Pathophysiology and pharmacotherapy of cardiovascular complications in metabolic syndrome.

Pharmacotherapy for metabolic dysfunction-associated steatohepatitis: heart-liver co-management.

Lipid-related indices and stroke risk among middle-aged and older Chinese adults: A nationwide cross-sectional and longitudinal study.

End-stage renal disease (ESRD) patients who undergo hemodialysis treatment experience accelerated atherosclerosis development, which results from two main causes: atherogenic dyslipidemia and chronic inflammation. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which serves as an essential innate immunity regulator, has links to cardiovascular disease development; yet researchers have not effectively studied its connection to atherogenic lipid profiles among dialysis patients. This study examined the association between NLRP3 inflammasome levels and the atherogenic index of plasma (AIP) in hemodialysis patients. This study at Mansoura University Hospital focused on adults with ESRD or chronic kidney disease (CKD) stage 5 undergoing hemodialysis. Participants over 18 years attended three sessions weekly, with exclusions for pregnant individuals, previous kidney transplant patients, those on different dialysis methods, active infection sufferers, and recent medication users. The research measured serum NLRP3 inflammasome levels, hematological parameters, and lipid profiles, calculating the AIP. Sequential multivariable linear regression sensitivity models with bootstrapping examined the association between NLRP3 levels and the atherogenic index, while ensuring accuracy by checking for multicollinearity using variance inflation factors (VIFs). Of 44 hemodialysis patients (median age 49 years, 57% female, 75% hypertensive), NLRP3 inflammasome levels showed wide variation (median 168.7 ng/L, IQR: 76.6-404.6), alongside atherogenic dyslipidemia marked by elevated indices: AIP 0.04 (-0.14 to 0.34), Castelli I 3.42 (3.01-4.61), remnant cholesterol 0.54 mmol/L (0.39-0.84), and atherogenic coefficient 2.42 (2.01-3.61), with lipids including TG 1.18 mmol/L (0.85-1.82), HDL-C 1.08 (0.92-1.21), LDL-C 2.14 (1.62-2.89). Sequential multivariable linear regression sensitivity models with bootstrapping revealed NLRP3 levels significantly associated with AIP (unadjusted B = 0.001, p < 0.001; age and gender-adjusted B = 0.001, p = 0.002; adjusted for smoking/uric acid/LDL-C/SBP B = 0.001, p = 0.016), robust via bootstrapping (2000 iterations, VIF < 1.5, no multicollinearity). Dialysis adequacy was good (Kt/V 1.48, urea reduction ratio [URR] 66.3%), with hypertensive nephropathy predominant (38.6%); complications like intradialytic hypotension (38.6%) were common. Metabolic syndrome affected 50%. Findings suggest NLRP3 inflammasome levels are associated with atherogenic dyslipidemia in maintenance hemodialysis patients. Further longitudinal studies are needed to determine causal relationships and whether NLRP3 inhibition could reduce cardiovascular risk in this population. In this exploratory single-center study, circulating NLRP3 levels were associated with AIP-defined atherogenic lipid abnormalities in maintenance hemodialysis patients. These findings support further prospective and mechanistic studies to clarify temporality, pathway specificity, and clinical relevance.

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects ~25-30% of adults worldwide and is increasingly recognized as a systemic cardiometabolic disorder rather than an isolated liver condition. While MASLD can progress to advanced fibrosis and cirrhosis, cardiovascular disease (CVD) is the leading cause of morbidity and mortality in this population, surpassing liver-related deaths. Beyond shared risk factors such as obesity, insulin resistance, and type 2 diabetes, MASLD is independently linked to atherosclerotic CVD, heart failure-particularly heart failure with preserved ejection fraction-and atrial arrhythmias through mechanisms including lipotoxicity, chronic inflammation, endothelial dysfunction, and atherogenic dyslipidemia. This review summarizes evidence connecting MASLD pathobiology with CVD and evaluates emerging pharmacologic strategies that target metabolic dysfunction with relevance to both hepatic and cardiovascular outcomes. We highlight 3 mechanistically complementary therapeutic classes: thyroid hormone receptor-β agonists, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors. Thyroid hormone receptor-β agonism (resmetirom) improves hepatic lipid handling, steatosis, and fibrosis while lowering apolipoprotein B-containing lipoproteins, though cardiovascular outcomes data remain pending. Glucagon-like peptide-1 receptor agonists reduce weight, improve insulin sensitivity, and lower major adverse cardiovascular events. Sodium-glucose cotransporter-2 inhibitors provide strong protection against heart failure and chronic kidney disease while improving metabolic and hepatic parameters. Together, these therapies reinforce MASLD as a cardiovascular-relevant metabolic disease and support integrated cardiometabolic approaches to reduce CVD risk.

Lean metabolic dysfunction-associated steatotic liver disease: Current insights and knowledge gaps.

Abstract Background Residual atherosclerotic cardiovascular disease (ASCVD) risk often remains even after low-density lipoprotein cholesterol (LDL-C) levels have been brought down to target levels. Remnant cholesterol (RC) and inflammation have been increasingly linked to the residual risk. We aimed to investigating whether the discriminative value of RC the ability of RC to discriminate and its claimed interactions with LDL-C are due to a real clinical phenotype or are affected by formula-dependent biases between the Friedewald and Sampson-NIH equations. Methods We performed a cross-sectional analysis of consecutively tested adults ( n = 3,342) using residual serum samples from routine clinical monitoring. To reduce analytical variability, all lipid profiles were analyzed using a single, dedicated reagent lot. We contrasted risk models with Friedewald-calculated versus Sampson-NIH-calculated LDL-C to assess equation-dependent differences. Lipid parameters, hemoglobin A1c (HbA1c), estimated glomerular filtration rate (eGFR), and C-reactive protein (CRP) were measured. ASCVD was defined using International Classification of Diseases, 10th Edition (ICD-10) codes. Missing covariate data were handled using multiple imputation by chained equations (m = 50), with additional complete-case sensitivity analyses for CRP-related models. To reduce bias, the observed ASCVD status was included as an auxiliary variable; the outcome itself was not imputed. The discriminative performance of nested logistic regression models was assessed through the pooled area under the receiver operating characteristic curve (AUC) and pooled DeLong p-values. Results The primary clinical focus was the presence of documented pre-existing ASCVD diagnoses, identified in 11.4% of the cohort, while 9.4% of participants met the criteria for atherogenic dyslipidemia (AD). In the primary analysis with Friedewald LDL-C, we detected a statistically significant ( p &lt; 0.001) negative interaction between LDL-C and RC, while logCRP remained an independent correlate in the adjusted model. Interestingly, when we verified this using the more accurate Sampson-NIH equation to minimize the possibility that the result would be solely due to calculation bias, the paradoxical interaction was still statistically significant ( p = 0.003) along with a strong model performance (AUC: 0.729). This indicates that the interaction is not entirely explained by the mathematical artifact of the Friedewald formula, but rather represents a consistent statistical pattern in this cohort. Conclusion RC adds statistically significant value to risk discrimination. The continuous inverse relationship of LDL-C with high RC identifies a statistical pattern consistent with persistent atherogenic burden despite apparently optimal calculated LDL-C levels. Awareness of this potential suppressor effect may aid in refining risk stratification in tertiary-care settings.

Background Increasing evidence shows that intermuscular adipose tissue (IMAT) and lean muscle mass (LMM) influence cardiometabolic health; however, their independent and/or combined associations with cardiovascular risk in individuals without pre-existing conditions remain unclear. Purpose To assess whether IMAT and LMM are associated with cardiometabolic risk factors in individuals without pre-existing conditions. Materials and Methods A total of 11 348 participants (6460 [56.9%] men; median age, 43.0 years; IQR, 33.5-52.5 years) without any known pre-existing conditions underwent whole-body 3-T MRI as part of a prospective multicenter population study (German National Cohort, or NAKO). LMM and IMAT were quantified on MRI-based paraspinal muscle segmentations with a deep learning model. Cardiometabolic risk factors (hypertension, dysglycemia, and atherogenic dyslipidemia) were defined on the basis of laboratory test results and clinical examinations. Age- and sex-corrected z scores of LMM and IMAT were calculated. Associations of LMM and IMAT percentage with physical activity and cardiometabolic risk factors were examined with univariable and multivariable analyses. Results The percentage of IMAT increased with age and was greater in women, whereas LMM decreased with age and was lower in women. After adjustments for age, sex, and study site, increased IMAT was associated with increased odds of hypertension (odds ratio [OR], 1.67; 95% CI: 1.49, 1.86; P < .001), atherogenic dyslipidemia (OR, 1.82; 95% CI: 1.65, 2.00; P < .001), and dysglycemia (OR, 0.51; 95% CI: 0.35, 0.76; P = .009) in both sexes, whereas increased LMM was associated with decreased odds of all risk factors (dysglycemia: OR, 0.51; 95% CI: 0.35, 0.76; P = .009; atherogenic dyslipidemia: OR, 0.49; 95% CI: 0.39, 0.62; P < .001; hypertension: OR, 0.34; 95% CI: 0.24, 0.48; P < .001) in male participants only. Across z score combinations, participants with higher IMAT and lower LMM showed the highest prevalence of cardiometabolic risk factors. Conclusion IMAT and LMM, assessed on MRI scans, were independently associated with cardiometabolic risk factors in individuals without pre-existing conditions. © RSNA, 2026 Supplemental material is available for this article. See also the editorial by Hu in this issue. See also the editorial by Mohajer and Bari in this issue.

Endometriosis is often treated as a localised gynaecological issue, but a growing body of evidence shows it has broader systemic effects including an increase in the risk of heart failure. The condition affects roughly 10% of women of reproductive age and is linked through large cohort studies and meta-analyses to elevated rates of ischaemic heart disease (IHD), stroke and arrhythmias (adjusted hazard ratios typically 1.1 to 1.5), with heart failure emerging as a signal in several nationwide registries. The connection appears to arise from three overlapping mechanisms; Persistent low-grade inflammation releases pro-inflammatory cytokines (notably IL-6, TNF-α, and IL-1β) into the circulation which promotes endothelial dysfunction and oxidative stress, Oestrogen dysregulation which plays a paradoxical role: locally, excessive production in endometriotic lesions sustains inflammation while systemic hormonal imbalance can undermine vascular protection and contribute to pro-thrombotic or arrhythmogenic effects. Concurrent cardiometabolic disturbances such as insulin resistance, atherogenic dyslipidaemia, central adiposity and elevated cardiometabolic index further strain the myocardium and predisposes one to diastolic dysfunction particularly in the heart failure with preserved ejection fraction phenotype that disproportionately affects women. Clinically, this means endometriosis should no longer be managed in isolation. Routine cardiovascular risk assessment such as blood pressure, lipid profile, glucose tolerance and possibly selected inflammatory markers should become standard in follow-up especially for younger patients or those with long disease duration or have had prior surgery. Closer collaboration between gynaecologists and cardiologists together with prospective studies that track true heart failure incidence and evaluate targeted interventions (anti-inflammatory strategies, optimised hormonal regimens, lifestyle modification) could substantially reduce preventable cardiac morbidity in this population.

Background: Malignant ventricular arrhythmias are serious complications of non–ST-elevation myocardial infarction. The plasma atherogenic index, derived from triglyceride and high-density lipoprotein cholesterol, reflects atherogenic dyslipidemia. Its role in predicting malignant arrhythmias is unclear. The primary aim of this study was to determine whether the plasma atherogenic index independently predicts malignant ventricular arrhythmias in patients with non–ST-elevation myocardial infarction. Methods: A total of 502 patients with non–ST-elevation myocardial infarction admitted between January 2024 and January 2025 were retrospectively analyzed. Patients were grouped by arrhythmia occurrence and tertiles of the plasma atherogenic index. Logistic regression identified predictors of arrhythmias. Cox regression identified predictors of malignant arrhythmias. Receiver operating characteristic analysis assessed discriminative performance, and Kaplan–Meier analysis evaluated survival. Results: Malignant ventricular arrhythmias occurred in 47 patients (9.4%). They had significantly higher plasma atherogenic index values (0.48 Å} 0.35 vs. 0.21 Å} 0.29, P &lt; .001). In multivariable analysis, multivessel disease, neutrophil, troponin T, low-density lipoprotein cholesterol, reduced ejection fraction, and the plasma atherogenic index independently predicted arrhythmias. For mortality, no-reflow, troponin T, malignant arrhythmia, and the plasma atherogenic index (hazard ratio 1.342, 95% confidence interval 1.211-1.487, P = .006) were independent predictors. The plasma atherogenic index had the highest discriminative value (area under the curve 0.721 for arrhythmias; 0.709 for mortality) with a cut-off of 0.32 (sensitivity 68%, specificity 68%). Kaplan–Meier analysis showed lower survival in the highest tertile. Conclusion: Elevated plasma atherogenic index independently predicts malignant arrhythmias and shortterm mortality in non–ST-elevation myocardial infarction. As a simple, widely available lipid marker, it may improve risk stratification in high-risk patients. Cite this article as: Taş A, Ateş MS, Tunca .. Plasma atherogenic index predicts malignant arrhythmias in non–ST-elevation myocardial infarction. Eurasian J Med. 2026, 58(3), 1315, doi: 10.5152/eurasianjmed.2026.251315.

Dangshen formula Shengmai-Yin suppresses atherosclerosis through restoring the gut microbiota and homeostatic efferocytosis.

Background: Cardiovascular disease remains a leading cause of morbidity and mortality after kidney transplantation. The relative contribution of metabolic abnormalities and inflammatory burden to cardiac remodeling and subsequent clinical outcomes in kidney transplant recipients (KTRs) remains incompletely understood. Methods: In this retrospective cohort study, 152 KTRs underwent comprehensive cardiovascular evaluation at a stable post-transplant time point (12 ± 4 months after transplantation). Metabolic phenotype was assessed using metabolic syndrome and indices of insulin resistance and atherogenic dyslipidemia (TyG index, TG/HDL ratio, and atherogenic index of plasma [AIP]). Inflammatory status was evaluated using hs-CRP and complete blood count-derived indices. Echocardiographic damage composite (EDC) was defined as the presence of left ventricular hypertrophy, diastolic dysfunction, or left atrial enlargement. Patients were followed for major adverse clinical outcome (MACO), defined as cardiovascular event, graft failure, or death, and major adverse cardiovascular and cerebrovascular events (MACCE). Results: At baseline, 78 patients (51.3%) met criteria for EDC. EDC was strongly associated with higher TyG, AIP, TG/HDL, LDL/HDL ratio, and metabolic syndrome, whereas inflammatory markers showed no association. In multivariable logistic regression adjusted for age, sex, eGFR, and proteinuria, TyG remained independently associated with EDC (OR 1.13 per 0.1 increase, 95% CI 1.05-1.21; p = 0.001), independent of hs-CRP. Similar results were observed when AIP was evaluated in place of TyG (OR 10.39, 95% CI 2.22-48.71; p = 0.003). During follow-up, 78 patients developed MACO and 49 developed MACCE. In Cox regression analysis, graft dysfunction and inflammatory markers independently predicted MACO, whereas TyG was no longer significant. In contrast, TyG remained an independent predictor of MACCE after adjustment for confounders and inflammatory markers (HR 1.10 per 0.1 increase, 95% CI 1.04-1.16; p < 0.001). Similar results were observed when AIP was tested in place of TyG (HR 10.8, 95% CI 3.06-38.11; p < 0.001). Echocardiographic damage did not independently predict outcomes after adjustment. Conclusions: In KTRs, metabolic abnormalities reflecting insulin resistance and atherogenic dyslipidemia are closely associated with cardiac remodeling one year after transplantation and remain specifically linked to subsequent cardiovascular events. In contrast, systemic inflammation and graft dysfunction are the primary determinants of overall adverse clinical outcomes. Simple metabolic indices such as TyG and AIP may provide practical tools for cardiovascular risk stratification in this population. In Cox proportional hazards models, TyG (HR 1.102, 95% CI 1.043-1.164, p = 0.001) and AIP (HR 10.8, 95% CI 3.06-38.11, p < 0.001) were independently associated with cardiovascular events during follow-up, underscoring the role of atherogenic dyslipidemia in cardiovascular risk.

Obesity and dyslipidemia are the most important components of cardiometabolic risk, formed against the background of complex pathophysiological interactions between visceral adipose tissue, lipid and carbohydrate metabolism, as well as endocrine regulation. In this review, we present current data on the relationship between obesity and atherogenic dyslipidemia, as well as systematic information on the clinical and metabolic efficacy of glucagon-like peptide-1 (arGPP-1) receptor agonists, in particular semaglutide, in overweight, obese and associated lipid metabolism disorders. The mechanisms of action of arGPP-1 in the correction of dyslipidemia are considered, the effect on lipid profile parameters and the potential of the drug in managing the risk of cardiovascular diseases are evaluated. Data from randomized controlled trials (including SELECT, SUSTAIN, STEP, PIONEER), meta-analyses, retrospective observational studies, and experimental studies were analyzed. It should be noted that long-term use of the drug semaglutide contributes to a decrease in body weight by 10-15% over 68 weeks of therapy. Based on the presented data, a significant positive effect of the use of semaglutide in relation to the correction of lipid profile parameters was noted. The mechanisms include suppression of lipogenesis, activation of lipolysis, and slowing gastric emptying. The drug reduces the levels of atherogenic lipid fractions — triglycerides (TG) by 12-18%, low-density lipoprotein cholesterol (LDL) by 5-7% and very low-density lipoprotein cholesterol (VLDL) by 21% — both on an empty stomach and in the postprandial period. In addition, the use of arGPP-1 is associated with a 20% reduction in the risk of serious adverse cardiovascular events in patients with obesity and cardiovascular diseases. The advantage of arGPP-1 use is not only in reducing body weight, but also in correcting dyslipidemia was shown, with prospects for its use as part of comprehensive, personalized strategies for the prevention and treatment of cardiometabolic disorders.

BackgroundThe increasing prevalence of diabetes in young adults raises concerns regarding its early cardiometabolic consequences. This study aimed to evaluate cardiac function, renal markers, lipid profile, insulin resistance, and vascular risk indicators in young adults with diabetes compared with non-diabetic controls.MethodsThis retrospective study included patients aged 18–45 years whose medical records were reviewed between 01/01/2012 and 31/12/2023. Clinical, metabolic, and cardiovascular parameters were analyzed to identify early cardiometabolic alterations associated with diabetes.ResultsYoung adults with diabetes demonstrated early signs of adverse cardiometabolic remodeling, characterized by mild reductions in ejection fraction, elevated myocardial stress biomarkers, atherogenic dyslipidemia, increased insulin resistance, and subtle renal alterations. Stent use was also more common among diabetic patients, reflecting greater cardiovascular burden. These differences remained consistent across multiple metabolic domains.ConclusionDiabetes in young adults is associated with an early and unfavorable cardiometabolic phenotype, highlighting the need for proactive cardiovascular risk assessment and targeted preventive strategies. Future longitudinal studies incorporating metabolic, inflammatory, and imaging markers are warranted to clarify progression patterns and guide precision-based interventions.

Background: Patients with type 2 diabetes mellitus (T2DM) have an increased risk of cardiovascular disease, largely driven by atherogenic dyslipidaemia. Vitamin D deficiency is highly prevalent in this population and has been implicated in adverse cardiometabolic profiles. The relationship between serum vitamin D levels and composite lipid risk markers such as the atherogenic index of plasma (AIP) remains insufficiently explored, particularly in Indian clinical settings. Objectives: To assess serum vitamin D levels and lipid profile parameters in patients with T2DM and to evaluate the association between vitamin D status and the atherogenic index of plasma. Methods: This prospective observational study was conducted in the Department of General Medicine, ACS Medical College and Hospital, Chennai, from December 2018 to March 2019. A total of 120 patients with T2DM were enrolled using consecutive sampling. Fasting blood samples were analyzed for lipid profile using enzymatic methods on a semi-autoanalyzer, and serum vitamin D levels were estimated by ELISA. The atherogenic index of plasma was calculated as log₁₀(triglycerides/HDL cholesterol). Associations were assessed using Pearson correlation analysis. Results: The mean serum vitamin D level was 20.0 ± 7.8 ng/mL. Serum vitamin D showed significant inverse correlations with triglycerides (r = −0.246, p = 0.007), VLDL cholesterol (r = −0.244, p = 0.007), and the atherogenic index (r = −0.278, p = 0.002). No significant correlations were observed between vitamin D levels and total cholesterol, HDL cholesterol, LDL cholesterol, fasting blood glucose, or post-prandial blood glucose. Conclusion: Lower serum vitamin D levels were associated with higher atherogenic index values in patients with T2DM, suggesting a link between vitamin D status and lipid-related cardiovascular risk. Evaluation of serum vitamin D alongside composite lipid indices may aid cardiovascular risk stratification in this population.

Importance and Management of Non-High-Density Lipoprotein Cholesterol in Dyslipidemia Treatment.

Chronic complication risk and benefits of fenofibrate in type 2 diabetes by a PPARα polymorphism (rs6008845, C/T): a FIELD trial substudy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease worldwide and is increasingly recognized as an important cardiovascular risk modifier. Cardiovascular disease is the leading cause of mortality among individuals with MASLD, reflecting shared pathophysiologic mechanisms with atherosclerotic cardiovascular disease. These include insulin resistance, lipotoxicity, oxidative stress, chronic inflammation, endothelial dysfunction, and progressive fibrogenesis, which contribute to both hepatic disease progression and atherosclerotic plaque development. Noninvasive biomarkers and imaging modalities provide complementary tools for integrated risk assessment. Serum measures of insulin resistance, atherogenic dyslipidemia, inflammation, and composite fibrosis scores are associated with both liver disease severity and cardiovascular risk. Vibration-controlled transient elastography enables noninvasive assessment of hepatic fibrosis and steatosis, while coronary artery calcium scoring is a robust predictor of subclinical atherosclerosis and cardiovascular events. Increasing evidence demonstrates a positive association between hepatic fibrosis severity and coronary artery calcium burden, supporting combined hepatic and cardiovascular evaluation in patients with MASLD. Therapeutic strategies targeting shared cardiometabolic pathways offer a potential dual benefit. Lifestyle modification remains foundational for improving hepatic disease activity and reducing cardiovascular risk. Statins are safe in MASLD and provide established cardiovascular protection. Glucagon-like peptide-1 receptor agonists and other emerging metabolic therapies demonstrate promise in improving liver disease activity while favorably modifying cardiometabolic risk factors. Recognition of MASLD as a systemic cardiometabolic disorder has important implications for cardiovascular risk stratification and multidisciplinary care.

Fatty liver disease is increasingly recognized as a hepatic manifestation of systemic metabolic dysfunction. This cross-sectional study, conducted among 165 adult patients with ultrasonographic evidence of fatty liver disease, evaluated metabolic risk factors and liver involvement using FibroScan for steatosis grading and liver stiffness measurement. The results revealed a high prevalence of metabolic syndrome, insulin resistance, dysglycemia and atherogenic dyslipidemia among participants, with moderate to severe hepatic steatosis being common. FibroScan grades showed a significant association between higher steatosis levels and worsening metabolic profiles, including body composition, glycemic parameters and insulin resistance. Thus, we show FibroScan as a valuable non-invasive tool for identifying patients at increased metabolic and hepatic risk, allowing for early risk stratification and management.

Cardiometabolic multimorbidity (CMM), defined as the coexistence of two or more cardiometabolic diseases, represents a growing challenge for population health and health systems worldwide. Insulin resistance and atherogenic dyslipidemia are key metabolic disturbances underlying CMM, yet their joint contribution to CMM development remains incompletely understood. A composite index integrating the triglyceride-glucose (TyG) index and the non-HDL-cholesterol-to-HDL-cholesterol ratio (NHHR), termed TyG-NHHR, was developed to examine its association with incident CMM in two population-based cohorts. Prospective data from the China Health and Retirement Longitudinal Study (2011-2018) and the English Longitudinal Study of Ageing (2008-2014) were analysed. After excluding participants with prevalent CMM or missing data, 9,297 adults aged 45 years and older were included. TyG-NHHR was calculated as TyG multiplied by NHHR. Incident CMM was defined as the new onset of at least two cardiometabolic conditions (heart disease, stroke, hypertension, or diabetes) during follow-up. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for sociodemographic characteristics, lifestyle factors, body mass index, and medication use. Baseline, cumulative, and trajectory patterns of TyG-NHHR were examined, with dose-response relationships assessed using restricted cubic splines. Joint effect and bidirectional mediation analyses were conducted to explore interrelationships between TyG and NHHR. During a median follow-up of 7 years, 1,851 participants (19.9%) developed CMM. Higher TyG-NHHR levels were consistently associated with increased CMM risk. Each standard deviation increase in baseline TyG-NHHR was associated with a 13% higher risk of CMM (HR 1.13, 95% CI 1.09-1.17). Participants in the highest quartile had a substantially elevated risk compared with those in the lowest quartile (HR 1.56, 95% CI 1.33-1.83), with stronger associations observed for cumulative exposure and persistently high trajectories. A linear dose-response relationship was identified. Joint-effect analysis indicated overlapping metabolic pathways between TyG and NHHR. Mediation analysis indicated that insulin resistance accounted for a substantial proportion of the association between atherogenic dyslipidemia and CMM, whereas the reverse pathway was limited. Findings were consistent across subgroups and sensitivity analyses. TyG-NHHR is a simple, routinely derived metabolic index associated with the risk of developing cardiometabolic multimorbidity in middle-aged and older adults across diverse populations. Integrated metabolic indicators such as TyG-NHHR may support early identification of individuals at elevated risk of CMM and inform population-level prevention strategies, particularly in resource-limited settings.