28.7% Weight Loss in New Retatrutide Study

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/


2. https://www.medclinrese.org/open-access/drug-discovery-and-development-of-semaglutide-and-tirzepatide-from-the-gila-monsters-heloderma-spp.pdf


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


9. https://www.prnewswire.com/news-releases/lillys-triple-agonist-retatrutide-delivered-weight-loss-of-up-to-an-average-of-71-2-lbs-along-with-substantial-relief-from-osteoarthritis-pain-in-first-successful-phase-3-trial-302638804.html

10. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183


11. https://www.nejm.org/doi/full/10.1056/NEJMoa2206038


12. https://medical.lilly.com/us/products/answers/has-dysesthesia-been-reported-in-patients-taking-mounjaro-tirzepatide-256308


13. https://www.nejm.org/doi/full/10.1056/NEJMoa2301972