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Abstract Background To evaluate the association between diabetic foot disease (DFD) and the incidence of fatal and non-fatal events in individuals with type 2 diabetes (T2DM) from primary-care settings. Methods We built a cohort of people with a first DFD episode during 2010–2015, followed up until 2018. These subjects were 1 to 1 propensity score matched to subjects with T2DM without DFD. The incidence of all-cause mortality, the occurrence of new DFD, amputations, cardiovascular diseases, or composite outcome, including all-cause mortality and/or cardiovascular events during the follow-up period, were calculated. A Cox proportional hazard analysis was conducted to evaluate the hazard ratios (HR) for different events. Results Overall, 11,117 subjects with T2DM with a first episode of DFD were compared with subjects without DFD. We observed higher incidence rates (IRs) for composite outcome (33.9 vs. 14.5 IR per 100 person-years) and a new DFD episode event (22.2 vs. 1.1 IR per 100 person-years) in the DFD group. Compared to those without DFD, those with a first episode of DFD had a higher HR for all events, with excess rates particularly for amputation and new DFD occurrence (HR: 19.4, 95% CI: 16.7–22.6, HR: 15.1, 95% CI: 13.8–16.5, respectively) was found. Conclusions Although DFD often coexists with other risk factors, it carries an intrinsic high risk of morbidity and mortality in individuals with T2DM. DFD should be regarded as a severe complication already at its onset, as it carries a poor clinical prognosis. Graphical Abstract

AimsWe aimed to describe and compare the incidence of the first cardiovascular event and its major subtypes, coronary heart disease (CHD), cerebrovascular disease, heart failure (HF), or peripheral artery disease (PAD), according to age and sex in a population-based cohort of individuals with type 2 diabetes (T2D) from a Mediterranean region.Material and methodsWe used linked primary care electronic medical reports, pharmacy-invoicing data, and hospital admission disease registry records from the SIDIAP database, which contains linked data for 74% of the Catalonian population. We selected individuals with T2D aged 30 to 89 years free of cardiovascular disease (CVD). The primary outcome was the first presentation of CVD.ResultsThe study cohort included 247,751 individuals (48.6% women, 66.8 ± 11.9 years). During a 6.99-year follow-up, the cumulative incidence of the first cardiovascular event was 23.4%. Men were at higher risk for CVD (hazard ratio [HR]: 1.47 95%CI: 1.45-1.50), CHD (HR: 1.52 95%CI: 1.47-1.57), cerebrovascular disease (HR:1.07 95%CI: 1.03-1.10) and PAD (HR: 2.30 95%CI: 2.21-2.39) than women but at a lower risk for HF (HR:0.70 95%CI: 0.68-0.73). CHD and PAD were the most frequent CVD presentations among men (28.1% and 27.5%) and HF (40.1%) in women. CHD predominated among young participants of both sexes, while HF predominated among women older than 65 and men older than 75.ConclusionsIn individuals with T2D, the overall risk and the type of first CVD manifestation largely varied by sex and age. This epidemiological evidence should be considered in clinical practice.

Abstract Diabetes microangiopathy, a hallmark complication of diabetes, is characterised by structural and functional abnormalities within the intricate network of microvessels beyond well-known and documented target organs, i.e., the retina, kidney, and peripheral nerves. Indeed, an intact microvascular bed is crucial for preserving each organ’s specific functions and achieving physiological balance to meet their respective metabolic demands. Therefore, diabetes-related microvascular dysfunction leads to widespread multiorgan consequences in still-overlooked non-traditional target organs such as the brain, the lung, the bone tissue, the skin, the arterial wall, the heart, or the musculoskeletal system. All these organs are vulnerable to the physiopathological mechanisms that cause microvascular damage in diabetes (i.e., hyperglycaemia-induced oxidative stress, inflammation, and endothelial dysfunction) and collectively contribute to abnormalities in the microvessels’ structure and function, compromising blood flow and tissue perfusion. However, the microcirculatory networks differ between organs due to variations in haemodynamic, vascular architecture, and affected cells, resulting in a spectrum of clinical presentations. The aim of this review is to focus on the multifaceted nature of microvascular impairment in diabetes through available evidence of specific consequences in often overlooked organs. A better understanding of diabetes microangiopathy in non-target organs provides a broader perspective on the systemic nature of the disease, underscoring the importance of recognising the comprehensive range of complications beyond the classic target sites.

Lipid functions can be influenced by genetics, age, disease states, and lifestyle factors, particularly dietary patterns, which are crucial in diabetes management. Lipidomics is an expanding field involving the comprehensive exploration of lipids from biological samples. In this cross-sectional study, 396 participants from a Mediterranean region, including individuals with type 1 diabetes (T1D), type 2 diabetes (T2D), and non-diabetic individuals, underwent lipidomic profiling and dietary assessment. Participants completed validated food frequency questionnaires, and lipid analysis was conducted using ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC/MS). Multiple linear regression models were used to determine the association between lipid features and dietary patterns. Across all subjects, acylcarnitines (AcCa) and triglycerides (TG) displayed negative associations with the alternate Healthy Eating Index (aHEI), indicating a link between lipidomic profiles and dietary habits. Various lipid species (LS) showed positive and negative associations with dietary carbohydrates, fats, and proteins. Notably, in the interaction analysis between diabetes and the aHEI, we found some lysophosphatidylcholines (LPC) that showed a similar direction with respect to aHEI in non-diabetic individuals and T2D subjects, while an opposite direction was observed in T1D subjects. The study highlights the significant association between lipidomic profiles and dietary habits in people with and without diabetes, particularly emphasizing the role of healthy dietary choices, as reflected by the aHEI, in modulating lipid concentrations. These findings underscore the importance of dietary interventions to improve metabolic health outcomes, especially in the context of diabetes management.

Abstract Background Knowledge of the characteristics of first-ever cardiovascular events in type 1 diabetes may impact primary prevention strategies. This study describes the first-ever manifestation of cardiovascular disease (CVD) in patients with type 1 diabetes (T1D) in Catalonia (Spain) and evaluates differences according to age and sex. Methods Retrospective cohort study of patients with T1D > 30 years without CVD before 2010 registered in the SIDIAP database. The occurrence of a first cardiovascular event up to the end of 2016, the type of CV event and associations with baseline characteristics were analysed. Results Of 8412 patients, 884 suffered a first CV event (incidence rate 1.62 per 100 persons-years). Overall, peripheral vascular disease (39.5%) was the most frequent event. We observed a higher proportion of heart failure in women (21.7%) than in men (10.1%). In women, heart failure was the most frequent event in those > 65 years (40.5%). Decreased glomerular filtration rate (hazard ratio [HR] 5.42 [95% CI 4.32;6.80]), elevated albumin/creatinine ratio (HR 3.39 [95% CI [2.47;4.66], microvascular complications (HR 3.27 [95% CI 2.85;3.75]), and hypertension (HR 3.21 [95% CI [2.80;3.67]) were most strongly associated with a first CV event. HbA1c > 7.0% was associated with incident CVD only in patients aged

Abstract Background Subjects with Type 1 diabetes mellitus (T1DM) have an increased incidence of heart failure (HF). Several pathophysiological mechanisms have been involved in its development. The aim of this study was to analyze the potential contribution of the advanced lipoprotein profile and plasma glycosylation (GlycA) to the presence of subclinical myocardial dysfunction in subjects with T1DM. Methods We included subjects from a Danish cohort of T1DM subjects (Thousand & 1 study) with either diastolic and/or systolic subclinical myocardial dysfunction, and a control group without myocardial dysfunction, matched by age, sex and HbA1c. All underwent a transthoracic echocardiogram and an advanced lipoprotein profile obtained by using the NMR-based Liposcale® test. GlycA NMR signal was also analyzed. Systolic dysfunction was defined as left ventricular ejection fraction ≤ 45% and diastolic dysfunction was considered as E/e′≥12 or E/e′ 8–12 + volume of the left atrium > 34 ml/m2. To identify a metabolic profile associated with the presence of subclinical myocardial dysfunction, a multivariate supervised model of classification based on least squares regression (PLS-DA regression) was performed. Results One-hundred forty-six subjects had diastolic dysfunction and 18 systolic dysfunction. Compared to the control group, patients with myocardial dysfunction had longer duration of diabetes (p = 0.005), and higher BMI (p = 0.013), serum NTproBNP concentration (p = 0.001), systolic blood pressure (p

Abstract Background It is not clear whether pre-existing macrovascular complications (ischemic heart disease, stroke or peripheral artery disease) are associated with health outcomes in people with diabetes mellitus hospitalized for COVID-19. Methods We conducted cohort studies of adults with pre-existing diabetes hospitalized for COVID-19 infection in the UK, France, and Spain during the early phase of the pandemic (between March 2020—October 2020). Logistic regression models adjusted for demographic factors and other comorbidities were used to determine associations between previous macrovascular disease and relevant clinical outcomes: mortality, intensive care unit (ICU) admission and use of invasive mechanical ventilation (IMV) during the hospitalization. Output from individual logistic regression models for each cohort was combined in a meta-analysis. Results Complete data were available for 4,106 (60.4%) individuals. Of these, 1,652 (40.2%) had any prior macrovascular disease of whom 28.5% of patients died. Mortality was higher for people with compared to those without previous macrovascular disease (37.7% vs 22.4%). The combined crude odds ratio (OR) for previous macrovascular disease and mortality for all four cohorts was 2.12 (95% CI 1.83–2.45 with an I2 of 60%, reduced after adjustments for age, sex, type of diabetes, hypertension, microvascular disease, ethnicity, and BMI to adjusted OR 1.53 [95% CI 1.29–1.81]) for the three cohorts. Further analysis revealed that ischemic heart disease and cerebrovascular disease were the main contributors of adverse outcomes. However, proportions of people admitted to ICU (adjOR 0.48 [95% CI 0.31–0.75], I2 60%) and the use of IMV during hospitalization (adjOR 0.52 [95% CI 0.40–0.68], I2 37%) were significantly lower for people with previous macrovascular disease. Conclusions This large multinational study of people with diabetes mellitus hospitalized for COVID-19 demonstrates that previous macrovascular disease is associated with higher mortality and lower proportions admitted to ICU and treated with IMV during hospitalization suggesting selective admission criteria. Our findings highlight the importance correctly assess the prognosis and intensive monitoring in this high-risk group of patients and emphasize the need to design specific public health programs aimed to prevent SARS-CoV-2 infection in this subgroup.

Abstract Cardiovascular diseases (CVDs) are the main cause of death among patients with type 2 diabetes mellitus (T2DM), particularly in low- and middle-income countries. To effectively prevent the development of CVDs in T2DM, considerable effort has been made to explore novel preventive approaches, individualized glycemic control and cardiovascular risk management (strict blood pressure and lipid control), together with recently developed glucose-lowering agents and lipid-lowering drugs. This review mainly addresses the important issues affecting the choice of antidiabetic agents and lipid, blood pressure and antiplatelet treatments considering the cardiovascular status of the patient. Finally, we also discuss the changes in therapy principles underlying CVDs in T2DM.

Abstract Background Diabetic foot and lower limb complications are an important cause of morbidity and mortality among persons with diabetes mellitus. Very few studies have been carried out in the primary care settings. The main objective was to assess the prognosis of diabetic foot ulcer (DFU) in patients from primary care centers in Catalonia, Spain, during a 12‐month follow‐up period. Methods We included participants with type 2 diabetes and a new DFU between February 2018 and July 2019. We estimated the incidence of mortality, amputations, recurrence and healing of DFU during the follow‐up period. A multivariable analysis was performed to assess the association of these outcomes and risk factors. Results During the follow‐up period, 9.7% of participants died, 12.1% required amputation, 29.2% had a DFU recurrence, and 73.8% healed. Having a caregiver, ischemia or infection were associated with higher mortality risk (hazard ratio [HR]:3.63, 95% confidence interval [CI]:1.05; 12.61, HR: 6.41, 95%CI: 2.25; 18.30, HR: 3.06, 95%CI: 1.05; 8.94, respectively). Diabetic retinopathy was an independent risk factor for amputation events (HR: 3.39, 95%CI: 1.37; 8.39). Increasing age decreased the risk for a DFU recurrence, while having a caregiver increased the risk for this event (HR: 0.97, 95%CI: 0.94; 0.99). The need for a caregiver and infection decreased the probability of DFU healing (HR: 0.57, 95%CI: 0.39; 0.83, HR: 0.64, 95%CI: 0.42; 0.98, respectively). High scores for PEDIS (≥7) or SINBAD (≥3) were associated with an increased risk for DFU recurrence and a lower probability of DFU healing, respectively. Conclusions We observed high morbidity among subjects with a new DFU in our primary healthcare facilities. Peripheral arterial disease, infection, and microvascular complications increased the risk of poor clinical outcomes among subjects with DFU.

ObjectiveTo investigate longitudinal changes in the liver stiffness measurement (LSM) in the general adult population without known liver disease and to describe its association with metabolic risk factors, with a special focus on subjects with non-alcoholic fatty liver disease (NAFLD) and dysglycemia.Material and MethodsA longitudinal adult population-based cohort study was conducted in Catalonia. LSM was measured by transient elastography (TE) at baseline and follow-up (median: 4.2 years). Subgroup with NAFLD and dysglycemia were analyzed. Moderate-to-advanced liver fibrosis was defined as LSM ≥8.0 kPa and LSM ≥9.2 kPa respectively.ResultsAmong 1.478 subjects evaluated, the cumulative incidence of LSM ≥8.0 kPa and ≥9.2 kPa at follow-up was 2.8% and 1.9%, respectively. This incidence was higher in NAFLD (7.1% for LSM ≥8.0 kPa and 5% for LSM ≥9.2 kPa) and dysglycemia (6.2% for LSM ≥8.0 kPa and 4.7% for LSM ≥9.2 kPa) subgroups. In the global cohort, the multivariate analyses showed that dysglycemia, abdominal obesity and atherogenic dyslipidemia were significantly associated with progression to moderate-to-advanced liver fibrosis. Female sex was negatively associated. In subjects with NAFLD, abdominal obesity and dysglycemia were associated with changes in LSM to ≥8.0 kPa and ≥9.2 kPa at follow-up. A decline in LSM value to

BackgroundOur study aimed to assess the prevalence of diabetic foot disease (DFD) and its associated risk factors among subjects attending primary care centers in Catalonia (Spain).MethodsWe undertook a cross-sectional analysis of data from the primary health care (SIDIAP) database. The presence of comorbidities and concomitant medication were analyzed for subjects with or without DFD. DFD prevalence was estimated from 1st January 2018 to 31st December 2018.ResultsDuring the 12-month observational period, out of 394,266 people with type 2 diabetes, we identified 3,277 (0.83%) active episodes of DFD in the database. The majority of these episodes were foot ulcers (82%). The mean age of patients with DFD was 70.3 (± 12.5) years and 55% were male. In the multivariable descriptive models, male gender, diabetes duration, hypertension, macrovascular, microvascular complications, and insulin and antiplatelet agents were strongly associated with DFD. A previous history of DFD was the stronger risk factor for DFD occurrence in subjects with T2DM (OR: 13.19, 95%CI: 11.81; 14.72).ConclusionsIn this real-world primary care practice database, we found a lower prevalence of DFD compared to similar previous studies. Risk factors such as male sex, duration of diabetes, diabetes complications and previous history of DFD were associated with the presence of DFD.

Abstract Background Evidence from prospective cardiovascular (CV) outcome trials in type 2 diabetes (T2DM) patients supports the use of sodium–glucose co-transporter-2 inhibitors (SGLT2i) to reduce the risk of CV events. In this study, we compared the risk of several CV outcomes between new users of SGLT2i and other glucose-lowering drugs (oGLDs) in Catalonia, Spain. Methods CVD-REAL Catalonia was a retrospective cohort study using real-world data routinely collected between 2013 and 2016. The cohorts of new users of SGLT2i and oGLDs were matched by propensity score on a 1:1 ratio. We compared the incidence rates and hazard ratio (HR) for all-cause death, hospitalization for heart failure, chronic kidney disease, and modified major adverse CV event (MACE; all-cause mortality, myocardial infarction, or stroke). Results After propensity score matching, 12,917 new users were included in each group. About 27% of users had a previous history of CV disease. In the SGLT2i group, the exposure time was 60% for dapagliflozin, 26% for empagliflozin and 14% for canagliflozin. The use of SGLT2i was associated with a lower risk of heart failure (HR: 0.59; 95% confidence interval [CI] 0.47–0.74; p

BackgroundAlthough European guidelines recommend vascular ultrasound for the assessment of cardiovascular risk in low-to-moderate risk individuals, no algorithm properly identifies patients who could benefit from it. The aim of this study is to develop a sex-specific algorithm to identify those patients, especially women who are usually underdiagnosed.MethodsClinical, anthropometrical, and biochemical data were combined with a 12-territory vascular ultrasound to predict severe atheromatosis (SA: ≥ 3 territories with plaque). A Personalized Algorithm for Severe Atheromatosis Prediction (PASAP-ILERVAS) was obtained by machine learning. Models were trained in the ILERVAS cohort (n = 8,330; 51% women) and validated in the control subpopulation of the NEFRONA cohort (n = 559; 47% women). Performance was compared to the Systematic COronary Risk Evaluation (SCORE) model.ResultsThe PASAP-ILERVAS is a sex-specific, easy-to-interpret predictive model that stratifies individuals according to their risk of SA in low, intermediate, or high risk. New clinical predictors beyond traditional factors were uncovered. In low- and high-risk (L&H-risk) men, the net reclassification index (NRI) was 0.044 (95% CI: 0.020–0.068), and the integrated discrimination index (IDI) was 0.038 (95% CI: 0.029–0.048) compared to the SCORE. In L&H-risk women, PASAP-ILERVAS showed a significant increase in the area under the curve (AUC, 0.074 (95% CI: 0.062–0.087), p-value: < 0.001), an NRI of 0.193 (95% CI: 0.162–0.224), and an IDI of 0.119 (95% CI: 0.109–0.129).ConclusionThe PASAP-ILERVAS improves SA prediction, especially in women. Thus, it could reduce the number of unnecessary complementary explorations selecting patients for a further imaging study within the intermediate risk group, increasing cost-effectiveness and optimizing health resources.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT03228459].

Atherosclerosis, a process in which macrophages play a key role, is accelerated in diabetes. Elevated concentrations of serum-oxidized low-density lipoproteins (oxLDL) represent a common feature of both conditions. The main goal of this study was to determine the contribution of oxLDL to the inflammatory response of macrophages exposed to diabetic-mimicking conditions. THP1 cells and peripheral blood monocytes purified from non-diabetic healthy donors were cultured under normal (5 mM) or high glucose (HG) (15 mM) with oxLDL. Then, foam cell formation, expression of CD80, HLADR, CD23, CD206, and CD163, as well as toll-like receptor 4 (TLR4) and co-receptors CD36 and CD14 (both at the cell surface and soluble (sCD14)), and inflammatory mediators’ production were measured by flow cytometry, RT-qPCR, or ELISA. Additionally, serum sCD14 was determined in subjects with subclinical atherosclerosis with and without diabetes by ELISA. Our results showed that oxLDL-mediated intracellular lipid accumulation via CD36 increased under HG and that HG + oxLDL enhanced TNF, IL1B, and IL8, and decreased IL10. Moreover, TLR4 was upregulated in macrophages under HG and monocytes of subjects with diabetes and atherosclerosis. Interestingly, HG-oxLDL upregulated CD14 gene expression, although its total cellular protein abundance remained unaltered. sCD14 shedding via PRAS40/Akt-dependent mechanisms, with pro-inflammatory activity, was significantly increased in cultured macrophages and plasma from subjects with diabetes and subclinical atherosclerosis or hypercholesterolemia. Our data support an enhanced synergistic pro-inflammatory effect induced by HG and oxLDL in cultured human macrophages, possibly explained by increased sCD14 shedding.

Background: Little is known about the prevalence of cerebral microangiopathy (CM), which is related to cognitive impairment, in an asymptomatic population. Pulsatility index (PI) is an easily measurable parameter of cerebral vascular resistance in transcranial duplex of the middle cerebral artery (MCA) study. We aimed to determine the prevalence of CM measured by PI of MCA in low to moderate vascular risk subjects.Methods: We included 3,721 subjects between 45 and 70 years without previous history of vascular disease or diabetes mellitus and with at least one other vascular risk factor from the cross-sectional study ILERVAS (Lleida, Spain). Patients underwent transcranial duplex to determine MCA-PI. Possible CM was defined by MCA-PI >1.1. Carotid and femoral arteries ultrasound registration was done to determine the presence, the number, and the area of atheromatous plaques. Body mass index (BMI), pulse pressure (PP) and laboratory data were also recorded.Results: 439 (11.8%) subjects were excluded due to the low quality of transcranial duplex images. Median age was 57 [IQR 52, 62] years. Possible CM was found in 424 (12.9%) subjects. CM patients had higher prevalence of plaques than non-CM (77.4 vs. 66.4%, p < 0.001). PI showed a positive linear correlation with the number of territories with plaques (r = 0.130, p < 0.001), and the total plaque area (r = 0.082, p < 0.001). The predictors of possible CM were the age, male gender, and PP.Conclusions: In low-to-moderate vascular risk asymptomatic population, the proportion of abnormal brain microvascular bed determined by MCA-PI is not negligible. The planned 10-year follow-up will describe the clinical relevance of these findings.

There is controversial information about the accumulation of advanced glycation end-products (AGEs) in obesity. We assessed the impact of total and abdominal adiposity on AGE levels via a cross-sectional investigation with 4254 middle-aged subjects from the ILERVAS project. Skin autofluorescence (SAF), a non-invasive assessment of subcutaneous AGEs, was measured. Total adiposity indices (BMI and Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE)) and abdominal adiposity (waist circumference and body roundness index (BRI)) were assessed. Lean mass was estimated using the Hume index. The area under the receiver operating characteristic (ROC) curve was evaluated for each index. Different cardiovascular risk factors (smoking, prediabetes, hypertension and dyslipidemia) were evaluated. In the study population, 26.2% showed elevated SAF values. No differences in total body fat, visceral adiposity and lean body mass were detected between patients with normal and high SAF values. SAF levels showed a very slight but positive correlation with total body fat percentage (estimated by the CUN-BAE formula) and abdominal adiposity (estimated by the BRI). However, none of them had sufficient power to identify patients with high SAF levels (area under the ROC curve

The aims of our study was compare adherence measured by the medical possession ratio (MPR), time until discontinuation and describe adverse events after adding a DPP-4i, SGLT-2i, or sulfonylureas (SU) to metformin in a primary care population with insufficient glycemic control. We used routinely-collected health data from the SIDIAP database. The included subjects were matched by propensity score. The follow-up period was up to 24 months or premature discontinuation. The primary outcomes were the percentage of subjects with good adherence, treatment discontinuation and adverse events among treatment groups. The proportion of patients with good adherence (MPR> 0.8) after the addition of DPP-4i, SGLT-2i or SU was 53.6%, 68.7%, and 43.0%, respectively. SGLT-2i users were 1.7 times more likely to achieve good adherence compared with DPP-4i users (odds ratio [OR]:1.72, 98% confidence interval [CI]:1.51, 1.96), and 2.8 times more likely compared with SU users (OR: 0.35, 98% CI: 0.07, 0.29). The discontinuation hazard ratios were 1.43 (98%CI: 1.26; 1.62) and 1.60 (98%CI: 1.42; 1.81) times higher among SGLT-2i and SU users than DPP-4i users during the follow-up period. No differences were observed for adverse events among the treatment groups. In conclusion, in our real-world setting, the combination of SGLT-2i with metformin was associated with better adherence. The mean time until discontinuation was longer in the SGLT-2i group in comparison with the DPP-4i or SU groups.

Abstract Background The management of hyperglycaemia and associated cardiovascular risk factors in patients with type 2 diabetes mellitus (T2DM) may reduce diabetes-related complications. The strategy to broaden the knowledge base of primary care professionals to improve health care has mainly been prompted by the current reality of limited resources and access to specialized care. The main objective of this study is to assess the effectiveness of comprehensive interventions focused on treatment intensification, decrease clinical inertia and reduce possible barriers to treatment adherence in patients with poorly controlled diabetes in a primary care setting. Methods This is a two-phase mixed method study, whose aims are the development of complex interventions and the assessment of their effectiveness. The main study outcome is a change in glycated haemoglobin (HbA1c) levels. The INTEGRA study is divided into two phases. Phase 1: A qualitative study with a phenomenological approach using semi-structured interviews with the objective of determining the factors related to the participants and health care professionals that influence the development and implementation of a specific intervention strategy aimed at patients with poor glycaemic control of T2DM in primary care. Phase 2: Exploratory intervention study to be conducted in Primary Health Care Centres in Catalonia (Spain), including 3 specific health care areas. The intervention study has two arms: Intervention Group 1 and 2. Each intervention group will recruit 216 participants (the same as in the control group) between the ages of 30 and 80 years with deficient glycaemic control (HbA1c > 9%). The control group will be established based on a randomized selection from the large SIDIAP (Sistema d’Informació per al desenvolupament de la Investigació en Atenció Primària) database of patients with comparable socio-demographic and clinical characteristics from the three provinces. Discussion This study is a comprehensive, pragmatic intervention based on glycaemic treatment intensification and the control of other cardiovascular risk factors. It is also aimed at improving treatment adherence and reducing clinical inertia, which could lead to improved glycaemic control and could likewise be feasible for implementation in the actual clinical practice of primary care. Trial registration Clinicaltrials.gov. registration number. NCT02663245; January 25, 2016.

Introducción: El presente estudio evaluó la frecuencia de onicocriptosis recurrente en pacientes con diabetes mellitus (DM). Pacientes y métodos: Estudio transversal observacional de prevalencia. 146 individuos, diagnosticados de cualquier tipo de DM, excepto DM gestacional, del área básica de salud de los centros de atención primaria de Bufalà y Dr. Robert de Badalona, atendidos en un centro de podología a través del programa de pie diabético del sistema público de salud en Cataluña. Dos individuos se descartaron por presentar criterios de exclusión. Se valoró la incidencia de onicocriptosis y el tipo de curas de los pies realizadas habitualmente, a través de un cuestionario respondido por el paciente. Presencia de signos de neuropatía y o isquemia en extremidades inferiores a través de exploración clínica. Resultados: Se encontró una frecuencia de onicocriptosis del 33 %. No se encontró relación entre presencia de onicocriptosis con la edad, años evolución de la DM, presencia de signos de polineuropatía o de isquemia, o el tipo de curas. De los pacientes con onicocriptosis, un 29 % y un 33 % presentaban signos de isquemia y polineuropatía, respectivamente. Conclusiones: Un tercio de los pacientes con DM remitidos presentaba o ha presentado onicocriptosis. Cerca de un tercio de estos pacientes presentan además factores de riesgo de pie diabético: polineuropatía e isquemia. Dos tercios de los pacientes con onicocriptosis se realizan medidas de autocuidado en los pies sin control profesional sanitario.

A large body of evidence demonstrates a relationship between hyperglycemia and increased concentrations of advanced glycation end-products (AGEs). However, there is little information about subcutaneous AGE accumulation in subjects with prediabetes, and whether or not this measurement could assist in the diagnosis of prediabetes is unclear. A cross-sectional study was conducted in 4181 middle-aged subjects without diabetes. Prediabetes (n = 1444) was defined as a glycosylated hemoglobin (HbA1c) level between 39 and 47 mmol/mol (5.7 to 6.4%), and skin autofluorescence (SAF) measurement was performed to assess AGEs. A multivariable logistic regression model and receiver operating characteristic curve were used. The cohort consisted of 50.1% women with an age of 57 [52;62] years, a BMI of 28.3 [25.4;31.6] kg/m2, and a prevalence of prediabetes of 34.5%. Participants with prediabetes showed higher SAF than control participants (2.0 [1.7;2.2] vs. 1.9 [1.7;2.2], p < 0.001). However, HbA1c was not significantly correlated with SAF levels (r = 0.026, p = 0.090). In addition, the SAF level was not independently associated with prediabetes (OR = 1.12 (0.96 to 1.30)). Finally, there was no good cutoff point for SAF to identify patients with prediabetes (AUC = 0.52 (0.50 to 0.54), sensitivity = 0.61, and 1-specificity = 0.56). Given all of this evidence, we can conclude that although there is an increase in SAF levels in participants with prediabetes, the applicability and clinical relevance of the results is low in this population.

Abstract Background Cardiovascular (CV) disease due to atherosclerosis is a major cause of morbidity and mortality in adult patients with diabetes, either type 1 or type 2 diabetes. The aim of the study was to assess the association of the frequency and the burden of subclinical carotid atherosclerotic disease in patients with type 1 diabetes according to the presence and severity of diabetic retinopathy (DR). Methods A cross-sectional study was conducted in 340 patients with type 1 diabetes (41.5% with DR), and in 304 non-diabetic individuals. All participants were free from previous CV disease and chronic kidney disease (CKD). B-mode carotid ultrasound imaging was performed in all the study subjects. Patients with type 1 diabetes underwent a full eye examination, and DR patients were divided into two groups: mild disease and advanced disease. Results In the group of patients with type 1 diabetes, the percentage of patients with carotid plaques was higher in those with DR compared with those without DR (44.7% vs. 24.1%, p

We aimed to assess the potential relationship between dietary patterns (i.e., Mediterranean diet and healthy eating) and the advanced lipoprotein profile (ALP) in a representative cohort of the Mediterranean population. Thus, ALP data from 1142 participants, including 222 with type 1 (19.4%) and 252 type 2 diabetes (22.1%), and 668 subjects without diabetes were used to study cross-sectional associations between quantitative characteristics of lipoproteins and adherence to the Mediterranean diet. The alternate Mediterranean diet score (aMED) and the alternate healthy eating index (aHEI) were calculated. The ALP was determined by nuclear magnetic resonance (NMR) spectrometry. Bivariable and multivariable analyses were performed. Participants in the third tertile of the aMED showed higher levels of low-density lipoprotein triglycerides (LDL-TG) (mean (SD) 17.5 (5.0); p = 0.037), large high-density lipoprotein particles (HDL-P) (0.3 (0.1); p = 0.037), and medium low-density lipoprotein particles (LDL-P) (434.0 (143.0); p = 0.037). In comparison with participants in the second and first tertiles of the aHEI, participants in the third tertile had higher levels of LDL-TG (17.7 (5.0); p = 0.010), and large HDL-P (0.3 (0.1); p = 0.002), IDL-C (11.8 (5.0); p = 0.001), intermediate-density lipoprotein triglycerides (IDL-TG) (13.2 (4.2); p < 0.001), LDL-TG (17.7(5.0); p = 0.010), high-density lipoprotein triglycerides (HDL-TG) (14.5 (4.4); p = 0.029,) large HDL-P (0.3 (0.1); p = 0.002) and very–low-density lipoprotein particles (VLDL-P) size (42.1 (0.2); p = 0.011). The adjusted-multivariable analysis for potential confounding variables did not show any association between the lipoproteins and dietary patterns (i.e., aMED and aHEI). In conclusion, none of the quantitative characteristics of lipoproteins were concomitantly associated with the extent of adherence to the Mediterranean diet measured using the aMED or aHEI scores in the studied population. Our findings also revealed that people with the highest adherence were older, had a higher body mass index (BMI) and more frequently had dyslipidemia, hypertension, or diabetes than those with the lowest adherence to the Mediterranean diet (MDiet). Thus, further research may be needed to assess the potential role of the dietary pattern on the ALP.

Abstract Background LADA is probably the most prevalent form of autoimmune diabetes. Nevertheless, there are few data about cardiovascular disease in this group of patients. The aim of this study was to investigate the frequency of carotid atherosclerotic plaques in patients with LADA as compared with patients with classic type 1 diabetes and type 2 diabetes. Methods Patients with LADA were matched for age and gender in different proportions to patients with type 2 diabetes, and classic type 1 diabetes. None of the patients had clinical cardiovascular disease. All subjects underwent B-mode carotid ultrasound to detect atheroma plaques. Demographics were obtained from all subjects. Results We included 71 patients with LADA, 191 patients with type 2 diabetes and 116 patients with type 1 diabetes. Carotid atherosclerosis was more frequent in patients with LADA compared with type 2 diabetes (73.2% vs. 56.9%, P = 0.0018) and classic type 1 diabetes (57.1%, P = 0.026); these changes occurred despite healthier macrovascular risk profiles in the former. Age (P

Abstract Despite normal to high bone mineral density, patients with type 2 diabetes (T2DM) have an increased fracture risk. T2DM medications could partially account for this excess risk. The aim of this study was to assess the association between insulin use and bone fracture risk in T2DM patients. A population-based matched cohort study based on a primary care records database validated for research use (Catalonia, Spain) was performed. Propensity score (PS) for insulin use was calculated using logistic regression including predefined predictors of fractures. A total of 2,979 insulin users and 14,895 non-users were observed for a median of 1.42 and 4.58 years respectively. Major fracture rates were 11.2/1,000 person-years for insulin users, compared with 8.3/1,000 among non-users. Matched models confirmed a significant association, with an adjusted subhazard ratio (adj SHR) of 1.38 [95% CI 1.06 to 1.80] for major fractures. No differences between types of insulin or different regimens were found. Estimated number needed to harm (fracture) was 82 (95% CI 32 to 416). Insulin use appears to be associated with a 38% excess fracture risk among T2DM patients in the early stages of the disease. Fracture risk should be included among the considerations to initiate insulin treatment.

Objective. Regulatory agencies require the assessment of cardiovascular (CV) safety for new type 2 diabetes (T2D) therapies through CV outcome trials (CVOTs). However, patients included in CVOTs assessing sodium-glucose cotransporter-2 inhibitors (SGLT2i) might not be representative of those seen in clinical practice. This study examined the proportion of patients that would have been enrolled into three main SGLT2i CVOTs to determine whether these trials’ eligibility criteria can be applied to a real-world Mediterranean T2D population. Methods. Cross-sectional, retrospective, cohort study of T2D patients registered in primary care centres of the Catalan Institute of Health using medical records from a population database (SIDIAP) that includes approximately 74% of the population in Catalonia (Spain). Eligibility criteria were according to those of three SGLT2i CVOTs: EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), and DECLARE-TIMI 58 (dapagliflozin). Results. By the end of 2016, the database included 373,185 patients with T2D with a mean age of 70±12 years, 54.9% male, with a mean duration of T2D of 9±6 years, and a mean glycated haemoglobin (HbA1c) of 7.12%±1.32 (59% with HbA1c

Prediabetes is closely related to excess body weight and adipose distribution. For this reason, we aimed to assess and compare the diagnostic usefulness of ten anthropometric adiposity indices to predict prediabetes. Cross-sectional study with 8188 overweight subjects free of type 2 diabetes from the ILERVAS project (NCT03228459). Prediabetes was diagnosed by levels of glycated hemoglobin (HbA1c). Total body adiposity indices [BMI, Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) and Deurenberg’s formula] and abdominal adiposity (waist and neck circumferences, conicity index, waist to height ratio, Bonora’s equation, A body shape index, and body roundness index) were calculated. The area under the receiver-operating characteristic (ROC) curve, the best cutoff and the prevalence of prediabetes around this value were calculated for every anthropometric index. All anthropometric indices other than the A body adiposity were higher in men and women with prediabetes compared with controls (p < 0.001 for all). In addition, a slightly positive correlation was found between indices and HbA1c in both sexes (r ≤ 0.182 and p ≤ 0.026 for all). None of the measures achieved acceptable levels of discrimination in ROC analysis (area under the ROC ≤ 0.63 for all). Assessing BMI, the prevalence of prediabetes among men increased from 20.4% to 36.2% around the cutoff of 28.2 kg/m2, with similar data among women (from 29.3 to 44.8% with a cutoff of 28.6 kg/m2). No lonely obesity index appears to be the perfect biomarker to use in clinical practice to detect individuals with prediabetes.

Diabetes mellitus entails increased atherosclerotic burden and medial arterial calcification, but the precise mechanisms are not fully elucidated. We aimed to investigate the implication of CD36 in inflammation and calcification processes orchestrated by vascular smooth muscle cells (VSMCs) under hyperglycemic and atherogenic conditions. We examined the expression of CD36, pro-inflammatory cytokines, endoplasmic reticulum (ER) stress markers, and mineralization-regulating enzymes by RT-PCR in human VSMCs, cultured in a medium containing normal (5 mM) or high glucose (22 mM) for 72 h with or without oxidized low-density lipoprotein (oxLDL) (24 h). The uptake of 1,1′-dioctadecyl-3,3,3′,3-tetramethylindocarbocyanine perchlorate-fluorescently (DiI) labeled oxLDL was quantified by flow cytometry and fluorimetry and calcification assays were performed in VSMC cultured in osteogenic medium and stained by alizarin red. We observed induction in the expression of CD36, cytokines, calcification markers, and ER stress markers under high glucose that was exacerbated by oxLDL. These results were confirmed in carotid plaques from subjects with diabetes versus non-diabetic subjects. Accordingly, the uptake of DiI-labeled oxLDL was increased after exposure to high glucose. The silencing of CD36 reduced the induction of CD36 and the expression of calcification enzymes and mineralization of VSMC. Our results indicate that CD36 signaling is partially involved in hyperglycemia and oxLDL-induced vascular calcification in diabetes.

Chronic kidney disease (CKD) patients, characterized by traditional and nontraditional risk factors, are prone to develop atheromatosis and thus cardiovascular events and mortality. The angiogenesis of the adventitial vasa vasorum (aVV) surrounding the carotid has been described as the atheromatosis initiator. Therefore, the aim of the study was to (1) evaluate if the carotid aVV in CKD patients increases in comparison to its physiological value of healthy patients; (2) explore which traditional or nontraditional risk factor including inflammation, bone and mineral metabolism, and anemia could be related to the aVV angiogenesis. CKD patients without previous cardiovascular events (44, stages 3-4; 37, stage 5D) and 65 healthy subjects were compared. The carotid aVV and the intima-media thickness (cIMT) were evaluated by ultrasound. CKD patients at stages 3-4 showed higher aVV of the right carotid artery even after adjusting for age. Importantly, a multiple linear regression model showed hemoglobin levels > 12.5 g/dL as the factor for an estimated higher aVV of the right carotid artery. In conclusion, the association of hemoglobin with higher aVV could suggest the role of high hemoglobin in the higher incidence of adverse cardiovascular outcomes in CKD patients.

This meeting comprised two sessions: the morning session centred around glucagon-like peptide-1 receptor (GLP-1R) agonists and SGLT-2 inhibitors, a new class of glucose-lowering compounds, while the afternoon session focused on new results of cardiovascular safety studies with diabetes medications, with special attention to the SAVOR-TIMI trial of saxagliptin.

Aim. To assess prescribing practices of noninsulin antidiabetic drugs (NIADs) in T2DM with several major contraindications according to prescribing information or clinical guidelines: renal failure, heart failure, liver dysfunction, or history of bladder cancer. Methods. Cross-sectional, descriptive, multicenter study. Electronic medical records were retrieved from all T2DM subjects who attended primary care centers pertaining to the Catalan Health Institute in Catalonia in 2013 and were pharmacologically treated with any NIAD alone or in combination. Results. Records were retrieved from a total of 255,499 pharmacologically treated patients. 78% of patients with some degree of renal impairment (glomerular filtration rate (GFR) < 60 mL/min) were treated with metformin and 31.2% with sulfonylureas. Even in the event of severe renal failure (GFR < 30 mL/min), 35.3% and 22.5% of patients were on metformin or sulfonylureas, respectively. Moreover, metformin was prescribed to more than 60% of patients with moderate or severe heart failure. Conclusion. Some NIADs, and in particular metformin, were frequently used in patients at high risk of complications when they were contraindicated. There is a need to increase awareness of potential inappropriate prescribing and to monitor the quality of prescribing patterns in order to help physicians and policymakers to yield better clinical outcomes in T2DM.

Presentamos la adaptación española realizada por el CEIPC de la Guía Europea de Prevención de las Enfermedades Cardiovasculares (ECV) 2008. Esta guía recomienda el modelo SCORE de bajo riesgo para la valoración del riesgo cardiovascular. El objetivo es prevenir la mortalidad y morbilidad debidas a las ECV mediante el manejo de sus factores de riesgo en la práctica clínica. La guía hace énfasis en la prevención primaria y en el papel del médico y la enfermería de atención primaria en la promoción de un estilo de vida cardiosaludable, basado el incremento de los niveles de actividad física, la adopción de una alimentación saludable y, en los fumadores, el abandono del tabaco. La meta terapéutica para la presión arterial es en general

Somatostatin receptors (ssts) are expressed in thyroid cancer cells, but their biological significance is not well understood. The aim of this study was to assess ssts in well differentiated (WDTC) and poorly differentiated thyroid cancer (PDTC) by means of imaging and molecular tools and its relationship with the efficacy of somatostatin analog treatment. Thirty-nine cases of thyroid carcinoma were evaluated (20 PDTC and 19 WDTC). Depreotide scintigraphy and mRNA levels of sst-subtypes, including the truncated variant sst5TMD4, were carried out. Depreotide scans were positive in the recurrent tumor in the neck in 6 of 11 (54%) PDTC, and in those with lung metastases in 5/11 cases (45.4%); sst5TMD4 was present in 18/20 (90%) of PDTC, being the most densely expressed sst-subtype, with a 20-fold increase in relation to sst2. In WDTC, sst2 was the most represented, while sst5TMD4 was not found; sst2 was significantly increased in PDTC in comparison to WDTC. Five depreotide positive PDTC received octreotide for 3-6 months in a pilot study with no changes in the size of the lesions in 3 of them, and a significant increase in the pulmonary and cervical lesions in the other 2. All PDTC patients treated with octreotide showed high expression of sst5TMD4. ROC curve analysis demonstrated that only sst5TMD4 discriminates between PDTC and WDTC. We conclude that sst5TMD4 is overexpressed in PDTC and may be involved in the lack of response to somatostatin analogue treatment.

The objective of this cross-sectional study was to assess differences in the control and treatment of modifiable cardiovascular risk factors (CVRF: HbA1c, blood pressure [BP], LDL-cholesterol, body mass index, and smoking habit) according to gender and the presence of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM) in Catalonia, Spain. The study included available data from electronic medical records for a total of 286,791 patients. After controlling for sex, age, diabetes duration, and treatment received, both men and women with prior CVD had worse cardiometabolic control than patients without previous CVD; women with prior CVD had worse overall control of CVRFs than men except for smoking; and women without prior CVD were only better than men at controlling smoking and BP, with no significant differences in glycemic control. Finally, although the proportion of women treated with lipid-lowering medications was similar to (with prior CVD) or even higher (without CVD) than men, LDL-cholesterol levels were remarkably uncontrolled in both women with and women without CVD. The results stress the need to implement measures to better prevent and treat CVRF in the subgroup of diabetic women, specifically with more intensive statin treatment in those with CVD.

Data on the prevalence of benign and malignant nodular thyroid disease in patients with acromegaly is a matter of debate. In the last decade an increasing incidence of thyroid cancer has been reported. The aim of this study was to evaluate the prevalence of goiter, thyroid nodules and thyroid cancer in a large series of patients with acromegaly with a cross-sectional study with a control group. Six Spanish university hospitals participated. One hundred and twenty three patients (50% men; mean age 59±13 years; disease duration 6.7±7.2 years) and 50 controls (51% males, mean age 58±15 years) were studied. All participants underwent thyroid ultrasound and fine needle aspiration. Cytological analysis was performed in suspicious nodules between 0.5 and 1.0 cm and in all nodules greater than 1.0 cm. Goiter was more frequently found in patients than in controls (24.9 vs. 8.3%, respectively; p

BackgroundCardiovascular (CV) diseases are the most common cause of death worldwide. This study aimed to investigate the incidence and type of first CV event in a broad cohort of Spaniards, focusing on age and sex differences.MethodsThis was a retrospective study using the SIDIAP database. Subjects aged 30–89 years in 2010 were included. Individuals with prevalent CV disease or atrial fibrillation were excluded. Subjects were followed until the occurrence of a CV event, death, or the study end (December 2016). CV outcomes (coronary heart disease [CHD], cerebrovascular or peripheral artery disease and heart failure [HF]) during follow-up were analyzed. Clinical, anthropometrical, and laboratory data were retrieved from clinical records.ResultsOverall, 3,769,563 at-risk individuals (51.2 ± 15.2 years) were followed for a median of 7 years. The cumulative incidence of a first CV event was 6.66% (men vs. women, 7.48% vs. 5.90%), with the highest incidence (25.97%) among individuals >75 years. HF (29%) and CHD (28.8%) were the most common first events overall; in men it was CHD (33.6%), while in women it was HF and cerebrovascular disease (37.4% and 27.4%). In younger age groups, CHD was more prevalent, with HF in older age groups. Baseline CV risks factors conferred more risk in younger ages and differed between men and women.ConclusionsThe incidence and type of the first CV event in this Mediterranean region were significantly influenced by age and sex. This information is relevant for tailoring primary prevention strategies including the treatment of risk factors.

Abstract Background In this study, we evaluated the lipidome alterations caused by type 1 diabetes (T1D) and type 2 diabetes (T2D), by determining lipids significantly associated with diabetes overall and in both sexes, and lipids associated with the glycaemic state. Methods An untargeted lipidomic analysis was performed to measure the lipid profiles of 360 subjects (91 T1D, 91 T2D, 74 with prediabetes and 104 controls (CT)) without cardiovascular and/or chronic kidney disease. Ultra-high performance liquid chromatography-electrospray ionization mass spectrometry (UHPLC-ESI-MS) was conducted in two ion modes (positive and negative). We used multiple linear regression models to (1) assess the association between each lipid feature and each condition, (2) determine sex-specific differences related to diabetes, and (3) identify lipids associated with the glycaemic state by considering the prediabetes stage. The models were adjusted by sex, age, hypertension, dyslipidaemia, body mass index, glucose, smoking, systolic blood pressure, triglycerides, HDL cholesterol, LDL cholesterol, alternate Mediterranean diet score (aMED) and estimated glomerular filtration rate (eGFR); diabetes duration and glycated haemoglobin (HbA1c) were also included in the comparison between T1D and T2D. Results A total of 54 unique lipid subspecies from 15 unique lipid classes were annotated. Lysophosphatidylcholines (LPC) and ceramides (Cer) showed opposite effects in subjects with T1D and subjects with T2D, LPCs being mainly up-regulated in T1D and down-regulated in T2D, and Cer being up-regulated in T2D and down-regulated in T1D. Also, Phosphatidylcholines were clearly down-regulated in subjects with T1D. Regarding sex-specific differences, ceramides and phosphatidylcholines exhibited important diabetes-associated differences due to sex. Concerning the glycaemic state, we found a gradual increase of a panel of 1-deoxyceramides from normoglycemia to prediabetes to T2D. Conclusions Our findings revealed an extensive disruption of lipid metabolism in both T1D and T2D. Additionally, we found sex-specific lipidome changes associated with diabetes, and lipids associated with the glycaemic state that can be linked to previously described molecular mechanisms in diabetes.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver disease, has increased worldwide along with the epidemics of obesity and related dysmetabolic conditions characterized by impaired glucose metabolism and insulin signaling, such as type 2 diabetes mellitus (T2D). MASLD can be defined as an excessive accumulation of lipid droplets in hepatocytes that occurs when the hepatic lipid metabolism is totally surpassed. This metabolic lipid inflexibility constitutes a central node in the pathogenesis of MASLD and is frequently linked to the overproduction of lipotoxic species, increased cellular stress, and mitochondrial dysfunction. A compelling body of evidence suggests that the accumulation of lipid species derived from sphingolipid metabolism, such as ceramides, contributes significantly to the structural and functional tissue damage observed in more severe grades of MASLD by triggering inflammatory and fibrogenic mechanisms. In this context, MASLD can further progress to metabolic dysfunction-associated steatohepatitis (MASH), which represents the advanced form of MASLD, and hepatic fibrosis. In this review, we discuss the role of sphingolipid species as drivers of MASH and the mechanisms involved in the disease. In addition, given the absence of approved therapies and the limited options for treating MASH, we discuss the feasibility of therapeutic strategies to protect against MASH and other severe manifestations by modulating sphingolipid metabolism.