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Glucagon-like peptide-1 (GLP-1) receptor agonists are efficacious glucose-lowering medications with salient benefits for body weight and cardiovascular events. This class of medications is now recommended as the top priority for patients with established cardiovascular disease or indicators of high risk. Until the advent of oral semaglutide, however, GLP-1 receptor agonists were available only in the form of subcutaneous injections. Aversion to needles, discomfort with self-injection, or skin problems at the injection site are commonly voiced problems in people with diabetes, and thus, attempts for non-invasive delivery strategies have continued. Herein, we review the evolution of GLP-1 therapy from its discovery and the development of currently approved drugs to the unprecedented endeavor to administer GLP-1 receptor agonists via the oral route. We focus on the pharmacokinetic and pharmacodynamic properties of the recently approved oral GLP-1 receptor agonist, oral semaglutide. Small molecule oral GLP-1 receptor agonists are currently in development, and we introduce how these chemicals have addressed the challenge posed by interactions with the large extracellular ligand binding domain of the GLP-1 receptor. We specifically discuss the structure and pharmacological properties of TT-OAD2, LY3502970, and PF-06882961, and envision an era where more patients could benefit from oral GLP-1 receptor agonist therapy.

Sho Tanaka,1 Midori Fujishiro,2 Yoshihiro Nakamura,1 Yoshinari Hatanaka,1 Masanori Abe1 1Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan; 2Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Tokyo, Japan Abstract: Aberrant cortisol secretion responses after exogenous stimuli such as upright posture, eating a mixed meal or receiving agents influencing aberrant G-protein-coupled receptors in adrenal glands, are often observed in patients with bilateral macronodular adrenal hyperplasia (BMAH). However, little is known about whether this aberrant response is retained after unilateral adrenalectomy. Here, we describe a 61-year-old postmenopausal Japanese woman with unsatisfactorily controlled hypertension who was referred to us for further investigation due to her pre-obesity characteristics (body mass index 28.4 kg/m2). Cushing’s signs and serum cortisol at 16.2 µg/dL with undetectable adrenocorticotropic hormone indicated adrenal Cushing’s syndrome. Adrenal imaging revealed bilaterally enlarged adrenal glands with 131-I adosterol uptake; hence, BMAH was diagnosed. Preoperatively, in vivo screening for aberrant adrenal receptors revealed an aberrant response of cortisol secretion on metoclopramide challenge. The patient underwent unilateral adrenalectomy; thereafter, glucocorticoid replacement therapy was reduced to hydrocortisone 15 mg/day at postoperative day 6. Fasting morning serum cortisol level measured at postoperative day 8 was 2.96 µg/dL, suggesting adrenal insufficiency. However, following metoclopramide administration serum cortisol level rose to 19.7 µg/dL, indicating potential efficient adrenal function. Aberrant cortisol secretory capacity was thus preserved in BMAH, even in a state of adrenal insufficiency after unilateral adrenalectomy. Caution should be exercised when assessing the hypothalamus-pituitary-adrenal axis, because in this patient, a high cortisol level did not guarantee appropriate adrenal function when the patient was challenged by exogenous stimuli. Keywords: adrenal glands, Cushing’s syndrome, glucocorticoids, hydrocortisone, metoclopramide, receptors, G-protein-coupled