Integrative Clinical, Hormonal and Molecular Data associate with Invasiveness in Acromegaly: REMAH Study.

INTRODUCTION: Growth-hormone (GH)-secreting pituitary-tumors (GHomas) are the most common acromegaly cause. At diagnosis, most of them are macroadenomas, and up to 56% display cavernous sinus invasion. Biomarkers assessment associated with tumor-growth and invasion are important to optimize their management. OBJECTIVES: To identify clinical/hormonal/molecular-biomarkers associated with tumor-size and invasiveness in GHomas, and to analyze the influence of pre-treatment with somatostatin-analogs or dopamine-agonists in key molecular biomarkers expression. METHODS: Clinical/analytical/radiological-variables were evaluated in 192 patients from the REMAH-study (ambispective multicenter post-surgery study of the Spanish Society of Endocrinology and Nutrition). Expression of somatostatin/ghrelin/dopamine-systems components, and key pituitary/proliferation-markers were evaluated in GHomas after the first surgery. Univariate/multivariate regression studies were performed to identify association between variables. RESULTS: 80% of patients harbor macroadenomas (63.8% with extrasellar-growth). Associations between larger and more invasive GHomas with younger age, visual-abnormalities, higher IGF1-levels, extrasellar/suprasellar-growth and/or cavernous-sinus invasion were found. Higher GH1 and lower PRL/POMC/CGA/AVPR1B/DRD2T/DRD2L expression levels (p<0.05) were associated to tumor invasiveness. LASSO´s penalized regression identified combinations of clinical and molecular features with AUCs between 0.67-0.82. Preoperative therapy with dopamine-agonist or somatostatin-analogs did not alter the expression of any of the markers analyzed except for DRD1/AVPR1B (up-regulated with dopamine-agonist), and FSHB/CRHR1 (down-regulated with somatostatin-analogs). CONCLUSIONS: A specific combination of clinical/analytical/molecular variables was found to be associated with tumor invasiveness and growth capacity in GHomas. Pre-treatment with first-line drugs for acromegaly did not significantly modify the expression of the most relevant biomarkers in our association model. These findings provide valuable insights for risk stratification and personalized management of GHomas.

Are New Ultra-Rapid-Acting Insulins Associated with Improved Glycemic Control and Reduced Hypoglycemia in Comparison to Conventional Rapid-Acting Insulins for Individuals with Type 1 and Type 2 Diabetes? A Systematic Review and Meta-Analysis.

Introduction: This study aimed to compare efficacy and safety of ultra-rapid-acting insulin analogs (URAIs; faster aspart [FAsp], ultra-rapid lispro [URLi], and technosphere insulin [TI]) with rapid-acting insulin analogs (RAI) in individuals with type 1 (T1D) or type 2 diabetes (T2D). Methods: Searching for randomized control trial comparing the effects of URAI versus RAI that lasted at least 12 weeks, we initially selected 15 studies for analysis. Three studies involving TI were excluded due to a high degree of heterogeneity. The final meta-analysis included only 12 studies with either FAsp or URLi. Results: Mealtime URAI significantly reduced overall early 1 h postprandial glycemia in individuals with T1D (-20.230 mg/dL [95% confidence interval, 95% CI -24.040 to -16.421]; P < 0.001; I2 = 33.42%) and those with T2D (-9.138 mg/dL [95% CI -12.612 to -5.663]; P < 0.001; I2 = 0%). However, the significant reduction in 2 h postprandial glucose remained only in individuals with T1D (-17.620 mg/dL [95% CI -26.047 to -9.193]; P < 0.001; I2 = 65.88%). These benefits were lost when URAI was administered postmeal. At 24-26 weeks, there was no significant difference in HbA1c between groups, but at 52 weeks, a slight reduction in HbA1c with mealtime URAI was observed (-0.080% [95% CI -0.147 to -0.013]; P = 0.019; I2 = 0%). No difference in weight or the rate of severe or confirmed hypoglycemia was observed. Only individuals with T1D showed a small, but significant increase in early 1-h hypoglycemia with URAI (1.468 [95% CI 1.235 to 1.747]; P < 0.001; I2 = 0%). Conclusion: Mealtime URAI improves 1 and 2 h postprandial glycemic control compared to RAI without increasing hypoglycemia or weight gain.

Semaglutide modulates prothrombotic and atherosclerotic mechanisms, associated with epicardial fat, neutrophils and endothelial cells network.

BACKGROUND: Obesity has increased in recent years with consequences on diabetes and other comorbidities. Thus, 1 out of 3 diabetic patients suffers cardiovascular disease (CVD). The network among glucose, immune system, endothelium and epicardial fat has an important role on pro-inflammatory and thrombotic mechanisms of atherogenesis. Since semaglutide, long-acting glucagon like peptide 1- receptor agonist (GLP-1-RA), a glucose-lowering drug, reduces body weight, we aimed to study its effects on human epicardial fat (EAT), aortic endothelial cells and neutrophils as atherogenesis involved-cardiovascular cells. METHODS: EAT and subcutaneous fat (SAT) were collected from patients undergoing cardiac surgery. Differential glucose consumption and protein cargo of fat-released exosomes, after semaglutide or/and insulin treatment were analyzed by enzymatic and TripleTOF, respectively. Human neutrophils phenotype and their adhesion to aortic endothelial cells (HAEC) or angiogenesis were analyzed by flow cytometry and functional fluorescence analysis. Immune cells and plasma protein markers were determined by flow cytometry and Luminex-multiplex on patients before and after 6 months treatment with semaglutide. RESULTS: GLP-1 receptor was expressed on fat and neutrophils. Differential exosomes-protein cargo was identified on EAT explants after semaglutide treatment. This drug increased secretion of gelsolin, antithrombotic protein, by EAT, modulated CD11b on neutrophils, its migration and endothelial adhesion, induced by adiposity protein, FABP4, or a chemoattractant. Monocytes and neutrophils phenotype and plasma adiposity, stretch, mesothelial, fibrotic, and inflammatory markers on patients underwent semaglutide treatment for 6 months showed a 20% reduction with statistical significance on FABP4 levels and an 80% increase of neutrophils-CD88. CONCLUSION: Semaglutide increases endocrine activity of epicardial fat with antithrombotic properties. Moreover, this drug modulates the pro-inflammatory and atherogenic profile induced by the adiposity marker, FABP4, which is also reduced in patients after semaglutide treatment.

Revisiting the usefulness of the short acute octreotide test to predict treatment outcomes in acromegaly.

Introduction: We previously described that a short version of the acute octreotide test (sAOT) can predict the response to first-generation somatostatin receptor ligands (SRLs) in patients with acromegaly. We have prospectively reassessed the sAOT in patients from the ACROFAST study using current ultra-sensitive GH assays. We also studied the correlation of sAOT with tumor expression of E-cadherin and somatostatin receptor 2 (SSTR2) . Methods: A total of 47 patients treated with SRLs for 6 months were evaluated with the sAOT at diagnosis and correlated with SRLs' response. Those patients whose IGF1 decreased to <3SDS from normal value were considered responders and those whose IGF1 was ≥3SDS, were considered non-responders. The 2 hours GH value (GH2h) after s.c. administration of 100 mcg of octreotide was used to define predictive cutoffs. E-cadherin and SSTR2 immunostaining in somatotropinoma tissue were investigated in 24/47 and 18/47 patients, respectively. Results: In all, 30 patients were responders and 17 were non-responders. GH2h was 0.68 (0.25-1.98) ng/mL in responders vs 2.35 (1.59-9.37) ng/mL in non-responders (p<0.001). GH2h = 1.4ng/mL showed the highest ability to identify responders (accuracy of 81%, sensitivity of 73.3%, and specificity of 94.1%). GH2h = 4.3ng/mL was the best cutoff for non-response prediction (accuracy of 74%, sensitivity of 35.3%, and specificity of 96.7%). Patients with E-cadherin-positive tumors showed a lower GH2h than those with E-cadherin-negative tumors [0.9 (0.3-2.1) vs 3.3 (1.5-12.1) ng/mL; p<0.01], and patients with positive E-cadherin presented a higher score of SSTR2 (7.5 ± 4.2 vs 3.3 ± 2.1; p=0.01). Conclusion: The sAOT is a good predictor tool for assessing response to SRLs and correlates with tumor E-cadherin and SSTR2 expression. Thus, it can be useful in clinical practice for therapeutic decision-making in patients with acromegaly.

Hypopituitarism after traumatic brain injury in adults: Clinical guidelines of the neuroendocrinology area of the Spanish Society of Endocrinology and Nutrition (SEEN).

Traumatic brain injury (TBI) is associated with hypopituitarism with a variable incidence, depending on the time and methods used to diagnosis, and on factors related to the trauma, such as its severity, its anatomical location and the drugs used in the acute phase. The pituitary gland can be damaged directly by the impact or secondary to factors such as ischemia, inflammation, excitotoxicity or immunity. In acute phases ACTH deficiency is the most relevant, since failure to detect and treat it can compromise the patient's life. Clinical manifestations are typical of each hormone deficient axes, although the combination hypopituitarism-trauma has been associated with cognitive deterioration, worse metabolic profile and greater impairment of quality of life. One of the clinical challenges is to determine which patients benefit from a systematic hormonal evaluation, and therefore from hormone replacement, and what is the appropriate time to do so and the most suitable diagnostic methods.

Should we suspect primary aldosteronism in patients with hypokalaemic rhabdomyolysis? A systematic review.

Severe hypokalaemia causing rhabdomyolysis (RML) in primary aldosteronism (PA) is a rare entity, and only a few cases have been reported over the last four decades. This systematic review and case report aims to gather all published data regarding a hypokalaemic RML as presentation of PA in order to contribute to the early diagnosis of this extremely rare presentation. With the use of PubMed Central, EMBASE, and Google Scholar, a thorough internet-based search of the literature was conducted to identify articles and cases with RML secondary to hypokalaemia due to PA between June 1976 and July 2023. The case study concerns a 68-year-old male patient with hypokalaemic RML at presentation of PA. In the systematic review of the literature, 37 cases of RML secondary to hypokalaemia due to PA have been reported to date. In summary, the median age was 47.5 years, the male/female ratio was 17/21, all patients presented symptoms (weakness and/or myalgia), all the patients were hypertensive, and only four patients had complications with acute kidney injury (AKI). Although PA rarely presents with RML, it should be suspected when marked hypokalaemia and hypertension are also present. Early detection and management are essential to reduce the frequency of manifestations such as AKI.

Diagnosis and Management of Malnutrition in Patients with Heart Failure.

Heart failure is a disease with an increasingly greater prevalence due to the aging population, the development of new drugs, and the organization of healthcare processes. Malnutrition has been identified as a poor prognostic factor in these patients, very often linked to frailty or to other comorbidities, meaning that early diagnosis and treatment are essential. This paper reviews some important aspects of the pathophysiology, detection, and management of malnutrition in patients with heart failure.

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.

GALIPDIA study: Reaching lipid targets in a population with type 2 diabetes (T2DM) from the Northwest of Spain.

AIM: To assess the degree of compliance with the European ESC/EAS 2016 and 2019 dyslipidaemia guidelines in patients with type 2 diabetes mellitus (T2DM). METHODS: Multicentre retrospective cross-sectional study, conducted in 380 adults with T2DM and dyslipidaemia in 7 Spanish health areas. INCLUSION CRITERIA: minimum follow-up of one year in Endocrinology Units, at least one visit in 2020 and a lipid profile measurement in the last 3 months. EXCLUSION CRITERIA: familial hypercholesterolaemia, recent hospitalisation, active oncological pathology and dialysis. RESULTS: According to the 2016 and 2019 guidelines the majority of patients were classified as being at very high cardiovascular risk (86.8% vs. 72.1%, respectively). LDL-c compliance was adequate in 62.1% of patients according to the 2016 guidelines and 39.7% according to the 2019 guidelines (p<0.001). Clinical conditions such as history of cardiovascular disease and therapy-related aspects (use of statins, especially high-potency statins, combination therapies and good adherence) were significantly associated with greater achievement of lipid targets. CONCLUSION: There is a discrepancy between dyslipidaemia guideline recommendations and the reality of lipid control in patients with T2DM, despite most of these patients being at very high cardiovascular risk. Strategies to optimise lipid-lowering treatments need to be implemented.

Gestational weight gain influences neonatal outcomes in women with obesity and gestational diabetes.

INTRODUCTION: Obesity and gestational diabetes mellitus (GDM) are associated with an increased risk of perinatal complications and obesity in the offspring. However, the impact of gestational weight gain (GWG) on maternal and foetal outcomes is controversial. PATIENTS AND METHODS: Retrospective study of 220 women with GDM and pre-pregnancy body mass index (BMI)>30kg/m2. Pregnant women were classified according to the Institute of Medicine (IOM) recommendations regarding their prior BMI and GWG. We evaluated the impact of GWG on perinatal and obstetric outcomes. RESULTS: Mean maternal age was 34.7±5.3 years. Pre-pregnancy obesity was classified as class I in 55.3% of the cases, class II in 32.0% and class III in 12.7%. GWG was adequate (5-9kg) in 24.2%, insufficient (<5kg) in 41.8% and excessive (>9kg) in 34.2%. Birth weight was within normal range in 81.9%, 3.6% were small for gestational age (microsomia) and 14.4% were large for gestational age (macrosomia). Insufficient GWG was associated with a higher rate of microsomal offspring, excessive GWG was associated to macrosomia and adequate GWG with normal birth weight. CONCLUSION: GWG in women with pre-pregnancy obesity and GDM impacts neonatal birthweight. Insufficient GWG is associated with microsomia and excessive GWG is associated with macrosomia. Women with adequate GWG according to the IOM guidelines obtained better perinatal outcomes.

Factors associated with therapeutic response in acromegaly diagnosed in the elderly in Spain.

Context: Some reports suggest that acromegaly in elderly patients has a more benign clinical behavior and could have a better response to first-generation long-acting somatostatin receptor ligands (SRL). However, there is no specific therapeutic protocol for this special subgroup of patients. Objective: This study aimed at identifying predictors of response to SRL in elderly patients. Design: Multicentric retrospective nationwide study of patients diagnosed with acromegaly at or over the age of 65 years. Results: One-hundred and eighteen patients (34 men, 84 women, mean age at diagnosis 71.7 ± 5.4 years old) were included. Basal insulin-like growth factor type 1 (IGF-1) above the upper limit of normal (ULN) and growth hormone (GH) levels (mean ± SD) were 2.7 ± 1.4 and 11.0 ± 11.9 ng/ml, respectively. The mean maximal tumor diameter was 12.3 ± 6.4 mm, and up to 68.6% were macroadenoma. Seventy-two out of 118 patients (61.0%) underwent surgery as primary treatment. One-third of patients required first-line medical treatment due to a rejection of surgical treatment or non-suitability because of high surgical risk. After first-line surgery, 45/72 (63.9%) were in disease remission, and 16/34 (46.7%) of those treated with SRL had controlled disease. Patients with basal GH at diagnosis ≤6 ng/ml had lower IGF-1 levels and had smaller tumors, and more patients in this group reached control with SRL (72.7% vs. 33.3%; p < 0.04) [OR: 21.3, IC: 95% (2.4-91.1)], while male patients had a worse response [OR: 0.09, IC 95% (0.01-0.75)]. The predictive model curve obtained for SRL response showed an AUC of 0.82 CI (0.71-0.94). Conclusions: The most frequent phenotype in newly diagnosed acromegaly in the elderly includes small adenomas and moderately high IGF-1 levels. GH at diagnosis ≤6 ng/ml and female gender, but not age per se, were associated with a greater chance of response to SRL.

Pituitary MRI Features in Acromegaly Resulting From Ectopic GHRH Secretion From a Neuroendocrine Tumor: Analysis of 30 Cases.

CONTEXT: Ectopic acromegaly is a consequence of rare neuroendocrine tumors (NETs) that secrete GHRH. This abnormal GHRH secretion drives GH and IGF-1 excess, with a clinical presentation similar to classical pituitary acromegaly. Identifying the underlying cause for the GH hypersecretion in the setting of ectopic GHRH excess is, however, essential for proper management both of acromegaly and the NET. Owing to the rarity of NETs, the imaging characteristics of the pituitary in ectopic acromegaly have not been analyzed in depth in a large series. OBJECTIVE: Characterize pituitary magnetic resonance imaging (MRI) features at baseline and after NET treatment in patients with ectopic acromegaly. DESIGN: Multicenter, international, retrospective. SETTING: Tertiary referral pituitary centers. PATIENTS: Thirty ectopic acromegaly patients having GHRH hypersecretion. INTERVENTION: None. MAIN OUTCOME MEASURE: MRI characteristics of pituitary gland, particularly T2-weighted signal. RESULTS: In 30 patients with ectopic GHRH-induced acromegaly, we found that most patients had hyperplastic pituitaries. Hyperplasia was usually moderate but was occasionally subtle, with only small volume increases compared with normal ranges for age and sex. T2-weighted signal was hypointense in most patients, especially in those with hyperplastic pituitaries. After treatment of the NET, pituitary size diminished and T2-weighted signal tended to normalize. CONCLUSIONS: This comprehensive study of pituitary MRI characteristics in ectopic acromegaly underlines the utility of performing T2-weighted sequences in the MRI evaluation of patients with acromegaly as an additional tool that can help to establish the correct diagnosis.

Factores predictores de formas graves de COVID-19 que requieren hospitalización en pacientes con diabetes mellitus / Predictor factors of severe forms of COVID-19 requiring hospitalisation in patients with diabetes mellitus

Aims: To identify possible risk factors of hospitalisation in patients with diabetes (DM) and 2019 novel coronavirus disease (COVID-19), to establish the prevalence of DM among infected patients and that of DM in patients requiring hospitalisation. Research design and methods: Between March-May 2020, 1202 consecutive subjects in the healthcare area of Santiago de Compostela and Barbanza (Galicia, Spain) were diagnosed with COVID- 19, among whom 136 patients with DM were identified. Demographic data, DM characteristics and complications during hospitalisation were collected and analysed. Results: The prevalence of DM among COVID-19 infected subjects was 11.3%. This ascended to 21.7% in inpatients, while only 8.1% of outpatients had DM (p<0.0001). Higher levels of glycated haemoglobin significantly increased the risk of hospitalisation (OR: 1.57; 95% CI: 1.03-2.41, p=0.037), with small differences making the difference between inpatients and outpatients (7.3 ± 1.3% vs 6.8 ± 0.9% [56 ± 14 vs 51 ± 10 mmol/mol], respectively, p=0.009). Obesity (BMI ≥ 30 kg/m2) was the only comorbidity associated to hospitalization (OR: 2.94; 95% CI: 1.17-7.30, p=0.021). There were no differences in the type and duration of DM, the type of glucose-lowering drugs, or in the presence of micro/macrovascular complications. Conclusion: DM does not increase the risk of suffering from COVID-19, but it can worsen the outcome, raising the hospitalisation rate. Thus, obesity and worse chronic glycaemic control, even with small variations, are independent and determining factors for severe forms which require hospitalisation. (AU)

Time-in-range for monitoring glucose control: Is it time for a change?

The HbA1c value has been the gold standard for evaluating glucose control for decades. However, it has limitations such as the lack of information on glycemic variability or the risk of hypoglycemia. The increasing use of continuous glucose monitoring has provided patients and healthcare professionals with a range of useful metrics for the management of diabetes. Among them, Time in Range (TIR) is a simple and intuitive metric that gives information regarding the quality of glucose control. It is defined as the time spent in an individual's target glucose range. TIR is strongly correlated with HbA1c, and it has been linked to the risk of developing microvascular and macrovascular complications. The International Consensus on Time in Range has recently set targets for different diabetes populations. For the majority of people with type 1 or type 2 diabetes, a TIR (70-180 mg/dL or 3.9-10.0 mmol/L) of >70%, a time below range (TBR) <70 mg/dL (<3.9 mmol/L) of <4% and a TBR <54 (<3.0 mmol/L) of <1% are recommended. In this review, we address the latest evidence for the use of TIR as an essential parameter in the management of diabetes.

Craniopharyngioma in the Elderly: A Multicenter and Nationwide Study in Spain.

BACKGROUND: Craniopharyngioma (CP) is a rare tumor in the elderly whose clinical features and prognosis are not well known in this population. AIM: To evaluate the clinicopathological features and therapeutic outcomes of CP diagnosed in the elderly. PATIENTS AND METHODS: This was a retrospective, multicenter, national study of CP patients diagnosed over the age of 65 years and surgically treated. RESULTS: From a total of 384 adult CP patients, we selected 53 (13.8%) patients (27 women [50.9%], mean age 72.3 ± 5.1 years [range 65-83 years]) diagnosed after the age of 65 years. The most common clinical symptoms were visual field defects (71.2%) followed by headache (45.3%). The maximum tumor diameter was 2.9 ± 1.1 cm. In most patients, the tumor was suprasellar (96.2%) and mixed (solid-cystic) (58.5%). The surgical approach most commonly used was transcranial surgery (52.8%), and more than half of the patients (54.7%) underwent subtotal resection (STR). Adamantinomatous CP and papillary CP were present in 51 and 45.1%, respectively, with mixed forms in the remaining. Surgery was accompanied by an improvement in visual field defects and in headaches; however, pituitary hormonal hypofunction increased, mainly at the expense of an increase in the prevalence of diabetes insipidus (DI) (from 3.9 to 69.2%). Near-total resection (NTR) was associated with a higher prevalence of DI compared with subtotal resection (87.5 vs. 53.6%, p = 0.008). Patients were followed for 46.7 ± 40.8 months. The mortality rate was 39.6% with a median survival time of 88 (95% CI: 57-118) months. DI at last visit was associated with a lower survival. CONCLUSION: CP diagnosed in the elderly shows a similar distribution by sex and histologic forms than that diagnosed at younger ages. At presentation, visual field alterations and headaches are the main clinical symptoms which improve substantially with surgery. However, surgery, mainly NTR, is accompanied by worsening of pituitary function, especially DI, which seems to be a predictor of mortality in this population.

LipoDDx: a mobile application for identification of rare lipodystrophy syndromes.

BACKGROUND: Lipodystrophy syndromes are a group of disorders characterized by a loss of adipose tissue once other situations of nutritional deprivation or exacerbated catabolism have been ruled out. With the exception of the HIV-associated lipodystrophy, they have a very low prevalence, which together with their large phenotypic heterogeneity makes their identification difficult, even for endocrinologists and pediatricians. This leads to significant delays in diagnosis or even to misdiagnosis. Our group has developed an algorithm that identifies the more than 40 rare lipodystrophy subtypes described to date. This algorithm has been implemented in a free mobile application, LipoDDx®. Our aim was to establish the effectiveness of LipoDDx®. Forty clinical records of patients with a diagnosis of certainty of most lipodystrophy subtypes were analyzed, including subjects without lipodystrophy. The medical records, blinded for diagnosis, were evaluated by 13 physicians, 1 biochemist and 1 dentist. Each evaluator first gave his/her results based on his/her own criteria. Then, a second diagnosis was given using LipoDDx®. The results were analysed based on a score table according to the complexity of each case and the prevalence of the disease. RESULTS: LipoDDx® provides a user-friendly environment, based on usually dichotomous questions or choice of clinical signs from drop-down menus. The final result provided by this app for a particular case can be a low/high probability of suffering a particular lipodystrophy subtype. Without using LipoDDx® the success rate was 17 ± 20%, while with LipoDDx® the success rate was 79 ± 20% (p < 0.01). CONCLUSIONS: LipoDDx® is a free app that enables the identification of subtypes of rare lipodystrophies, which in this small cohort has around 80% effectiveness, which will be of help to doctors who are not experts in this field. However, it will be necessary to analyze more cases in order to obtain a more accurate efficiency value.

GLP1 Receptor Agonist and SGLT2 Inhibitor Combination: An Effective Approach in Real-world Clinical Practice.

PURPOSE: The aim of this study was to evaluate the effectiveness and safety of combination therapy with a sodium-glucose cotransporter-2 (SGLT2) inhibitor and a glucagon-like peptide-1 receptor agonist (GLP1RA) in patients with inadequately controlled type 2 diabetes. METHODS: A retrospective search of electronic prescriptions of patients undergoing GLP1RA and SGLT2 inhibitor combination therapy was conducted. Once the patients had been identified, demographic data, blood and urine analyses (glycosylated hemoglobin [HbA1c], glucose, renal function, albuminuria, lipid profile, liver enzymes, and uric acid), physical examination (weight, body mass index, and blood pressure), and adverse effects were obtained from their electronic clinical records according to each of the following 3 periods: before the initiation of the combination, the first visit after initiation, and the last available visit. The influence of the duration of diabetes and the drug combination sequence on the effectiveness of the treatment was also analyzed. Statistical analysis was performed with SPSS version 21.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York). Quantitative variables are presented as mean and SD and were compared by using the Student t test, one-way ANOVA, or repeated measures ANOVA with Bonferroni correction. Categorical variables are expressed as percentages and were compared by using the χ2 test. RESULTS: A total of 212 patients were included, with women accounting for 52.4%. The mean age (SD) of the population was 61.5 (9.6) years. A significant reduction in HbA1c (-12 mmol/mol [-1.1%]) was observed with combined therapy (P < 0.001). The target of HbA1c <53 mmol/mol (<7%) was achieved in 42% of the participants. Mean weight loss was -3.5 kg, and almost 40% of the patients attained the weight loss goal of ≥5% (P < 0.001 in all analyses). Transaminase levels and renal parameters also improved. These benefits persisted over time and bore no relation to the evolution of diabetes. Simultaneous initiation of a combination of a GLP1RA and SGLT2 inhibitor led to faster weight loss and a greater decrease in HbA1c than when they are used sequentially; however, the long-term benefits in terms of metabolic control were similar. Adverse events were rare, and a tendency for a reduced insulin dose was observed. IMPLICATIONS: The findings of this study reveal the combined benefits of a GLP1RA and SGLT2 inhibitor in real-world clinical practice. In general, the combined treatment was well tolerated, and few adverse events were detected.

Experiencia clínica con distintas dosis iniciales de tolvaptán en SIADH / Clinical experience with different initial doses of tolvaptan in SIADH

No disponible

Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegaly.

BACKGROUND: Acromegaly is produced by excess growth hormone secreted by a pituitary adenoma of somatotroph cells (ACRO). First-line therapy, surgery and adjuvant therapy with somatostatin analogs, fails in 25% of patients. There is no predictive factor of resistance to therapy. New therapies are investigated using few dispersed tumor cells in acute primary cultures in standard conditions where the cells do not grow, or using rat pituitary cell lines that do not maintain the full somatotroph phenotype. The RET/PIT1/p14ARF/p53 pathway regulates apoptosis in normal pituitary somatotrophs whereas the RET/GDNF pathway regulates survival, controlling PIT1 levels and blocking p14ARF (ARF) and p53 expression. METHODS: We investigated these two RET pathways in a prospective series of 32 ACRO and 63 non-functioning pituitary adenomas (NFPA), studying quantitative RNA and protein gene expression for molecular-clinical correlations and how the RET pathway might be implicated in therapeutic success. Clinical data was collected during post-surgical follow-up. We also established new'humanized' pituitary cultures, allowing 20 repeated passages and maintaining the pituitary secretory phenotype, and tested five multikinase inhibitors (TKI: Vandetanib, Lenvatinib, Sunitinib, Cabozantinib and Sorafenib) potentially able to act on the GDNF-induced RET dimerization/survival pathway. Antibody arrays investigated intracellular molecular pathways. FINDINGS: In ACRO, there was specific enrichment of all genes in both RET pathways, especially GDNF. ARF and GFRA4 gene expression were found to be opposing predictors of response to first-line therapy. ARF cut-off levels, calculated categorizing by GNAS mutation, were predictive of good response (above) or resistance (below) to therapy months later. Sorafenib, through AMPK, blocked the GDNF/AKT survival action without altering the RET apoptotic pathway. INTERPRETATION: Tumor ARF mRNA expression measured at the time of the surgery is a prognosis factor in acromegaly. The RET inhibitor, Sorafenib, is proposed as a potential treatment for resistant ACRO. FUND: This project was supported by national grants from Agencia Estatal de Investigación (AEI) and Instituto Investigación Carlos III, with participation of European FEDER funds, to IB (PI150056) and CVA (BFU2016-76973-R). It was also supported initially by a grant from the Investigator Initiated Research (IIR) Program (WI177773) and by a non-restricted Research Grant from Pfizer Foundation to IB. Some of the pituitary acromegaly samples were collected in the framework of the Spanish National Registry of Acromegaly (REMAH), partially supported by an unrestricted grant from Novartis to the Spanish Endocrine Association (SEEN). CVA is also supported from a grant of Medical Research Council UK MR/M018539/1.