Tirzepatide vs Semaglutide for Weight Loss

With obesity being one of the most common health conditions nationwide, it’s no wonder that GLP-1 receptor agonist medications are making waves as the latest highly effective, low-side-effect weight loss solution.

The two most prominent active ingredients within this class of drugs are semaglutide and tirzepatide. Semaglutide is used in well-known branded medications like the injectable Ozempic and Wegovy, while tirzepatide is used in Mounjaro and Zepbound.

While originally approved for the treatment of type 2 diabetes, GLP-1 RAs regulate appetite with relatively low side effects, making them extremely effective for weight loss.

‍Options vary in cost, strength, and method of administration. Injectables or oral, brand-name or compounded, tirzepatide or semaglutide? Making a decision can be overwhelming, but we’re here to help. Here’s a breakdown of the key differences between semaglutide and tirzepatide and how to decide which medication is right for you.

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Semaglutide Explained

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Semaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist, meaning that it mimics our natural GLP-1 hormone that is released after eating. This stimulates the release of insulin to help regulate blood sugar, slow the emptying of food from the stomach, and decrease appetite. It is used for improved glycemic (blood sugar) control in patients with type 2 diabetes and chronic weight management for patients with obesity. Clinical trials have proven its safety and efficacy in combating obesity and its related comorbidities.

There are three brand-name semaglutide products, in addition to other more readily available compounded options:

• Ozempic: Once-weekly injectable FDA-approved for type 2 diabetes, but can be used off label for weight loss (1)
• Wegovy: Once-weekly injectable FDA-approved for obesity treatment (2)
• Rybelsus: Oral tablet FDA-approved for type 2 diabetes, administered once daily (3)
• Compounded semaglutide: These options fill an important gap as they are often more affordable and accessible. Ozempic and Wegovy are often in shortage, making it difficult for patients to stay on their treatment plan (4). It is important to select a trustworthy pharmacy that uses the same base formulations as the brand-name medications. Learn how to access safe and effective compounded medications here.

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Tirzepatide Explained

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Tirzepatide is a compound which not only acts on GLP-1 receptors, but also a second receptor known as GIP, or glucose-dependent insulinotropic polypeptide. It acts like a key that can unlock two distinct doors, compared with semaglutide which only works on a single lock. This unique dual action mechanism significantly enhances its ability to manage weight and blood sugar levels. 

There are two brand-name tirzepatide medications, in addition to other more readily available compounded options:

• Mounjaro: Once-weekly injectable FDA-approved for type 2 diabetes, but can be used off label for weight loss (5)
• Zepbound: Once-weekly injectable FDA-approved for obesity treatment (6)
• Compounded tirzepatide: Similar to semaglutide, this is a helpful alternative when medications are in short supply or as an affordable option for patients whose insurance will not cover their prescription.

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Differences in Effectiveness Between Tirzepatide and Semaglutide

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While tirzepatide and semaglutide are both GLP-1 receptor agonists, they possess distinct pharmacological properties. Their differing mechanisms may influence the treatment choice for individual patients. Understanding these nuances is essential in tailoring therapeutic approaches to effectively meet the specific needs of each patient.

Both medications prompt increased insulin release, enhanced satiety, and reduced gastric emptying. As a result, they contribute to improved blood sugar control and weight loss. Mimicking natural incretins, these medications target GLP-1 receptors in various organs, such as the pancreas, stomach, brain, and liver  (6, 7). 

In terms of effectiveness, tirzepatide is the stronger of the two. Because it targets GIP receptors as well as GLP-1, it has a broader spectrum of metabolic benefits than semaglutide (8).  What’s more, recent research has demonstrated a synergistic relationship between GIP and GLP-1 receptor agonists, further enhancing tirzepatide’s ability to enhance metabolic health and promote weight loss (9, 10). 

Tirzepatide can be especially useful for patients with a higher starting BMI who need to achieve a higher level of weight loss. The desired weight goal differs from patient to patient and everyone experiences the effects of the medication differently, from weight loss to the severity of side effects. Always discuss your options with a provider.

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Clinical Trials

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Based on clinical trials, here are the key takeaways:

• All tirzepatide doses outperformed semaglutide in reducing HbA1c (a measure of blood sugar control).
• More patients achieved target HbA1c levels with tirzepatide.
• Tirzepatide induced greater weight reduction compared to semaglutide.

In the SURPASS-2 Trial, a study published in the NEJM, the efficacy and safety of once-weekly tirzepatide was compared to that of Semaglutide.

The trial examined 1879 participants and administered tirzepatide injections at doses of 5mg, 10mg, and 15mg, alongside semaglutide injections at 1mg. Before starting medication, baseline HbA1c levels were measured. The findings unequivocally demonstrated tirzepatide's across-the-board enhancement of blood sugar management, with all doses exhibiting significant reductions in HbA1c levels.

Moreover, tirzepatide yielded notably superior weight loss outcomes compared to Semaglutide. Across the specified dosage ranges, individuals experienced weight reductions of 1.9kg (4.2 lbs), 3.6kg (7.9 lbs), and 5.5kg (12.1 lbs) more than those on weekly Semaglutide at 1mg  (11).

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While acknowledging the efficacy of Semaglutide in managing obesity and blood sugar, it's crucial to consider future studies examining tirzepatide against higher doses of semaglutide. Nonetheless, this clinical trial highlights how tirzepatide's dual action mechanism may offer additional benefits in weight loss management, blood sugar regulation, and mitigating cardiovascular risks.

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Tirzepatide and Semaglutide Cost and Insurance Coverage

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Brand-name weight loss medications Mounjaro (Tirzepatide), Ozempic (Semaglutide), or Wegovy (Semaglutide) often come with a hefty price tag. While Mounjaro typically ranges from $1,000 to $1,200 monthly, Ozempic starts at around $1,030, and Wegovy at $1350 monthly. Given that they need to be administered weekly and are designed for long-term use, the pharmacy bill can rack up quickly.

Fortunately, pharmaceutical companies like Eli Lilly and Novo Nordisk offer savings options for patients – but only if they already have commercial insurance coverage. Eli Lilly's savings card program for Mounjaro allows you to pay as little as $25 for a one-month, two-month, or three-month prescription fill, with maximum monthly savings of up to $150 to $450 and an annual maximum savings of up to $1,800. Novo Nordisk also provides savings cards for Ozempic and Wegovy.

However, if you are uninsured, the out-of-pocket cost can be daunting. Luckily, some pharmacies offer compound versions of these medications at significantly lower prices. For instance, Mochi Health works with FDA-approved pharmacies that offer compounded semaglutide at only $175 per month and compounded tirzepatide at $325 per month. This substantial cost difference makes compound medications a more affordable option for uninsured patients seeking effective treatment. 

Consult your healthcare provider to explore coverage options and alternatives if necessary. The team at Mochi Health can help you find out if your insurance covers medications, apply for coverage, and connect you with a provider to create your personalized weight managment plan and prescription.

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Tirzepatide vs. Semaglutide Dosage and Administration

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When administering your medication regimen of Semaglutide and Tirzepatide, it's essential to follow a precise protocol to ensure optimal effectiveness and safety. 

It’s important to talk with your provider before starting on these medications and throughout the course of administration. Both semaglutide and tirzepatide are long-term solutions to treat chronic health conditions, not short-term use. 

‍Here’s what to expect based on the general recommended starting dosage and administration:

‍Begin with Semaglutide at a starting dose of 0.25 mg for the initial 4 weeks, then escalate to 0.5 mg from week 5 for another 4 weeks. Your healthcare provider may adjust this dosage gradually, with increments up to a maximum of 2.4 mg, maintaining each dose for at least 4 weeks (12).

Similarly, Tirzepatide starts at 2.5 mg for 4 weeks, increasing to 5 mg from week 5 for another 4 weeks, with potential increments of 2.5 mg up to a maximum of 15 mg (13).

Both medications are administered once weekly via an easy-to-use injection device. To use it, remove the base cap, cleanse the injection site with an alcohol wipe, place the pen flat, and unlock it. Then, press and hold the button for up to 10 seconds, listening for the two clicks indicating the start and completion of the injection.

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Side Effects of Tirzepatide vs. Semaglutide

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Regarding adverse events, both Tirzepatide and Semaglutide demonstrated comparable safety profiles, with GI events being the most frequently reported. 

17-22% of Tirzepatide recipients and 18% of Semaglutide recipients experience nausea, the most common side effect.

‍Diarrhea was observed in 13-16%  in tirzepatide patients and 12% in semaglutide patients. Vomiting rates were 6-10% for tirzepatide and 8% for semaglutide. Most reported GI events were mild to moderate in severity and predominantly occurred during the dose-escalation phase across all treatment groups (11).

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Key Takeaways

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Ultimately, tirzepatide promotes a higher level of weight loss, but also typically results in slightly more severe side effects.

‍Each patient may lose weight at a different rate and experience different side effects. As results vary with age, BMI, lifestyle, and genetic factors, your provider can assess your health history and provide guidance on the right option for your needs.

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More About Medication-Assisted Weight Loss

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Want to learn more about GLP-1 medications and find out if medication-assisted weight management is right for you? The team at Mochi Health is here to help. Our board-certified obesity medicine physicians are ready to offer expert guidance tailored to your needs. Take the first step towards a healthier, happier you and find out if you’re eligible today.

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Sources:

1. OZEMPIC (semaglutide) injection, for subcutaneous use. (n.d.-a). https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/209637s012lbl.pdf 
2. WEGOVY (semaglutide) injection, for subcutaneous use. (n.d.-a). https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215256s005lbl.pdf 
3. RYBELSUS (semaglutide) tablets, for oral use.  (n.d.-a). https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/213051s012lbl.pdf Center for Drug Evaluation and Research. (n.d.). Drug compounding and drug shortages. U.S. Food and Drug Administration. https://www.fda.gov/drugs/human-drug-compounding/drug-compounding-and-drug-shortages 
4. MOUNJAROTM (tirzepatide) injection, for subcutaneous use. (n.d.-a). https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf 
5. ZEPBOUNDTM (tirzepatide) Injection, for subcutaneous use . (n.d.-d). https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217806s000lbl.pdf 
6. Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., McGowan, B. M., Rosenstock, J., Tran, M. T. D., Wadden, T. A., Wharton, S., Yokote, K., Zeuthen, N., & Kushner, R. F. (2021). Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine, 384(11), 989–1002. https://doi.org/10.1056/nejmoa2032183
7. Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., Kiyosue, A., Zhang, S., Liu, B., Bunck, M. C., & Stefanski, A. (2022). Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine, 387(3), 205–216. https://doi.org/10.1056/nejmoa2206038
8. Rosenstock, J., Wysham, C., Frías, J. P., Kaneko, S., Lee, C. J., Fernández Landó, L., Mao, H., Cui, X., Karanikas, C. A., & Thieu, V. T. (2021). Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. The Lancet (British Edition), 398(10295), 143–155. https://doi.org/10.1016/S0140-6736(21)01324-6
9. Zaffina, I., Pelle, M. C., Armentaro, G., Giofrè, F., Cassano, V., Sciacqua, A., & Arturi, F. (2023). Effect of dual glucose-dependent insulinotropic peptide/glucagon-like peptide-1 receptor agonist on weight loss in subjects with obesity. Frontiers in Endocrinology (Lausanne), 14, 1095753–1095753. https://doi.org/10.3389/fendo.2023.1095753
10. Rizvi, A. A., & Rizzo, M. (2022). The Emerging Role of Dual GLP-1 and GIP Receptor Agonists in Glycemic Management and Cardiovascular Risk Reduction. Diabetes, Metabolic Syndrome and Obesity, 15, 1023–1030. https://doi.org/10.2147/DMSO.S351982
11. Frías, J. P., Davies, M. J., Rosenstock, J., Pérez Manghi, F. C., Fernández Landó, L., Bergman, B. K., Liu, B., Cui, X., & Brown, K. (2021). Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. The New England Journal of Medicine, 385(6), 503–515. https://doi.org/10.1056/NEJMoa2107519
12. Dosing schedule: Ozempic® (SEMAGLUTIDE) injection. Dosing Schedule | Ozempic® (semaglutide) injection. (n.d.). https://www.ozempic.com/how-to-take/ozempic-dosing.html 
13. How to use, dosing & side effects: Mounjaro® (tirzepatide). How to Use, Dosing & Side Effects | Mounjaro® (tirzepatide). (n.d.). https://mounjaro.lilly.com/how-to-use-mounjaro#dosing 

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