Introduction
Obesity has become a critical public health problem worldwide, increasing the risk of various diseases and reducing life quality and expectancy. Weight loss can significantly reduce obesity-related complications, and interventions like diet control, exercise, and medication are employed. Among these, glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as promising agents for treating obesity due to their effectiveness in managing blood glucose and promoting weight loss. These drugs have gained popularity, but it is important to understand their mechanisms, types, benefits, and potential risks.
Understanding GLP-1 Receptor Agonists
What are GLP-1 Agonists?
GLP-1 agonists are a class of medications primarily used to manage blood sugar levels in individuals with Type 2 diabetes. Some GLP-1 agonists are also approved to treat obesity. These medications mimic the naturally occurring GLP-1 hormone, which is produced in the small intestine and plays several crucial roles in the body.
How GLP-1 Agonists Work
GLP-1 agonists work by mimicking the GLP-1 hormone, which has several functions:
- Triggering Insulin Release: GLP-1 stimulates the pancreas to release insulin, which helps the body use glucose for energy and lowers blood sugar levels.
- Blocking Glucagon Secretion: GLP-1 inhibits the secretion of glucagon, a hormone that raises blood sugar levels.
- Slowing Stomach Emptying: GLP-1 slows down digestion, leading to a slower release of glucose into the bloodstream.
- Increasing Satiety: GLP-1 affects the brain, increasing the feeling of fullness after eating.
By mimicking these effects, GLP-1 agonists help manage blood sugar levels, reduce appetite, and promote weight loss.
The Entero-Insular Axis
GLP-1 receptor agonists are based on the entero-insular axis, where circulating peptides mediate insulinotropic activity. This mechanism makes GLP-1R agonists promising alternatives for treating obese subjects.
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GLP-1 and the Central Nervous System
In the central nervous system, proglucagon-derived peptides, including GLP-1, are present in a small group of neurons in the nucleus tractus solitarius. These neurons connect the "visceral sensory" brainstem to the hypothalamic nucleus, participating in energy homeostasis. Animal experiments have shown that intraventricular administration of GLP-1 can significantly reduce food intake.
Impact on Gastric Function
GLP-1 can inhibit postprandial gastric emptying, reduce gastric acid secretion, and inhibit gastric and duodenal peristalsis by inhibiting the vagus nerve. It also increases the pressure of the pylorus, reducing appetite and contributing to weight loss through the "ileal braking" effect.
Impact on Adipose Tissue
GLP-1 analogs like liraglutide (LIR) can stimulate thermogenesis in brown adipose tissue and promote the browning of white adipose cells. This process increases the thermogenesis and utilization of triacylglycerol-derived fatty acids and glucose in brown adipocytes, reducing lipid content.
Types of GLP-1 Receptor Agonists
GLP-1R agonists are classified into short-acting and long-acting preparations based on their duration of action and injection frequency.
Short-Acting Preparations
- Beinaglutide (BN): Typically injected 2-3 times a day.
- Exenatide (EX): Usually injected 2-3 times a day.
Long-Acting Preparations
- Lixisenatide (LIXI): Injected once daily.
- Liraglutide (LIR): Injected once daily.
- Semaglutide (SMG): Injected once weekly.
- Dulaglutide (DUL): Injected once weekly.
- Exenatide Long-Acting Release (EX-LAR): Injected once weekly.
- Polyethylene Glycol Loxenatide (PEX-168): Injected once weekly.
Specific GLP-1 Receptor Agonists and Their Effects
Beinaglutide (BN)
Beinaglutide is a recombinant human GLP-1 analog used for hypoglycemic intervention in Type 2 diabetes. It is recommended for mealtime injection, especially for patients with poor blood glucose control on metformin alone. Studies have shown that BN can significantly reduce BMI, fasting blood glucose, glycosylated hemoglobin, and visceral and subcutaneous fat. It also has anti-inflammatory effects.
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Exenatide (EX)
Exenatide is a synthetic product of exendin-4, a compound derived from the Gila monster. It inhibits glucagon release, slows gastric emptying, decreases appetite, and increases glucose-dependent insulin secretion. Clinical studies have demonstrated that EX improves glycemic control, reduces weight, and improves β-cell function in patients with Type 2 diabetes. It has also shown potential for weight loss in non-diabetic obese individuals.
Lixisenatide (LIXI)
Lixisenatide is a once-daily GLP-1R agonist, a synthetic analog of exendin-4. It has a high binding affinity to the GLP-1R and a slow dissociation rate, prolonging its pharmacological effects.
Clinical Applications of GLP-1 Agonists
GLP-1 Agonists for Type 2 Diabetes
The FDA approves GLP-1 agonists to manage Type 2 diabetes due to their ability to lower blood sugar levels. They may be recommended if metformin is ineffective or unsafe, or if the patient's A1C is higher than the target. Effective management of Type 2 diabetes involves lifestyle modifications, exercise, and medications, often including GLP-1 agonists.
GLP-1 Agonists for Obesity
Semaglutide and high-dose liraglutide are FDA-approved to treat obesity due to their weight loss effects. They may also be prescribed for people with overweight and other health conditions if weight loss can help manage these conditions. Management of obesity often requires dietary changes, exercise, medications, and behavior modification programs.
Benefits of GLP-1 Receptor Agonists
Glycemic Control
GLP-1R agonists effectively lower blood glucose levels in patients with Type 2 diabetes. They stimulate insulin release and inhibit glucagon secretion, contributing to better glycemic control.
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Weight Loss
These drugs promote weight loss by reducing appetite, slowing gastric emptying, and increasing satiety. They can be beneficial for individuals with obesity or overweight, helping them achieve and maintain a healthy weight.
Cardiovascular Health
Some studies suggest that GLP-1R agonists may have cardiovascular benefits. They can improve blood pressure and lipid profiles, reducing the risk of cardiovascular events in patients with Type 2 diabetes.
Metabolic Improvements
GLP-1R agonists can improve various metabolic parameters, including reducing visceral and subcutaneous fat, improving insulin sensitivity, and enhancing lipid metabolism.
Potential Risks and Side Effects
Common Side Effects
The most common side effects of GLP-1R agonists are gastrointestinal issues such as nausea, vomiting, diarrhea, abdominal pain, and constipation. These side effects are often dose-dependent and may decrease over time as the body adjusts to the medication.
Dosing Errors
There have been reports of adverse events related to dosing errors with compounded semaglutide products. These errors result from patients measuring and self-administering incorrect doses or healthcare professionals miscalculating doses.
Long-Term Side Effects
The long-term side effects of GLP-1R agonists are not yet well-studied. Further research is needed to fully understand the potential risks associated with long-term use.
"Ozempic Face"
Some individuals taking GLP-1 drugs have reported a side effect known as "Ozempic face," characterized by sagging and wrinkled skin on the face due to rapid weight loss.
Concerns with Compounded GLP-1 Drugs
Lack of FDA Approval
Compounded drugs are not FDA-approved, meaning they are not reviewed for safety, effectiveness, or quality before being marketed. This raises concerns about the quality and safety of compounded GLP-1 drugs.
Storage Issues
Injectable GLP-1 drugs require refrigeration. There have been complaints about compounded GLP-1 drugs arriving warm or with inadequate ice packs, which can compromise their quality.
Counterfeit Products
There have been reports of counterfeit drugs claiming to be authentic but containing the wrong ingredients or no active ingredient. These illegal products pose a significant risk to public health.
Illegal Online Sales
The FDA monitors the internet for fraudulent or unapproved drugs and has issued warning letters to stop the distribution of illegally marketed semaglutide and tirzepatide. Consumers are urged to purchase drugs only from state-licensed pharmacies.
Use of Salt Forms
Some compounders may use salt forms of semaglutide, such as semaglutide sodium and semaglutide acetate. The FDA does not have information on whether these salts have the same properties as the active ingredient in approved drugs and is not aware of any lawful basis for their use in compounding.
FDA Recommendations
For Healthcare Professionals
Healthcare providers should be vigilant when prescribing compounded semaglutide or tirzepatide products, ensuring appropriate doses, titration, and dosing schedules for patients.
For Consumers
Consumers should be vigilant about the source of their medicine and carefully check labels for warning signs such as spelling errors or incorrect addresses. They should ensure their medicine is provided by a licensed pharmacy and prescribed by a licensed healthcare provider.
Alternative Weight Loss Programs
Balancing Innovation and Affordability
Researchers are analyzing the potential impact of alternative weight loss programs to challenge the assumption that patients must remain on GLP-1RA drugs indefinitely.