Effectiveness in Real World of Once Weekly Semaglutide in People with Type 2 Diabetes: Glucagon-Like Peptide Receptor Agonist Naïve or Switchers from Other Glucagon-Like Peptide Receptor Agonists: Results from a Retrospective Observational Study in Umbria.

INTRODUCTION: To complement results of the SUSTAIN program, this study assessed effectiveness and safety of once weekly subcutaneous semaglutide in people with type 2 diabetes (T2D) managed under routine care. METHODS: This was a multicenter, observational, retrospective study including all patients treated with semaglutide. Changes in clinical outcomes from baseline to 6 and 12 months were assessed in patients who were glucagon-like peptide receptor agonist (GLP-1RA) naïve or switching from another GLP-1RA. Discontinuation rate was assessed. RESULTS: Overall, 216 patients (mean age 64 years, 65.7% men) were evaluated: 135 (61.5%) naïve and 81 (38.5%) switchers from another GLP-1RA. In the naïve cohort, after 6 months from semaglutide initiation, levels of HbA1c significantly decreased by - 1.31% (p < 0.0001). All obesity indices improved, with mean reductions in body weight of - 3.92 kg, in BMI of - 1.43 kg/m2, and in waist circumference of - 5.03 cm. In the switcher cohort, statistically significant improvements in HbA1c (- 0.78%), body weight (- 2.64 kg), and waist circumference (- 3.03 cm) were obtained after 6 months. Reductions were sustained after 12 months in both cohorts (mean semaglutide dose: 0.86 mg in naïve and 0.96 mg in switcher cohort). Blood pressure and lipid profile mean levels decreased after 12 months from semaglutide initiation in both cohorts. No severe hypoglycemia occurred; 6.5% of patients discontinued semaglutide (2.8% due to gastrointestinal side effects). CONCLUSION: Effectiveness and tolerability of semaglutide have been confirmed in the real world irrespective of diabetes duration and severity. As expected, more marked reductions in HbA1c and obesity indices were obtained in naïve patients, but it is noteworthy that relevant improvements were also obtained in patients already treated with GLP-1RAs.

Autoantibody response against NALP5/MATER in primary ovarian insufficiency and in autoimmune Addison's disease.

CONTEXT: NACHT leucine-rich-repeat protein 5 (NALP5)/maternal antigen that embryo requires (MATER) is an autoantigen in hypoparathyroidism associated with autoimmune polyendocrine syndrome type 1 (APS1) but is also expressed in the ovary. Mater is an autoantigen in experimental autoimmune oophoritis. OBJECTIVES: The objectives of the study were to determine the frequency of NALP5/MATER autoantibodies (NALP5/MATER-Ab) in women with premature ovarian insufficiency (POI) and in patients with autoimmune Addison's disease (AAD) and to evaluate whether inhibin chains are a target for autoantibodies in POI. METHODS: Autoantibodies against NALP5/MATER and inhibin chains-α and -ßA were determined by radiobinding assays in 172 patients with AAD without clinical signs of gonadal insufficiency, 41 women with both AAD and autoimmune POI [steroidogenic cell autoimmune POI (SCA-POI)], 119 women with idiopathic POI, 19 patients with APS1, and 211 healthy control subjects. RESULTS: NALP5/MATER-Ab were detected in 11 of 19 (58%) sera from APS1 patients, 12 of 172 (7%) AAD sera, 5 of 41 (12%) SCA-POI sera, 0 of 119 idiopathic POI sera and 1 of 211 healthy control sera (P < .001). None of 160 POI sera, including 41 sera from women with SCA-POI and 119 women with idiopathic POI, and none of 211 healthy control sera were positive for inhibin chain-α/ßA autoantibodies. CONCLUSIONS: NALP5/MATER-Ab are associated with hypoparathyroidism in APS1 but are present also in patients with AAD and in women with SCA-POI without hypoparathyroidism. Inhibin chains do not appear to be likely candidate targets of autoantibodies in human POI.

Diagnosis and classification of autoimmune hypophysitis.

Autoimmmune hypophysitis (AH) is the consequence of an immune-mediated inflammation of the pituitary gland. The initial pituitary enlargement, secondary to infiltration and oedema, can evolve to remission, for spontaneous or pharmacological resolution of the inflammation, or evolve to progressive diffuse destruction with gland atrophy for fibrotic replacement, thus leading to various degrees of pituitary dysfunction. The autoimmune process against the pituitary gland is made evident by the appearance of circulating autoantibodies (APA), mainly detected by indirect immunofluorescence on cryostatic sections of human or primate pituitary. Among the target autoantigens recognized by APA are alpha-enolase, gamma-enolase, the pituitary gland specific factors (PGSF) 1 and 2 and corticotroph-specific transcription factor (TPIT). However, the low diagnostic sensitivity and specificity of APA for AH strongly limit the clinical use of this marker. AH should be considered in the differential diagnosis of non-secreting space-occupying lesions of sella turcica, to avoid misdiagnosis that may lead to an aggressive surgery approach, since endocrine dysfunction and the compressive effect may be transient.

A novel variation in the AVP gene resulting in familial neurohypophyseal diabetes insipidus in a large Italian kindred.

Familial neurohypophyseal diabetes insipidus (FNDI) is mostly an autosomal dominant inherited disorder presenting with severe polydipsia and polyuria typically in early childhood. To date, 69 different variations in the AVP gene encoding the AVP prohormone have been identified in autosomal dominant FNDI (adFNDI). In this study we present a family of seven generations, in which a novel variation in the AVP gene seems to cause adFNDI. Clinical assessment by 24 h urine collection, water deprivation test, desmopressin (dDAVP) challenge, and magnetic resonance imaging (MRI) of the posterior pituitary are presented. The diagnosis of adFNDI was confirmed by direct DNA sequence analysis of the AVP gene. Inheritance pattern and clinical history clearly pointed towards adFNDI. Inability of concentrating urine upon dehydration was demonstrated by a water deprivation test, and neurohypophyseal diabetes insipidus was strongly suspected after dDAVP administration, during which renal concentration ability quadrupled. MRI revealed a very weak pituitary "bright spot" in each of six subjects and a further reduction in the size of the neurohypophysis in a 7-year follow-up MRI scan in one subject. DNA sequence analysis revealed heterozygousity for a novel g.1785T > C gene variation predicting a p.Leu63Pro substitution in four affected subjects. Genetic testing in the diagnostic evaluation of families in which diabetes insipidus segregates is highly recommended in that interpretation of clinical assessments can be difficult. Furthermore, presymptomatic diagnosis can ease the parental concern of the carrier status of their offspring, and also avoid unnecessary surveillance of those being unaffected.

Therapy of adrenal insufficiency: an update.

Adrenal insufficiency may be caused by the destruction or altered function of the adrenal gland with a primary deficit in cortisol secretion (primary adrenal insufficiency) or by hypothalamic-pituitary pathologies determining a deficit of ACTH (secondary adrenal insufficiency). The clinical picture is determined by the glucocorticoid deficit, which may in some conditions be accompanied by a deficit of mineralcorticoids and adrenal androgens. The substitutive treatment is aimed at reducing the signs and symptoms of the disease as well as at preventing the development of an addisonian crisis, a clinical emergency characterized by hypovolemic shock. The oral substitutive treatment should attempt at mimicking the normal circadian profile of cortisol secretion, by using the lower possible doses able to guarantee an adequate quality of life to patients. The currently available hydrocortisone or cortisone acetate preparations do not allow an accurate reproduction of the physiological secretion pattern of cortisol. A novel dual-release formulation of hydrocortisone, recently approved by EMEA, represents an advancement in the optimization of the clinical management of patients with adrenal insufficiency. Future clinical trials of immunomodulation or immunoprevention will test the possibility to delay (or prevent) the autoimmune destruction of the adrenal gland in autoimmune Addison's disease.

Progressive decline of residual follicle pool after clinical diagnosis of autoimmune ovarian insufficiency.

CONTEXT: In approximately 5-8% patients with primary ovarian insufficiency (POI), the disease is caused by an autoimmune process made evident by the appearance of autoantibodies against steroidogenic enzymes (SCA-POI). Anti-müllerian hormone (AMH) is the best marker of the residual follicular pool. OBJECTIVE: To evaluate the rate of loss of the residual follicle pool in women with SCA-POI after clinical diagnosis. DESIGN AND METHODS: One hundred and thirty-two women with POI were tested for 21-hydroxylase autoantibodies, 17α-hydroxylase autoantibodies and P450scc autoantibodies, and 35 patients with SCA-POI were identified. AMH was analysed at the time of the first visit in all women with POI, and in follow-up, serum samples were taken 1-3 years after in 11 women with SCA-POI and detectable AMH. RESULTS: 12/35 (35%) women with SCA-POI had AMH levels within the normal range at the time of first sampling, as compared to 6/97 (6%) with idiopathic POI (P < 0·001). 11/17 (65%) women with SCA-POI with <6 years disease duration had normal serum AMH concentration. A progressive decline in AMH concentration was observed at longitudinal follow-up in all 11 AMH-positive women with SCA-POI, at an estimated average rate of 1·6 µg/l AMH/year (corresponding to an average 57% of preserved follicle pool/previous year) (R(2)  = 0·219, P = 0·028). After 6 years of disease duration, only 1/18 (6%) women with SCA-POI had detectable levels of AMH, similar to women with idiopathic POI (5/78, 6%). CONCLUSION: Most women with SCA-POI present at clinical diagnosis with a preserved follicle pool that is progressively lost within a few years.