3d • General discussion
𝗥𝗘𝗧𝗔𝗧𝗥𝗨𝗧𝗜𝗗𝗘 + 𝗖𝗔𝗚𝗥𝗜𝗟𝗜𝗡𝗧𝗜𝗗𝗘: 𝗧𝗛𝗜𝗦 𝗡𝗘𝗪 𝗦𝗧𝗨𝗗𝗬 𝗜𝗦 𝗥𝗘𝗔𝗟𝗟𝗬 𝗜𝗡𝗧𝗘𝗥𝗘𝗦𝗧𝗜𝗡𝗚 🧬
This is super interesting.
A brand-new study published in Nature Metabolism looked at something I know a lot of people in the peptide world have been talking about:
𝗪𝗵𝗮𝘁 𝗵𝗮𝗽𝗽𝗲𝗻𝘀 𝘄𝗵𝗲𝗻 𝘆𝗼𝘂 𝗰𝗼𝗺𝗯𝗶𝗻𝗲 𝗥𝗲𝘁𝗮𝘁𝗿𝘂𝘁𝗶𝗱𝗲 𝘄𝗶𝘁𝗵 𝗖𝗮𝗴𝗿𝗶𝗹𝗶𝗻𝘁𝗶𝗱𝗲?
This is the first published study specifically looking at this combination, and there are some 𝗥𝗘𝗔𝗟𝗟𝗬 interesting findings.
Let’s make this ridiculously simple.
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🧠 𝗥𝗘𝗧𝗔𝗧𝗥𝗨𝗧𝗜𝗗𝗘 𝗔𝗡𝗗 𝗖𝗔𝗚𝗥𝗜𝗟𝗜𝗡𝗧𝗜𝗗𝗘 𝗗𝗢 𝗗𝗜𝗙𝗙𝗘𝗥𝗘𝗡𝗧 𝗧𝗛𝗜𝗡𝗚𝗦
Retatrutide works through 𝘁𝗵𝗿𝗲𝗲 𝗿𝗲𝗰𝗲𝗽𝘁𝗼𝗿𝘀:
𝗚𝗟𝗣-𝟭
𝗚𝗜𝗣
𝗚𝗹𝘂𝗰𝗮𝗴𝗼𝗻
Think of these as three different switches involved in hunger, blood sugar, energy balance and metabolism.
Cagrilintide works through a completely different system called 𝗮𝗺𝘆𝗹𝗶𝗻.
Your body naturally releases amylin along with insulin after you eat. One of its jobs is basically telling your brain:
𝗪𝗲 𝗮𝘁𝗲. 𝗪𝗲’𝗿𝗲 𝗴𝗼𝗼𝗱. 𝗬𝗼𝘂 𝗰𝗮𝗻 𝘀𝘁𝗼𝗽 𝗻𝗼𝘄.
So Retatrutide and Cagrilintide can both influence how much you eat, but they don’t get there through exactly the same biological pathway.
𝗔𝗻𝗱 𝗧𝗛𝗔𝗧 𝗶𝘀 𝘄𝗵𝗮𝘁 𝗺𝗮𝗸𝗲𝘀 𝘁𝗵𝗶𝘀 𝘀𝘁𝘂𝗱𝘆 𝗶𝗻𝘁𝗲𝗿𝗲𝘀𝘁𝗶𝗻𝗴.
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🔬 𝗪𝗛𝗔𝗧 𝗗𝗜𝗗 𝗧𝗛𝗘 𝗦𝗧𝗨𝗗𝗬 𝗙𝗜𝗡𝗗?
Researchers used obese male rats and compared Retatrutide, Cagrilintide and the combination.
Over 16 days:
𝗥𝗲𝘁𝗮𝘁𝗿𝘂𝘁𝗶𝗱𝗲 + 𝗖𝗮𝗴𝗿𝗶𝗹𝗶𝗻𝘁𝗶𝗱𝗲: 𝟮𝟮.𝟲% 𝘄𝗲𝗶𝗴𝗵𝘁 𝗹𝗼𝘀𝘀
𝗥𝗲𝘁𝗮𝘁𝗿𝘂𝘁𝗶𝗱𝗲 𝗮𝗹𝗼𝗻𝗲: 𝟭𝟯.𝟮%
𝗖𝗮𝗴𝗿𝗶𝗹𝗶𝗻𝘁𝗶𝗱𝗲 𝗮𝗹𝗼𝗻𝗲: 𝟲.𝟰%
𝗖𝗼𝗻𝘁𝗿𝗼𝗹 𝗴𝗿𝗼𝘂𝗽: 𝗚𝗔𝗜𝗡𝗘𝗗 𝗮𝗯𝗼𝘂𝘁 𝟰%
So the combination produced substantially more weight loss than either compound alone at those doses.
𝗕𝘂𝘁 𝘁𝗵𝗮𝘁’𝘀 𝗻𝗼𝘁 𝗲𝘃𝗲𝗻 𝘁𝗵𝗲 𝗽𝗮𝗿𝘁 𝗜 𝗳𝗼𝘂𝗻𝗱 𝗺𝗼𝘀𝘁 𝗶𝗻𝘁𝗲𝗿𝗲𝘀𝘁𝗶𝗻𝗴.
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🤯 𝗦𝗔𝗠𝗘 𝗖𝗔𝗟𝗢𝗥𝗜𝗘𝗦. 𝗩𝗘𝗥𝗬 𝗗𝗜𝗙𝗙𝗘𝗥𝗘𝗡𝗧 𝗪𝗘𝗜𝗚𝗛𝗧 𝗟𝗢𝗦𝗦.
Researchers did something called “pair feeding.”
Sounds complicated. It isn’t.
They gave another group of rats the 𝗦𝗔𝗠𝗘 𝗮𝗺𝗼𝘂𝗻𝘁 𝗼𝗳 𝗳𝗼𝗼𝗱 the treated rats were eating.
Why?
Because now you can separate:
𝗧𝗵𝗲𝘆 𝗹𝗼𝘀𝘁 𝘄𝗲𝗶𝗴𝗵𝘁 𝗯𝗲𝗰𝗮𝘂𝘀𝗲 𝘁𝗵𝗲𝘆 𝗮𝘁𝗲 𝗹𝗲𝘀𝘀.
from:
𝗦𝗼𝗺𝗲𝘁𝗵𝗶𝗻𝗴 𝗲𝗹𝘀𝗲 𝗺𝗲𝘁𝗮𝗯𝗼𝗹𝗶𝗰𝗮𝗹𝗹𝘆 𝗰𝗵𝗮𝗻𝗴𝗲𝗱.
And look what happened:
𝗣𝗮𝗶𝗿-𝗳𝗲𝗱 𝗿𝗮𝘁𝘀: 𝟭𝟬.𝟲% 𝘄𝗲𝗶𝗴𝗵𝘁 𝗹𝗼𝘀𝘀
𝗧𝗿𝗲𝗮𝘁𝗲𝗱 𝗿𝗮𝘁𝘀: 𝟭𝟴.𝟭% 𝘄𝗲𝗶𝗴𝗵𝘁 𝗹𝗼𝘀𝘀
Think about that.
𝗦𝗔𝗠𝗘 𝗙𝗢𝗢𝗗 𝗜𝗡.
𝗩𝗘𝗥𝗬 𝗗𝗜𝗙𝗙𝗘𝗥𝗘𝗡𝗧 𝗪𝗘𝗜𝗚𝗛𝗧 𝗟𝗢𝗦𝗦 𝗢𝗨𝗧.
That tells us the effects seen in the treated animals weren’t explained by reduced food intake alone.
Something else was happening metabolically.
One important area researchers are looking at is Retatrutide’s glucagon activity and its effects on energy metabolism.
In plain English:
𝗥𝗲𝘁𝗮𝘁𝗿𝘂𝘁𝗶𝗱𝗲 𝗺𝗮𝘆 𝗯𝗲 𝗱𝗼𝗶𝗻𝗴 𝗺𝗼𝗿𝗲 𝘁𝗵𝗮𝗻 𝘀𝗶𝗺𝗽𝗹𝘆 𝗺𝗮𝗸𝗶𝗻𝗴 𝗮𝗻 𝗮𝗻𝗶𝗺𝗮𝗹 𝗹𝗲𝘀𝘀 𝗵𝘂𝗻𝗴𝗿𝘆.
And that’s a BIG distinction.
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🔥 𝗡𝗢𝗪 𝗛𝗘𝗥𝗘’𝗦 𝗪𝗛𝗘𝗥𝗘 𝗜𝗧 𝗚𝗘𝗧𝗦 𝗥𝗘𝗔𝗟𝗟𝗬 𝗜𝗡𝗧𝗘𝗥𝗘𝗦𝗧𝗜𝗡𝗚
𝗠𝗼𝗿𝗲 𝘄𝗮𝘀𝗻’𝘁 𝗮𝘂𝘁𝗼𝗺𝗮𝘁𝗶𝗰𝗮𝗹𝗹𝘆 𝗯𝗲𝘁𝘁𝗲𝗿.
At the highest Retatrutide exposure studied, adding Cagrilintide didn’t add much additional weight loss.
The extra benefit from Cagrilintide was much more noticeable when Retatrutide exposure was 𝗟𝗢𝗪𝗘𝗥.
For the last few years everyone has been asking:
𝗛𝗼𝘄 𝗵𝗶𝗴𝗵 𝘀𝗵𝗼𝘂𝗹𝗱 𝗥𝗲𝘁𝗮𝘁𝗿𝘂𝘁𝗶𝗱𝗲 𝗴𝗼?
4 mg?
9 mg?
12 mg?
But maybe we’re asking the wrong question.
Maybe instead of asking:
𝗛𝗼𝘄 𝗵𝗮𝗿𝗱 𝗰𝗮𝗻 𝘄𝗲 𝗽𝘂𝘀𝗵 𝗢𝗡𝗘 𝗽𝗮𝘁𝗵𝘄𝗮𝘆?
We should be asking:
𝗖𝗮𝗻 𝘄𝗲 𝘁𝗮𝗿𝗴𝗲𝘁 𝗠𝗨𝗟𝗧𝗜𝗣𝗟𝗘 𝗽𝗮𝘁𝗵𝘄𝗮𝘆𝘀 𝘄𝗶𝘁𝗵𝗼𝘂𝘁 𝗵𝗮𝘃𝗶𝗻𝗴 𝘁𝗼 𝗺𝗮𝘅 𝗼𝘂𝘁 𝗮𝗻𝘆 𝘀𝗶𝗻𝗴𝗹𝗲 𝗼𝗻𝗲?
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🔊 𝗧𝗛𝗜𝗡𝗞 𝗔𝗕𝗢𝗨𝗧 𝗜𝗧 𝗟𝗜𝗞𝗘 𝗔 𝗦𝗢𝗨𝗡𝗗 𝗦𝗬𝗦𝗧𝗘𝗠
Imagine you have one speaker.
You keep turning it up:
𝟱𝟬% → 𝟳𝟬% → 𝟵𝟬% → 𝟭𝟬𝟬%
Eventually, you’re getting very little additional benefit.
You’re mostly getting more distortion.
𝗕𝘂𝘁 𝘄𝗵𝗮𝘁 𝗶𝗳 𝘆𝗼𝘂 𝗮𝗱𝗱𝗲𝗱 𝗮𝗻𝗼𝘁𝗵𝗲𝗿 𝘀𝗽𝗲𝗮𝗸𝗲𝗿?
Now you can create more total sound without forcing one speaker to do everything.
That’s basically the research question here.
𝗥𝗲𝘁𝗮𝘁𝗿𝘂𝘁𝗶𝗱𝗲:
GLP-1 + GIP + Glucagon
𝗖𝗮𝗴𝗿𝗶𝗹𝗶𝗻𝘁𝗶𝗱𝗲:
Amylin
𝗗𝗶𝗳𝗳𝗲𝗿𝗲𝗻𝘁 𝘀𝗶𝗴𝗻𝗮𝗹𝘀. 𝗗𝗶𝗳𝗳𝗲𝗿𝗲𝗻𝘁 𝗿𝗲𝗰𝗲𝗽𝘁𝗼𝗿𝘀. 𝗣𝗼𝘁𝗲𝗻𝘁𝗶𝗮𝗹𝗹𝘆 𝗰𝗼𝗺𝗽𝗹𝗲𝗺𝗲𝗻𝘁𝗮𝗿𝘆 𝗲𝗳𝗳𝗲𝗰𝘁𝘀.
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⚠️ 𝗪𝗛𝗬 𝗟𝗢𝗪𝗘𝗥 𝗥𝗘𝗧𝗔𝗧𝗥𝗨𝗧𝗜𝗗𝗘 𝗘𝗫𝗣𝗢𝗦𝗨𝗥𝗘 𝗜𝗦 𝗔𝗡 𝗜𝗡𝗧𝗘𝗥𝗘𝗦𝗧𝗜𝗡𝗚 𝗤𝗨𝗘𝗦𝗧𝗜𝗢𝗡
We already have human Retatrutide data showing that side effects generally increase with dose.
In Lilly’s TRIUMPH-1 data, discontinuation because of adverse events was approximately:
𝗔𝘁 𝟰 𝗺𝗴 → 𝟰%
𝗔𝘁 𝟵 𝗺𝗴 → 𝟳%
𝗔𝘁 𝟭𝟮 𝗺𝗴 → 𝟭𝟭%
Dysesthesia — unusual skin sensations like sensitivity, tingling or burning — was approximately:
𝗔𝘁 𝟰 𝗺𝗴 → 𝟱%
𝗔𝘁 𝟵 𝗺𝗴 → 𝟭𝟮%
𝗔𝘁 𝟭𝟮 𝗺𝗴 → 𝟭𝟯%
So here’s the question I think is worth researching:
𝗖𝗼𝘂𝗹𝗱 𝗮𝗱𝗱𝗶𝗻𝗴 𝗮𝗻𝗼𝘁𝗵𝗲𝗿 𝗺𝗲𝘁𝗮𝗯𝗼𝗹𝗶𝗰 𝗽𝗮𝘁𝗵𝘄𝗮𝘆 𝗲𝘃𝗲𝗻𝘁𝘂𝗮𝗹𝗹𝘆 𝗽𝗿𝗼𝗱𝘂𝗰𝗲 𝘀𝘁𝗿𝗼𝗻𝗴𝗲𝗿 𝗼𝘃𝗲𝗿𝗮𝗹𝗹 𝗲𝗳𝗳𝗲𝗰𝘁𝘀 𝗪𝗜𝗧𝗛𝗢𝗨𝗧 𝗻𝗲𝗲𝗱𝗶𝗻𝗴 𝘁𝗼 𝗸𝗲𝗲𝗽 𝗽𝘂𝘀𝗵𝗶𝗻𝗴 𝗥𝗲𝘁𝗮𝘁𝗿𝘂𝘁𝗶𝗱𝗲 𝗵𝗶𝗴𝗵𝗲𝗿?
We don’t know.
This rat study does NOT prove that it works that way in humans.
But now we have a legitimate scientific reason to ask the question.
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🧬 𝗧𝗛𝗘 𝗕𝗜𝗚𝗚𝗘𝗥 𝗣𝗜𝗖𝗧𝗨𝗥𝗘
Look at how metabolic peptide research has evolved:
𝗚𝗟𝗣-𝟭
↓
𝗚𝗟𝗣-𝟭 + 𝗚𝗜𝗣
↓
𝗚𝗟𝗣-𝟭 + 𝗚𝗜𝗣 + 𝗚𝗟𝗨𝗖𝗔𝗚𝗢𝗡
↓
𝗚𝗟𝗣-𝟭 + 𝗚𝗜𝗣 + 𝗚𝗟𝗨𝗖𝗔𝗚𝗢𝗡 + 𝗔𝗠𝗬𝗟𝗜𝗡?
That may be where this entire field is heading.
Instead of asking:
𝗛𝗼𝘄 𝗺𝘂𝗰𝗵 𝗺𝗼𝗿𝗲 𝗱𝗿𝘂𝗴 𝗰𝗮𝗻 𝘄𝗲 𝘂𝘀𝗲?
The better question may eventually become:
𝗛𝗼𝘄 𝗺𝗮𝗻𝘆 𝗰𝗼𝗺𝗽𝗹𝗲𝗺𝗲𝗻𝘁𝗮𝗿𝘆 𝗯𝗶𝗼𝗹𝗼𝗴𝗶𝗰𝗮𝗹 𝘀𝗶𝗴𝗻𝗮𝗹𝘀 𝗰𝗮𝗻 𝘄𝗲 𝘁𝗮𝗿𝗴𝗲𝘁 𝗶𝗻𝘁𝗲𝗹𝗹𝗶𝗴𝗲𝗻𝘁𝗹𝘆?
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💡 𝗠𝗬 𝗕𝗜𝗚𝗚𝗘𝗦𝗧 𝗧𝗔𝗞𝗘𝗔𝗪𝗔𝗬
I would NOT read this study and conclude:
𝗘𝘃𝗲𝗿𝘆𝗼𝗻𝗲 𝘀𝗵𝗼𝘂𝗹𝗱 𝗰𝗼𝗺𝗯𝗶𝗻𝗲 𝗥𝗲𝘁𝗮𝘁𝗿𝘂𝘁𝗶𝗱𝗲 𝗮𝗻𝗱 𝗖𝗮𝗴𝗿𝗶𝗹𝗶𝗻𝘁𝗶𝗱𝗲.
That’s not what this research proves.
𝗧𝗵𝗲𝘀𝗲 𝘄𝗲𝗿𝗲 𝗿𝗮𝘁𝘀. 𝗡𝗼𝘁 𝗵𝘂𝗺𝗮𝗻𝘀.
But I think this study raises a much more interesting question than simply asking what the maximum Retatrutide dose should be.
Maybe the future isn’t:
𝗠𝗢𝗥𝗘 𝗥𝗘𝗧𝗔𝗧𝗥𝗨𝗧𝗜𝗗𝗘.
Maybe it’s:
𝗕𝗘𝗧𝗧𝗘𝗥 𝗣𝗔𝗧𝗛𝗪𝗔𝗬 𝗖𝗢𝗩𝗘𝗥𝗔𝗚𝗘.
Instead of hammering one biological pathway harder and harder, researchers may eventually discover that activating several complementary pathways at moderate levels produces a better overall result.
𝗔𝗻𝗱 𝗧𝗛𝗔𝗧 𝗶𝘀 𝘀𝗼𝗺𝗲𝘁𝗵𝗶𝗻𝗴 𝘄𝗼𝗿𝘁𝗵 𝘄𝗮𝘁𝗰𝗵𝗶𝗻𝗴.
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📚 𝗧𝗛𝗘 𝗕𝗢𝗧𝗧𝗢𝗠 𝗟𝗜𝗡𝗘
Here is the entire study in 20 seconds:
𝗥𝗲𝘁𝗮𝘁𝗿𝘂𝘁𝗶𝗱𝗲 𝗵𝗶𝘁𝘀 𝗚𝗟𝗣-𝟭 + 𝗚𝗜𝗣 + 𝗴𝗹𝘂𝗰𝗮𝗴𝗼𝗻.
𝗖𝗮𝗴𝗿𝗶𝗹𝗶𝗻𝘁𝗶𝗱𝗲 𝗵𝗶𝘁𝘀 𝗮𝗺𝘆𝗹𝗶𝗻.
Combining them produced greater weight loss in obese rats at certain doses.
The additional benefit from Cagrilintide was strongest when Retatrutide exposure wasn’t already maxed out.
And the pair-feeding experiment showed that the weight-loss difference couldn’t simply be explained by eating fewer calories.
Does that mean we now have a proven human Retatrutide + Cagrilintide protocol?
𝗡𝗢.
Does it give researchers a very interesting new direction to investigate?
𝗔𝗕𝗦𝗢𝗟𝗨𝗧𝗘𝗟𝗬.
This is exactly what I want 𝗧𝗵𝗲 𝗛𝗲𝗮𝗹𝘁𝗵 𝗦𝘆𝗻𝗱𝗶𝗰𝗮𝘁𝗲 to be about.
𝗡𝗼𝘁 𝗵𝘆𝗽𝗲.
𝗡𝗼𝘁 𝗯𝗹𝗶𝗻𝗱𝗹𝘆 𝗰𝗼𝗽𝘆𝗶𝗻𝗴 𝘀𝗼𝗺𝗲𝗼𝗻𝗲’𝘀 𝗽𝗿𝗼𝘁𝗼𝗰𝗼𝗹.
Understanding what the research 𝗔𝗖𝗧𝗨𝗔𝗟𝗟𝗬 𝘀𝗵𝗼𝘄𝘀 — and just as importantly, what it doesn’t show yet.
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📚 𝗥𝗘𝗦𝗘𝗔𝗥𝗖𝗛
Petersen J, Merrild C, Holm SK, et al.
Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats.
Nature Metabolism. 2026.
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