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Semaglutide changed everything — but researchers pushing the boundaries of the possible are never quite satisfied. Tirzepatide was the result of a question that’s simultaneously obvious and super ambitious. “Can we do better?”
A rumor has been going around that the Eli Lilly researchers who developed it nicknamed their compound “King Kong.” The real giant of novel weight loss and diabetes management options. It’s not hard to see why. Tirzepatide allows people on the highest dose to lose just over 22 percent of their starting weight. On the diabetes front, the peptide gets HbA1c down to prediabetic levels.
It’s not really like the gorilla monster, though. Tirzepatide doesn’t do brute force. It’s a single compound that targets two gut hormones at once — and as a “twincretin” that binds to GIP as well as GLP-1, it gives patients who need a little more than Semaglutide can offer a treatment option that, in some cases, allows them to avoid bariatric surgery.
It suppresses appetite and slows digestion. It normalizes insulin and keeps glucagon in check — all things Semaglutide also does. On top of that, Tirzepatide has also demonstrated an uncanny ability to manipulate how fat gets stored and used. A biology impacted by obesity is complex. The body actually throws everything it has — including through built-in redundancies — to defend a state it fails to recognize as dangerous. Tirzepatide fights back in new ways, and with results that can truly, without exaggeration, be described as revolutionary.
A (Very) Brief History of Tirzepatide
Eli Lilly researchers, including the famous Richard DiMarchi, started work on Tizepatide with two things in mind. They knew GLP-1 agonists were effective for type 2 diabetes, but they were also quite sure that they’d hit a plateau. To get even better results, they couldn’t just keep targeting GLP-1.
GIP (short for glucose-dependent insulinotropic polypeptide) hadn’t proven to be a particularly effective stand-alone target in diabetes treatment, but the team thought it deserved another look. Their hypothesis? Pairing a GIP agonist with a GLP-1 peptide might make both a whole lot more potent.
They weren’t wrong — and the results probably blew the development team away as much as they impressed everyone else. Successful preclinical research opened the door to human trials.
SURPASS, for type 2 diabetes, saw participants achieve better long-term blood sugar control and wow-worthy weight loss to the tune of 15 percent.
The results from the SURMOUNT trial, for obesity, were just as interesting. Participants on the highest dose of 15 mg lost 20+ percent of the weight they started out with on average. That didn’t happen overnight (the trial took 72 weeks), but it happened. Tirzepatide can do things that simply weren’t possible before. [1, 2]
How Tirzepatide Achieves These Impressive Results
Incretins are hard at work to balance the body after eating in the “wild.”
GLP-1 reacts to high blood sugar levels by releasing insulin. It keeps blood sugar-raising glucagon levels down, and it also has a mechanism to stop people from eating too much. On the physical side, it keeps food in the stomach longer for a “don’t eat more” message — and in the brain, it says “you really don’t want to eat more.” GIP strengthens that same message. It’s got a role in insulin management, too, but besides that, it also seems to shift fat metabolism toward “burn more, store less.”
Tirzepatide is one lab-engineered compound that “impersonates” them both — while making them stronger, more powerful than they naturally are.
The Observed Effects of Tirzepatide — and Some of the Most Exciting Research to Date
Work on developing Tirzepatide spanned the 2010s. Large-scale human trials followed, and the peptide now continues to prove itself in clinical settings every day. The science isn’t quite settled though, because new research continues to emerge. Tirzepatide is a potent weight loss and type 2 diabetes management option doctors are glad to have in their arsenals, but studies also hint at potential use cases beyond those two areas.
Curious mind in search of answers? We’ve picked out the most exciting findings so far.
The SURMOUNT Trials and the Potential for Unprecedented Weight Loss
We know — journalists, excited scientists, and others love to throw the word “unprecedented” around. Tirzepatide earned it. You’ve seen the headline-grabbing results already. After 72 weeks, participants lost:
- 15 percent with a 5 mg dose
- 19.5 percent with a 10 mg dose
- 20.9 percent with a dose of 15 mg, the highest dose
Look a bit deeper, and the weight loss results get even more interesting. Over half of people on the highest dose lost at least 20 percent, and a third a full quarter or more. They also benefited from improved metabolic health — more about that later. [3] The point? Tirzepatide didn’t only work very well for a small few. It helped most participants get results that were out of reach with any intervention short of bariatric surgery before.
But Tirzepatide Could Also SURPASS Other Type 2 Diabetes Treatments
The SURPASS program tackled the type 2 diabetes side. It demonstrated that Tirzepatide was more effective than placebo (you’d hope so!), but also more effective than the next-gen diabetes treatments developed before it.
Tirzepatide (researchers tested 5, 10, and 15 mg for diabetes, too), had a stronger effect than Semaglutide. Most exciting? Over half of SUPASS participants taking the highest dose actually saw their HbA1c drop to below 5.7 percent. That’s less than prediabetic levels. Diabetes remission seemed like a distant dream before Tirzepatide. Now, we’re very close. [4, 5]
Tirzepatide Also Improves Cardiometabolic Outcomes
Neither obesity nor type 2 diabetes neatly stay confined to one area. They’re chronic diseases with a nasty habit of starting a cascade of negative health effects. Might Tirzepatide put an end to that? Indeed, research so far shows that the compound has powerful systemic effects.
In all the different trials completed so far, participants on Tirzepatide bring their blood pressure down to healthier levels. They also have lower triglyceride levels, less liver fat, and reduced systemic inflammation. [6]
Headline might tout Tirzepatide as an appetite suppressant, but that would be the understatement of the century. Research has already shown its effects go far deeper. Tirzepatide is a multi-system metabolic reset button.
The most interesting data is still in the works. The SURPASS-CVOT trial is researching how Tirzepatide improves overall cardiovascular results, and although we’re still waiting for the final results, the data in so far are impressive.
Tirzepatide shows similar results as Dulaglutide, but with some extra benefits. This peptide reduces the risk of “major adverse cardiovascular events” (heart attack, stroke, cardiovascular-related death). It’s now also a major compound of interest for the treatment of non-alcoholic fatty liver disease, and studies are looking at its potential to slash systemic inflammation and even reverse liver fibrosis. [7, 8]
What Are the Potential Side Effects of Tirzepatide Like?
You’ve joined us for a look at the amazing efficacy Tirzepatide has demonstrated. That’s one half of the equation. Before a compound is approved as a medication, the side effects also have to be evaluated — the compound has to be generally well tolerated, in relation to its benefits, to succeed.
The side effects of Tirzepatide are essentially the same as those of GLP-1 agonists. They’re dose-dependent and predictable. What matters just as much is that they’re very often transient. For many, they wear off.
So, Tirzepatide partly works because it keeps the stomach busy for longer and sends “I’m full” signals to the brain. It only makes sense, then, that the main side effects are gastrointestinal. Nausea is the most common side effect, and 12 to 23 percent of participants have it. For a minority, that crosses into vomiting. Diarrhea and constipation are also quite common.
These “GI annoyances” mostly happened while researchers were escalating dosing. A slow dosing ladder helps here, and many patients adapt and stop having these side effects after a while. Research and prescription protocols take this into account, and increasing the dose by 2.5 mg every four weeks minimizes the side effects.
Working with Tirzepatide: Administration in Research (and Beyond)
Tirzepatide was designed to be a weekly, convenient, subcutaneous injection. SubQ administration allows for the best possible bioavailability profile and it is practical because Tirzepatide has a long half life that enables it to constantly work on the GIP and GLP-1 receptors it targets.
Researchers generally used the lyophilized form. This is freeze-dried Tirzepatide that researchers have to reconstitute (prepare for research) by mixing it with a sterile solvent. Bacteriostatic water is suitable for Tirzepatide and makes multi-dose experiments safe.
In “real world use,” outside of the lab, Tirzepatide is even more convenient for patients. It’s prescribed as a single dose “pen” that patients can quite easily learn to use themselves. That way, they don’t have to go to the doctor to get their weekly dose.
What Are the Most Common Dosing Protocols for Tirzepatide?
All dosing protocols are centered on weekly delivery and gradual escalation (which, as we saw before, helps to minimize side effects). Thanks to extensive clinical trials and now real world use among patients, protocols have been standardized effectively already.
Tirzepatide is effective at doses of 1-5, 10, and 15 mg. Programs don’t start with the final dose, though.
Here’s how it looks:
- Weeks one to four generally see a dose of ~1-2.5 mg.
- Starting with week five, that goes up to 5mg until the eighth week.
- Then the dose can be increased by 2.5 or 5 mg every month until the target dose.
The final goal is often 15 mg because that’s the maximum dose at which Tirzepatide was tested most effective for weight loss and diabetes.
Programs tend to have a duration of somewhere between 52 and 72 weeks, but both dosing and research cycles are also adjusted depending on the goal. On the other hand, the research data is so rich that all researchers can learn a lot from already established dosing. Even when the goal falls outside the established research (for example, researchers might investigate sleep apnea or cognitive impacts), the gradual dose escalation we’ve looked at is kept because it works and increases compliance.
FAQs
Timelines are quite individual, but the SURMOUNT trial saw participants lose, on average, 20 percent after 72 weeks. Someone who starts with 200 lbs could lose 40lbs (~18kg) by the end. Or 20lbs (~9kg) in ~36 weeks.
Not in the strict sense that there are things patients taking Tirzepatide cannot eat, as such. Trial participants and patients prescribed Tirzepatide do get coached on healthy diets and creating a calorie deficit, on the other hand, so in that sense, the “restrictions” are a weight loss oriented and healthy diet. This new eating pattern should be easier to stick to thanks to the appetite suppression of Tirzepatide.
Research done to date has made it clear that there are a few contraindications. Tirzepatide is not suitable for people with a (personal OR family) history of medullary thyroid carcinoma or with MEN 2. People with pancreatitis, diabetic retinopathy, or gallbladder disease should not take Tirzepatide either. All these groups should be excluded from trials and not prescribed the compound in clinical practice.
The benefit of Tirzepatide is not limited to morbidly obese people with extreme weight loss ahead of them. That is where the results are strongest, but trials can also explore groups with more modest weight loss needs.
Tirzepatide set new records for both weight loss and blood sugar control, but there’s now a newer peptide that’s even stronger for weight loss. Retatrutide is a triple agonist that has enabled a 24 percent weight reduction.
Scientific References and Sources
- https://pubmed.ncbi.nlm.nih.gov/38654653/[↩]
- https://www.drugs.com/history/zepbound.html[↩]
- https://www.nejm.org/doi/full/10.1056/NEJMoa2206038[↩]
- https://www.nejm.org/doi/full/10.1056/NEJMoa2107519[↩]
- https://sjdem.sljol.info/articles/10.4038/sjdem.v15i2.7553[↩]
- https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.14174[↩]
- https://www.sciencedirect.com/science/article/pii/S0002870323002806[↩]
- https://www.nejm.org/doi/abs/10.1056/NEJMoa2401943[↩]