Impact of CFTR modulator therapy on body composition as assessed by thoracic computed tomography: A follow-up study.

OBJECTIVE: Treatment with cystic fibrosis transmembrane conductance regulator (CFTR) modulators in individuals with cystic fibrosis (CF) has brought a significant change in forced expiratory volume in 1 second (FEV1) and clinical parameters. However, it also results in weight gain. The aim of our study is to evaluate the effect of CFTR modulator treatment on body composition, measured by computed tomography (CT). METHODS: Adult subjects with CF under follow-up at La Princesa University Hospital were recruited. All of them were on elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA) treatment. Body composition analysis was conducted using CT scans and an open-source software. The results were then compared with bioimpedance estimations, as well as other clinical and spirometry data. RESULTS: Our sample consisted of 26 adult subjects. The fat mass compartments on CT scans correlated with similar compartments on bioimpedance, and normal-density muscle mass exhibited a strong correlation with phase angle. Higher levels of very low-density muscle prior to treatment were associated with lower final FEV1 and less improvement in FEV1 after therapy. We observed an increase in total body area (P < 0.001), driven by increases in total fat mass (P < 0.001), subcutaneous fat (P < 0.001), visceral fat (P = 0.002), and intermuscular fat (P = 0.022). The only muscle compartment that showed an increase after treatment was very low-density muscle (P = 0.032). CONCLUSIONS: CT scans represent an opportunity to assess body composition on CF. Combination treatment with CFTR modulators, leads to an improvement in FEV1 and to an increase in body mass in all compartments primarily at the expense of fat mass.

Impact of socioeconomic status on chronic control and complications of type 1 diabetes mellitus in users of glucose flash systems: a follow-up study.

BACKGROUND: This study investigates the association between socioeconomic status (SES) and glycemic control in individuals with type 1 diabetes (T1D) using flash glucose monitoring (FGM) devices within a public health system where these technologies are freely available and utilized according to recommended guidelines. METHODS: A follow-up study of 1060 adults (mean age 47.4 ± 15.0 years, 49.0% women) with T1D, receiving care at three Spanish university hospitals that regularly employ the FGM system. SES was assessed using the Spanish Deprivation Index and the average annual net income per person. Glycemic data were collected over a 14-day follow-up period, including baseline glycated hemoglobin (HbA1c) levels prior to sensor placement, the last available HbA1c levels, and FGM-derived glucose metrics. Individuals with sensor usage time < 70% were excluded. Chronic micro and macrovascular complications related to diabetes were documented. Regression models, adjusted for clinical variables, were employed to determine the impact of SES on optimal sensor control (defined as time in range (TIR) ≥ 70% with time below range < 4%) and disease complications. RESULTS: The average follow-up was of 2 years. The mean TIR and the percentage of individuals with optimal control were higher in individuals in the highest SES quartile (64.9% ± 17.8% and 27.9%, respectively) compared to those in the lowest SES quartile (57.8 ± 17.4% and 12.1%) (p < 0.001). Regression models showed a higher risk of suboptimal control (OR 2.27, p < 0.001) and ischemic heart disease and/or stroke (OR 3.59, p = 0.005) in the lowest SES quartile. No association was observed between SES and the risk of diabetic nephropathy and retinopathy. FGM system improved HbA1c levels across all SES quartiles. Although individuals in the highest SES quartile still achieved a significantly lower value at the end of the follow-up 55 mmol/mol (7.2%) compared to those in the lowest SES quartile 60 mmol/mol (7.6%) (p < 0.001), the significant disparities in this parameter between the various SES groups were significantly reduced after FGM technology use. CONCLUSIONS: Socioeconomic status plays a significant role in glycemic control and complications in individuals with T1D, extending beyond access to technology and its proper utilization. The free utilization of FGM technology helps alleviate the impact of social inequalities on glycemic control.

Renin as a Biomarker to Guide Medical Treatment in Primary Aldosteronism Patients. Findings from the SPAIN-ALDO Registry.

INTRODUCTION: Primary aldosteronism (PA) is associated with several cardiometabolic comorbidities. Specific treatment by mineralocorticoid receptor antagonists (MRA) or adrenalectomy has been reported to reduce the cardiometabolic risk. However, the cardiovascular benefit could depend on plasma renin levels in patients on MRA. AIM: To compare the development of cardiovascular, renal and metabolic complications between medically treated patients with PA and those who underwent adrenalectomy, taking the renin status during MRA treatment into account. METHODS: A multicenter retrospective study (SPAIN-ALDO Register) of patients with PA treated at 35 Spanish tertiary hospitals. Patients on MRA were divided into two groups based on renin suppression (n = 90) or non-suppression (n = 70). Both groups were also compared to unilateral PA patients (n = 275) who achieved biochemical cure with adrenalectomy. RESULTS: Adrenalectomized patients were younger, had higher plasma aldosterone concentration, and lower potassium levels than MRA group. Patients on MRA had similar baseline characteristics when stratified into treatment groups with suppressed and unsuppressed renin. 97 (55.1%) of 176 patients without comorbidities at diagnosis, developed at least one comorbidity during follow-up (median 12 months vs. 12.5 months' follow-up after starting MRA and surgery, respectively). Surgery group had a lower risk of developing new cardiovascular events (HR 0.40 [95% CI 0.18-0.90]) than MRA group. Surgical treatment improved glycemic and blood pressure control, increased serum potassium levels, and required fewer antihypertensive drugs than medical treatment. However, there were no differences in the cardiometabolic profile or the incidence of new comorbidities between the groups with suppressed and unsuppressed renin levels (HR 0.95 [95% CI 0.52-1.73]). CONCLUSION: Cardiovascular, renal, and metabolic events were comparable in MRA patients with unsuppressed and suppressed renin. Effective surgical treatment of PA was associated with a decreased incidence of new cardiovascular events when compared to MRA therapy.

Scans per day as predictors of optimal glycemic control in people with type 1 diabetes mellitus using flash glucose monitoring: what number of scans per day should raise a red flag?

AIMS: This study aimed to determine the minimum frequency of flash glucose monitoring (FGM) scans necessary for optimal glycemic control in patients with type 1 diabetes (T1D). METHODS: Data were collected from 692 patients (47.5% female, with a median age of 47.4 years) who used FGM systems daily and recorded their clinical variables and device data. RESULTS: Logistic regression models showed that performing more than 12 scans per day was associated with improved T1D control (OR = 4.22, p < 0.001) and a reduction in HbA1c (7.6 vs 7.0%, 60-53 mmol/mol p < 0.001). However, those performing less than 6 scans showed no improvement in HbA1c (7.9 vs 7.8%, 63-61 mmol/mol p = 0.514). Thirteen daily scans were determined as the optimal cutoff point for predicting optimal glycemic control using a maximally selected rank algorithm. Significant reductions were observed in mean glucose (< 0.001), coefficient of variation (< 0.001), HbA1c (< 0.001), and an increase in TIR (< 0.001) in patients who performed more than 12 daily scans. CONCLUSIONS: The results suggest that a higher frequency of daily scans by T1D patients using FGM systems leads to improved chronic glycemic control. The minimum recommended frequency for optimal control is 13 scans per day, and more than 6 daily scans are needed to improve HbA1c.

Is adrenal venous sampling always necessary to differentiate between unilateral and bilateral primary aldosteronism? Lesson from the SPAIN-ALDO register.

PURPOSE: To evaluate whether the clinical, biochemical and radiological features of patients with primary aldosteronism (PA) can predict both main subtypes of PA. METHODS: A retrospective multicenter study of PA patients followed in 27 Spanish tertiary hospitals (SPAIN-ALDO Register). Only patients with confirmed unilateral or bilateral PA based on adrenal venous sampling (AVS) and/or postsurgical biochemical cure after adrenalectomy were included. Supervised regression techniques were used for model development. RESULTS: 328 patients [270 unilateral PA (UPA), 58 bilateral PA (BPA)] were included. The area under the curve (AUC) for aldosterone/potassium ratio and aldosterone responses following saline infusion test were 0.602 [95%CI 0.520 to 0.684] and 0.574 [95% CI 0.446-0.701], respectively, to differentiate UPA from BPA. The AUC was 0.825 [95% 0.764-0.886] when the prediction model with seven parameters - comorbidities (dyslipidemia, cerebrovascular disease, sleep apnea syndrome [SAS]), systolic blood pressure (SBP), plasma aldosterone levels (PAC), hypokalemia and unilateral adrenal nodule >1 cm and normal contralateral adrenal gland on CT/MRI - was used. In patients without comorbidities, hypokalemia, SBP > 160 mmHg, PAC > 40 ng/dL, and unilateral adrenal lesions were associated with a likelihood of having a UPA of 98.5%. The chance of BPA was higher in individuals with comorbidities, SBP < 140 mmHg, normokalemia, low PAC levels, and no adrenal tumors on the CT/MRI (91.5%). CONCLUSION: A combination of high PAC, SBP > 160 mmHg, low serum potassium, a unilateral adrenal nodule>1 cm and no comorbidities could predict a UPA with a 98.5% accuracy.

Autonomous cortisol secretion in patients with primary aldosteronism: prevalence and implications on cardiometabolic profile and on surgical outcomes.

Purpose: The aim of this study was to evaluate the prevalence of autonomous cortisol secretion (ACS) in patients with primary aldosteronism (PA) and its implications on cardiometabolic and surgical outcomes. Methods: This is a retrospective multicenter study of PA patients who underwent 1 mg dexamethasone-suppression test (DST) during diagnostic workup in 21 Spanish tertiary hospitals. ACS was defined as a cortisol post-DST >1.8 µg/dL (confirmed ACS if >5 µg/dL and possible ACS if 1.8-5 µg/dL) in the absence of specific clinical features of hypercortisolism. The cardiometabolic profile was compared with a control group with ACS without PA (ACS group) matched for age and DST levels. Results: The prevalence of ACS in the global cohort of patients with PA (n = 176) was 29% (ACS-PA; n = 51). Ten patients had confirmed ACS and 41 possible ACS. The cardiometabolic profile of ACS-PA and PA-only patients was similar, except for older age and larger tumor size of the adrenal lesion in the ACS-PA group. When comparing the ACS-PA group (n = 51) and the ACS group (n = 78), the prevalence of hypertension (OR 7.7 (2.64-22.32)) and cardiovascular events (OR 5.0 (2.29-11.07)) was higher in ACS-PA patients than in ACS patients. The coexistence of ACS in patients with PA did not affect the surgical outcomes, the proportion of biochemical cure and clinical cure being similar between ACS-PA and PA-only groups. Conclusion: Co-secretion of cortisol and aldosterone affects almost one-third of patients with PA. Its occurrence is more frequent in patients with larger tumors and advanced age. However, the cardiometabolic and surgical outcomes of patients with ACS-PA and PA-only are similar.

Continuous Glucose Monitoring as an Additional Tool in Early Cystic Fibrosis-Related Diabetes Monitoring and in Evaluation of Short-Term Sitagliptin Response.

Cystic fibrosis-related diabetes (CFRD) is a complication associated with a negative prognosis in patients with cystic fibrosis (CF). Although the oral glucose tolerance test (OGTT) is the widely recommended screening test for CFRD diagnosis, continuous glucose monitoring (CGM) is increasingly considered a useful and easy-to-perform test for diagnosis and follow-up in clinical practice. Regarding CFRD treatment, although insulin is the classic approved pharmacological option, incretins could also be a helpful alternative in early stages. CGM could be also a useful tool to measure the early response to this therapy. METHODS: We studied 25 CF patients with abnormal OGTT results and compared glucose and insulin levels during the OGTTs with CGM results as a tool for early CFRD diagnosis. In addition, we evaluated glycaemic control with CGM before and after treatment with sitagliptin. RESULTS: A correlation was found between lower plasma insulin levels during the OGTTs and higher average sensor glucose (p = 0.009) and hyperglycaemic excursions (p = 0.017). The CGM data on sitagliptin treatment (n = 25) showed an average glycaemic improvement from 124.2 to 117.2 mg/dL (p = 0.002) with a 5.6-point standard deviation of glucose decrease (p < 0.001). Hyperglycaemic excursions ≥200 mg/dL diminished 57.1% (p = 0.021). Both time in range and time above 180 mg/dL improved during treatment (p = 0.036 and p = 0.006, respectively). CONCLUSION: CGM is a useful tool that offers valuable information for both the diagnosis and the management of CFRD. Lower plasma insulin levels during OGTTs are associated with a poor ambulatory glucose profile in CGM. Sitagliptin could play an important role in the treatment of the early stages of CFRD.

Chronic Treatment with Somatostatin Analogues in Recurrent Type 1 Gastric Neuroendocrine Tumors.

BACKGROUND: Type 1 gastric neuroendocrine tumors (GC-1) represent an uncommon subtype of neoplasms. Endoscopic resection has been proposed as the treatment of choice; active surveillance may be performed in those smaller than 1 cm, while gastric surgery may be performed for those with frequent recurrences. The antiproliferative effect of somatostatin analogues (SSA) is well known, and their action on GC-1s has been postulated as a chronic treatment to reduce recurrence. METHODS: A two-centered, retrospective, observational study that included nine patients (55.6% women) diagnosed with GC-1, receiving long-term treatment with SSA, with a median follow-up from baseline of 22 months, was undertaken. Endoscopic follow-up, extension study, and analytical values of chromogranin A (Cg A) and gastrin were collected. RESULTS: In total, 88.9% of patients presented partial or complete response. Treatment with SSA was the only independent factor with a trend to prevent tumor recurrence (Odds Ratio 0.054; p = 0.005). A nonsignificant tendency toward a decrease in CgA and gastrin was observed; lack of significance was probably related to concomitant treatment with proton pump inhibitors in some patients. CONCLUSIONS: Chronic treatment with SSA is a feasible option for recurrent GC-1s that are difficult to manage using endoscopy or gastrectomy. Randomized clinical trials to provide more scientific evidence are still needed.

Nonfunctioning adrenal incidentalomas with cortisol post-dexamethasone suppression test >0.9 µg/dL have a higher prevalence of cardiovascular disease than those with values ≤0.9 µg/dL.

PURPOSE: To analyze the differences in the cardiometabolic profile in patients with nonfunctioning adrenal incidentalomas (NFAI) with post-dexamethasone suppression test (DST) cortisol ≤1.4 µg/dL (NFAI ≤ 1.4) and those with post-DST cortisol >1.4 µg/dL (NFAI > 1.4) and between NFAI with post-DST cortisol ≤0.9 µg/dL (NFAI ≤ 0.9) and those with levels >0.9 µg/dL (NFAI > 0.9). METHODS: Multicenter retrospective observational study of patients with NFAIs. NFAI was defined as an adrenal incidentaloma with negative hormonal study (including metanephrines, post-DST cortisol ≤1.8 µg/dL and aldosterone/renin ratio when screening was indicated). Autonomous cortisol secretion (ACS) development was defined as an NFAIs in which post-DST serum cortisol >1.8 µg/dL were evidenced during hormonal follow-up evaluation. RESULTS: A total of 593 NFAI were included. Based on the 1.4 µg/dL threshold in the DST, most of the NFAI were classified as NFAI ≤ 1.4 (74.5%). Patients in the NFAI > 1.4 group were older than those in the NFAI ≤ 1.4 group, but there was no difference in the cardiometabolic profile after adjusting for age. A total of 69.5% of the patients had DST > 0.9 µg/dl. They were older and had a higher prevalence of cardiovascular disease than NFAI ≤ 0.9, even after adjusting by age (adjusted OR = 2.23 [1.10-4.53]). Patients in the NFAI > 1.4 group developed ACS more commonly than the NFAI ≤ 1.4 group (23.5% vs. 7.44%, P < 0.001). However, when the threshold of 0.9 µg/dL was considered, no difference was found between NFAI ≤ 0.9 and NFAI > 0.9 (P = 0.126). CONCLUSION: The threshold of 1.4 µg/dL in the DST is useful to predict which patients with NFAI had a higher risk of ACS development during follow-up; and the threshold of 0.9 µg/dL to identify those patients with NFAI with a higher cardiovascular risk.

Impact of Change in Body Composition during Follow-Up on the Survival of GEP-NET.

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are heterogeneous rare diseases causing malnutrition and cachexia in which the study of body composition may have an impact in prognosis. Aim: Evaluation of muscle and fat tissues by computed tomography (CT) at the level of the third lumbar (L3 level) at diagnosis and at the end of follow-up in GET-NET patients and their relationships with clinical and biochemical variables as predictors of survival. Methodology: Ninety-eight GEP-NET patients were included. Clinical and biochemical parameters were evaluated. Total body, subcutaneous, visceral and total fat areas and very low-density, low-density, normal density, high-density, very high-density and total muscle areas were obtained from CT images. Results: Body composition measures and overall mortality correlated with age, ECOG (Eastern Cooperative Oncology Group performance status) metastases, lactate dehydrogenase (LDH), albumin and urea levels. Although there was no relationship between body composition variables at diagnosis and overall and specific mortality, an increase in low-density muscle and a decrease in normal-density muscle during follow-up were independently correlated to overall (p <0.05) and tumor-cause mortality (p < 0.05). Conclusion: Although body composition measures obtained by CT at diagnosis did not impact survival of GEP-NET patients, a loss of good quality muscle during follow-up was associated with an increased overall and tumor-related mortality. Nutritional status should therefore be supervised by nutrition specialists and an increase in good quality muscle could improve prognosis.

Predictors of Tumour Growth and Autonomous Cortisol Secretion Development during Follow-Up in Non-Functioning Adrenal Incidentalomas.

PURPOSE: To assess the risk of developing autonomous cortisol secretion (ACS) and tumour growth in non-functioning adrenal incidentalomas (NFAIs). METHODS: Multicentre retrospective observational study of patients with NFAIs. ACS was defined as serum cortisol >1.8 µg/dL after 1 mg-dexamethasone suppression test (DST) without specific data on Cushing's syndrome. Tumour growth was defined as an increase in maximum tumour diameter >20% from baseline; and of at least 5 mm. RESULTS: Of 654 subjects with NFAIs included in the study, both tumour diameter and DST were re-evaluated during a follow-up longer than 12 months in 305 patients. After a median follow-up of 41.3 (IQR 24.7-63.1) months, 10.5% of NFAIs developed ACS. The risk for developing ACS was higher in patients with higher serum cortisol post-DST levels (HR 6.45 for each µg/dL, p = 0.001) at diagnosis. Significant tumour growth was observed in 5.2% of cases. The risk of tumour growth was higher in females (HR 10.7, p = 0.004). CONCLUSIONS: The frequency of re-evaluation with DST in NFAIs during the initial 5 years from diagnosis can probably be tailored to the serum cortisol post-DST level at presentation. Re-evaluation of NFAIs with imaging studies, on the other hand, seems unnecessary in most cases, particularly if the initial imaging demonstrates features specific to typical adenoma, given the low rate of significant tumour growth.

Accuracy of the dexamethasone suppression test for the prediction of autonomous cortisol secretion-related comorbidities in adrenal incidentalomas.

PURPOSE: The aim of this study was to evaluate the diagnostic accuracy of the 1 mg dexamethasone suppression test (DST) for the prediction of autonomous cortisol secretion (ACS)-related comorbidities in patients with adrenal incidentalomas (AIs). METHODS: This was a retrospective multicenter study. We recruited patients with AI/s ≥ 1 cm, excluding those who, during the study, were found during the extension study of an extra-adrenal cancer, with a known diagnosis of hereditary syndromes characterized by adrenal tumors, those presenting with overt hormonal excess syndromes, and those in whom the DST results were missing. RESULTS: A total of 823 patients met the inclusion criteria. Based on the 1.8, 3.0, and 5.0 µg/dl post-DST cortisol thresholds, the prevalence of ACS was 33.5%, 13.7%, and 5.6%, respectively. The prevalence of hypertension (OR = 1.8, 95% CI = 1.3-2.4), diabetes (OR = 1.6, 95% CI = 1.2-2.2), and dyslipidemia (OR = 1.4, 95% CI = 1.0-1.9) was higher with cortisol post-DST ≥ 1.8 µg/dl; the prevalence of hypertension (OR = 2.1, 95% CI = 1.4-3.3) and diabetes (OR = 1.7, 95% CI = 1.1-2.6) was higher with values ≥ 3.0 µg/dl; and the prevalence of hypertension (OR = 2.0, 95% CI = 1.0-3.7) was higher with levels ≥ 5.0 µg/dl. However, the diagnostic accuracy of the DST for the prediction of cardiometabolic comorbidities in patients with AIs was poor, with areas under the ROC curve < 0.61. CONCLUSIONS: The DST is a poor predictor of cardiometabolic comorbidities in patients with AIs regardless of the cortisol cut-off values applied. This finding suggests that the diagnosis of ACS should not be based solely on the results of the DST. Other clinical, metabolic, or imaging markers showing a better performance for the prediction of the development and progression of cardiometabolic comorbidities in AIs need to be identified.

Cardiometabolic profile of non-functioning and autonomous cortisol-secreting adrenal incidentalomas. Is the cardiometabolic risk similar or are there differences?

OBJECTIVE: To study the differences in the cardiometabolic profile between patients with non-functioning adrenal incidentalomas (NFAI) and incidentalomas with autonomous cortisol secretion (ACS). METHODS: A total of 149 patients with adrenal incidentalomas were retrospectively evaluated and followed-up for a mean time of 34.6 months at Departments of Endocrinology and Metabolic Diseases Units of four tertiary Spanish hospitals. Patients were grouped as NFAI or ACS adenomas based on two cutoffs in the dexamethasone suppression test (DST): 3.0 µg/dl (NFAIDST3 or ACSDST3) and 1.8 µg/dl (ACSDST1.8 and NFAIDST1.8). RESULTS: The mean age of both groups was 62.0 (10.31) and was similar in ACS and NFAI. The prevalence of diabetes, high blood pressure, cardiovascular, and cerebrovascular disease was higher in ACS than in NFAI, but differences only reached statistical significance for cerebrovascular disease using the 3.0 µg/dl cutoff (15.8% vs 2.3%, p = 0.01) and for diabetes using the 1.8 µg/dl cutoff (38.0% vs 22.0%, p = 0.04). No differences were found in the prevalence of dyslipidemia. The prevalence of obesity was lower in patients with ACS than in NFAI 26.3% vs 39.2%, p = 0.18 (NFAIDST3 vs ACSDST3) and 32.1% vs 40.6%, p = 0.56 (ACSDST1.8 vs NFAIDST1.8), but the differences did not reach statistical significance. Maximum adenoma diameter (R-squared = 0.15, p < 0.001) and cerebrovascular disease (OR = 1.59, p = 0.04) were the only parameters that could be predicted by the DST. The DST was an inadequate predictor of clinical (systolic and diastolic blood pressure, body mass index), hormonal (DHEAS, ACTH, UFC, and basal serum cortisol), biochemical (glucose, cholesterol, LDL, HDL, and triglycerides), and other radiological (laterality, lipid content) parameters. Throughout the follow-up, patients did not develop overt Cushing's Syndrome; three NFAIDST3 developed ACSDST3, eight NFAIDST1.8 developed ACSDST1.8, and one NFAIDST1.8 progressed to ACSDST3. In both groups (NFAI and ACS) the metabolic profile remained stable. CONCLUSIONS: Our data suggest higher prevalence of diabetes and cerebrovascular disease in ACS patients compared with NFAI. However, probably because of the small sample size, the differences only reached statistical significance using the cutoffs of 1.8 µg/dl for diabetes and 3.0 µg/dl for cerebrovascular disease. Patients with ACS and NFAI rarely progress to more aggressive forms of hypercortisolism, and the metabolic profile usually remains stable during the follow-up.

Autonomous cortisol secretion in adrenal incidentalomas.

Adrenal incidentalomas (AI) are one of the most frequent reasons for consultation in Endocrinology, as they are present in 3-10% of the general population. Up to 20% of them may have autonomous cortisol secretion (ACS), a term that refers to AI carriers with biochemical evidence of excess cortisol, but without the "specific" clinical signs of Cushing's syndrome. As ACS is associated with an increased risk of diabetes, obesity, high blood pressure (HBP), osteoporosis, cardiovascular events, and global mortality; its correct identification is of great importance. There are different laboratory assays to detect ACS, but all of them have some limitations. The dexamethasone suppression test is the most accepted for screening. However, there is no consensus on the cutoff point that should be used. Low levels of ACTH and DHEA-S and high urinary free cortisol are also associated with ACS, but in isolation they are of little value to establish the diagnosis. Considering its clinical implications and the lack of consensus in the diagnosis and in which is the most appropriate management of these patients, this review offers a quick reference guide of ACS, presenting an exhaustive review of the topic: its definition, epidemiology, diagnosis, clinical implications, treatment, and follow-up.