A freshly published study has demonstrated a staggering 28.7% weight loss over a 68-week time period from a drug called retatrutide. Even more surprising, it also brought profound relief from knee arthritis pain.
But the first thought that should go off in our minds is: what’s the downside?
Let’s take a look at the results and see how this new treatment compares to what’s already on the market.
Table of Contents
- A new approach
- The new trial
- Comparison With Other Medications
- Side Effects and Safety
- Retatrutide vs Tirzepatide: What’s the Real Comparison?
- Conclusion
- Reference list
A New Approach
Retatrutide is a complex drug. It’s a triple agonist — but what does that mean, and is it safe?
It means that it contains three classes of agonists:
- Glucagon-like peptide-1 (GLP-1)
- Gastric inhibitory polypeptide (GIP)
-
Glucagon receptor agonists
Let’s walk through each.
GLP-1: The Foundation
We already know a lot about GLP-1. The most famous drug that only targets this receptor is Ozempic (semaglutide). GLP-1 medications have been used in clinical medicine to treat type 2 diabetes since 2005 [1].
The big innovation with GLP-1 medications was figuring out how to stop the peptide from being broken down so quickly. Endogenous GLP-1 is naturally degraded within minutes by the DPP-4 enzyme, giving it a half-life of only 2 minutes [1].
That’s why supplements claiming to increase GLP-1 are largely a waste of money — the peptide doesn’t last long in the body.
But researchers found a promising lead in an unusual place: the venom of the Gila monster.
In it, they discovered a structurally similar compound called exendin-4, which resists breakdown and binds to the same receptors that GLP-1 does [2].
This discovery led to a cascade of drug development. We moved from:
- Twice-daily injections (e.g., Byetta®)
-
To once-weekly formulations like Bydureon® [1]
Over time, researchers noticed that GLP-1 medications didn’t just control blood sugar — they also promoted weight loss.
How GLP-1 Promotes Weight Loss
The mechanisms are complex. GLP-1 medications:
- Stimulate insulin release
- Act on brain receptors to increase satiety and suppress appetite
- Slow gastric emptying, making us feel full longer
-
Alter reward pathways, reducing our drive to eat for pleasure rather than hunger [1][3][4]
This “reward-hacking” effect is particularly interesting. GLP-1 receptor activation has been shown to reduce hedonic eating, meaning we crave food less even when we’re not hungry [4].
GIP: Dual-Agonist Strategy
With the success of GLP-1 meds, researchers asked: what else could we add to increase weight loss?
Enter gastric inhibitory polypeptide (GIP) — the second agonist.
Like GLP-1, GIP stimulates insulin release in response to nutrients [5].
The combination of GLP-1 + GIP is what’s found in tirzepatide, a dual-agonist medication. Early trials suggested it offered even greater weight loss than GLP-1 medications alone.
Glucagon Receptor: The Third Arm
Retatrutide takes this concept further by adding a third receptor target: glucagon.
Glucagon plays a somewhat counterintuitive role:
-
It stimulates the liver to release glucose and raise blood sugar — which is why it hasn’t been historically useful in treating type 2 diabetes [6].
But on the flip side, glucagon also:
- Increases energy expenditure
- Promotes fat breakdown
-
Prevents fat formation [6]
So researchers hypothesized: Could we pair glucagon signaling with GLP-1 and GIP to amplify fat loss — without spiking blood sugar?
The answer seems to be yes.
Combining all three targets allows for synergistic metabolic benefits, while GLP-1 and GIP help buffer the blood sugar–raising effect of glucagon [7].
This is the three-pronged approach of retatrutide.
The New Trial
That’s the theory. But does it work in practice? And more importantly — is it safe?
Phase 1 and 2 Results
Early results were promising. A phase 1 study showed clinically meaningful reductions in both blood glucose and body weight [8].
A phase 2 trial raised some safety questions, including a possible signal for cardiac arrhythmias — we’ll revisit this shortly [13].
Phase 3 Trial Overview
The new phase 3 trial included 445 overweight or obese adults who did not have diabetes but did have knee osteoarthritis [9].
Participants were randomly assigned to:
- 9 mg or 12 mg of retatrutide
- Or placebo
-
Duration: 68 weeks
Let’s look at the results.
Weight Loss Results
-
12 mg retatrutide group:
- Average weight loss: 28.7%, or 32 kg / 71 lbs
-
9 mg group:
- Weight loss: 26.4%
-
Placebo group:
-
Weight loss: 2.1% [9]
-
Pain Reduction (WOMAC Score)
Pain levels from knee osteoarthritis also improved significantly.
- Retatrutide groups: ~75% reduction in WOMAC pain score
- Placebo group: 40.3% reduction [9]
Comparison With Other Medications
Semaglutide (Ozempic)
- 68-week trial
-
~15% average weight loss
- In overweight/obese participants without diabetes [10]
Tirzepatide
- 72-week trial
-
Highest dose (15 mg): ~21% average weight loss
- 2,539 participants without diabetes [11]
Takeaway
Retatrutide clearly sets a new bar for weight loss effectiveness — but that’s not the full story.
Side Effects and Safety
Let’s examine safety and tolerability — because these matter as much as effectiveness.
Discontinuation Rates
- Retatrutide 12 mg: 18.2% discontinued
-
Retatrutide 9 mg: 12.2%
- Placebo: 4% [9]
For comparison:
- Semaglutide: 4.5% discontinued [10]
-
Tirzepatide: ~7% discontinued at highest dose [11]
That 18.2% discontinuation rate for Retatrutide is strikingly high.
Authors noted that discontinuation was correlated with baseline BMI — those with lower BMI were more likely to drop out, sometimes due to excessive weight loss. Among participants with BMI ≥35, the discontinuation rate fell to 12.1% [9].
Still, this is notably higher than for tirzepatide or semaglutide.
Diarrhea
A common side effect for all GLP-1/GIP drugs.
-
Retatrutide:
- 9 mg: 34.7%
- 12 mg: 33.1%
- Placebo: 13.4% [9]
Compare that to:
- Semaglutide: 31.5% [10]
- Tirzepatide: 23% at highest dose [11]
In general, tirzepatide shows lower rates of common side effects.
Dysesthesia: A Red Flag?
This is an uncommon side effect not typically associated with semaglutide or tirzepatide.
Dysesthesia is a touch-related disorder that causes pain, itching, tingling, or burning sensations when the skin is touched.
Reported rates:
-
Retatrutide:
- 9 mg: 8.8%
- 12 mg: 20.9%
- Placebo: 0.7% [9]
For comparison:
- Tirzepatide: 0.4% in two major studies [12]
This significant jump raises a clear red flag, even though most symptoms were reported as mild and rarely led to discontinuation [9].
Cardiac Arrhythmias?
The phase 2 trial of retatrutide showed elevated rates of heart rhythm problems at certain doses [13].
We don’t yet have complete phase 3 data to confirm whether this signal persists — but it’s something to watch closely.
Retatrutide vs Tirzepatide: What’s the Real Comparison?
At a glance:
- Retatrutide (12 mg): 28.7% weight loss
- Tirzepatide (15 mg): 20.9% weight loss
But — this isn’t a fair comparison.
The 28.7% figure for Retatrutide is based on the efficacy estimand — meaning: what if everyone followed the protocol perfectly?
But in real life, not everyone does.
That’s why the treatment-regimen estimand (aka intention-to-treat analysis) is more meaningful for clinical relevance.
Real-world estimates:
- Retatrutide (12 mg): 23.7% weight loss
-
Tirzepatide (15 mg): 20.9% [9][11]
So the difference shrinks considerably when you factor in real-world adherence.
Conclusion
Here’s the bottom line:
Retatrutide offers exceptional weight loss potential, possibly the most powerful we’ve seen so far. For individuals not reaching their goals with tirzepatide, it may represent a next step.
But…
- It comes with significantly higher discontinuation rates
- A concerning rate of dysesthesia
-
And potential cardiac safety issues that require further investigation
The headline 28.7% weight loss is impressive — but the real-world difference vs tirzepatide is only about 3%, and side effects may be more pronounced.
Until we have more safety data, tirzepatide remains the more balanced and better-tolerated option.
Reference List
1. https://pmc.ncbi.nlm.nih.gov/articles/PMC4509428/
3. https://www.sciencedirect.com/science/article/abs/pii/S2352154616300274
4. https://www.ncbi.nlm.nih.gov/sites/books/NBK279127/
5. https://pmc.ncbi.nlm.nih.gov/articles/PMC12507501/
6. https://www.ncbi.nlm.nih.gov/sites/books/NBK279127/
7. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.868037/full
8. https://www.sciencedirect.com/science/article/abs/pii/S014067362301053X
10. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
