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Background To assess the impact of glycated hemoglobin A1c (HbA1c) in individuals without diabetes and at the extremes of cardiovascular risk factor (CVRF) burden on the incidence of atherosclerotic cardiovascular disease (ASCVD) and all-cause mortality. Methods We studied 20,360 U.S. adults, initially free of diabetes and ASCVD from the CARDIA, MESA, ARIC, and FOS cohorts, all with available HbA1c data. The mean (standard deviation) age was 57.1 (9.1) years [56.2% women and 21.9% Black]. Using multivariable Cox proportional hazard regression, ASCVD and all-cause mortality were analyzed over a median 16.7-year follow-up across categories of CVRF burden (0, 1, 2, or 3 of dyslipidemia, smoking, and hypertension) and HbA1c levels (< 5.0%, 5.0–5.4% [reference], 5.5–5.9%, and 6.0–6.4%). Results During follow-up, 3592 ASCVD events (17.6%) and 6627 deaths (32.6%) occurred. The hazard ratios (HRs) and 95% confidence intervals (CIs) for HbA1c levels of 5.5–5.9% and 6.0–6.4% for ASCVD were 1.17 (1.09–1.26) and 1.59 (1.42–1.78), respectively. The corresponding HRs for mortality were 1.14 (1.07–1.20) and 1.35 (1.24–1.47). HbA1c < 5.0% was also associated with an elevated mortality risk (HR, 95% CI 1.17, 1.07–1.28). Among individuals with 0 CVRFs, the HRs for ASCVD risks ranged from 1.26 (1.02–1.55) for HbA1c 5.5–5.9% to 1.68 (1.12–2.54) for HbA1c 6.0–6.4%. For those with 3 CVRFs, the corresponding HRs were 1.22 (0.88–1.69) and 2.00 (1.35–2.97). Similar findings were observed for all-cause mortality. Subgroup analysis revealed that HbA1c ≥ 5.5% was associated with an increased mortality risk in non-Black individuals but did not reach statistical significance in Black individuals ( P interaction < 0.001). Conclusions HbA1c testing in individuals without diabetes may help identify those at higher risk for ASCVD and mortality, even at the extremes of CVRF burden. Graphical abstract

Objective To investigate the associations between the triglyceride-glucose (TyG) index and its obesity-related derivatives with the risk of incident cardio-renal-metabolic multimorbidity (CRMM) in a Middle Eastern adult population initially free of cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD). Methods In this prospective cohort analysis of 5845 Iranian adults from the Tehran Lipid and Glucose Study, we evaluated the associations of the TyG index and its combinations with body mass index (BMI), waist circumference (WC), waist-height ratio (WHtR), and waist-hip ratio (WHR) with the incidence of CRMM. Multivariable Cox proportional hazards models were used to estimate the associations between TyG indices and CRMM risk. The Wald test was used to formally compare the effect sizes of each TyG-related index with that of the TyG index in multivariable models. The predictive performance of these indices was evaluated using Harrell’s C-index and the integrated discrimination improvement (IDI). Results Over a median follow-up of 15.3 years (IQR: 11.9–16.4), 344 individuals (5.9%) developed CRMM. Restricted cubic spline models demonstrated significant linear associations between TyG indices and CRMM risk. The corresponding HRs (95% CI) per 1-SD increase were 1.41 (1.24–1.60) for the TyG index, 1.52 (1.36–1.71) for TyG-BMI, 1.57 (1.38–1.78) for TyG-WC, 1.57 (1.38–1.78) for TyG-WHtR, and 1.42 (1.24–1.63) for TyG-WHR (all P  < 0.001). The inclusion of anthropometric measures alongside the TyG index did not substantially enhance its association with CRMM risk (all P for differences ≥ 0.05). Incremental predictive performance analyses showed modest but statistically significant improvements when adding TyG and TyG-obesity indices to conventional risk factors (all P  < 0.05), whereas incorporating anthropometric-based indices to a model already containing TyG did not yield additional predictive improvement (all P  > 0.05). The majority of associations remained robust after adjustment for homeostatic model assessment of insulin resistance and in sensitivity analyses. The association between TyG-WHR and CRMM was more pronounced among non-obese than obese individuals ( P for interaction < 0.001). Conclusions Higher levels of TyG and TyG-obesity indices were independently associated with an increased risk of CRMM; however, incorporating obesity indices did not confer substantial improvement over the TyG index alone.

Aims To assess the risk of difference between 2 h post‐load plasma glucose (2 h‐PG) and fasting plasma glucose (FPG) on incident prediabetes/type 2 diabetes (T2DM) among normoglycemic individuals. Methods Among 4,971 individuals aged ≥20 years, the associations of the difference between 2 h‐PG and FPG with outcomes were examined using multivariable‐adjusted Cox regression analysis. Participants were categorized into three groups: a low post‐load group (2 h‐PG ≤ FPG, as the reference group); a high post‐load group (2 h‐PG > FPG and ≥75th percentile of the difference); and a medium post‐load group (2 h‐PG > FPG and <75th percentile of the difference), which was further categorized into three groups by equal ranges. Results Over a median of 11.5 years of follow‐up, 2,331 new cases of prediabetes/type 2 diabetes and 360 cases of type 2 diabetes occurred. Greater risks of incident prediabetes/type 2 diabetes in second (9–16 mg/dL) and third (17–24 mg/dL) medium post‐load, as well as high post‐load (≥25 mg/dL) categories, were found, with hazard ratios (95% confidence intervals) of 1.26 (1.11–1.44), 1.32 (1.15–1.51), and 1.69 (1.51–1.90), respectively; the issue was more prominent among women (P for interaction = 0.005). The risk of incident type 2 diabetes was also higher for these categories. After further adjustment for the homeostasis model assessment of insulin resistance, result remained essentially unchanged. Even among individuals with low normal FPG (i.e., <90 mg/dL), ≥9 mg/dL difference between 2 h‐PG and FPG increased the risk of composite prediabetes/ type 2 diabetes. Conclusions Greater levels of 2 h‐PG as low as 9 mg/dL than FPG among normoglycemic individuals is a harbinger of prediabetes/type 2 diabetes development. A small increase in 2 h‐PG levels compared with FPG among normoglycemic individuals is associated with a higher risk of developing prediabetes/type 2 diabetes. These findings remained consistent even after adjusting for insulin resistance. Furthermore, the study observed a stronger association between the 2 h‐PG to FPG difference and incident prediabetes/type 2 diabetes among women. The novel finding of this paper is that greater levels of 2 h‐PG as low as 9 mg/dL than FPG among normoglycemic individuals, especially those with a FPG <90 mg/dL, is a harbinger of prediabetes/type 2 diabetes development.

Background To evaluate the impact of different definitions of metabolic syndrome (MetS) and their components on the risk of sudden cardiac death (SCD) among the Iranian population according to the World Health Organization (WHO), International Diabetes Federation (IDF), Adult Treatment Panel III (ATP III), and Joint Interim Statement (JIS) criteria. Methods The study population included a total of 5,079 participants (2,785 women) aged ≥ 40 years, free of cardiovascular disease (CVD) at baseline. Participants were followed for incident SCD annually up to 20 March 2018 . Multivariable Cox proportional hazards regression models were applied to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of MetS and its components for incident SCD. Results The prevalence of MetS ranged from 27.16% to 50.81%, depending on the criteria used. Over a median of 17.9 years of follow-up, 182 SCD events occurred. The WHO, IDF, and JIS definitions were strong predictors of SCD with multivariable-adjusted HRs (95% CI) of 1.68 (1.20–2.35), 1.51 (1.12–2.03), and 1.47 (1.08–1.98), respectively; these associations significantly attenuated after further adjustment for MetS components. MetS by the ATP III definition was not associated with the risk of SCD after controlling for antihypertensive, glucose-lowering, and lipid-lowering medication use. Among the components of MetS, high blood pressure (WHO definition), high waist circumference (using the national cutoff of ≥ 95 cm), and high glucose component by the JIS/IDF definitions remained independent predictors of SCD with HRs of 1.79 (1.29–2.48), 1.46 (1.07–2.00), and 1.52 (1.12–2.05), respectively. Conclusions The constellation of MetS, except for when defined with ATP III definition, is a marker for identifying individuals at higher risk for SCD; however, not independent of its components. Among MetS components, abdominal obesity using the population-specific cutoff point, high glucose component (JIS/IDF definitions), and high blood pressure (WHO definition) were independent predictors of SCD.

Background We aimed to assess the relationship between Metabolic Score for Insulin Resistance (METS-IR) and the incidence of coronary heart disease (CHD), stroke, mortality, diabetes, hypertension, and chronic kidney disease (CKD) in a population from the Middle East and North Africa (MENA) region. Method Individuals aged ≥ 20 years were enrolled. Cox proportional hazards regression models were applied to assess the association between METS-IR and incident CHD, stroke, all-cause mortality, diabetes, hypertension, and CKD. Results Over a median follow-up period of 9–18 years, 1080 (10.6%), 267 (2.6%), 1022 (9.6%), 1382 (16.4%), 2994 (58.5%), and 2002 (23.0%) CHD, stroke, all-cause mortality, diabetes, hypertension, and CKD events occurred, respectively. Compared to the lowest quartile (reference), the hazard ratios (HR) associated with the highest quartile of METS-IR were 1.527 (95% confidence interval [CI]: 1.208–1.930, P for trend 0.001), 1.393 (0.865–2.243, > 0.05), 0.841 (0.682–1.038, > 0.05), 3.277 (2.645–4.060, < 0.001), 1.969 (1.752–2.214, < 0.001), and 1.020 (0.874–1.191, > 0.05) for CHD, stroke, all-cause mortality, diabetes, hypertension, and CKD, respectively. METS-IR, as a continuous variable, was significantly associated with the risk of incident CHD [HR, 95% CI: 1.106, 1.034–1.184], diabetes [1.524, 1.438–1.616], and hypertension [1.321, 1.265–1.380]. These associations were also independent of metabolic syndrome (METS) and remained unchanged in a subgroup of individuals without METS and/or diabetes. Conclusions Increasing levels of METS-IR were significantly associated with a greater risk of incident CHD, diabetes, and hypertension; therefore, this index can be a useful tool for capturing the risk of these clinical outcomes.

Background Glycemic variability (GV) is developing as a marker of glycemic control, which can be utilized as a promising predictor of complications. To determine whether long-term GV is associated with incident eGFR decline in two cohorts of Tehran Lipid and Glucose Study (TLGS) and Multi-Ethnic Study of Atherosclerosis (MESA) during a median follow-up of 12.2 years. Methods Study participants included 4422 Iranian adults (including 528 patients with T2D) aged ≥ 20 years from TLGS and 4290 American adults (including 521 patients with T2D) aged ≥ 45 years from MESA. The Multivariate Cox proportional hazard models were used to assess the risk of incident eGFR decline for each of the fasting plasma glucose (FPG) variability measures including standard deviation (SD), coefficient of variation (CV), average real variability (ARV), and variability independent of the mean (VIM) both as continuous and categorical variables. The time of start for eGFR decline and FPG variability assessment was the same, but the event cases were excluded during the exposure period. Results In TLGS participants without T2D, for each unit change in FPG variability measures, the hazards (HRs) and 95% confidence intervals (CI) for eGFR decline ≥ 40% of SD, CV, and VIM were 1.07(1.01–1.13), 1.06(1.01–1.11), and 1.07(1.01–1.13), respectively. Moreover, the third tertile of FPG-SD and FPG-VIM parameters was significantly associated with a 60 and 69% higher risk for eGFR decline ≥ 40%, respectively. In MESA participants with T2D, each unit change in FPG variability measures was significantly associated with a higher risk for eGFR decline ≥ 40%.Regarding eGFR decline ≥ 30% as the outcome, in the TLGS, regardless of diabetes status, no association was shown between FPG variability measures and risk of eGFR decline in any of the models; however, in the MESA the results were in line with those of GFR decline ≥ 40%.Using pooled data from the two cohorts we found that generally FPG variability were associated with higher risk of eGFR decline ≥ 40% only among non-T2D individuals. Conclusions Higher FPG variability was associated with an increased risk of eGFR decline in the diabetic American population; however, this unfavorable impact was found only among the non-diabetic Iranian population.

Introduction While type 2 diabetes (T2DM) has become a major health issue in the North American and Caribbean region, the effects of weight change on incident T2DM, conditional on either initial or attained weight, are poorly addressed. Therefore, we aimed to assess the impact of 3‐year weight change on incident T2DM over 6 years among US individuals. Methods A total of 8377 participants aged 45–64 years (4601 women), free of T2DM or cancer at baseline from the Atherosclerosis Risk in Communities (ARIC) study were included. Weight measurements were taken at baseline (visit 1, 1987–89) and approximately 3 years later (visit 2, 1990–92). Participants were categorised based on their weight change ratio into ≥ 5% weight loss, stable (±5%), and ≥ 5% weight gain. Cox proportional hazards models, adjusting for known diabetes risk factors, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident T2DM, with stable weight (±5%) as the reference category. Results During a median follow‐up period of 6 years, participants were classified into three categories: 361 persons remained stable (±5%), 47 with ≥ 5% loss, and 135 with ≥ 5% gain. In multivariable analysis, after adjustment with initial weight, ≥ 5% weight gain and loss were significantly associated with higher [HR (95% CI): 1.68 (1.36–2.06), p‐value < 0.0001] and lower [0.73 (0.53–1.00), p‐value = 0.05] risks of incident T2DM, respectively. When adjusted for attained weight, weight gain ≥ 5% remained a significant risk factor for T2DM [1.51 (1.21–1.88)]; however, weight loss ≥ 5% lost statistical significance [0.84 (0.60–1.17), p‐value = 0.31]. Conclusions We found a robust association between weight gain and incident T2DM; however, the beneficial impact of weight loss was significantly attenuated after considering the attained weight. The current study suggests that each 4.5 kg of weight gain during 3 years (1‐SD increase) increases the risk of developing type 2 diabetes (T2DM) by about 30% among American population. Moreover, weight gain ≥ 5% of baseline weight during 3 years increases the risk of developing T2DM by about 1.3 fold, even after considering attained weight.

Background We aimed to assess the gender-specific impact of 3-year changes in fasting plasma glucose (FPG) status on the risk of all-cause, cardiovascular (CV), and cancer mortality in individuals without type 2 diabetes (T2DM) during an 18-year follow-up. Methods The study population included 14,378 participants aged 30–60 years (8272 women) from three population-based cohort studies, including Atherosclerosis Risk in Communities, Multi-Ethnic Study of Atherosclerosis, and Tehran Lipid and Glucose Study. Subjects were classified into six categories based on the approximately three-year changes in FPG status: (1) normal FPG (NFG) to NFG (reference category); (2) NFG to impaired fasting glucose (IFG) (i.e., 126 > FPG ≥ 100 mg/dl); (3) NFG to T2DM; (4) IFG to NFG; (5) IFG to IFG; (6) IFG to T2DM. Multivariable stratified Cox regression, adjusting for age, body mass index (BMI), BMI-Change, smoking status, hypertension, and hypercholesterolemia was used to estimate hazard ratios (HRs (95% CI)) for all-cause and cause-specific mortality events. Women-to-men ratios of HRs (RHRs) for each category were also estimated. Results During follow-up, 2,362 all-cause mortality events were recorded. Among women, all categories of FPG change, excluding IFG-NFG (HR, 95%CI 1.24 (0.98–1.57), p = 0.07), were associated with a higher risk of all-cause mortality compared to the NFG-NFG category. Moreover, women in IFG-T2DM group were at increased risk for CV mortality (2.21 (1.42–3.44)). We also found that women in NFG-IFG (1.52 (1.20–1.91)), NFG-T2DM (2.90 (1.52–5.51)), and IFG-IFG (1.30 (1.02–1.66)) categories had a higher risk for cancer mortality. However, among men, a higher risk of all-cause mortality was found for only two groups of NFG-T2DM (1.78 (1.15–2.74)) and IFG-T2DM (1.34 (1.04–1.72)). Women with IFG-IFG had a 24% higher risk for all-cause mortality events than their men counterparts (RHR; 1.24 (1.01–1.54)). After further adjustment for physical activity, results were in line with the main findings, excluding T2DM up to six years after the measurement period and early mortality events. Conclusion In women, the IFG status, whether as incident, persistent, or converted to T2DM, had a higher risk for mortality events; however, among men, only conversion to T2DM conferred an excess risk of all-cause mortality.

Aims/Introduction To evaluate the association between ideal cardiovascular health metrics (ICVHM) and incident type 2 diabetes mellitus among Iranian men and women. Materials and Methods The study population included 7,488 Iranian adults aged ≥20 years (4,236 women) free from diabetes at baseline. The ICVHM was defined according to the American Heart Association's 2020 impact goals. The multivariable Cox proportional hazards regression analysis was used to calculate the hazard ratios (HRs) for ICVHM both as continuous and categorical variables. Results Over the median of 9.1 years of follow‐up, we identified 922 new cases of type 2 diabetes mellitus (526 women). Body mass index <30 kg/m2, untreated systolic/diastolic blood pressure <120/80 mmHg in both sexes, and physical activity ≥1,500 MET min/week (only among men) were significantly associated with a lower risk of type 2 diabetes mellitus. Each additional unit in the ICVHM was associated with a 21 and 15% lower risk of type 2 diabetes mellitus in men and women, respectively (P‐values <0.05). Compared with participants having poor cardiovascular health, the HR for type 2 diabetes mellitus risk was 0.69 (95% confidence interval [CI] 0.56–0.85) and 0.35 (95% CI 0.21–0.59) for men with intermediate and ideal CVHM, respectively. The corresponding values for women were 0.79 (95% CI 0.65–0.97) and 0.30 (95% CI 0.15–0.60), respectively. In a subpopulation with nutritional data (n = 2,236), ideal and intermediate nutritional status was associated with 83 and 77% lower risk of type 2 diabetes mellitus only among women (P‐values <0.05). Conclusion We found a strong inverse association between having higher global ICVHM with incident type 2 diabetes mellitus; which is mainly attributable to normal blood pressure, normal body weight, and intensive physical activity (only for men). Type 2 diabetes mellitus persists as a world epidemic, which is associated with increased risk of mortality and morbidity, particularly from cardiovascular diseases. Adherence to the American Heart Association cardiovascular health metrics, including body mass index, smoking status, physical activity, diet, total cholesterol, fasting plasma glucose, and blood pressure, is associated with a lower risk of cardiovascular disease and all‐cause mortality. In the current study, we examined the impact of sex on the association between ideal cardiovascular health metrics and the risk of type 2 diabetes mellitus. We found a strong inverse association between having higher global ideal cardiovascular health metrics with incident type 2 diabetes mellitus; the issue is mainly attributable to normal blood pressure, normal bodyweight and intensive physical activity (only for men).

Overweight and obesity is a global epidemic. Forecasting future trajectories of the epidemic is crucial for providing an evidence base for policy change. In this study, we examine the historical trends of the global, regional, and national prevalence of adult overweight and obesity from 1990 to 2021 and forecast the future trajectories to 2050. Leveraging established methodology from the Global Burden of Diseases, Injuries, and Risk Factors Study, we estimated the prevalence of overweight and obesity among individuals aged 25 years and older by age and sex for 204 countries and territories from 1990 to 2050. Retrospective and current prevalence trends were derived based on both self-reported and measured anthropometric data extracted from 1350 unique sources, which include survey microdata and reports, as well as published literature. Specific adjustment was applied to correct for self-report bias. Spatiotemporal Gaussian process regression models were used to synthesise data, leveraging both spatial and temporal correlation in epidemiological trends, to optimise the comparability of results across time and geographies. To generate forecast estimates, we used forecasts of the Socio-demographic Index and temporal correlation patterns presented as annualised rate of change to inform future trajectories. We considered a reference scenario assuming the continuation of historical trends. Rates of overweight and obesity increased at the global and regional levels, and in all nations, between 1990 and 2021. In 2021, an estimated 1·00 billion (95% uncertainty interval [UI] 0·989–1·01) adult males and 1·11 billion (1·10–1·12) adult females had overweight and obesity. China had the largest population of adults with overweight and obesity (402 million [397–407] individuals), followed by India (180 million [167–194]) and the USA (172 million [169–174]). The highest age-standardised prevalence of overweight and obesity was observed in countries in Oceania and north Africa and the Middle East, with many of these countries reporting prevalence of more than 80% in adults. Compared with 1990, the global prevalence of obesity had increased by 155·1% (149·8–160·3) in males and 104·9% (95% UI 100·9–108·8) in females. The most rapid rise in obesity prevalence was observed in the north Africa and the Middle East super-region, where age-standardised prevalence rates in males more than tripled and in females more than doubled. Assuming the continuation of historical trends, by 2050, we forecast that the total number of adults living with overweight and obesity will reach 3·80 billion (95% UI 3·39–4·04), over half of the likely global adult population at that time. While China, India, and the USA will continue to constitute a large proportion of the global population with overweight and obesity, the number in the sub-Saharan Africa super-region is forecasted to increase by 254·8% (234·4–269·5). In Nigeria specifically, the number of adults with overweight and obesity is forecasted to rise to 141 million (121–162) by 2050, making it the country with the fourth-largest population with overweight and obesity. No country to date has successfully curbed the rising rates of adult overweight and obesity. Without immediate and effective intervention, overweight and obesity will continue to increase globally. Particularly in Asia and Africa, driven by growing populations, the number of individuals with overweight and obesity is forecast to rise substantially. These regions will face a considerable increase in obesity-related disease burden. Merely acknowledging obesity as a global health issue would be negligent on the part of global health and public health practitioners; more aggressive and targeted measures are required to address this crisis, as obesity is one of the foremost avertible risks to health now and in the future and poses an unparalleled threat of premature disease and death at local, national, and global levels. Bill & Melinda Gates Foundation.