Differential Effects of Cardiometabolic Risk Factors on All-Cause Mortality in United States Adults With Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Health hazards of obesity have been recognized for centuries, appearing, for example, in writings attributed to Hippocrates. From the later decades of the 20th century through the present, there have been numerous epidemiological studies of the relationship between excess weight and the total, or all-cause, mortality rate,1 a critical cumulative measure of the public health impact of any health condition. Using body mass index (BMI), an indicator of relative weight for height (weight [kg]/height [m]2) and a frequently used surrogate for assessment of excess body fat, these studies have found linear, U-shaped, or J-shaped relationships between total mortality and BMI. That is, in some studies, both the thin and the obese were more likely to die than those in between. There is, however, always a point at which increasing BMI is associated with increasing mortality risk, but the BMI at which this occurs varies across studies and populations.2 Currently,3 overweight in adults is defined as a BMI of 25.0 to <30.0 kg/m2 and obesity as a BMI of ≥30.0 kg/m2 (Table 1). A number of studies have found no significant relationship between BMI in the overweight range and mortality rate4 and have shown the nadir of mortality risk to be in the overweight range. In particular, commentaries in both the lay press5–7 and scientific literature2,8,9 subsequent to recent reports from National Health and Nutrition Examination Surveys (NHANES)10,11 have highlighted the confusion and controversy regarding this issue. Some have interpreted the recent data to mean that overweight is not detrimental to health and is not in itself a public health concern and that drawing attention to the need for weight loss in this range will have negative effects on the health and well-being of the general population.8 Others have argued …

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease. Body mass index (BMI) is the most used obesity index but has important limitations. The weight-adjusted waist index (WWI) is a novel obesity metric and accurately reflects body composition. We explored the association of WWI with all-cause and cardiovascular disease (CVD) mortality in MASLD. Adult participants with MASLD were included from NHANES 1999-2018. WWI was calculated by dividing the waist circumference (WC) by the square root of body weight. MASLD was diagnosed by the presence of hepatic steatosis and at least one cardiometabolic risk factor in the absence of other causes of steatosis. A fatty liver index ≥60 suggested the presence of hepatic steatosis. Mortality data was obtained by prospectively linking to the National Death Index. Multivariate Cox proportional hazards regression analyses were used to explore these associations and multiple adjustment models were constructed including crude, partial, and fully adjusted models. After adjusting for all covariates including BMI, WWI remained positively and linearly associated with all-cause and CVD mortality in MASLD (hazard ratios [HR] 1.247 and 1.218, respectively). Higher WWI was associated with a significantly increased risk of mortality (both p for trend <0.05). There was an "obesity paradox" between BMI and all-cause mortality in MASLD, with significantly lower all-cause mortality in those with overweight/obesity compared to normal BMI (HR 0.625 and 0.596, respectively, p for trend = 0.024), and no association between BMI and CVD mortality. Interaction analyses indicated that these associations were influenced by several demographic variables and disease status. Time-dependent receiver operating characteristic curves indicated that the predictive value of WWI for mortality in MASLD was higher than that of BMI, WC, and waist-to-height ratio across all follow-up durations. WWI was positively and linearly associated with all-cause and CVD mortality in MASLD, whereas BMI did not accurately reflect mortality risk. WWI provided the optimal predictive value for mortality compared to traditional obesity indicators. These findings emphasize the potential use of WWI as a novel obesity indicator for mortality risk assessment, stratification, and prevention in MASLD.

Impact of cardiometabolic risk factors for metabolic dysfunction-associated steatotic liver disease on mortality.

Cohort studies about the sleep duration on the risk of death among Chinese older adults are still lacking. The aim of this study was to examine whether extremely long or short sleep duration was associated with mortality in Chinese adults aged 65 years or older. We included participants aged 65 years or older in 2011 at baseline in 23 provinces from the Chinese Longitudinal Healthy Longevity Survey who were followed up in 2014/2018 in China. Sleep duration was categorized as short sleep duration (< 7 hours) and long sleep duration (> 8 hours). We used the Cox proportional hazards model and restricted cubic spline analysis to explore the association between sleep duration and mortality. Among 9578 participants, short sleep duration was associated with an 11% higher risk of death (adjusted hazard ratio [aHR]: 1.11; 95% confidence interval [CI]: 1.02-1.20) and long sleep duration was associated with a 24% higher risk of death (aHR: 1.24; 95% CI: 1.15-1.34), after adjustment for all covariates. There was a U-shaped association between sleep duration and all-cause mortality (nonlinear, P < .0001). Stratified analyses showed that the risk was higher among older people who smoked and with a higher level of education both for short and long sleepers than for those who never smoked and were illiterate (P value for interaction < .05). There was a U-shaped association between sleep duration and all-cause mortality in Chinese older adults, especially in more educated individuals and smokers. Du M, Liu M, Liu J. The association between sleep duration and the risk of mortality in the Chinese older adults: a national cohort study. J Clin Sleep Med. 2021;17(9):1821-1829.

Background/ObjectivesThe term metabolic dysfunction-associated steatotic liver disease (MASLD) reflects the key role of cardiometabolic dysfunction in steatotic liver disease. We aim to assess the association between cardiometabolic dysfunction burden and mortality outcomes in MASLD.MethodsParticipants with MASLD were selected from the National Health and Nutrition Examination Survey (NHANES) database between 1999 and 2018. The mortality outcomes of participants with different numbers of cardiometabolic risk factors were compared by using Kaplan-Meier curves and Cox regression analysis.ResultsThis study included 9,017 participants with MASLD (4,613 men and 4,404 women, median age 49.0). With a median 115-month follow-up, 1,447 all-cause deaths and 407 cardiovascular-specific deaths were observed. Multivariate regression analysis showed that participants with five cardiometabolic risk factors had significantly increased all-cause mortality risk compared to those with one risk factor (adjusted hazard ratio [aHR] = 3.57, 95% confidence interval [CI]: 2.04–6.24, P < 0.001). Similarly, the cardiovascular mortality risk was markedly higher for participants with five risk factors (aHR = 7.72, 95% CI: 1.89–31.53, P = 0.004). Among participants with the same number of cardiometabolic risk factors, those with blood glucose or blood pressure abnormalities showed the lowest survival rates than other subgroups. Besides, participants with younger ages were more vulnerable to the harmful prognostic effects of cardiometabolic dysfunction burden on the mortality risks.ConclusionsThe MASLD population with high cardiometabolic dysfunction burdens exhibits increased mortality risk. Assessing cardiometabolic dysfunction, particularly abnormalities in blood glucose and blood pressure, is crucial for effective management in this population.

Cardiorespiratory fitness: an independent and additive marker of risk stratification and health outcomes.

Mortality risk associated with MASLD, MASLD type and different cardiometabolic risk factors in IBD patients: A long-term prospective cohort study

EXAGGERATED CARDIOMETABOLIC RISK FACTORS AND CARDIOVASCULAR DISEASE IN CANADIAN PRIMARY CARE PATIENTS WITH DIABETES AND ABDOMINAL OBESITY

Liver-related Events and Outcomes in Patients With Metabolic Dysfunction-associated Steatotic Liver Disease Varies With the Type of Cardiometabolic Risk Factor.

Accumulating evidence shows that NAFLD might play a role in the etiology and progression of CVD, but little is known on the association of NAFLD and CVD mortality in patients with a history of a myocardial infarction (MI). Therefore, we studied the relationship of Fatty Liver Index (FLI), as indicator for non-alcoholic fatty liver disease (NAFLD), with 12-year risk of cardiovascular disease (CVD) and all-cause mortality in post-MI patients. We included 4165 Dutch patients from the Alpha Omega Cohort aged 60-80 years who had an MI ≤10 years prior to study enrolment. NAFLD was defined as FLI ≥60. Patients were followed for cause-specific mortality from enrolment (2002-2006) through December 2018. Hazard ratios for CVD and all-cause mortality were obtained by multivariable Cox regression using FLI <30 (indicating absence of NAFLD) as the reference. Baseline FLI as a continuous measure was studied with mortality using restricted cubic splines analyses. The median (IQR) FLI was 68 (48-84). Sixty percent of the patients had FLI ≥60, who were more likely to be male and more often had diabetes, high blood pressure, and high serum cholesterol levels. During 12 years of follow-up, 2042 deaths occurred of which 846 from CVD. Patients with NAFLD were at increased risk of CVD mortality (HR: 1.55 [1.19, 2.03]) and all-cause mortality (HR: 1.21 [1.03; 1.41]) compared to patients without NAFLD. Results remained consistent after excluding patients with obesity and diabetes. To conclude, the adverse association of FLI with CVD mortality was stronger in female than in male patients with conventional cut-off points. FLI ≥60, indicating NAFLD, was a predictor for CVD and all-cause mortality in post-MI patients, independent of other cardiometabolic risk factors. However, cut-off points might differ between male and female patients for predicting CVD mortality.

Managed care organizations (MCOs) have access to treatment and diagnosis information from administrative claims data but generally have limited or no access to clinical information about laboratory values or biometric values such as body mass index (BMI) or waist circumference. Thus, MCOs are generally unable to identify overweight patients with cardiometabolic risk factors that put them at a high risk of poor outcomes. The National Heart, Lung, and Blood Institute defines normal body weight as a BMI (ratio of weight in kilograms to height in meters squared [kg/m2]) from 18.5 to 24.9 kg/m2, overweight as 25.0 to 29.9 kg/m2, and obesity as a BMI of 30 kg/m2 or greater. Current guidelines for weight-loss pharmacotherapy, including U.S. Food and Drug Administration-approved label indications, specify use in patients with a BMI of 30 kg/m2 or greater, or a BMI > 27 kg/m2 and at least 1 concomitant cardiometabolic risk factor such as controlled hypertension, diabetes, or dyslipidemia. To evaluate the association of cardiometabolic risk factors with BMI as recorded in a database of electronic medical records (EMRs). Each patient had a minimum look-back observation period of 2 years from the last date of activity in the EMR. Patients with a BMI of 18 kg/m2 or greater recorded in the EMR at any time during the 10-year period from January 1996 through December 2005 were stratified into groups by the number of cardiometabolic risk factors and by individual cardiometabolic risk for those with just 1 risk factor. Cardiometabolic risk factors were identified from diagnoses and prescription orders in the EMR associated with high triglyceride levels, low high-density lipoprotein cholesterol (HDL-C) levels, type 2 diabetes, or hypertension. Unadjusted and adjusted odds ratios (ORs) of having a BMI >27 kg/m2 were calculated for each risk factor group and for patients with no risk factors. Using logistic regression analysis, ORs were adjusted for age, gender, insurance type, region, medications associated with weight gain or weight loss, and diseases that modify weight. A total of 499,593 patients with a BMI of 18 kg/m2 or greater were identified; 56.4% (n = 281,988) had a BMI > 27 kg/m2, whereas 43.6% (n = 217,605) had a BMI between 18 and 27 kg/m2. Compared with patients with no risk factors (n = 289,960), patients with 1-4 risk factors (n = 209,633) were significantly more likely to have a BMI > 27 kg/m2; 48.4% of patients without cardiometabolic risk factors had a BMI > 27 kg/m2, compared with 63.3%, 79.8%, 84.6%, and 88.5% for patients with 1-4 cardiometabolic risk factors, respectively (all comparisons P < 0.001). Adjusted ORs for having a BMI > 27 kg/m2 were 2.64 (95% confidence interval [CI] = 2.51-2.77) for type 2 diabetes, 2.21 (95% CI = 2.05-2.37) for elevated triglycerides, 1.91 (95% CI = 1.88-1.94) for hypertension, and 1.45 (95% CI = 1.29-1.63) for low HDL-C. Adjusted ORs for having a BMI > 27 kg/m2 were 3.58 (95% CI = 3.47-3.69), 4.24 (95% CI = 3.93-4.59), and 5.07 (95% CI = 3.77-6.81) for patients with any 2, 3, and 4 risk factors respectively, relative to patients with no cardiometabolic risk factors. For patients with cardiometabolic risk factors, compared with patients with no risk factors, the odds of having a BMI > 27 kg/m2 were multiplied by 1.45-5.07, depending on the type and number of risk factors. Diagnoses and treatment indicators for cardiometabolic risk factors are potential indicators of obesity.

Background & AimsIt is unclear to what extent lifestyle and genetic factors affect incidence of chronic liver disease (CLD) in a general population and if lifestyle affects CLD independently of underlying cardiometabolic perturbations and genetic predisposition. MethodsWe examined 27,991 men and women aged 44-73 years from the Malmö Diet and Cancer Study recruited between 1991-1996 and followed until end of 2020 using registry-linkage (median follow-up time 25.1 years; 382 incident first-time CLD events). Associations between cardiometabolic factors, polygenic risk scores (PRSs), and lifestyle factors in relation to CLD were examined using multivariable Cox proportional hazards regression models. ResultsIncidence of CLD increased with number of cardiometabolic risk factors (the hazard ratio (HR) per each additional cardiometabolic risk factor was 1.33 (95% CI: 1.21-1.45; p= 5.1 x 10-10). Two novel polygenic risk scores (PRS) for metabolic dysfunction-associated steatotic liver disease (MASLD) and a PRS for liver cirrhosis associated with higher risk of CLD but provided marginal predictive utility on top of other risk factors and compared to the PNPLA3 rs738409 genetic variant. An unhealthy lifestyle (high alcohol intake, current smoking, physical inactivity and unhealthy diet) markedly increased risk of CLD (HR=3.97, 95% CI: 2.59-6.10). Observed associations between examined lifestyle factors and CLD were largely independent of cardiometabolic perturbations and polygenic risk. ConclusionsWe confirmed the importance of cardiometabolic dysfunction in relation to risk of CLD in a general population. Lifestyle risk factors were shown to independently associate with CLD and added predictive information on top of cardiometabolic risk factors. Information on the polygenic risk of liver disease does not currently add to prediction of CLD in a general population. Lay summaryIn this large longitudinal study of a general population, we found that cardiometabolic, genetic and lifestyle risk factors all contribute to the development of chronic liver disease (CLD). Our results suggest that an unhealthy lifestyle, including alcohol consumption, smoking, physical inactivity, and an unhealthy diet, substantially increase risk of CLD independently of underlying genetic risk or cardiometabolic health. This suggest that a large proportion of CLD cases are potentially preventable through adoption of healthy lifestyle changes. Impact and implicationsThis large population-based prospective study suggests largely independent roles of cardiometabolic, lifestyle, and genetic risk factors in the development of chronic liver disease. Findings strengthen the evidence base for a beneficial effect of modification of high-risk lifestyle behaviors in the primary prevention of chronic liver disease in the general population.

Relation Between Self-Reported Physical Activity Level, Fitness, and Cardiometabolic Risk

BackgroundNeutrophil-to-lymphocyte ratio (NLR) is considered a biomarker of systemic inflammation and immune activation. However, its relationship with the risk of mortality in patients with chronic obstructive pulmonary disease (COPD) remains unclear. This study aimed to investigate the association between NLR and the risk of all-cause and cardiovascular mortality in patients with COPD.MethodsData were collected from the National Health and Nutrition Examination Survey (NHANES) from January 1999 to December 2018. The calculation method of NLR involves dividing the neutrophil count by the lymphocyte count in the total blood cell count. The optimal NLR threshold associated with survival outcomes was determined using the maximally selected rank statistics method (MSRSM). The relationship between NLR and the risk of all-cause mortality and cardiovascular mortality in COPD was investigated using a weighted multivariable Cox regression model. Additionally, restricted cubic spline (RCS) was employed to discuss the potential relationship between NLR patients in different groups and the risk of mortality.ResultsIn this study, 716 adults with COPD were included using the maximally selected rank statistics method, among whom 208 had higher NLR (≥2.56) and 508 had lower NLR (<2.56). During a median follow-up of 111.5 months, 162 COPD patients died from all causes, and 49 patients died from cardiovascular diseases. After adjusting for demographic, socioeconomic status, and lifestyle factors, the risk of all-cause mortality (HR = 2.07, 95%CI: 1.46–2.94) and cardiovascular mortality (HR = 3.03, 95%CI: 1.63–5.65) in patients with higher NLR was increased by 2–3 times compared to those with lower NLR. Kaplan–Meier analysis revealed significantly lower survival rates in patients with higher NLR for all-cause mortality and cardiovascular mortality (p < 0.05). Restricted cubic spline analysis showed a linear correlation between NLR and the risk of all-cause mortality and cardiovascular mortality.ConclusionNLR has a high value in independently predicting long-term all-cause and cardiovascular mortality risks in community-dwelling COPD patients. Therefore, NLR can serve as a cost-effective and widely available indicator for assessing the prognosis of COPD patients.

BackgroundMetabolic dysfunction-associated steatotic liver disease (MASLD), primarily driven by insulin resistance (IR), is emerging as a significant public health concern. While the estimated glucose disposal rate (eGDR), a novel marker of IR, could be useful in predicting adverse outcomes in diabetes, its role in MASLD remains unclear.MethodsWe used data from the National Health and Nutrition Examination Survey (NHANES) collected from 1999 to 2018, and combined cross-sectional and cohort study designs to explore the associations between eGDR, cardiovascular disease (CVD) outcomes in US adults with MASLD. Here, MASLD was defined using the fatty liver index or hepatic steatosis index along with cardiometabolic risk factors. We applied survey-weighted logistic regression to evaluate CVD prevalence and used Cox proportional hazards models to assess mortality risk. We analysed nonlinear associations between eGDR, CVD, and mortality outcomes using restricted cubic splines. Lastly, we compared the predictive performance of eGDR with traditional IR markers, including the triglyceride-glucose (TyG) index and HOMA-IR, via C-statistics.ResultsLogistic regression and Cox proportional hazards models showed that lower eGDR levels were consistently associated with increased risks of CVD prevalence (P < 0.001) and mortality (P < 0.001), even after adjusting for potential confoundersin both MASLD models. eGDR also outperformed TyG and HOMA-IR in predicting all-cause and CVD mortality (P < 0.001), underscoring its superior prognostic value in MASLD populations (P < 0.001). Moreover, incorporating eGDR into the baseline model significantly enhanced predictive accuracy and reclassification (P < 0.001), further validating its potential to improve risk prediction.ConclusionsLower eGDR levels are associated with higher risks of CVD and mortality in MASLD. The eGDR outperforms traditional IR markers in predicting all-cause mortality and improves risk prediction models, highlighting its potential usefulness for clinical risk stratification in MASLD.