Advances in GLP-1 treatment: focus on oral semaglutide

Abstract Background There is currently a large arsenal of antidiabetic drugs available to treat type 2 diabetes (T2D). However, this is a serious chronic disease that affects millions of adults worldwide and is responsible for severe complications, comorbidities, and low quality of life when uncontrolled due mainly to delays in initiating treatment or inadequate therapy. This review article aims to clarify the therapeutic role of the oral formulation of the glucagon-like peptide 1 receptor agonist (GLP-1 RA) semaglutide in treating typical T2D patients. The discussion focused on metabolic, glycemic, and weight alteration effects and the safety of the therapy with this drug. Main text Therapy with glucagon-like peptide 1 receptor agonist (GLP-1 RA) promotes strategic changes in the pathophysiological pathway of T2D and improves the secretion of glucagon and insulin, which results in a reduction in blood glucose levels and the promotion of weight loss. Until recently, the only route for semaglutide administration was parenteral. However, an oral formulation of GLP-1 RA was recently developed and approved by the Brazilian Health Regulatory Agency (ANVISA) and the Food and Drug Administration (FDA) based on the Peptide Innovation for Early Diabetes Treatment (PIONEER) program results. A sequence of 10 clinical studies compared oral semaglutide with placebo or active standard-of-care medications (empagliflozin 25 mg, sitagliptin 100 mg, or liraglutide 1.8 mg) in different T2D populations. Conclusions Oral semaglutide effectively reduces glycated hemoglobin (HbA1c) levels and body weight in a broad spectrum of patients with T2D and shows cardiovascular safety. Oral semaglutide broadens therapy options and facilitates the adoption of earlier GLP-1 RA treatment once T2D patients present low rates of treatment discontinuation. The main adverse events reported were related to the gastrointestinal tract, common to GLP-1 RA class drugs.

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The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect

Cardiovascular Diabetology ◽

10.1186/s12933-021-01412-5 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Enrique Z. Fisman ◽

Alexander Tenenbaum

Keyword(s):

Receptor Agonist ◽

Therapeutic Option ◽

Insulin Response ◽

Glucagon Secretion ◽

Long Term Effects ◽

Glucose Levels ◽

Lower Glucose ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Gip Receptor

AbstractIncretin hormones are peptides released in the intestine in response to the presence of nutrients in its lumen. The main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 stimulates insulin secretion, inhibits glucagon secretion at pancreatic α cells and has also extrapancreatic influences as slowing of gastric emptying which increases the feeling of satiety. GIP is the main incretin hormone in healthy people, causative of most the incretin effects, but the insulin response after GIP secretion in type 2 diabetes mellitus (T2DM) is strongly reduced. Therefore, in the past GIP has been considered an unappealing therapeutic target for T2DM. This conception has been changing during recent years, since it has been reported that resistance to GIP can be reversed and its effectiveness restored by improving glycemic control. This fact paved the way for the development of a GIP receptor agonist-based therapy for T2DM, looking also for the possibility of finding a combined GLP-1/GIP receptor agonist. In this framework, the novel dual GIP and GLP-1 receptor agonist tirzepatide seems to be not just a new antidiabetic medication. Administered as a subcutaneous weekly injection, it is a manifold single pharmacological agent that has the ability to significantly lower glucose levels, as well as improve insulin sensitivity, reduce weight and amend dyslipidemia favorably modifying the lipid profile. Tirzepatide and additional dual GLP-1/GIP receptor agonists that could eventually be developed in the future seem to be a promising furthest advance for the management of several cardiometabolic settings. Obviously, it is too early to be overly hopeful since it is still necessary to determine the long-term effects of these compounds and properly verify the potential cardiovascular benefits. Anyway, we are currently facing a novel and very appealing therapeutic option.

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Cardiovascular effects of glucagon-like peptide 1 receptor agonists: from mechanistic studies in humans to clinical outcomes

Cardiovascular Research ◽

10.1093/cvr/cvz323 ◽

2019 ◽

Vol 116 (5) ◽

pp. 916-930 ◽

Cited By ~ 9

Author(s):

Valerie D Heuvelman ◽

Daniël H Van Raalte ◽

Mark M Smits

Keyword(s):

Cardiovascular Disease ◽

Blood Glucose ◽

Cardiovascular Effects ◽

Lifestyle Changes ◽

Mechanistic Studies ◽

Receptor Agonists ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract Type 2 diabetes mellitus (T2DM) is currently one of the most prevalent diseases, with as many as 415 million patients worldwide. T2DM is characterized by elevated blood glucose levels and is often accompanied by several comorbidities, such as cardiovascular disease. Treatment of T2DM is focused on reducing glucose levels by either lifestyle changes or medical treatment. One treatment option for T2DM is based on the gut-derived hormone glucagon-like peptide 1 (GLP-1). GLP-1 reduces blood glucose levels by stimulating insulin secretion, however, it is rapidly degraded, and thereby losing its glycaemic effect. GLP-1 receptor agonists (GLP-1RAs) are immune to degradation, prolonging the glycaemic effect. Lately, GLP-1RAs have spiked the interest of researchers and clinicians due to their beneficial effects on cardiovascular disease. Preclinical and clinical data have demonstrated that GLP-1 receptors are abundantly present in the heart and that stimulation of these receptors by GLP-1 has several effects. In this review, we will discuss the effects of GLP-1RA on heart rate, blood pressure, microvascular function, lipids, and inflammation, as measured in human mechanistic studies, and suggest how these effects may translate into the improved cardiovascular outcomes as demonstrated in several trials.

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Glucose-Responsive Microneedle Patches for Diabetes Treatment

Journal of Diabetes Science and Technology ◽

10.1177/1932296818778607 ◽

2018 ◽

Vol 13 (1) ◽

pp. 41-48 ◽

Cited By ~ 15

Author(s):

Guojun Chen ◽

Jicheng Yu ◽

Zhen Gu

Keyword(s):

Drug Delivery ◽

Blood Glucose ◽

Release Kinetics ◽

Blood Glucose Control ◽

Diabetes Therapy ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Treatment Of Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Antidiabetic therapeutics, including insulin as well as glucagon-like peptide 1 (GLP-1) and its analogs, are essential for people with diabetes to regulate their blood glucose levels. Nevertheless, conventional treatments based on hypodermic administration is commonly associated with poor blood glucose control, a lack of patient compliance, and a high risk of hypoglycemia. Closed-loop drug delivery strategies, also known as self-regulated administration, which can intelligently govern the drug release kinetics in response to the fluctuation in blood glucose levels, show tremendous promise in diabetes therapy. In the meantime, the advances in the development and use of microneedle (MN)-array patches for transdermal drug delivery offer an alternative method to conventional hypodermic administration. Hence, glucose-responsive MN-array patches for the treatment of diabetes have attracted increasing attentions in recent years. This review summarizes recent advances in glucose-responsive MN-array patch systems. Their opportunities and challenges for clinical translation are also discussed.

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Glucagon-Like Peptide-1 Receptor Agonist Prevented the Progression of Hepatocellular Carcinoma in a Mouse Model of Nonalcoholic Steatohepatitis

International Journal of Molecular Sciences ◽

10.3390/ijms21165722 ◽

2020 ◽

Vol 21 (16) ◽

pp. 5722

Author(s):

Motoyasu Kojima ◽

Hirokazu Takahashi ◽

Takuya Kuwashiro ◽

Kenichi Tanaka ◽

Hitoe Mori ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Nonalcoholic Steatohepatitis ◽

Fasting Blood Glucose ◽

Saline Control ◽

Control Group ◽

Receptor Agonists ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) receptor agonists are used to treat diabetes, but their effects on nonalcoholic steatohepatitis (NASH) and the development of hepatocellular carcinoma (HCC) remain unclear. In this study, mice with streptozotocin- and high-fat diet-induced diabetes and NASH were subcutaneously treated with liraglutide or saline (control) for 14 weeks. Glycemic control, hepatocarcinogenesis, and liver histology were compared between the groups. Fasting blood glucose levels were significantly lower in the liraglutide group than in the control group (210.0 ± 17.3 mg/dL vs. 601.8 ± 123.6 mg/dL), and fasting insulin levels were significantly increased by liraglutide (0.18 ± 0.06 ng/mL vs. 0.09 ± 0.03 ng/mL). Liraglutide completely suppressed hepatocarcinogenesis, whereas HCC was observed in all control mice (average tumor count, 5.5 ± 3.87; average tumor size, 8.1 ± 5.0 mm). Liraglutide significantly ameliorated steatosis, inflammation, and hepatocyte ballooning of non-tumorous lesions in the liver compared with the control findings, and insulin-positive β-cells were observed in the pancreas in liraglutide-treated mice but not in control mice. In conclusion, liraglutide ameliorated NASH and suppressed hepatocarcinogenesis in diabetic mice. GLP-1 receptor agonists can be used to improve the hepatic outcome of diabetes.

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Renal hemodynamic effects of glucagon-like peptide-1 agonist are mediated by nitric oxide but not prostaglandin

AJP Renal Physiology ◽

10.1152/ajprenal.00258.2017 ◽

2017 ◽

Vol 313 (4) ◽

pp. F854-F858 ◽

Cited By ~ 3

Author(s):

Scott C. Thomson ◽

Ali Kashkouli ◽

Zhi Zhao Liu ◽

Prabhleen Singh

Keyword(s):

Nitric Oxide ◽

Degradation Products ◽

Prostaglandin E ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Cox Inhibitor ◽

Nos Inhibitor ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

The Impact

The incretin hormone, glucagon-like peptide-1 (GLP-1), is known for responding to dietary fat and carbohydrate. It elicits effects on pancreas, gut, and brain to stabilize blood glucose levels. We have previously reported that the GLP-1 agonist, exenatide, vasodilates the kidney and suppresses proximal reabsorption. The present study was undertaken to determine whether the renal effects of exenatide are mediated by nitric oxide (NO) and/or prostaglandins. Inulin clearance (glomerular filtration rate, GFR) and urine flow rate (UV) were measured in anesthetized rats before and during exenatide infusion (1 nmol/h iv). Animals were pretreated with cyclooxygenase (COX) inhibitor (meclofenamate), NO synthase (NOS) inhibitor ( NG-monomethyl-l-arginine, l-NMMA), NO clamp (l-NMMA + sodium nitroprusside), or placebo. Effectiveness of COX inhibition was tested by measuring urinary prostaglandin E2 (UPGE2). Effectiveness of NOS blockade and NO clamp was determined by urinary NO degradation products (UNOx). Exenatide increased GFR, UV, UPGE2, and UNOx. Pretreatment with meclofenamate reduced UPGE2 by 75% and reduced the effect of exenatide on UPGE2 by 30% but did not modify the effects of exenatide on GFR or UV. Pretreatment with l-NMMA reduced UNOx and the impact of exenatide on GFR and UV by 50%. Pretreatment by NO clamp did not prevent UNOx from increasing during exenatide but blunted the effects of exenatide on GFR and UV. In conclusion, exenatide is a potent renal vasodilator and diuretic in the rat. These effects of exenatide are insensitive to COX inhibition but are mediated, in part, by NO.

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Incretins today: multiple effects and therapeutic potential

Diabetes Mellitus ◽

10.14341/dm9841 ◽

2019 ◽

Vol 22 (1) ◽

pp. 70-78

Author(s):

Oksana V. Tsygankova ◽

Varvara V. Veretyuk ◽

Alexander S. Ametov

Keyword(s):

Therapeutic Potential ◽

Incretin Hormones ◽

Alcoholic Fatty Liver ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

The 1960S ◽

Insulinotropic Peptide

Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are the incretin hormones initially discovered in the 1960s. GIP and GLP-1 have gained great scientific interest due to their properties in increasing insulin secretion and lowering blood glucose levels. The study of these incretin hormones has progressed substantially in recent decades, in that their systemic effects has begun to be actively discussed. In particular, incretins are involved in the pathogenesis of obesity and non-alcoholic fatty liver disease. Moreover, incretins are able to improve cognitive function, suppress the formation of -amyloid plaques and provide an oncoprotective effect. Recent data show promising oncoprotective effect of GLP-1 agonists on prostate and breast cancer. This review provides systematisation of recent data on the role and mechanisms of action of incretin hormones on carbohydrate metabolism, as well as effects not related to glucose homeostasis, which contributes to a better understanding of potential vectors for the development of incretinotropic therapy. In addition, this review offers insight into pathogenic prerequisites and highlights the current issues in creating innovative polyagonists for treatment of type 2 diabetes mellitus.

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Effects of E2HSA, a Long-Acting Glucagon Like Peptide-1 Receptor Agonist, on Glycemic Control and Beta Cell Function in Spontaneous Diabetic db/db Mice

Journal of Diabetes Research ◽

10.1155/2015/817839 ◽

2015 ◽

Vol 2015 ◽

pp. 1-17 ◽

Cited By ~ 5

Author(s):

Shaocong Hou ◽

Caina Li ◽

Yi Huan ◽

Shuainan Liu ◽

Quan Liu ◽

...

Keyword(s):

Receptor Agonist ◽

Cell Function ◽

Similar Efficacy ◽

Glucose Lowering ◽

Glucose Levels ◽

Weekly Treatment ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Long Acting ◽

Upregulated Genes

Glucagon like peptide-1 (GLP-1) receptor agonists such as exendin-4 have been widely used but their short half-life limits their therapeutic value. The recombinant protein, E2HSA, is a novel, long-acting GLP-1 receptor agonist generated by the fusion of exendin-4 with human serum albumin. In mouse pancreatic NIT-1 cells, E2HSA activated GLP-1 receptor with similar efficacy as exendin-4. After single-dose administration in ICR mice, E2HSA showed prolonged glucose lowering effects which lasted up to four days and extended inhibition on gastric emptying for at least 72 hours. Chronic E2HSA treatment in db/db mice significantly improved glucose tolerance, reduced elevated nonfasting and fasting plasma glucose levels, and also decreased HbA1c levels. E2HSA also increased insulin secretion and decreased body weight and appetite. Furthermore, immunofluorescence analysis showed that E2HSA increasedβ-cell area, improved islet morphology, and reducedβ-cell apoptosis. In accordance with the promotion ofβ-cell function and survival, E2HSA upregulated genes such as Irs2, Pdx-1, Nkx6.1, and MafA and downregulated the expression levels of FoxO1 and proapoptotic Bcl-2 family proteins. In conclusion, with prolonged glucose lowering effects and promotingβ-cell function and survival, the fusion protein, E2HSA, is a promising new therapeutic for once weekly treatment of type 2 diabetes.

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Oral Semaglutide, the First Ingestible Glucagon-Like Peptide-1 Receptor Agonist: Could It Be a Magic Bullet for Type 2 Diabetes?

International Journal of Molecular Sciences ◽

10.3390/ijms22189936 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9936

Author(s):

Hwi Seung Kim ◽

Chang Hee Jung

Keyword(s):

Type 2 Diabetes ◽

Insulin Secretion ◽

Receptor Agonist ◽

Body Weight Loss ◽

Glucagon Secretion ◽

Magic Bullet ◽

Early Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The gastrointestinal tract secretes gut hormones in response to food consumption, and some of these stimulate insulin secretion. Glucagon-like peptide-1 (GLP-1) is an incretin peptide hormone released from the lower digestive tract that stimulates insulin secretion, suppresses glucagon secretion, and decreases hunger. GLP-1 receptor agonist (GLP-1RA) mimics the action of endogenous GLP-1, consequently reversing hyperglycemia and causing weight reduction, demonstrating its efficacy as an antidiabetic and antiobesity agent. Previously restricted to injection only, the invention of the absorption enhancer sodium N-(8-[2-hydroxybenzoyl]amino) caprylate resulted in the development of oral semaglutide, the first ingestible GLP-1RA. Oral semaglutide demonstrated its efficacy in glycemic management and body weight loss with a low risk of hypoglycemia as a monotherapy and in combination with other hypoglycemic medications in its clinical trial programs named Peptide Innovation for Early Diabetes Treatment. Consistent with other injectable GLP-1RAs, gastrointestinal side effects were often reported. Additionally, cardiovascular safety was established by demonstrating that oral semaglutide was not inferior to a placebo in terms of cardiovascular outcomes. Thus, oral semaglutide represents a novel treatment option that is particularly well-suited for patients with type 2 diabetes and/or obesity.

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