Barriers to early diagnosis of chronic kidney disease and use of sodium-glucose cotransporter-2 inhibitors for renal protection: A comprehensive review and call to action.

Chronic kidney disease (CKD) affects approximately 13% of people globally, including 20%-48% with type 2 diabetes (T2D), resulting in significant morbidity, mortality, and healthcare costs. There is an urgent need to increase early screening and intervention for CKD. We are experts in diabetology and nephrology in Central Europe and Israel. Herein, we review evidence supporting the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors for kidney protection and discuss barriers to early CKD diagnosis and treatment, including in our respective countries. SGLT2 inhibitors exert cardiorenal protective effects, demonstrated in the renal outcomes trials (EMPA-KIDNEY, DAPA-CKD, CREDENCE) of empagliflozin, dapagliflozin, and canagliflozin in patients with CKD. EMPA-KIDNEY demonstrated cardiorenal efficacy across the broadest renal range, regardless of T2D status. Renoprotective evidence also comes from large real-world studies. International guidelines recommend first-line SGLT2 inhibitors for patients with T2D and estimated glomerular filtration rate (eGFR) ≥20 mL/min/1.73 m2, and that glucagon-like peptide-1 receptor agonists may also be administered if required for additional glucose control. Although these guidelines recommend at least annual eGFR and urine albumin-to-creatinine ratio screening for patients with T2D, observational studies suggest that only half are screened. Diagnosis is hampered by asymptomatic early CKD and under-recognition among patients with T2D and clinicians, including limited knowledge/use of guidelines and resources. Based on our experience and on the literature, we recommend robust screening programmes, potentially with albuminuria self-testing, and SGLT2 inhibitor reimbursement at general practitioner (GP) and specialist levels. High-tech tools (artificial intelligence, smartphone apps, etc.) are providing exciting opportunities to identify high-risk individuals, self-screen, detect abnormalities in images, and assist with prescribing and treatment adherence. Better education is also needed, alongside provision of concise guidelines, enabling GPs to identify who would benefit from early initiation of renoprotective therapy; although, regardless of current renal function, cardiorenal protection is provided by SGLT2 inhibitor therapy.

Parental practices and children's lifestyle correlates of childhood overweight/obesity in Europe: The Feel4Diabetes study.

BACKGROUND: Parental influences on children's eating and physical activity (PA) and consequently on their weight are fundamental. The present study aimed to identify the predominant correlates of childhood overweight/obesity among a variety of parental practices and children's lifestyle indices in a large sample of children in Europe. METHODS: Families from low socio-economic status regions were recruited through schools, located in six European countries (Belgium, Finland, Greece, Spain, Bulgaria and Hungary). Seven thousand three hundred ninety-seven children 4-12 years old and their parents were selected using the FINDRISC-questionnaire. Parental practices assessed included parental role modelling, permissiveness and reward. Children's dietary intake and lifestyle behaviours were assessed through parent-reported questionnaires. RESULTS: Regarding parental practices, it was revealed that being sometimes (odds ratio [OR] = 1.26; 95% confidence interval [CI] = 1.10-1.43) or rarely (OR = 1.43; 95% CI = 1.21-1.69) physically active with the child was associated with greater overweight/obesity risk, whereas rare permission of computer/mobile/tablet (OR = 0.81; 95% CI = 0.67-0.98) and sometimes (OR = 0.77; 95% CI = 0.68-0.88) or rare (OR = 0.77; 95% CI = 0.66-0.91) reward with PA were associated with lower risk. Regarding children's lifestyle factors, consuming > 3 cups/week fresh fruit juices (OR = 1.28; 95% CI = 1.13-1.45), skipping breakfast (OR = 1.37; 95% CI = 1.17-1.61), absence of 1 h of daily PA (OR = 1.40; 95% CI = 1.24-1.58) and increased daily screen time (ST) (OR = 1.23; 95% CI = 1.09-1.39) were associated with greater overweight/obesity risk. All the variables were adjusted for maternal education, child's sex and age. CONCLUSIONS: These findings emphasize the necessity of family-centered approaches in health promotion and obesity prevention programs for children. Such programs should focus on parents as the primary role models in exerting positive influence and encouraging healthy eating habits, PA, and ST behaviors in their children, which in turn, may have a substantial impact on children's overall weight status.

The Relationship Between Dietary Patterns and Glycemic Variability in People with Impaired Glucose Tolerance.

BACKGROUND: Diurnal glucose fluctuations are increased in prediabetes and might be affected by specific dietary patterns. OBJECTIVES: The present study assessed the relationship between glycemic variability (GV) and dietary regimen in people with normal glucose tolerance (NGT) and impaired glucose tolerance (IGT). METHODS: Forty-one NGT (mean age: 45.0 ± 9.0 y, mean BMI: 32.0 ± 7.0 kg/m2) and 53 IGT (mean age: 48.4 ± 11.2 y, mean BMI: 31.3 ± 5.9 kg/m2) subjects were enrolled in this cross-sectional study. The FreeStyleLibre Pro sensor was used for 14 d, and several parameters of GV were calculated. The participants were provided with a diet diary to record all meals. ANOVA analysis, Pearson correlation, and stepwise forward regression were performed. RESULTS: Despite no difference in diet patterns between the 2 groups, GV parameters were higher in IGT than in NGT. GV worsened with an increase in overall daily carbohydrate and refined grain consumption and improved with the increase in whole grain intake in IGT. GV parameters were positively related [r = 0.14-0.53; all P < 0.02 for SD, continuous overall net glycemic action 1 (CONGA1), J-index, lability index (LI), glycemic risk assessment diabetes equation, M-value, and mean absolute glucose (MAG)], and low blood glucose index (LBGI) inversely (r = -0.37, P = 0.006) related to the total percentage of carbohydrate, but not to the distribution of carbohydrate between the main meals in the IGT group. A negative relationship existed between total protein consumption and GV indices (r = -0.27 to -0.52; P < 0.05 for SD, CONGA1, J-index, LI, M-value, and MAG). The total EI was related to GV parameters (r = 0.27-0.32; P < 0.05 for CONGA1, J-index, LI, and M-value; and r = -0.30, P = 0.028 for LBGI). CONCLUSIONS: The primary outcome results showed that insulin sensitivity, calories, and carbohydrate content are predictors of GV in individuals with IGT. Overall, the secondary analyses suggested that carbohydrate and daily consumption of refined grains might be associated with higher GV, whereas whole grains and daily protein intake were related to lower GV in people with IGT.

A lifestyle pattern characterised by high consumption of sweet and salty snacks, sugar sweetened beverages and sedentary time is associated with blood pressure in families at risk for type 2 diabetes mellitus in Europe. The Feel4Diabetes Study.

BACKGROUND: Individuals from families at high-risk for type 2 diabetes mellitus (T2DM) are also at high risk for hypertension (HTN) and cardiovascular disease. Studies identifying lifestyle patterns (LPs) combining dietary, physical activity or sedentary variables and examining their possible role with respect to developing blood pressure (BP) are limited. The present study aimed to examine the association of different LPs with BP levels in families at high risk for T2DM in Europe. METHODS: In total, 1844 adults (31.6% males) at high-risk for T2DM across six European countries were included in this cross-sectional study using data from the baseline assessment of the Feel4Diabetes Study. BP measurements and dietary and physical activity assessments were conducted, and screen times were surveyed. LPs were revealed with principal component analysis of various data regarding diet, physical activity, screen time and smoking. RESULTS: Three LPs were identified. LP3 (high consumption of sweet and salty snacks, sugar sweetened soft drinks and juices, and high amount of screen time) was positively associated with diastolic BP (B, 0.52; 95% confidence interval = 0.05-0.99) and the existence of HTN (odds ratio = 1.12; 95% confidence interval = 1.00-1.25). Participants in the highest tertile of LP3 spent mean 3 h of screen time, consumed 1.5 portions of sweet and/or salty snacks and 1 L of soft drinks on a daily basis, were associated with 12% higher risk of HTN. CONCLUSIONS: Focusing on the combination of eating and lifestyle behaviours may more accurately identify, and therefore guide preventive measures tailored to the specific needs of high-risk populations.

Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycaemia in type 2 diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional healthcare team providing diabetes care in the USA and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the healthcare system and physical activity behaviours including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. After a summary listing of consensus recommendations, practical tips for implementation are provided.

Insulin secretion and action affect glucose variability in the early stages of glucose intolerance.

AIMS: Since it is unknown whether glucose variability (GV) is increased and whether this is related to worsening of insulin secretion and action in prediabetes, we have assessed insulin secretion and sensitivity, and daily GV in early stages of dysglycemia. MATERIALS AND METHODS: Twenty subjects with normal glucose tolerance (NGT; age 45.0 ± 9.5 years; BMI 31.1 ± 6.4 kg/m2), 25 with NGT and 1hrOGTT>8.6 mmol/L (1hrOGTT; 45.7 ± 8.5 years; 32.4 ± 7.0 kg/m2), and 59 with isolated impaired glucose tolerance (iIGT; 47.7 ± 11.2 years; 31.3 ± 6.1 kg/m2) underwent OGTT and MMTT. CGM was performed with blinded FreeStyle Libre Pro for 24 h under standard conditions. Parameters of beta-cell function, insulin sensitivity and GV were calculated. RESULTS: Overall insulin secretion and action as well as GV progressively worsened across glucose tolerance categories. On a matrix analysis, GV parameters were inversely related to ISSI-2; r = -0.37 to -0.52; p < 0.0001; and IGI; r = -0.28 to -0.48; p < 0.0001 for CV, SD, J-index, LI, HBGI and MAGE. Insulin secretion (IGI) and b-cell function (ISSI-2) emerged as independent contributors to GV in early stage of dysglycemia accounting for about 16%-38% of its variability. CONCLUSIONS: Our results show that daily GV worsens already with mild impairment of glucose tolerance. The increase in GV is inversely related to insulin secretion and action.

Sociodemographic, anthropometric, and lifestyle correlates of prediabetes and type 2 diabetes in europe: The Feel4Diabetes study.

BACKGROUND AND AIMS: The current work aimed to identify the predominant correlates of prediabetes and T2DM among a variety of socio-demographic, anthropometric and lifestyle indices, in a large sample of adults from families at high risk for T2DM. METHODS AND RESULTS: In this cross-sectional study, 2816 adults were recruited from low-socioeconomic areas in high-income countries (HICs) (Belgium-Finland), HICs under austerity measures (Greece-Spain), and low/middle-income countries (LMICs) (Bulgaria-Hungary). A positive association between the male sex (OR, 95% C.I.2.77 (1.69-4.54)) and prediabetes was revealed compared to females, while there was a negative association between younger age (<45 years) (OR, 95% C.I. 0.58 (0.37-0.92)), and low/medium levels of waist circumference (OR, 95% C.I. 0.44 (0.22-0.89)) with prediabetes compared to older age and high levels of waist circumference, respectively. Concerning T2DM, 0-0.5 cups/day of fruits and berries (OR, 95% C.I.2. 13 (1.16-3.91)) and 150-300 g fish/week (OR, 95% C.I. 2.55 (1.01-6.41)) have a positive association compared to higher consumptions, respectively. Conversely, <1 cup/week legumes (OR, 95% C.I. 0.55 (0.31-0.99) as well as 0-0.5 servings (OR, 95% C.I. 0.34 (0.12-0.95) and 0.5-1 servings (OR, 95% C.I. 0.37 (0.19-0.71) of full-fat dairy/day have a negative association compared to higher consumptions, respectively. CONCLUSION: These findings indicate the need for diabetes prevention measures targeting young adults and especially men, above 45 years of age, with central obesity and poor dietary habits and prioritize vulnerable groups and populations living in LMICs. NATIONAL CLINICAL TRIAL NUMBER: NCT02393872.

Parental insulin resistance is associated with unhealthy lifestyle behaviours independently of body mass index in children: The Feel4Diabetes study.

Parental health is associated with children's health and lifestyles. Thus, the aim of the present study was to assess lifestyle behaviours of children of parents with insulin resistance (IR) and at risk of type 2 diabetes. 2117 European families from the Feel4Diabetes-study were identified as being at risk for diabetes with the FINDRISC questionnaire and included in the present study. One parent and one child per family were included. Parental IR was considered when homeostasis model assessment (HOMA) was equal or higher than 2.5. Children's screen-time, physical activity and diet were assessed and clustered by K-means. Weight and height were measured and children's body mass index (BMI) was calculated. For children, a Healthy Diet Score (HDS) was calculated. Linear regression and multilevel logistic regression analyses were performed to assess the associations between parental IR and children's lifestyle behaviours in 2021. Children of parents with IR had higher BMI (p < 0.001) and spent more screen time (p = 0.014) than those of non-IR parents. Children of parents with IR had a lower value in the breakfast and vegetable components of the HDS (p = 0.008 and p = 0.05). Four lifestyle clusters were found. Children of IR parents had higher odds of being in a non-healthy cluster (OR: 1.19; 95%CI: 1.001-1.437). CONCLUSION: Having an IR parent was associated with a high screen time and an increased probability of having an unhealthy lifestyle pattern in children. These data point out that children's lifestyles should be assessed in families with IR parents to provide tailored interventions. WHAT IS KNOWN: • Children with diabetic or insulin-resistant parents could also develop this condition. • Unhealthy lifestyles are directly related with insulin resistance even in children. WHAT IS NEW: • Children from parents with insulin resistance have higher chances of unhealthy lifestyles. • A higher BMI was found for those children with an insulin-resistant parent.

Frequency of family meals and food consumption in families at high risk of type 2 diabetes: the Feel4Diabetes-study.

A family meal is defined as a meal consumed together by the members of a family or by having ≥ 1 parent present during a meal. The frequency of family meals has been associated with healthier food intake patterns in both children and parents. This study aimed to investigate in families at high risk for developing type 2 diabetes across Europe the association (i) between family meals' frequency and food consumption and diet quality among parents and (ii) between family meals' frequency and children's food consumption. Moreover, the study aimed to elucidate the mediating effect of parental diet quality on the association between family meals' frequency and children's food consumption. Food consumption frequency and anthropometric were collected cross-sectionally from a representative sample of 1964 families from the European Feel4Diabetes-study. Regression and mediation analyses were applied by gender of children. Positive and significant associations were found between the frequency of family meals and parental food consumption (ß = 0.84; 95% CI 0.57, 1.45) and diet quality (ß = 0.30; 95% CI 0.19, 0.42). For children, more frequent family meals were significantly associated with healthier food consumption (boys, ß = 0.172, p < 0.05; girls, ß = 0.114, p < 0.01). A partial mediation effect of the parental diet quality was shown on the association between the frequency of family meals and the consumption of some selected food items (i.e., milk products and salty snacks) among boys and girls. The strongest mediation effect of parental diet quality was found on the association between the frequency of family breakfast and the consumption of salty snacks and milk and milk products (62.5% and 37.5%, respectively) among girls. CONCLUSIONS: The frequency of family meals is positively associated with improved food consumption patterns (i.e., higher intake of fruits and vegetables and reduced consumption of sweets) in both parents and children. However, the association in children is partially mediated by parents' diet quality. The promotion of consuming meals together in the family could be a potentially effective strategy for interventions aiming to establish and maintain healthy food consumption patterns among children. TRIAL REGISTRATION: The Feel4Diabetes-study is registered with the clinical trials registry (NCT02393872), http://clinicaltrials.gov , March 20, 2015. WHAT IS KNOWN: • Parents' eating habits and diet quality play an important role in shaping dietary patterns in children • Family meals frequency is associated with improved diet quality of children in healthy population What is New: • Frequency of family meals was significantly associated with healthier food consumption among parents and children in families at high risk of type 2 diabetes in six European countries. • Parental diet quality mediates the association between family meals frequency and the consumption of some selected food items among children.

Parental food consumption and diet quality and its association with children's food consumption in families at high risk of type 2 diabetes: the Feel4Diabetes-study.

OBJECTIVE: To examine the parental food consumption and diet quality and its associations with children's consumption in families at high risk for developing type 2 diabetes mellitus across Europe. Also, to compare food frequency consumption among parents and children from high-risk families to the European Dietary guidelines/recommendations. DESIGN: Cross-sectional study using Feel4diabetes FFQ. SETTING: Families completed FFQ and anthropometric measures were obtained. Linear regression analyses were applied to investigate the relations between parental food consumption and diet quality and their children's food consumption after consideration of potential confounders. PARTICIPANTS: 2095 European families (74·6 % mothers, 50·9 % girls). The participants included parent and one child, aged 6-8 years. RESULTS: Parental food consumption was significantly associated with children's intake from the same food groups among boys and girls. Most parents and children showed under-consumption of healthy foods according to the European Dietary Guidelines. Parental diet quality was positively associated with children's intake of 'fruit' (boys: ß = 0·233, P < 0·001; girls: ß = 0·134, P < 0·05) and 'vegetables' (boys: ß = 0·177, P < 0·01; girls: ß = 0·234, P < 0·001) and inversely associated with their 'snacks' consumption (boys: ß = -0·143, P < 0·05; girls: ß = -0·186, P < 0·01). CONCLUSION: The present study suggests an association between parental food consumption and diet quality and children's food intake. More in-depth studies and lifestyle interventions that include both parents and children are therefore recommended for future research.

Fathers' daily intake of fruit and vegetables is positively associated with children's fruit and vegetable consumption patterns in Europe: The Feel4Diabetes Study.

BACKGROUND: Past research has focused on the relationship between mothers' and children's eating habits, although little is known about fathers as potential agents. The present study aimed to investigate the relationship between fathers' and children's fruit and vegetable (FV) intake in the context of fathers' education level and family income insecurity. METHODS: Cross-sectional analysis using baseline data from the multicentre Feel4Diabetes Study were collected in 2016. Participants were parent-dyads (fathers, n = 10,038) and school children (n = 12,041) from six European countries. Socio-demographic and dietary data were collected using questionnaires. Associations were assessed applying the multinomial logistic regression model. RESULTS: Overall, European children have low FV intake, especially in Southern European countries (Greece, Spain and Hungary). Children with fathers consuming FV daily were more likely to consume fresh fruit (odds ratio [OR] = 2.75; 95% confidence interval [CI] = 1.95-3.88) and vegetables (OR = 2.55; 95% CI = 1.80-3.60) 1-2 times per day. After adjusting for paternal educational level and family income insecurity significant associations remained for fresh fruit (ORadj = 2.59; 95% CI = 1.82-3.69) and vegetables (ORadj = 1.98; 95% CI = 1.38-2.86). Country differences showed that fathers' educational level and income insecurity might be important factors worth considering for FV intake in Greece. CONCLUSIONS: The present study showed that fathers' FV intake was positively associated with children's daily intake of these foods. Implementation of future population-based strategies promoting FV intake not only in mothers, but also in fathers could be an effective public health initiative to increase FV intake in children. Policy-makers should give special attention to families dwelling in Southern European regions.

The efficacy and safety of dapagliflozin in women and men with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Women remain underrepresented in clinical trials and those with type 2 diabetes mellitus are at high risk for cardiovascular (CV) events. The sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin reduces the risk of CV death or heart failure hospitalisations in individuals with type 2 diabetes. Here, we performed a pre-specified analysis to examine whether sex modifies these effects. METHODS: The DECLARE-TIMI 58 trial randomised 17,160 patients with type 2 diabetes with or at risk for atherosclerotic disease to dapagliflozin or placebo (median follow-up 4.2 years). The dual efficacy outcomes were CV death or heart failure hospitalisations, and major adverse cardiovascular events (MACE; CV death, myocardial infarction or ischaemic stroke). The renal-specific composite outcome was a sustained ≥40% drop in eGFR to <60 ml min-1 [1.73 m]-2, new end-stage renal disease or renal death. Cox models were run separately by sex with treatment-by-sex interaction testing for each outcome. RESULTS: At baseline, women (n = 6422, 37.4%) had higher HbA1c, longer type 2 diabetes duration, and were on fewer glucose-lowering medications. There was no evidence of modification of the effect of dapagliflozin by sex for (1) CV death or heart failure hospitalisations: women (3.8% vs 4.5%; HR 0.84, 95% CI 0.66, 1.07) and men (5.3% vs 6.4%; HR 0.83, 95% CI 0.71, 0.96; pinteraction = 0.90); (2) MACE: women (6.3% vs 6.8%; HR 0.93, 95% CI 0.77, 1.12) and men (10.0% vs 10.7%; HR 0.93, 95% CI 0.83, 1.05; pinteraction = 0.99); or (3) renal-specific composite: women (1.4% vs 2.8%; HR 0.50, 95% CI 0.35, 0.70) and men (1.5% vs 2.5%; HR 0.55, 95% CI 0.42, 0.73; pinteraction = 0.64). The overall safety profile of dapagliflozin was similar for women and men. CONCLUSIONS/INTERPRETATION: Dapagliflozin offers comparable CV and renal benefits and a comparable safety profile in women and men. FUNDING: AstraZeneca. TRIAL REGISTRATION: clinicaltrials.gov NCT01730534.

Does SGLT2 Inhibition Affect Sympathetic Nerve Activity in Type 2 Diabetes?

SGLT2 inhibitors increase renal glucose excretion and thus decrease both fasting and postprandial plasma glucose levels. The effects of SGLT2 inhibition outweigh those on glycemic control and are also associated with the induction of hemodynamic changes that improve cardiovascular and renal function in people with type 2 diabetes. The exact mechanisms have not yet been completely clarified. This review is focused on the potential relationship between SGLT2 inhibition and sympathetic nerve activity. There is accumulating evidence for a suppressive effect of SGLT2 inhibitors on the sympathetic nerve tone, which might be a putative mechanism for cardiovascular protection in subjects with type 2 diabetes.

Cost-effectiveness analysis of a school- and community-based intervention to promote a healthy lifestyle and prevent type 2 diabetes in vulnerable families across Europe: the Feel4Diabetes-study.

The Feel4Diabetes-study implemented a school- and community-based intervention to promote healthy lifestyle and prevent type 2 diabetes mellitus (T2DM) in six European countries. The intervention included a special focus on families at increased T2DM risk. The current study evaluates the intervention's cost-effectiveness. A Markov-type health economic model was developed to predict the incidence of T2DM and its complications. Incremental cost-effectiveness ratios (lifetime horizon, societal perspective) were calculated based on the overall intervention effect on health behaviour, and stratified for low- and high-risk families. Sensitivity analyses captured input parameters uncertainty. A budget impact analysis was performed. The increase in children's water consumption and physical activity led to a modest gain in quality adjusted life years (QALYs) at a low intervention cost and budget impact. Medical cost savings due to avoided illness could only be achieved on the very long-term (>30 years). The intervention in its entirety was cost-effective (more QALYs at a reasonable investment) in Belgium, Finland, Bulgaria, and Hungary, while being dominant (net savings and more QALYs) in Greece and Spain. Results were cost-effective for the low-risk families, who only received the school- and community-based intervention component. Results for the high-risk families were only cost-effective (with considerable uncertainty) in Greece and Spain, but not when the intervention would need to be repeated. The Feel4Diabetes-intervention is potentially cost-effective, especially in countries with a high overweight and obesity prevalence, at a limited budget impact. The incremental financial investments to reach and support high-risk families did not result in the hoped-for health benefits.

European Childhood Obesity Risk Evaluation (CORE) index based on perinatal factors and maternal sociodemographic characteristics: the Feel4Diabetes-study.

The aim of this study was to develop and examine the predictive accuracy of an index that estimates obesity risk in childhood based on perinatal factors and maternal sociodemographic characteristics. Analysis was conducted by using cross-sectional and retrospective data collected from a European cohort of 2775 schoolchildren and their families participating in the Feel4Diabetes-study. The cohort was randomly divided by using two-thirds of the sample for the development of the index and the remaining one third for assessing its predictive accuracy. Logistic regression analyses determined a prediction model for childhood obesity. The area under the receiver operating characteristic curve (AUC-ROC), sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated. Cut-off analysis was applied to identify the optimal value of the index score that predicts obesity with the highest possible sensitivity and specificity. Eight factors were found to be significantly associated with obesity and were included as components in the European "Childhood Obesity Risk Evaluation" (CORE) index: region of residence, maternal education, maternal pre-pregnancy weight status, gestational weight gain, maternal smoking during pregnancy, birth weight for gestational age, infant growth velocity, and exclusive breastfeeding during the first 6 months. Risk score ranged from 0 to 22 corresponding to a risk from 0.9 to 54.6%. The AUC-ROC was 0.725 with optimal cut-off ≥9 (sensitivity = 74.1%, specificity = 61.0%, PPV = 11.3%, NPV = 97.2%).Conclusion: The European CORE index can be used as a screening tool for the identification of infants at high-risk for becoming obese at 6-9 years. This tool could assist healthcare professionals in initiating preventive measures from the early life.Trial registration: The Feel4Diabetes-intervention is registered at https://clinicaltrials.gov/ ; number, CT02393872; date, March 20, 2015. What is Known: • As prevention of obesity should start early in life, there is a compelling rationale for the early identification of high-risk children to facilitate targeted intervention. What is New: • This study developed and assessed the predictive accuracy of an index for the Childhood Obesity Risk Evaluation (CORE), combining certain perinatal factors and maternal sociodemographic characteristics in a large European cohort. • The European CORE index can be used as a screening tool for identifying infants at high-risk for becoming obese at 6-9 years and assist health professionals in initiating early prevention strategies.

The relationship between endogenous secretory RAGE and cardiac autonomic function in prediabetes.

AIMS: The putative protective role of esRAGE for cardiac autonomic function (CAF) remains unclear. To address this question, the present study has assessed the relationship of serum AGEs, sRAGE and esRAGE, and tissue AGEs with CAF in a high-risk population without diabetes. MATERIAL AND METHODS: This study enrolled 48 subjects of mean age 52.7 ± 11.2 years and mean BMI 28.4 ± 6.3 kg/m2 , divided into two groups according to glucose tolerance: 16 with normal glucose tolerance (NGT) and 24 with prediabetes. A standard oral glucose tolerance test (OGTT) was performed. The glucose tolerance was defined according to 2006 WHO criteria. Fasting, 120-minutes glucose, lipids, creatinine, and HbA1c were measured. eGFR was calculated (CKD-EPI). Fasting, 120-minutes insulin (ECLIA method), advanced glycation end products (AGEs), plasma-soluble receptor for AGE (sRAGE), and endogenous secreted isoform of the receptor for AGE (esRAGE), (ELISA method) were assessed. HOMA-IR was calculated. Tissue AGEs were assessed by skin autofluorescence (AGE-Reader, DiagnOpticsTM). CAF was evaluated with ANX 3.0 autonomic nervous-monitoring system (ANSAR), applying deep breathing, Valsalva, and standing. RESULTS: There was a significant decline in CAF in prediabetes in comparison with NGT. Serum and tissue AGEs, sRAGE, and esRAGE levels were similar between groups. On the matrix analysis, both sympathetic and parasympathetic activities at baseline and after standing and sympathetic tone during Valsalva were positively related to esRAGE in prediabetes. Multivariate regression analysis showed that esRAGE is an independent contributor to sympathetic, parasympathetic, and total autonomic tone in prediabetes accounting for about 28%, 34%, and 35% of their variances, respectively. CONCLUSION: Our results have demonstrated that CAF is decreased in prediabetes. esRAGE, but not sRAGE, is reciprocally related to CAF, probably opposing the negative effects of glycation.

Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes.

The disclosure of proven cardiorenal benefits with certain antidiabetic agents was supposed to herald a new era in the management of type 2 diabetes (T2D), especially for the many patients with T2D who are at high risk for cardiovascular and renal events. However, as the evidence in favour of various sodium-glucose transporter-2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) accumulates, prescriptions of these agents continue to stagnate, even among eligible, at-risk patients. By contrast, dipeptidyl peptidase-4 inhibitors (DPP-4i) DPP-4i remain more widely used than SGLT2i and GLP-1 RA in these patients, despite a similar cost to SGLT2i and a large body of evidence showing no clear benefit on cardiorenal outcomes. We are a group of diabetologists united by a shared concern that clinical inertia is preventing these patients from receiving life-saving treatments, as well as placing them at greater risk of hospitalisation for heart failure and progression of renal disease. We propose a manifesto for change, in order to increase uptake of SGLT2i and GLP-1 RA in appropriate patients as a matter of urgency, especially those who could be readily switched from an agent without proven cardiorenal benefit. Central to our manifesto is a shift from linear treatment algorithms based on HbA1c target setting to parallel, independent considerations of atherosclerotic cardiovascular disease, heart failure and renal risks, in accordance with newly updated guidelines. Finally, we call upon all colleagues to play their part in implementing our manifesto at a local level, ensuring that patients do not pay a heavy price for continued clinical inertia in T2D.

Endothelial and Autonomic Dysfunction at Early Stages of Glucose Intolerance and in Metabolic Syndrome.

This study evaluated sE-selectin, Endothelin-1, and cardiovascular autonomic neuropathy (CAN) at early stages of glucose intolerance and in metabolic syndrome (MetS). A total of 87 subjects - 39 males, of mean age 45.7±11.6 years and mean BMI 31.4±6.6 kg/m2, divided according to glucose tolerance and the presence of MetS were enrolled. Glucose tolerance was studied during OGTT. Anthropometric indices, blood pressure, HbA1c, lipids, hsCRP, sE-selectin, Endothelin-1, and immunoreactive insulin were measured. Body composition was assessed by a bioimpedance method (InBody 720, BioSpace). Tissue AGEs accumulation was evaluated by skin autofluorescence (AGE-Reader, DiagnOpticsTM). CAN was assessed by ANX-3.0 technology. In the groups, according to glucose tolerance, the prevalence of CAN was 5.7% in normal glucose tolerance (NGT), 8.6% in prediabetes, and 23.5% in newly diagnosed type 2 diabetes (NDD). In the groups, according to the presence of MetS, the prevalence of CAN was 12.3% in those with MetS and 4.8% in those without MetS. Parasympathetic activity was diminished at rest (p=0.048, 0.015, respectively) in NDD as compared to prediabetes and NGT; and there was a numerically elevated heart rate at rest in NDD in comparison to NGT. There was a negative correlation between parasympathetic tone and waist circumference, BMI, and visceral and total fat. There was no difference in the measured endothelial function markers in the groups according to glucose tolerance and MetS. sE-selectin correlated with HOMA-IR (r=0.275, p=0.048). No association between Endothelin-1 levels and assessed metabolic parameters was observed. There is a high prevalence of CAN at early stages of glucose intolerance and in MetS, due to decreased parasympathetic activity. Slight elevation of glycemia and MetS probably do not affect endothelial function, since sE-selectin seems to be related to insulin resistance.

Two-stage, school and community-based population screening successfully identifies individuals and families at high-risk for type 2 diabetes: the Feel4Diabetes-study.

BACKGROUND: The implementation of population screening and early prevention strategies targeting individuals at high-risk for type 2 diabetes (T2D) seems to be a public health priority. The current work aimed to describe the screening procedure applied in the Feel4Diabetes-study and examine its effectiveness in identifying individuals and families at high risk, primarily for T2D and secondarily for hypertension, among vulnerable populations in low to middle-income countries (LMICs) and high-income countries (HICs) across Europe. METHODS: A two-stage screening procedure, using primary schools as the entry-point to the community, was applied in low socioeconomic status (SES) regions in LMICs (Bulgaria-Hungary), HICs (Belgium-Finland) and HICs under austerity measures (Greece-Spain). During the first-stage screening via the school-setting, a total of 20,501 parents (mothers and/or fathers) of schoolchildren from 11,396 families completed the Finnish Diabetes Risk Score (FINDRISC) questionnaire, while their children underwent anthropometric measurements in the school setting. Parents from the identified "high-risk families" (n = 4484) were invited to participate in the second-stage screening, including the measurement of fasting plasma glucose (FPG) and blood pressure (BP). In total, 3153 parents participated in the second-stage screening (mean age 41.1 ± 5.6 years, 65.8% females). RESULTS: Among parents who attended the second-stage screening, the prevalence of prediabetes (as defined by impaired fasting glucose; FPG 100-125 mg/dl) and T2D (FPG > 126 mg/dl) was 23.2 and 3.0% respectively, and it was found to be higher in the higher FINDRISC categories. The percentage of undiagnosed T2D among the participants identified with T2D was 53.5%. The prevalence of high normal BP (systolic BP 130-139 mmHg and/ or diastolic BP 85-89 mmHg) and hypertension (systolic BP ≥ 140 mmHg and/ or diastolic BP ≥ 90 mmHg) was 14 and 18.6% respectively, which was also higher in the higher FINDRISC categories. The percentage of cases not receiving antihypertensive treatment among the participants identified with hypertension was 80.3%. CONCLUSION: The findings of the current study indicate that the two-stage school and community-based screening procedure followed, effectively identified high-risk individuals and families in vulnerable populations across Europe. This approach could be potentially scalable and sustainable and support initiatives for the early prevention of T2D and hypertension. TRIAL REGISTRATION: The Feel4Diabetes-intervention is registered at https://clinicaltrials.gov/ (NCT02393872; date of trial registration: March 20, 2015).

Sociodemographic and lifestyle-related risk factors for identifying vulnerable groups for type 2 diabetes: a narrative review with emphasis on data from Europe.

BACKGROUND: Type 2 diabetes mellitus (T2DM) comprises the vast majority of all diabetes cases in adults, with alarmingly increasing prevalence over the past few decades worldwide. A particularly heavy healthcare burden of diabetes is noted in Europe, where 8.8% of the population aged 20-79 years is estimated to have diabetes according to the International Diabetes Federation. Multiple risk factors are implicated in the pathogenesis of T2DM with complex underlying interplay and intricate gene-environment interactions. Thus, intense research has been focused on studying the role of T2DM risk factors and on identifying vulnerable groups for T2DM in the general population which can then be targeted for prevention interventions. METHODS: For this narrative review, we conducted a comprehensive search of the existing literature on T2DM risk factors, focusing on studies in adult cohorts from European countries which were published in English after January 2000. RESULTS: Multiple lifestyle-related and sociodemographic factors were identified as related to high T2DM risk, including age, ethnicity, family history, low socioeconomic status, obesity, metabolic syndrome and each of its components, as well as certain unhealthy lifestyle behaviors. As Europe has an increasingly aging population, multiple migrant and ethnic minority groups and significant socioeconomic diversity both within and across different countries, this review focuses not only on modifiable T2DM risk factors, but also on the impact of pertinent demographic and socioeconomic factors. CONCLUSION: In addition to other T2DM risk factors, low socioeconomic status can significantly increase the risk for prediabetes and T2DM, but is often overlooked. In multinational and multicultural regions such as Europe, a holistic approach, which will take into account both traditional and socioeconomic/socioecological factors, is becoming increasingly crucial in order to implement multidimensional public health programs and integrated community-based interventions for effective T2DM prevention.