The Drug After Ozempic Loses More Weight. Not for the Reason You’ve Been Told.
The newest weight-loss drug adds a hormone meant to make you burn more. The evidence so far points somewhere plainer.
In clinic this week, a patient and I went through her medications. She was on retatrutide, an experimental drug still in trials, and had been on Ozempic before it.
Then she asked what many people ask me: is all of this just marketing? I told her no, it comes down to neuroscience, and the full answer has a twist.
Three hormones, and the brake they fight
Ozempic copies one gut hormone, GLP-1, and Mounjaro adds a second. Retatrutide adds a third, glucagon, meant to make you burn more as well as eat less.
Burning more matters because of what happens after you lose weight. Fat makes a hormone called leptin, and when fat shrinks, leptin falls and your hypothalamus reads the drop as a sign that food is running out.
So it puts on the brake: you burn less and feel hungrier. In a small 2005 study, topping leptin back up in ten people who had lost weight brought their energy use back to normal.1
The hormone added to push back
Glucagon was added to push against that brake. On camera I said the extra pathways theoretically help, and theoretically is still the right word.
In obese mice the idea holds: retatrutide raised their calorie burn, and blocking glucagon’s receptor took that extra burn away. In people, one hour of glucagon raised resting burn by 15% in eleven healthy men.3
But an hour is not a treatment. The clearest test over weeks gave people cotadutide, a GLP-1 and glucagon drug, for six weeks, and they ate 41% less while the calories they burned were no different from those on placebo.4
| Year | Study | Finding |
|---|---|---|
| 2016 | Salem et al. Diabetes Obes Metab | Eleven healthy men, glucagon for under an hour. Resting burn rose 15%, about the same as cold exposure. |
| 2022 | Coskun et al. Cell Metab | Obese mice. Blocking glucagon’s receptor wiped out retatrutide’s extra burn and cut its weight loss. |
| 2024 | Golubic et al. Diabetes Obes Metab | Cotadutide, GLP-1 plus glucagon, for 42 days. Intake fell 41% against placebo. Total burn by doubly labelled water: no different. |
| 2025 | Ravussin et al. Cell Metab | Tirzepatide, no glucagon, against a structured diet for 18 weeks. Metabolism fell only in step with weight lost, as on the diet. Fat burning rose. |
| 2026 | Eli Lilly Company release | Retatrutide, phase 3: an average 28.3% of body weight off at 80 weeks on the 12 mg dose. Investigational, trials only. |
These do not disagree. The only six-week test used a different drug, cotadutide, in just nineteen people, and no calorie burn numbers for retatrutide itself have been published yet.
Here is the chain the third hormone was meant to break, and where the human evidence runs out.
- Weight comes off From a drug or a diet, fat stores shrink.
- Leptin falls Less fat means less leptin in the blood.
- The brain puts on the brake The hypothalamus reads the drop as starvation, so burn goes down and hunger goes up.
- Glucagon is added to push back In obese mice the extra burn is real, and one hour of glucagon raised it in people too.3
- Over six weeks in people, burn did not rise The weight still came off, because people ate about 41% less.4
Where this gets ahead of the evidence
“It works by revving up your metabolism.”
Unproven
In mice, yes, and for an hour in people. Over six weeks the burn did not rise, but not yet shown is not the same as false.4
“So it beats Ozempic.”
Untested
Semaglutide took off about 15% of body weight in one trial and retatrutide up to 28% in another. No trial has put them side by side.6
“I can get it now.”
Trials only
Not yet. Retatrutide is still being tested and has not been approved.
“If the weight stalls, the drug failed.”
Not proof
A stall fits the body’s documented defence of its weight. Raise it with your prescriber, and never stop on your own.1
The weight loss is not marketing. So far, the evidence says it comes from eating less.
References
- Rosenbaum M, et al. Low-dose leptin reverses skeletal muscle, autonomic, and neuroendocrine adaptations to maintenance of reduced weight. J Clin Invest, 2005
- 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
- Salem V, et al. Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. Diabetes Obes Metab, 2016
- Golubic R, et al. Dual glucagon-like peptide-1 and glucagon receptor agonism reduces energy intake in type 2 diabetes with obesity. Diabetes Obes Metab, 2024
- Ravussin E, et al. Tirzepatide did not impact metabolic adaptation in people with obesity, but increased fat oxidation. Cell Metab, 2025
- Eli Lilly and Company. Lilly’s triple agonist, retatrutide, delivered powerful weight loss in pivotal Phase 3 obesity trial. Press release, 21 May 2026. lilly.com
- Garvey WT, et al. Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial. Nat Med, 2022
Figure. Hypothalamus location, by BruceBlaus, licensed CC BY 3.0, via Wikimedia Commons.