Everything you need to know about Retatrutide, the newest GLP1 agonist
A physician explains how retatrutide, a triple agonist in Phase 3 trials, works, how its Phase 2 weight-loss results compare with tirzepatide, and where he sees pros and cons.
With Dr. Kevin Joseph (DO)
Key moments
Tap a moment to play the video from there.
- 0:00Introducing retatrutide as triple agonistJoseph describes retatrutide as a triple agonist from Eli Lilly, finished with Phase 2 and now in Phase 3. He says the video will cover mechanism, benefits, side effects and trial results.
- 0:45How GLP-1 and GIP receptors workJoseph says these receptors in the brain, gut and pancreas drive reduced food noise, earlier fullness, slower gastric emptying and better insulin response.
- 2:54What the glucagon receptor addsHe says glucagon acts opposite to insulin and may raise fat breakdown. He adds that activity in brown adipose tissue may increase energy expenditure.
- 4:47Phase 2 weight-loss resultsJoseph reports almost 18% weight loss at 24 weeks on 8 mg and almost 24% at 48 weeks on 12 mg. He compares this with the tirzepatide result of 21% over 72 weeks.
- 7:16Benefits for patientsHe argues that faster weight loss may let patients come off medication sooner. He says a lower risk of low blood sugar is another benefit.
- 9:44Hope for non-respondersJoseph describes people with no response at maximum doses, or severe side effects at the lowest doses, as groups who might benefit from an alternate pathway.
- 11:20Weaker binding and side effectsHe says weaker binding at GLP-1 and GIP receptors may mean fewer GI side effects. He worries it could also reduce appetite suppression.
- 13:19Small trial and approval statusJoseph points out that the Phase 2 trial had 330 participants and that the drug is still in Phase 3. He hopes larger trials will show unknown side effects or benefits.
- 14:39His overall outlookHe says he expects the added glucagon pathway to help patients who do not respond to current medications, and he is waiting on Phase 3 and FDA approval.
What the video says
Dr. Kevin Joseph, who says he has lost over 140 pounds using GLP-1 medications, walks through retatrutide. He describes it as a triple agonist being developed by Eli Lilly that has finished Phase 2 trials and is now in Phase 3. He frames the topic around what it could mean for patients and for his own practice.
On mechanism, Joseph explains that GLP-1 and GIP receptors sit in the hypothalamus, the GI tract and pancreatic beta cells. He says activating them reduces food noise, brings earlier fullness, slows gastric emptying and helps beta cells respond to high blood sugar. What he says sets retatrutide apart is its action on the glucagon receptor, found mainly in the liver and kidney, with smaller amounts in fatty tissue and brown adipose tissue. He says this pathway may increase fat breakdown and energy expenditure.
For the Phase 2 obesity trial, Joseph reports that the primary endpoint was weight loss at 24 weeks, with almost 18% of body weight lost on the 8 mg group. At 48 weeks, he says the 12 mg group lost almost 24%. He compares this with the tirzepatide obesity trial, where he says participants lost 21% over 72 weeks, and concludes that retatrutide produced more loss in less time. He also notes that the dose figures are study groups, and that participants started around 1 or 2 mg and ramped up.
Joseph lists possible benefits: faster weight loss, a lower risk of low blood sugar because glucagon raises glucose, possible help for people who do not respond to semaglutide or tirzepatide, and fewer GI side effects because of weaker binding at the GLP-1 and GIP receptors. On the downside, he worries the same weaker binding could mean less appetite suppression, that the Phase 2 trial had only 330 participants, and that the drug is still unapproved. He says he is looking forward to the Phase 3 results.
On each compound
Retatrutide0:45
Joseph describes it as a triple agonist of the GLP-1, GIP and glucagon receptors. He reports almost 18% weight loss at 24 weeks on 8 mg and almost 24% at 48 weeks on 12 mg in the Phase 2 trial.
See how your DNA reads RetatrutideTirzepatide4:47
Joseph uses the tirzepatide obesity trial as his comparison, saying participants lost 21% of starting weight over 72 weeks. He also says it binds the GLP-1 and GIP receptors more strongly than retatrutide.
See how your DNA reads TirzepatideSemaglutide11:20
Joseph says patients report more side effects on semaglutide than on tirzepatide. He attributes this to how strongly it binds the GLP-1 receptor, and he mentions the 2.4 mg maximum and 0.25 mg lowest dose.
See how your DNA reads SemaglutideWhat this video doesn’t settle
- The weight-loss comparison with tirzepatide sets two separate trials of different length side by side, so it does not show a direct head-to-head result.
- The Phase 2 trial had 330 participants, and Joseph says this is too small to predict how the average person would respond.
- His claims about fewer side effects and possible help for non-responders are expectations from mechanism and patient reports, not trial findings shown in the video.
Questions this video answers
How is retatrutide different from semaglutide and tirzepatide?
Joseph says retatrutide acts on the glucagon receptor in addition to the GLP-1 and GIP receptors. He says this extra pathway may raise energy expenditure and fat breakdown, and that it binds less strongly to the GLP-1 and GIP receptors.
How much weight did people lose in the retatrutide Phase 2 trial?
Joseph reports almost 18% of body weight lost at 24 weeks on 8 mg, and almost 24% at 48 weeks on 12 mg. He compares this with 21% over 72 weeks in the tirzepatide obesity trial.
Could retatrutide lower the risk of low blood sugar?
Joseph says glucagon raises blood sugar by releasing glucose stored in the liver, so he expects a lower risk of low blood sugar than with semaglutide or tirzepatide. He says this is his expectation for patients who get overnight lows.
What are the downsides of retatrutide according to Joseph?
He cites possibly weaker appetite and food noise suppression because of weaker GLP-1 and GIP binding. He also notes the small Phase 2 trial of 330 participants and that the drug is still in Phase 3 trials.
Video by Dr. Kevin Joseph, DO on YouTube, embedded as published. The summary is written by PeptidesDNA from the video; every claim in it is the speaker’s. Not affiliated with or endorsed by the creator. Not medical advice.
