Makindo Medical Notes

GLP-1 Receptor Agonists: Overview

GLP-1 (Glucagon-like Peptide-1) receptor agonists are a class of medications used primarily for the treatment of type 2 diabetes mellitus (T2DM) and, more recently, for weight management in obesity. These drugs mimic the action of the endogenous incretin hormone GLP-1, which enhances glucose-dependent insulin secretion, suppresses glucagon secretion, slows gastric emptying, and promotes satiety.

Mechanism of Action

GLP-1 receptor agonists work by mimicking the actions of the natural GLP-1 hormone, produced in the gut. They exert their effects in the following ways:

• Stimulation of Insulin Secretion: GLP-1 receptor agonists increase insulin secretion from pancreatic beta cells in response to elevated blood glucose levels. This glucose-dependent mechanism helps to reduce the risk of hypoglycemia.
• Inhibition of Glucagon Secretion: They suppress glucagon release from pancreatic alpha cells, reducing hepatic glucose production and helping to control postprandial blood glucose levels.
• Slowing Gastric Emptying: GLP-1 agonists delay gastric emptying, slowing down the absorption of glucose from the gastrointestinal tract and contributing to postprandial glucose control.
• Promotion of Satiety: They act on the hypothalamus to increase feelings of fullness (satiety), which can lead to reduced caloric intake and subsequent weight loss.

Indications

GLP-1 receptor agonists are indicated for the following conditions:

• Type 2 Diabetes Mellitus (T2DM): Used as monotherapy or in combination with other antidiabetic agents to improve glycemic control in adults with type 2 diabetes.
• Obesity and Weight Management: Certain GLP-1 agonists (such as liraglutide) have been approved for the treatment of obesity, as they help promote weight loss by reducing appetite and caloric intake.
• Cardiovascular Risk Reduction: Some GLP-1 agonists (such as liraglutide and semaglutide) are indicated for reducing cardiovascular events in patients with type 2 diabetes and established cardiovascular disease.

Common GLP-1 Receptor Agonists

• Exenatide (Byetta, Bydureon): One of the first GLP-1 agonists developed, available in twice-daily (Byetta) and once-weekly (Bydureon) formulations.
• Liraglutide (Victoza, Saxenda): Administered once daily, liraglutide is approved for both T2DM (Victoza) and weight management (Saxenda).
• Semaglutide (Ozempic, Rybelsus, Wegovy): Available as a weekly injection (Ozempic) or an oral formulation (Rybelsus), semaglutide is also approved for weight loss (Wegovy).
• Dulaglutide (Trulicity): A once-weekly GLP-1 agonist used for glycemic control and cardiovascular risk reduction in T2DM.
• Albiglutide (Tanzeum): A less commonly used once-weekly GLP-1 receptor agonist.
• Lixisenatide (Adlyxin): A once-daily GLP-1 agonist used for glycemic control in T2DM.

Benefits

• Improved Glycemic Control: GLP-1 agonists significantly reduce HbA1c levels, especially in combination with other antidiabetic medications.
• Weight Loss: These drugs promote weight loss through their appetite-suppressing effects, making them particularly beneficial for overweight and obese individuals with T2DM.
• Low Risk of Hypoglycemia: Since their insulin-secretion mechanism is glucose-dependent, they pose a lower risk of hypoglycemia compared to other therapies like insulin or sulfonylureas.
• Cardiovascular Benefits: Some GLP-1 agonists have been shown to reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes and cardiovascular disease.
• Potential for Renal Protection: Some studies suggest GLP-1 agonists may offer benefits for kidney health, reducing albuminuria and slowing the progression of diabetic kidney disease.

Adverse Effects

• Gastrointestinal Symptoms: Nausea, vomiting, and diarrhoea are the most common side effects, especially in the initial weeks of therapy. These effects often diminish over time.
• Injection Site Reactions: Redness, itching, or discomfort at the injection site can occur, particularly with injectable forms.
• Pancreatitis Risk: There have been reports of pancreatitis with GLP-1 agonists, though this is rare. Patients with a history of pancreatitis should use caution.
• Medullary Thyroid Carcinoma (MTC): GLP-1 receptor agonists are contraindicated in patients with a personal or family history of MTC or in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2), due to concerns about thyroid C-cell tumours in animal studies.
• Hypersensitivity Reactions: Rare cases of anaphylaxis and angioedema have been reported.

Clinical Considerations

• Combination Therapy: GLP-1 agonists are often combined with metformin, SGLT2 inhibitors, or basal insulin for enhanced glycemic control.
• Administration: Injectable GLP-1 agonists are typically administered subcutaneously (SC), with different formulations requiring daily, weekly, or twice-daily dosing.
• Contraindications: GLP-1 agonists are contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2).

Conclusion

GLP-1 receptor agonists are an important class of medications in the management of type 2 diabetes and obesity. Their ability to improve glycemic control, promote weight loss, and reduce cardiovascular risks has made them a valuable option in modern diabetes care. While generally well-tolerated, they are associated with gastrointestinal side effects and have specific contraindications, such as a history of medullary thyroid carcinoma or pancreatitis.