To assess the effects of early management of hyperglycaemia with antidiabetic drugs plus lifestyle intervention compared with lifestyle alone, on microvascular function in adults with pre-diabetes. Trial design: International, multicenter, randomised, partially double-blind, placebo-controlled, clinical trial. Males and females aged 45–74 years with IFG, IGT or IFG+IGT, recruited from primary care centres in Australia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and Turkey. Participants were randomized to placebo; metformin 1.700 mg/day; linagliptin 5 mg/day or fixed-dose combination of linagliptin/metformin. All patients were enrolled in a lifestyle intervention program (diet and physical activity). Drug intervention will last 2 years. Primary Outcome: composite end-point of diabetic retinopathy estimated by the Early Treatment Diabetic Retinopathy Study Score, urinary albumin to creatinine ratio, and skin conductance in feet estimated by the sudomotor index. Secondary outcomes in a subsample include insulin sensitivity, beta-cell function, biomarkers of inflammation and fatty liver disease, quality of life, cognitive function, depressive symptoms and endothelial function. One thousand three hundred ninety one individuals with hyperglycaemia were assessed for eligibility, 424 excluded after screening, 967 allocated to placebo, metformin, linagliptin or to fixed-dose combination of metformin + linagliptin. A total of 809 people (91.1%) accepted and initiated the assigned treatment. Study sample after randomization was well balanced among the four groups. No statistical differences for the main risk factors analysed were observed between those accepting or rejecting treatment initiation. At baseline prevalence of diabetic retinopathy was 4.2%, severe neuropathy 5.3% and nephropathy 5.7%. ePREDICE is the first -randomized clinical trial with the aim to assess effects of different interventions (lifestyle and pharmacological) on microvascular function in people with pre-diabetes. The trial will provide novel data on lifestyle modification combined with glucose lowering drugs for the prevention of early microvascular complications and diabetes. - ClinicalTrials.Gov Identifier: NCT03222765 - EUDRACT Registry Number: 2013-000418-39

To understand user needs, system requirements and organizational conditions towards successful design and adoption of Clinical Decision Support Systems for Type 2 Diabetes (T2D) care built on top of computerized risk models. The holistic and evidence-based CEHRES Roadmap, used to create eHealth solutions through participatory development approach, persuasive design techniques and business modelling, was adopted in the MOSAIC project to define the sequence of multidisciplinary methods organized in three phases, user needs, implementation and evaluation. The research was qualitative, the total number of participants was ninety, about five-seventeen involved in each round of experiment. Prediction models for the onset of T2D are built on clinical studies, while for T2D care are derived from healthcare registries. Accordingly, two set of DSSs were defined: the first, T2D Screening, introduces a novel routine; in the second case, T2D Care, DSSs can support managers at population level, and daily practitioners at individual level. In the user needs phase, T2D Screening and solution T2D Care at population level share similar priorities, as both deal with risk-stratification. End-users of T2D Screening and solution T2D Care at individual level prioritize easiness of use and satisfaction, while managers prefer the tools to be available every time and everywhere. In the implementation phase, three Use Cases were defined for T2D Screening, adapting the tool to different settings and granularity of information. Two Use Cases were defined around solutions T2D Care at population and T2D Care at individual, to be used in primary or secondary care. Suitable filtering options were equipped with “attractive” visual analytics to focus the attention of end-users on specific parameters and events. In the evaluation phase, good levels of user experience versus bad level of usability suggest that end-users of T2D Screening perceived the potential, but they are worried about complexity. Usability and user experience were above acceptable thresholds for T2D Care at population and T2D Care at individual. By using a holistic approach, we have been able to understand user needs, behaviours and interactions and give new insights in the definition of effective Decision Support Systems to deal with the complexity of T2D care.

Objective: To compare the effect of glucose-lowering drugs on peripheral nerve and kidney function in prediabetes. Methods: Multicenter, randomized, placebo-controlled trial in 658 adults with prediabetes treated for 1 year with metformin, linagliptin, their combination or placebo. Endpoints are small fiber peripheral neuropathy (SFPN) risk estimated by foot electrochemical skin conductance (FESC < 70 μSiemens) and estimated glomerular filtration rate (eGFR). Results: Compared to the placebo, the proportion of SFPN was reduced by 25.1% (95% CI:16.3–33.9) with metformin alone, by 17.3% (95% CI 7.4–27.2) with linagliptin alone, and by 19.5% (95% CI 10.1–29.0) with the combination linagliptin/metformin (p < 0.0001 for all comparisons). eGFR remained +3.3 mL/min (95% CI: 0.38–6.22) higher with the combination linagliptin/metformin than with the placebo (p = 0.03). Fasting plasma glucose (FPG) decreased more with metformin monotherapy −0.3 mmol/L (95%CI: −0.48; 0.12, p = 0.0009) and with the combination metformin/linagliptin −0.2 mmol/L (95% CI: −0.37; −0.03) than with the placebo (p = 0.0219). Body weight (BW) decreased by −2.0 kg (95% CI: −5.65; −1.65, p = 0.0006) with metformin monotherapy, and by −1.9 kg (95% CI: −3.02; −0.97) with the combination metformin/linagliptin as compared to the placebo (p = 0.0002). Conclusions: in people with prediabetes, a 1 year treatment with metformin and linagliptin, combined or in monotherapy, was associated with a lower risk of SFPN, and with a lower decrease in eGFR, than treatment with placebo.

Aims/hypothesis Fasting hyperinsulinaemia is a key feature of obesity and is implicated in diabetes progression. However, the following aspects of insulin secretion remain unclear: (1) which index of obesity is most important; (2) what is the shape of the dose–response curve between obesity and insulin secretion; (3) what physiological mechanisms sustain insulin hypersecretion; (4) what are the underlying causes; and (5) whether sex-related differences exist. Methods We analysed data from 1250 healthy participants (547 men, 703 women) of the EGIR-RISC cohort followed up for 3.5 years, with age 30–60 years and BMI 18.5–40.0 kg/m². Assessments included body composition, insulin secretion, beta cell function modelling from an OGTT and clamp-derived insulin sensitivity. Endogenous glucose production (EGP) was measured in a subset of 368 participants. Multivariable regression models and stratifications for BMI, body fat per cent, WHR and fat mass were applied to evaluate the effect of obesity on insulin secretion and beta cell function. Results The impact of obesity on fasting insulin secretion (FIS) was continuous across the full spectrum of BMI and WHR values and was greater in men than women. Among adiposity indices, fat mass (standardised β coefficient [Stβ] 0.27, p<0.0001) and waist circumference (Stβ 0.21, p<0.0001) were the strongest predictors of FIS. Insulin secretion increased 2.4-fold across BMI deciles, and adiposity-associated insulin hypersecretion appeared to be driven by the combination of hyperglycaemia and an increase in a specific beta cell function variable (insulin secretion rate at 5 mmol/l glucose [ISR@5]). In the follow-up cohort, weight gain (mean ± SD ∆ weight=+5.1 ± 3.8 kg) was associated with an increase in FIS and fasting glucose (+0.20 ± 0.63 mmol/l, p<0.03), whereas weight loss (−4.7 ± 2.8 kg) led to a reduction in FIS and fasting glucose (+0.06 ± 0.55 mmol/l, p<0.006). ISR@5 declined in both weight losers and those with stable weight (−0.17 ± 1.9 and −0.16 ± 1.0 U/h, respectively; p<0.002 for both) but not in weight gainers (−0.06 ± 1.1 U/h). Peripheral insulin resistance, plasma NEFA and leptin accounted for only part of obesity’s effect on insulin secretion. Subset analysis of fasting and clamp EGP data suggested a rightwards shift in the dose–response curve across fat mass quintiles, indicating progressive hepatic glucose overproduction despite a preserved hepatic insulin response. Conclusions/interpretation The effect of body mass on insulin secretion is continuous, more pronounced in men, driven by fat mass and waist, sustained by hyperglycaemia and by an upregulation of beta cell insulin secretion and is only partially explained by typical hormonal and metabolic consequences of obesity. We suggest that hepatic glucose overproduction contributes to the fasting hyperinsulinaemia observed in individuals with obesity. Graphical Abstract

Background: Cardiovascular risk estimation in people over 70 years is problematic. Most scores have been derived from cohorts of middle-aged people, with older persons under-represented. The predictive power of classical cardiovascular risk factors reduce with age. The aim is to develop a specific score for the elderly populationMethods: Population-based cohort established in 1995. Setting: Three geographical areas of Spain (Madrid, Ávila and Lugo). Participants: 3,729 people older than 64 years, free of any cardiovascular diseases (CVD), at baseline. Measurements: Suspected fatal and nonfatal CVD (both coronary heart disease and stroke) were yearly investigated and confirmed using the WHO-MONICA criteria. All participants were followed until the occurrence of the first CVD event, until death or until December 31th 2015 if alive.Results: Age was the strongest predictor of 10-year CVD both in men and women. In men, variables associated to CVD were high blood pressure treatment (HR: 1,35; 95% CI: 1,067 , 1,710), diabetes (HR: 1,359; 95% CI: 0,997 , 1,852) and smoking (HR:1,207; 95%CI: 0,945 , 1,541), and in women smoking (HR: 1,881 95%CI: 1,356 , 2,609) and diabetes (HR:1,285; 95%CI:0,967 , 1,707). Total-cholesterol did not increased the risk of CVD either in males or females. However, total-cholesterol level (>200mg/dl) were negatively associated both in men and women.Conclusions: In old Spanish men, 10-year total CVD is significantly increased by age, diabetes and antihypertensive treatment, and in old women by diabetes and smoking. Total-cholesterol levels did not increased the risk of CVD either in males or females.