Background Oral semaglutide is the first oral glucagon-like peptide-1 (GLP-1) receptor agonist for glycaemic control in patients with type 2 diabetes. Type 2 diabetes is commonly associated with renal impairment, restricting treatment options. We aimed to investigate the efficacy and safety of oral semaglutide in patients with type 2 diabetes and moderate renal impairment. Methods This randomised, double-blind, phase 3a trial was undertaken at 88 sites in eight countries. Patients aged 18 years and older, with type 2 diabetes, an estimated glomerular filtration rate of 30-59 mL/min per 1•73 m², and who had been receiving a stable dose of metformin or sulfonylurea, or both, or basal insulin with or without metformin for the past 90 days were eligible. Participants were randomly assigned (1:1) by use of an interactive web-response system, with stratification by glucose-lowering medication and renal function, to receive oral semaglutide (dose escalated to 14 mg once daily) or matching placebo for 26 weeks, in addition to background medication. Participants and site staff were masked to assignment. Two efficacy-related estimands were defined: treatment policy (regardless of treatment discontinuation or rescue medication) and trial product (on treatment without rescue medication) in all participants randomly assigned. Endpoints were change from baseline to week 26 in HbA1c (primary endpoint) and bodyweight (confirmatory secondary endpoint), assessed in all participants with sufficient data. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on ClinicalTrials.gov, number NCT02827708, and the European Clinical Trials Registry, number EudraCT 2015-005326-19, and is now complete.
Advances in immunocytochemistry, electron microscopy, cell culture, and molecular techniques have demonstrated that 80 to 90% of the clinically nonfunctioning pituitary adenomas are gonadotrope-derived and recently recognized as gonadotropinomas, which account for as many as 40 to 50% of all pituitary macroadenomas. Patients usually present with mass effects including visual field loss and headache, hypogonadism, and hypopituitarism. Commonly, the tumor is found incidentally. Recently, a few patients with gonadotropinomas were reported to have hormonal hypersecretion syndromes such as ovarian hyperstimulation, testicular enlargement, and precocious puberty. The tumors can be divided into two broad categories: functioning gonadotropinomas with positive immunostaining for follicle-stimulating hormone, leutinizing hormone, and/or their subunits; and nonfunctioning gonadotropinomas or null cell tumors with negative immunostaining for all pituitary hormones but positive nuclear immunostaining for steroid factor-1 or DAX-1 characteristic of gonadotrope differentiation, with evidence of gonadotropin production or gene expression at the mRNA level. Gonadotropinomas are monoclonal in origin but the pathogenesis of these tumors is unknown and factors that stimulate clonal proliferation not yet determined. A new pituitary oncogene, pituitary tumor transforming gene, has recently been found to be overexpressed in about two thirds of these tumors but it is also detected in all other pituitary tumor subtypes. Alterations of tumor hormone receptors and local growth factors may also play a role in the tumor development and/or progression. Transphenoidal surgery remains the principal therapy for the macroadenomas. Radiosurgery using gamma knife, the linear accelerator, or proton beam therapy showed promising results, especially for controlling the residual or recurrent tumors. Medical therapy with somatostatin analogs, dopamine agonists, and gonadotropin-releasing hormone agonists and antagonists are rarely effective in reducing tumor size. Experimental therapy with intraoperative local chemotherapy or potential gene therapy requires further investigation.
Recent data indicate that epidermal growth factor (EGF) is a potent mitogen to normal pituitary cells. Its receptor (EGFR or c-erbB-1), a cellular homologue of a viral oncoprotein erbB, is knonw to be overexpressed in many tumors, but little is known about the expression of EGF and EGFR in pituitary tumors. Immunocytochemical analyses of EGF, EGFR, and c-erbB-2 (an EGFR-related oncoprotein) were carried out on paraffin-embedded sections of 54 pituitary tumors. In sections from normal pituitary, EGF was localized mainly in the gonadotrophs and thyrotrophs. EGFR was detected in only 5-10% of the cells in all of the normal pituitary sections and was almost undetectable in all (34/34) of the hormone-secreting tumors (19 GH-, 9 ACTH-, 4 PRL- and 2 TSH-secreting tumors). However, in 16/20 of the samples from clinically nonfunctioning tumors, EGFR was markedly overexpressed. The EGFR found in these tumors and in the normal tissue was not the truncated form of the EGFR because all sections stained positively with monoclonal antisera to both the intra- and extracellular domains of the EGFR. EGF was coexpressed in the same NFT samples that stained positively for EGFR and was also found in 2/19 GH-, 2/4 PRL-, and 1/2 of TSH-secreting tumors. The expression of c-erbB-2 was detected in all normal tissue, all NFT, and about half of GH-secreting tumors. No correlation was found with clinical parameters other than tumor categories. Because the overexpression of structurally intact EGFR was confined to NFT, the response of the tumor cells to EGF in vitro was examined. The addition of 1 nM EGF to NFT-derived cells resulted in an increase in [3H]thymidine uptake to 237.5 +/- 19.8% (mean +/- SEM, n = 3) of the control value. EGF also stimulated EGFR messenger RNA levels, shown by Northern blot analysis. In contrast, the expression of glycoprotein hormone common alpha-subunit gene in the tumor cells was reduced by EGF, T3, and 17 beta-estradiol. The novel findings of overexpression of EGFR in most NFT combined with the in vitro response to EGF resulting in an increase in tumor cell growth, up-regulation of EGFR gene and suppression of hormone gene expression implicate a role for EGF and its receptor in the development and/or progression of NFT.
The mitogenic and regulatory effects of estrogen (E2) in adenohypophysial cells are known to be mediated through the nuclear estrogen receptor (ER alpha). Expression of ER alpha and several of its messenger ribonucleic acid (RNA) alternate splice variants has been shown to be restricted to prolactinomas and gonadotroph tumors. However, little is known about gene expression patterns of the novel nuclear hormone receptor ER beta in the neoplastic pituitary. ER beta has high homology to ER alpha in the DNA- and ligand-binding domains, but encodes a distinct transcriptional activating function-1 (AF-1) domain. Using RT-PCR analysis of total RNA from 38 human pituitary adenomas, we found that ER beta messenger RNA was coexpressed with ER alpha and its splice variants in 60% of prolactinomas, 100% of mixed GH/PRL tumors, and 29% of gonadotroph tumors. ER beta gene expression was not limited to ER alpha-positive tumor subtypes, however, and was also found in 100% of null cell tumors, 80% of somatotroph tumors, and 60% of corticotroph tumors. Because ER beta is coexpressed with ER alpha and its splice variants in prolactinomas and gonadotroph tumors, we functionally characterized the potential interactions between ER beta and ER alpha. We also examined the potential cooperative effects on ER beta-mediated gene expression of a tumor-specific truncated delta 5ER alpha splice variant that has been shown to be coexpressed in the majority of ER alpha-positive tumors. This exon 5 splice variant encodes the AF-1 domain as well as regions critical for DNA binding and nuclear localization, but lacks the ligand-binding and AF-2 domains. Mammalian expression vectors encoding ER alpha, delta 5ER alpha, and/or ER beta complementary DNAs were transiently transfected along with an E2 response element promoter-luciferase (ERELuc) reporter into human ER alpha/ER beta-negative osteosarcoma U2-OS cells. ER beta was less potent than ER alpha in activating E2-stimulated ERELuc activity (4-vs. 14-fold relative to basal control levels). However, when delta 5ER alpha was coexpressed with ER beta or ER alpha, E2-stimulated ERELuc activity was markedly increased to 8- and 57-fold, respectively, relative to basal control levels when each full-length isoform was expressed alone. Finally, coexpression of ER beta with ER alpha did not significantly alter the E2-stimulated ERELuc activity induced by ER alpha alone. Cotreatment with tamoxifen markedly inhibited all E2-stimulated ERELuc responses to baseline levels. Together, these data suggest that ER beta has a minor role in mediating E2 responses in ER alpha-positive tumors, but may be the main mediator of E2-stimulated gene expression when expressed alone in somatotroph, corticotroph, and null cell tumors. This low, but significant, level of ER beta trans-activation potential may be enhanced by coexpression of delta 5ER alpha in neoplastic pituitary. Therefore, E2-mediated gene expression in normal and neoplastic pituitary appears to be highly dependent on the expression of ER alpha and ER beta isof...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.