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    Health Systems Approaches to Preventing Chronic Disease: New Partners, New Tools, and New Strategies. Michener J Lloyd,Briss Peter Preventing chronic disease 10.5888/pcd16.190248
    Evaluating the cost-effectiveness of lifestyle modification versus metformin therapy for the prevention of diabetes in Singapore. Png May Ee,Yoong Joanne Su-Yin PloS one BACKGROUND:In Singapore, as diabetes is an increasingly important public health issue, the cost-effectiveness of pursuing lifestyle modification programs and/or alternative prevention strategies is of critical importance for policymakers. While the US Diabetes Prevention Program (DPP) compared weight loss through lifestyle modification with oral treatment of diabetes drug metformin to prevent/delay the onset of type 2 diabetes in pre-diabetic subjects, no data on either the actual or potential cost effectiveness of such a program is available for East or South-east Asian populations. This study estimates the 3-year cost-effectiveness of lifestyle modification and metformin among pre-diabetic subjects from a Singapore health system and societal perspective. METHODOLOGY:Cost effectiveness was analysed from 2010-2012 using a decision-based model to estimate the rates of getting diabetes, healthcare costs and health-related quality of life. Cost per quality-adjusted life year (QALY) was estimated using costs relevant to the time horizon of the study from Singapore. All costs are expressed in 2012 US dollars. PRINCIPAL FINDINGS:The total economic cost for non-diabetic subjects from the societal perspective was US$25,867, US$28,108 and US$26,177 for placebo, lifestyle modification and metformin intervention respectively. For diabetic patients, the total economic cost from the societal perspective was US$32,921, US$35,163 and US$33,232 for placebo, lifestyle modification and metformin intervention respectively. Lifestyle modification relative to placebo is likely to be associated with an incremental cost per QALY gained at US$36,663 while that of metformin intervention is likely to be US$6,367 from a societal perspective. CONCLUSION:Based on adaptation of the DPP data to local conditions, both lifestyle modification and metformin intervention are likely to be cost-effective and worth implementing in Singapore to prevent or delay the onset of type 2 diabetes. However, the cost of lifestyle modification from the societal perspective would have to be reduced in order to match the cost-effectiveness of metformin intervention. 10.1371/journal.pone.0107225
    Correction. Circulation In the article by Mozaffarian et al, “Heart Disease and Stroke Statistics—2015 Update: A Report From the American Heart Association,” which published online December 17, 2014, and appeared in the January 27, 2015, issue of the journal (Circulation. 2015;131:e29–e322. DOI:10.1161/ CIR.0000000000000152), several corrections were needed. These corrections have been made to the current online version of the article, which is available at http://circ.ahajournals.org/content/131/4/e29.full. 10.1161/CIR.0000000000000219
    Ernst A,Schlattmann P,Waldfahrer F,Westhofen M Laryngo- rhino- otologie The BEMED study (BMJ 2016; 352: DOI 10.1136) was designed as multi-centric, double-blind, plaebo-controlled study in patients with Menière's disease. It should compare a low-level (2 × 24 mg/d) vs. high-level (3 × 48 mg/d) betahstine intake vs. placebo. The primary endpoint was the "number of vertigo attacks lasting longer than 20 min as documented in a patient's diary". The main finding of the study was that betahistine did not significantly better reduced the number of vertigo attacks than placebo. Therefore, the BEMED study should be critically discussed in the present paper. 10.1055/s-0043-113690
    Effectiveness of Program Modification Strategies of the Diabetes Prevention Program: A Systematic Review. Neamah Hind H,Sebert Kuhlmann Anne K,Tabak Rachel G The Diabetes educator PURPOSE:The purpose of this study is to review the effectiveness of commonly used program modifications classified under cultural adaptation and program translational strategies for the Diabetes Prevention Program (DPP) in terms of risk reduction for type 2 diabetes. METHODS:Authors extracted data about weight, body mass index (BMI), and 5 areas of program modification strategies from 28 interventions and analyzed them in SPSS software. Bivariate analyses examined the odds of achieving a significant reduction in outcomes by each modification of the DPP and by presence of a maintenance component, as well as the mean reduction of weight and BMI by more versus fewer modifications and by the presence of a maintenance component. RESULTS:There were no statistically significant differences in achieving a significant reduction in weight or BMI by any type of modification or by the presence of a maintenance component. Programs with fewer modifications reported significantly greater reduction in mean weight at 12 months postintervention and the furthest time point extracted. Programs with a maintenance component achieved significantly greater reduction in mean weight measured at the furthest time point extracted. CONCLUSIONS:The DPP appears to be programmatically robust to a variety of cultural adaptation and translational strategies. Potentially cost-saving modifications do not seem to reduce effectiveness, which should encourage implementation on a broader scale. Program planners should, however, make efforts to include maintenance components because they appear to significantly reduce risk for acquiring type 2 diabetes. 10.1177/0145721716630386
    The Effectiveness and Cost of Lifestyle Interventions Including Nutrition Education for Diabetes Prevention: A Systematic Review and Meta-Analysis. Sun Yu,You Wen,Almeida Fabio,Estabrooks Paul,Davy Brenda Journal of the Academy of Nutrition and Dietetics BACKGROUND:Type 2 diabetes is a significant public health concern. With the completion of the Diabetes Prevention Program, there has been a proliferation of studies attempting to translate this evidence base into practice. However, the cost, effectiveness, and cost-effectiveness of these adapted interventions is unknown. OBJECTIVE:The purpose of this systematic review was to conduct a comprehensive meta-analysis to synthesize the effectiveness, cost, and cost-effectiveness of lifestyle diabetes prevention interventions and compare effects by intervention delivery agent (dietitian vs non-dietitian) and channel (in-person vs technology-delivered). METHODS:English and full-text research articles published up to July 2015 were identified using the Cochrane Library, PubMed, Education Resources Information Center, CAB Direct, Science Direct, and Google Scholar. Sixty-nine studies met inclusion criteria. Most employed both dietary and physical activity intervention components (four of 69 were diet-only interventions). Changes in weight, fasting and 2-hour blood glucose concentration, and hemoglobin A1c were extracted from each article. Heterogeneity was measured by the I index, and study-specific effect sizes or mean differences were pooled using a random effects model when heterogeneity was confirmed. RESULTS:Participants receiving intervention with nutrition education experienced a reduction of 2.07 kg (95% CI 1.52 to 2.62; P<0.001; I=90.99%, 95% CI 88.61% to 92.87%) in weight at 12 months with effect sizes over time ranging from small (0.17, 95% CI 0.04 to 0.30; P=0.012; I= 86.83%, 95% CI 80.42% to 91.14%) to medium (0.65, 95% CI 0.49 to 0.82; P<0.001; I=98.75%, 95% CI 98.52% to 98.94). Effect sizes for 2-hour blood glucose and hemoglobin A1c level changes ranged from small to medium. The meta-regression analysis revealed a larger relative weight loss in dietitian-delivered interventions than in those delivered by nondietitians (full sample: -1.0 kg; US subsample: -2.4 kg), and did not find statistical evidence that the delivery channel was an important predictor of weight loss. The average cost per kilogram weight loss ranged from $34.06 over 6 months to $1,005.36 over 12 months. The cost of intervention per participant delivered by dietitians was lower than interventions delivered by non-dietitians, although few studies reported costs. CONCLUSIONS:Lifestyle interventions are effective in reducing body weight and glucose-related outcomes. Dietitian-delivered interventions, compared with those delivered by other personnel, achieved greater weight reduction. No consistent trend was identified across different delivery channels. 10.1016/j.jand.2016.11.016
    Preventing type 2 diabetes: systematic review of studies of cost-effectiveness of lifestyle programmes and metformin, with and without screening, for pre-diabetes. Roberts Samantha,Barry Eleanor,Craig Dawn,Airoldi Mara,Bevan Gwyn,Greenhalgh Trisha BMJ open OBJECTIVE:Explore the cost-effectiveness of lifestyle interventions and metformin in reducing subsequent incidence of type 2 diabetes, both alone and in combination with a screening programme to identify high-risk individuals. DESIGN:Systematic review of economic evaluations. DATA SOURCES AND ELIGIBILITY CRITERIA:Database searches (Embase, Medline, PreMedline, NHS EED) and citation tracking identified economic evaluations of lifestyle interventions or metformin alone or in combination with screening programmes in people at high risk of developing diabetes. The International Society for Pharmaco-economics and Outcomes Research's Questionnaire to Assess Relevance and Credibility of Modelling Studies for Informing Healthcare Decision Making was used to assess study quality. RESULTS:27 studies were included; all had evaluated lifestyle interventions and 12 also evaluated metformin. Primary studies exhibited considerable heterogeneity in definitions of pre-diabetes and intensity and duration of lifestyle programmes. Lifestyle programmes and metformin appeared to be cost effective in preventing diabetes in high-risk individuals (median incremental cost-effectiveness ratios of £7490/quality-adjusted life-year (QALY) and £8428/QALY, respectively) but economic estimates varied widely between studies. Intervention-only programmes were in general more cost effective than programmes that also included a screening component. The longer the period evaluated, the more cost-effective interventions appeared. In the few studies that evaluated other economic considerations, budget impact of prevention programmes was moderate (0.13%-0.2% of total healthcare budget), financial payoffs were delayed (by 9-14 years) and impact on incident cases of diabetes was limited (0.1%-1.6% reduction). There was insufficient evidence to answer the question of (1) whether lifestyle programmes are more cost effective than metformin or (2) whether low-intensity lifestyle interventions are more cost effective than the more intensive lifestyle programmes that were tested in trials. CONCLUSIONS:The economics of preventing diabetes are complex. There is some evidence that diabetes prevention programmes are cost effective, but the evidence base to date provides few clear answers regarding design of prevention programmes because of differences in denominator populations, definitions, interventions and modelling assumptions. 10.1136/bmjopen-2017-017184
    Economic Evaluation of Combined Diet and Physical Activity Promotion Programs to Prevent Type 2 Diabetes Among Persons at Increased Risk: A Systematic Review for the Community Preventive Services Task Force. Li Rui,Qu Shuli,Zhang Ping,Chattopadhyay Sajal,Gregg Edward W,Albright Ann,Hopkins David,Pronk Nicolaas P Annals of internal medicine BACKGROUND:Diabetes is a highly prevalent and costly disease. Studies indicate that combined diet and physical activity promotion programs can prevent type 2 diabetes among persons at increased risk. PURPOSE:To systematically evaluate the evidence on cost, cost-effectiveness, and cost-benefit estimates of diet and physical activity promotion programs. DATA SOURCES:Cochrane Library, EMBASE, MEDLINE, PsycINFO, Sociological Abstracts, Web of Science, EconLit, and CINAHL through 7 April 2015. STUDY SELECTION:English-language studies from high-income countries that provided data on cost, cost-effectiveness, or cost-benefit ratios of diet and physical activity promotion programs with at least 2 sessions over at least 3 months delivered to persons at increased risk for type 2 diabetes. DATA EXTRACTION:Dual abstraction and assessment of relevant study details. DATA SYNTHESIS:Twenty-eight studies were included. Costs were expressed in 2013 U.S. dollars. The median program cost per participant was $653. Costs were lower for group-based programs (median, $417) and programs implemented in community or primary care settings (median, $424) than for the U.S. DPP (Diabetes Prevention Program) trial and the DPP Outcomes Study ($5881). Twenty-two studies assessed the incremental cost-effectiveness ratios (ICERs) of the programs. From a health system perspective, 16 studies reported a median ICER of $13 761 per quality-adjusted life-year (QALY) saved. Group-based programs were more cost-effective (median, $1819 per QALY) than those that used individual sessions (median, $15 846 per QALY). No cost-benefit studies were identified. LIMITATION:Information on recruitment costs and cost-effectiveness of translational programs implemented in community and primary care settings was limited. CONCLUSION:Diet and physical activity promotion programs to prevent type 2 diabetes are cost-effective among persons at increased risk. Costs are lower when programs are delivered to groups in community or primary care settings. PRIMARY FUNDING SOURCE:None. 10.7326/M15-0469
    2. Classification and Diagnosis of Diabetes: . Diabetes care The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee (https://doi.org/10.2337/dc20-SPPC), a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. 10.2337/dc20-S002
    Preventing type 2 diabetes in communities across the U.S.: the National Diabetes Prevention Program. Albright Ann L,Gregg Edward W American journal of preventive medicine There are as many as 79 million people in the U.S. with prediabetes, and their risk of developing type 2 diabetes is four to 12 times higher than it is for people with normal glucose tolerance. Although advances in diabetes treatment are still needed, there is a critical need to implement effective strategies to stem the current and projected growth in new cases of type 2 diabetes. RCTs and translation studies have demonstrated that type 2 diabetes can be prevented or delayed in those at high risk, through a structured lifestyle intervention that can be delivered cost effectively. In order to bring this compelling lifestyle intervention to communities across America, Congress authorized the CDC to establish and lead the National Diabetes Prevention Program. Several aspects of the etiology of type 2 diabetes suggest that strategies addressing both those at high risk and the general population are necessary to make a major impact on the diabetes epidemic. 10.1016/j.amepre.2012.12.009
    Impact of the Berkeley Excise Tax on Sugar-Sweetened Beverage Consumption. Falbe Jennifer,Thompson Hannah R,Becker Christina M,Rojas Nadia,McCulloch Charles E,Madsen Kristine A American journal of public health OBJECTIVES:To evaluate the impact of the excise tax on sugar-sweetened beverage (SSB) consumption in Berkeley, California, which became the first US jurisdiction to implement such a tax ($0.01/oz) in March 2015. METHODS:We used a repeated cross-sectional design to examine changes in pre- to posttax beverage consumption in low-income neighborhoods in Berkeley versus in the comparison cities of Oakland and San Francisco, California. A beverage frequency questionnaire was interviewer administered to 990 participants before the tax and 1689 after the tax (approximately 8 months after the vote and 4 months after implementation) to examine relative changes in consumption. RESULTS:Consumption of SSBs decreased 21% in Berkeley and increased 4% in comparison cities (P = .046). Water consumption increased more in Berkeley (+63%) than in comparison cities (+19%; P < .01). CONCLUSIONS:Berkeley's excise tax reduced SSB consumption in low-income neighborhoods. Evaluating SSB taxes in other cities will improve understanding of their public health benefit and their generalizability. 10.2105/AJPH.2016.303362
    Beverages Sales in Mexico before and after Implementation of a Sugar Sweetened Beverage Tax. Colchero M A,Guerrero-López Carlos Manuel,Molina Mariana,Rivera Juan Angel PloS one OBJECTIVE:To estimate changes in sales of sugar sweetened beverages (SSB) and plain water after a 1 peso per liter excise SSB tax was implemented in Mexico in January 2014. MATERIAL AND METHODS:We used sales data from the Monthly Surveys of the Manufacturing Industry from January 2007 to December 2015. We estimated Ordinary Least Squares models to assess changes in per capita sales of SSB and plain water adjusting for seasonality and the global indicator of economic activity. RESULTS:We found a decrease of 7.3% in per capita sales of SSB and an increase of 5.2% of per capita sales of plain water in 2014-2015 compared to the pre-tax period (2007-2013). CONCLUSIONS:Adjusting for variables that change over time and that are associated with the demand for SSB, we found the tax was associated with a reduction in per capita sales of SSB. The effectiveness of the tax should be evaluated in the medium and long term. 10.1371/journal.pone.0163463
    An economic evaluation for prevention of diabetes mellitus in a developing country: a modelling study. Liu Xiaoqian,Li Changping,Gong Hui,Cui Zhuang,Fan Linlin,Yu Wenhua,Zhang Cui,Ma Jun BMC public health BACKGROUND:The serious consequences of diabetes mellitus, and the subsequent economic burden, call for urgent preventative action in developing countries. This study explores the clinical and economic outcomes of strategies that could potentially prevent diabetes based on Chinese circumstances. It aims to provide indicators for the long-term allocation of healthcare resources for authorities in developing countries. METHODS:A representative sample of Chinese adults was used to create a simulated population of 20,000 people aged 25 years and above. The hybrid decision tree Markov model was developed to compare the long-term clinical and economic outcomes of four simulated diabetes prevention strategies with a control group, where no prevention applied. These preventive strategies were the following: (i) one-off screening for undiagnosed diabetes and impaired glucose tolerance (IGT), with lifestyle interventions on diet, (ii) on exercise, (iii) on diet combined exercise (duo-intervention) respectively in those with IGT, and (iv) one-off screening alone. Independent age-specific models were simulated based on diverse incidences of diabetes, mortalities and health utilities. The reported outcomes were the following: the remaining survival years, the quality-adjusted life years (QALYs) per diabetes or IGT subjects, societal costs per simulated subject and the comparisons between preventions and control over 40 years. Sensitivity analyses were performed based on variations of all assumptions, in addition to the performance and the compliance of screening. RESULTS:Compared with the control group, all simulated screening programmes prolonged life expectancy at the initiation ages of 25 and 40 years, postponed the onset of diabetes and increased QALYs at every initiation age. Along with an assumption of six years intervention, prevention programmes were associated with cost-saving compared with the control group, especially in the population aged 25 years. The savings were at least US$2017 per subject, but no statistically significant difference was observed among the intervention strategies within each age groups. The cost savings were reduced when screening was affected by poor performance and noncompliance. CONCLUSIONS:Developing countries have few effective strategies to manage the prevention of diabetes. One-off screening for undiagnosed diabetes and IGT, with appropriate lifestyle interventions for those with IGT are cost saving in China, especially in young adults. 10.1186/1471-2458-13-729
    Estimating the cost-effectiveness of lifestyle intervention programmes to prevent diabetes based on an example from Germany: Markov modelling. Neumann Anne,Schwarz Peter,Lindholm Lars Cost effectiveness and resource allocation : C/E BACKGROUND:Type 2 diabetes mellitus (T2D) poses a large worldwide burden for health care systems. One possible tool to decrease this burden is primary prevention. As it is unethical to wait until perfect data are available to conclude whether T2D primary prevention intervention programmes are cost-effective, we need a model that simulates the effect of prevention initiatives. Thus, the aim of this study is to investigate the long-term cost-effectiveness of lifestyle intervention programmes for the prevention of T2D using a Markov model. As decision makers often face difficulties in applying health economic results, we visualise our results with health economic tools. METHODS:We use four-state Markov modelling with a probabilistic cohort analysis to calculate the cost per quality-adjusted life year (QALY) gained. A one-year cycle length and a lifetime time horizon are applied. Best available evidence supplies the model with data on transition probabilities between glycaemic states, mortality risks, utility weights, and disease costs. The costs are calculated from a societal perspective. A 3% discount rate is used for costs and QALYs. Cost-effectiveness acceptability curves are presented to assist decision makers. RESULTS:The model indicates that diabetes prevention interventions have the potential to be cost-effective, but the outcome reveals a high level of uncertainty. Incremental cost-effectiveness ratios (ICERs) were negative for the intervention, ie, the intervention leads to a cost reduction for men and women aged 30 or 50 years at initiation of the intervention. For men and women aged 70 at initiation of the intervention, the ICER was EUR27,546/QALY gained and EUR19,433/QALY gained, respectively. In all cases, the QALYs gained were low. Cost-effectiveness acceptability curves show that the higher the willingness-to-pay threshold value, the higher the probability that the intervention is cost-effective. Nonetheless, all curves are flat. The threshold value of EUR50,000/QALY gained has a 30-55% probability that the intervention is cost-effective. CONCLUSIONS:Lifestyle interventions for primary prevention of type 2 diabetes are cost-saving for men and women aged 30 or 50 years at the start of the intervention, and cost-effective for men and women aged 70 years. However, there is a high degree of uncertainty around the ICERs. With the conservative approach adopted for this model, the long-term effectiveness of the intervention could be underestimated. 10.1186/1478-7547-9-17
    Cost-effectiveness of alternative thresholds of the fasting plasma glucose test to identify the target population for type 2 diabetes prevention in adults aged ≥45 years. Zhuo Xiaohui,Zhang Ping,Kahn Henry S,Gregg Edward W Diabetes care OBJECTIVE:The study objective was to evaluate the cost-effectiveness of alternative fasting plasma glucose (FPG) thresholds to identify adults at high risk for type 2 diabetes for diabetes preventive intervention. RESEARCH DESIGN AND METHODS:We used a validated simulation model to examine the change in lifetime quality-adjusted life years (QALYs) and medical costs when the FPG threshold was progressively lowered in 5-mg/dL decrements from 120 to 90 mg/dL. The study sample includes nondiabetic adults aged ≥45 years in the United States using 2006-2010 data from the National Health and Nutrition Examination Survey. High-risk individuals were assumed to receive a lifestyle intervention, as that used in the Diabetes Prevention Program. We calculated cost per QALY by dividing the incremental cost by incremental QALY when lowering the threshold to the next consecutive level. Medical costs were assessed from a health care system perspective. We conducted univariate and probabilistic sensitivity analyses to assess the robustness of the results using different simulation scenarios and parameters. RESULTS:Progressively lowering the FPG threshold would monotonically increase QALYs, cost, and cost per QALY. Reducing (in 5-mg/dL decrements) the threshold from 120 to 90 mg/dL cost $30,100, $32,900, $42,300, $60,700, $81,800, and $115,800 per QALY gained, respectively. The costs per QALY gained were lower for all thresholds under a lower-cost and less-effective intervention scenario. CONCLUSIONS:Lowering the FPG threshold leads to a greater health benefit of diabetes prevention but reduces the cost-effectiveness. Using the conventional benchmark of $50,000 per QALY, a threshold of 105 mg/dL or higher would be cost effective. A lower threshold could be selected if the intervention cost could be lowered. 10.2337/dc13-0497
    Medicare's intensive behavioral therapy for obesity: an exploratory cost-effectiveness analysis. Hoerger Thomas J,Crouse Wesley L,Zhuo Xiaohui,Gregg Edward W,Albright Ann L,Zhang Ping American journal of preventive medicine INTRODUCTION:Medicare coverage recently was expanded to include intensive behavioral therapy for obese individuals in primary care settings. PURPOSE:To examine the potential cost effectiveness of Medicare's intensive behavioral therapy for obesity, accounting for uncertainty in effectiveness and utilization. METHODS:A Markov simulation model of type 2 diabetes was used to estimate long-term health benefits and healthcare system costs of intensive behavioral therapy for obesity in the Medicare population without diabetes relative to an alternative of usual care. Cohort statistics were based on the 2005-2008 National Health and Nutrition Examination Survey. Model parameters were derived from the literature. Analyses were conducted in 2014 and reported in 2012 U.S. dollars. RESULTS:Based on assumptions for the maximal intervention effectiveness, intensive behavioral therapy is likely to be cost saving if costs per session equal the current reimbursement rate ($25.19) and will provide a cost-effectiveness ratio of $20,912 per quality-adjusted life-year if costs equal the rate for routine office visits. The intervention is less cost effective if it is less effective in primary care settings or if fewer intervention sessions are supplied by providers or used by participants. CONCLUSIONS:If the effectiveness of the intervention is similar to lifestyle interventions tested in other settings and costs per session equal the current reimbursement rate, intensive behavioral therapy for obesity offers good value. However, intervention effectiveness and the pattern of implementation and utilization strongly influence cost effectiveness. Given uncertainty regarding these factors, additional data might be collected to validate the modeling results. 10.1016/j.amepre.2014.11.008
    The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention: an intent-to-treat analysis of the DPP/DPPOS. Diabetes care OBJECTIVE:The Diabetes Prevention Program (DPP) and its Outcomes Study (DPPOS) demonstrated that either intensive lifestyle intervention or metformin could prevent type 2 diabetes in high-risk adults for at least 10 years after randomization. We report the 10-year within-trial cost-effectiveness of the interventions. RESEARCH DESIGN AND METHODS:Data on resource utilization, cost, and quality of life were collected prospectively. Economic analyses were performed from health system and societal perspectives. RESULTS:Over 10 years, the cumulative, undiscounted per capita direct medical costs of the interventions, as implemented during the DPP, were greater for lifestyle ($4,601) than metformin ($2,300) or placebo ($769). The cumulative direct medical costs of care outside the DPP/DPPOS were least for lifestyle ($24,563 lifestyle vs. $25,616 metformin vs. $27,468 placebo). The cumulative, combined total direct medical costs were greatest for lifestyle and least for metformin ($29,164 lifestyle vs. $27,915 metformin vs. $28,236 placebo). The cumulative quality-adjusted life-years (QALYs) accrued over 10 years were greater for lifestyle (6.81) than metformin (6.69) or placebo (6.67). When costs and outcomes were discounted at 3%, lifestyle cost $10,037 per QALY, and metformin had slightly lower costs and nearly the same QALYs as placebo. CONCLUSIONS:Over 10 years, from a payer perspective, lifestyle was cost-effective and metformin was marginally cost-saving compared with placebo. Investment in lifestyle and metformin interventions for diabetes prevention in high-risk adults provides good value for the money spent. 10.2337/dc11-1468
    Alternative HbA1c cutoffs to identify high-risk adults for diabetes prevention: a cost-effectiveness perspective. Zhuo Xiaohui,Zhang Ping,Selvin Elizabeth,Hoerger Thomas J,Ackermann Ronald T,Li Rui,Bullard Kai McKeever,Gregg Edward W American journal of preventive medicine BACKGROUND:New recommendations about the use of hemoglobin A1c (HbA1c) for diagnosing diabetes have stimulated a debate about the optimal HbA1c cutoff to identify prediabetes for preventive intervention. PURPOSE:To assess the cost effectiveness associated with the alternative HbA1c cutoffs for identifying prediabetes. METHODS:A Markov simulation model was used to examine the cost effectiveness associated with a progressive 0.1% decrease in the HbA1c cutoff from 6.4% to 5.5%. The target population was the U.S. nondiabetic population aged ≥18 years. The simulation sample was created using the data of nondiabetic American adults from the National Health and Nutritional Examination Survey (NHANES 1999-2006). People identified as having prediabetes were assumed to receive a preventive intervention, with effectiveness the same as that in the Diabetes Prevention Program study under a high-cost intervention (HCI) scenario and in the Promoting a Lifestyle of Activity and Nutrition for Working to Alter the Risk of Diabetes study under a low-cost intervention (LCI) scenario. The analysis was conducted for a lifetime horizon from a healthcare system perspective. RESULTS:Lowering the HbA1c cutoff would increase the health benefits of the preventive interventions at higher costs. For the HCI, lowering the HbA1c cutoff from 6.0% to 5.9% and from 5.9% to 5.8% would result in $27,000 and $34,000 per QALY gained, respectively. Continuing to decrease the cutoff from 5.8% to 5.7%, from 5.7% to 5.6%, and from 5.6% to 5.5% would cost $45,000, $58,000, and $96,000 per QALY gained, respectively. For the LCI, lowering the HbA1c cutoff from 6.0% to 5.9% and from 5.9% to 5.8% would result in $24,000 and $27,000 per QALY gained, respectively. Continuing to lower the cutoff from 5.8% to 5.7%, 5.7% to 5.6%, and 5.6% to 5.5% would cost $34,000, $43,000 and $70,000 per QALY gained, respectively. CONCLUSIONS:Lowering the HbA1c cutoff for prediabetes leads to less cost-effective preventive interventions. Assuming a conventional $50,000/QALY cost-effectiveness benchmark, the HbA1c cutoffs of 5.7% and higher were found to be cost effective. Lowering the cutoff from 5.7% to 5.6% also may be cost effective, however, if the costs of preventive interventions were to be lowered. 10.1016/j.amepre.2012.01.003
    The impact of Type 2 diabetes prevention programmes based on risk-identification and lifestyle intervention intensity strategies: a cost-effectiveness analysis. Breeze P R,Thomas C,Squires H,Brennan A,Greaves C,Diggle P J,Brunner E,Tabak A,Preston L,Chilcott J Diabetic medicine : a journal of the British Diabetic Association AIMS:To develop a cost-effectiveness model to compare Type 2 diabetes prevention programmes targeting different at-risk population subgroups with a lifestyle intervention of varying intensity. METHODS:An individual patient simulation model was constructed to simulate the development of diabetes in a representative sample of adults without diabetes from the UK population. The model incorporates trajectories for HbA , 2-h glucose, fasting plasma glucose, BMI, systolic blood pressure, total cholesterol and HDL cholesterol. Patients can be diagnosed with diabetes, cardiovascular disease, microvascular complications of diabetes, cancer, osteoarthritis and depression, or can die. The model collects costs and utilities over a lifetime horizon. The perspective is the UK National Health Service and personal social services. We used the model to evaluate the population-wide impact of targeting a lifestyle intervention of varying intensity to six population subgroups defined as high risk for diabetes. RESULTS:The intervention produces 0.0003 to 0.0009 incremental quality-adjusted life years and saves up to £1.04 per person in the general population, depending upon the subgroup targeted. Cost-effectiveness increases with intervention intensity. The most cost-effective options are to target individuals with HbA > 42 mmol/mol (6%) or with a high Finnish Diabetes Risk (FINDRISC) probability score (> 0.1). CONCLUSION:The model indicates that diabetes prevention interventions are likely to be cost-effective and may be cost-saving over a lifetime. In the model, the criteria for selecting at-risk individuals differentially impact upon diabetes and cardiovascular disease outcomes, and on the timing of benefits. These findings have implications for deciding who should be targeted for diabetes prevention interventions. 10.1111/dme.13314
    Different strategies for screening and prevention of type 2 diabetes in adults: cost effectiveness analysis. Gillies Clare L,Lambert Paul C,Abrams Keith R,Sutton Alex J,Cooper Nicola J,Hsu Ron T,Davies Melanie J,Khunti Kamlesh BMJ (Clinical research ed.) OBJECTIVE:To compare four potential screening strategies, and subsequent interventions, for the prevention and treatment of type 2 diabetes: (a) screening for type 2 diabetes to enable early detection and treatment, (b) screening for type 2 diabetes and impaired glucose tolerance, intervening with lifestyle interventions in those with a diagnosis of impaired glucose tolerance to delay or prevent diabetes, (c) as for (b) but with pharmacological interventions, and (d) no screening. DESIGN:Cost effectiveness analysis based on development and evaluation of probabilistic, comprehensive economic decision analytic model, from screening to death. SETTING:A hypothetical population, aged 45 at time of screening, with above average risk of diabetes. DATA SOURCES:Published clinical trials and epidemiological studies retrieved from electronic bibliographic databases; supplementary data obtained from the Department of Health statistics for England and Wales, the screening those at risk (STAR) study, and the Leicester division of the ADDITION study. METHODS:A hybrid decision tree/Markov model was developed to simulate the long term effects of each screening strategy, in terms of both clinical and cost effectiveness outcomes. The base case model assumed a 50 year time horizon with discounting of both costs and benefits at 3.5%. Sensitivity analyses were carried out to investigate assumptions of the model and to identify which model inputs had most impact on the results. RESULTS:Estimated costs for each quality adjusted life year (QALY) gained (discounted at 3.5% a year for both costs and benefits) were pound14,150 (euro17 560; $27,860) for screening for type 2 diabetes, pound6242 for screening for diabetes and impaired glucose tolerance followed by lifestyle interventions, and pound7023 for screening for diabetes and impaired glucose tolerance followed by pharmacological interventions, all compared with no screening. At a willingness-to-pay threshold of pound20,000 the probability of the intervention being cost effective was 49%, 93%, and 85% for each of the active screening strategies respectively. CONCLUSIONS:Screening for type 2 diabetes and impaired glucose tolerance, with appropriate intervention for those with impaired glucose tolerance, in an above average risk population aged 45, seems to be cost effective. The cost effectiveness of a policy of screening for diabetes alone, which offered no intervention to those with impaired glucose tolerance, is still uncertain. 10.1136/bmj.39545.585289.25
    Using an economic model of diabetes to evaluate prevention and care strategies in Australia. Colagiuri Stephen,Walker Agnes E Health affairs (Project Hope) The health benefits and costs of a national diabetes screening and prevention scenario are estimated among Australians ages 45-74. The Australian Diabetes Cost-Benefit Model is used to compare baseline and scenario outcomes from 2000 to 2010. Those newly diagnosed in 2000 receive intensive care, resulting in lower complication rates. People "at high risk" of developing diabetes are offered lifestyle intervention, reducing the numbers developing diabetes. A total of 115,000 people became "newly diagnosed." Among those deemed at high risk, 53,000 avoided developing diabetes by 2010. Average yearly intervention and incremental treatment cost was AU$179 million, with a cost per disability-adjusted life-year of AU$50,000. 10.1377/hlthaff.27.1.256
    Screening adults for pre-diabetes and diabetes may be cost-saving. Diabetes care OBJECTIVE:The economic costs of hyperglycemia are substantial. Early detection would allow management to prevent or delay development of diabetes and diabetes-related complications. We investigated the economic justification for screening for pre-diabetes/diabetes. RESEARCH DESIGN AND METHODS:We projected health system and societal costs over 3 years for 1,259 adults, comparing costs associated with five opportunistic screening tests. All subjects had measurements taken of random plasma and capillary glucose (RPG and RCG), A1C, and plasma and capillary glucose 1 h after a 50 g oral glucose challenge test without prior fasting (GCT-pl and GCT-cap), and a subsequent diagnostic 75 g oral glucose tolerance test (OGTT). RESULTS:Assuming 70% specificity screening cutoffs, Medicare costs for testing, retail costs for generic metformin, and costs for false negatives as 10% of reported costs associated with pre-diabetes/diabetes, health system costs over 3 years for the different screening tests would be GCT-pl $180,635; GCT-cap $182,980; RPG $182,780; RCG $186,090; and A1C $192,261; all lower than costs for no screening, which would be $205,966. Under varying assumptions, projected health system costs for screening and treatment with metformin or lifestyle modification would be less than costs for no screening as long as disease prevalence is at least 70% of that of our population and false-negative costs are at least 10% of disease costs. Societal costs would equal or exceed costs of no screening depending on treatment type. CONCLUSIONS:Screening appears to be cost-saving compared to no screening from a health system perspective, and potentially cost-neutral from a societal perspective. These data suggest that strong consideration should be given to screening-with preventive management-and that use of GCTs may be cost-effective. 10.2337/dc10-0054
    Cost-effectiveness of interventions to prevent and control diabetes mellitus: a systematic review. Diabetes care OBJECTIVE:To synthesize the cost-effectiveness (CE) of interventions to prevent and control diabetes, its complications, and comorbidities. RESEARCH DESIGN AND METHODS:We conducted a systematic review of literature on the CE of diabetes interventions recommended by the American Diabetes Association (ADA) and published between January 1985 and May 2008. We categorized the strength of evidence about the CE of an intervention as strong, supportive, or uncertain. CEs were classified as cost saving (more health benefit at a lower cost), very cost-effective (<or=$25,000 per life year gained [LYG] or quality-adjusted life year [QALY]), cost-effective ($25,001 to $50,000 per LYG or QALY), marginally cost-effective ($50,001 to $100,000 per LYG or QALY), or not cost-effective (>$100,000 per LYG or QALY). The CE classification of an intervention was reported separately by country setting (U.S. or other developed countries) if CE varied by where the intervention was implemented. Costs were measured in 2007 U.S. dollars. RESULTS:Fifty-six studies from 20 countries met the inclusion criteria. A large majority of the ADA recommended interventions are cost-effective. We found strong evidence to classify the following interventions as cost saving or very cost-effective: (I) Cost saving- 1) ACE inhibitor (ACEI) therapy for intensive hypertension control compared with standard hypertension control; 2) ACEI or angiotensin receptor blocker (ARB) therapy to prevent end-stage renal disease (ESRD) compared with no ACEI or ARB treatment; 3) early irbesartan therapy (at the microalbuminuria stage) to prevent ESRD compared with later treatment (at the macroalbuminuria stage); 4) comprehensive foot care to prevent ulcers compared with usual care; 5) multi-component interventions for diabetic risk factor control and early detection of complications compared with conventional insulin therapy for persons with type 1 diabetes; and 6) multi-component interventions for diabetic risk factor control and early detection of complications compared with standard glycemic control for persons with type 2 diabetes. (II) Very cost-effective- 1) intensive lifestyle interventions to prevent type 2 diabetes among persons with impaired glucose tolerance compared with standard lifestyle recommendations; 2) universal opportunistic screening for undiagnosed type 2 diabetes in African Americans between 45 and 54 years old; 3) intensive glycemic control as implemented in the UK Prospective Diabetes Study in persons with newly diagnosed type 2 diabetes compared with conventional glycemic control; 4) statin therapy for secondary prevention of cardiovascular disease compared with no statin therapy; 5) counseling and treatment for smoking cessation compared with no counseling and treatment; 6) annual screening for diabetic retinopathy and ensuing treatment in persons with type 1 diabetes compared with no screening; 7) annual screening for diabetic retinopathy and ensuing treatment in persons with type 2 diabetes compared with no screening; and 8) immediate vitrectomy to treat diabetic retinopathy compared with deferred vitrectomy. CONCLUSIONS:Many interventions intended to prevent/control diabetes are cost saving or very cost-effective and supported by strong evidence. Policy makers should consider giving these interventions a higher priority. 10.2337/dc10-0843
    A systematic review of real-world diabetes prevention programs: learnings from the last 15 years. Aziz Zahra,Absetz Pilvikki,Oldroyd John,Pronk Nicolaas P,Oldenburg Brian Implementation science : IS BACKGROUND:The evidence base for the prevention of type 2 diabetes mellitus (T2DM) has progressed rapidly from efficacy trials to real-world translational studies and practical implementation trials over the last 15 years. However, evidence for the effective implementation and translation of diabetes programs and their population impact needs to be established in ways that are different from measuring program effectiveness. We report the findings of a systematic review that focuses on identifying the critical success factors for implementing diabetes prevention programs in real-world settings. METHODS:A systematic review of programs aimed at diabetes prevention was undertaken in order to evaluate their outcomes using the penetration, implementation, participation, and effectiveness (PIPE) impact metric. A search for relevant articles was carried out using PubMed (March 2015) and Web of Science, MEDLINE, CENTRAL, and EMBASE. A quality coding system was developed and included studies were rated independently by three researchers. RESULTS:Thirty eight studies were included in the review. Almost all (92 %) provided details on participation; however, only 18 % reported the coverage of their target population (penetration). Program intensity or implementation-as measured by frequency of contacts during first year and intervention duration-was identified in all of the reported studies, and 84 % of the studies also reported implementation fidelity; however, only 18 % of studies employed quality assurance measures to assess the extent to which the program was delivered as planned. Sixteen and 26 % of studies reported 'highly' or 'moderately' positive changes (effectiveness) respectively, based on weight loss. Six (16 %) studies reported 'high' diabetes risk reduction but 'low' to 'moderate' weight loss only. CONCLUSION:Our findings identify that program intensity plays a major role in weight loss outcomes. However, programs that have high uptake-both in terms of good coverage of invitees and their willingness to accept the invitation-can still have considerable impact in lowering diabetes risk in a population, even with a low intensity intervention that only leads to low or moderate weight loss. From a public health perspective, this is an important finding, especially for resource constrained settings. More use of the PIPE framework components will facilitate increased uptake of T2DM prevention programs around the world. 10.1186/s13012-015-0354-6
    Role of insulin autoantibody affinity as a predictive marker for type 1 diabetes in young children with HLA-conferred disease susceptibility. Siljander Heli,Härkönen Taina,Hermann Robert,Simell Satu,Hekkala Anne,Salonsaari Riikka-Tiina,Simell Tuula,Simell Olli,Ilonen Jorma,Veijola Riitta,Knip Mikael Diabetes/metabolism research and reviews BACKGROUND:Insulin autoantibodies (IAA) are early markers of prediabetic autoimmunity. As transient and fluctuating IAA positivity are common among young children, distinguishing non-progressive IAA from destruction-related IAA is essential when preventive measures are considered. We tested whether children progressing rapidly to type 1 diabetes (progressors) are characterized by a higher prediabetic IAA affinity than IAA-positive children remaining unaffected or progressing more slowly to diabetes (non-progressors), and whether IAA affinity increases towards diagnosis. METHODS:Finnish children with HLA-conferred diabetes susceptibility were observed from birth for diabetes-associated autoantibodies and progression to overt type 1 diabetes. IAA levels and affinities of the first IAA-positive prediabetic samples and samples obtained closest to the diagnosis in 64 progressors were compared with corresponding values in 64 matched IAA-positive non-progressors. RESULTS:The median age at diagnosis was 3.9 years in progressors and the median follow-up time 7.6 years among unaffected subjects. In the first samples the median IAA affinity was 1.4 x 10(10) L/mol in both groups (p = 0.33), while at the second sampling it was 1.1 x 10(10) L/mol in progressors and 1.2 x 10(10) L/mol in unaffected subjects (p = 0.46). No changes in affinity levels were observed (p = 0.33 and p = 0.84, respectively). IAA titers increased towards diagnosis among progressors (from a median of 13.6 to 20.1 relative units; p = 0.02). CONCLUSIONS:Among young IAA-positive children with HLA-conferred disease susceptibility IAA affinity failed to distinguish rapid progressors from slowly or non-progressing subjects. In relation to IAA affinity, no maturation of the humoral immune response was observed over time from seroconversion to diagnosis. 10.1002/dmrr.998
    'Insulin autoantibody affinity measurement using a single concentration of unlabelled insulin competitor discriminates risk in relatives of patients with type 1 diabetes. Curnock R M,Reed C R,Rokni S,Broadhurst J W,Bingley P J,Williams A J K Clinical and experimental immunology Development of high-risk combinations of multiple islet autoantibodies and type 1 diabetes is associated with high-affinity insulin autoantibodies (IAA), but IAA affinity measurements require large serum volumes. We therefore investigated whether a simplified method of IAA affinity measurement using a low concentration of unlabelled insulin (ULI) competitor discriminated between moderate-high- and low-affinity IAA and identified individuals at highest risk of disease. Samples were assayed by radiobinding microassay using high (4·0 × 10(-5) mol/l) and low (7 × 10(-9) mol/l) ULI concentrations for competitive displacement in three cohorts of IAA-positive individuals; (1) 68 patients with newly-diagnosed type 1 diabetes; (2) 40 healthy schoolchildren; and (3) 114 relatives of patients with type 1 diabetes followed prospectively for disease development (median follow-up 13 years). IAA results obtained with low ULI were expressed as a percentage of those obtained with high ULI and this was used to classify samples as low or moderate-high affinity (0-50% and >50%, respectively). Sixty-eight patient samples were positive with high and 67 (99%) with low ULI. Forty schoolchildren were IAA-positive with high and 22 (55%) with low ULI (P < 0·001). Of the relatives, 113 were positive with high and 83 (73%) with low ULI (P < 0·001). In relatives, moderate-high affinity IAA were associated with multiple islet antibodies (P < 0·001) and greater diabetes risk than low affinity IAA (P < 0·001). A single low concentration of ULI competitor can act as a surrogate for complex IAA affinity measurements and identifies those IAA-positive relatives at highest risk of disease progression. 10.1111/j.1365-2249.2011.04495.x
    Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes. Achenbach Peter,Koczwara Kerstin,Knopff Annette,Naserke Heike,Ziegler Anette-G,Bonifacio Ezio The Journal of clinical investigation Children at risk for type 1 diabetes can develop early insulin autoantibodies (IAAs). Many, but not all, of these children subsequently develop multiple islet autoantibodies and diabetes. To determine whether disease progression is reflected by autoantibody maturity, IAA affinity was measured by competitive radiobinding assay in first and subsequent IAA-positive samples from children followed from birth in the BABYDIAB cohort. IAA affinity in first positive samples ranged from less than 10(6) l/mol to more than 10(11) l/mol. High affinity was associated with HLA DRB1*04, young age of IAA appearance, and subsequent progression to multiple islet autoantibodies or type 1 diabetes. IAA affinity in multiple antibody-positive children was on average 100-fold higher than in children who remained single IAA positive or became autoantibody negative. All high-affinity IAAs required conservation of human insulin A chain residues 8-13 and were reactive with proinsulin. In contrast, most lower-affinity IAAs were dependent on COOH-terminal B chain residues and did not bind proinsulin. These data are consistent with the concept that type 1 diabetes is associated with sustained early exposure to (pro)insulin in the context of HLA DR4 and show that high-affinity proinsulin-reactive IAAs identify children with the highest diabetes risk. 10.1172/JCI21307
    Fiscal policy to improve diets and prevent noncommunicable diseases: from recommendations to action. Thow Anne Marie,Downs Shauna M,Mayes Christopher,Trevena Helen,Waqanivalu Temo,Cawley John Bulletin of the World Health Organization The World Health Organization has recommended that Member States consider taxing energy-dense beverages and foods and/or subsidizing nutrient-rich foods to improve diets and prevent noncommunicable diseases. Numerous countries have either implemented taxes on energy-dense beverages and foods or are considering the implementation of such taxes. However, several major challenges to the implementation of fiscal policies to improve diets and prevent noncommunicable diseases remain. Some of these challenges relate to the cross-sectoral nature of the relevant interventions. For example, as health and economic policy-makers have different administrative concerns, performance indicators and priorities, they often consider different forms of evidence in their decision-making. In this paper, we describe the evidence base for diet-related interventions based on fiscal policies and consider the key questions that need to be asked by both health and economic policy-makers. From the health sector's perspective, there is most evidence for the impact of taxes and subsidies on diets, with less evidence on their impacts on body weight or health. We highlight the importance of scope, the role of industry, the use of revenue and regressive taxes in informing policy decisions. 10.2471/BLT.17.195982
    3. Prevention or Delay of Type 2 Diabetes: . Diabetes care The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC. 10.2337/dc20-S003
    The global economic burden of diabetes in adults aged 20-79 years: a cost-of-illness study. Bommer Christian,Heesemann Esther,Sagalova Vera,Manne-Goehler Jennifer,Atun Rifat,Bärnighausen Till,Vollmer Sebastian The lancet. Diabetes & endocrinology BACKGROUND:Differences in methods and data used in past studies have limited comparisons of the cost of illness of diabetes across countries. We estimate the full global economic burden of diabetes in adults aged 20-79 years in 2015, using a unified framework across all countries. Our objective was to highlight patterns of diabetes-associated costs as well as to identify the need for further research in low-income regions. METHODS:Epidemiological and economic data for 184 countries were used to estimate the global economic burden of diabetes, regardless of diabetes type. Direct costs were derived using a top-down approach based on WHO general health expenditure figures and prevalence data from the 2015 International Diabetes Federation Diabetes Atlas. Indirect costs were assessed using a human-capital approach, including diabetes-associated morbidity and premature mortality. FINDINGS:We estimate the global cost of diabetes for 2015 was US$1·31 trillion (95% CI 1·28-1·36) or 1·8% (95% CI 1·8-1·9) of global gross domestic product (GDP). Notably, indirect costs accounted for 34·7% (95% CI 34·7-35·0) of the total burden, although substantial variations existed both in the share and the composition of indirect costs across countries. North America was the most affected region relative to GDP and also the largest contributor to global absolute costs. However, on average, the economic burden as percentage of GDP was larger in middle-income countries than in high-income countries. INTERPRETATION:Our results suggest a substantial global economic burden of diabetes. Although limited data were available for low-income and middle-income countries, our findings suggest that large diabetes-associated costs are not only a problem in high-income settings but also affect poorer world regions. FUNDING:None. 10.1016/S2213-8587(17)30097-9
    GAD autoantibody affinity and epitope specificity identify distinct immunization profiles in children at risk for type 1 diabetes. Mayr Anja,Schlosser Michael,Grober Natalie,Kenk Heidrun,Ziegler Anette G,Bonifacio Ezio,Achenbach Peter Diabetes OBJECTIVE:Autoantibodies to insulin and GAD are features of preclinical type 1 diabetes in children. For insulin autoantibodies, the antibody affinity and epitope specificity predict which children progress to diabetes. We asked whether autoantibodies to GAD (GADAs) are heterogeneous in affinity and epitope recognition and whether diabetes-related GADA are restricted to high-affinity responses. RESEARCH DESIGN AND METHODS:GADA affinity was measured by competitive binding experiments with [(125)I]-labeled and -unlabeled recombinant human GAD65 in the first GADA-positive sample from 95 children with a type 1 diabetes family history who were prospectively followed from birth and in follow-up samples from 65 of these children. RESULTS:At first GADA appearance, affinity ranged from 10(7) to 10(10) l/mol. Affinity was higher in multiple islet autoantibody-positive children (P < 0.0001) and in HLA DR3-positive children (P = 0.006). GADA affinities were >10(9) l/mol in 52 of 53 multiple autoantibody-positive children. In contrast, children who were single GADA positive often had lower affinity GADA and/or GADA with specificities that were restricted to minor NH(2)-terminal GAD65 epitopes. At follow-up, affinity increased from low to high in 3 of 65 children. All 24 children who developed diabetes had high-affinity GADAs before diabetes onset. CONCLUSIONS:Children develop discrete, heterogeneous antibody responses to GAD that could arise from distinct immunization events, only some of which are diabetes relevant. Subtyping the GADA responses using affinity measurement will improve type 1 diabetes risk assessment. 10.2337/db06-1715
    Response to comment on Liu et al. Latent autoimmune diabetes in adults with low-titer GAD antibodies: similar disease progression with type 2 diabetes: a nationwide, multicenter prospective study (LADA China Study 3). Diabetes Care 2015;38:16-21. Li Xia,Liu Lingjiao,Xiang Yufei,Huang Gan,Leslie R David,Zhou Zhiguang Diabetes care 10.2337/dc14-2861
    Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality. Kuller L H,Velentgas P,Barzilay J,Beauchamp N J,O'Leary D H,Savage P J Arteriosclerosis, thrombosis, and vascular biology Previously diagnosed diabetes mellitus, newly diagnosed diabetes mellitus, and impaired glucose tolerance are important determinants of the risk of clinical cardiovascular disease (CVD). We have evaluated the relation of patients with subclinical CVD, diabetes, and impaired glucose tolerance and "normal" subjects and the risk of clinical CVD in the Cardiovascular Health Study. Diabetes (1343), impaired glucose tolerance (1433), and normal (2421) were defined by World Health Organization criteria at baseline in 1989 to 1990. The average follow-up was 6.4 years (mean age 73 years). Diabetics had a higher prevalence of clinical and subclinical CVD at baseline. Compared with diabetes in the absence of subclinical disease, the presence of subclinical CVD and diabetes was associated with significant increased adjusted relative risk of death (1.5, CI 0.93 to 2.41), relative risk of incident coronary heart disease (1.99, CI 1.25 to 3.19), and incident myocardial infarction (1.93, CI 0.96 to 3.91). The risk of clinical events was greater for participants with a history of diabetes compared with newly diagnosed diabetics at baseline. Compared with nondiabetic nonhypertensive subjects without subclinical disease, patients with a combination of diabetes, hypertension, and subclinical disease had a 12-fold increased risk of stroke. Fasting blood glucose levels were a weak predictor of incident coronary heart disease as were most other risk factors. Subclinical CVD was the primary determinant of clinical CVD among diabetics in the Cardiovascular Health Study.
    Diabetes mellitus, coronary heart disease incidence, and death from all causes in African American and European American women: The NHANES I epidemiologic follow-up study. Gillum R F,Mussolino M E,Madans J H Journal of clinical epidemiology Few data are available on risk for coronary heart disease in African American women with diabetes mellitus, a well-established coronary risk factor in European American women. This study tests the hypothesis that medical history of diabetes predicts coronary heart disease incidence in African American women in a national cohort. Participants in the NHANES I Epidemiologic Follow-up Study in this analysis were 1035 African American and 5732 European American women aged 25-74 years without a history of coronary heart disease. Average follow-up for survivors was 19 years (maximum 22 years). Risk of incident coronary heart disease by baseline diabetes status was estimated. Proportional hazards analyses for African American women aged 25-74 revealed significant associations of coronary heart disease risk with diabetes after adjusting for age (RR = 2.40; 95% CI, 1.58-3.64, P < 0.01). After adjusting for age, smoking, and low education, there was an elevated risk in diabetics age 25-74 (RR = 2. 34; 95% CI, 1.54-3.56, P < 0.01); this association did not differ significantly from that for European American women. Excess coronary incidence in African American compared to European American women aged 25-64 was statistically explained by controlling for diabetes history, age, education, and smoking but only partly explained by age and diabetes history. In African American women aged 25-74, diabetes was also associated with increased coronary heart disease, cardiovascular, and all-cause mortality. The population attributable risk of coronary heart disease incidence associated with a medical history of diabetes was 8.7% in African American women and 6.1% in European American women. Medical history of diabetes was a significant predictor of coronary heart disease incidence and mortality in African American women and explained some of the excess coronary incidence in younger African American compared to European American women.
    Trends in the prevalence and incidence of self-reported diabetes mellitus -- United States, 1980-1994. MMWR. Morbidity and mortality weekly report Diabetes mellitus is associated with severe microvascular complications (e.g., kidney disease and eye disease) and macrovascular complications (e.g., stroke and ischemic heart disease). These complications can result in severe long-term complications (e.g., amputation, disability, and blindness) and account for a substantial economic burden. This report uses data from CDC's National Health Interview Survey (NHIS) to examine trends in the incidence and prevalence of self-reported diabetes in the United States during 1980-1994. The findings document increases in both the incidence and prevalence of diabetes during this period and suggest that most of the increase was attributable to factors other than the aging of the U.S. population.
    Electrochemiluminescence Assays for Human Islet Autoantibodies. Gu Yong,Zhao Zhiyuan,Miao Dongmei,High Hilary,Yang Tao,Yu Liping Journal of visualized experiments : JoVE Pinpointing islet autoantibodies associated with type 1 diabetes (T1D) leads the way to project and deter this disease in the general population. A novel ECL assay is a nonradioactive fluid phase assay for islet autoantibodies with higher sensitivity and specificity than the current 'gold' standard radio-binding assay (RBA). ECL assays can more precisely define the onset of presymptomatic T1D by distinguishing the high-risk, high-affinity autoantibodies from the low-risk, low-affinity autoantibodies generated in RBAs, and conventional enzyme-linked immunosorbent assays (ELISA). The antigen protein used in this ECL assay is labeled with Sulfo-tag and Biotin, respectively. Each ECL autoantibody assay that uses a particular antigen protein needs an optimization step before it can be used for laboratory application. This step is especially vital in determining the requirements for serum acid treatments, concentrations, and ratios of the two different antigens labeled with Sulfo-tag and Biotin. To perform the assay, serum samples are mixed with Sulfo-tag-conjugated and biotinylated capture antigen protein in phosphate buffered solution (PBS), containing 5% Bovine Serum Albumin (BSA). Afterwards, the samples are incubated overnight at 4 °C. The same day, a streptavidin-coated plate is prepared with blocker buffer and incubated overnight at 4 °C. On the second day, wash the streptavidin plate and transfer the serum-antigen mixture onto the plate. Place the plate on the plate shaker, set it at low speed, and incubate at room temperature for 1 h. Subsequently, the plate is washed again, and reader buffer is added. The plate is then counted on the plate reader machine. The results are conveyed through an index, which is generated from internal standard positive and negative control serum samples. 10.3791/57227
    Pharmacologic therapy for type 2 diabetes mellitus. DeFronzo R A Annals of internal medicine Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. An elevated rate of basal hepatic glucose production in the presence of hyperinsulinemia is the primary cause of fasting hyperglycemia; after a meal, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia. In the United States, five classes of oral agents, each of which works through a different mechanism of action, are currently available to improve glycemic control in patients with type 2 diabetes. The recently completed United Kingdom Prospective Diabetes Study (UKPDS) has shown that type 2 diabetes mellitus is a progressive disorder that can be treated initially with oral agent monotherapy but will eventually require the addition of other oral agents, and that in many patients, insulin therapy will be needed to achieve targeted glycemic levels. In the UKPDS, improved glycemic control, irrespective of the agent used (sulfonylureas, metformin, or insulin), decreased the incidence of microvascular complications (retinopathy, neuropathy, and nephropathy). This review examines the goals of antihyperglycemic therapy and reviews the mechanism of action, efficacy, nonglycemic benefits, cost, and safety profile of each of the five approved classes of oral agents. A rationale for the use of these oral agents as monotherapy, in combination with each other, and in combination with insulin is provided. 10.7326/0003-4819-131-4-199908170-00008
    Predictors of progression from impaired glucose tolerance to NIDDM: an analysis of six prospective studies. Edelstein S L,Knowler W C,Bain R P,Andres R,Barrett-Connor E L,Dowse G K,Haffner S M,Pettitt D J,Sorkin J D,Muller D C,Collins V R,Hamman R F Diabetes Risk factors associated with the progression from impaired glucose tolerance (IGT) to NIDDM were examined in data from six prospective studies. IGT and NIDDM were defined in all studies by World Health Organization (WHO) criteria, and baseline risk factors were measured at the time of first recognition of IGT. The studies varied in size from 177 to 693 participants with IGT, and included men and women followed from 2 to 27 years after the recognition of IGT. Across the six studies, the incidence rate of NIDDM was 57.2/1,000 person-years and ranged from 35.8/1,000 to 87.3/1,000 person-years. Although baseline measures of fasting and 2-h postchallenge glucose levels were both positively associated with NIDDM incidence, incidence rates were sharply higher for those in the top quartile of fasting plasma glucose levels, but increased linearly with increasing 2-h postchallenge glucose quartiles. Incidence rates were higher among the Hispanic, Mexican-American, Pima, and Nauruan populations than among Caucasians. The effect of baseline age on NIDDM incidence rates differed among the studies; the rates did not increase or rose only slightly with increasing baseline age in three of the studies and formed an inverted U in three studies. In all studies, estimates of obesity (including BMI, waist-to-hip ratio, and waist circumference) were positively associated with NIDDM incidence. BMI was associated with NIDDM incidence independently of fasting and 2-h post challenge glucose levels in the combined analysis of all six studies and in three cohorts separately, but not in the three studies with the highest NIDDM incidence rates. Sex and family history of diabetes were generally not related to NIDDM progression. This analysis indicates that persons with IGT are at high risk and that further refinement of risk can be made by other simple measurements. The ability to identify persons at high risk of NIDDM should facilitate clinical trials in diabetes prevention. 10.2337/diab.46.4.701
    Harmonization of glutamic acid decarboxylase and islet antigen-2 autoantibody assays for national institute of diabetes and digestive and kidney diseases consortia. Bonifacio Ezio,Yu Liping,Williams Alastair K,Eisenbarth George S,Bingley Polly J,Marcovina Santica M,Adler Kerstin,Ziegler Anette G,Mueller Patricia W,Schatz Desmond A,Krischer Jeffrey P,Steffes Michael W,Akolkar Beena The Journal of clinical endocrinology and metabolism BACKGROUND/RATIONALE:Autoantibodies to islet antigen-2 (IA-2A) and glutamic acid decarboxylase (GADA) are markers for diagnosis, screening, and measuring outcomes in National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) consortia studies. A harmonization program was established to increase comparability of results within and among these studies. METHODS:Large volumes of six working calibrators were prepared from pooled sera with GADA 4.8-493 World Health Organization (WHO) units/ml and IA-2A 2-235 WHO units/ml. Harmonized assay protocols for IA-2A and GADA using (35)S-methionine-labelled in vitro transcribed and translated antigens were developed based on methods in use in three NIDDK laboratories. Antibody thresholds were defined using sera from patients with recent onset type 1 diabetes and healthy controls. To evaluate the impact of the harmonized assay protocol on concordance of IA-2A and GADA results, two laboratories retested stored TEDDY study sera using the harmonized assays. RESULTS:The harmonized assays gave comparable but not identical results in the three laboratories. For IA-2A, using a common threshold of 5 DK units/ml, 549 of 550 control and patient samples were concordantly scored as positive or negative, specificity was greater than 99% with sensitivity 64% in all laboratories. For GADA, using thresholds equivalent to the 97th percentile of 974 control samples in each laboratory, 1051 (97.9%) of 1074 samples were concordant. On the retested TEDDY samples, discordance decreased from 4 to 1.8% for IA-2A (n = 604 samples; P = 0.02) and from 15.4 to 2.7% for GADA (n = 515 samples; P < 0.0001). CONCLUSION:Harmonization of GADA and IA-2A is feasible using large volume working calibrators and common protocols and is an effective approach to ensure consistency in autoantibody measurements. 10.1210/jc.2010-0293
    Islet cell antibodies identify latent type I diabetes in patients aged 35-75 years at diagnosis. Groop L C,Bottazzo G F,Doniach D Diabetes One hundred fifty-four selected patients with nonketotic diabetes diagnosed between the ages of 35 and 75 yr and treated with diet or oral hypoglycemic agents for at least 1 yr were investigated for parameters of glycemic control (weight loss, blood glucose, and glycosylated hemoglobin), islet cell function (fasting and glucagon-stimulated C-peptide responses), and immunologic markers of insulitis (total ICA and CF-ICA) or autoimmunity (thyroid and gastric antibodies). These parameters were all repeated in 9 of 22 ICA-positive patients after a 2-yr follow-up and correlated with secondary drug failure. The antibody tests were also done on 51 nondiabetic controls matched for age and body weight. The 22 (14%) diabetic subjects having positive islet cell antibodies (ICA) included more women than men with a shorter duration of symptoms, lower body weight, more associated thyroid autoimmunity, and a tendency to have more type I diabetes in their families, although glycemic control, age at onset, and family history of type II diabetes were the same as in the 132 ICA-negative cases. Patients with ICA had lower initial C-peptide levels and showed little rise after glucagon stimulation. Beta cell function deteriorated significantly during the 2-yr follow-up in 9 of 22 positive patients and more ICA-positive patients required insulin. It is suggested that these latent type I diabetic patients are characterized by persistent ICA, progressive loss of beta cells, and a high frequency of thyrogastric autoimmunity. The determination of ICA may be of clinical value in the diagnosis and treatment of nonketotic diabetes with onset in later life. 10.2337/diab.35.2.237
    Electrochemiluminescence assays for insulin and glutamic acid decarboxylase autoantibodies improve prediction of type 1 diabetes risk. Miao Dongmei,Steck Andrea K,Zhang Li,Guyer K Michelle,Jiang Ling,Armstrong Taylor,Muller Sarah M,Krischer Jeffrey,Rewers Marian,Yu Liping, Diabetes technology & therapeutics We recently developed new electrochemiluminescence (ECL) insulin autoantibody (IAA) and glutamic acid decarboxylase 65 autoantibody (GADA) assays that discriminate high-affinity, high-risk diabetes-specific autoantibodies from low-affinity, low-risk islet autoantibodies (iAbs) detected by radioassay (RAD). Here, we report a further validation of the ECL-IAA and -GADA assays in 3,484 TrialNet study participants. The ECL assay and RAD were congruent in those with prediabetes and in subjects with multiple autoantibodies, but only 24% (P<0.0001) of single RAD-IAA-positive and 46% (P<0.0001) of single RAD-GADA-positive were confirmed by the ECL-IAA and -GADA assays, respectively. During a follow-up (mean, 2.4 years), 51% of RAD-IAA-positive and 63% of RAD-GADA-positive subjects not confirmed by ECL became iAb negative, compared with only 17% of RAD-IAA-positive (P<0.0001) and 15% of RAD-GADA-positive (P<0.0001) subjects confirmed by ECL assays. Among subjects with multiple iAbs, diabetes-free survival was significantly shorter if IAA or GADA was positive by ECL and negative by RAD than if IAA or GADA was negative by ECL and positive by RAD (P<0.019 and P<0.0001, respectively). Both positive and negative predictive values in terms of progression to type 1 diabetes mellitus were superior for ECL-IAA and ECL-GADA, compared with RADs. The prevalence of the high-risk human leukocyte antigen-DR3/4, DQB1*0302 genotype was significantly higher in subjects with RAD-IAA or RAD-GADA confirmed by ECL. In conclusion, both ECL-IAA and -GADA are more disease-specific and better able to predict the risk of progression to type 1 diabetes mellitus than the current standard RADs. 10.1089/dia.2014.0186
    Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. Tuomilehto J,Lindström J,Eriksson J G,Valle T T,Hämäläinen H,Ilanne-Parikka P,Keinänen-Kiukaanniemi S,Laakso M,Louheranta A,Rastas M,Salminen V,Uusitupa M, The New England journal of medicine BACKGROUND:Type 2 diabetes mellitus is increasingly common, primarily because of increases in the prevalence of a sedentary lifestyle and obesity. Whether type 2 diabetes can be prevented by interventions that affect the lifestyles of subjects at high risk for the disease is not known. METHODS:We randomly assigned 522 middle-aged, overweight subjects (172 men and 350 women; mean age, 55 years; mean body-mass index [weight in kilograms divided by the square of the height in meters], 31) with impaired glucose tolerance to either the intervention group or the control group. Each subject in the intervention group received individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fat and increasing intake of fiber and physical activity. An oral glucose-tolerance test was performed annually; the diagnosis of diabetes was confirmed by a second test. The mean duration of follow-up was 3.2 years. RESULTS:The mean (+/-SD) amount of weight lost between base line and the end of year 1 was 4.2+/-5.1 kg in the intervention group and 0.8+/-3.7 kg in the control group; the net loss by the end of year 2 was 3.5+/-5.5 kg in the intervention group and 0.8+/-4.4 kg in the control group (P<0.001 for both comparisons between the groups). The cumulative incidence of diabetes after four years was 11 percent (95 percent confidence interval, 6 to 15 percent) in the intervention group and 23 percent (95 percent confidence interval, 17 to 29 percent) in the control group. During the trial, the risk of diabetes was reduced by 58 percent (P<0.001) in the intervention group. The reduction in the incidence of diabetes was directly associated with changes in lifestyle. CONCLUSIONS:Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects. 10.1056/NEJM200105033441801
    Islet Autoantibody Detection by Electrochemiluminescence (ECL) Assay. Yu Liping Methods in molecular biology (Clifton, N.J.) Two fundamental aspects for precisely predicting the risk of developing type 1 diabetes by islet autoantibodies are assay sensitivity and disease specificity. We have recently developed electrochemiluminescent (ECL) insulin autoantibody (IAA) and GAD65 autoantibody (GADA) assays. ECL assays are sensitive, able to identify the initiation of islet autoimmunity earlier in life among high-risk young children before clinical onset of diabetes and are more disease specific because they are able to discriminate high-affinity, high-risk diabetes specific islet autoantibodies from low-affinity, low-risk autoantibodies. 10.1007/7651_2015_296
    Preventing non-insulin-dependent diabetes. Knowler W C,Narayan K M,Hanson R L,Nelson R G,Bennett P H,Tuomilehto J,Scherstén B,Pettitt D J Diabetes Many risk factors for non-insulin-dependent diabetes mellitus (NIDDM), such as obesity, physical inactivity, and high-fat diet, can potentially be modified. Furthermore, some of the metabolic abnormalities, such as insulin resistance and impaired glucose tolerance, that predict diabetes can be improved by behavior modification and drug treatment. Thus, at least to some extent, NIDDM may be preventable. Several small clinical trials have addressed the hypothesis that NIDDM can be prevented by dietary modification, physical activity, or drug treatment. Some studies suggest a preventive effect, but the conclusions are limited by considerations of sample size, randomization, or intensity of the interventions. Consequently, the hypothesis that NIDDM is preventable requires further testing. 10.2337/diab.44.5.483
    Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults. The Third National Health and Nutrition Examination Survey, 1988-1994. Harris M I,Flegal K M,Cowie C C,Eberhardt M S,Goldstein D E,Little R R,Wiedmeyer H M,Byrd-Holt D D Diabetes care OBJECTIVE:To evaluate the prevalence and time trends for diagnosed and undiagnosed diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults by age, sex, and race or ethnic group, based on data from the Third National Health and Nutrition Examination Survey, 1988-1994 (NHANES III) and prior Health and Nutrition Examination Surveys (HANESs). RESEARCH DESIGN AND METHODS:NHANES III contained a probability sample of 18,825 U.S. adults > or = 20 years of age who were interviewed to ascertain a medical history of diagnosed diabetes, a subsample of 6,587 adults for whom fasting plasma glucose values were obtained, and a subsample of 2,844 adults between 40 and 74 years of age who received an oral glucose tolerance test. The Second National Health and Nutrition Examination Survey, 1976-1980, and Hispanic HANES used similar procedures to ascertain diabetes. Prevalence was calculated using the 1997 American Diabetes Association fasting plasma glucose criteria and the 1980-1985 World Health Organization (WHO) oral glucose tolerance test criteria. RESULTS:Prevalence of diagnosed diabetes in 1988-1994 was estimated to be 5.1% for U.S. adults > or = 20 years of age (10.2 million people when extrapolated to the 1997 U.S. population). Using American Diabetes Association criteria, the prevalence of undiagnosed diabetes (fasting plasma glucose > or = 126 mg/dl) was 2.7% (5.4 million), and the prevalence of impaired fasting glucose (110 to < 126 mg/dl) was 6.9% (13.4 million). There were similar rates of diabetes for men and women, but the rates for non-Hispanic blacks and Mexican-Americans were 1.6 and 1.9 times the rate for non-Hispanic whites. Based on American Diabetes Association criteria, prevalence of diabetes (diagnosed plus undiagnosed) in the total population of people who were 40-74 years of age increased from 8.9% in the period 1976-1980 to 12.3% by 1988-1994. A similar increase was found when WHO criteria were applied (11.4 and 14.3%). CONCLUSIONS:The high rates of abnormal fasting and postchallenge glucose found in NHANES III, together with the increasing frequency of obesity and sedentary lifestyles in the population, make it likely that diabetes will continue to be a major health problem in the U.S. 10.2337/diacare.21.4.518
    Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): a nationwide, multicenter, clinic-based cross-sectional study. Zhou Zhiguang,Xiang Yufei,Ji Linong,Jia Weiping,Ning Guang,Huang Gan,Yang Lin,Lin Jian,Liu Zhenqi,Hagopian William A,Leslie R David, Diabetes Adult non-insulin requiring diabetes includes latent autoimmune diabetes of adults (LADA), distinguished from type 2 diabetes by the presence of islet autoantibodies. LADA China determined the characteristics of Chinese LADA. This nationwide, multicenter, clinic-based cross-sectional study was conducted in 46 university-affiliated hospitals in 25 Chinese cities. All 4,880 ketosis-free diabetic patients (<1 year postdiagnosis, without insulin therapy for >6 months, aged ≥30 years) had GAD antibody (GADA) and HLA-DQ genotype measured centrally with clinical data collected locally. GADA-positive subjects were classified as LADA. Of the patients, 5.9% were GADA positive with LADA. LADA showed a north-south gradient. Compared with GADA-negative type 2 diabetes, LADA patients were leaner, with lower fasting C-peptide and less metabolic syndrome. Patients with high GADA titers are phenotypically different from those with low GADA titers, while only a higher HDL distinguished the latter from those with type 2 diabetes. HLA diabetes-susceptible haplotypes were more frequent in LADA, even in those with low-titer GADA. HLA diabetes-protective haplotypes were less frequent in LADA. Our study implicates universal immunogenetic effects, with some ethnic differences, in adult-onset autoimmune diabetes. Autoantibody positivity and titer could be important for LADA risk stratification and accurate therapeutic choice in clinical practice. 10.2337/db12-0207
    Titre and combination of ICA and autoantibodies to glutamic acid decarboxylase discriminate two clinically distinct types of latent autoimmune diabetes in adults (LADA). Lohmann T,Kellner K,Verlohren H J,Krug J,Steindorf J,Scherbaum W A,Seissler J Diabetologia UNLABELLED:ABSTRACT AIMS/HYPOTHESIS: This study aimed to define the immunological parameters which could be used to identify patients with the distinct metabolic features of adult latent autoimmune diabetes. METHODS:Sera of 312 patients with short-term diabetes (duration < 5 years) over 35 years of age at diagnosis were screened for ICA, GAD- and IA2-Ab by antibody assays validated in workshops. The antibody status was correlated with age, BMI, residual beta-cell function, measured by fasting C-peptide, onset of diabetes-related complications and markers of the metabolic syndrome (hypertension and hyperlipidaemia). RESULTS:A total of 51 antibody positive patients were identified. These patients had lower fasting C-peptide and less neuropathy and hypertension compared with matched antibody-negative patients. However, only patients with two or more antibodies had reduced residual beta-cell function compared with antibody-negative or single antibody-positive (ICA or GAD-Ab only) patients. Patients with two or more antibodies were also leaner and had diabetes-related complications or hypertension less frequently than single antibody-positive or antibody negative-patients. IA2 antibody status did not substantially contribute to the diagnosis or differentiation of LADA patients. CONCLUSION/INTERPRETATION:We concluded that the combination of ICA and GAD antibodies and high titre of GAD antibodies are characteristic of patients with insulin deficiency with the clinical features of Type I (insulin-dependent) diabetes mellitus (LADA-type 1). Single antibody positivity and low titre antibodies are markers for LADA-type 2 associated with the clinical and metabolic phenotype of Type II (non-insulin-dependent) diabetes patients. 10.1007/s001250100602
    Beta-cell protection and therapy for latent autoimmune diabetes in adults. Cernea Simona,Buzzetti Raffaella,Pozzilli Paolo Diabetes care 10.2337/dc09-S317
    Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and relationship with metabolic control (UKPDS 70). Davis T M E,Wright A D,Mehta Z M,Cull C A,Stratton I M,Bottazzo G F,Bosi E,Mackay I R,Holman R R Diabetologia AIMS/HYPOTHESIS:We examined the prevalence of islet autoantibodies and their relationship to glycaemic control over 10 years in patients diagnosed clinically with new-onset type 2 diabetes. METHODS:Patient clinical characteristics and autoantibody status were determined at entry to the UK Prospective Diabetes Study (UKPDS) before randomisation to different glucose control policies. Patients were followed for 10 years. RESULTS:Data available on 4,545 of the 5,102 UKPDS patients showed that 11.6% had antibodies to at least one of three antigens: islet cell cytoplasm, glutamic acid decarboxylase and islet autoantibody 2A (IA-2A). Autoantibody-positive patients were younger, more often Caucasian and leaner, with lower beta cell function and higher insulin sensitivity than autoantibody-negative patients. They also had higher HbA1c, and HDL-cholesterol levels, and lower blood pressure, total cholesterol and plasma triglyceride levels. Despite relative hyperglycaemia, autoantibody-positive patients were less likely to have the metabolic syndrome (as defined by the National Cholesterol Education Program Adult Treatment Program III), reflecting a more beneficial overall risk factor profile. Of 3,867 patients with post-dietary run-in fasting plasma glucose (FPG) values between 6.0 and 14.9 mmol/l and no hyperglycaemic symptoms, 9.4% were autoantibody-positive, compared with 25.1% of 678 patients with FPG values of 15.0 mmol/l or higher, or hyperglycaemic symptoms. In both groups, no differences were seen between those with and without autoantibodies in changes to HbA1c over time, but autoantibody-positive patients required insulin treatment earlier, irrespective of the allocated therapy (p<0.0001). CONCLUSIONS/INTERPRETATION:Autoantibody-positive patients can be treated initially with sulphonylurea, but are likely to require insulin earlier than autoantibody-negative patients. 10.1007/s00125-005-1690-x
    Small doses of subcutaneous insulin as a strategy for preventing slowly progressive beta-cell failure in islet cell antibody-positive patients with clinical features of NIDDM. Kobayashi T,Nakanishi K,Murase T,Kosaka K Diabetes We report a pilot study to determine the preventive effect of small doses of insulin injected subcutaneously on slowly progressive beta-cell damage in islet cell antibody (ICA)-positive patients with apparent NIDDM. Ten NIDDM patients who were ICA' were divided into two groups of five. In the insulin group (age: 51 +/- 8 years [mean +/- SD], sex: 3 men and 2 women), intermediate-type insulin (3-16 U/day) was given once or twice daily as a subcutaneous injection. The sulfonylurea (SU) group (age: 48 +/- 11 years, sex: 3 men and 2 women) was initially treated with a SU agent. Changes in beta-cell function, as indicated by serum C-peptide responses and blood glucose values during a 100-g oral glucose tolerance test, as well as ICA and GAD antibody status, were evaluated for up to 30 months in both groups. ICA status became negative in four of five patients in the insulin group. ICA status did not become negative in any of the patients in the SU group (P = 0.047 vs. insulin group). ICA status was persistently positive in two patients whose beta-cell function eventually progressed to an insulin-dependent state and fluctuated in the remaining three patients. In the insulin group, GAD antibody status became negative in one of four initially GAD antibody-positive NIDDM patients. In the SU group, GAD antibody status was persistently positive in three NIDDM patients (NS vs. insulin group). The serum C-peptide response improved significantly within 6 and 12 months in the insulin group, whereas it decreased progressively in the SU group. The changes in C-peptide response were significantly different between the two groups at 6, 12, 24, and 30 months. Two-hour blood glucose and HbA1 values were unchanged in the insulin group, but they increased in the SU group. Subcutaneous small doses of insulin, resulting in a high rate of negative conversion of ICA and an improved serum C-peptide response, may be effective in treating ICA+ NIDDM patients who are at high risk for slowly progressive beta-cell failure. 10.2337/diab.45.5.622
    Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Tuomi T,Carlsson A,Li H,Isomaa B,Miettinen A,Nilsson A,Nissén M,Ehrnström B O,Forsén B,Snickars B,Lahti K,Forsblom C,Saloranta C,Taskinen M R,Groop L C Diabetes The aim of the study was 1) to establish the prevalence of GAD antibodies (GADab) in a population-based study of type 2 diabetes in western Finland, 2) to genetically and phenotypically characterize this subgroup, and 3) to provide a definition for latent autoimmune diabetes in adults (LADA). The prevalence of GADab was 9.3% among 1,122 type 2 diabetic patients, 3.6% among 558 impaired glucose tolerance (IGT) subjects, and 4.4% among 383 nondiabetic control subjects. Islet antigen 2 antibodies (IA2ab) or islet cell antibodies were detected in only 0.5% of the GADab- patients. The GADab+ patients had lower fasting C-peptide concentrations (median [interquartile range]: 0.46 [0.45] vs. 0.62 [0.44] nmol/l, P = 0.0002) and lower insulin response to oral glucose compared with GADab- patients. With respect to features of the metabolic syndrome, the GADab+ patients had lower systolic (140 [29.1] vs. 148 [26.0] mmHg, P = 0.009) and diastolic (79.2 [17.6] vs. 81.0 [13.1] mmHg, P = 0.030) blood pressure values, as well as lower triglyceride concentrations (1.40 [1.18] vs. 1.75 [1.25] mmol/l, P = 0.003). GADab+ men had a lower waist-to-hip ratio compared with GADab- patients. Compared with GADab- patients and control subjects, the GADab+ patients had an increased frequency HLA-DQB1*0201/0302 (13 vs. 4%; P = 0.002) and other genotypes containing the *0302 allele (22 vs. 12%; P = 0.010). However, the frequency of these high-risk genotypes was significantly lower in GADab+ type 2 patients than in type 1 diabetes of young or adult onset (0201/0302 or 0302/X: 36 vs. 66 vs. 64%, P < 0.001). The GADab+ type 2 group did not differ from control subjects with respect to genotypes containing the protective DQB1-alleles *0602 or *0603, nor with respect to the type 1 high-risk genotype in the IDDM1 (Hph1 +/+). We conclude that GADab+ patients differ from both GADab- type 2 diabetic patients and type 1 diabetic patients with respect to beta-cell function, features of the metabolic syndrome, and type 1 diabetes susceptibility genes. Further, we propose that LADA be defined as GADab positivity (>5 relative units) in patients older than 35 years at onset of type 2 diabetes. 10.2337/diabetes.48.1.150
    Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Bingley P J,Bonifacio E,Williams A J,Genovese S,Bottazzo G F,Gale E A Diabetes Strategies for assessing risk of progression to IDDM, based on single and combined autoantibody measurement, were evaluated in 2,855 schoolchildren (median age 11.4 years) and 256 children with newly diagnosed IDDM (median age 10.2 years), recruited to a population-based study in the Oxford region. In 256 children with IDDM, levels of antibodies > or =97.5th centile of the schoolchild population were found in 225 (88%) for islet cell antibodies (ICAs), in 190 (74%) for antibodies to GAD, in 193 (75%) for antibodies to protein tyrosine phosphatase IA-2 (IA-2), and in 177 (69%) for autoantibodies to insulin (IAAs). Estimates of risk of progression to IDDM within 10 years, derived by comparing the distribution of antibody markers in the two populations (schoolchildren and children with IDDM), were 6.7% (ICAs), 6.6% (GAD antibodies), 5.6% (IA-2 antibodies), and 4.8% (IAAs) for schoolchildren with levels above the 97.5th centile, increasing to 20, 23, 24, and 11%, respectively, for antibody levels >99.5th centile. Most children with IDDM had multiple antibody markers, and 89% of those diagnosed over age 10 years had > or =2 antibodies above the 97.5th centile, as compared against 0.7% of schoolchildren, in whom this combination gave a 27% 10-year estimated risk of IDDM. Risk increased but sensitivity fell as combined antibody thresholds were raised, or the number of antibodies above the threshold was increased. Strategies based on detection of > or =2 antibodies with primary testing for GAD and IA-2 antibodies and second line testing for ICAs and/or IAAs were evaluated. Detection of at least two markers selected from GAD antibodies > or =97.5th centile and/or IA-2 antibodies > or =99.5th centile and/or ICAs > or =97.5th centile identified 0.25% of schoolchildren and 83% of children with newly diagnosed IDDM, with an estimated risk of 71% (95% CI 57-91). Although confirmation from prospective studies is still needed, this analysis suggests that antibody combinations can predict diabetes in the general population. 10.2337/diab.46.11.1701
    UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK Prospective Diabetes Study Group. Turner R,Stratton I,Horton V,Manley S,Zimmet P,Mackay I R,Shattock M,Bottazzo G F,Holman R Lancet (London, England) BACKGROUND:Autoantibodies to islet-cell cytoplasm (ICA) and glutamic acid decarboxylase (GADA) can occur in apparently typical, non-insulin dependent diabetes mellitus (type 2). We investigated whether the presence of either or both antibodies characterises a subtype of diabetes and provides better prediction of requirement for insulin therapy by 6 years' follow-up than clinical variables. METHODS:We measured ICA and GADA at diagnosis of diabetes in a representative population of 3672 white patients with type 2 diabetes, aged between 25 and 65 years. The phenotype was assessed by age of onset, body-mass index, percentage haemoglobin A1c (HbA1c), and islet beta-cell function. We investigated the need for insulin therapy among 1538 patients not assigned insulin and followed up for 6 years from diagnosis. FINDINGS:The proportion of patients with ICA and GADA decreased with increasing age at diagnosis (from 33 [21%] of 157 patients aged 25-34 [corrected] to 66 [4%] of 1769 aged 55-65 for ICA; from 53 [34%] to 122 [7%] for GADA). Among patients younger than 35 at diagnosis, those with ICA or GADA had lower body-mass index than those without (mean 24.9 [SD 6.0] vs 31.7 [7.3] kg/m2; p < 0.0001 and had higher percentage of HbA1c (9.7 vs 8.7%, p < 0.05). 94% of patients with ICA and 84% of those with GADA required insulin therapy by 6 years, compared with 14% of those without the antibodies (p < 0.0001). Among patients older than 55 at diagnosis, the difference between those with and without antibodies in body-mass index was smaller (27.2 [5.4] vs 28.6 [4.8] kg/m2, p < 0.001); 44% of those with ICA, 34% of those with GADA, and 5% with neither antibody required insulin therapy by 6 years (p < 0.0001). Among patients older than 45 years, body-mass index and HbA1c provided little predictive information for insulin requirement, whereas the positive predictive values of GADA (> or = 60 U/L) alone, or both GADA (> or = 20 U/L) and ICA (> 5 U/L), for insulin therapy were 52% and 68%. INTERPRETATION:Among young adults with type 2 diabetes, the phenotype of those with ICA or GADA antibodies was similar to that of classic juvenile-onset insulin-dependent diabetes, and either phenotype or antibodies predicted insulin requirement. In older adults, the phenotype was closer to that of patients without antibodies and only the presence of antibodies predicted an increased likelihood of insulin requirement. 10.1016/s0140-6736(97)03062-6
    Pancreatic islet-cell antibody as a marker for asymptomatic and latent diabetes and prediabetes. Irvine W J,Gray R S,McCallum C J Lancet (London, England) Pancreatic islet-cell antibodies (I.C.Ab) were detected in 31 patients with organ-specific autoimmune disorders, 4 first-degree relatives of I.C.Ab-positive diabetics, and 1 apparently normal subject, none of whom had clinical evidence of diabetes. 10 of these 36 subjects were found to have diabetic glucose-tolerance tests (G.T.T.S), 4 had lag storage, and 22 had normal G.T.T.S.2 had latent diabetes, as evidenced by diabetic G.T.T.S during pregnancy and thyrotoxicosis; another 2 subsequently developed insulin-dependent diabetes (I.D.D.) Serum from 26 subjects had been stored for 1-11 yr before the G.T.T.S were done. The titres in some were shown to rise and fall over the years, while in others they remained remarkably constant. There was no correlation between the titre, change in titre or the duration of I.C.Ab or the presence of HLA-B8, BW15, or CW3 and the result of the G.T.T. In addition to acting as a marker for asymptomatic and latent diabetes and prediabetes, it seems that the presence of I.C.Ab in the serum may define a new group of potential diabetics with normal G.T.T.S. Many such subjects have one or more organ-specific autoimmune disorders (irrespective of diabetic family history), but some are first-degree relatives of I.C.Ab-positive subjects (mainly I.D.D.). About 0-5% of the general population also have I.C.Ab in their serum. 10.1016/s0140-6736(76)91084-9
    HLA-linked genes and islet-cell antibodies in diabetes mellitus. Lendrum R,Walker G,Cudworth A G,Woodrow J C,Gamble D R British medical journal In a random series of 139 insulin-dependent diabetics aged 30 or under at the onset of disease islet-cell antibody (ICA) was detected in 33 cases (24%). In 27 patients who had had diabetes for less than one year 16 (59%) had ICA. Only one out of 51 patients with maturity onset diabetes who were not dependent on insulin were positive for ICA. Four out of 19 patients with late onset insulin-dependent diabetes had ICA. There was no association between the presence of ICA and any particular HLA phenotype. Within families containing two or more HLA haploidentical siblings with juvenile onset diabetes ICA was a variable finding both in its occurrence and in its relation to the duration of disease. A possible mode of action for the HLA-linked gene may be to permit a rapid immunological destructive process, possibly associated with viral infection. 10.1136/bmj.1.6025.1565
    Lawrence Lecture. The Emperor's new genes: 1993 RD Lawrence Lecture. Todd J A Diabetic medicine : a journal of the British Diabetic Association
    Control of glycaemia: from molecules to men. Minkowski Lecture 2003. Stumvoll M Diabetologia Regulation of glycaemia represents a fundamental biological principle, and its failure underlies Type 2 diabetes. The complex aetiology of Type 2 diabetes, which probably involves a medley of molecular mechanisms, requires dissection out of diabetes-associated subphenotypes, such as the non-obese with increased liver fat or the obese with low plasma adiponectin. The concepts of the hyperbolic relationship of insulin secretion and insulin sensitivity with glucose allostasis help us to establish the pathophysiological framework within which such mechanisms must operate. The translation of burgeoning new basic science findings into a physiological and clinical context calls for novel and imaginative clinical experimental tools. For the purpose of this review, four molecules (adiponectin [APM1], stearoyl CoA desaturase-1 [SCD1], insulin receptor substrate-1 [IRS1], peroxisome proliferator-activated receptor-gamma [PPARG]), each with a plausible role in the disease process, have been selected to illustrate the use of such techniques in humans. These include procedures as diverse as isotope dilution for turnover studies (e.g. glycerol turnover as a proxy for lipolysis), conventional and modified clamp procedures, association studies of functionally relevant single nucleotide polymorphisms in candidate genes (e.g. IRS-1 and PPAR gamma), multivariate correlational analyses (as with plasma adiponectin), magnetic resonance spectroscopy to quantify intra-tissue lipid deposition and regional fat distribution, and gas chromatography to determine fatty acid patterns in selected lipid fractions as proxy for intrahepatic enzyme activity. A concerted effort by scientists from many disciplines (genetics and cell biology, physiology and epidemiology) will be required to bridge the growing gap between basic scientific concepts of biological modifiers of glycaemia and concepts that are truly relevant for human Type 2 diabetes. 10.1007/s00125-004-1400-0
    Epidemiological studies of diabetes mellitus in Denmark: 4. Clinical characteristics of insulin-treated diabetes. Green A,Hougaard P Diabetologia We report the clinical characteristics of all insulin-treated diabetic patients (783 males and 716 females) living on July 1 1973 in a Danish county. In 18 patients diabetes was believed to be secondary to another disease or condition. Of all patients, 43% of the males and 55% of the females were greater than age 50 years and 42% and 36% of males and females, respectively, had a disease duration of less than 10 years. The overall proportion of patients treated permanently with insulin from diagnosis was 85% and 79% in males and females, respectively, but within the subgroup of patients with current age less than 30 years these proportions were 99% and 96%, respectively. Statistical analysis indicated that insulin-treated diabetes is a clinically heterogeneous group of diseases; thus, low age at onset combined with immediate and permanent insulin treatment delineate one subtype, while relatively high age at onset and late start and/or interruption of insulin treatment delineate other subtype(s). It is estimated that the proportion of patients with truly Type 1 (insulin-dependent) diabetes is greater than 50% in this cross-sectional population of insulin-treated patients.
    Insulin dependence: problems with the classification of 100 consecutive patients. Wilson R M,Van der Minne P,Deverill I,Heller S R,Gelsthrope K,Reeves W G,Tattersall R B Diabetic medicine : a journal of the British Diabetic Association We have evaluated the clinical and immunogenetic features of 100 consecutive patients presenting to an adult diabetic clinic who were judged clinically to need insulin therapy but were not sufficiently ill to be admitted to hospital. Over this same period 15 newly diagnosed patients (aged 13-70 years) were started on insulin as in-patients of whom ten were in ketoacidosis. The 100 out-patients, aged 11-75 years at the time of starting insulin, were followed for at least a year. Fifty-six had islet cell antibodies and/or were heterozygous for HLA DR3 and DR4 (Group A) whereas 44 had neither of these markers (Group B). Islet cell antibodies and/or DR3, DR4 heterozygosity were most common in the 70 patients diagnosed below the age of 40 years but were also found in older patients. Patients in Group A were significantly younger at diagnosis (29 vs. 43 years), had a shorter duration of symptoms (17 vs. 61 weeks), were more likely to have ketonuria, and had a lower random C-peptide level at diagnosis (0.2 vs. 0.31 nmol/l). The two groups could not be distinguished by weight, haemogloblin A1 or blood glucose at diagnosis or by diabetic control or insulin dose after one year. The National Diabetes Data Group (NDDG) definition of insulin dependence stresses the importance of HLA types and islet cell antibodies although we found their prevalence to be low in the 30 patients diagnosed over 40 years who clinically were indistinguishable from the younger patients.(ABSTRACT TRUNCATED AT 250 WORDS)
    Latent autoimmune diabetes in adults (LADA) should be less latent. Fourlanos S,Dotta F,Greenbaum C J,Palmer J P,Rolandsson O,Colman P G,Harrison L C Diabetologia 'Latent autoimmune diabetes in adults' (LADA) is the term coined to describe adults who have a slowly progressive form of autoimmune or type 1 diabetes that can be treated initially without insulin injections. The diagnosis of LADA is currently based on three clinical criteria: (1) adult age at onset of diabetes; (2) the presence of circulating islet autoantibodies, which distinguishes LADA from type 2 diabetes; and (3) insulin independence at diagnosis, which distinguishes LADA from classic type 1 diabetes. The prevalence of LADA in adults presenting with non-insulin-requiring diabetes is approximately 10%. Recognition of LADA expands the concept and prevalence of autoimmune diabetes, but LADA remains poorly understood at both a clinical and research level. In this perspective, we review the nomenclature, diagnostic criteria, genetics, pathology and therapy of LADA, to arrive at recommendations that might advance knowledge and management of this form of diabetes. 10.1007/s00125-005-1960-7
    Cost-effectiveness of Diabetes Prevention Interventions Targeting High-risk Individuals and Whole Populations: A Systematic Review. Zhou Xilin,Siegel Karen R,Ng Boon Peng,Jawanda Shawn,Proia Krista K,Zhang Xuanping,Albright Ann L,Zhang Ping Diabetes care OBJECTIVE:We conducted a systematic review of studies evaluating the cost-effectiveness (CE) of interventions to prevent type 2 diabetes (T2D) among high-risk individuals and whole populations. RESEARCH DESIGN AND METHODS:Interventions targeting high-risk individuals are those that identify people at high risk of developing T2D and then treat them with either lifestyle or metformin interventions. Population-based prevention strategies are those that focus on the whole population regardless of the level of risk, creating public health impact through policy implementation, campaigns, and other environmental strategies. We systematically searched seven electronic databases for studies published in English between 2008 and 2017. We grouped lifestyle interventions targeting high-risk individuals by delivery method and personnel type. We used the median incremental cost-effectiveness ratio (ICER), measured in cost per quality-adjusted life year (QALY) or cost saved to measure the CE of interventions. We used the $50,000/QALY threshold to determine whether an intervention was cost-effective or not. ICERs are reported in 2017 U.S. dollars. RESULTS:Our review included 39 studies: 28 on interventions targeting high-risk individuals and 11 targeting whole populations. Both lifestyle and metformin interventions in high-risk individuals were cost-effective from a health care system or a societal perspective, with median ICERs of $12,510/QALY and $17,089/QALY, respectively, compared with no intervention. Among lifestyle interventions, those that followed a Diabetes Prevention Program (DPP) curriculum had a median ICER of $6,212/QALY, while those that did not follow a DPP curriculum had a median ICER of $13,228/QALY. Compared with lifestyle interventions delivered one-on-one or by a health professional, those offered in a group setting or provided by a combination of health professionals and lay health workers had lower ICERs. Among population-based interventions, taxing sugar-sweetened beverages was cost-saving from both the health care system and governmental perspectives. Evaluations of other population-based interventions-including fruit and vegetable subsidies, community-based education programs, and modifications to the built environment-showed inconsistent results. CONCLUSIONS:Most of the T2D prevention interventions included in our review were found to be either cost-effective or cost-saving. Our findings may help decision makers set priorities and allocate resources for T2D prevention in real-world settings. 10.2337/dci20-0018
    Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes. Cervin Camilla,Lyssenko Valeriya,Bakhtadze Ekaterine,Lindholm Eero,Nilsson Peter,Tuomi Tiinamaija,Cilio Corrado M,Groop Leif Diabetes OBJECTIVE:Latent autoimmune diabetes in adults (LADA) is often considered a slowly progressing subtype of type 1 diabetes, although the clinical picture more resembles type 2 diabetes. One way to improve classification is to study whether LADA shares genetic features with type 1 and/or type 2 diabetes. RESEARCH DESIGN AND METHODS:To accomplish this, we studied whether LADA shares variation in the HLA locus or INS VNTR and PTPN22 genes with type 1 diabetes or the TCF7L2 gene with type 2 diabetes in 361 LADA, 718 type 1 diabetic, and 1,676 type 2 diabetic patients, as well as 1,704 healthy control subjects from Sweden and Finland. RESULTS:LADA subjects showed, compared with type 2 diabetic patients, increased frequency of risk for the HLA-DQB1 *0201/*0302 genotype (27 vs. 6.9%; P < 1 x 10(-6)), with similar frequency as with type 1 diabetes (36%). In addition, LADA subjects showed higher frequencies of protective HLA-DQB1 *0602(3)/X than type 1 diabetic patients (8.1 vs. 3.2%, P = 0.003). The AA genotype of rs689, referring to the class I allele in the INS VNTR, as well as the CT/TT genotypes of rs2476601 in the PTPN22 gene, were increased both in type 1 diabetic (P = 3 x 10(-14) and P = 1 x 10(-10), respectively) and LADA (P = 0.001 and P = 0.002) subjects compared with control subjects. Notably, the frequency of the type 2 diabetes-associated CT/TT genotypes of rs7903146 in the TCF7L2 were increased in LADA subjects (52.8%; P = 0.03), to the same extent as in type 2 diabetic subjects (54.1%, P = 3 x 10(-7)), compared with control subjects (44.8%) and type 1 diabetic subjects (43.3%). CONCLUSIONS:LADA shares genetic features with both type 1 (HLA, INS VNTR, and PTPN22) and type 2 (TCF7L2) diabetes, which justifies considering LADA as an admixture of the two major types of diabetes. 10.2337/db07-0299
    Glutamic Acid Decarboxylase Autoantibody Detection by Electrochemiluminescence Assay Identifies Latent Autoimmune Diabetes in Adults with Poor Islet Function. Zhu Yuxiao,Qian Li,Liu Qing,Zou Jing,Zhou Ying,Yang Tao,Huang Gan,Zhou Zhiguang,Liu Yu Diabetes & metabolism journal BACKGROUND:The detection of glutamic acid decarboxylase 65 (GAD65) autoantibodies is essential for the prediction and diagnosis of latent autoimmune diabetes in adults (LADA). The aim of the current study was to compare a newly developed electrochemiluminescence (ECL)-GAD65 antibody assay with the established radiobinding assay, and to explore whether the new assay could be used to define LADA more precisely. METHODS:Serum samples were harvested from 141 patients with LADA, 95 with type 1 diabetes mellitus, and 99 with type 2 diabetes mellitus, and tested for GAD65 autoantibodies using both the radiobinding assay and ECL assay. A glutamic acid decarboxylase antibodies (GADA) competition assay was also performed to assess antibody affinity. Furthermore, the clinical features of these patients were compared. RESULTS:Eighty-eight out of 141 serum samples (62.4%) from LADA patients were GAD65 antibody-positive by ECL assay. Compared with ECL-GAD65 antibody-negative patients, ECL-GAD65 antibody-positive patients were leaner (<0.0001), had poorer β-cell function (<0.05), and were more likely to have other diabetes-associated autoantibodies. The β-cell function of ECL-GAD65 antibody-positive patients was similar to that of type 1 diabetes mellitus patients, whereas ECL-GAD65 antibody-negative patients were more similar to type 2 diabetes mellitus patients. CONCLUSION:Patients with ECL-GAD65 antibody-negative share a similar phenotype with type 2 diabetes mellitus patients, whereas patients with ECL-GAD65 antibody-positive resemble those with type 1 diabetes mellitus. Thus, the detection of GADA using ECL may help to identify the subtype of LADA. 10.4093/dmj.2019.0007
    Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. Bhatt Deepak L,Szarek Michael,Pitt Bertram,Cannon Christopher P,Leiter Lawrence A,McGuire Darren K,Lewis Julia B,Riddle Matthew C,Inzucchi Silvio E,Kosiborod Mikhail N,Cherney David Z I,Dwyer Jamie P,Scirica Benjamin M,Bailey Clifford J,Díaz Rafael,Ray Kausik K,Udell Jacob A,Lopes Renato D,Lapuerta Pablo,Steg P Gabriel, The New England journal of medicine BACKGROUND:The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied. METHODS:We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding. RESULTS:Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo. CONCLUSIONS:In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.). 10.1056/NEJMoa2030186
    Teplizumab improves and stabilizes beta cell function in antibody-positive high-risk individuals. Science translational medicine We analyzed the effects of a single 14-day course of teplizumab treatment on metabolic function and immune cells among participants in a previously reported randomized controlled trial of nondiabetic relatives at high risk for type 1 diabetes (T1D). In an extended follow-up (923-day median) of a previous report of teplizumab treatment, we found that the median times to diagnosis were 59.6 and 27.1 months for teplizumab- and placebo-treated participants, respectively (HR = 0.457, = 0.01). Fifty percent of teplizumab-treated but only 22% of the placebo-treated remained diabetes-free. Glucose tolerance, C-peptide area under the curve (AUC), and insulin secretory rates were calculated, and relationships to T cell subsets and function were analyzed. Teplizumab treatment improved beta cell function, reflected by average on-study C-peptide AUC (1.94 versus 1.72 pmol/ml; = 0.006). Drug treatment reversed a decline in insulin secretion before enrollment, followed by stabilization of the declining C-peptide AUC seen with placebo treatment. Proinsulin:C-peptide ratios after drug treatment were similar between the treatment groups. The changes in C-peptide with teplizumab treatment were associated with increases in partially exhausted memory KLRG1TIGITCD8 T cells ( = 0.44, = 0.014) that showed reduced secretion of IFNγ and TNFα. A single course of teplizumab had lasting effects on delay of T1D diagnosis and improved beta cell function in high-risk individuals. Changes in CD8 T cell subsets indicated that partially exhausted effector cells were associated with clinical response. Thus, this trial showed improvement in metabolic responses and delay of diabetes with immune therapy. 10.1126/scitranslmed.abc8980
    Latent autoimmune diabetes in adults: a guide for the perplexed. Gale E A M Diabetologia 10.1007/s00125-005-1954-5
    An Anti-CD3 Antibody, Teplizumab, in Relatives at Risk for Type 1 Diabetes. Herold Kevan C,Bundy Brian N,Long S Alice,Bluestone Jeffrey A,DiMeglio Linda A,Dufort Matthew J,Gitelman Stephen E,Gottlieb Peter A,Krischer Jeffrey P,Linsley Peter S,Marks Jennifer B,Moore Wayne,Moran Antoinette,Rodriguez Henry,Russell William E,Schatz Desmond,Skyler Jay S,Tsalikian Eva,Wherrett Diane K,Ziegler Anette-Gabriele,Greenbaum Carla J, The New England journal of medicine BACKGROUND:Type 1 diabetes is a chronic autoimmune disease that leads to destruction of insulin-producing beta cells and dependence on exogenous insulin for survival. Some interventions have delayed the loss of insulin production in patients with type 1 diabetes, but interventions that might affect clinical progression before diagnosis are needed. METHODS:We conducted a phase 2, randomized, placebo-controlled, double-blind trial of teplizumab (an Fc receptor-nonbinding anti-CD3 monoclonal antibody) involving relatives of patients with type 1 diabetes who did not have diabetes but were at high risk for development of clinical disease. Patients were randomly assigned to a single 14-day course of teplizumab or placebo, and follow-up for progression to clinical type 1 diabetes was performed with the use of oral glucose-tolerance tests at 6-month intervals. RESULTS:A total of 76 participants (55 [72%] of whom were ≤18 years of age) underwent randomization - 44 to the teplizumab group and 32 to the placebo group. The median time to the diagnosis of type 1 diabetes was 48.4 months in the teplizumab group and 24.4 months in the placebo group; the disease was diagnosed in 19 (43%) of the participants who received teplizumab and in 23 (72%) of those who received placebo. The hazard ratio for the diagnosis of type 1 diabetes (teplizumab vs. placebo) was 0.41 (95% confidence interval, 0.22 to 0.78; P = 0.006 by adjusted Cox proportional-hazards model). The annualized rates of diagnosis of diabetes were 14.9% per year in the teplizumab group and 35.9% per year in the placebo group. There were expected adverse events of rash and transient lymphopenia. KLRG1+TIGIT+CD8+ T cells were more common in the teplizumab group than in the placebo group. Among the participants who were HLA-DR3-negative, HLA-DR4-positive, or anti-zinc transporter 8 antibody-negative, fewer participants in the teplizumab group than in the placebo group had diabetes diagnosed. CONCLUSIONS:Teplizumab delayed progression to clinical type 1 diabetes in high-risk participants. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01030861.). 10.1056/NEJMoa1902226
    Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. The New England journal of medicine BACKGROUND:Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction. METHODS:In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. RESULTS:During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin. CONCLUSIONS:Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.). 10.1056/NEJMoa2022190
    Finerenone and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Type 2 Diabetes. Filippatos Gerasimos,Anker Stefan D,Agarwal Rajiv,Pitt Bertram,Ruilope Luis M,Rossing Peter,Kolkhof Peter,Schloemer Patrick,Tornus Ingo,Joseph Amer,Bakris George L, Circulation BACKGROUND:The FIDELIO-DKD trial (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) evaluated the effect of the nonsteroidal, selective mineralocorticoid receptor antagonist finerenone on kidney and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes with optimized renin-angiotensin system blockade. Compared with placebo, finerenone reduced the composite kidney and cardiovascular outcomes. We report the effect of finerenone on individual cardiovascular outcomes and in patients with and without history of atherosclerotic cardiovascular disease (CVD). METHODS:This randomized, double-blind, placebo-controlled trial included patients with type 2 diabetes and urine albumin-to-creatinine ratio 30 to 5000 mg/g and an estimated glomerular filtration rate ≥25 to <75 mL per min per 1.73 m, treated with optimized renin-angiotensin system blockade. Patients with a history of heart failure with reduced ejection fraction were excluded. Patients were randomized 1:1 to receive finerenone or placebo. The composite cardiovascular outcome included time to cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. Prespecified cardiovascular analyses included analyses of the components of this composite and outcomes according to CVD history at baseline. RESULTS:Between September 2015 and June 2018, 13 911 patients were screened and 5674 were randomized; 45.9% of patients had CVD at baseline. Over a median follow-up of 2.6 years (interquartile range, 2.0-3.4 years), finerenone reduced the risk of the composite cardiovascular outcome compared with placebo (hazard ratio, 0.86 [95% CI, 0.75-0.99]; =0.034), with no significant interaction between patients with and without CVD (hazard ratio, 0.85 [95% CI, 0.71-1.01] in patients with a history of CVD; hazard ratio, 0.86 [95% CI, 0.68-1.08] in patients without a history of CVD; value for interaction, 0.85). The incidence of treatment-emergent adverse events was similar between treatment arms, with a low incidence of hyperkalemia-related permanent treatment discontinuation (2.3% with finerenone versus 0.8% with placebo in patients with CVD and 2.2% with finerenone versus 1.0% with placebo in patients without CVD). CONCLUSIONS:Among patients with chronic kidney disease and type 2 diabetes, finerenone reduced incidence of the composite cardiovascular outcome, with no evidence of differences in treatment effect based on preexisting CVD status. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02540993. 10.1161/CIRCULATIONAHA.120.051898
    Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. The New England journal of medicine BACKGROUND:Finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, reduced albuminuria in short-term trials involving patients with chronic kidney disease (CKD) and type 2 diabetes. However, its long-term effects on kidney and cardiovascular outcomes are unknown. METHODS:In this double-blind trial, we randomly assigned 5734 patients with CKD and type 2 diabetes in a 1:1 ratio to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300, an estimated glomerular filtration rate (eGFR) of 25 to less than 60 ml per minute per 1.73 m of body-surface area, and diabetic retinopathy, or they had a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of 25 to less than 75 ml per minute per 1.73 m. All the patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary composite outcome, assessed in a time-to-event analysis, was kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes. The key secondary composite outcome, also assessed in a time-to-event analysis, was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. RESULTS:During a median follow-up of 2.6 years, a primary outcome event occurred in 504 of 2833 patients (17.8%) in the finerenone group and 600 of 2841 patients (21.1%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.93; P = 0.001). A key secondary outcome event occurred in 367 patients (13.0%) and 420 patients (14.8%) in the respective groups (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P = 0.03). Overall, the frequency of adverse events was similar in the two groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone than with placebo (2.3% and 0.9%, respectively). CONCLUSIONS:In patients with CKD and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo. (Funded by Bayer; FIDELIO-DKD ClinicalTrials.gov number, NCT02540993.). 10.1056/NEJMoa2025845
    Cardiovascular Protection With Sodium-Glucose Cotransporter-2 Inhibitors and Mineralocorticoid Receptor Antagonists in Chronic Kidney Disease: A Milestone Achieved. Sarafidis Pantelis,Papadopoulos Christodoulos E,Kamperidis Vasilios,Giannakoulas George,Doumas Michael Hypertension (Dallas, Tex. : 1979) Chronic kidney disease (CKD) and cardiovascular disease are intimately linked. They share major risk factors, including age, hypertension, and diabetes, and common pathogenetic mechanisms. Furthermore, reduced renal function and kidney injury documented with albuminuria are independent risk factors for cardiovascular events and mortality. In major renal outcome trials and subsequent meta-analyses in patients with CKD, ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) were shown to effectively retard CKD progression but not to significantly reduce cardiovascular events or mortality. Thus, a high residual risk for cardiovascular disease progression under standard-of-care treatment is still present for patients with CKD. In contrast to the above, several outcome trials with SGLT-2 (sodium-glucose cotransporter-2) inhibitors and MRAs (mineralocorticoid receptor antagonists) clearly suggest that these agents, apart from nephroprotection, offer important cardioprotection in this population. This article discusses existing evidence on the effects of SGLT-2 inhibitors and MRAs on cardiovascular outcomes in patients with CKD that open new roads in cardiovascular protection of this heavily burdened population. 10.1161/HYPERTENSIONAHA.121.17005
    Dapagliflozin in Patients with Chronic Kidney Disease. Heerspink Hiddo J L,Stefánsson Bergur V,Correa-Rotter Ricardo,Chertow Glenn M,Greene Tom,Hou Fan-Fan,Mann Johannes F E,McMurray John J V,Lindberg Magnus,Rossing Peter,Sjöström C David,Toto Roberto D,Langkilde Anna-Maria,Wheeler David C, The New England journal of medicine BACKGROUND:Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known. METHODS:We randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes. RESULTS:The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed. CONCLUSIONS:Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (Funded by AstraZeneca; DAPA-CKD ClinicalTrials.gov number, NCT03036150.). 10.1056/NEJMoa2024816
    Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Bomback Andrew S,Kshirsagar Abhijit V,Amamoo M Ahinee,Klemmer Philip J American journal of kidney diseases : the official journal of the National Kidney Foundation BACKGROUND:The use of mineralocorticoid receptor blockers (MRBs) in patients with chronic kidney disease is growing, but data for efficacy in decreasing proteinuria are limited by a relative paucity of studies, many of which are small and uncontrolled. STUDY DESIGN:We performed a systematic review using the MEDLINE database (inception to November 1, 2006), abstracts from national meetings, and selected reference lists. SETTING & POPULATION:Adult patients with chronic kidney disease and proteinuria. SELECTION CRITERIA FOR STUDIES:English-language studies investigating the use of MRBs added to long-term angiotensin-converting enzyme (ACE)-inhibitor and/or angiotensin receptor blocker (ARB) therapy in adult patients with proteinuric kidney disease. INTERVENTION:MRBs as additive therapy to conventional renin-angiotensin-aldosterone system blockade in patients with chronic kidney disease. OUTCOMES:Changes in proteinuria as the primary outcome; rates of hyperkalemia, changes in blood pressure, and changes in glomerular filtration rate as secondary outcomes. RESULTS:15 studies met inclusion criteria for our review; 4 were parallel-group randomized controlled trials, 4 were crossover randomized controlled trials, 2 were pilot studies, and 5 were case series. When MRBs were added to ACE-inhibitor and/or ARB therapy, the reported proteinuria decreases from baseline ranged from 15% to 54%, with most estimates in the 30% to 40% range. Hyperkalemic events were significant in only 1 of 8 randomized controlled trials. MRB therapy was associated with statistically significant decreases in blood pressure and glomerular filtration rate in approximately 40% and 25% of included studies, respectively. LIMITATIONS:Reported results were insufficient for meta-analysis, with only 2 studies reporting sufficient data to calculate SEs of their published estimates. We were unable to locate studies that showed no effect of MRB treatment over placebo, raising concern for publication bias. CONCLUSIONS:Although data suggest that adding MRBs to ACE-inhibitor and/or ARB therapy yields significant decreases in proteinuria without adverse effects of hyperkalemia and impaired renal function, routine use of MRBs as additive therapy in patients with chronic kidney disease cannot be recommended yet. However, the findings of this review promote interesting hypotheses for future study. 10.1053/j.ajkd.2007.10.040
    Addendum. 10. Cardiovascular Disease and Risk Management: . Diabetes Care 2021;44(Suppl. 1):S125-S150. Diabetes care 10.2337/dc21-ad09a
    Addendum. 11. Microvascular Complications and Foot Care: : Diabetes Care 2021;44(Suppl. 1):S151-S167. Diabetes care 10.2337/dc21-ad09b
    Addendum. 2. Classification and Diagnosis of Diabetes: . Diabetes Care 2021;44(Suppl. 1):S15-S33. Diabetes care 10.2337/dc21-ad09