Background People with cystic fibrosis-related diabetes (CFRD) are at risk of hypoglycaemia related to insulin therapy; and hypoglycaemia is also prevalent in those without CFRD. Although people with other forms of diabetes mellitus are at risk of hypoglycaemia within 48 h after exercise, this has not been objectively measured in people with CF. This study investigated the prevalence of post-exercise hypoglycaemia in adults with CF (pre- and post-commencement of elexacaftor/tezacaftor/ivacaftor (ETI)), compared to healthy controls. Methods Participants completed a 20-min supervised, moderate-intensity cycling session and wore a continuous flash glucose sensor. The prevalence of hypoglycaemia was defined as the number of participants and percentage of time glucose levels were < 3.9 mmol/L and < 3.0 mmol/L within the 48 h after exercise. Results 15 adults with CF pre-ETI (abnormal glucose tolerance (impaired glucose tolerance, n = 2, or CFRD, n = 5)), 32 adults with CF post-ETI (21 abnormal glucose tolerance (impaired glucose tolerance, n = 10, or CFRD, n = 11)) and 15 healthy controls completed the study. There were no significant differences in the prevalence or duration of hypoglycaemia post-exercise between the CF and control groups; and no change after commencing ETI. There was also no significant increase in the prevalence or duration of hypoglycaemia for people with CF with abnormal glucose tolerance when comparing the 48 h post-exercise period to the 48 h period with the least exercise. Conclusions The absence of any increase in significant hypoglycaemia in the post-exercise period should be reassuring for people with CF who have abnormal glucose tolerance, whether prescribed ETI or not, and their clinicians.
Although diabetic ketoacidosis (DKA) is more frequent among racial and ethnic minority populations, continuous glucose monitoring (CGM) use is lower in such groups. We sought to determine if care navigation support increases CGM utilization in patients with recurrent admissions for DKA. Using Technology to Address Disparities and Promote Healthcare Equity in Type 1 Diabetes (EquiT1D) is a prospective, single-arm study conducted at an academic medical center. Adult patients with type 1 diabetes (T1D) at high risk for DKA were recruited for participation. From November 2020 to April 2022, patients were consented to participate in an intervention which involved regular contact and care navigation to address barriers to CGM utilization. The primary study outcome was CGM utilization (percentage of days with sensor data). At 12 months, navigation support was associated with an increase in model-estimated mean (SE) CGM utilization from 17.5% (6.8%) at baseline to 51.4% (6.9%) at 12 months (P < 0.001). This study suggests that navigation support may be an effective way to increase CGM utilization among patients at high risk for DKA recurrence. Additional studies are needed to address barriers to CGM utilization.Trial Registration: clinicaltrials.gov, NCT06899984 (https://clinicaltrials.gov/study/NCT06899984?term=equit1d&rank=1#study-overview).
Purpose To determine whether gender-affirming hormone therapy (GAHT) influences tear system health in transgender individuals. Methods This retrospective cohort observational study analyzed data from transgender men and women ages ≥18-years between 2004 and 2024 via electronic medical record (EMR) data. Following propensity score matching, subjects on hormone therapy included 23,623 transgender men, 15,933 transgender women, and an equal number in each matched control group. Results Among transgender men and women, respectively, tear system disorders occurred in 0.90% and 0.94% of those using GAHT and 0.90% and 1.17% of those not using GAHT (p = 0.211, p = 0.072). There was no significant difference in those with documented utilization of GAHT versus no GAHT, for both transgender men and women, respectively, in lacrimal system disorder (p = 0.427, p = 0.292), meibomian gland dysfunction (p = 0.687, p = 0.255), keratoconjunctivitis sicca (p = 0.685, p = 0.576), and combined tear disorders (p = 0.527, p = 0.168). Conclusions In this cohort, EMR-documented masculinizing or feminizing GAHT was not associated with an increased incidence of recorded tear-system disorders.
The molecular drivers of thyroid cancer are predominantly involved in the MAP kinase pathway, especially the BRAF and RAS pathogenic variants. The DNA repair pathways are rarely implicated in thyroid tumorigenesis. The MRE11-RAD50-NBS1 (MRN) complex is a key mediator of homologous recombination mode of double-strand break repair, and its role in thyroid cancer is poorly understood. We describe a patient with radioactive iodine-refractory, metastatic oncocytic thyroid carcinoma with an NBN gene (c.2166_2167delGCinsAT) pathogenic variant, who developed progressive disease despite receiving systemic therapy with lenvatinib and pembrolizumab. A gene query analysis for the three MRN complex genes (MRE11, RAD50, and NBN) across three thyroid cancer repositories on the cBioPortal database showed a prevalence of pathogenic variants in one or more MRN complex genes in 35/762 (4.6%) patients, and all the 35 patients had anaplastic thyroid cancer (ATC). Upon filtering the dataset to include only ATCs, the pathogenic variant prevalence increased to 22.2% (35/158 patients). The overall survival in ATC patients with MRN complex gene alterations was similar to ATC patients without the altered MRN complex genes [HR: 1.42 (95% CI: 0.93-2.17)]. A mutual exclusivity analysis demonstrated a tendency for pathogenic variants in one MRN complex genes to co-occur with pathogenic variants in the other two MRN complex genes. In conclusion, the MRN complex pathogenic variants could be potentially oncogenic in TCs and may be linked to aggressive forms of TC.
Currently, no clinical early predictive biomarkers of GDM exist. A key challenge is that many candidate biomarkers fluctuate during pregnancy. Previous studies with a single time point identified several miRNAs in early pregnancy associated with insulin sensitivity between 24 and 29 weeks of gestation, suggesting they serve as potential predictive biomarkers for GDM. However, the lack of longitudinal data limits our understanding of how these miRNAs behave over time. We conducted a longitudinal pilot study to evaluate the patterns of ten miRNAs, previously identified as potential early predictors of GDM. Blood samples were collected from 18 GDM women and 18 healthy pregnancies at 4 time points (GDM diagnosis, 28 weeks, 32 weeks, and one day before delivery). The levels of four placenta-specific C19MC miRNAs (miRNA-519d-5p, miRNA-512-3p, miRNA-516a-5p, and miRNA-517-5p) and six non-C19MC miRNAs (miRNA-141-3p, miRNA-143-3p, miRNA-218-5p, miRNA-221-3p, miRNA-483-5p, and miRNA-489-3p) were measured. The relative expressions of four C19MC miRNAs were significantly increased in GDM women at diagnosis, at 28 weeks of gestation, and one day before delivery. The relative expression of non-C19MC miRNA-221-3p was significantly decreased across all time points. The expression of non-C19MC miRNA-143-3p increased significantly at diagnosis and 28 weeks, and then declined before delivery. In contrast, the levels of non-C19MC miRNA-483-5p, miRNA-218-5p, and miRNA-489-3p were significantly decreased across all time points. No changes in miRNA-141-3p level were observed. Our pilot longitudinal study supports the predictive potential of C19MC miRNAs (miRNA-512-3p, miRNA-516a-5p, miRNA-517-5p) and non-C19MC miRNA-221-3p, which were previously identified as having elevated levels in early gestation.
Background:Irisin is a metabolism-related myokine associated with lipid metabolism and insulin resistance. However, its changes during glucagon-like peptide-1 (GLP-1) receptor agonist therapy remain unclear. Methods:This exploratory analysis of a multicenter trial included 189 adults with T2DM inadequately controlled with metformin and/or insulin secretagogue. The participants received the GLP-1 receptor agonist exenatide as an add-on therapy for 16 weeks. Serum irisin and glycolipid metabolism were evaluated. Comparison was performed between two subgroups of the participants stratified by a median change from baseline in serum irisin level. Associations between change in irisin level and changes in metabolic parameters were assessed using Pearson or Spearman correlation analysis and multivariable linear regression analysis. Results:After the 16-week exenatide treatment, serum irisin level significantly declined from baseline (3.22 ± 0.53 ng/mL vs. 3.35 ± 0.64 ng/mL, P = 0.031). Change in irisin level was positively associated with change in high-density lipoprotein cholesterol (HDL-C) level (r = 0.154, P = 0.035), and negatively associated with changes in triglyceride (TG) level (r = -0.159, P = 0.029) and TG/HDL-C ratio (r = -0.172, P = 0.018). These associations for TG level and TG/HDL-C ratio remained significant after multivariable adjustment. No significant association was observed between change in irisin level and glycemic control parameters. Conclusions:Serum irisin level declines during the exenatide treatment in patients with T2DM, and this reduction is associated with change in lipid metabolism but not glycemic control, suggesting a potential link between dynamic change of irisin and lipid metabolism during the exenatide treatment.
Transition from pediatric to adult care is a critical period for young adults with type 2 diabetes mellitus (T2DM). This study included a retrospective chart review of 139 patients aged 17-25 years with T2DM followed in pediatric endocrinology between 2021 and 2022. Patients were categorized as transitioned to adult care, remained in pediatric care, or lost to follow-up. Of the cohort, 33.8% transitioned to adult care, 27.3% remained in pediatric care, and 38.9% were lost to follow-up. Among those who transitioned to adult care, 48.9% established care with family medicine, 27.7% with adult endocrinology, and 23.4% with internal medicine. The mean time to transition to adult care was 19.9 ± 19.3 months, and mean HbA1c at first adult visit was 8.9 ± 3.1%. Nearly 40% of young adults were lost to follow-up, and transitions to adult care were characterized by prolonged gaps in care, suggesting the need for structured transition pathways.
Background:Overweight and obesity rates have increased drastically among people with cystic fibrosis (CF), in part due to advancements in care, including highly effective modulator therapies (HEMT). Ethnic differences in the prevalence of overweight/obesity in CF are unknown. Methods:To determine the prevalence of overweight/obesity by ethnicity, we performed a cross-sectional retrospective chart review of patients ≥ 2yrs old with CF at the University of Texas Health San Antonio CF Center. Logistic regression stratified by age group (children: 2-17 yr, adults: ≥18 yr) was used to evaluate factors associated with overweight/obesity among Hispanics and non-Hispanic whites after adjustment for confounders. Results:One hundred seventy-two patients (68 children/104 adults, 49% Hispanic, 47% female) were assessed. Overweight/obesity was prevalent in 35% of children and 42% of adults. Multivariable analysis revealed that the odds of overweight/obesity were lower in children (p = 0.032) and adults (p = 0.007) who used supplemental feeds, but higher among adults using HEMT (p = 0.037) and adults with higher FEV1pp (p = 0.016). Ethnic differences in overweight/obesity prevalence were not apparent in either age group. Conclusion:The odds of overweight/obesity were lower among children and adults using supplemental feeds, whereas HEMT use and having higher lung function were associated with increased odds among adults. Multi-center studies performed in diverse CF populations are essential to understand factors associated with overweight/obesity.
Endogenous Cushing’s syndrome (CS) is characterized by chronic hypercortisolism. After achieving remission, morbidity remains increased and quality of life remains impaired. Moreover, the incidence of inflammatory disorders increases after remission of CS. Despite these immune-mediated clinical consequences, the course of innate immune cell function after remission of CS is poorly known. In this study we aimed to assess changes in innate immune cell function and systemic inflammatory markers after achieving remission of CS. Blood samples were collected from nine CS patients (six adrenal CS and three Cushing’s disease) at diagnosis and after achieving remission and fully tapering off glucocorticoid suppletion. Peripheral blood mononuclear cell (PBMC) cellularity and monocyte-derived cytokine responses upon 24 h of ex vivo stimulation were compared between at diagnosis and after achieving remission. Changes in circulating inflammation-related proteins were assessed by proximity extension assay proteomics and ELISA. After achieving remission of CS, the PBMC fraction showed higher percentages of lymphocytes and lower percentages of monocytes. Production of pro-inflammatory cytokines IL-6 and IL-8 by monocytes after 24 h of stimulation with microbial stimuli was higher after achieving remission, while production of anti-inflammatory cytokines IL-10 and IL-1Ra was lower. Proteomic analysis of plasma identified seven inflammation-related proteins with increased expression and eleven proteins with decreased expression after achieving remission. Concentrations of circulating IL-6, IL-8 and CRP did not change after remission. In conclusion, increased pro-inflammatory cytokine production by monocytes and persistent systemic inflammation could partially explain increased morbidity and incidence of inflammatory disorders after achieving remission of CS.
Objective: Sporadic medullary thyroid carcinoma (sMTC) is predominantly driven by somatic RET or RAS mutations, although the molecular basis of disease heterogeneity remains incompletely understood. Our study aims to characterize molecular heterogeneity in sMTC in order to identify pathways that may improve patient’s stratification and support more personalized clinical management strategies. Methods: Deep targeted next-generation sequencing of 31 neuroendocrine- and cancer-related genes was performed on tumor samples from 94 patients with sMTC to characterize the somatic mutational landscape beyond canonical drivers. Results: RET and RAS mutations were detected in 53% and 29% of cases, respectively, while 18% of tumors lacked both alterations. Variant allele frequency (VAF) analysis demonstrated a significant positive correlation between driver mutation burden and tumor size in both RET- and RAS-mutant tumors, supporting the clonal contribution of these alterations. Additional oncogenic variants were identified in genes involved in DNA damage response and epigenetic regulation, including ATM and KMT2A. Notably, within the RAS-mutant subgroup, the presence of co-occurring oncogenic alterations was associated with more advanced T status (T3-T4, p = 0.0181) at diagnosis and lower biochemical cure rates (p = 0.02) at the follow-up compared with tumors harboring isolated RAS mutations, supporting the clinical relevance of extended genomic profiling in RAS-mutant sMTC. Conclusions: Overall, these findings highlight additional oncogenic alterations potentially involved in tumor progression and suggest that extended targeted profiling may provide clinically relevant information on molecular heterogeneity in sMTC, particularly within RAS-mutant tumors.
Background:Early detection of diabetic nephropathy (DN) remains a major clinical challenge. Conventional indicators such as serum creatinine and urinary albumin excretion often identify renal impairment only after significant structural damage has occurred. Increasing evidence suggests that tubular injury may precede glomerular dysfunction in diabetic kidney disease. Neutrophil gelatinase-associated lipocalin (NGAL), a biomarker released from injured renal tubular epithelial cells, has therefore emerged as a potential early indicator of renal injury. Objective:This study aimed to evaluate the diagnostic performance of urinary NGAL as an early biomarker of diabetic nephropathy in patients with type 2 diabetes mellitus and to compare its performance with conventional renal function markers. Methods:A cross-sectional study was conducted including 90 participants: 72 patients with type 2 diabetes mellitus and 18 healthy controls. Diabetic patients were categorized into four stages of nephropathy according to estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR) based on KDIGO criteria. Urinary NGAL concentrations were measured using a sandwich enzyme-linked immunosorbent assay (ELISA). Statistical analysis included correlation analysis, receiver operating characteristic (ROC) curve assessment, and multivariate logistic regression. Results:Urinary NGAL levels increased progressively with the severity of diabetic nephropathy, rising from 49.1 ± 14.2 ng/mL in controls (within the normal reference range < 70 ng/mL) to 547.7 ± 31.7 ng/mL in patients with stage IV disease (p < 0.001). NGAL demonstrated a strong positive correlation with serum creatinine (r = 0.81) and urinary ACR (r = 0.76), and a significant negative correlation with eGFR (r = - 0.79). ROC curve analysis showed that NGAL exhibited excellent diagnostic performance (AUC = 1.00), outperforming ACR (AUC = 0.97) and serum creatinine (AUC = 0.83). An optimal cutoff value of 107.3 ng/mL provided high sensitivity and specificity for detecting diabetic nephropathy in this cohort. Conclusion:Urinary NGAL appears to be a sensitive biomarker of renal tubular injury and may allow earlier identification of diabetic nephropathy compared with conventional markers. Incorporation of NGAL measurement into clinical evaluation may improve early detection of diabetic kidney disease, although larger prospective studies are required to confirm these findings.
Background: Thyroid hormones (TH) and neurotransmitter orexin (ORX) are implicated in the regulation of metabolism. Abdominal weight gain is common in primary hypothyroidism (PH). Methods: Our aim was to investigate whether TH affected peripheral weight gain, waist circumference (WC) and low-density lipoprotein cholesterol (LDL-C), before and 6 months after L-thyroxine substitution therapy. A secondary aim was to investigate the role of ORX. Results: Weight gain was positively correlated with improvement in QoL (r = 0.72, p = 0.003) and with CSF ORX levels in the 15 included patients (r = 0.78, p = 0.001). Increased WC, which was not associated with QoL changes, correlated negatively with free thyroxine levels, after 6 months of treatment, in both CSF (r = -0.71, p = 0.003) and serum (r = -0.64, p = 0.0097). Increased LDL-C correlated negatively with CSF free thyroxine levels after 6 months of treatment (r = -0.74, p = 0.003). Conclusion: The marked correlations with CSF levels of thyroxine and ORX suggest that hypothalamic mechanisms participate in the regulation of WC and weight during L-thyroxine therapy, highlighting the need for individualized treatment of the metabolic disturbances seen in PH. Short communication: Through evaluating the dynamics of body weight and waist circumference during the initial treatment of primary hypothyroidism, a positive correlation was found between orexin levels in CSF and the change in body weight. Furthermore, negative correlations were found between CSF free thyroxine levels and the changes in waist circumference and serum LDL-C levels. These findings emphasize the importance of finding future individualized treatment strategies in primary hypothyroidism, particularly regarding metabolic disturbances.
Background:Glucocorticoid-induced osteoporosis (GIO) is a serious complication of long-term glucocorticoid therapy. Although the risks of glucocorticoid therapy are well recognized, screening rates for GIO are low. Objective:This study aimed to evaluate the current state of GIO screening in patients treated with long-term glucocorticoids and the factors associated with higher screening rates. Methods:We conducted a retrospective cohort study of 8923 patients ≥ 40 years who received long-term glucocorticoid therapy (≥2.5 mg prednisone daily or equivalent dose for ≥ 3 months) within the M Health Fairview health system from 2017 to 2022. Demographics, comorbidities, and dual-energy x-ray absorptiometry (DXA) screening data were extracted from the electronic health record and analyzed. We identified factors associated with DXA screening by logistic regression analysis. Results:15.4% of patients received DXA screening within 2 years before and 1 year after glucocorticoid initiation. 3.8% of patients were screened within 6 months of starting treatment. Factors significantly associated with DXA screening included female sex (OR 2.51, 2.16-2.91, p < 0.001), greater age (OR 1.02, 1.01-1.02, p < 0.001), White race (OR 1.71, p < 0.001), and the presence of additional comorbidities (OR 1.84, 1.74-1.93, p < 0.001). Conclusions:Screening for GIO in high-risk patients remains suboptimal, despite longstanding efforts at increasing awareness of this condition. Factors such as older age, female sex, White race, and higher comorbidity burden were associated with increased screening. Our findings highlight that interventions to date have been insufficient in improving GIO screening and that novel approaches are needed to make a meaningful change in longstanding low screening rates.
Background:Type 1 diabetes (T1D) results in the loss of endogenous production of insulin and C-peptide, which are co-secreted by pancreatic β cells. Serum C-peptide following mixed-meal tolerance tests is commonly used in T1D trials to assess residual insulin secretion. Urine C-peptide (UCP) offers a non-invasive alternative suitable for home collection. Here, we aimed to optimize urine handling practices to support remote urine C-peptide monitoring in clinical trial settings. Methods:Randomly-voided urine was collected from 18 non-diabetic participants (mean age: 46.6 years; 94.4% female). Samples were treated with no preservative (NP), boric acid (BA), or sodium carbonate (SC) and incubated at 4°C or room temperature (RT, 22°C) for up to 72 h. Use of cold packs after initial refrigeration was also tested. UCP was quantified using the TOSOH immunoenzymatic assay and normalized to urine creatinine (UCP:Cr). Stability was expressed as percent change from baseline (%UCP:Cr). Results:NP samples lost %UCP:Cr more rapidly at RT, with decreases at 48 h (-16%, P < 0.05) and 72 h (-21%, P = 0.02) compared to 4°C. BA-preserved samples had declined %UCP:Cr at 72 h (-16%; P = 0.04) compared to 4°C. SC maintained UCP:Cr stability, showing no significant change in %UCP:Cr between 4°C and RT. Samples kept on cold packs following initial refrigeration showed no significant loss in %UCP:Cr compared to samples continuously refrigerated for 72 h. Conclusions:Cold storage of urine slows UCP:Cr degradation, and SC stabilizes UCP:Cr at room temperature. Our findings suggest that UCP:Cr offers a practical option for at-home urine collection in clinical studies.
Background:There has been increasing public interest in a functional medicine (FM) approach to the care of type 2 diabetes (T2D). However, it is unclear if this approach can further improve diabetes management beyond conventional diabetes care. This study compared the addition of a FM approach (intensive lifestyle modifications and tailored dietary supplements) plus usual care (FM) to conventional endocrinology management alone (usual care, UC). Methods:In a 24-month unblinded randomized trial, participants with type 2 diabetes (T2D) were randomized to receive either FM or UC. The primary endpoint was discontinuation of insulin with no increase in HbA1c or HbA1c < 7% at 12 months. Secondary endpoints included changes in HbA1c, insulin dosage by weight, cardiometabolic biomarkers, hypoglycemic episodes, total number of medications and quality-of-life scores. Results:A total of 107 individuals were screened - 34 were randomized into FM and 37 into UC. Participants were 46% female and median age was 62 years. Median baseline HbA1c was 7.75%. Of those randomized, 47 participants completed the study (FM: 20; UC: 27); 15.8% of patients in FM arm achieved the primary endpoint compared to 11.1% in the UC arm (p = 0.68). Secondary exploratory endpoints including change in HbA1c, insulin dosage by weight, hypoglycemia, BMI, weight and quality-of-life did not differ significantly between arms. Conclusion:The addition of FM did not lead to significant improvement in glycemic, metabolic or quality-of-life outcomes compared to usual care for individuals with type 2 diabetes.
Diabetic kidney disease (DKD) represents a prevalent and severe complication of diabetes mellitus, with growing evidence highlighting the critical role of lipid metabolic dysregulation in its pathogenesis. This review systematically examines the complex interplay between aberrant lipid metabolism and DKD progression, focusing on three major pathways: fatty acid metabolism disturbances, cholesterol homeostasis imbalance, and sphingolipid signaling alterations. We detail how these metabolic perturbations contribute to renal cell injury through multiple mechanisms, including in podocytes, tubular epithelial cells, and mesangial cells. Emerging therapeutic strategies targeting these metabolic pathways are comprehensively evaluated. Special emphasis is placed on recent advances in understanding cell-specific lipid metabolic reprogramming and its clinical implications. The review also discusses current challenges in translating these findings into clinical practice and proposes future research directions for developing personalized therapeutic approaches based on lipid metabolic profiling in DKD patients.
Introduction:Men generally have higher plasma uric acid (PUA) concentrations and are at greater risk for hyperuricemia-related diseases. Sex hormones may underlie this difference, though mechanisms remain unclear. Sex hormone therapy offers a unique opportunity to study these effects. Methods:Participants were included from two prospective observational cohorts: ENIGI (n = 544, 12 months of feminizing [n = 260] or masculinizing [n = 284] hormone therapy) and KNIGHT (n = 28, 3 months of feminizing [n = 15] or masculinizing [n = 13] hormone therapy). Outcomes included changes in PUA (ENIGI), uric acid clearance (UAC; KNIGHT), fractional excretion of uric acid (FE-UA; KNIGHT), fat distribution (ENIGI), and PUA-associated plasma proteomics (KNIGHT). Results:PUA decreased during feminizing hormone therapy (-86 μmol/L [95% CI, -95; -77]) and increased during masculinizing hormone therapy (+61 μmol/L [95% CI, 53; 70]). During feminizing therapy, UAC increased (+1.1 mL/min [95% CI, 0.1; 2.1]) without changing FE-UA. During masculinizing therapy UAC and FE-UA decreased (UAC: -1.0 mL/min [95% CI, -1.7; -0.3]; FE-UA: -0.8% [95% CI, -1.3; -0.4]). Android-to-gynoid and visceral-to-subcutaneous fat ratios decreased with feminizing and increased with masculinizing therapy (p < 0.05) and correlated positively with PUA changes (p < 0.001). Proteomics identified 126 PUA-associated proteins differentially expressed during sex hormone therapy. While proteins directly involved in uric acid production were unchanged, proteins related to fat distribution (adiponectin, leptin, SHBG) associated with PUA changes. Discussion:PUA significantly changes during sex hormone therapy, most likely through changes in UAC and fat distribution. These findings emphasize the role of sex hormones in uric acid metabolism and provide insight into sex differences in hyperuricemia-related conditions. Trial registration knight:Dutch Trial Register (ID: NL9517); ClinicalTrials.gov (ID: NCT04482920).
Background Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, improves renal and cardiovascular outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). However, evidence on its use in clinical practice remains limited. Within the FOUNTAIN platform (NCT05526157; EUPAS48148), this study aimed to characterize the profiles and treatment patterns of patients initiating finerenone in the United States following its regulatory approval in 2021. Methods This observational study used Optum’s de-identified Clinformatics® Data Mart Database to identify adults with T2D and CKD who initiated finerenone between July 2021 and September 2023. Baseline demographic and clinical characteristics (e.g., estimated glomerular filtration rate, urine albumin-to-creatine ratio [uACR]) were assessed, and treatment utilization patterns were described. Results Among 3,591 new finerenone users, mean age was 72.2 years and 47.5% were female. Most (62.4%) had stage 3 CKD, and of those with recorded uACR, 86.5% had moderate/severe albuminuria (≥30 mg/g). Renin-angiotensin-aldosterone system inhibitors (RAASi; 80.0%), sodium-glucose cotransporter 2 inhibitors (SGLT2i; 41.4%), and glucagon-like peptide-1 receptor agonists (GLP-1 RA; 30.2%) usage was common in the 90 days preceding finerenone initiation. Finerenone was typically initiated as an add-on to RAASi (58.5%), SGLT2i (28.0%), or GLP-1 RA (21.1%); monotherapy usage was infrequent (8.5%). Among those with ≥ 12 months’ follow-up, 56.0% remained on finerenone at 12 months and 16.7% had titrated from 10 mg to 20 mg. Conclusions Finerenone was primarily prescribed as a pillar of therapy that is used in combination with complementary medications in patients with T2D and CKD, aligning with clinical guidelines and regulatory labeling.
Background:Familial glucocorticoid deficiency (FGD; MIM: 614736) is a genetic disease of glucocorticoid insufficiency, with autosomal recessive mode of inheritance. The FGD is genetically heterogeneous disorder that involves multiple genes related to the pathway that regulates the signaling from pituitary to the adrenal cortex, or the specific redox reactions in mitochondria. The phenotypic spectrum for FGD is also diverse with considerable variability in clinical features. Among the genetic determinants of this disease, pathogenic mutations in NNT gene results in Familial glucocorticoid deficiency type 4. Here we report three consanguineous families with single nucleotide variants in NNT that manifest as familial glucocorticoid deficiency in multiple family members. Method:Prospective cohort of three families from different tribes were identified with clinical diagnosis of familial glucocorticoid deficiency (FGD). Whole exome sequencing (WES) done for affected family members followed by validation of discovered variant by Sanger sequencing and subsequent functional studies including quantitative PCR analysis and protein Modelling. Results:The screening of entire coding region of the genomes of probands in each family revealed three distinct mutations, including one novel missense variant (c.1067 C > T; p.Thr356Ile), classified as variant of uncertain significance (VUS; Class-3) and two recurrent variants (c.1025 T > C; p.Val342Ala and c.98dup; p.Leu33Phefs*13), classified as pathogenic [Class-I]. Computational protein modelling of these mutations (c.98dup and c.1025 T > C) suggests atypical changes in the structure of the mutant proteins that likely disrupt the physiological role of NNT in mitochondria of adrenal cortex. Conclusion:The exome sequencing genetically characterized the autosomal recessive sub-type 4 of hereditary glucocorticoid deficiency in families showing the features of cortisol deficiency, including the development of hypoglycemia and adrenal crisis. This strongly supports the pathogenicity of these variants. In addition, this suggests importance of mitochondrial function in post developmental maintenance of cortisol significance in terms of cellular metabolism, carried out by NNT protein. Identifying individuals with hereditary glucocorticoid deficiency is essential to start life-saving glucocorticoid replacement.
