Mechanism of action of GLP-1 agonists

Physiology

The term “incretin effect” refers to the amplification of insulin secretion instigated by oral glucose ingestion compared to an equivalent amount of glucose delivered intravenously. This effect is primarily mediated by two incretin hormones, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Originating in the gut, these hormones are secreted in response to nutrient intake.

Proglucagon, a 160-residue peptide produced by the pancreas’ α-cells and the small intestine’s K and L cells, undergoes selective posttranslational modifications to produce these essential incretin hormones. Specifically, GIP is synthesized by the K cells in the upper intestine, while GLP-1 is generated by the L cells in the lower intestine.

GLP-1 and GIP execute their effects on glucose metabolism via their interaction with specific G protein-coupled receptors (GPCRs) located on pancreatic beta cells. The binding of incretins to GPCRs triggers a cascade of intracellular events, including cyclic AMP production and the consequent activation of protein kinase A. This kinase facilitates a series of downstream intracellular activities, culminating in enhanced insulin secretion from pancreatic beta cells.

GLP-1 and GIP stimulate insulin secretion from these cells in a glucose-dependent manner, meaning that insulin release intensifies in response to heightened plasma glucose levels. This unique trait helps in maintaining glucose homeostasis, especially post-absorption.

Additionally, incretins impede glucagon release from pancreatic alpha cells, thereby curbing hepatic glucose production. Moreover, these hormones contribute to beta cell proliferation and longevity, which is particularly relevant in type 2 diabetes where beta cell function is compromised.

Extrapancreatic impacts of incretins also facilitate glucose regulation. GLP-1 and GIP can decelerate gastric emptying, thus moderating the rate of nutrient absorption and aiding glycemic control. They can also instigate a sense of satiety, leading to weight reduction and improved glucose regulation.

In summary, incretins serve as integral contributors to glucose metabolism by promoting insulin release, inhibiting glucagon secretion, supporting beta cell function and survival, and mitigating appetite and food consumption.

Mechanism of Action of GLP-1 agonists

GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors comprise two drug categories routinely utilized in the clinical setting. Semaglutide and liraglutide serve as examples of GLP-1 receptor agonists, while sitagliptin and saxagliptin are commonly used DPP-4 inhibitors.

GLP-1 receptor agonists emulate the physiological functions of GLP-1 by activating the GLP-1 receptor. On the other hand, DPP-4 inhibitors augment the half-life of endogenous GLP-1 by impeding its degradation. Each of these pharmaceutical classes can enhance glycemic control and carry ancillary benefits, including weight reduction and decreased cardiovascular risk.

Mechanism of action of Tirzepatide

Tirzepatide, a novel investigational medication as of my knowledge cutoff in September 2021, is a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. This dual agonist approach enhances its potential for glycemic control and weight loss in patients with type 2 diabetes.

The mechanism of action of tirzepatide leverages the physiological roles of both GIP and GLP-1. These hormones, known collectively as incretins, are secreted by the gut in response to nutrient ingestion and play crucial roles in metabolic regulation.

Upon binding to their respective receptors on pancreatic beta cells, GIP and GLP-1 enhance insulin secretion in a glucose-dependent manner. They consequently improve postprandial hyperglycemia. Additionally, GLP-1 receptor activation suppresses glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production.

Practice Pearl(s)

The dosing regimen of glucagon-like peptide-1 (GLP-1) agonists is characterized by careful initiation and titration to ensure optimal glycemic control while minimizing potential adverse effects. Here are the initial and titrated doses for a selection of GLP-1 agonists:

• Liraglutide (Victoza): Initiation requires a subcutaneous administration of 0.6 mg daily. If additional glycemic control is required after one week, the dosage may be increased to 1.2 mg daily. In case further glycemic control is still needed, the dose can be augmented to 1.8 mg daily.
• Semaglutide (Ozempic): An initial dose of 0.25 mg is administered subcutaneously on a weekly basis for the first month, which is then increased to 0.5 mg weekly. If required, this can be further adjusted up to 1 mg and ultimately 2mg (the maximum dose for diabetes treatment) weekly.
• Exenatide extended-release (Bydureon): This medication is given at a fixed dose of 2 mg subcutaneously once weekly.
• Exenatide immediate-release (Byetta): Initiation involves a 5 mcg dose administered subcutaneously twice daily, which can be increased to 10 mcg twice daily after a month if required.
• Oral Semaglutide (Rybelsus): The starting dose is 3 mg daily for the initial month, which is then increased to 7 mg daily for the next two months. If additional glycemic control is necessary, the dose can be increased to 14 mg daily.
• Dulaglutide (Trulicity): The initial dose is 0.75 mg subcutaneously once weekly, which can be increased to 1.5 mg weekly after four weeks if required.
• Tirzepatide (Mounjaro): Commence with 5 mg subcutaneously once weekly, with subsequent weekly titration up to 15 mg or 20 mg, depending on patient response and tolerability.

Patient monitoring for potential adverse effects like gastrointestinal disturbances, hypoglycemia, and injection site reactions is essential during treatment with GLP-1 agonists. Also, these medications should be used with caution in individuals with a history of pancreatitis or thyroid C-cell tumors due to a potential increased risk associated with these conditions.

References

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