A risk analysis of alpelisib-induced hyperglycemia in patients with advanced solid tumors and breast cancer.

BACKGROUND: Hyperglycemia is an on-target effect of PI3Kα inhibitors. Early identification and intervention of treatment-induced hyperglycemia is important for improving management of patients receiving a PI3Kα inhibitor like alpelisib. Here, we characterize incidence of grade 3/4 alpelisib-related hyperglycemia, along with time to event, management, and outcomes using a machine learning model. METHODS: Data for the risk model were pooled from patients receiving alpelisib ± fulvestrant in the open-label, phase 1 X2101 trial and the randomized, double-blind, phase 3 SOLAR-1 trial. The pooled population (n = 505) included patients with advanced solid tumors (X2101, n = 221) or HR+/HER2- advanced breast cancer (SOLAR-1, n = 284). External validation was performed using BYLieve trial patient data (n = 340). Hyperglycemia incidence and management were analyzed for SOLAR-1. RESULTS: A random forest model identified 5 baseline characteristics most associated with risk of developing grade 3/4 hyperglycemia (fasting plasma glucose, body mass index, HbA1c, monocytes, age). This model was used to derive a score to classify patients as high or low risk for developing grade 3/4 hyperglycemia. Applying the model to patients treated with alpelisib and fulvestrant in SOLAR-1 showed higher incidence of hyperglycemia (all grade and grade 3/4), increased use of antihyperglycemic medications, and more discontinuations due to hyperglycemia (16.7% vs. 2.6% of discontinuations) in the high- versus low-risk group. Among patients in SOLAR-1 (alpelisib + fulvestrant arm) with PIK3CA mutations, median progression-free survival was similar between the high- and low-risk groups (11.0 vs. 10.9 months). For external validation, the model was applied to the BYLieve trial, for which successful classification into high- and low-risk groups with shorter time to grade 3/4 hyperglycemia in the high-risk group was observed. CONCLUSIONS: A risk model using 5 clinically relevant baseline characteristics was able to identify patients at higher or lower probability for developing alpelisib-induced hyperglycemia. Early identification of patients who may be at higher risk for hyperglycemia may improve management (including monitoring and early intervention) and potentially lead to improved outcomes. REGISTRATION: ClinicalTrials.gov: NCT01219699 (registration date: October 13, 2010; retrospectively registered), ClinicalTrials.gov: NCT02437318 (registration date: May 7, 2015); ClinicalTrials.gov: NCT03056755 (registration date: February 17, 2017).

The usefulness of the retina for identifying people with type 2 diabetes with prodromal stages of dementia.

Type 2 diabetes (T2D) is associated with cognitive impairment and dementia. The detection of cognitive impairment is important because this population is at higher risk of experiencing difficulties in the self-management of diabetes. Mild cognitive impairment (MCI) often remains undiagnosed due to lack of simple tools for screening at large scale. This represents an important gap in the patients' management because subjects with diabetes and MCI are at high risk of progressing to dementia. Due to its developmental origin as a brain-derived tissue, the retina has been proposed as a potential means of non-invasive and readily accessible exploration of brain pathology. Recent evidence showed that retinal imaging and/or functional tests are correlated with the cognitive function and brain changes in T2D. Simple retinal functional tests (i.e. retinal microperimetry) have proven to be useful as reliable tool for the cognitive evaluation and monitoring in patients with T2D>65 years. This review gives an overall update on the usefulness of retinal imaging in identifying patients with T2D at risk of developing dementia.

Hyponatremia after COVID-19 is frequent in the first year and increases re-admissions.

Hyponatremia on admission has been related to worse outcomes in patients with COVID-19 infection. However, little is known about the frequency and the associated risk factors of hyponatremia after COVID-19 discharge. We performed an observational 24-month follow-up study of patients admitted during the first COVID-19 wave. Kaplan-Meier curves and Cox proportional hazard models were used to assess the main variables in predicting hyponatremia on follow-up (HYPO-FU). A total of 161 out of 683 (24.4%) developed HYPO-FU. The group with HYPO-FU comprised of more men [(62.3%) vs. (49.2%); p < 0.01], older [65.6 ± 18.2 vs. 60.3 ± 17.0; p < 0.01] and more frequently re-admitted [(16.2%) vs. (3.8%); p < 0.01). The rate of HYPO-FU was higher in the first year 23.6 per 100 individuals per year. After Cox regression analysis, the independent risk factors of HYPO-FU were diabetes [OR 2.12, IC 95% (1.48-3.04)], hypertension [OR 2.18, IC 95% (1.53-3.12)], heart failure [OR 3.34, IC 95% (1.72-6.48)] and invasive ventilation support requirement [OR: 2.38, IC 95% (1.63-3.50)]. To conclude, HYPO-FU was frequent in the first year after COVID-19 infection, and the risk was higher in older men with comorbidities, increasing rehospitalisation. Further studies aimed at evaluating the beneficial effects of correcting hyponatremia in these patients are warranted.

A New Approach to Staging Diabetic Eye Disease: Staging of Diabetic Retinal Neurodegeneration and Diabetic Macular Edema.

Topic: The goal of this review was to summarize the current level of evidence on biomarkers to quantify diabetic retinal neurodegeneration (DRN) and diabetic macular edema (DME). Clinical relevance: With advances in retinal diagnostics, we have more data on patients with diabetes than ever before. However, the staging system for diabetic retinal disease is still based only on color fundus photographs and we do not have clear guidelines on how to incorporate data from the relatively newer modalities into clinical practice. Methods: In this review, we use a Delphi process with experts to identify the most promising modalities to identify DRN and DME. These included microperimetry, full-field flash electroretinogram, spectral-domain OCT, adaptive optics, and OCT angiography. We then used a previously published method of determining the evidence level to complete detailed evidence grids for each modality. Results: Our results showed that among the modalities evaluated, the level of evidence to quantify DRN and DME was highest for OCT (level 1) and lowest for adaptive optics (level 4). Conclusion: For most of the modalities evaluated, prospective studies are needed to elucidate their role in the management and outcomes of diabetic retinal diseases. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Standardising personalised diabetes care across European health settings: A person-centred outcome set agreed in a multinational Delphi study.

OBJECTIVE: Standardised person-reported outcomes (PRO) data can contextualise clinical outcomes enabling precision diabetes monitoring and care. Comprehensive outcome sets can guide this process, but their implementation in routine diabetes care has remained challenging and unsuccessful at international level. We aimed to address this by developing a person-centred outcome set for Type 1 and Type 2 diabetes, using a methodology with prospects for increased implementability and sustainability in international health settings. METHODS: We used a three-round questionnaire-based Delphi study to reach consensus on the outcome set. We invited key stakeholders from 19 countries via purposive snowball sampling, namely people with diabetes (N = 94), healthcare professionals (N = 65), industry (N = 22) and health authorities (N = 3), to vote on the relevance and measurement frequency of 64 previously identified clinical and person-reported outcomes. Subsequent consensus meetings concluded the study. RESULTS: The list of preliminary outcomes was shortlisted via the consensus process to 46 outcomes (27 clinical outcomes and 19 PROs). Two main collection times were recommended: (1) linked to a medical visit (e.g. diabetes-specific well-being, symptoms and psychological health) and (2) annually (e.g. clinical data, general well-being and diabetes self management-related outcomes). CONCLUSIONS: PROs are often considered in a non-standardised way in routine diabetes care. We propose a person-centred outcome set for diabetes, specifically considering psychosocial and behavioural aspects, which was agreed by four international key stakeholder groups. It guides standardised collection of meaningful outcomes at scale, supporting individual and population level healthcare decision making. It will be implemented and tested in Europe as part of the H2O project.

Efficacy of Insulin Titration Driven by SMS in Improving Glycemic Control in People with Type 2 Diabetes.

AIM: To evaluate the efficacy of the self-management of insulin titration based on information received by the Short Message Service (SMS). METHODS: A case-control study including 59 subjects in each arm with 16 weeks of follow-up was performed. The inclusion criteria were: (1) Subjects with type 2 diabetes (T2D) under basal insulin treatment; (2) Suboptimal glycemic control: HbA1c ≥ 7.5% and fasting capillary blood glucose (FCBG) > 140 mg/dL (>3 times per week). Subjects were invited to use an insulin titration service based on SMS feedback aimed at optimizing glycemic control depending on fasting blood glucose levels. Psychological aspects were evaluated in the interventional group by means of validated questionnaires (DDS, HADS and SF-12). RESULTS: The intervention group achieved a lower mean FCBG (126 mg/dL ± 34 vs. 149 mg/dL ± 46, p = 0.001) and lower HbA1c (7.5% ± 1.3 vs. 7.9% ± 0.9, p = 0.021) than the control group. In addition, the intervention group showed a significant improvement in psychological aspects related to Emotional Burden (p = 0.031), Regimen Distress (p < 0.001), Depression (p = 0.049) and Mental Health (p < 0.01). CONCLUSIONS: The SMS-guided titration was effective in terms of improving glucometric parameters in comparison with the standard of care and improved significant psychological aspects-mainly, the stress associated with insulin treatment.

Blocking Hemopexin With Specific Antibodies: A New Strategy for Treating Diabetic Retinopathy.

Hemopexin (HPX) is overexpressed in the retina of patients with diabetes and induces the breakdown of the blood-retinal barrier in vitro. The aim of this study was to evaluate whether HPX blockade by specific antibodies (aHPX) could avoid vascular leakage in vivo and microvascular angiogenesis in vitro and ex vivo. For this purpose, the effect of intravitreal (IVT) injections of aHPX on vascular leakage was evaluated in db/db mice and rats with streptozotocin-induced diabetes using the Evans Blue method. Retinal neurodegeneration and inflammation were also evaluated. The antiangiogenic effect of aHPX on human retinal endothelial cells (HRECs) was tested by scratch wound healing and tube formation using standardized methods, as well as by choroidal sprouting assays from retinal explants obtained in rats. We found that IVT injection of aHPX significantly reduced vascular leakage, retinal neurodegeneration, and inflammation. In addition, treatment with aHPX significantly reduced HREC migration and tube formation induced by high glucose concentration and suppressed choroidal sprouting even after vascular endothelial growth factor stimulation, with this effect being higher than obtained with bevacizumab. The antipermeability and antiangiogenic effects of IVT injection of aHPX suggest the blockade or inhibition of HPX as a new strategy for the treatment of advanced stages of diabetic retinopathy. ARTICLE HIGHLIGHTS: Hemopexin (HPX) is the best-characterized permeability factor in steroid-sensitive nephrotic syndrome. We have previously reported that HPX is overexpressed in the retina of patients with diabetes and induces the breakdown of the blood-retinal barrier in vitro. Here, we report that intravitreal injection of anti-HPX antibodies significantly reduces vascular leakage, retinal neurodegeneration, and inflammation in diabetic murine models and that the immunoneutralization of HPX exerts a significant antiangiogenic effect in vitro and in retinal explants. The blockade of HPX can be considered as a new therapy for advanced stages of diabetic retinopathy.

Structural and Metabolic Retinal Changes Associated With Mild Cognitive Impairment in Type 2 Diabetes.

Type 2 diabetes is associated with cognitive impairment and a twofold increased risk of dementia compared with age-matched individuals without diabetes. Given that the eye and the brain share similar embryologic origin and anatomical features, the retina offers a unique window to the brain. In this study, we wanted to determine whether there was a difference in retinal imaging-based neuronal and vascular markers in individuals with type 2 diabetes with or without mild cognitive impairment (MCI). We included 134 persons with type 2 diabetes. Based on neuropsychological tests, the prevalence of MCI was 28%. We performed seven-field color fundus photos, optical coherence tomography (OCT), OCT-angiography (OCT-A), and retinal oximetry to analyze retinal markers. In a multivariable cluster analysis, persons with MCI had a significantly thinner macular retinal nerve fiber layer and macular ganglion cell layer, and less venular oxygen saturation in the nasal quadrant compared with those without MCI. There were no differences in retinal vessel density, fractal dimension, width, tortuosity, or OCT-A markers. People with type 2 diabetes and MCI demonstrate alterations in retinal structure and metabolism, suggesting noninvasive retinal markers may be useful to detect people with type 2 diabetes at risk for cognitive dysfunction. ARTICLE HIGHLIGHTS: Type 2 diabetes is associated with mild cognitive impairment (MCI). Therefore, retinal and cerebral neurodegeneration may run in parallel. To assess whether there was a difference in retinal structure, vessel, and metabolic parameters in individuals with MCI. We found those with MCI had a thinner macular retinal nerve fiber layer, macular ganglion cell layer, and less venular oxygen saturation. We suggest noninvasive retinal markers may be useful to detect those at risk of cognitive dysfunction.

Assessment of dyspneic sensation in patients with type 2 diabetes.

Introduction: Individuals with type 2 diabetes (T2D) should be considered a susceptible group for pulmonary dysfunction. So, we aimed to evaluate the sensation of breathlessness in this population by administering two well-validated questionnaires. Methods: This is a crosssectional study with 592 people without known respiratory disease (353 with T2D) who answered the modified Medical Research Council (mMRC) questionnaire. In addition, 47% also responded to the St George Respiratory Questionnaire, a specific instrument designed to be applied to patients with obstructive airway disease. Results: Patients with T2D showed a higher mMRC score in comparison to the control group [1.0 (0.0 - 4.0) vs. 0.0 (0.0 - 4.0), p<0.001]. A higher prevalence of subjects with mMRC ≥2 was observed in T2D that in the control group (20.2% vs. 11.6%, p=0.004). Participants with T2D and mMRC ≥2 showed a higher HbA1c (8.2 ± 1.6% vs. 7.8 ± 1.6%, p=0.048), longer T2D evolution and higher prevalence of nephropathy. In the multivariate analysis, the presence of T2D [OR=1.95 (1.19 to 3.22), p=0.008] in all the population, and HbA1c [OR=1.19 (1.01 to 1.41), p=0.034] and the presence of diabetic nephropathy [OR=2.00 (1.14 to 3.52), p=0.015] in patients with T2D, predicted a mMRC ≥2. Finally, no differences were observed regarding the SGRQ score among groups. Conclusions: Patients with T2D showed a greater sensation of dyspnea than subjects with normal carbohydrate metabolism. Risk factors included poor metabolic control and the presence of renal disease.

Contribution of Dynamic and Genetic Tests for Short Stature Diagnosing: A Case Report.

Genetic tests have led to the discovery of many novel genetic variants related to growth failure, but the clinical significance of some results is not always easy to establish. The aim of this report is to describe both clinical phenotype and genetic characteristics in an adult patient with short stature associated with a homozygous variant in disintegrin and metalloproteinase with thrombospondin motifs type 17 gene (ADAMTS17) combined with a homozygous variant in the GH secretagogue receptor (GHS-R). The index case had severe short stature (SS) (-3.0 SD), small hands and feet, associated with eye disturbances. Genetic tests revealed homozygous compounds for ADAMTS17 responsible for Weill-Marchesani-like syndrome but a homozygous variant in GHS-R was also detected. Dynamic stimulation with an insulin tolerance test showed a normal elevation of GH, while the GH response to macimorelin stimulus was totally flattened. We show the implication of the GHS-R variant and review the molecular mechanisms of both entities. These results allowed us to better interpret the phenotypic spectrum, associated co-morbidities, its implications in dynamic tests, genetic counselling and treatment options not only to the index case but also for her relatives.

Comparison of computed tomography and dual-energy X-ray absorptiometry in the evaluation of body composition in patients with obesity.

Objective: a) To evaluate the accuracy of the pre-existing equations (based on cm2 provided by CT images), to estimate in kilograms (Kg) the body composition (BC) in patients with obesity (PwO), by comparison with Dual-energy X-ray absorptiometry (DXA). b) To evaluate the accuracy of a new approach (based on both cm2 and Hounsfield Unit parameters provided by CT images), using an automatic software and artificial intelligence to estimate the BC in PwO, by comparison with DXA. Methods: Single-centre cross-sectional study including consecutive PwO, matched by gender with subjects with normal BMI. All the subjects underwent BC assessment by Dual-energy X-ray absorptiometry (DXA) and skeletal-CT at L3 vertebrae. CT images were processed using FocusedON-BC software. Three different models were tested. Model 1 and 2, based on the already existing equations, estimate the BC in Kg based on the tissue area (cm2) in the CT images. Model 3, developed in this study, includes as additional variables, the tissue percentage and its average Hounsfield unit. Results: 70 subjects (46 PwO and 24 with normal BMI) were recruited. Significant correlations for BC were obtained between the three models and DXA. Model 3 showed the strongest correlation with DXA (r= 0.926, CI95% [0.835-0.968], p<0.001) as well as the best agreement based on Bland - Altman plots. Conclusion: This is the first study showing that the BC assessment based on skeletal CT images analyzed by automatic software coupled with artificial intelligence, is accurate in PwO, by comparison with DXA. Furthermore, we propose a new equation that estimates both the tissue quantity and quality, that showed higher accuracy compared with those currently used, both in PwO and subjects with normal BMI.

Rapid Reduction of HbA1c and Early Worsening of Diabetic Retinopathy: A Real-world Population-Based Study in Subjects With Type 2 Diabetes.

OBJECTIVE: Early worsening of diabetic retinopathy (EWDR) due to the rapid decrease of blood glucose levels is a concern in diabetes treatment. The aim of the current study is to evaluate whether this is an important issue in subjects with type 2 diabetes with mild or moderate nonproliferative DR (NPDR), who represent the vast majority of subjects with DR attended in primary care. RESEARCH DESIGN AND METHODS: This is a retrospective nested case-control study of subjects with type 2 diabetes and previous mild or moderate NPDR. Using the SIDIAP ("Sistema d'informació pel Desenvolupament de la Recerca a Atenció Primària") database, we selected 1,150 individuals with EWDR and 1,150 matched control subjects (DR without EWDR). The main variable analyzed was the magnitude of the reduction of HbA1c in the previous 12 months. The reduction of HbA1c was categorized as rapid (>1.5% reduction in <12 months) or very rapid (>2% in <6 months). RESULTS: We did not find any significant difference in HbA1c reduction between case and control subjects (0.13 ± 1.21 vs. 0.21 ± 1.18; P = 0.12). HbA1c reduction did not show significant association with worsening of DR, neither in the unadjusted analyses nor in adjusted statistical models that included the main confounding variables: duration of diabetes, baseline HbA1c, presence of hypertension, and antidiabetic drugs. In addition, when stratification by baseline HbA1c was performed, we did not find that those patients with higher levels of HbA1c presented a higher risk to EWDR. CONCLUSIONS: Our results suggest that the rapid reduction of HbA1c is not associated with progression of mild or moderate NPDR.

Impact of ectopic fat on brain structure and cognitive function: A systematic review and meta-analysis from observational studies.

Ectopic fat, defined as a specific organ or compartment with the accumulation of fat tissue surrounding organs, is highly associated with obesity which has been identified as a risk factor for cognitive impairment and dementia. However, the relationship between ectopic fat and changes in brain structure or cognition is yet to be elucidated. Here, we investigated the effects of ectopic fat on brain structure and cognitive function via systemic review and meta-analysis. A total of 21 studies were included from electronic databases up to July 9, 2022. We found ectopic fat was associated with decreased total brain volumeand increased lateral ventricle volume. In addition, ectopic was associated with decreased cognitive scores and negatively correlated with cognitive function. More specifically, dementia development were correlated with increased levels of visceral fat. Overall, our data suggested that increased ectopic fat was associated with prominent structural changes in the brain and cognitive decline, an effect driven mainly by increases in visceral fat, while subcutaneous fat may be protective. Our results suggest that patients with increased visceral fat are at risk of developing cognitive impairment and, therefore, represent a subset of population in whom appropriate and timely preventive measures could be implemented.

What else can we do to prevent diabetic retinopathy?

The classical modifiable factors associated with the onset and progression of diabetic retinopathy are the suboptimal control of blood glucose levels and hypertension, as well as dyslipidaemia. However, there are other less recognised modifiable factors that can play a relevant role, such as the presence of obesity or the abnormal distribution of adipose tissue, and others related to lifestyle such as the type of diet, vitamin intake, exercise, smoking and sunlight exposure. In this article we revisit the prevention of diabetic retinopathy based on modulating the modifiable risk factors, as well as commenting on the potential impact of glucose-lowering drugs on the condition. The emerging concept that neurodegeneration is an early event in the development of diabetic retinopathy points to neuroprotection as a potential therapeutic strategy to prevent the advanced stages of the disease. In this regard, the better phenotyping of very early stages of diabetic retinopathy and the opportunity of arresting its progression using treatments targeting the neurovascular unit (NVU) are discussed.

Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with increased risk of cognitive decline although the pathogenic basis for this remains obscure. Deciphering diabetes-linked molecular mechanisms in cells of the cerebral cortex could uncover novel therapeutic targets. METHODS: Single-cell transcriptomic sequencing (scRNA-seq) was conducted on the cerebral cortex in a mouse model of type 2 diabetes (db/db mice) and in non-diabetic control mice in order to identify gene expression changes in distinct cell subpopulations and alterations in cell type composition. Immunohistochemistry and metabolic assessment were used to validate the findings from scRNA-seq and to investigate whether these cell-specific dysfunctions impact the neurovascular unit (NVU). Furthermore, the behavioural and cognitive alterations related to these dysfunctions in db/db mice were assessed via Morris water maze and novel object discrimination tests. Finally, results were validated in post-mortem sections and protein isolates from individuals with type 2 diabetes. RESULTS: Compared with non-diabetic control mice, the db/db mice demonstrated disrupted brain function as revealed by losses in episodic and spatial memory and this occurred concomitantly with dysfunctional NVU, neuronal circuitry and cerebral atrophy. scRNA-seq of db/db mouse cerebral cortex revealed cell population changes in neurons, glia and microglia linked to functional regulatory disruption including neuronal maturation and altered metabolism. These changes were validated through immunohistochemistry and protein expression analysis not just in the db/db mouse cerebral cortex but also in post-mortem sections and protein isolates from individuals with type 2 diabetes (74.3 ± 5.5 years) compared with non-diabetic control individuals (87.0 ± 8.5 years). Furthermore, metabolic and synaptic gene disruptions were evident in cortical NVU cell populations and associated with a decrease in vascular density. CONCLUSIONS/INTERPRETATION: Taken together, our data reveal disruption in the cellular and molecular architecture of the cerebral cortex induced by diabetes, which can explain, at least in part, the basis for progressive cognitive decline in individuals with type 2 diabetes. DATA AVAILABILITY: The single-cell sequencing data that supports this study are available at GEO accession GSE217665 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE217665 ).

Inflammation: The Link between Neural and Vascular Impairment in the Diabetic Retina and Therapeutic Implications.

The etiology of diabetic retinopathy (DR) is complex, multifactorial and compromises all the elements of the retinal neurovascular unit (NVU). This diabetic complication has a chronic low-grade inflammatory component involving multiple inflammatory mediators and adhesion molecules. The diabetic milieu promotes reactive gliosis, pro-inflammatory cytokine production and leukocyte recruitment, which contribute to the disruption of the blood retinal barrier. The understanding and the continuous research of the mechanisms behind the strong inflammatory component of the disease allows the design of new therapeutic strategies to address this unmet medical need. In this context, the aim of this review article is to recapitulate the latest research on the role of inflammation in DR and to discuss the efficacy of currently administered anti-inflammatory treatments and those still under development.

Switching from treatment with sensor augmented pump to hybrid closed loop system in type 1 diabetes: Impact on glycemic control and neuropsychological tests in the real world.

AIMS: The aim of this study is to assess in the real world the impact of initiating hybrid closed loop (HCL) on glycemic control and quality of life in patients using sensor-augmented pump (SAP). METHODS: In this prospective study, patients using SAP changed to an HCL system in a specialized hospital. HCL devices used were Medtronic 780G®, Tandem Control-IQ® and Diabeloop® system. Glucometric data and hypoglycemia and neuropsychological tests were assessed at baseline and 3 months after initiating HCL. RESULTS: A total of 66 consecutive patients were included (74% women, mean age 44 ± 11 years, diabetes duration 27.2 ± 11 years). Significant improvements were observed in coefficient of variation (from 35.6% to 33.1%), time in range (from 62.2 % to 73.8%), time above 180 mg/dl (from 26.9% to 18%), time below 70 mg/dl (from 3.3% to 2.1%) and time below 55 mg/dl (from 0.7% to 0.3%). In addition, significant improvements were observed in fear of hypoglycemia and grade of distress associated to treatment and to interpersonal sphere. CONCLUSIONS: Switching from SAP to HCL system improves time in range and reduces time in hypoglycemia and glycemic variability at 3 months. These changes are accompanied by significant reduction of neuropsychological burden related to diabetes.

Caffeine and the Risk of Diabetic Retinopathy in Type 2 Diabetes Mellitus: Findings from Clinical and Experimental Studies.

The aim of this study was to assess the potential benefits of caffeine intake in protecting against the development of diabetic retinopathy (DR) in subjects with type 2 diabetes (T2D). Furthermore, we tested the effect of topical administration of caffeine on the early stages of DR in an experimental model of DR. In the cross-sectional study, a total of 144 subjects with DR and 147 individuals without DR were assessed. DR was assessed by an experienced ophthalmologist. A validated food frequency questionnaire (FFQ) was administered. In the experimental model, a total of 20 mice were included. One drop (5 µL) of caffeine (5 mg/mL) (n = 10) or vehicle (5 µL PBS, pH 7.4) (n = 10) was randomly administered directly onto the superior corneal surface twice daily for two weeks in each eye. Glial activation and retinal vascular permeability were assessed using standard methods. In the cross-sectional study in humans, the adjusted-multivariable model showed that a moderate and high (Q2 and Q4) caffeine intake had a protective effect of DR (odds ratio (95% confidence interval) = 0.35 (0.16-0.78); p = 0.011 and 0.35 (0.16-0.77); p = 0.010, respectively). In the experimental model, the administration of caffeine did not improve either reactive gliosis or retinal vascular permeability. Our results suggest a dose-dependent protective effect of caffeine in the development of DR, while the potential benefits of antioxidants in coffee and tea should also be considered. Further research is needed to establish the benefits and mechanisms of caffeinated beverages in the development of DR.

Mortality in Acromegaly Diagnosed in Older Individuals in Spain Is Higher in Women Compared to the General Spanish Population.

CONTEXT: There are no data on mortality of acromegaly diagnosed in older individuals. OBJECTIVE: This work aimed to compare clinical characteristics, growth hormone-related comorbidities, therapeutic approaches, and mortality rate of patients diagnosed before or after 2010 and to assess overall mortality rate compared with the general Spanish population. METHODS: A retrospective evaluation was conducted among Spanish tertiary care centers of 118 patients diagnosed with acromegaly at age 65 or older. Kaplan-Meier curves were constructed to trace survival, and Cox proportional hazard models were used to assess the risk factors associated with mortality. We also compared mortality with that of the Spanish population by using age- and sex-adjusted standardized mortality ratios (SMRs). RESULTS: No differences were found in first-line treatment or biochemical control, between both periods except for faster biochemical control after 2010. Twenty-nine (24.6%) patients died, without differences between groups, and had a median of follow-up 8.6 years (103, [72.3] months). Overall SMR was 1.02 (95% CI, 0.57-1.54), (0.60; 95% CI, 0.35-1.06) for men and (1.80; 95% CI, 1.07-2.94) for women. The most common cause of death was cardiovascular disease (CVD). CONCLUSION: The mortality in patients with acromegaly diagnosed in older individuals was no different between both periods, and there was no overall SMR difference compared with the general Spanish population. However, the SMR was higher in women. As CVD is the leading cause of mortality, it seems advisable to initiate an intense CVD protective treatment as soon as acromegaly is diagnosed, particularly in women, in addition to tight acromegaly control to prevent excess mortality.