GLP-1 dosing protocols are designed to help your body gradually adapt, minimizing side effects while achieving the best possible results. This guide will give you a clear roadmap for navigating GLP-1 dosing. For explanation of units and dosing calculations, check my previous GLP-1 posts.

1. Dosing Protocol for GLP-1:

• Starting Dose: Most GLP-1 medications, like semaglutide and tirzepatide, start with a low dose to help the body gradually adjust and reduce side effects like nausea. Typically, this starting dose lasts for about four weeks.
• Titration (Increasing the Dose): After the initial period, the dose is gradually increased in set intervals (usually every 4 weeks), depending on the medication and the patient’s response. This titration period can last for several months until reaching the maintenance dose, which is the effective therapeutic level for the patient.

2. How GLP-1 Medications Work in the Body:

• Mimicking the GLP-1 Hormone: GLP-1 receptor agonists mimic the natural GLP-1 hormone in the body, which plays a key role in blood glucose regulation and appetite control. It:
  • Stimulates insulin secretion from the pancreas when blood glucose is high.
  • Suppresses glucagon release (a hormone that raises blood sugar) in a glucose-dependent manner.
  • Slows gastric emptying, which prolongs feelings of fullness.
  • Reduces appetite through its effects on the brain, which can lead to reduced calorie intake and weight loss.

3. What is a Starting Dose?

• Starting Dose Defined: A starting dose is an initial, lower dose of a medication given to acclimate the patient to a medication and slowly increase concentration in the bloodstream to therapeutic levels. Patients may not feel appetite suppression or experience weight loss on a starting dose of GLP-1 drugs. GLP-1 medications use a gradual increase in dosing over several weeks to allow the body to adapt, minimize side effects, and reach a steady concentration safely.

4. Concentration Levels Over Time:

• Early Stages: During the initial dosing and titration, the drug concentration in the body gradually increases with each dose increase. This slow build-up helps the body acclimate to the medication.
• Steady State: After several weeks at the maintenance dose, the drug reaches a “steady state,” where the amount of drug administered matches the amount metabolized and excreted, maintaining a consistent concentration in the bloodstream.
• Pharmacokinetics of GLP-1: GLP-1 medications, especially long-acting ones, maintain therapeutic levels in the body with weekly dosing because they are released gradually and have a longer half-life, providing a sustained effect on blood sugar and appetite.
• Tools like glp1plotter can help you visualize your specific doses over time.

5. Effects of Increasing the Dose:

• Positive Effects: A gradual increase in the dose allows the patient to achieve better blood sugar control and, for many, increased weight loss as the higher dose further suppresses appetite and maintains blood sugar stability.
• Potential Side Effects: Higher doses can increase the likelihood or severity of side effects, particularly gastrointestinal discomfort. Healthcare providers monitor for side effects to determine if the patient is ready to move up to the next dose.

6. Stopping GLP-1 Medications:

• The time it takes for GLP-1 medications to leave the body depends on the specific drug, its half-life, and dosing frequency. Generally, GLP-1 medications are eliminated over several days to weeks after the last dose:
  • Semaglutide (Ozempic/Wegovy): Semaglutide has a long half-life of about 7 days, meaning it can take approximately 4-5 weeks to be fully cleared from the body after the last dose.
  • Tirzepatide (Mounjaro/Zepbound): Although it’s a dual GLP-1/GIP agonist, tirzepatide has a half-life of about 5 days, so it may also take around 2-3 weeks to clear the body.
• Generally, it takes about 4-5 half-lives for a medication to leave the system fully. The exact clearance time may vary based on individual factors like metabolism, kidney function, and dose level.

7. Restarting GLP-1 After a Break:

• Re-initiation Protocol: GLP-1 medications are generally not designed to be stopped and restarted, as some users report that the medication does not work as effectively after a break. If GLP-1 treatment is paused and then resumed, many protocols recommend starting at a lower dose and re-titrating gradually. This approach helps minimize the risk of severe side effects since the body may have adjusted to lower baseline levels during the break.
• Reaching Steady State Again: When restarting, the therapeutic concentration needs to be re-established in the body, which can take several weeks. The process of reaching a steady-state concentration might be slower and less predictable if the break was lengthy, impacting the medication’s initial effectiveness.
• Adjusting for Side Effects and Efficacy: Restarting GLP-1 may reintroduce side effects that had previously diminished, requiring additional adjustments to help the body reacclimate. Additionally, some users may experience a reduced response or benefit from the medication after a pause. Patients and providers should monitor for any changes in effectiveness and manage side effects closely to adjust expectations for symptom management and treatment outcomes.

How Dosing Protocols are Created

GLP-1 dosing protocols are developed by a combination of researchers, clinical experts, and regulatory bodies to ensure the medications are both safe and effective for patients. The dosing protocols for compounded medications like semaglutide or tirzepatide mimic the protocols for their brand name counterpart, and come from the pharmaceutical company that owns that developed the drug. Here’s a closer look at who plays a role:

1. Pharmaceutical Companies: During the development of GLP-1 medications, pharmaceutical companies conduct extensive clinical trials to determine the safest and most effective dosing schedules. These studies explore different doses, administration frequencies, and titration schedules to identify the protocol that best balances efficacy with tolerability.
2. Regulatory Agencies: After clinical trials, agencies like the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and others review the evidence on dosing protocols. They ensure these protocols meet safety and efficacy standards before approving the medication. Sometimes they also mandate post-marketing studies to monitor long-term safety.
3. Endocrinologists and Clinical Researchers: Medical experts specializing in diabetes and metabolic diseases, along with clinical researchers, contribute to protocol recommendations. Their input often helps refine dosing guidelines in response to real-world patient data, adapting protocols based on patient tolerability, treatment outcomes, and side-effect profiles observed in clinical practice.
4. Guidelines from Medical Societies: Professional organizations, like the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), often provide clinical guidelines. These guidelines offer practical dosing recommendations to healthcare providers, based on the latest research and expert consensus.
5. Healthcare Providers: While dosing protocols are standardized, healthcare providers play an essential role in adapting protocols to individual patients, especially when managing side effects, adjusting doses, or restarting after a break in treatment.

This collaborative process ensures that GLP-1 dosing protocols are rigorously tested, evidence-based, and continuously refined to provide the best possible outcomes for patients.

Weight Loss Dosing Protocols

Tirzepatide

The dosing schedule for tirzepatide involves a gradual increase in dose to help the body adjust and minimize side effects. The standard weight loss dosing schedule generally follows these steps:

1. Starting Dose:
   • Begin with 2.5 mg once weekly for 4 weeks.
   • This initial dose is meant to help the body acclimate to the medication and reduce the likelihood of gastrointestinal side effects.
2. Titration Schedule:
   • Week 5-8: Increase to 5 mg once weekly.
   • Week 9-12: Increase to 7.5 mg once weekly.
   • Week 13-16: Increase to 10 mg once weekly.
   • Week 17-20: Increase to 12.5 mg once weekly, if well tolerated.
   • Week 21 and beyond: Increase to the maximum dose of 15 mg once weekly, as tolerated.
3. Maintenance Dose:
   • The maintenance dose is typically 10 mg to 15 mg once weekly, based on tolerance and effectiveness. Most patients will continue at this dose for optimal weight loss results.

Semaglutide

The dosing schedule for semaglutide also involves gradually increasing the dose over several weeks to help minimize side effects and allow the body to adjust. Here is the typical schedule:

1. Starting Dose:
   • Begin with 0.25 mg once weekly for 4 weeks.
   • This low dose helps the body acclimate and reduces the risk of gastrointestinal side effects like nausea.
2. Titration Schedule:
   • Week 5-8: Increase to 0.5 mg once weekly.
   • Week 9-12: Increase to 1 mg once weekly.
   • Week 13-16: Increase to 1.7 mg once weekly.
   • Week 17 and beyond: Increase to the full dose of 2.4 mg once weekly.
3. Maintenance Dose:
   • The maintenance dose for weight loss is 2.4 mg once weekly.
   • Patients continue this dose for optimal weight management and metabolic benefits.

In summary, GLP-1 medications follow a dosing protocol designed for gradual adjustment, with dosing that affects blood sugar, appetite, and gastric emptying over time. If restarting, patients usually return to a lower dose to avoid side effects and ensure a gradual reacclimation, allowing the medication to reach therapeutic levels safely once again.