CONTEXT:Impaired brain leptin transport is proposed as a mechanism in obesity-related leptin resistance. OBJECTIVES:We sought to evaluate plasma and cerebrospinal fluid (CSF) leptin dynamics before and 1 year after bariatric surgery (BS) and to explore their relationship with short-term weight loss and mid-term weight trajectories. METHODS:In this prospective longitudinal cohort study conducted between 2017 and 2025 at a tertiary hospital, we included 33 women with obesity eligible for BS (OB-group) and 13 age-matched control women (HC-group). Study procedures were conducted at baseline and 1 year after BS, including dual-energy x-ray absorptiometry body composition analysis and plasma/CSF sampling. Leptin levels were measured, and the CSF-to-plasma leptin ratio was calculated to assess brain leptin transport efficiency. OB-group participants were followed annually for 4 years, with body weight recorded at each visit. Weight change from year 1 to 4 was calculated, along with weight regains (WR) from nadir weight to year 4. RESULTS:At baseline, the OB-group exhibited elevated plasma and CSF leptin concentrations and reduced CSF-to-plasma leptin ratio. Following BS, leptin transport efficiency markedly improved. Although both plasma and CSF leptin decreased, the CSF leptin reduction was less pronounced. Neither baseline CSF leptin nor the CSF-to-plasma leptin ratio predicted weight loss at 1 year. Postsurgical CSF leptin levels and CSF-to-plasma leptin ratio were not associated with post-BS mid-term weight trajectories. CONCLUSION:Our findings indicate that obesity-related alterations in leptin transport are primarily attributable to the obese state rather than an intrinsic defect of the transport system and are potentially reversible through weight loss.

Preclinical studies show that dietary or central administration of monounsaturated (MUFAs) and polyunsaturated fatty acids (PUFAs) can reduce food intake, enhance energy expenditure and attenuate hypothalamic inflammation (HI), whereas saturated fatty acids (SFAs) promote weight gain, HI, and neuronal injury. However, whether hypothalamic exposure to different fatty acids similarly influences HI and body weight in humans remains unclear. In this longitudinal study, we compared cerebrospinal fluid (CSF) free fatty acid (FFA) profiles between nineteen normal-weight controls and forty-four individuals with obesity, both at baseline and one year after bariatric surgery (BS). We also examined associations between CSF-FFA composition, MRI-based markers of HI—increased hypothalamic mean diffusivity (MD) and volume—and postoperative weight loss. At baseline, individuals with obesity had similar CSF concentrations of total FFA, SFA, and MUFA compared to controls, but significantly lower PUFA levels, mainly due to reduced docosahexaenoic acid (DHA). BS did not substantially alter CSF-FFA profiles. Lower baseline CSF-DHA levels were associated with higher hypothalamic MD and independently predicted less weight loss at one year. Postoperative increases in CSF-DHA correlated with reductions in hypothalamic MD. These findings suggest that brain DHA may influence hypothalamic microstructure and contribute to body weight regulation in human obesity.

Metabolic and bariatric surgery (MBS) is the most effective treatment for severe obesity, but long-term success is often limited by recurrent weight gain (RWG). This study evaluates the association between metabolic adaptation (MA) and long-term RWG. Body composition (via bioimpedance) and resting energy expenditure (REE) via indirect calorimetry were assessed at baseline (n = 95), 2 (n = 29), and 12 months (n = 46) after gastric bypass (GBP, n = 68) or sleeve gastrectomy (SG, n = 27). Body weight was measured throughout the subsequent 4 years of follow-up. RWG was defined as the difference between maximum weight in years 3–5 and nadir in years 1–2. On average, MA (kcal/day) was − 130 (95

A 90-year-old male was admitted to the hospital due to recurrent symptomatic hypoglycemia. After ruling out the most common outpatient causes of hypoglycemia, endogenous hyperinsulinism was confirmed. An abdominal computed tomography (CT) scan revealed a 15 mm solid nodular lesion in the pancreatic tail. The (68)Ga-DOTA-TOC PET-CT findings led to the diagnosis of insulinoma. A multidisciplinary committee considered the patient unfit for surgery. The treatment was started with a low dose of diazoxide; however, side effects appeared as the dose was gradually increased. Consequently, a dietary approach was prioritized, incorporating modified cornstarch (Glycosade®) in fractionated doses administered under the guidance of continuous glucose monitoring. This strategy allowed for a reduction in the diazoxide dosage and effectively prevented further hypoglycemic episodes without additional side effects. Since the initial medical treatment was successful, the patient and his family preferred to avoid other possible minimally invasive treatments unless pharmacological and dietary approaches failed.

This study aimed to evaluate the effect of preoperative total body weight loss (TBWL) following a structured 6-month lifestyle change programme (LCP) on the level of TBWL at 12 months and its maintenance at 60 months post bariatric surgery (BS), as well as its impact on operation time, hospital stay, surgical complications and obesity-associated pathology remission. This retrospective, single-centre study analysed patients undergoing primary BS between 2013 and 2014. Outcomes were compared between patients participating in the LCP (LCP group) and those receiving standard preoperative education (Control group: CG). Data collected included anthropometric measurements, obesity-related pathologies, surgical complications, and weight-related outcomes. Among 340 BS procedures performed, 165 patients met the inclusion criteria; 59 in the LCP group and 106 in the CG. The mean age was 47 ( ± 11.6) years in the LCP group and 45 ( ± 11.1) years in the CG with no significant differences in baseline clinical characteristics. At surgery, the LCP group showed significant weight reduction (–5.9 kg vs. –0.72 kg in controls, p = 0.008) and their BMI was significantly lower (46.55 vs. 49.47 kg/m², p = 0.002). Postoperatively, weight-related outcomes [BMI and TBWL] were better in the LCP group at 1 and 5 years. Additionally, patients achieving a preoperative TBWL > 5

Following bariatric surgery (BS) patients have an increased risk of alcohol misuse. This 1-year cross-sectional study in potential BS candidates had several objectives: (a) assess the prevalence of risky drinking, alcohol use disorder (AUD), and other substance use/disorder; (b) compare the prevalence of these behaviors to that of the general Spanish population; (c) determine the proportion of patients with positive results in toxicology tests; and (d) study the predictive factors of risky drinking. Setting: tertiary university hospital. Alcohol and other substance use were evaluated with the AUDIT-C and ASSIST questionnaires. Urine tests analyzed several markers (ethyl-glucoronide [EtG] ≥ 500 ng/ml, amphetamine, benzodiazepine, cannabinoid, cocaine, and opioid). The Mini-International-Neuropsychiatric-Interview (5.0.0) was employed to assess psychiatric diagnoses. Among 308 candidates for BS, 196 were accepted to participate (69

BACKGROUND:In Down syndrome (DS) and Alzheimer's disease (AD), nerve growth factor precursor protein (proNGF) accumulates in the brain. However, its non-invasive detection using neuron-derived extracellular vesicles (NDEVs) from plasma remains unexplored. METHODS:We included 139 adults with DS (45 asymptomatic [aDS], 94 symptomatic for AD [sDS]) and 37 healthy controls. NDEVs were isolated from plasma. ProNGF and tetraspanin (CD81) were quantified by enzyme-linked immunosorbent assay. We assessed proNGF/CD81 changes with age, along the AD continuum (aDS and sDS), and associations with cerebrospinal fluid (CSF), plasma biomarkers, episodic memory, and basal forebrain volume. RESULTS:In DS, proNGF/CD81 levels increased with age and were higher in NDEVs from asymptomatic and symptomatic individuals compared to controls, with the highest levels in the symptomatic group. ProNGF correlated with CSF phosphorylated tau (p-tau)181, plasma p-tau217, neurofilament light chain, and episodic memory. DISCUSSION:ProNGF/CD81 levels in NDEVs increase along the AD continuum in DS and parallel tau pathology, indicating the potential as a promising biomarker for monitoring disease progression in plasma. HIGHLIGHTS:Nerve growth factor precursor protein (ProNGF)/tetraspanin (CD81) ratio increased in the third decade of life, 20 years before Alzheimer's disease (AD) symptom onset in Down syndrome (DS). proNGF/CD81 concentrations were significantly higher in individuals with DS compared to controls and were notably elevated in individuals with DS and symptomatic AD compared to asymptomatic AD. proNGF/CD81 concentrations were associated with tau pathology and neuronal injury.

INTRODUCTION:Approximately 25-30% of patients undergoing bariatric surgery (BS) experience weight regain or suboptimal weight loss. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a therapeutic option in these cases. AIM:To evaluate the effectiveness of GLP-1 RAs in managing weight regain and suboptimal weight response after BS in a real-world setting. MATERIALS AND METHODS:Retrospective study of BS patients treated with GLP-1 RAs due to weight regain or suboptimal weight response. RESULTS:A total of 953 patients underwent BS between 2015 and 2020; 122 initiated treatment with GLP-1 RAs. The cohort was composed 78% women, with a mean age of 50.4±10.6 years and a baseline BMI of 44.7±6.3kg/m2. At the start of treatment, 41.9±20.5 months post-BS, the mean weight loss was 18.6±10%; 52% had lost <20% of their initial weight and 82% had regained >20% of the weight lost. 35% received liraglutide (LIRA) (1.8±0.5mg/day) and 65% semaglutide (SEMA) (1.0±0.8mg/week), with a mean treatment duration of 19.3±17.3 months. Maximum weight loss was 4.7±4.8% with LIRA vs. 8.3±5.9% with SEMA (p=0.01). Total weight loss (BS+GLP-1 RA) was 21.6±9.2% with LIRA vs. 25.6±10.5% with SEMA. The proportion of patients with a suboptimal weight response after BS+pharmacotherapy (<20%) significantly decreased (from 52% to 31%). CONCLUSIONS:SEMA led to greater weight reduction than LIRA, positioning it as a more effective option for managing post-BS weight regain.

Introducción Aproximadamente el 25-30% de los pacientes sometidos a cirugía bariátrica (CB) experimentan recuperación de peso o una pérdida subóptima. Los análogos del receptor de GLP-1 (arGLP1) han surgido como una opción terapéutica en estos casos. Objetivo Evaluar la eficacia de los arGLP1 en la recuperación de peso y pérdida de peso subóptima tras la CB en vida real. Materiales y métodos Estudio retrospectivo en pacientes con CB tratados con arGLP1 debido a recuperación de peso o pérdida insuficiente. Resultados Un total de 953 pacientes fueron intervenidos de CB entre los años 2015 y 2020, 122 iniciaron tratamiento con arGLP1. La cohorte incluyó un 78% de mujeres, con una edad media de 50,4±10,6 años e IMC inicial de 44,7±6,3kg/m2. Al inicio del tratamiento, 41,9±20,5 meses post-CB, la pérdida de peso fue 18,6±10%, el 52% mostró pérdida <20% del peso inicial y el 82% recuperó >20% del peso perdido.El 35% recibió liraglutida (LIRA) (1,8±0,5mg/día) y el 65% semaglutida (SEMA) (1,0±0,8mg/semana), con una duración media de 19,3±17,3 meses. La máxima pérdida de peso fue 4,7±4,8% con LIRA vs. 8,3±5,9% con SEMA (p=0,01). La pérdida total (CB+arGLP1) fue 21,6±9,2% con LIRA vs. 25,6±10,5% con SEMA. La proporción de pérdida insuficiente (<20%) disminuyó significativamente (52% a 31%). Conclusiones SEMA mostró una mayor reducción de peso que LIRA, posicionándose como una opción más efectiva en la recuperación de peso post-CB.

Objectives: To assess retinal microvascular changes in patients with Grade II and III obesity before and after bariatric surgery using Optical Coherence Tomography Angiography (OCTA), and to compare these metrics with age- and sex-matched healthy controls. Methods: Prospective, consecutive, longitudinal cohort study with a 12-month follow-up. Grade II and III obese patients scheduled for bariatric surgery underwent comprehensive ophthalmic examinations, including OCTA imaging, prior to the surgery and postoperatively at 1 month, 6 months, and 12 months post-surgery. Results: A total of 43 eyes from 43 patients with obesity (one eye per patient) were included at baseline. At 12 months post-surgery, there was a significant increase in vessel density (VD) (16.70 vs. 17.68; p < 0.01) and perfusion density (PD) (0.406 vs. 0.433; p < 0.01), reaching values comparable to those of the control group (17.73 and 0.434, respectively). Significant reductions were also observed in body mass index (BMI) (43.74 vs. 29.53; p < 0.01), body weight (122.44 kg vs. 81.90 kg; p < 0.01), and intraocular pressure (IOP) (15.72 mmHg vs. 14.16 mmHg; p < 0.01). Conclusions: This study demonstrates a compelling association between obesity and retinal microvascular impairment, highlighting the efficacy of bariatric surgery not only in achieving substantial weight loss but also in improving the retinal perfusion of these patients, achieving metrics at 12 months comparable to age- and sex-matched healthy controls at baseline. These findings raise the hypothesis of the potential utility of OCTA as a monitoring tool for tracking the microvascular status in patients with obesity undergoing bariatric surgery in a longitudinal manner.

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.

OBJECTIVE: Preclinical research implicates hypothalamic inflammation (HI) in obesity and type 2 diabetes pathophysiology. However, their pathophysiological relevance and potential reversibility need to be better defined. We sought to evaluate the effect of bariatric surgery (BS) on radiologic biomarkers of HI and the association between the severity of such radiologic alterations and post-BS weight loss (WL)-trajectories. The utility of cerebrospinal fluid large extracellular vesicles (CSF-lEV) enriched for microglial and astrocyte markers in studying HI was also explored. RESEARCH DESIGN AND METHODS: We included 72 individuals with obesity (20 with/52 without type 2 diabetes) and 24 controls. Participants underwent lumbar puncture and 3T magnetic resonance imaging at baseline and 1-year post-BS. We assessed mean hypothalamic diffusivity (MD) (higher values indicate lesser microstructural integrity) and the volume of the whole and main hypothalamic subregions. CSF-lEV enriched for glial and astrocyte markers were determined by flow cytometry. RESULTS: Compared with controls, obesity and type 2 diabetes groups showed a larger volume and higher MD in the hypothalamic tubular inferior region, the area encompassing the Arcuate nucleus. These radiological alterations were positively associated with baseline anthropometric and metabolic measures and improved post-BS. A larger baseline tubular inferior hypothalamic volume was independently related to lesser WL one and two years after BS. CSF-lEV did not differ between groups and were unrelated to WL-trajectories. CONCLUSIONS: These findings suggest HI improvement after BS and may support a role for HI in modulating the weight loss response to these interventions.

Introducción y objetivos Más de un 50% de primeros eventos cardiovasculares (ECV) ocurren en población identificada como de riesgo bajo o intermedio por las ecuaciones de riesgo, por lo que se ha propuesto la inclusión de variables adicionales, como puntuaciones de riesgo poligénicos (PRP), para mejorar la capacidad predictiva de estas ecuaciones. El objetivo de este estudio fue evaluar si una PRP, independientemente o junto a las ecuaciones de riesgo clínico, se asocia a la presencia, gravedad y extensión de aterosclerosis subclínica. Métodos Se seleccionó a 109 sujetos con aterosclerosis de la cohorte ILERVAS (prevención primaria) y se aparearon con 109 participantes sin aterosclerosis de la misma edad, sexo y nivel de riesgo SCORE2. Se evaluó y cuantificó la aterosclerosis en 12 territorios mediante ecografía vascular de pared arterial y se estimó la PRP mediante el Cardio inCode Score®. Se estimaron la capacidad de predicción de presencia de aterosclerosis subclínica y la asociación entre la extensión y gravedad de la aterosclerosis con la PRP y el riesgo clínico (SCORE2). Resultados La PRP fue similar entre participantes con o sin aterosclerosis (p=0,525). No encontramos una asociación entre la PRP y el SCORE2 (r=–0,29, p=0,709), y la adición de la PRP al SCORE2 no mejoró la predicción de aterosclerosis (AUC [IC del 95%])=0,566 (0,477, 0,654, p=0,148). La extensión de la aterosclerosis se relacionó con el SCORE2 (p=0,009), pero no con la PRP (p=0,709). Conclusiones La PRP seleccionada no se asocia con la presencia de aterosclerosis ni con el riesgo clínico, sugiriendo que su contribución adicional al riesgo de ECV se mediaría por mecanismos independientes al desarrollo de aterosclerosis. Se necesitan biomarcadores adicionales para mejorar la predicción de aterosclerosis subclínica sin recurrir a pruebas de imagen como primer paso en la evaluación personalizada.

The excessive accumulation and malfunctioning of visceral adipose tissue (VAT) is a major determinant of increased risk of obesity-related comorbidities. Thus, risk stratification of people living with obesity according to their amount of VAT is of clinical interest. Currently, the most common VAT measurement methods include mathematical formulae based on anthropometric dimensions, often biased by human measurement errors, bio-impedance, and image techniques such as X-ray absorptiometry (DXA) analysis, which requires specialized equipment. However, previous studies showed the possibility of classifying people living with obesity according to their VAT through blood chemical concentrations by applying machine learning techniques. In addition, most of the efforts were spent on men living with obesity while little was done for women. Therefore, this study aims to compare the performance of the multilinear regression model (MLR) in estimating VAT and six different supervised machine learning classifiers, including logistic regression (LR), support vector machine and decision tree-based models, to categorize 149 women living with obesity. For clustering, the study population was categorized into classes 0, 1, and 2 according to their VAT and the accuracy of each MLR and classification model was evaluated using DXA-data (DXAdata), blood chemical concentrations (BLDdata), and both DXAdata and BLDdata together (ALLdata). Estimation error and R2\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hbox {R}<^>{2}$$\end{document} were computed for MLR, while receiver operating characteristic (ROC) and precision-recall curves (PR) area under the curve (AUC) were used to assess the performance of every classification model. MLR models showed a poor ability to estimate VAT with mean absolute error >= 401.40\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\ge 401.40$$\end{document} and R2 <= 0.62\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\hbox {R}<^>{2} \le 0.62$$\end{document} in all the datasets. The highest accuracy was found for LR with values of 0.57, 0.63, and 0.53 for ALLdata, DXAdata, and BLDdata, respectively. The ROC AUC showed a poor ability of both ALLdata and DXAdata to distinguish class 1 from classes 0 and 2 (AUC = 0.31, 0.71, and 0.85, respectively) as also confirmed by PR (AUC = 0.24, 0.57, and 0.73, respectively). However, improved performances were obtained when applying LR model to BLDdata (ROC AUC >=\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\ge $$\end{document} 0.61 and PR AUC >=\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\ge $$\end{document} 0.42), especially for class 1. These results seem to suggest that, while a direct and reliable estimation of VAT was not possible in our cohort, blood sample-derived information can robustly classify women living with obesity by machine learning-based classifiers, a fact that could benefit the clinical practice, especially in those health centres where medical imaging devices are not available. Nonetheless, these promising findings should be further validated over a larger population.

The use of gut-hormone receptors agonists as new therapeutic options for obesity and some of its related comorbidities, such as type 2 diabetes, has resulted in an unprecedented efficacy in the medical management of people living with obesity (PLWO). Appraisal of the safety of these drugs is of utmost importance considering the large number of PLWO, and the potentially long exposure to these pharmacotherapies. In this narrative review we summarize the evidence on the safety of liraglutide, semaglutide, and tirzepatide as derived from randomized clinical trials conducted in adults living with obesity. Additionally, the safety of these drugs is put into perspective with that of other drugs currently approved for the treatment of PLWO. Overall, the available data support a favorable efficacy versus safety balance for gut-hormone hormone receptor analogues in the treatment of these subjects. Nonetheless, it should be acknowledged that in the context of a chronic disease that has reached epidemic proportions, data from randomized clinical trials aimed primarily at proving the efficacy of these drugs may have been insufficient to unveil all the safety issues. Thus, continuous surveillance on the adverse effects of liraglutide, semaglutide, and tirzepatide is required as we use these drugs in a broader population than that represented in currently available clinical trials.

INTRODUCTION AND OBJECTIVES:More than 50% of first cardiovascular events (CVE) occur in populations identified as at low or intermediate risk by the risk equations, so the inclusion of additional variables, such as polygenic risk scores (PRS), has been proposed to improve the predictive capacity of these equations. The aim of this study was to assess whether a PRS, independently or with clinical risk equations, is associated with the presence, severity and extent of subclinical atherosclerosis. METHODS:109 subjects with atherosclerosis were selected from the ILERVAS cohort (primary prevention) and matched with 109 participants without atherosclerosis of the same age, sex and SCORE2 risk level. Atherosclerosis was assessed and quantified by arterial wall vascular ultrasound in 12 territories, and PRS was estimated using the Cardio inCode Score®. The predictive capacity of the presence of subclinical atherosclerosis was estimated, as well as the association between the extent and severity of atherosclerosis with PRS and clinical risk (SCORE2). RESULTS:PRS was similar between participants with or without atherosclerosis (P=0.525). We did not find an association between PRS and SCORE2 (r=-0.29, P=0.709), and the addition of PRS to SCORE2 did not improve the prediction of atherosclerosis [AUC (95% CI)=0.566 (0.477, 0.654), P=0.148]. The extent of atherosclerosis was related to SCORE2 (P=0.009), but not to PRS (P=0.709). CONCLUSIONS:The Selected PRS is not associated with the presence of atherosclerosis or clinical risk, suggesting that its additional contribution to CVE risk would be mediated by mechanisms independent of the development of atherosclerosis. Additional biomarkers are needed to improve the prediction of subclinical atherosclerosis without using imaging tests as a first step in personalized assessment.

The Framingham Risk Score (FRS) and Pooled Cohort Equations (PCEs) overestimate risk in many contemporary cohorts.This study sought to determine if recalibration of these scores using contemporary population-level data improves risk stratification for statin therapy.Five-year FRS and PCEs were recalibrated using a cohort of Ontario residents alive January 1, 2011, who were 30 to 79 years of age without cardiovascular disease. Scores were externally validated in a primary care cohort of routinely collected electronic medical record data from January 1, 2010, to December 31, 2014. The relative difference in mean predicted and observed risk, number of statins avoided, and number needed to treat with statins to reduce a cardiovascular event at 5 years were reported.The FRS was recalibrated in 6,938,971 Ontario residents (51.6% women, mean age 48 years) and validated in 71,450 individuals (56.1% women, mean age 52 years). Recalibration reduced overestimation from 109% to 49% for women and 131% to 32% for men. The recalibrated FRS was estimated to reduce statin prescriptions in up to 26 per 1,000 low-risk women and 80 per 1,000 low-risk men, as well as reduce the number needed to treat from 61 to 47 in women and from 53 to 41 in men. In contrast, after recalibration of the PCEs, risk remained overestimated by 217% in women and 128% in men.Recalibration is a feasible solution to improve risk prediction but is dependent on the model being used. Recalibration of the FRS but not the PCEs reduced overestimation and may improve utilization of statins.