 2011-2020 waves of the China Health and Retirement Longitudinal Study (CHARLS). Participants with baseline lipid and fasting glucose measurements were included and followed prospectively for incident heart disease, stroke, diabetes, and cardiometabolic multimorbidity (≥ 2 conditions). FI was calculated using the cumulative deficit approach, and CHG was incorporated according to established procedures. Multivariable Cox regression estimated associations; CHG-FI interaction was assessed on multiplicative and additive scales. Incremental predictive utility of CHG, FI, TYG‑FI, and CHG‑FI was compared using receiver operating characteristic (ROC) curves, net reclassification improvement (NRI), and decision curve analysis (DCA). Stratified and sensitivity analyses evaluated robustness. RESULTS: Over a median follow‑up of 9.0 years, we observed 1,304 heart disease events, 554 strokes, 932 diabetes cases, and 467 CMM cases. Each 1-unit increase in CHG-FI was associated with higher risk: heart disease (HR 1.34, 95% CI 1.23-1.45), stroke (HR 1.85, 95% CI 1.65-2.06), diabetes (HR 1.29, 95% CI 1.17-1.42), and CMM (HR 1.79, 95% CI 1.58-2.04). Associations showed dose-response patterns and nonlinearity. The multiplicative interaction between CHG and FI for CMM was 0.54 (95% CI 0.35-0.83), reflecting a "risk saturation" or ceiling effect. Despite this, the combined CHG -FI index offered superior predictive performance for CMM relative to individual components: AUC 0.652 (95% CI 0.627-0.678), with significant improvement in reclassification (NRI 0.329, 95% CI 0.236-0.423) and discrimination (IDI 0.011, 95% CI 0.008-0.015). CHG -FI and TyG -FI showed broadly comparable performance across outcomes. CONCLUSION: The combined CHG-frailty index was significantly associated with incident cardiometabolic multimorbidity and its individual components, demonstrating predictive performance comparable to established combined indices. As an accessible tool integrating routine metabolic and physiologic reserve measures, CHG-FI offers a practical alternative approach for risk stratification.
Longitudinal associations of cumulative and repeated-measure patterns of insulin resistance surrogate indices with biological age acceleration and incident cardiovascular disease across cardiovascular-kidney-metabolic syndrome stages 0-3: evidence from CHARLS 2011-2020.
Han SS, Liu Q, Zhou MQ … +5 more , Liu Y, Guo TT, Hu YK, Gao TA, Zeng ZM
Cardiovasc Diabetol · 2026 May · PMID 42143308 · Full text
BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome stages 0-3 represent a critical window for preventing progression to overt cardiovascular disease (CVD). Insulin resistance (IR) is central to CKM pathophysiolog...
BACKGROUND: Cardiovascular-kidney-metabolic (CKM) syndrome stages 0-3 represent a critical window for preventing progression to overt cardiovascular disease (CVD). Insulin resistance (IR) is central to CKM pathophysiology, yet the comparative utility of longitudinal IR patterns (cumulative burden and longitudinal pattern groups) across multiple surrogates, and the mediating role of biological ageing, remain unexamined in this preclinical population. METHODS: We included 3948 participants with CKM stages 0-3 from the CHARLS 2011-2020. Twelve IR surrogates (TyG and derivatives, METS-IR, CTI, eGDR, TG/HDL-C) were assessed via cumulative exposure and K-means-derived pattern groups. Associations with incident CVD were evaluated using Fine-Gray competing risk models, spline regression, receiver operating characteristic analyses, and quantile-based models. Mediation analyses quantified the contribution of biological age acceleration. RESULTS: 756 (19.1%) of 3948 participants with CKM stages 0-3 developed incident CVD. Higher cumulative levels and the least favorable pattern groups of TyG-based indices, METS-IR, CTI, and TG/HDL-C were consistently associated with increased CVD risk, whereas elevated cumulative eGDR was protective. Cumulative eGDR demonstrated superior predictive performance for CVD risk (AUC: 0.613; all DeLong P < 0.05 vs. other indices) and was consistently identified as the top contributor by both WQS and Qgcomp analyses. Both KDM- and Light-BioAgeAccel partially mediated several IR-CVD associations (up to 45.8% and 25.9%, respectively). CONCLUSIONS: Sustained IR burden and unfavorable longitudinal IR patterns are linked to higher CVD risk in CKM stages 0-3, partly through accelerated biological aging. Integrating longitudinal IR profiling with aging metrics may sharpen early risk stratification and support scalable prevention targeting upstream metabolic drivers.
Drug targets for lipid modification and risk of type 2 diabetes: a cis-Mendelian randomization study.
Chen Z, Triatin RD, Luo L … +7 more , Snieder H, Schmidt AF, Ditmarsch M, Kastelein JJP, Dullaart RPF, Kuivenhoven JA, Thio CHL
Cardiovasc Diabetol · 2026 May · PMID 42135799 · Full text
BACKGROUND AND AIMS: Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) is the cornerstone in the prevention of coronary artery disease (CAD) but may also increase risk of type 2 diabetes (T2D). A comp...
BACKGROUND AND AIMS: Reducing plasma levels of low-density lipoprotein cholesterol (LDL-C) is the cornerstone in the prevention of coronary artery disease (CAD) but may also increase risk of type 2 diabetes (T2D). A comprehensive examination of the genetic evidence of T2D related side-effects of all current lipid-modifying drugs, including those in development, has not yet been performed. METHODS: This cis-Mendelian randomization study used individual level data from the UK Biobank, Lifelines, and publicly available genome-wide association data. We identified loci that are either targeted directly with drugs, or alternatively, targeting their gene products (mRNA and/or protein). Included are, in alphabetical order, the loci ACLY, ANGPTL3, ANGPTL4, APOB, APOC3, CETP, HMGCR, LDLR, LIPG, LPA, MTTP, NPC1L1, and PCSK9. We used cis-genetic instruments weighted for LDL-C, HDL-C, triglycerides, and apolipoproteins as downstream proxies for the drug targets. Main outcomes were prevalent and incident T2D, with CAD as a contrast outcome. RESULTS: Lipid modification through HMGCR is predicted to reduce CAD risk and increase T2D risk. Modification through targeting APOC3, LDLR, LPA, MTTP, NPC1L1, and PCSK9 is predicted to reduce CAD risk without a change in T2D risk. Modification through ANGPTL4 and CETP is predicted to reduce risk of both CAD and T2D. For ACLY, ANGPTL3, APOB, and LIPG, we found evidence for neither CAD nor T2D. CONCLUSIONS: This study provides genetic evidence for variation in diabetes-related side-effects of different lipid-modifying drugs, with potential relevance for future clinical trials and individual treatment decisions.
Beyond glycemic control: rethinking the diabetic heart : Comment on: "Dapagliflozin-induced integrated improvements in left ventricular diastole, endothelial function, and arterial load: a randomized clinical trial".
Rossi VA
Cardiovasc Diabetol · 2026 May · PMID 42129830 · Full text
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Correction: The mineralocorticoid receptor antagonist finerenone enhances cardiovascular recovery upon food intake normalization in obese mice.
Monmirel-Fauconnier M, Pieronne-Deperrois M, Bonnard B … +13 more , Frimat C, Linghui K, Dheasmhunaigh AN, Nicol L, Morchid S, Renet S, Dumesnil A, Richard V, Fève B, Jaisser F, Boulkroun S, Mulder P, Ouvrard-Pascaud A
Cardiovasc Diabetol · 2026 May · PMID 42129780 · Full text
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Association of cumulative exposure and dynamic trajectories of the C-reactive protein-triglyceride-glucose and its modified indices with cardiovascular disease in individuals with cardiovascular-kidney-metabolic syndrome stages 0-3: a longitudinal analysis based on CHARLS.
Yin X, Yang J, Li R … +3 more , Zhang M, Cao H, Yang B
Cardiovasc Diabetol · 2026 May · PMID 42116161 · Full text
BACKGROUND: To evaluate the incremental predictive value of modifying the C-reactive protein-triglyceride-glucose (CTI) index with obesity parameters for incident cardiovascular disease (CVD) across Cardiovascular-Kidney...
BACKGROUND: To evaluate the incremental predictive value of modifying the C-reactive protein-triglyceride-glucose (CTI) index with obesity parameters for incident cardiovascular disease (CVD) across Cardiovascular-Kidney-Metabolic (CKM) syndrome stages. METHODS: Based on the longitudinal CHARLS cohort, Cox proportional hazards was utilized. Predictive increments were assessed using time-dependent Nearest Neighbor Estimation (NNE) AUC with Bootstrap resampling, cNRI, and IDI. Pathophysiological mechanisms were explored via Weighted Quantile Sum (WQS) regression and causal mediation analyses. RESULTS: After adjusting for demographic and clinical confounders, CTI and its modified indices all maintained robust, independent associations with incident CVD. Specifically, except for CTI-BMI, the new index, which incorporates the obesity index, transforms the dose-response relationship from a complex, nonlinear pattern to a threshold linear association. While increments in overall discrimination (AUC) were marginal, both baseline and cumulative CTI-CVAI significantly improved risk reclassification(cNRI: 0.093-0.126, IDI: 0.024-0.026, P < 0.001). The CKM stratification reveals stage-dependent predictive effects, with amplified relative risks in CKM 0-2 stages and stronger incremental value for risk reclassification in the CKM 3 stage. WQS confirmed visceral adiposity as the dominant risk driver, and physical frailty was identified as a significant pathophysiological mediator of the observed associations. CONCLUSIONS: Incorporating obesity indicators, particularly CVAI, into the CTI framework significantly improves the reclassification of CVD risk in early to moderate CKM stages. However, the lack of significant discriminative (AUC) improvement necessitates a careful clinical trade-off between adopting complex composite metrics and maintaining screening feasibility. TRIAL REGISTRATION: Not applicable.
Evaluation of the lipid accumulation product for MASLD risk stratification in type 2 diabetes: establishing sex-specific thresholds and clinical utility.
Qu X, Li G, Tao H … +7 more , Ye X, Huang J, Chen Q, Xu J, Jiang M, Jia W, Xie Q
Cardiovasc Diabetol · 2026 May · PMID 42116040 · Full text
BACKGROUND: While visceral adiposity and lipid dysregulation are established drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), the clinical utility of the lipid accumulation product (LAP) for i...
BACKGROUND: While visceral adiposity and lipid dysregulation are established drivers of metabolic dysfunction-associated steatotic liver disease (MASLD), the clinical utility of the lipid accumulation product (LAP) for identifying prevalent MASLD in patients with type 2 diabetes mellitus (T2DM) remains insufficiently characterized. This study aimed to characterize the dose-response relationship between LAP and MASLD in T2DM, establish optimal sex-specific diagnostic thresholds, and evaluate its clinical net benefit to guide non-invasive screening. METHODS: This study included 495 inpatients with T2DM. logLAP was prioritized using the Boruta algorithm. Diagnostic cut-offs were determined via ROC analysis. The mathematical reliability of these thresholds was evaluated using 1,000-run stratified bootstrapping (internal validation), while the biological generalizability of LAP was further examined in an independent NHANES cohort (external validation). The dose-response relationship was characterized by restricted cubic splines (RCS). Clinical utility and stability were assessed using decision curve analysis (DCA) and subgroup analyses. RESULTS: Through a systematic feature-selection approach using the Boruta algorithm, logLAP was objectively identified as the most robust indicator for MASLD.logLAP was independently associated with MASLD (OR 1.83, 95% CI 1.43-2.35). Optimal sex-specific cut-offs were 20.4 for men and 27.0 for women, yielding a positive predictive value of 85.93%. RCS analysis revealed a significant linear association, with MASLD probability increasing monotonically with logLAP. DCA demonstrated a consistently higher net benefit for the LAP-based model over the "screen-all" strategy at threshold probabilities > 0.20. Subgroup analyses confirmed robustness across age and BMI strata, with the highest discriminative power in patients aged < 55 years (AUC 0.855) and reliable performance in non-obese individuals (AUC 0.711). External analysis in the NHANES cohort (N = 630) demonstrated consistent independent associations between LAP and MASLD risk (P < 0.05). CONCLUSIONS: logLAP is a robust linear predictor of MASLD in T2DM. Implementing tailored thresholds provides superior diagnostic precision and clinical net benefit, particularly for younger and non-obese populations, supporting its use as a prioritized non-invasive screening tool.
Multi-omics uncovers the pleiotropic genetic mechanisms linking MASLD and cardiometabolic syndromes.
Yin K, Zhang C, Liu B … +4 more , Xu R, Zeng J, Eslam M, Ni J
Cardiovasc Diabetol · 2026 May · PMID 42106791 · Full text
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular-kidney-metabolic (CKM) syndrome are interrelated conditions with shared pathophysiological features; however, the genetic ar...
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.
Integrative proteogenomic and observational analysis identifies potential biomarkers for latent autoimmune diabetes in adults.
Yang Y, Lu J, Wang Z … +6 more , Lu T, Ding J, Wang R, Zhou S, Zhou Z, Hu J
Cardiovasc Diabetol · 2026 May · PMID 42106685 · Full text
BACKGROUND: Latent autoimmune diabetes in adults (LADA) shares core genetic and immunological features with type 1 diabetes (T1D) but is frequently misdiagnosed as type 2 diabetes (T2D). With few biomarkers for its timel...
BACKGROUND: Latent autoimmune diabetes in adults (LADA) shares core genetic and immunological features with type 1 diabetes (T1D) but is frequently misdiagnosed as type 2 diabetes (T2D). With few biomarkers for its timely diagnosis and management, this study integrated proteome-wide Mendelian randomisation (MR) and observational clinical analysis to identify potential LADA biomarkers. METHODS: We performed proteome-wide MR using cis-protein quantitative trait loci (cis-pQTLs) for 1,389 plasma proteins from the deCODE study (n = 35,559) and genome-wide association study (GWAS) data for LADA (2,634 cases and 5,947 controls, European ancestry). Robustness was enhanced via multiple sensitivity analyses. Pathway enrichment analysis, druggability evaluation, phenome-wide MR, and interaction analyses were performed to investigate the clinical relevance and biological context of candidate proteins. Candidate proteins were further evaluated using enzyme-linked immunosorbent assays in a matched Chinese clinical study (n = 241) to assess their discriminative ability for LADA. RESULTS: Proteome-wide MR and colocalisation analyses indicated associations between genetically predicted plasma levels of C-X-C motif chemokine ligand 10 (CXCL10; OR [95% CI] per 1-SD increase in protein levels: 5.49 [1.74,17.32]), serum amyloid A1 (SAA1; 1.28 [1.14,1.45]), and SAA2 (1.22 [1.11,1.34]) with LADA risk. Replication, multi-tissue eQTL, and multivariable MR supported CXCL10's association. Druggability evaluation suggested CXCL10 as a drug target under investigation, and phenome-wide MR of 1,006 diseases and traits indicated no major safety concerns for CXCL10 as a potential biomarker. In the observational clinical study, CXCL10 differentiated LADA from healthy controls (area under the receiver operating characteristic curve [ROC-AUC]: 0.889; precision-recall area under the curve [PR-AUC]: 0.919) and T2D (ROC-AUC: 0.838; PR-AUC: 0.921), with both models showing adequate calibration. CONCLUSIONS: This study suggests that CXCL10 is a putative biomarker associated with LADA, demonstrating discriminative ability to distinguish LADA from T2D in an observational clinical cohort. These findings contribute to understanding the autoimmune molecular aetiology of LADA and support its diagnostic potential in resolving the clinical ambiguity between LADA and T2D.
Correction: BDH1 overexpression alleviates diabetic cardiomyopathy through inhibiting H3K9bhb-mediated transcriptional activation of LCN2.
Xu BT, Wan SR, Wu Q … +7 more , Xing YH, He YQ, Huang W, Long Y, Zhang C, Xu Y, Jiang ZZ
Cardiovasc Diabetol · 2026 May · PMID 42104359 · Full text
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CVOT Summit Report 2025: advances along the cardiovascular-kidney-metabolic disease continuum.
Schnell O, Agarwal A, Azizi M … +49 more , Ballwieser D, Barnard-Kelly K, Battelino T, Ballwieser D, Blüher M, Bugianesi E, Cebrian A, Ceriello A, Choudhary P, Danne T, Dayan CM, Del Prato S, Eckel RH, Fioretto P, Garvey T, Green JB, Heerspink HJL, Holman RR, Itzhak B, Jacob S, Jhund PS, Ji L, Judge PK, Khunti K, Korenjak M, Krentz AJ, Lambrinou E, Libby P, Mader JK, Mann JFE, Marx N, Mathieu C, McMurray JJV, Müller-Wieland D, Papanas N, Patel DC, Pfeiffer AFH, Reger-Tan S, Rodbard HW, Rosano GMC, Saboo B, Sato N, Solomon SD, Standl E, Tacke F, Topsever P, Wanner C, Wharton S, Young V
Cardiovasc Diabetol · 2026 May · PMID 42092956 · Full text
The 11th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 20-21, 2025. The Summit provided a multidisciplinary forum to review and disc...
The 11th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 20-21, 2025. The Summit provided a multidisciplinary forum to review and discuss recent outcome trials investigating emerging pharmacological therapies targeting diseases of the cardiovascular-kidney-metabolic (CKM) continuum. This report highlights the unique developments of 2025 discussed during the Summit, including the first head-to-head CVOT (SURPASS-CVOT), the growing evidence base for combination therapies across the disease spectrum, new insights into the inflammatory component of the CKM syndrome, and relevant policy developments. The first part of this report summarizes pioneering clinical trials addressing combination therapy with finerenone and empagliflozin (CONFIDENCE), the oral glucagon-like peptide-1 (GLP-1) receptor agonists orforglipron (ATTAIN-1), and the aldosterone synthase inhibitor (ASI) baxdrostat (BaxHTN). The second part presents recent guideline and policy developments discussed by experts in endocrinology, diabetology, cardiology, nephrology, hepatology, and general practice. In addition, advances in medical technology, particularly in continuous glucose and ketone monitoring, are highlighted, as well as emerging therapies for diseases of the CKM continuum. These include pharmacological agents for a broad spectrum of metabolic disorders such as metabolic liver disease and type 1 Diabetes (T1D) alongside emphasis on the importance of early detection and innovative treatment strategies. The 12th Cardiovascular Outcome Trial Summit will be held virtually on 19-20 November 2026 ( http://www.cvot.org ).
Associations of nine insulin resistance-related indices with the incidence and progression of cardiovascular-liver-metabolic multimorbidity: a large prospective cohort study.
Sun C, Li H, Zhou K … +4 more , He Q, Shen Y, Ma S, Li B
Cardiovasc Diabetol · 2026 May · PMID 42092898 · Full text
BACKGROUND: Cardiovascular-liver-metabolic (CLM) diseases are interrelated, yet prior studies have mostly examined single-disease outcomes. We aimed to investigate the associations of insulin resistance (IR)-related indi...
BACKGROUND: Cardiovascular-liver-metabolic (CLM) diseases are interrelated, yet prior studies have mostly examined single-disease outcomes. We aimed to investigate the associations of insulin resistance (IR)-related indices with the incidence and progression of CLM multimorbidity (CLMM), while secondarily evaluating comparative predictive performance and exploring potential biological domains. METHODS: This prospective study included 371,207 UK Biobank participants from England, Scotland, and Wales who were recruited between 2006 and 2010 and were free of CLM diseases at baseline. CLMM was defined as the coexistence of ≥ 2 CLM conditions. Outcomes were ascertained through linkage to national inpatient hospital records and death registries. Nine IR-related indices were computed, including the triglyceride-glucose (TyG) index and its derivatives (e.g., TyG-WC and TyG-WHtR). Associations with CLMM incidence and progression were assessed using Cox proportional hazards and multistate models. Secondary predictive analyses assessed incremental value and discrimination, and exploratory mediation analyses examined whether inflammatory, hepatic, and renal biomarkers were statistically related to the associations between IR-related indices and CLMM risk. RESULTS: During a median follow-up of 16.4 years, 8651 participants developed CLMM. All nine IR-related indices were positively associated with both CLMM incidence and progression (all P < 0.001), with TyG-WHtR and TyG-WC demonstrating comparatively stronger associations. For incident CLMM, each SD increase in TyG-WHtR and TyG-WC was associated with hazard ratios (HRs) of 2.08 (95% CI 2.04-2.12) and 2.14 (95% CI 2.10-2.19), respectively. In multistate analyses, each SD increase in TyG-WHtR and TyG-WC was associated with 59% (HR 1.59, 95% CI 1.58-1.60) and 62% (HR 1.62, 95% CI 1.61-1.63) higher risks of transitioning from a healthy state to a first CLM disease, 44% (HR 1.44, 95% CI 1.41-1.46) and 44% (HR 1.44, 95% CI 1.41-1.47) higher risks of progressing to CLMM, and 24% (HR 1.24, 95% CI 1.15-1.34) and 22% (HR 1.22, 95% CI 1.13-1.31) higher risks of progression to triple CLM diseases, respectively. Secondary predictive analyses indicated that all indices significantly improved incremental value and discrimination, with TyG-WHtR and TyG-WC exhibiting comparatively better performance (all P < 0.001). Biomarkers reflecting systemic inflammation and liver- and kidney-related function might statistically contribute to the observed associations, although these findings are exploratory and primarily hypothesis-generating. CONCLUSION: Nine IR-related indices were positively associated with the incidence and progression of CLMM, with TyG-WHtR and TyG-WC showing comparatively stronger associations and better predictive performance. These findings support their relevance for comparative CLMM risk assessment, while further validation is warranted. Exploratory biomarker analyses provided hypothesis-generating clues regarding biological domains potentially relevant to the associations.
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