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Triple Agonists (GLP-1/GIP/Glucagon) Titration and Tapering Algorithms

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At a glance

  • Retatrutide status / not a component of an FDA-approved drug; not permitted in compounding [1]
  • Retatrutide phase 2 trial doses / 1, 4, 8 or 12 mg once weekly for 48 weeks; initial doses of 2 mg or 4 mg in some arms [7]
  • Approved incretin dosing / start low, step up over weeks to limit GI effects [2][3]
  • Wegovy injection / 0.25 mg weekly for 4 weeks, then every 4 weeks toward 2.4 mg [2]
  • Foundayo / 0.8 mg daily, then at least every 30 days to a 17.2 mg maximum [3]
  • Labeled stopping / suspected pancreatitis; recognized pregnancy for weight and CV use [2][3]

Is there a labeled titration schedule for a triple agonist?

No. Retatrutide is not a component of an FDA-approved drug [1]. In its phase 2 trial, adults with obesity or overweight were randomized to subcutaneous retatrutide once weekly at 1 mg; 4 mg (initial dose 2 mg or 4 mg); 8 mg (initial dose 2 mg or 4 mg); or 12 mg (initial dose 2 mg), or to placebo, for 48 weeks. The most common adverse events were gastrointestinal, were dose-related, and were mostly mild to moderate [7]. A 2015 study of a designed peptide that acted at GLP-1, GIP and glucagon receptors tested it in rodent models of obesity [4].

How do approved incretin labels handle dose steps?

Approved GLP-1 and dual GIP/GLP-1 products escalate gradually. The Wegovy injection label starts at 0.25 mg once weekly for 4 weeks and titrates every 4 weeks toward a maintenance dose of 2.4 mg [2]. The Foundayo (orforglipron) label starts at 0.8 mg once daily, increases to 2.5 mg after at least 30 days, then to 5.5 mg after at least 30 days, then may increase to 9, 14.5 or 17.2 mg at intervals of at least 30 days; the maximum is 17.2 mg [3]. The Foundayo label says this escalation is followed to reduce the risk of GI adverse reactions [3]. These are labeled doses for those products, not a triple-agonist schedule. The Zepbound label calls tirzepatide a dual GIP and GLP-1 receptor agonist [5].

Does any label describe a taper?

Neither the Wegovy nor the Foundayo label describes a taper; they call for stopping in specific situations. Both say to discontinue if pancreatitis is suspected [2][3]. The Foundayo label says to discontinue when pregnancy is recognized, and the Wegovy label says the same for weight reduction or cardiovascular risk reduction while giving separate guidance for MASH [2][3].

What happens after stopping an incretin drug?

The closest controlled data are with semaglutide, not a triple agonist. In STEP 4, 803 adults who reached semaglutide 2.4 mg were randomized to continue semaglutide or switch to placebo for 48 weeks. Weight changed -7.9% with continued semaglutide and +6.9% with placebo, a difference of -14.8 percentage points [6]. The trial did not test a taper. It shows that stopping semaglutide can lead to substantial weight regain [6].

Frequently asked questions

Is retatrutide FDA approved?
No. FDA states retatrutide has not been found safe and effective for any condition [1].
What doses of retatrutide were tested?
In the phase 2 obesity trial, adults received 1 mg, 4 mg, 8 mg or 12 mg once weekly or placebo for 48 weeks, with initial doses of 2 mg or 4 mg in some arms [7].
How is tirzepatide different from a triple agonist?
The Zepbound label calls tirzepatide a dual GIP and GLP-1 receptor agonist [5]. A triple agonist acts at three receptors, not two.
What happens to weight after stopping semaglutide?
In STEP 4, 803 adults who reached semaglutide 2.4 mg were randomized to continue or switch to placebo for 48 weeks. Weight changed -7.9% with continued semaglutide and +6.9% with placebo, a difference of -14.8 percentage points [6].

References

  1. FDA’s Concerns with Unapproved GLP-1 Drugs Used for Weight Loss | FDA. FDA’s Concerns with Unapproved GLP-1 Drugs Used for Weight Loss | FDA
  2. U.S. National Library of Medicine, DailyMed. Wegovy injection and tablets prescribing information. Wegovy injection and tablets label
  3. U.S. National Library of Medicine, DailyMed. Foundayo (orforglipron) tablets prescribing information. Foundayo (orforglipron) tablets label
  4. Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015;21(1):27-36. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents
  5. U.S. National Library of Medicine, DailyMed. Zepbound injection (tirzepatide) prescribing information. Zepbound injection (tirzepatide) label
  6. Rubino D, Abrahamsson N, Davies M, Hesse D, Greenway FL, Jensen C, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021;325(14):1414-1425. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial
  7. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial
Evidence overview for Triple Agonists (GLP-1/GIP/Glucagon) Titration and Tapering Algorithms