So this was originally going to be a much deeper dive into the differences between semaglutide, tirzepatide and retatrutide, however, I realized that might be too high level for many folks, so instead I’m going to highlight some key differences between the 3 peptides, briefly discuss a few points and then link back to actual scientific articles I used to collect this information and allow folks to read that dense material if they so desire.

So let’s get some easy stuff out of the way first, single agonist, dual agonist and triple agonist.

Semaglutide is a single agonist, it only affects GLP-1 receptors(GLP-1R) and of the 3 peptides it has the highest affinity for its target site. Without getting too deep in the weeds, it binds to GLP-1 with about 2 fold greater affinity than tirzepatide. On its face this would explain why many people notice the GLP-1 effects more with semaglutide. But we need to slam on the brakes right there. These peptides are NOT equivalent. Semaglutide is ~94% identical to human created GLP-1. For all intents and purposes it is a modified GLP-1 molecule in a longer acting form with all the effects that GLP-1 produces. Decreased hunger and food noise, delayed gastric emptying, increased satiety, decreased glucagon secretion, increased pancreatic beta cell function, and on and on. Source: Semaglutide, a glucagon like peptide-1 receptor agonist with cardiovascular benefits for management of type 2 diabetes - PMC https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8736331/#:~:text=Semaglutide

Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide | Journal of Medicinal Chemistry https://pubs.acs.org/doi/10.1021/acs.jmedchem.5b00726

But tirzepatide isn’t GLP-1. It’s actually a 39 amino acid modified GIP molecule that has GLP-1 activity added to the molecule. That is why we call it a dual agonist. It’s having an effect on two incretin receptors. That means tirzepatide is binding to the native GIP receptor(GIP-R) with essentially equal affinity as our body’s own GIP molecule. However, the GLP-1 binding is about 5 times weaker than what our body creates. It is an imbalanced dual agonist with preferential activity at GIP over GLP-1. Again, trying to keep this at an easier to understand level, but what this means is that the drug is a full agonist of GIP-R, and only a partial agonist of GLP-1R. That partial agonist effect means you’re not fully saturating the receptor site, which means you don’t get the full effect. The estimates from the research is that it would take about 10mg of tirzepatide to reach the same level of GLP-1R agonism as 1mg of semaglutide. Now, that’s not a precise number, it’s a best guess from the research currently available.

However, that GIP molecule has more work to do. It has an anti-emetic/anti-nausea effect which may explain why some people experience less side effects, especially at lower doses of tirzepatide. It also has other effects, it is neuroprotective, increases bone formation, decreases stomach acid secretion, increases insulin release, stimulates fatty acid synthesis, and seems to promote the weight loss effect of GLP-1R activation.

Source: Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist - PMC. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526454/#:~:text=For GLP-1R, tirzepatide was,nM (1.86, 3)

LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept - PMC https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308032/#appsec2

GIP and GLP‐1, the two incretin hormones: Similarities and differences - PMC https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4020673/

That brings us to retatrutide. As we know, it is a triple agonist, acting on GLP-1R, GIP-R and glucagon receptors (GCGR). Structurally, it is nearly identical to tirzepatide. It is also a 39 amino acid modified GIP molecule but with changes to the amino acid structure to allow for activity at the GCGR site as well. It is also an imbalanced agonist. It is 8.9 fold more potent at GIP-R than human GIP!! So this drug is far and away more potent than tirzepatide at GIP-R agonism which means it further enhances any of the GIP-R effects AND the GLP-1 effects in a synergistic manner.

Continuing on, it is 2.9 fold less potent than human glucagon and 2.5 fold less potent than human GLP-1. So this drug is an imbalanced GIP agonist, but balanced when comparing GLP-1 and GCGR activation, that’s probably important for multiple things, namely side effects, cardiovascular effects and allowing GLP-1R and GCGR to work together as well.

So let's focus on the GLP-1 part first, comparisons to semaglutide aren’t necessarily going to be accurate and the research has not been done yet BUT we could speculate that about 6mg of retatrutide would have the same level of GLP-1 agonism as 1 mg of semaglutide, but we need someone to actually do that research first, which probably won’t happen until the phase 3 trials for retatrutide are over. But even that isn’t a fair comparison because of the GCGR activity as well.

The GCGR part along with the heavy GIP-R potency are probably the real secret sauce here. Let’s quickly review what glucagon does in our body. If you took any high school or college level biology class you’ll know that glucagon is the ying to insulin’s yang. The two counterbalance each other out. When your blood sugar drops, your body will start cranking out glucagon, and vice versa, when blood sugar is high, glucagon is suppressed. But it does FAR more than that as we’re discovering.

Glucagon increases heart rate and cardiac output/contractility, and lowers pulmonary vascular resistance. If this sounds like a performance enhancement for exercise you would be correct, except native glucagon is rapidly degraded by our body within minutes. The catch is you don’t want high doses of glucagon because it will crank your heart rate up which is why every drug company running a trial with GCGR agonism is being so hypervigilant about cardiac side effects. It is also why it’s not a bad thing that retatrutide is less potent than glucagon. Allowing dose escalation to happen slowly allows something called tachyphylaxis to occur and allow our bodies to adjust to it. Tachyphylaxis is why most people eventually have less side effects with GLP-1 drugs, their body quite literally gets used to the drug and you don’t have the side effects at the same intensity. It may also explain why some folks switching between these drugs may not notice the “effects” as intensely as when they first took a dose of a GLP-1 drug.

Anecdotally, I’ve lost about 24 pounds so far in the Triumph-1 trial and my running speed and efficiency has noticeably gone up. Some of that is because I’m carrying less weight for sure, but I bet a shiny nickel that some of it is due to the GCGR effect of retatrutide. I’ve been running some of my favorite running routes around town at my ‘easy’ pace and effort the last 2 weeks. I’m not only about 45 seconds faster per mile on all of the routes, but my heart rate for these routes is about 10-15BPM slower than before, even when I look back on 5 years of data(Thanks for that Strava)

Anyways, back to the other important effects of glucagon. Like GLP-1 it increases satiety, slows gastric emptying, and changes our appetite preferences. It, like GLP-1 can also cause nausea. So maybe now you’re connecting the dots as to why the over potent GIP-R agonism effect of retatrutide may be important. Remember, it has an anti-nausea effect.

Most importantly, glucagon has a multitude of effects on the liver and brown and white adipose tissue(aka fat). In the liver it increases liver cell survival, increases lipolysis which creates free fatty acids which our body then turns into ketones for energy. In fat cells it increases thermogenesis and lipolysis which further drives that free fatty acids to ketone bodies cycle. It’s literally forcing your body to burn excess fat. Most studies will tell you this effect is probably in the neighborhood of an extra 150-200 calories of excess energy expenditure per day. It is probably why in the phase 2 study that people were still dropping weight. 200 calories a day is nothing to sneeze at. That’s 1400 calories a week! This is probably why you’re seeing such substantial weight loss with retatrutide. The synergistic effect of the imbalanced agonism is working in such a way to maximize the benefits of each incretin hormone while trying to mask the side effects.

Sources: LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept - ScienceDirect https://www.sciencedirect.com/science/article/pii/S1550413122003126?via=ihub#sec1

Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial https://www.nejm.org/doi/pdf/10.1056/NEJMoa2301972

The novel GIP, GLP‐1 and glucagon receptor agonist retatrutide delays gastric emptying - Urva - 2023 - Diabetes, Obesity and Metabolism https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.15167

Hemodynamic Effects of Glucagon: A Literature Review | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic https://academic.oup.com/jcem/article/103/5/1804/4931669

Day 1 - Video 4: GLUCAGON ACTION THE KNOWN UNKNOWNS by Daniel Drucker https://www.youtube.com/watch?v=4U0OorK9Gb4

Wrapping this up, let me shoot from the hip here, this is drug development in action. Each drug is slightly different based upon what we learned from prior drugs and attempts are made to decrease side effects and increased efficacy. It’s clear that Eli Lilly thinks they have something with using the GIP molecule as the backbone and so far it looks like they’re right. Nothing else has been able to touch tirzepatide and retatrutide in terms of weight loss and now you’re seeing other drug makers trying to pivot towards that, or hope that their GLP-1/GCGR dual agonists in development can at least come close.

My final point is this, all of these drugs are the same but very very different. Please don’t try to compare doses. We have best guesses in the research but there is no 1:1 comparison because they’re different drugs. Even with retatrutide and tirzepatide they’re incredibly similar but that glucagon agonism makes a literal whole world of difference. Please read up on the literature, talk to your doctor. One last research I’d suggest is www.glucagon.com it’s run by a scientist who has devoted his life to GLP-1 drugs and it’s a fantastic place to get lost in a sea of data.