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The Magic of Semaglutide (GLP-1) and Tirzepatide (GLP-1/GIP)

Semaglutide and Tirzepatide (GLP-1/GIP)The Magic of Semaglutide (GLP-1) and Tirzepatide (GLP-1/GIP) is gaining interest among scientists this year. Semaglutide (GLP-1) and Tirzepatide (GLP-1/GIP). The human GLP-1 analogue Semaglutide (semaglutide) and the chimeric human/human GIP-GLP-1 analogue Tirzepatide (TZP-101) are incretin therapies that have proven clinical efficacy in both type 2 diabetes and type 1 diabetes (T1D).

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What is Semaglutide (GLP-1) and Tirzepatide

They represent a significant advance in the treatment of type 2 diabetes. The first clinical results have been published of Semaglutide in monotherapy and in combination with metformin (Lilly SLE-5 study) (Keller et al. JAMA Intern Med 2015; 175:5-14 and Sato et al. N. Engl. J. Med. 2016; 375:1821-30) and in T1D (Novo Nordisk study) (Sato et al. J. Clin. Endocrinol. Metab. 2016; 101:3499-3510). The results are very encouraging. In the UK, Semaglutide has recently been approved as monotherapy for type 2 diabetes, with the hope of replacing Sulfonylureas and Glucosidase inhibitors (glinides). Clinical trials are already ongoing to assess the efficacy and safety of Semaglutide as add-on therapy to metformin and as an insulin-sparing agent in T1D. In this article, we review the mechanism of action and current indications of Semaglutide and TZP-101 and discuss future directions. GLP-1 and GLP-1 R Agonists.

The first incretin therapies to be approved for the treatment of type 2 diabetes were Glucagon-like peptide-1 (GLP-1) analogues and their orally active, long-lasting counterparts, the Glucagon-like peptide-1 receptor agonists (GLP-1 RAs). They lower blood glucose levels primarily by increasing the insulin secretion and reducing glucagon secretion. GLP-1 RAs also have important effects on beta cell mass and function. GLP-1 RAs mimic the actions of GLP-1, but they have a longer half-life, less tendency to cause hypoglycemia, and improved oral bioavailability. The mechanism of action of GLP-1 involves complex interactions between multiple neurotransmitters and other gastrointestinal hormones, including GIP and glucagon. GLP-1 RAs are a heterogeneous group of molecules and a thorough understanding of the role of each molecule and the complexity of the GLP-1 system in the pancreas is beyond the scope of this review.

GLP-1 RAs are the most commonly used incretin therapies, and the clinical effects of these molecules have been covered in many publications.1,2 However, as we review here, the molecular and clinical actions of GLP-1 and the GLP-1 RAs overlap. GLP-1 and the GLP-1 RAs do not fully mimic the action of GLP-1.

In addition to the well-characterized actions on insulin and glucagon secretion, GLP-1 and GLP-1 RAs exert some effects on energy metabolism. These include slowing gastric emptying and stimulation of adipose tissue lipolysis. GLP-1 RAs also lower food intake and slow gastric emptying, which may be beneficial in obese patients. GLP-1 RAs, in general, are well-tolerated with the exception of gastrointestinal symptoms and hypoglycemia. Most are taken once daily and do not require dose adjustments over a lifetime, unlike long-acting insulin. GLP-1 RAs are not, however, as safe as once-daily injectable insulin. Gastrointestinal side effects of GLP-1 RAs are usually mild and mostly resolve with time.

The GLP-1 RAs, in general, have a low risk of hypoglycemia, with the exception of the DPP-4 inhibitors. Hypoglycemia is a major concern of GLP-1 RAs. There have been several reports of unexpected or severe hypoglycemia associated with use of GLP-1 RAs, in particular after initiating, or after uptitrating the dose, of the GLP-1 RAs, liraglutide and lixisenatide. For the sake of safety, GLP-1 RAs are to be avoided in patients with hypoglycemia unawareness. This issue is highlighted by the recent publication of a randomized clinical trial, the DIAMOND, which showed an increase in the rate of severe hypoglycemia and a reduced event-free survival with liraglutide compared with sitagliptin.3 Gastric bypass and GLP-1 RAs: A Perfect Match. Both obesity and T2D are related to low-grade inflammation and are associated with low-grade chronic subclinical gut inflammation, which can cause symptoms, such as bloating, early satiety, or abdominal discomfort. Recent evidence suggests that GLP-1 is involved in energy regulation and the satiety process.

The Magic of Semaglutide (GLP-1) and Tirzepatide (GLP-1/GIP)

This is a key issue when treating T2D and obesity, as many T2D patients have coexisting obesity. Dipeptidyl peptidase-4 (DPP-4) is an enzyme that inactivates incretins, including GLP-1 and GIP, and it is highly expressed in the gastrointestinal tract. However, its expression in fat, the liver, the heart, and the brain makes DPP-4 an enzyme with a variety of biological functions. The incretin-based therapies, in general, suppress plasma DPP-4 activity. There are two classes of incretin therapies. One is the GLP-1 receptor agonists, which are small synthetic compounds that mimic the effects of GLP-1 and include exenatide (Byetta), exenatide extended release (Bydureon), liraglutide, albiglutide, semaglutide, and TZP-101 (Tirzepatide).

The other is the glucagon-like peptide-1 (GLP-1) and GIP chimeric compound, which has a long peptide chain and is highly specific for the GLP-1 receptor. The two groups of incretin therapies show differences in pharmacokinetics and pharmacodynamics. With GLP-1, the drug enters the systemic circulation and achieves full biological activity (GLP-1 receptor agonism). The GLP-1 and GIP chimera is a large protein molecule.

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