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First-in-Human Evaluation of Positron Emission Tomography/Computed Tomography With [18F]FB(ePEG12)12-Exendin-4: A Phase 1 Clinical Study Targeting GLP-1 Receptor Expression Cells in Pancreas.
Fujimoto, H, Fujita, N, Hamamatsu, K, Murakami, T, Nakamoto, Y, Saga, T, Ishimori, T, Shimizu, Y, Watanabe, H, Sano, K, et al
Frontiers in endocrinology. 2021;:717101
Abstract
Pancreatic β-cell mass (BCM) has a central importance in the pathophysiology of diabetes mellitus. Recently, pancreatic β-cell-specific imaging, especially positron emission tomography (PET) with exendin-based probes, has emerged for non-invasive evaluation of BCM. We developed a novel exendin-based probe labeled with fluorine-18, [18F]FB(ePEG12)12-exendin-4 (18F-Ex4) for PET imaging. We subsequently conducted a first-in-human phase 1 study of 18F-Ex4 PET/computed tomography (CT) and investigated the safety and utility for visualizing the pancreas. Six healthy male subjects were enrolled in this study. A low dose (37.0 MBq) of 18F-Ex4 PET/CT was administered (first cohort: n = 2), and subsequently a higher dose (74.0 MBq) was administered (second cohort: n = 4). In the first and second cohorts, 38.6 ± 4.8 and 71.1 ± 4.8 MBq of 18F-Ex4 were administered, respectively. No serious adverse events were observed in both groups. Only one participant in the first cohort showed transient hypoglycemia during the PET scans. 18F-Ex4 PET/CT successfully visualized the pancreas in all participants. The mean standardized uptake value of the pancreas was found to be higher than that in the surrounding organs, except for the bladder and kidney, during the observation. Dosimetry analyses revealed the effective systemic doses of 18F-Ex4 as 0.0164 ± 0.0019 mSv/MBq (first cohort) and 0.0173 ± 0.0020 mSv/MBq (second cohort). 18F-Ex4 PET/CT demonstrated the safety and utility for non-invasive visualization of the pancreas in healthy male subjects. 18F-Ex4 is promising for clinical PET imaging targeting pancreatic β cells.
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Long-term safety and efficacy of the sodium-glucose cotransporter 2 inhibitor, tofogliflozin, added on glucagon-like peptide-1 receptor agonist in Japanese patients with type 2 diabetes mellitus: A 52-week open-label, multicenter, post-marketing clinical study.
Terauchi, Y, Fujiwara, H, Kurihara, Y, Suganami, H, Tamura, M, Senda, M, Gunji, R, Kaku, K
Journal of diabetes investigation. 2019;(6):1518-1526
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Abstract
AIMS/INTRODUCTION Tofogliflozin is a potent and highly selective sodium-glucose cotransporter 2 inhibitor that is currently used to treat patients with type 2 diabetes mellitus. The aim of the present study was to evaluate the safety and efficacy of tofogliflozin add-on to glucagon-like peptide-1 (GLP-1) receptor agonist monotherapy. MATERIALS AND METHODS In this 52-week, prospective, multicenter, single arm, post-marketing clinical study, Japanese patients who had already been receiving GLP-1 receptor agonist monotherapy for ≥8 weeks, glycated hemoglobin ≥7.0 and <10.5%, and body mass index ≥18.5 and <35.0 kg/m2 were enrolled. Tofogliflozin 20 mg was orally administered once daily for 52 weeks with GLP-1 receptor agonist. Primary end-points were safety and change in glycated hemoglobin from baseline to week 52. Safety was assessed on the basis of the adverse events. Changes from baseline in fasting plasma glucose, bodyweight, blood pressure, uric acid and lipid parameters were assessed as secondary efficacy end-points. RESULTS Of the 67 patients enrolled, 63 patients completed the study. Overall, 26 adverse drug reactions occurred in 17 patients (25.4%). Adverse drug reactions with a frequency of two or more patients (3.0%) were constipation, thirst, dehydration and pollakiuria. Hypoglycemia (n = 1) was limited. With the addition of tofogliflozin to GLP-1 receptor agonist, the subsequent mean (standard deviation) reduction in glycated hemoglobin was -0.6% (1.0%; P < 0.0001). Fasting plasma glucose, bodyweight and blood pressure were significantly improved. CONCLUSIONS Tofogliflozin add-on to GLP-1 receptor agonist monotherapy is an effective treatment option with an acceptable safety profile.
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Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner.
Wei, R, Ma, S, Wang, C, Ke, J, Yang, J, Li, W, Liu, Y, Hou, W, Feng, X, Wang, G, et al
American journal of physiology. Endocrinology and metabolism. 2016;(11):E947-57
Abstract
Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9-39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9-39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.