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    "Prediabetes": Are There Problems With This Label? Yes, the Label Creates Further Problems! Yudkin John S Diabetes care The category of "prediabetes" defined by the American Diabetes Association comprises a range of intermediate hyperglycemia based on fasting or 2-h postload glucose or on HbA1c Over the recent past, the "cut points" identifying this stage have changed, i.e., a lower fasting glucose level is used. On one hand, it can be argued that the change to a lower cut point identifies a group of individuals still at higher risk and provides heightened awareness for a condition associated with higher risk for cardiovascular disease. In addition, identification of individuals at this stage may represent a chance of earlier intervention in the disease. However, the argument against this definition of "prediabetes" is that it disguises the differences in the three subcategories and creates problems in interpreting observations on interventions and outcomes. In addition, it can be argued that the enormous numbers of people identified with the criteria far exceeds the capacity of health care systems to respond through individual care, particularly without evidence that interventions benefit any category other than impaired glucose tolerance. Thus, there does not appear to be consensus on the definition using the cut points identified. Controversy also remains as to whether there are glycemic metrics beyond HbA1c that can be used in addition to HbA1c to help assess risk of an individual developing diabetes complications. Given the current controversy, a Point-Counterpoint debate on this issue is provided herein. In the point narrative below, Dr. Yudkin provides his argument that there are significant problems with this label. In the counterpoint narrative that follows Dr. Yudkin's contribution, Dr. Cefalu argues that the cut points are appropriate and do provide useful and important information in trying to reduce the future burden of diabetes.-William T. CefaluEditor in Chief, Diabetes Care. 10.2337/dc15-2113
    Comparative prognostic performance of definitions of prediabetes: a prospective cohort analysis of the Atherosclerosis Risk in Communities (ARIC) study. Warren Bethany,Pankow James S,Matsushita Kunihiro,Punjabi Naresh M,Daya Natalie R,Grams Morgan,Woodward Mark,Selvin Elizabeth The lancet. Diabetes & endocrinology BACKGROUND:No consensus on definitions of prediabetes exists among international organisations. Analysis of associations with different definitions and clinical complications can inform the comparative value of different prediabetes definitions. We compared the risk of future outcomes across different prediabetes definitions based on fasting glucose concentration, HbA, and 2 h glucose concentration during over two decades of follow-up in the community-based Atherosclerosis Risk in Communities (ARIC) study. We aimed to analyse the associations of definitions with outcomes to provide a comparison of different definitions. METHODS:We did a prospective cohort study of participants in the ARIC study who did not have diagnosed diabetes and who attended visit 2 (1990-92; n=10 844) and who attended visit 4 (1996-98; n=7194). ARIC participants were enrolled from four communities across the USA. Fasting glucose concentration and HbA were measured at visit 2 and fasting glucose concentration and 2 h glucose concentration were measured at visit 4. We compared prediabetes definitions based on fasting glucose concentration (American Diabetes Association [ADA] fasting glucose concentration cutoff 5·6-6·9 mmol/L and WHO fasting glucose concentration cutoff 6·1-6·9 mmol/L), HbA (ADA HbA cutoff 5·7-6·4% [39-46 mmol/mol] and International Expert Committee [IEC] HbA cutoff 6·0-6·4% [42-46 mmol/mol]), and 2 h glucose concentration (ADA and WHO 2 h glucose concentration cutoff 7·8-11·0 mmol/L). FINDINGS:Prediabetes defined using the ADA fasting glucose concentration cutoff (prevalence 4112 [38%] of 10 844 people; 95% CI 37·0-38·8) was the most sensitive for major clinical outcomes, whereas using the ADA HbA cutoff (2027 [19%] of 10 884 people; 18·0-19·4) and IEC HbA cutoff (970 [9%] of 10 844 people; 8·4-9·5), and the WHO fasting glucose concentration cutoff (1213 [11%] of 10 844 people; 10·6-11·8) were more specific. After demographic adjustment, HbA-based definitions of prediabetes had higher hazard ratios and better risk discrimination for chronic kidney disease, cardiovascular disease, peripheral arterial disease, and all-cause mortality than did fasting glucose concentration-based definitions (all p<0·05). The C-statistic for incident chronic kidney disease was 0·636 for ADA fasting glucose concentration clinical categories and 0·640 for ADA HbA clinical categories (difference -0·005, 95% CI -0·008 to -0·001). The C-statistics were 0·662 for ADA fasting glucose clinical concentration categories and 0·672 for ADA HbA clinical categories for atherosclerotic cardiovascular disease, 0·701 for ADA fasting glucose concentration clinical categories and 0·722 for ADA HbA clinical categories for peripheral arterial disease, and 0·683 for ADA fasting glucose concentration clinical categories and 0·688 for ADA HbA clinical categories for all-cause mortality. Prediabetes defined using the ADA HbA cutoff showed a significant overall improvement in the net reclassification index for cardiovascular outcomes and death compared with prediabetes defined with glucose-based definitions. ADA fasting glucose concentration clinical categories, WHO fasting glucose concentration clinical categories, and ADA and WHO 2 h glucose concentrations clinical categories were not significantly different in terms of risk discrimination for chronic kidney disease, cardiovascular outcomes, or mortality outcomes. INTERPRETATION:Our results suggest that prediabetes definitions using HbA were more specific and provided modest improvements in risk discrimination for clinical complications. The definition of prediabetes using the ADA fasting glucose concentration cutoff was more sensitive overall. FUNDING:US National Institutes of Health. 10.1016/S2213-8587(16)30321-7
    Prevalence of Prediabetes and Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease. Newton Kimberly P,Hou Jiayi,Crimmins Nancy A,Lavine Joel E,Barlow Sarah E,Xanthakos Stavra A,Africa Jonathan,Behling Cynthia,Donithan Michele,Clark Jeanne M,Schwimmer Jeffrey B, JAMA pediatrics Importance:Nonalcoholic fatty liver disease (NAFLD) is a major chronic liver disease in children in the United States and is associated with insulin resistance. In adults, NAFLD is also associated with type 2 diabetes. To our knowledge, the prevalence of type 2 diabetes in children with NAFLD is unknown. Objective:To determine the prevalence of type 2 diabetes and prediabetes in children with NAFLD and assess type 2 diabetes and prediabetes as risk factors for nonalcoholic steatohepatitis (NASH). Design, Setting, and Participants:This was a multicenter, cross-sectional study at 12 pediatric clinical centers across the United States participating in the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network. Children younger than 18 years with biopsy-confirmed NAFLD enrolled in the NASH Clinical Research Network. Main Outcomes and Measures:The presence of type 2 diabetes and prediabetes as determined by American Diabetes Association screening criteria using clinical history and fasting laboratory values. Results:There were 675 children with NAFLD included in the study with a mean age of 12.6 years and mean body mass index (calculated as weight in kilograms divided by height in meters squared) of 32.5. Most of the children were boys (480 of 675) and Hispanic (445 of 675).The estimated prevalence of prediabetes was 23.4% (95% CI, 20.2%-26.6%), and the estimated prevalence of type 2 diabetes was 6.5% (95% CI, 4.6%-8.4%). Girls with NAFLD had 1.6 (95% CI, 1.04-2.40) times greater odds of having prediabetes and 5.0 (95% CI, 2.49-9.98) times greater odds of having type 2 diabetes than boys with NAFLD. The prevalence of NASH was higher in those with type 2 diabetes (43.2%) compared with prediabetes (34.2%) or normal glucose (22%) (P < .001). The odds of having NASH were significantly higher in those with prediabetes (OR, 1.9; 95% CI, 1.21-2.9) or type 2 diabetes (OR, 3.1; 95% CI, 1.5-6.2) compared with those with normal glucose. Conclusions and Relevance:In this study, nearly 30% of children with NAFLD also had type 2 diabetes or prediabetes. These children had greater odds of having NASH and thus were at greater long-term risk for adverse hepatic outcomes. 10.1001/jamapediatrics.2016.1971
    Phenotypes of prediabetes and stratification of cardiometabolic risk. Stefan Norbert,Fritsche Andreas,Schick Fritz,Häring Hans-Ulrich The lancet. Diabetes & endocrinology Prediabetes is associated with increased risks of type 2 diabetes, cardiovascular disease, dementia, and cancer, and its prevalence is increasing worldwide. Lifestyle and pharmacological interventions in people with prediabetes can prevent the development of diabetes and possibly cardiovascular disease. However, prediabetes is a highly heterogeneous metabolic state, both with respect to its pathogenesis and prediction of disease. Improved understanding of these features and precise phenotyping of prediabetes could help to improve stratification of disease risk. In this Personal View, we focus on the extreme metabolic phenotypes of metabolically healthy obesity and metabolically unhealthy normal weight, insulin secretion failure, insulin resistance, visceral obesity, and non-alcoholic fatty liver disease. We present new analyses aimed at improving characterisation of phenotypes in lean, overweight, and obese people with prediabetes. We discuss evidence from lifestyle intervention studies to explore whether these phenotypes can also be used for individualised prediction and prevention of cardiometabolic diseases. 10.1016/S2213-8587(16)00082-6
    Cardiovascular and renal burdens of prediabetes in the USA: analysis of data from serial cross-sectional surveys, 1988-2014. Ali Mohammed K,Bullard Kai McKeever,Saydah Sharon,Imperatore Giuseppina,Gregg Edward W The lancet. Diabetes & endocrinology BACKGROUND:There is controversy over the usefulness of prediabetes as a diagnostic label. Using data from US National Health and Nutrition Examination Surveys (NHANES) between 1988 and 2014, we examined the cardiovascular and renal burdens in adults with prediabetes over time and compared patterns with other glycaemic status groups. METHODS:We analysed cross-sectional survey data from non-pregnant adults aged 20 years and older from the NHANES survey periods 1988-94, 1999-2004, 2005-10, and 2011-14. We defined diagnosed diabetes as patients' self-report that they had been previously diagnosed by a physician or health professional; among those with no self-reported diabetes, prediabetes was defined as a fasting plasma glucose (FPG) concentration of 100-125 mg/dL (5·6-6·9 mmol/L) or an HbA of 5·7-6·4% (39-47 mmol/mol); undiagnosed diabetes as an FPG of 126 mg/dL (7·0 mmol/L) or higher or an HbA of 6·5% (48 mmol/mol) or higher; and normal glycaemic status as an FPG of less than 100 mg/dL (5·6 mmol/L) and an HbA of less than 5·7% (39 mmol/mol). We repeated the analyses using varying definitions of prediabetes (FPG 110-125 mg/dL [6·1-6·9 mmol/L] or HbA 5·7-6·4% [39-47 mmol/mol], FPG 110-125 mg/dL [6·1-6·9 mmol/L] or HbA 6·0-6·4% [42-47 mmol/mol], and FPG 100-125 mg/dL [5·6-6·9 mmol/L] and HbA 5·7-6·4% [39-47 mmol/mol]). For each group over time, we estimated the prevalences of hypertension and dyslipidaemia; and among individuals with those conditions, we estimated the proportions who had been treated and who were achieving care goals. By glycaemic group, we estimated those who were current, former, and never smokers; mean 10-year risk of cardiovascular disease (using estimators from the Framingham Heart Study, the United Kingdom Prospective Diabetes Study (UKPDS), and the ACC/AHA ASCVD guidelines); albuminuria (median and albumin-to-creatinine ratio ≥30 mg/g), estimated glomerular filtration rate (eGFR; mean and <60 mL/min per 1·73m); and prevalence of myocardial infarction and stroke. For all estimates, we calculated predicted changes between 1988-94 and 2011-14 using logistic regression models adjusted for age, sex, and race or ethnic group. FINDINGS:We obtained data for 27 971 eligible individuals. In 2011-14, in the population of adults with prediabetes, 36·6% (95% CI 32·8-40·5) had hypertension, 51·2% (47·0-55·3) had dyslipidaemia, 24·3% (21·7-27·3) smoked; 7·7% (6·8-8·8) had albuminuria; 4·6% (3·7-5·9) had reduced eGFR; and 10-year cardiovascular event risk ranged from 5% to 7%. From 1988-94 to 2011-14, adults with prediabetes showed significant increases in hypertension (+9·7 percentage points [95% CI 5·4-14·0]); no change in dyslipidaemia; decreases in smoking (-6·4 percentage points [-10·7 to -2·1]); increased use of treatment to lower blood pressure (54·2% [49·0-59·3] to 81·4% [76·7-85·3], +27·2 percentage points [20·5-33·8] p<0·0001) and to reduce lipids (6·6% to 40·2%, +33·6 percentage points [30·2-37·0], p<0·0001); and increased goal achievements for blood pressure (25·8% to 62·0%, +36·2 percentage points [30·7-41·8], p<0·0001) and lipids (1·0% to 32·8%, +31·8 percentage points [29·1-34·4, p<0·0001]). People with prediabetes also showed decreases in cardiovascular risk (ASCVD -1·9 percentage points [-2·5 to -1·3] to UKPDS -2·7 [-3·5 to -1·9], p<0·0001); but no change in prevalence of albuminuria, reduced eGFR, myocardial infarction, or stroke. Prevalence and patterns were consistent across all prediabetes definitions examined. Compared with adults with prediabetes, adults with diagnosed diabetes showed much larger improvements in cardiovascular and renal risk treatments, apart from smoking, which did not decline. INTERPRETATION:Over 25 years, cardiovascular and renal risks and disease have become highly prevalent in adults with prediabetes, irrespective of the definitions used. Identification of people with prediabetes might increase the opportunity for cardiovascular and renal risk reduction. FUNDING:None. 10.1016/S2213-8587(18)30027-5
    Duration of Diabetes and Prediabetes During Adulthood and Subclinical Atherosclerosis and Cardiac Dysfunction in Middle Age: The CARDIA Study. Reis Jared P,Allen Norrina B,Bancks Michael P,Carr J Jeffrey,Lewis Cora E,Lima Joao A,Rana Jamal S,Gidding Samuel S,Schreiner Pamela J Diabetes care OBJECTIVE:To determine whether the duration of diabetes and duration of prediabetes estimated during a 25-year period in early adulthood are each independently associated with coronary artery calcified plaque (CAC) and abnormalities in left ventricular structure and function later in life. RESEARCH DESIGN AND METHODS:Participants were 3,628 white and black adults aged 18-30 years without diabetes or prediabetes at baseline (1985-1986) in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Durations of diabetes and prediabetes were estimated based on their identification at examinations 7, 10, 15, 20, and 25 years later. CAC was identified by computed tomography at years 15, 20, and 25. Left ventricular structure and function were measured via echocardiogram at year 25. RESULTS:Of the 3,628 individuals, 12.7% and 53.8% developed diabetes and prediabetes, respectively; average (SD) duration was 10.7 (10.7) years and 9.5 (5.4) years. After adjustment for sociodemographic characteristics and other cardiovascular risk factors, and mutual adjustment for each other, the hazard ratio for the presence of CAC was 1.15 (95% CI 1.06, 1.25) and 1.07 (1.01, 1.13) times higher for each 5-year-longer duration of diabetes and prediabetes, respectively. Diabetes and prediabetes duration were associated with worse subclinical systolic function (longitudinal strain [ < 0.001 for both]) and early diastolic relaxation (e' [ 0.004 and 0.002, respectively]). Duration of diabetes was also associated with a higher diastolic filling pressure (E-to-e' ratio [ 0.001]). CONCLUSIONS:Durations of diabetes and prediabetes during adulthood are both independently associated with subclinical atherosclerosis and left ventricular systolic and diastolic dysfunction in middle age. 10.2337/dc17-2233
    Prevalence and Ethnic Pattern of Diabetes and Prediabetes in China in 2013. Wang Limin,Gao Pei,Zhang Mei,Huang Zhengjing,Zhang Dudan,Deng Qian,Li Yichong,Zhao Zhenping,Qin Xueying,Jin Danyao,Zhou Maigeng,Tang Xun,Hu Yonghua,Wang Linhong JAMA Importance:Previous studies have shown increasing prevalence of diabetes in China, which now has the world's largest diabetes epidemic. Objectives:To estimate the recent prevalence and to investigate the ethnic variation of diabetes and prediabetes in the Chinese adult population. Design, Setting, and Participants:A nationally representative cross-sectional survey in 2013 in mainland China, which consisted of 170 287 participants. Exposures:Fasting plasma glucose and hemoglobin A1c levels were measured for all participants. A 2-hour oral glucose tolerance test was conducted for all participants without diagnosed diabetes. Main Outcomes and Measures:Primary outcomes were total diabetes and prediabetes defined according to the 2010 American Diabetes Association criteria. Awareness and treatment were also evaluated. Hemoglobin A1c concentration of less than 7.0% among treated diabetes patients was considered adequate glycemic control. Minority ethnic groups in China with at least 1000 participants (Tibetan, Zhuang, Manchu, Uyghur, and Muslim) were compared with Han participants. Results:Among the Chinese adult population, the estimated standardized prevalence of total diagnosed and undiagnosed diabetes was 10.9% (95% CI, 10.4%-11.5%); that of diagnosed diabetes, 4.0% (95% CI, 3.6%-4.3%); and that of prediabetes, 35.7% (95% CI, 34.1%-37.4%). Among persons with diabetes, 36.5% (95% CI, 34.3%-38.6%) were aware of their diagnosis and 32.2% (95% CI, 30.1%-34.2%) were treated; 49.2% (95% CI, 46.9%-51.5%) of patients treated had adequate glycemic control. Tibetan and Muslim Chinese had significantly lower crude prevalence of diabetes than Han participants (14.7% [95% CI, 14.6%-14.9%] for Han, 4.3% [95% CI, 3.5%-5.0%] for Tibetan, and 10.6% [95% CI, 9.3%-11.9%] for Muslim; P < .001 for Tibetan and Muslim compared with Han). In the multivariable logistic models, the adjusted odds ratios compared with Han participants were 0.42 (95% CI, 0.35-0.50) for diabetes and 0.77 (95% CI, 0.71-0.84) for prediabetes for Tibetan Chinese and 0.73 (95% CI, 0.63-0.85) for diabetes and 0.78 (95% CI, 0.71-0.86) for prediabetes in Muslim Chinese. Conclusions and Relevance:Among adults in China, the estimated overall prevalence of diabetes was 10.9%, and that for prediabetes was 35.7%. Differences from previous estimates for 2010 may be due to an alternate method of measuring hemoglobin A1c. 10.1001/jama.2017.7596
    Regression From Prediabetes to Normal Glucose Regulation and Prevalence of Microvascular Disease in the Diabetes Prevention Program Outcomes Study (DPPOS). Perreault Leigh,Pan Qing,Schroeder Emily B,Kalyani Rita R,Bray George A,Dagogo-Jack Samuel,White Neil H,Goldberg Ronald B,Kahn Steven E,Knowler William C,Mathioudakis Nestoras,Dabelea Dana, Diabetes care OBJECTIVE:Regression from prediabetes to normal glucose regulation (NGR) was associated with reduced incidence of diabetes by 56% over 10 years in participants in the Diabetes Prevention Program Outcomes Study (DPPOS). In an observational analysis, we examined whether regression to NGR also reduced risk for microvascular disease (MVD). RESEARCH DESIGN AND METHODS:Generalized estimating equations were used to examine the prevalence of aggregate MVD at DPPOS year 11 in people who regressed to NGR at least once (vs. never) during the Diabetes Prevention Program (DPP). Logistic regression assessed the relationship of NGR with retinopathy, nephropathy, and neuropathy, individually. Generalized additive models fit smoothing splines to describe the relationship between average A1C during follow-up and MVD (and its subtypes) at the end of follow-up. RESULTS:Regression to NGR was associated with lower prevalence of aggregate MVD in models adjusted for age, sex, race/ethnicity, baseline A1C, and treatment arm (odds ratio [OR] 0.78, 95% CI 0.65-0.78, = 0.011). However, this association was lost in models that included average A1C during follow-up (OR 0.95, 95% CI 0.78-1.16, = 0.63) or diabetes status at the end of follow-up (OR 0.92, 95% CI 0.75-1.12, = 0.40). Similar results were observed in examination of the association between regression to NGR and prevalence of nephropathy and retinopathy, individually. Risk for aggregate MVD, nephropathy, and retinopathy increased across the A1C range. CONCLUSIONS:Regression to NGR is associated with a lower prevalence of aggregate MVD, nephropathy, and retinopathy, primarily due to lower glycemic exposure over time. Differential risk for the MVD subtypes begins in the prediabetes A1C range. 10.2337/dc19-0244
    Risk of Cardiovascular Disease and Death in Individuals With Prediabetes Defined by Different Criteria: The Whitehall II Study. Vistisen Dorte,Witte Daniel R,Brunner Eric J,Kivimäki Mika,Tabák Adam,Jørgensen Marit E,Færch Kristine Diabetes care OBJECTIVE:We compared the risk of cardiovascular disease (CVD) and all-cause mortality in subgroups of prediabetes defined by fasting plasma glucose (FPG), 2-h plasma glucose (2hPG), or HbA. RESEARCH DESIGN AND METHODS:In the Whitehall II cohort, 5,427 participants aged 50-79 years and without diabetes were followed for a median of 11.5 years. A total of 628 (11.6%) had prediabetes by the World Health Organization (WHO)/International Expert Committee (IEC) criteria (FPG 6.1-6.9 mmol/L and/or HbA 6.0-6.4%), and 1,996 (36.8%) by the American Diabetes Association (ADA) criteria (FPG 5.6-6.9 mmol/L and/or HbA 5.7-6.4%). In a subset of 4,730 individuals with additional measures of 2hPG, 663 (14.0%) had prediabetes by 2hPG. Incidence rates of a major event (nonfatal/fatal CVD or all-cause mortality) were compared for different definitions of prediabetes, with adjustment for relevant confounders. RESULTS:Compared with that for normoglycemia, incidence rate in the context of prediabetes was 54% higher with the WHO/IEC definition and 37% higher with the ADA definition ( < 0.001) but declining to 17% and 12% after confounder adjustment ( ≥ 0.111). Prediabetes by HbA was associated with a doubling in incidence rate for both the IEC and ADA criteria. However, upon adjustment, excess risk was reduced to 13% and 17% ( ≥ 0.055), respectively. Prediabetes by FPG or 2hPG was not associated with an excess risk in the adjusted analysis. CONCLUSIONS:Prediabetes defined by HbA was associated with a worse prognosis than prediabetes defined by FPG or 2hPG. However, the excess risk among individuals with prediabetes is mainly explained by the clustering of other cardiometabolic risk factors associated with hyperglycemia. 10.2337/dc17-2530
    Prevalence of prediabetes and diabetes in children and adolescents with biopsy-proven non-alcoholic fatty liver disease. Nobili Valerio,Mantovani Alessandro,Cianfarani Stefano,Alisi Anna,Mosca Antonella,Sartorelli Maria Rita,Maffeis Claudio,Loomba Rohit,Byrne Christopher D,Targher Giovanni Journal of hepatology BACKGROUND & AIMS:We undertook a cross-sectional study of children/adolescents with and without non-alcoholic fatty liver disease (NAFLD) to compare the prevalence of prediabetes and diabetes, and to examine the role of abnormal glucose tolerance as a predictor of liver disease severity. METHODS:We recruited a cohort of 599 Caucasian children/adolescents with biopsy-proven NAFLD, and 118 children/adolescents without NAFLD, who were selected to be similar for age, sex, body mass index and waist circumference to those with NAFLD. The diagnosis of prediabetes and diabetes was based on either hemoglobin A1c, fasting plasma glucose or 2 h post-load glucose concentrations. RESULTS:Children/adolescents with NAFLD had a significantly higher prevalence of abnormal glucose tolerance (prediabetes or diabetes) than those without NAFLD (20.6% vs. 11%, p = 0.02). In particular, 124 (20.6%) children/adolescents with NAFLD had abnormal glucose tolerance, with 19.8% (n = 119) satisfying the diagnostic criteria for prediabetes and 0.8% (n = 5) satisfying the criteria for diabetes. The combined presence of prediabetes and diabetes was associated with a nearly 2.2-fold increased risk of non-alcoholic steatohepatitis (NASH; unadjustedodds ratio 2.19; 95% CI 1.47-3.29; p <0.001). However, this association was attenuated (but remained significant) after adjustment for age, sex, waist circumference (adjustedodds ratio 1.69, 95% CI 1.06-2.69, p = 0.032), and the PNPLA3 rs738409 polymorphism. Both this PNPLA3 polymorphism and waist circumference were strongly associated with NASH. CONCLUSIONS:Abnormal glucose tolerance (especially prediabetes) is highly prevalent among children/adolescents with biopsy-proven NAFLD. These children also have a higher risk of NASH, though central adiposity is the factor that is most strongly associated with NASH. LAY SUMMARY:Children with biopsy-proven non-alcoholic fatty liver disease (NAFLD) have a higher prevalence of abnormal glucose tolerance (prediabetes or type 2 diabetes) than children without NAFLD. Children with biopsy-proven NAFLD and abnormal glucose tolerance also have a higher prevalence of the progressive form of disease, non-alcoholic steatohepatitis, than those with normal glucose tolerance, though central adiposity is the factor that is most strongly associated with non-alcoholic steatohepatitis. 10.1016/j.jhep.2019.06.023
    Benefit of lifestyle-based T2DM prevention is influenced by prediabetes phenotype. Campbell Matthew D,Sathish Thirunavukkarasu,Zimmet Paul Z,Thankappan Kavumpurathu R,Oldenburg Brian,Owens David R,Shaw Jonathan E,Tapp Robyn J Nature reviews. Endocrinology The prevention of type 2 diabetes mellitus (T2DM) is a target priority for the WHO and the United Nations and is a key priority in the 2018 Berlin Declaration, which is a global call for early actions related to T2DM. Health-care policies advocate that individuals at high risk of developing T2DM undertake lifestyle modification, irrespective of whether the prediabetes phenotype is defined by hyperglycaemia in the postprandial state (impaired glucose tolerance) and/or fasting state (impaired fasting glucose) or by intermediate HbA levels. However, current evidence indicates that diabetes prevention programmes based on lifestyle change have not been successful in preventing T2DM in individuals with isolated impaired fasting glucose. We propose that further research is needed to identify effective lifestyle interventions for individuals with isolated impaired fasting glucose. Furthermore, we call for the identification of innovative approaches that better identify people with impaired glucose tolerance, who benefit from the currently available lifestyle-based diabetes prevention programmes. 10.1038/s41574-019-0316-1
    Ideal Cardiovascular Health Metrics and Major Cardiovascular Events in Patients With Prediabetes and Diabetes. Wang Tiange,Lu Jieli,Su Qing,Chen Yuhong,Bi Yufang,Mu Yiming,Chen Lulu,Hu Ruying,Tang Xulei,Yu Xuefeng,Li Mian,Xu Min,Xu Yu,Zhao Zhiyun,Yan Li,Qin Guijun,Wan Qin,Chen Gang,Dai Meng,Zhang Di,Gao Zhengnan,Wang Guixia,Shen Feixia,Luo Zuojie,Qin Yingfen,Chen Li,Huo Yanan,Li Qiang,Ye Zhen,Zhang Yinfei,Liu Chao,Wang Youmin,Wu Shengli,Yang Tao,Deng Huacong,Li Donghui,Lai Shenghan,Bloomgarden Zachary T,Shi Lixin,Ning Guang,Zhao Jiajun,Wang Weiqing, JAMA cardiology Importance:Whether optimal cardiovascular health metrics may counteract the risk of cardiovascular events among patients with prediabetes or diabetes is unclear. Objective:To investigate the associations of ideal cardiovascular health metrics (ICVHMs) with subsequent development of cardiovascular disease (CVD) among participants with prediabetes or diabetes as compared with participants with normal glucose regulation. Design, Setting, and Participants:The China Cardiometabolic Disease and Cancer Cohort Study was a nationwide, population-based, prospective cohort study of 20 communities from various geographic regions in China. The study included 111 765 participants who were free from CVD or cancer at baseline. Data were analyzed between 2011 and 2016. Exposures:Prediabetes and diabetes were defined according to the American Diabetes Association 2010 criteria. Seven ICVHMs were adapted from the American Heart Association recommendations. Main Outcomes and Measures:The composite of incident fatal or nonfatal CVD, including cardiovascular death, myocardial infarction, stroke, and hospitalized or treated heart failure. Results:Of the 111 765 participants, 24 881 (22.3%) had normal glucose regulation, 61 024 (54.6%) had prediabetes, and 25 860 (23.1%) had diabetes. Mean (SD) age ranged from 52.9 (8.6) years to 59.4 (8.7) years. Compared with participants with normal glucose regulation, among participants with prediabetes, the multivariable-adjusted hazard ratio for CVD was 1.34 (95% CI, 1.16-1.55) for participants who had 1 ICVHM or less and 0.57 (95% CI, 0.43-0.75) for participants who had at least 5 ICVHMs; among participants with diabetes, the hazard ratios for CVD were 2.05 (95% CI, 1.76-2.38) and 0.80 (95% CI, 0.56-1.15) for participants who had 1 ICVHM or less and at least 5 ICVHMs, respectively. Such pattern of association between ICVHMs and CVD was more prominent for participants younger than 55 years (prediabetes and at least 5 ICVHMs: hazard ratio [HR], 0.32; 95% CI, 0.16-0.63; 1 ICVHM or less: HR, 1.58; 95% CI, 1.13-2.21; diabetes and at least 5 ICVHMs: HR, 0.99; 95% CI, 0.44-2.26; 1 ICVHM or less: HR, 2.46; 95% CI, 1.71-3.54; compared with normal glucose regulation) than for participants 65 years or older (prediabetes and at least 5 ICVHMs: HR, 0.80; 95% CI, 0.50-1.26; 1 ICVHM or less: HR, 1.01; 95% CI, 0.79-1.31; diabetes and at least 5 ICVHMs: HR, 0.79; 95% CI, 0.46-1.35; 1 ICVHM or less: HR, 1.73; 95% CI, 1.36-2.22, compared with normal glucose regulation; P values for interaction ≤.02). Additionally, the hazard ratio for CVD per additional ICVHM was 0.82 (95% CI, 0.79-0.86) among participants with prediabetes and was 0.85 (95% CI, 0.80-0.89) among participants with diabetes. Conclusions and Relevance:Participants with prediabetes or diabetes who had 5 or more ICVHMs exhibited lower or no significant excess CVD risks compared with the participants with normal glucose regulation. 10.1001/jamacardio.2019.2499
    Prediabetes, Diabetes, and the Risk of All-Cause and Cause-Specific Mortality in a Japanese Working Population: Japan Epidemiology Collaboration on Occupational Health Study. Islam Zobida,Akter Shamima,Inoue Yosuke,Hu Huan,Kuwahara Keisuke,Nakagawa Tohru,Honda Toru,Yamamoto Shuichiro,Okazaki Hiroko,Miyamoto Toshiaki,Ogasawara Takayuki,Sasaki Naoko,Uehara Akihiko,Yamamoto Makoto,Kochi Takeshi,Eguchi Masafumi,Shirasaka Taiki,Shimizu Makiko,Nagahama Satsue,Hori Ai,Imai Teppei,Nishihara Akiko,Tomita Kentaro,Sone Tomofumi,Konishi Maki,Kabe Isamu,Mizoue Tetsuya,Dohi Seitaro, Diabetes care OBJECTIVE:Prediabetes has been suggested to increase risk for death; however, the definitions of prediabetes that can predict death remain elusive. We prospectively investigated the association of multiple definitions of prediabetes with the risk of death from all causes, cardiovascular disease (CVD), and cancer in Japanese workers. RESEARCH DESIGN AND METHODS:The study included 62,785 workers who underwent a health checkup in 2010 or 2011 and were followed up for death from 2012 to March 2019. Prediabetes was defined according to fasting plasma glucose (FPG) or glycated hemoglobin (HbA) values or a combination of both using the American Diabetes Association (ADA) or World Health Organization (WHO)/International Expert Committee (IEC) criteria. The Cox proportional hazards regression model was used to investigate the associations. RESULTS:Over a 7-year follow-up, 229 deaths were documented. Compared with normoglycemia, prediabetes defined according to ADA criteria was associated with a higher risk of all-cause mortality (hazard ratio [HR] 1.53; 95% CI 1.12-2.09) and death due to cancer (HR 2.37; 95% CI 1.45-3.89) but not with death due to CVD. The results were materially unchanged when prediabetes was defined according to ADA FPG, ADA HbA, WHO FPG, or combined WHO/IEC criteria. Diabetes was associated with the risk of all-cause, CVD, and cancer deaths. CONCLUSIONS:In a cohort of Japanese workers, FPG- and HbA-defined prediabetes, according to ADA or WHO/IEC, were associated with a significantly increased risk of death from all causes and cancer but not CVD. 10.2337/dc20-1213
    Glycated Hemoglobin, Prediabetes, and the Links to Cardiovascular Disease: Data From UK Biobank. Welsh Claire,Welsh Paul,Celis-Morales Carlos A,Mark Patrick B,Mackay Daniel,Ghouri Nazim,Ho Fredrick K,Ferguson Lyn D,Brown Rosemary,Lewsey James,Cleland John G,Gray Stuart R,Lyall Donald M,Anderson Jana J,Jhund Pardeep S,Pell Jill P,McGuire Darren K,Gill Jason M R,Sattar Naveed Diabetes care OBJECTIVE:HbA levels are increasingly measured in screening for diabetes; we investigated whether HbA may simultaneously improve cardiovascular disease (CVD) risk assessment, using QRISK3, American College of Cardiology/American Heart Association (ACC/AHA), and Systematic COronary Risk Evaluation (SCORE) scoring systems. RESEARCH DESIGN AND METHODS:UK Biobank participants without baseline CVD or known diabetes ( = 357,833) were included. Associations of HbA1c with CVD was assessed using Cox models adjusting for classical risk factors. Predictive utility was determined by the C-index and net reclassification index (NRI). A separate analysis was conducted in 16,596 participants with known baseline diabetes. RESULTS:Incident fatal or nonfatal CVD, as defined in the QRISK3 prediction model, occurred in 12,877 participants over 8.9 years. Of participants, 3.3% ( = 11,665) had prediabetes (42.0-47.9 mmol/mol [6.0-6.4%]) and 0.7% ( = 2,573) had undiagnosed diabetes (≥48.0 mmol/mol [≥6.5%]). In unadjusted models, compared with the reference group (<42.0 mmol/mol [<6.0%]), those with prediabetes and undiagnosed diabetes were at higher CVD risk: hazard ratio (HR) 1.83 (95% CI 1.69-1.97) and 2.26 (95% CI 1.96-2.60), respectively. After adjustment for classical risk factors, these attenuated to HR 1.11 (95% CI 1.03-1.20) and 1.20 (1.04-1.38), respectively. Adding HbA to the QRISK3 CVD risk prediction model (C-index 0.7392) yielded a small improvement in discrimination (C-index increase of 0.0004 [95% CI 0.0001-0.0007]). The NRI showed no improvement. Results were similar for models based on the ACC/AHA and SCORE risk models. CONCLUSIONS:The near twofold higher unadjusted risk for CVD in people with prediabetes is driven mainly by abnormal levels of conventional CVD risk factors. While HbA adds minimally to cardiovascular risk prediction, those with prediabetes should have their conventional cardiovascular risk factors appropriately measured and managed. 10.2337/dc19-1683
    Prediabetes and Risk for Cardiovascular Disease by Hypertension Status in Black Adults: The Jackson Heart Study. Hubbard Demetria,Colantonio Lisandro D,Tanner Rikki M,Carson April P,Sakhuja Swati,Jaeger Byron C,Carey Robert M,Cohen Laura P,Shimbo Daichi,Butler Mark,Bertoni Alain G,Langford Aisha T,Booth John N,Kalinowski Jolaade,Muntner Paul Diabetes care OBJECTIVE:Recent studies have suggested that prediabetes is associated with an increased risk for cardiovascular disease (CVD) only among individuals with concomitant hypertension. RESEARCH DESIGN AND METHODS:We analyzed the association between prediabetes and CVD by hypertension status among 3,313 black adults in the Jackson Heart Study (JHS) without diabetes or a history of CVD at baseline (2000-2004). Prediabetes was defined as fasting plasma glucose between 100 and 125 mg/dL or hemoglobin A between 5.7 and 6.4% (39 and 46 mmol/mol). Hypertension was defined as systolic/diastolic blood pressure ≥140/90 mmHg and/or self-reported antihypertensive medication use. Participants were followed for incident CVD events and all-cause mortality through 31 December 2014. RESULTS:Overall, 35% of JHS participants did not have prediabetes or hypertension, 18% had prediabetes alone, 22% had hypertension alone, and 25% had both prediabetes and hypertension. Compared with participants without either condition, the multivariable-adjusted hazard ratios for CVD events among participants with prediabetes alone, hypertension alone, and both prediabetes and hypertension were 0.86 (95% CI 0.51, 1.45), 2.09 (1.39, 3.14), and 1.93 (1.28, 2.90), respectively. Among participants with and without hypertension, there was no association between prediabetes and an increased risk for CVD (0.78 [0.46, 1.34] and 0.94 [0.70, 1.26], respectively). No association was present between prediabetes and all-cause mortality among participants with or without hypertension. CONCLUSIONS:Regardless of hypertension status, prediabetes was not associated with an increased risk for CVD or all-cause mortality in this cohort of black adults. 10.2337/dc19-1074
    Relative Risk of Cardiovascular Disease Is Higher in Women With Type 2 Diabetes, but Not in Those With Prediabetes, as Compared With Men. Succurro Elena,Fiorentino Teresa Vanessa,Miceli Sofia,Perticone Maria,Sciacqua Angela,Andreozzi Francesco,Sesti Giorgio Diabetes care OBJECTIVE:Most but not all studies suggest that women with type 2 diabetes have higher relative risk (RR) for cardiovascular disease (CVD) than men. More uncertainty exists on whether the RR for CVD is higher in women with prediabetes compared with men with prediabetes. RESEARCH DESIGN AND METHODS:In a cross-sectional study, in 3,540 adults with normal glucose tolerance (NGT), prediabetes, and diabetes, we compared the RR for prevalent nonfatal CVD between men and women. In a longitudinal study including 1,658 adults with NGT, prediabetes, and diabetes, we compared the RR for incidences of major adverse outcomes, including all-cause death, coronary heart disease, and cerebrovascular disease events, after 5.6 years of follow-up. RESULTS:Women with prediabetes and diabetes exhibited greater relative differences in BMI, waist circumference, blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, fasting glucose, hs-CRP, and white blood cell count than men with prediabetes and diabetes when compared with their NGT counterparts. We found a higher RR for prevalent CVD in women with diabetes (RR 9.29; 95% CI 4.73-18.25; < 0.0001) than in men (RR 4.56; 95% CI 3.07-6.77; < 0.0001), but no difference in RR for CVD was observed comparing women and men with prediabetes. In the longitudinal study, we found that women with diabetes, but not those with prediabetes, have higher RR (RR 5.25; 95% CI 3.22-8.56; < 0.0001) of incident major adverse outcomes than their male counterparts (RR 2.72; 95% CI 1.81-4.08; < 0.0001). CONCLUSIONS:This study suggests that women with diabetes, but not those with prediabetes, have higher RR for prevalent and incident major adverse outcomes than men. 10.2337/dc20-1401
    Both Prediabetes and Type 2 Diabetes Are Associated With Lower Heart Rate Variability: The Maastricht Study. Coopmans Charlotte,Zhou Tan Lai,Henry Ronald M A,Heijman Jordi,Schaper Nicolaas C,Koster Annemarie,Schram Miranda T,van der Kallen Carla J H,Wesselius Anke,den Engelsman Robert J A,Crijns Harry J G M,Stehouwer Coen D A Diabetes care OBJECTIVE:Low heart rate variability (HRV), a marker for cardiac autonomic dysfunction, is a known feature of type 2 diabetes, but it remains incompletely understood whether this also applies to prediabetes or across the whole glycemic spectrum. Therefore, we investigated the association among prediabetes, type 2 diabetes, and measures of glycemia and HRV. RESEARCH DESIGN AND METHODS:In the population-based Maastricht Study ( = 2,107; mean ± SD age 59 ± 8 years; 52% men; normal glucose metabolism [ = 1,226], prediabetes [ = 331], and type 2 diabetes [ = 550, oversampled]), we determined 24-h electrocardiogram-derived HRV in time and frequency domains (individual -scores, based upon seven and six variables, respectively). We used linear regression with adjustments for age, sex, and major cardiovascular risk factors. RESULTS:After adjustments, both time and frequency domain HRV were lower in prediabetes and type 2 diabetes as compared with normal glucose metabolism (standardized β [95% CI] for time domain: -0.15 [-0.27; -0.03] and -0.34 [-0.46; -0.22], respectively, for trend <0.001; for frequency domain: -0.14 [-0.26; -0.02] and -0.31 [-0.43; -0.19], respectively, for trend <0.001). In addition, 1-SD higher glycated hemoglobin, fasting plasma glucose, and 2-h postload glucose were associated with lower HRV in both domains (time domain: -0.16 [-0.21; -0.12], -0.16 [-0.21; -0.12], and -0.15 [-0.20; -0.10], respectively; frequency domain: -0.14 [-0.19; -0.10], -0.14 [-0.18; -0.09], and -0.13 [-0.18; -0.08], respectively). CONCLUSIONS:Both prediabetes and type 2 diabetes were independently associated with lower HRV. This is further substantiated by independent continuous associations between measures of hyperglycemia and lower HRV. These data strongly suggest that cardiac autonomic dysfunction is already present in prediabetes. 10.2337/dc19-2367
    Prevalence of Prediabetes Among Adolescents and Young Adults in the United States, 2005-2016. Andes Linda J,Cheng Yiling J,Rolka Deborah B,Gregg Edward W,Imperatore Giuseppina JAMA pediatrics Importance:Individuals with prediabetes are at increased risk of developing type 2 diabetes, chronic kidney disease, and cardiovascular disease. The incidence and prevalence of type 2 diabetes in the US adolescent population have increased in the last decade. Therefore, it is important to monitor the prevalence of prediabetes and varying levels of glucose tolerance to assess the future risk of type 2 diabetes in the youngest segment of the population. Objective:To examine the prevalence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and increased glycated hemoglobin A1c (HbA1c) levels in US adolescents (aged 12-18 years) and young adults (aged 19-34 years) without diabetes. Design, Setting, and Participants:This cross-sectional analyses of the 2005-2016 National Health and Nutrition Examination Survey assessed a population-based sample of adolescents and young adults who were not pregnant, did not have diabetes, and had measured fasting plasma glucose, 2-hour plasma glucose after a 75-g oral glucose tolerance test, and HbA1c levels. Analysis began in April 2017. Main Outcomes and Measures:Impaired fasting glucose was defined as fasting plasma glucose of 100 mg/dL to less than 126 mg/dL, IGT as 2-hour plasma glucose of 140 mg/dL to less than 200 mg/dL, and increased HbA1c level as HbA1c level between 5.7% and 6.4%. The prevalence of IFG, isolated IFG, IGT, isolated IGT, increased HbA1c level, isolated increased HbA1c level, and prediabetes (defined as having IFG, IGT, or increased HbA1c level) were estimated. Fasting insulin levels and cardiometabolic risk factors across glycemic abnormality phenotypes were also compared. Obesity was defined as having age- and sex-specific body mass index (calculated as weight in kilograms divided by height in meters squared) in the 95th percentile or higher in adolescents or 30 or higher in young adults. Results:Of 5786 individuals, 2606 (45%) were adolescents and 3180 (55%) were young adults. Of adolescents, 50.6% (95% CI, 47.6%-53.6%) were boys, and 50.6% (95% CI, 48.8%-52.4%) of young adults were men. Among adolescents, the prevalence of prediabetes was 18.0% (95% CI, 16.0%-20.1%) and among young adults was 24.0% (95% CI, 22.0%-26.1%). Impaired fasting glucose constituted the largest proportion of prediabetes, with prevalence of 11.1% (95% CI, 9.5%-13.0%) in adolescents and 15.8% (95% CI, 14.0%-17.9%) in young adults. In multivariable logistic models including age, sex, race/ethnicity, and body mass index, the predictive marginal prevalence of prediabetes was significantly higher in male than in female individuals (22.5% [95% CI, 19.5%-25.4%] vs 13.4% [95% CI, 10.8%-16.5%] in adolescents and 29.1% [95% CI, 26.4%-32.1%] vs 18.8% [95% CI, 16.5%-21.3%] in young adults). Prediabetes prevalence was significantly higher in individuals with obesity than in those with normal weight (25.7% [95% CI, 20.0%-32.4%] vs 16.4% [95% CI, 14.3%-18.7%] in adolescents and 36.9% [95% CI, 32.9%-41.1%] vs 16.6% [95% CI, 14.2%-19.4%] in young adults). Compared with persons with normal glucose tolerance, adolescents and young adults with prediabetes had significantly higher non-high-density lipoprotein cholesterol levels, systolic blood pressure, central adiposity, and lower insulin sensitivity (P < .05 for all). Conclusions and Relevance:In the United States, about 1 of 5 adolescents and 1 of 4 young adults have prediabetes. The adjusted prevalence of prediabetes is higher in male individuals and in people with obesity. Adolescents and young adults with prediabetes also present an unfavorable cardiometabolic risk profile, putting them both at increased risk of type 2 diabetes and cardiovascular diseases. 10.1001/jamapediatrics.2019.4498
    Mortality Implications of Prediabetes and Diabetes in Older Adults. Tang Olive,Matsushita Kunihiro,Coresh Josef,Sharrett A Richey,McEvoy John W,Windham B Gwen,Ballantyne Christie M,Selvin Elizabeth Diabetes care OBJECTIVE:Diabetes in older age is heterogeneous, and the treatment approach varies by patient characteristics. We characterized the short-term all-cause and cardiovascular mortality risk associated with hyperglycemia in older age. RESEARCH DESIGN AND METHODS:We included 5,791 older adults in the Atherosclerosis Risk in Communities Study who attended visit 5 (2011-2013; ages 66-90 years). We compared prediabetes (HbA 5.7% to <6.5%), newly diagnosed diabetes (HbA ≥6.5%, prior diagnosis <1 year, or taking antihyperglycemic medications <1 year), short-duration diabetes (duration ≥1 year but <10 years [median]), and long-standing diabetes (duration ≥10 years). Outcomes were all-cause and cardiovascular mortality (median follow-up of 5.6 years). RESULTS:Participants were 58% female, and 24% had prevalent cardiovascular disease. All-cause mortality rates, per 1,000 person-years, were 21.2 (95% CI 18.7, 24.1) among those without diabetes, 23.7 (95% CI 20.8, 27.1) for those with prediabetes, 33.8 (95% CI 25.2, 45.5) among those with recently diagnosed diabetes, 29.6 (95% CI 25.0, 35.1) for those with diabetes of short duration, and 48.6 (95% CI 42.4, 55.7) for those with long-standing diabetes. Cardiovascular mortality rates, per 1,000 person-years, were 5.8 (95% CI 4.6, 7.4) among those without diabetes, 6.6 (95% CI 5.2, 8.5) for those with prediabetes, 11.5 (95% CI 7.0, 19.1) among those with recently diagnosed diabetes, 8.2 (95% CI 5.9, 11.3) for those with diabetes of short duration, and 17.3 (95% CI 13.8, 21.7) for those with long-standing diabetes. After adjustment for other cardiovascular risk factors, prediabetes and newly diagnosed diabetes were not significantly associated with a higher risk of all-cause mortality (hazard ratio [HR] 1.03 [95% CI 0.85, 1.23] and HR 1.31 [95% CI 0.94, 1.82], respectively) or cardiovascular mortality (HR 1.00 [95% CI 0.70, 1.43] and HR 1.35 [95% CI 0.74, 2.49], respectively). Excess mortality risk was primarily concentrated among those with long-standing diabetes (all-cause: HR 1.71 [95% CI 1.40, 2.10]; cardiovascular: HR 1.72 [95% CI 1.18, 2.51]). CONCLUSIONS:In older adults, long-standing diabetes has a substantial and independent effect on short-term mortality. Older individuals with prediabetes remained at low mortality risk over a median 5.6 years of follow-up. 10.2337/dc19-1221
    Not Only Diabetes but Also Prediabetes Leads to Functional Decline and Disability in Older Adults. Shang Ying,Fratiglioni Laura,Vetrano Davide Liborio,Dove Abigail,Welmer Anna-Karin,Xu Weili Diabetes care OBJECTIVE:Diabetes is linked to functional decline, but the impact of prediabetes on physical function is unknown. We aimed to examine and compare the impact of prediabetes and diabetes on physical function and disability progression and to explore whether cardiovascular diseases (CVDs) mediate these associations. RESEARCH DESIGN AND METHODS:A cohort of 2,013 participants aged ≥60 from the Swedish National Study on Aging and Care in Kungsholmen, an ongoing population-based longitudinal study, was monitored for up to 12 years. Physical function was measured with chair stand (s) and walking speed (m/s) tests, and disability was measured by summing the numbers of impaired basic and instrumental activities of daily living. Diabetes was identified through medical examinations or clinical records, medication use, or glycated hemoglobin (HbA) ≥6.5%. Prediabetes was defined as HbA ≥5.7-6.4% in participants free of diabetes. CVDs were ascertained through clinical examinations and the National Patient Register. Data were analyzed using mixed-effect models and mediation models. RESULTS:At baseline, 650 (32.3%) had prediabetes and 151 had diabetes (7.5%). In multiadjusted mixed-effect models, prediabetes was associated with an increased chair stand time (β 0.33, 95% CI 0.05-0.61), a decreased walking speed (β -0.006, 95% CI -0.010 to -0.002), and an accelerated disability progression (β 0.05, 95% CI 0.01-0.08), even after controlling for the future development of diabetes. Diabetes led to faster functional decline than prediabetes. In mediation analyses, CVDs mediated 7.1%, 7.8%, and 20.9% of the associations between prediabetes and chair stand, walking speed, and disability progression, respectively. CONCLUSIONS:Prediabetes, in addition to diabetes, is associated with faster functional decline and disability, independent of the future development of diabetes. This association may be in part mediated by CVDs. 10.2337/dc20-2232
    Risk of Progression to Diabetes Among Older Adults With Prediabetes. Rooney Mary R,Rawlings Andreea M,Pankow James S,Echouffo Tcheugui Justin B,Coresh Josef,Sharrett A Richey,Selvin Elizabeth JAMA internal medicine Importance:The term prediabetes is used to identify individuals at increased risk for diabetes. However, the natural history of prediabetes in older age is not well characterized. Objectives:To compare different prediabetes definitions and characterize the risks of prediabetes and diabetes among older adults in a community-based setting. Design, Setting, and Participants:In this prospective cohort analysis of 3412 older adults without diabetes from the Atherosclerosis Risk in Communities Study (baseline, 2011-2013), participants were contacted semiannually through December 31, 2017, and attended a follow-up visit between January 1, 2016, and December 31, 2017 (median [range] follow-up, 5.0 [0.1-6.5] years). Exposures:Prediabetes defined by a glycated hemoglobin (HbA1c) level of 5.7% to 6.4%, impaired fasting glucose (IFG) level (FG level of 100-125 mg/dL), either, or both. Main Outcomes and Measures:Incident total diabetes (physician diagnosis, glucose-lowering medication use, HbA1c level ≥6.5%, or FG level ≥126 mg/dL). Results:A total of 3412 participants without diabetes (mean [SD] age, 75.6 [5.2] years; 2040 [60%] female; and 572 [17%] Black) attended visit 5 (2011-2013, baseline). Of the 3412 participants at baseline, a total of 2497 participants attended the follow-up visit or died. During the 6.5-year follow-up period, there were 156 incident total diabetes cases (118 diagnosed) and 434 deaths. A total of 1490 participants (44%) had HbA1c levels of 5.7% to 6.4%, 1996 (59%) had IFG, 2482 (73%) met the HbA1c or IFG criteria, and 1004 (29%) met both the HbA1c and IFG criteria. Among participants with HbA1c levels of 5.7% to 6.4% at baseline, 97 (9%) progressed to diabetes, 148 (13%) regressed to normoglycemia (HbA1c, <5.7%), and 207 (19%) died. Of those with IFG at baseline, 112 (8%) progressed to diabetes, 647 (44%) regressed to normoglycemia (FG, <100 mg/dL), and 236 (16%) died. Of those with baseline HbA1c levels less than 5.7%, 239 (17%) progressed to HbA1c levels of 5.7% to 6.4% and 41 (3%) developed diabetes. Of those with baseline FG levels less than 100 mg/dL, 80 (8%) progressed to IFG (FG, 100-125 mg/dL) and 26 (3%) developed diabetes. Conclusions and Relevance:In this community-based cohort study of older adults, the prevalence of prediabetes was high; however, during the study period, regression to normoglycemia or death was more frequent than progression to diabetes. These findings suggest that prediabetes may not be a robust diagnostic entity in older age. 10.1001/jamainternmed.2020.8774
    Metformin Should Not Be Used to Treat Prediabetes. Davidson Mayer B Diabetes care Based on the results of the Diabetes Prevention Program Outcomes Study (DPPOS), in which metformin significantly decreased the development of diabetes in individuals with baseline fasting plasma glucose (FPG) concentrations of 110-125 vs. 100-109 mg/dL (6.1-6.9 vs. 5.6-6.0 mmol/L) and A1C levels 6.0-6.4% (42-46 mmol/mol) vs. <6.0% and in women with a history of gestational diabetes mellitus, it has been suggested that metformin should be used to treat people with prediabetes. Since the association between prediabetes and cardiovascular disease is due to the associated nonglycemic risk factors in people with prediabetes, not to the slightly increased glycemia, the only reason to treat with metformin is to delay or prevent the development of diabetes. There are three reasons not to do so. First, approximately two-thirds of people with prediabetes do not develop diabetes, even after many years. Second, approximately one-third of people with prediabetes return to normal glucose regulation. Third, people who meet the glycemic criteria for prediabetes are not at risk for the microvascular complications of diabetes and thus metformin treatment will not affect this important outcome. Why put people who are not at risk for the microvascular complications of diabetes on a drug (possibly for the rest of their lives) that has no immediate advantage except to lower subdiabetes glycemia to even lower levels? Rather, individuals at the highest risk for developing diabetes-i.e., those with FPG concentrations of 110-125 mg/dL (6.1-6.9 mmol/L) or A1C levels of 6.0-6.4% (42-46 mmol/mol) or women with a history of gestational diabetes mellitus-should be followed closely and metformin immediately introduced only when they are diagnosed with diabetes. 10.2337/dc19-2221
    An investigation of causal relationships between prediabetes and vascular complications. Mutie Pascal M,Pomares-Millan Hugo,Atabaki-Pasdar Naeimeh,Jordan Nina,Adams Rachel,Daly Nicole L,Tajes Juan Fernandes,Giordano Giuseppe N,Franks Paul W Nature communications Prediabetes is a state of glycaemic dysregulation below the diagnostic threshold of type 2 diabetes (T2D). Globally, ~352 million people have prediabetes, of which 35-50% develop full-blown diabetes within five years. T2D and its complications are costly to treat, causing considerable morbidity and early mortality. Whether prediabetes is causally related to diabetes complications is unclear. Here we report a causal inference analysis investigating the effects of prediabetes in coronary artery disease, stroke and chronic kidney disease, complemented by a systematic review of relevant observational studies. Although the observational studies suggest that prediabetes is broadly associated with diabetes complications, the causal inference analysis revealed that prediabetes is only causally related with coronary artery disease, with no evidence of causal effects on other diabetes complications. In conclusion, prediabetes likely causes coronary artery disease and its prevention is likely to be most effective if initiated prior to the onset of diabetes. 10.1038/s41467-020-18386-9
    Prediabetes and What It Means: The Epidemiological Evidence. Echouffo-Tcheugui Justin B,Selvin Elizabeth Annual review of public health Prediabetes is an intermediate stage between normal glycemia and diabetes and is highly prevalent, especially in older age groups and obese individuals. Five different definitions of prediabetes are used in current practice, which are based on different cut points of HbA, fasting glucose, and 2-h glucose. A major challenge for the field is a lack of guidance on when one definition might be preferred over another. Risks of major complications in persons with prediabetes, including diabetes, cardiovascular disease, kidney disease, and death, also vary depending on the prediabetes definition used. Randomized clinical trials have demonstrated that lifestyle and pharmacologic interventions can be cost-effective, prevent diabetes, and improve cardiovascular risk factors in adults with prediabetes. However, the practical implementation of lifestyle modification or the use of metformin for treating prediabetes is inadequate and complicated by a lack of agreement on how to define the condition. Establishing consensus definitions for prediabetes should be a priority and will help inform expansion of insurance coverage for lifestyle modification and improve current screening and diagnostic practices. 10.1146/annurev-publhealth-090419-102644