The history and science of GLP-1

• 1980s: GLP-1 was discovered, revealing its potential to stimulate insulin secretion in response to elevated blood glucose levels.

• 1990s: Early research faced challenges due to the short half-life of GLP-1 in the body, leading to the development of GLP-1 receptor agonists resistant to rapid degradation.

• 2005: Exenatide (Byetta) was the first GLP-1 receptor agonist approved by the FDA, requiring twice-daily injections.

• 2010: Liraglutide (Victoza) offered a more convenient once-daily dosing and demonstrated cardiovascular benefits.

• 2017: Semaglutide (Ozempic) was approved as a once-weekly injection, showing significant benefits in reducing HbA1c levels and promoting weight loss.

• 2019: Oral semaglutide (Rybelsus) became the first oral GLP-1 receptor agonist, increasing patient adherence with its daily pill form.

• 2021: Semaglutide (Wegovy) was approved for chronic weight management in adults with obesity or overweight with weight-related conditions.

GLP-1 works by mimicking the natural hormone GLP-1, enhancing insulin secretion, suppressing glucagon, slowing gastric emptying, and promoting satiety. These actions collectively help manage blood glucose levels and support weight loss.

Key Mechanisms and Their Impact on Weight Loss

• Delayed Gastric Emptying:

  • How It Works: Semaglutide slows the rate at which food leaves the stomach and enters the small intestine.

  • Impact: When the stomach empties more slowly, you feel full for a longer period after eating. This reduces the frequency and quantity of meals, which helps lower overall caloric intake.

• Enhanced Satiety and Appetite Suppression:

  • How It Works: Semaglutide acts on receptors in the brain’s hypothalamus, the area responsible for regulating appetite, to enhance feelings of fullness and reduce hunger.

  • Impact: This means you feel satisfied with smaller portions of food and are less likely to snack between meals, leading to a natural reduction in overall food intake.

• Reduced Glucagon Secretion:

  • How It Works: Semaglutide inhibits the release of glucagon, a hormone that signals the liver to produce glucose.

  • Impact: With less glucagon, the liver releases less glucose into the blood. This helps keep blood sugar levels stable, reducing hunger triggered by sudden spikes and drops in blood glucose levels.

• Enhanced Insulin Secretion:

  • How It Works: Semaglutide stimulates the pancreas to release insulin when blood glucose levels are high, which helps lower blood sugar levels.

  • Impact: This improved insulin response helps your body use glucose more effectively, reducing the amount stored as fat and aiding in weight management.

• Behavioral and Psychological Effects:

  • How It Works: Semaglutide influences brain areas involved in reward and eating behavior, which can help curb cravings.

  • Impact: By reducing cravings for high-calorie, sugary foods, semaglutide helps you make healthier food choices and adopt better eating habits.

• Nausea

  • Feeling queasy or sick to your stomach, often occurring when starting the medication but usually subsiding over time.

• Vomiting

  • Instances of throwing up, which can occur along with nausea, especially in the initial weeks of treatment.

• Diarrhea

  • Increased frequency and liquidity of bowel movements, a common gastrointestinal side effect that generally improves with continued use.

• Constipation

  • Difficulty in passing stools, which some people may experience while taking these medications.

• Abdominal Pain

  • Discomfort or pain in the stomach area, often associated with gastrointestinal side effects like nausea and vomiting.

• Decreased Appetite

  • Reduced desire to eat, which can contribute to weight loss but may also cause unintentional reduction in caloric intake.

• Indigestion (Dyspepsia)

  • A feeling of fullness or discomfort in the upper abdomen, sometimes accompanied by bloating, belching, or heartburn.

• Fatigue

  • Feeling unusually tired or weak, which can sometimes occur as the body adjusts to the medication.

• Injection-Site Reactions (for injectable forms)

  • Localized reactions where the medication is injected, including redness, swelling, or itching at the injection site.

While GLP-1 receptor agonists, including semaglutide, offer significant benefits, they also come with potential side effects. Here are some of the major and serious ones:

• Gastrointestinal Issues: Common side effects include nausea, vomiting, diarrhea, and constipation. These usually decrease over time as your body adjusts to the medication.

• Pancreatitis: There have been reports of acute pancreatitis (inflammation of the pancreas), which can cause severe abdominal pain, nausea, and vomiting. If you have a history of pancreatitis, you should use these medications cautiously.

• Gallbladder Disease: There is an increased risk of developing gallstones and gallbladder inflammation (cholecystitis).

• Thyroid C-cell Tumors: Some rodent studies have shown an increased risk of thyroid tumors, but it's unclear if this risk applies to humans. These medications are not recommended for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

• Hypoglycemia: This is particularly a risk when used in combination with other diabetes medications like sulfonylureas or insulin, which can lower blood sugar too much.

• Renal Impairment: There have been cases of acute kidney injury, especially in patients who experience severe gastrointestinal side effects leading to dehydration.

• Hypersensitivity Reactions: Rare but serious allergic reactions, including anaphylaxis and angioedema, have been reported.

• Injection-Site Reactions: Some people may experience localized reactions at the injection site, such as redness, swelling, and itching.

• Gradual Dose Increase: Starting with a lower dose and gradually increasing it as recommended by your healthcare provider can help minimize side effects.

• Hydration: Drinking plenty of fluids can help manage gastrointestinal side effects like nausea and diarrhea.

• Dietary Adjustments: Eating smaller, more frequent meals and avoiding high-fat or spicy foods can reduce nausea and indigestion.

• Medication Timing: Taking the medication at the same time each day, as directed, can help your body adjust and reduce side effects.

What is Compound GLP-1 ?

• Semaglutide is a medication belonging to the GLP-1 receptor agonists class, primarily used to manage type 2 diabetes and aid in weight loss. It mimics the action of the natural hormone GLP-1, enhancing insulin secretion, suppressing glucagon release, slowing gastric emptying, and promoting satiety.

Why Compounding GLP is Possible?

• Compounding refers to the custom preparation of a medication to fit the unique needs of a patient. This can involve altering the form, dosage, or combining it with other ingredients. Compounding semaglutide may be considered for several reasons:

• Customized Dosage Forms: Patients might require specific dosages not commercially available.

• Alternative Delivery Methods: Some patients may prefer or require a different delivery method (e.g., oral versus injectable) due to medical conditions or personal preferences.

• Ingredient Sensitivities: Compounding can help eliminate non-essential ingredients that some patients might be allergic to or sensitive to.

• Addressing Shortages: During periods of medication shortages, compounding can provide an alternative source of the medication when commercial products are unavailable.

Types of Pharmacies for Compounded Semaglutide: 503A and 503B Pharmacies

• When considering compounded semaglutide, it’s crucial to choose a reputable pharmacy to ensure safety, efficacy, and quality. Here are the specific types of pharmacies that can compound semaglutide:

• 503A Compounding Pharmacies:

  • Patient-Specific Prescriptions: 503A pharmacies compound medications based on individual prescriptions for specific patients. They adhere to traditional compounding practices, preparing medications tailored to the unique needs of each patient.

  • Regulation and Oversight: These pharmacies are regulated primarily by state boards of pharmacy and must comply with the standards set by the United States Pharmacopeia (USP) for non-sterile and sterile compounding.

  • Quality and Safety: Ensure the 503A pharmacy is accredited and follows stringent quality control measures to maintain high standards for compounded medications.

• 503B Outsourcing Facilities:

  • Batch Compounding: 503B facilities are allowed to compound medications in larger batches for distribution to healthcare providers, hospitals, and clinics without patient-specific prescriptions.

  • FDA Registration: These facilities are registered with the FDA and are subject to Current Good Manufacturing Practices (cGMP), similar to pharmaceutical manufacturers, ensuring a higher level of quality and safety.

  • Sterile Compounding: 503B facilities often specialize in sterile compounding, making them an excellent choice for injectable semaglutide formulations.

FDA Regulations and Compounding

• The FDA allows the compounding of semaglutide to provide tailored medical solutions for patients with unique needs that cannot be met by commercially available products. By regulating the practice of compounding and enforcing strict safety and quality standards, the FDA ensures that compounded medications are a safe and effective option for patients requiring customized treatments. This flexibility supports personalized healthcare, ensuring that all patients have access to the medications they need in the form that best suits their individual circumstances.

Addressing the Shortage in the U.S.

• Current Shortages: Recently, there has been a notable shortage of commercially available semaglutide products in the U.S., primarily due to increased demand and supply chain disruptions. This shortage has made it challenging for patients to access their prescribed medications.

• Role of Compounding: Compounding pharmacies have stepped in to help address these shortages by providing custom-prepared semaglutide. By compounding semaglutide, these pharmacies can offer an alternative source for patients who might otherwise be unable to obtain their medication.

Things to consider about Semaglutide and Tirzepatide. 

• When considering options for weight management care, two medications that often come up are Semaglutide and Tirzepatide. Both are highly effective, but they have distinct mechanisms and benefits, making them suitable for different patients.

Semaglutide Overview:

• Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. GLP-1 is a hormone naturally produced in the body, primarily in response to eating. It plays a crucial role in regulating blood sugar levels by:

  • Increasing Insulin Secretion: GLP-1 stimulates the pancreas to release insulin, particularly after meals when blood sugar levels rise.

  • Reducing Glucagon Release: Glucagon is a hormone that signals the liver to release stored glucose into the bloodstream. By reducing glucagon release, GLP-1 helps prevent excessive glucose levels.

  • Slowing Gastric Emptying: GLP-1 slows down the movement of food from the stomach to the intestines, helping to control appetite and prolong the feeling of fullness.

Tirzepatide Review:

• Tirzepatide is a newer medication that combines the actions of GLP-1 and another hormone called glucose-dependent insulinotropic polypeptide (GIP). Like GLP-1, GIP is an incretin hormone, released after eating to enhance insulin secretion. However, GIP has additional effects that make it unique:

  • Enhancing Insulin Sensitivity: GIP improves the body's response to insulin, particularly in fat tissue, helping to reduce insulin resistance, a key issue in type 2 diabetes.

  • Modulating Fat Storage: GIP also influences fat metabolism and storage, which can impact body weight and composition.

  • By targeting both GLP-1 and GIP receptors, Tirzepatide offers a dual approach to managing blood sugar levels and supporting weight loss. This combination may lead to more significant effects on blood sugar control and weight reduction compared to GLP-1 alone.

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Key Differences 

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• Mechanism of Action:

  • Semaglutide acts solely on GLP-1 receptors, focusing on enhancing insulin secretion, reducing glucagon release, and slowing gastric emptying to manage blood sugar and promote weight loss.

  • Tirzepatide activates both GLP-1 and GIP receptors. This dual action not only covers the benefits of GLP-1 but also adds the insulin-sensitizing and fat metabolism effects of GIP, potentially leading to better overall outcomes in glucose control and weight loss.

• Efficacy: Clinical trials have indicated that Tirzepatide may provide greater weight loss compared to Semaglutide. For instance, a head-to-head trial showed that participants using Tirzepatide lost more weight on average than those using Semaglutide, though individual results can vary.

• Approval: Semaglutide has been on the market longer, with well-established use in both diabetes management and weight loss. Tirzepatide, while newer, is gaining attention for its enhanced dual-action approach.

Semaglutide and Tirzepatide agonists represent a significant advancement in managing obesity and weight loss. Their multifaceted mechanisms not only improve blood glucose control but also support weight loss through prolonged satiety, reduced appetite, and stabilized blood glucose levels. While potential side effects exist, the benefits for many patients outweigh the risks, making these medications a valuable tool in the fight against diabetes and obesity.

If you're considering either of these medications, we encourage you to do a free consult with our healthcare professionals at Achieve Weight Goals to determine the most appropriate treatment for your unique situation. 

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• FDA. (2017). FDA approves new treatment for type 2 diabetes.(https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-2-diabetes)

• Novo Nordisk. (2019). Rybelsus (oral semaglutide) prescribing information. (https://www.novonordisk-us.com/products/rybelsus.html)
  - American Diabetes Association. (2021). Standards of Medical Care in Diabetes—2021. [Link](https://care.diabetesjournals.org/content/44/Supplement_1)

• Mayo Clinic. (2021). GLP-1 agonists: Diabetes drugs and weight loss. (https://www.mayoclinic.org/diseases-conditions/diabetes/expert-answers/GLP-1-agonists/faq-20436926)

• National Institutes of Health. (2021). Semaglutide and its cardiovascular benefits. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297081/)

• "Semaglutide." Mayo Clinic. Available at: https://www.mayoclinic.org/drugs-supplements/semaglutide-injection-route/description/drg-20477458.

• "Tirzepatide: First Global Approval." Drugs.com. Available at: https://www.drugs.com/newdrugs/eli-lilly-wins-u-s-fda-approval-mounjaro-tirzepatide-type-2-diabetes-5739.html.

• "Comparative effectiveness of Tirzepatide versus Semaglutide." New England Journal of Medicine. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2107519.

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