GLP-1 vs GLP-3: What’s the Difference?

How GLP-1 drugs such as semaglutide compare with retatrutide, the investigational triple agonist informally called GLP-3, on mechanism, trial weight loss, side effects and FDA status.

By the GLP3 Weight Loss Editorial Team · Updated October 29, 2026

"GLP-1" refers to medications that activate the GLP-1 receptor, such as semaglutide (Wegovy). "GLP-3" is not a hormone: it is an informal name for retatrutide, an investigational drug that activates three receptors (GLP-1, GIP and glucagon). In separate trials, semaglutide 2.4 mg produced a mean weight reduction of 14.9% at 68 weeks [3] and retatrutide 12 mg produced 25.0% at 80 weeks [5]. No completed head-to-head trial of the two has reported results. Semaglutide is FDA-approved for chronic weight management; retatrutide is not FDA-approved [11][13].

Every figure on this page is a group average reported under trial conditions. No figure predicts an individual outcome, and nothing here is medical advice.

GLP-1 vs GLP-3 at a glance

Tirzepatide, a dual agonist sometimes informally called "GLP-2" online, is included because it activates two of the three receptors.

FeatureGLP-1 (semaglutide)Dual agonist (tirzepatide)"GLP-3" (retatrutide)
Receptors activatedGLP-1GLP-1 and GIPGLP-1, GIP and glucagon
Brand (weight management)WegovyZepboundNone (investigational)
FDA status for weight managementApproved June 4, 2021 [13]Approved November 8, 2023 [12]Not approved; FDA submission planned Q1 2027 [11]
How it is givenOnce-weekly injection [3]Once-weekly injection [4]Once-weekly injection, in trials [5]
Pivotal obesity trialSTEP 1, 1,961 adultsSURMOUNT-1, 2,539 adultsTRIUMPH-1, 2,339 adults
Mean weight change vs placebo (highest dose)−14.9% vs −2.4% at 68 weeks [3]−20.9% vs −3.1% at 72 weeks [4]−25.0% vs −3.9% at 80 weeks [5]

All three weight figures count every randomized participant, including those who stopped treatment (the treatment-regimen, or treatment-policy, estimand). They come from different trials with different durations, so they are not a head-to-head comparison.

Is there a GLP-2 or GLP-3 hormone?

The body makes GLP-1 and GLP-2. The proglucagon gene, active in gut and pancreatic cells, encodes glucagon, GLP-1, GLP-2, oxyntomodulin and glicentin [1]; none of these is called GLP-3. GLP-2 is a real gut hormone whose main known action is promoting intestinal growth. Its drug analogue, teduglutide, is used for short bowel syndrome, not weight loss [14].

"GLP-3" and "GLP3" became shorthand online for retatrutide because it adds a third receptor target. By the same logic, tirzepatide is sometimes called "GLP-2", which is easily confused with the real GLP-2 hormone. On this site, "GLP-3" always means retatrutide. The GLP3 overview covers the other labels in circulation, such as GLP3-R and GLP3-B.

How GLP-1 and GLP-3 drugs work

  • GLP-1, and the drugs that mimic it, increase insulin release after meals and reduce glucagon secretion; GLP-1 also acts in the brain to regulate energy balance [1].
  • Tirzepatide activates the GLP-1 and GIP receptors; the FDA describes it as reducing appetite and food intake [12].
  • Retatrutide adds the glucagon receptor. In obese mice, glucagon-receptor activity increased energy expenditure on top of the reduced food intake driven by the GIP and GLP-1 receptors [2]. These were animal findings.

For a receptor-by-receptor explanation, see how retatrutide works.

GLP-1 vs GLP-3 for weight loss

No published trial has compared retatrutide with semaglutide or tirzepatide directly. The closest evidence comes from three sources:

  • Separate placebo-controlled trials, summarized in the table above. Retatrutide 12 mg had the largest mean reduction. The trials differed in length (68 to 80 weeks) and population, so the comparison is indirect.
  • SURMOUNT-5, the head-to-head trial of the two approved drugs: 751 adults with obesity, open-label, 72 weeks. Mean weight change was −20.2% with tirzepatide vs −13.7% with semaglutide [6].
  • Retatrutide vs dulaglutide, another GLP-1 drug, in a Phase 2 type 2 diabetes trial: weight fell by 16.94% with retatrutide 12 mg at 36 weeks, vs 2.02% with dulaglutide 1.5 mg [7].

Two head-to-head studies are listed on ClinicalTrials.gov as active and not recruiting: retatrutide vs tirzepatide in adults with obesity [15], and retatrutide vs semaglutide in type 2 diabetes [16]. Neither has reported results.

See the retatrutide clinical trials page for every reported retatrutide result.

Is GLP-3 better than GLP-1?

The trial data do not answer that yet. Retatrutide trials have reported larger average weight reductions than semaglutide trials, but no head-to-head trial against semaglutide has reported results, its long-term safety is not established, and it is not approved. Semaglutide and tirzepatide are FDA-approved. Whether any of these medications is appropriate for a particular person is a decision for a licensed clinician.

GLP-1 vs GLP-3 side effects

Gastrointestinal effects were the most frequent adverse events with all three drugs [3][4][5]; nausea and diarrhea were the most common in STEP 1 [3] and TRIUMPH-2 [8]. Gastrointestinal events in STEP 1 were mostly mild to moderate and subsided over time; in SURMOUNT-1 they were mostly mild to moderate and occurred mainly during dose escalation [3][4]. The trials reported discontinuation in different ways:

  • Semaglutide (STEP 1): 4.5% stopped because of gastrointestinal events, vs 0.8% with placebo [3].
  • Tirzepatide (SURMOUNT-1): 6.2% at 15 mg stopped because of any adverse event, vs 2.6% with placebo [4].
  • Retatrutide (TRIUMPH-1): 11.3% at 12 mg stopped because of any adverse event, vs 4.9% with placebo, per Lilly [9].

Retatrutide trials have also reported:

  • Dysesthesia, an abnormal skin sensation: 7% at 12 mg vs 1% with placebo in TRIUMPH-2 [8], and 20.9% at 12 mg vs 0.7% with placebo in TRIUMPH-4 [10].
  • A dose-related rise in heart rate, which peaked at 24 weeks and declined thereafter in the Phase 2 obesity trial [17].

See retatrutide safety and risks and the contraindications reported for this drug class.

"GLP-3 peptide" products sold online

Retatrutide is a peptide, and vials labeled "GLP-3", "GLP3-R" or "GLP-3 RT" are sold online as research chemicals. These products are labeled for research use only, are not FDA-approved for human use, and are not the investigational product supplied in Lilly's trials; their identity and purity are not FDA-verified. The trial results and safety data above do not apply to them. See the black-market retatrutide warning.

GLP-1 vs GLP-3 questions

GLP-1 drugs such as semaglutide activate one receptor, the GLP-1 receptor, and are FDA-approved. "GLP-3" is an informal name for retatrutide, an investigational drug that activates three receptors: GLP-1, GIP and glucagon. Retatrutide is not FDA-approved [11].

In separate trials, retatrutide 12 mg produced a mean weight reduction of 25.0% at 80 weeks [5], and semaglutide 2.4 mg produced 14.9% at 68 weeks [3]. No completed head-to-head trial of the two has reported results, so the difference is an indirect comparison.

The evidence does not settle this. Retatrutide trials reported larger average weight reductions, but no head-to-head trial against semaglutide has reported results, its long-term safety is not established, and it is not approved. Semaglutide and tirzepatide are FDA-approved. Whether any of these medications suits a particular person is a decision for a licensed clinician.

Yes. GLP-2 is a real gut hormone made from the same gene as GLP-1. Its main known action is promoting intestinal growth, and its drug analogue, teduglutide, is used for short bowel syndrome, not weight loss [14]. Online, "GLP-2" is sometimes used loosely for tirzepatide, which activates the GLP-1 and GIP receptors.

Gastrointestinal effects were the most frequent adverse events with both [3][5]; nausea and diarrhea were the most common in STEP 1 and TRIUMPH-2 [3][8]. Retatrutide trials have also reported dysesthesia, an abnormal skin sensation, and a dose-related rise in heart rate [8][17]. In TRIUMPH-1, 11.3% of participants on retatrutide 12 mg stopped because of adverse events, vs 4.9% on placebo [9]. The trials measured discontinuation differently, so the rates are not directly comparable.

No. Retatrutide is investigational. Lilly plans to submit it to the FDA in Q1 2027 [11]. Semaglutide (Wegovy) has been FDA-approved for chronic weight management since June 2021, and tirzepatide (Zepbound) since November 2023 [12][13].

Sources

  1. Sandoval DA, D'Alessio DA. Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease. Physiol Rev. 2015. PMID 25834231.
  2. Coskun T, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: from discovery to clinical proof of concept. Cell Metab. 2022. PMID 35985340.
  3. Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). N Engl J Med. 2021. PMID 33567185.
  4. Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). N Engl J Med. 2022. PMID 35658024.
  5. Jastreboff AM, et al. Retatrutide, a Triple Hormone Receptor Agonist, for Treatment of Obesity (TRIUMPH-1). N Engl J Med. 2026. PMID 42814954.
  6. Aronne LJ, et al. Tirzepatide as Compared with Semaglutide for the Treatment of Obesity (SURMOUNT-5). N Engl J Med. 2025. PMID 40353578.
  7. Rosenstock J, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a phase 2 trial. Lancet. 2023. PMID 37385280.
  8. Bellido V, et al. Retatrutide in adults with obesity and type 2 diabetes (TRIUMPH-2). Lancet. 2026. PMID 42810372.
  9. Eli Lilly and Company. TRIUMPH-1 topline press release. May 21, 2026.
  10. Eli Lilly and Company. TRIUMPH-4 topline press release. December 11, 2025.
  11. Eli Lilly and Company. TRIUMPH-2 and TRIUMPH-3 topline press release (includes the Q1 2027 FDA submission plan). July 23, 2026.
  12. U.S. Food and Drug Administration. FDA Approves New Medication for Chronic Weight Management (Zepbound). November 8, 2023.
  13. U.S. Food and Drug Administration. Wegovy (semaglutide) NDA 215256 approval letter. June 4, 2021.
  14. Drucker DJ. The Discovery of GLP-2 and Development of Teduglutide for Short Bowel Syndrome. ACS Pharmacol Transl Sci. 2019. PMID 32219218.
  15. ClinicalTrials.gov. A Study of Retatrutide Compared to Tirzepatide in Adults Who Have Obesity, NCT06662383. Accessed October 29, 2026.
  16. ClinicalTrials.gov. Effect of Retatrutide Compared With Semaglutide in Adults With Type 2 Diabetes, NCT06260722. Accessed October 29, 2026.
  17. Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023. PMID 37366315.

Written and maintained by the GLP3 Weight Loss Editorial Team. Last updated October 29, 2026. Educational content only, not medical advice. GLP3 Weight Loss is not a healthcare provider and does not prescribe, dispense or sell retatrutide for human use.