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

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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Physiology of Proglucagon Peptides: Role of Glucagon and GLP-1 in Health and Disease

Physiological Reviews ◽

10.1152/physrev.00013.2014 ◽

2015 ◽

Vol 95 (2) ◽

pp. 513-548 ◽

Cited By ~ 180

Author(s):

Darleen A. Sandoval ◽

David A. D'Alessio

Keyword(s):

Glucose Homeostasis ◽

Energy Homeostasis ◽

Glucose Production ◽

Glucagon Secretion ◽

The Body ◽

Pharmacological Interaction ◽

Glucose Levels ◽

Health And Disease ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The preproglucagon gene ( Gcg) is expressed by specific enteroendocrine cells (L-cells) of the intestinal mucosa, pancreatic islet α-cells, and a discrete set of neurons within the nucleus of the solitary tract. Gcg encodes multiple peptides including glucagon, glucagon-like peptide-1, glucagon-like peptide-2, oxyntomodulin, and glicentin. Of these, glucagon and GLP-1 have received the most attention because of important roles in glucose metabolism, involvement in diabetes and other disorders, and application to therapeutics. The generally accepted model is that GLP-1 improves glucose homeostasis indirectly via stimulation of nutrient-induced insulin release and by reducing glucagon secretion. Yet the body of literature surrounding GLP-1 physiology reveals an incompletely understood and complex system that includes peripheral and central GLP-1 actions to regulate energy and glucose homeostasis. On the other hand, glucagon is established principally as a counterregulatory hormone, increasing in response to physiological challenges that threaten adequate blood glucose levels and driving glucose production to restore euglycemia. However, there also exists a potential role for glucagon in regulating energy expenditure that has recently been suggested in pharmacological studies. It is also becoming apparent that there is cross-talk between the proglucagon derived-peptides, e.g., GLP-1 inhibits glucagon secretion, and some additive or synergistic pharmacological interaction between GLP-1 and glucagon, e.g., dual glucagon/GLP-1 agonists cause more weight loss than single agonists. In this review, we discuss the physiological functions of both glucagon and GLP-1 by comparing and contrasting how these peptides function, variably in concert and opposition, to regulate glucose and energy homeostasis.

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Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00014.2004 ◽

2004 ◽

Vol 286 (6) ◽

pp. E882-E890 ◽

Cited By ~ 58

Author(s):

David A. D'Alessio ◽

Torsten P. Vahl

Keyword(s):

Insulin Secretion ◽

Blood Glucose ◽

Cell Mass ◽

Insulin Response ◽

Gastrointestinal Hormones ◽

Glucose Production ◽

Glucagon Secretion ◽

Treatment Of Diabetes ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide 1 (GLP-1) is a product of proglucagon that is secreted by specialized intestinal endocrine cells after meals. GLP-1 is insulinotropic and plays a role in the incretin effect, the augmented insulin response observed when glucose is absorbed through the gut. GLP-1 also appears to regulate a number of processes that reduce fluctuations in blood glucose, such as gastric emptying, glucagon secretion, food intake, and possibly glucose production and glucose uptake. These effects, in addition to the stimulation of insulin secretion, suggest a broad role for GLP-1 as a mediator of postprandial glucose homeostasis. Consistent with this role, the most prominent effect of experimental blockade of GLP-1 signaling is an increase in blood glucose. Recent data also suggest that GLP-1 is involved in the regulation of β-cell mass. Whereas other insulinotropic gastrointestinal hormones are relatively ineffective in stimulating insulin secretion in persons with type 2 diabetes, GLP-1 retains this action and is very effective in lowering blood glucose levels in these patients. There are currently a number of products in development that utilize the GLP-1-signaling system as a mechanism for the treatment of diabetes. These compounds, GLP-1 receptor agonists and agents that retard the metabolism of native GLP-1, have shown promising results in clinical trials. The application of GLP-1 to clinical use fulfills a long-standing interest in adapting endogenous insulinotropic hormones to the treatment of diabetes.

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Advances in GLP-1 treatment: focus on oral semaglutide

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-021-00713-9 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Freddy G. Eliaschewitz ◽

Luis Henrique Canani

Keyword(s):

Receptor Agonist ◽

Standard Of Care ◽

Oral Formulation ◽

Early Diabetes ◽

Glucose Levels ◽

Blood Glucose Levels ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Glucagon And Insulin ◽

Spectrum Of Patients

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 Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion—A Review

International Journal of Molecular Sciences ◽

10.3390/ijms20174092 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4092 ◽

Cited By ~ 9

Author(s):

David S. Mathiesen ◽

Jonatan I. Bagger ◽

Natasha C. Bergmann ◽

Asger Lund ◽

Mikkel B. Christensen ◽

...

Keyword(s):

Weight Loss ◽

Body Weight Loss ◽

Glucagon Secretion ◽

Therapeutic Effects ◽

Haemoglobin A1c ◽

Cell Secretion ◽

Glucose Levels ◽

Glucagon Like Peptide 1 ◽

Meal Ingestion ◽

Gip Receptor

The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP acts glucagonotropically at low glucose levels. A dual incretin receptor agonist designed to co-activate GLP-1 and GIP receptors was recently shown to elicit robust improvements of glycemic control (mean haemoglobin A1c reduction of 1.94%) and massive body weight loss (mean weight loss of 11.3 kg) after 26 weeks of treatment with the highest dose (15 mg once weekly) in a clinical trial including overweight/obese patients with type 2 diabetes. Here, we describe the mechanisms by which the two incretins modulate alpha cell secretion of glucagon, review the effects of co-administration of GLP-1 and GIP on glucagon secretion, and discuss the potential role of glucagon in the therapeutic effects observed with novel unimolecular dual GLP-1/GIP receptor agonists. For clinicians and researchers, this manuscript offers an understanding of incretin physiology and pharmacology, and provides mechanistic insight into future antidiabetic and obesity treatments.

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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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