Medically reviewed by a licensed healthcare professional. Last updated March 2026.

Key Takeaways

  • Tirzepatide (Zepbound) produced the highest average weight loss in clinical trials: 22.5% of body weight over 72 weeks [1].
  • Semaglutide (Wegovy) produced 14.9% average weight loss and has cardiovascular outcome data from the SELECT trial [2].
  • The SURMOUNT-5 head-to-head trial showed tirzepatide outperformed semaglutide by 6.5 percentage points [3].
  • "Best" depends on your medical history, insurance coverage, tolerability, and treatment goals — not trial averages alone.
  • Consult a qualified provider to determine which medication is appropriate for your specific situation.

FDA-Approved GLP-1 Medications for Weight Loss

As of 2025, the FDA has approved two GLP-1 receptor agonists specifically for chronic weight management in adults: semaglutide (marketed as Wegovy) and tirzepatide (marketed as Zepbound). A third medication, liraglutide (Saxenda), holds older approval but produces more modest results and is prescribed less frequently [4].

Understanding what each medication offers — and its limitations — is essential before starting treatment.

Tirzepatide (Zepbound)

Tirzepatide is a dual GIP/GLP-1 receptor agonist, meaning it activates two incretin pathways rather than one. The FDA approved Zepbound for chronic weight management in November 2023 [5].

Clinical evidence: In the SURMOUNT-1 trial, participants taking the highest dose (15 mg) lost an average of 22.5% of their body weight over 72 weeks, compared to 3.1% with placebo [1]. Approximately 63% of participants achieved at least 20% weight loss.

Limitations: There is no completed cardiovascular outcomes trial for tirzepatide in patients with obesity. The SURPASS-CVOT trial is ongoing. Tirzepatide is also newer to market, meaning long-term safety data beyond 72 weeks is more limited than semaglutide.

Semaglutide (Wegovy)

Semaglutide is a GLP-1 receptor agonist administered as a weekly injection (2.4 mg) or, as of December 2025, as a daily oral tablet. The FDA first approved Wegovy for weight management in June 2021 [6].

Clinical evidence: In the STEP 1 trial, participants lost an average of 14.9% of body weight over 68 weeks [2]. The SELECT trial subsequently demonstrated a 20% reduction in major adverse cardiovascular events in adults with obesity and established cardiovascular disease [7].

Advantages: Semaglutide has the longest clinical track record among modern GLP-1 weight loss medications and is the only one with proven cardiovascular benefit. The oral tablet formulation offers a needle-free option.

Liraglutide (Saxenda)

Liraglutide was the first GLP-1 approved for weight management in 2014. It requires daily injections and produces average weight loss of 5-10% of body weight [4]. Given the superior efficacy of newer agents, Saxenda is typically considered when semaglutide and tirzepatide are not options due to contraindications, cost, or insurance restrictions.

Head-to-Head: Tirzepatide vs. Semaglutide

The SURMOUNT-5 trial provides the most direct comparison available. This randomized, open-label trial enrolled adults with obesity (BMI ≥30) and compared tirzepatide (up to 15 mg) against semaglutide (2.4 mg) over 72 weeks [3].

Results:

  • Tirzepatide group: 20.2% average weight loss
  • Semaglutide group: 13.7% average weight loss
  • Difference: 6.5 percentage points favoring tirzepatide

For a 220-pound individual, this translates to approximately 44 pounds lost with tirzepatide versus 30 pounds with semaglutide. Both groups experienced clinically meaningful weight loss.

It is important to note that these are population averages. Individual responses vary considerably based on genetics, adherence, lifestyle factors, and starting weight.

How to Choose: A Clinical Framework

There is no single "best" GLP-1 medication that applies to everyone. The right choice depends on several factors that only you and your healthcare provider can evaluate together.

When tirzepatide may be preferred

  • Maximum weight loss is the primary treatment goal
  • You have type 2 diabetes in addition to obesity (dual incretin benefit)
  • Semaglutide was previously ineffective or poorly tolerated
  • Your insurance covers Zepbound or cash-pay pricing through LillyDirect fits your budget

When semaglutide may be preferred

  • You have established cardiovascular disease (SELECT trial evidence [7])
  • You prefer an oral medication rather than injections (oral Wegovy)
  • Your insurance covers Wegovy but not Zepbound
  • You value the longer real-world safety track record

When the decision is unclear

If both medications are equally accessible, discuss your complete medical history with your provider. In many cases, the medication your insurance covers at the lowest out-of-pocket cost is a reasonable starting point. If that medication proves ineffective or intolerable after an adequate trial (typically 3-6 months at target dose), switching to the alternative is common and clinically appropriate.

Browse our medication guide for detailed dosing, side effect, and pricing information on each FDA-approved option. You can also compare clinics that prescribe both semaglutide and tirzepatide to find a provider in your area.

What the Evidence Does Not Tell Us

Clinical trials have important limitations that patients should understand:

  • Trial populations are not representative of all patients. Most trials excluded individuals with severe kidney disease, active eating disorders, and certain psychiatric conditions. Your response may differ.
  • Long-term data beyond 2-3 years is limited. We do not yet know the full safety profile of these medications over a decade or more of use.
  • Weight regain after discontinuation is common. The STEP 1 extension study found that participants regained approximately two-thirds of lost weight within one year of stopping semaglutide [8]. These medications currently require ongoing use to maintain results.
  • Lifestyle factors matter. Patients who combined GLP-1 therapy with structured diet and exercise programs consistently outperformed those who relied on medication alone.

Next Steps

If you are considering GLP-1 therapy, the most important step is a thorough medical evaluation with a qualified provider. Search our GLP-1 clinic directory to find verified providers who offer both semaglutide and tirzepatide, with transparent pricing and patient reviews.

Medical Disclaimer: This content is for informational purposes only and does not constitute medical advice, diagnosis, or treatment. Individual results vary. Always consult a qualified healthcare provider before starting, stopping, or changing any medication. If you are experiencing a medical emergency, call 911.

Sources

  1. Jastreboff AM, et al. "Tirzepatide Once Weekly for the Treatment of Obesity." New England Journal of Medicine. 2022;387:205-216. https://www.nejm.org/doi/full/10.1056/NEJMoa2206038
  2. Wilding JPH, et al. "Once-Weekly Semaglutide in Adults with Overweight or Obesity." New England Journal of Medicine. 2021;384:989-1002. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
  3. Aronne LJ, et al. "Tirzepatide vs Semaglutide for Weight Loss in Adults with Obesity (SURMOUNT-5)." ClinicalTrials.gov NCT05822609. https://clinicaltrials.gov/study/NCT05822609
  4. FDA. "FDA Approves Weight-Management Drug for Patients Aged 12 and Older" (Saxenda). https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-weight-management-drug-patients-aged-12-and-older
  5. FDA. "FDA Approves New Medication for Chronic Weight Management." November 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management
  6. FDA. "FDA Approves New Drug Treatment for Chronic Weight Management." June 2021. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
  7. Lincoff AM, et al. "Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT)." New England Journal of Medicine. 2023;389:2221-2232. https://www.nejm.org/doi/full/10.1056/NEJMoa2307563
  8. Wilding JPH, et al. "Weight Regain and Cardiometabolic Effects after Withdrawal of Semaglutide (STEP 1 Extension)." Diabetes, Obesity and Metabolism. 2022;24:1553-1564. https://doi.org/10.1111/dom.14725