The difference between 2-hour post-challenge and fasting plasma glucose associates with the risk of cardiovascular disease in a normoglycemic population: the Tehran lipid and glucose study.

BACKGROUND: Elevated fasting plasma glucose (FPG) and 2-hour post-challenge glucose (2hPG) levels are known to be independent risk factors for cardiovascular disease (CVD). However, there is limited data on the association of the difference between these measures and the risk of CVD. This study aims to investigate this association in normoglycemic Iranian adults, particularly in those with low-normal FPG levels. METHODS: This prospective cohort study included 4,594 30-65-year-old participants from the Tehran Lipid and Glucose Study. Using multivariable Cox proportional hazards regression models adjusting for age, sex, body mass index, hypertension, hypercholesterolemia, smoking, education level and FPG, hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated for the association between 2hPG-FPG, both as continuous and categorical variables, and the CVD risk. Analyses of receiver operating characteristic curves were undertaken to determine the optimal 2hPG-FPG cut-off value. RESULTS: During a median of 17.9 years of follow-up, 459 CVD events occurred. A one-unit increase in 2hPG-FPG was significantly associated with an elevated risk of cardiovascular disease in both normoglycemic (HR 1.10, 95% CI (1.01-1.19)) and low-normal FPG individuals (HR 1.16, 95% CI (1.04-1.30)); this association resisted adjustment for Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) among normoglycemic individuals. However, those with 2hPG levels greater than FPG levels had a non-significant increased risk of incident CVD compared to those with 2hPG levels of less than or equal to FPG, with corresponding HR values of 1.18 (95% CI: 0.95-1.46) in normoglycemic and 1.32 (95% CI: 0.98-1.79) in low-normal FPG, respectively. For incident CVD, the optimal cut-off value for the 2hPG-FPG was found to be 1.06 mmol/L, which was applicable for both normoglycemic and low FPG populations; using this criterion, the corresponding risks for incident CVD were 1.36 (95% CI: 1.12-1.64) and 1.57 (95% CI: 1.22-2.03), respectively. CONCLUSIONS: The difference between 2hPG and FPG levels within the normoglycemic range is related to an increased risk of CVD, an issue that was independent of HOMA-IR. A cut-off point for 2hPG-FPG > 1.06 mmol/L may stratify persons at higher risk. These findings were particularly notable in those with low-normal FPG.

Gender differences in midlife to later-life cumulative burden and variability of obesity measures and risk of all-cause and cause-specific mortality.

BACKGROUND/OBJECTIVES: Previous studies have reported the gender-specific association between general and central obesity measures, using snapshot assessments, and mortality events. This study seeks to further explore this link by examining how the longitudinal cumulative burden and variability of obesity measures from midlife to later-life impact mortality events in the Atherosclerosis Risk in Communities (ARIC) study population, specifically in relation to gender differences. SUBJECTS/METHODS: Using data from the ARIC study, a total of 7615 (4360 women) participants free of cardiovascular disease, cancer, and early mortality events were included in the data analysis. Longitudinal cumulative burden (estimated by the area under the curve (AUC) using a quadratic mixed-effects method) and variability (calculated according to average successive variability (ASV)) were considered as exposures, separately and all together. Cox proportional hazard regression models were used to estimate multivariable-adjusted standardized hazard ratios. RESULTS: The mean age was 62.4 and the median follow-up was 16.9 years. In men, AUCs of waist-related obesity measures, and also ASVs of all obesity measures were associated with increased all-cause mortality risk. In women, waist circumference and waist-to-height ratio AUCs were associated with increased all-cause mortality risk. Regarding cardiovascular mortality, all adiposity measures ASVs in both genders and waist-related obesity measures AUCs in men were associated with increased risk. Significant gender differences were found for the associations between cumulative and variability of waist-to-hip ratio for all-cause mortality and all adiposity measures ASVs for cardiovascular mortality risk with higher impact among men. CONCLUSIONS: Cumulative burden and variability in general and central obesity measures were associated with higher all-cause and cardiovascular mortalities among men. In women, general obesity measures variability, as well as cumulative and variability of central adiposity measure, increased all-cause mortality risk.

Gender differences in the impact of 3-year status changes of metabolic syndrome and its components on incident type 2 diabetes mellitus: a decade of follow-up in the Tehran Lipid and Glucose Study.

Background: The aim of this study was to examine the gender differences in the association between status changes of metabolic syndrome (MetS) and its components, using Joint Interim Statement (JIS) criteria, with the risk of type 2 diabetes mellitus (T2DM) among an urban population. Methods: The study included 4,463 Iranian adult participants (2,549 women) aged ≥20 years. Based on status changes of MetS and its components during 3 years, subjects were categorized into four groups: MetS-free (reference), MetS-developed, MetS-recovery, and MetS-stable. A similar categorization was applied to MetS components. Multivariable Cox regression models were used for estimating hazard ratios (HRs) and women-to-men ratios of HRs (RHRs). Results: During a median follow-up of 9.3 years, 625 T2DM events (351 women) occurred. Compared with the reference, the HRs of the MetS-developed, -recovery, and -stable groups among men for incident T2DM were 2.90, 2.60, and 4.92; the corresponding values for women were 2.73, 2.88, and 5.21, respectively (all p-values < 0.01), without significant gender difference in these relationships. In both genders, the fasting plasma glucose (FPG) component, regardless of the change in status, was strongly and significantly associated with incident T2DM with HRs ranging from 2.49 to 9.42; a similar association was also found for high waist circumference (WC)-recovery and -stable groups, with HRs ranging from 1.58 to 2.85 (p-values ≤ 0.05). Regarding gender differences, the development and persistence of high blood pressure (BP) status exposed men to greater T2DM risk than women with women-to-men RHRs of 0.43 (0.26-0.72) and 0.58 (0.39-0.86), respectively. Moreover, stable low levels of high-density lipoprotein cholesterol (HDL-C) and high triglyceride (TG) levels conferred higher T2DM risk in women than in men, with women-to-men RHRs of 1.67 (0.98-2.86) and 1.44 (0.98-2.14), respectively (both p-values = 0.06). Conclusion: Among Tehranian adults, in both genders, all status changes of MetS, even those recovered from MetS, have a higher risk of T2DM compared to those who never had MetS. Also, all statuses of high FPG, in addition to recovered and stable high WC, were strongly associated with T2DM risk. Specifically, men with stable or developed high BP and women with stable dyslipidemic status were at differentially increased risk of incident T2DM.

Effect of C-reactive protein on the risk of Heart failure: a mendelian randomization study.

BACKGROUND: Traditional observational studies have shown positive associations between c-reactive protein (CRP) and heart failure (HF) risk. However, this association has not been fully elucidated. Therefore, Mendelian randomization was used to examine CRP's possible etiological roles with HF. METHODS: We implemented a two-sample Mendelian randomization framework to examine the causality of the association between CRP and HF based on summary statistics by large-scale genome-wide association studies (GWAS) datasets of European ancestry through inverse-variance weighted, weighted median, MREgger regression, and MR-PRESSO methods. The summary statistics dataset on the association of genetic variants with CRP was used from the published GWAS of European descent in UK Biobank participants (N = 427,367) and the CHARGE consortium (N = 575,531). The GWAS dataset used to identify genetic variants underlying HF from the HERMES consortium includes 977,323 participants (47,309 cases and 930,014 controls). The odds ratio (OR) with 95% confidence intervals (CIs) was employed to examine this association. RESULTS: The results of our IVW indicated that CRP was strongly associated with HF (OR = 4.18, 95% CI = 3.40-5.13, p < 0.001). The Cochran heterogeneity test showed significant heterogeneity among SNPs of CRP (Q = 317.55, p < 0.001; I2 = 37.6%), and no considerable pleiotropy was detected for the association of CRP with HF [intercept = 0.003; p = 0.234]. This finding remained consistent using different Mendelian randomization methods and sensitivity analyses. CONCLUSION: Our MR study did identify convincing evidence to support CRP associated with HF risk. Human genetic data suggest that CRP is a causative factor in HF. Hence, CRP assessment may offer additional prognostic information as an adjuvant to overall risk assessment in HF patients. These findings prompt significant questions about the function of inflammation in the progression of HF. More research into the role of inflammation in HF is needed to guide trials of anti-inflammation management.

The Trend of Risk for Cardiovascular Diseases During the Past Decade in Iran, Applying No-Lab and Lab-Based Prediction Models.

Background: As a surrogate for all relevant risk factors, it is preferable to show trends in the mean cardiovascular disease(CVD) risk rather than to examine each risk factor trend separately. Objectives: Using national representative data, this study aimed to determine the changes in the World Health Organization (WHO) CVD risk during the last decade considering both laboratory and non-laboratory risk scoring. Methods: We used data from five rounds of the WHO STEPwise approach to surveillance surveys (2007-2016). In all, 62,076 (31,660 women) participants aged 40-65 years were included and their absolute CVD risk were calculated. The generalized linear model was performed to assess the trend of CVD risk in men and women, and also in diabetic and non-diabetic individuals. Results: We showed significant declining trends in the mean CVD risk in the laboratory (from 10.5% to 8.8%) and non-laboratory (10.1% to 9.4%) models in men. In women, a significant reduction was observed in the laboratory-based model (from 8.4% to 7.8%). The laboratory model showed a greater decrease in men than women (P-for interaction < 0.001) and in diabetic patients (from 16.1% to 13.6%) than non-diabetic individuals (from 8.2% to 7%) (p-for interaction = 0.002). The proportion of high-risk individuals (risk ≥ 10%) decreased from 40% in 2007 to 31.5% in 2016 in men and from 29.8% to 26.1% in women based on the laboratory-model. Conclusions: During the last decade, CVD risk had a significant decrease in men and women. The reduction was more evident in men and diabetic population. However, still, one-third of our population is considered high-risk.

Are HOMA-IR and HOMA-B good predictors for diabetes and pre-diabetes subtypes?

BACKGROUND: To investigate the association between the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and Homeostasis Model Assessment of Beta-cell function (HOMA-B) with the incidence of diabetes and pre-diabetes subtypes. METHODS: A total of 3101 normoglycemic people aged 20-70 years were included in the 6-year follow-up study. Multinomial logistic regression was used to calculate the incidence possibility of isolated Impaired Fasting Glucose (iIFG), isolated Impaired Glucose Tolerance (iIGT), Combined impaired fasting glucose & impaired glucose tolerance (CGI), and Diabetes Mellitus (DM) per standard deviation (SD) increment in HOMA-IR and HOMA-B in the crude and multivariable model. RESULTS: In the multivariate model, an increase in one SD change in HOMA-IR was associated with a 43, 42, 75, and 92% increased risk of iIFG, iIGT, CGI, and DM, respectively. There was a positive correlation between the increase in HOMA-B and the incidence of iIGT; however, after adjusting the results for metabolic syndrome components, it was inversely correlated with the incidence of iIFG [Odds Ratio = 0.86(0.75-0.99)]. CONCLUSIONS: HOMA-IR is positively correlated with diabetes and pre-diabetes subtypes' incidence, and HOMA-B is inversely correlated with the incidence of iIFG but positively correlated with iIGT incidence. However, none of these alone is a good criterion for predicting diabetes and pre-diabetes.

Changes in Fasting plasma glucose status and risk of mortality events in individuals without diabetes over two decades of Follow-up: a pooled cohort analysis.

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.

Determinants of the progression to type 2 diabetes and regression to normoglycemia in people with pre-diabetes: A population-based cohort study over ten years.

AIMS: To determine the rates and predictors of the regression to normoglycemia and progression to diabetes among subjects with pre-diabetes. METHODS: A 10-year longitudinal population-based study was conducted among 1329 participants with pre-diabetes in the Tehran Lipid and Glucose Study. Pre-diabetes was divided into isolated IFG (iIFG), isolated IGT (iIGT), and combined IFG/IGT. Univariate and stepwise multivariable Cox regression was used to evaluate predictors of glycemic conversions. RESULTS: The cumulative incidences of normoglycemia and diabetes were 43.7% (95%CI 40.9-46.4) and 40.1% (37.3-42.7), respectively. Isolated IGT returned to normoglycemia more than iIFG (HR:1.26, 1.05-1.51), but there was no difference in how quickly they progressed to diabetes. Regression to normoglycemia was associated with younger age, female sex, lower BMI, no familial history of diabetes, higher HDL-C, and ex-smoking. Older age, higher BMI, diastolic blood pressure, total cholesterol, lower HDL-C, and familial history for diabetes were associated with progression to diabetes. The influence of BMI on glycemic status conversions diminished with age. At approximately above 60 years old, the hazards of BMI for any conversions faded out. CONCLUSIONS: The modifiable predictors of regression to normoglycemia and progression to diabetes are roughly the same. The importance of BMI attenuates in elderly subjects.

Are the determinants of the progression to type 2 diabetes and regression to normoglycemia in the populations with pre-diabetes the same?

Background: We aimed to determine the predictors of regression to normoglycemia and progression to diabetes among subjects with pre-diabetes in a single model concurrently. Methods: The present study included 1329 participants aged 20 to 70 years with prediabetes from the population-based cohort of the Tehran Lipid and Glucose Study, with a 10-year follow-up. Glycemic status at follow-up was categorized as regression to normoglycemia: fasting plasma glucose [FPG] of <5.55 and 2h-plasma glucose [PG] of <7.77 mmol/L, and not taking antidiabetic medications. Glycemic status at follow-up was categorized as progression to diabetes: FPG ≥7 or 2h-PG of ≥11.1 mmol/L, or taking antidiabetic medications. Glycemic status determined whether the patients remained in prediabetes category (isolated impaired fasting glycaemia [iIFG] [(5.55≤FPG<7 and 2h-PG<7.77 mmol/L); isolated impared glucose tolarence [iIGT] (7.77 ≤ 2h-PG<11.1 and FGP<5.55 mmol/L)]. With prediabetes as a reference, multinomial logistic regression was utilized to identify the determinants of glycemic changes. Results: Approximately 40% of participants returned to normoglycemia (n = 578), and similar percentage of participants progressed to diabetes (n = 518). Based on the multivariable multinomial model, regression to normoglycemia was associated with age (relative risk ratio [RRR] = 0.97; 95% CI, 0.95-0.99), female sex (RRR = 1.72; 95% CI, 1.18-2.50), high education level of ≥12 years (RRR = 2.10; 95% CI, 1.19-3.70), and combined IFG/impaired glucose tolerance (IGT) versus IFG (RRR = 0.45; 95% CI, 0.29-0.70). The risk of progression to diabetes increased with body mass index (RRR = 1.10; 95% CI, 1.05-1.15), waist circumference (RRR = 0.97; 95% CI, 0.96-0.99), positive familial history of diabetes (RRR = 1.62; 95% CI, 1.07-2.45), and combined IFG/IGT versus IFG (RRR = 2.54; 95% CI, 1.71-3.77). Conclusion: A small percentage of patients with prediabetes remain in this condition, but the majority go on to develop diabetes or regress to normoglycemia. Both directions had distinct predictors.

The trend of 10-year cardiovascular risk among diabetic and non-diabetic participants in Tehran Lipid and glucose study: 1999-2018.

BACKGROUND: Assessing the risk of cardiovascular disease (CVD) is crucial in preventive cardiology. We aimed to determine the trend of CVD risk among individuals with and without diabetes during two decades of follow-up in a Middle Eastern cohort. METHODS: We studied 8,450 individuals (55.5% women) aged 40-75 years who participated in the Tehran Lipid and Glucose Study (TLGS). Diabetes status and CVD risk factors were evaluated in six examinations from 1999 to 2018. The individual 10-year CVD risk score was calculated using the ACC/AHA recommended risk equation. We used generalized estimating equation models (GEE) to assess the time trends of CVD risk factors and CVD risk scores in diabetic and non-diabetic groups separately. RESULTS: The age-adjusted ACC/AHA risk score significantly decreased in non-diabetic women and men (from 3.2% to 1.6% in women and 6.8% to 5.0% in men; p for trend < 0.001). Whereas the risk significantly decreased among diabetics men (from 13.8% to 11.5%), it increased somehow among diabetics women (from 5.3% to 5.5%). Furthermore, in both sexes, diabetic individuals compared to non-diabetic ones had better control on their systolic blood pressure, total cholesterol, and fasting plasma glucose during the last two decades. CONCLUSIONS: The CVD risk and most CVD risk factors improved in individuals with and without diabetes in the past two decades; however, they have not reached the targets yet. So, more stringent lifestyle modifications and treatment strategies are needed, especially for primary prevention in the general population.

Abnormal Transcript Levels of Cytokines Among Iranian COVID-19 Patients.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 and the related disorder i.e. "coronavirus disease 2019" (COVID-19) has encouraged researchers to unravel the molecular mechanism of disease severity. Several lines of evidence support the impact of "cytokine storm" in the pathogenesis of severe forms of the disorder. We aimed to assess expression levels of nine cytokine coding genes in COVID-19 patients admitted in a hospital. We collected clinical data of patients from their medical reports. Then, we assessed expression of genes using real-time PCR. Expression levels of IFN-G, IL-2, IL-4, IL-6, IL-17, TGF-B, IL-8, and IL-1B were significantly higher in COVID-19 patients compared with healthy controls and in both female and male patients compared with sex-matched controls. However, expression level of TNF-A was not different between COVID-19 patients and healthy controls. Expression of none of these cytokines was different between ICU-admitted patients and other patients except for IL-6 whose expression was lower in the former group compared with the latter (ratio of means = 0.33, P value = 4.82E-02). Then, we assessed diagnostic power of cytokine coding genes in differentiating between COVID-19 patients and controls. The area under curve (AUC) values ranged from 0.94 for IFN-G to 1.0 for IL-2 and IL-1B. After combining the transcript levels of all cytokines, AUC, sensitivity, and specificity values reached 100%, 100%, and 99%, respectively. For differentiation between ICU-admitted patients and other patients, IL-4 with AUC value of 0.68 had the best diagnostic power among cytokine coding genes. Expression of none of cytokine coding genes was correlated with the available clinical/demographic data including age, gender, ICU admission, or erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) levels. This study provides further evidence for contribution of "cytokine storm" in the pathobiology of moderate/severe forms of COVID-19.