🌟 Editor's Note
This will be part one of multiple parts covering all the announcements at the American Diabetes Association 2026 scientific conference, up first Retatrutide
Triumph 1- A phase 3 clinical trial of retatrutide in patients with obesity
Transcend T2D-1A phase 3 clinical trial of retatrutide in patients with obesity and treatment naive Type 2 diabetes
What do you do when you’re already the toast of the town thanks to Tirzepatide? Triple down with with a triple receptor agonist.
If you’re new here, or new to incretin retatrutide is a triple hormone receptor agonist acting on the GLP-1, GIP and Glucagon receptors taken as a once weekly injection.
We can now confidently say we have a drug that matches bariatric surgery outcomes. Pun intended that it is a triumph of science and medicine. But while the world is going to just continue to yell about the weight loss numbers, I want to discuss the fact that this drug seems to be about as close to a metabolic fix it all, unlike anything we’ve seen before.
Both trials presented at ADA, Transcend T2D-1 and Triumph-1, I think, only painted a partial picture of the potential of this drug, but that partial picture is incredible. The reason I say this is because with Triumph-1 Eli Lilly only had the raw trial data for a couple weeks, so they scrambled to pull out the stuff that’s relevant to a conference such as this meaning any deeper exploration on the liver and kidney were left out. With Transcend, Lilly had a full picture of data, to the point that they published the data in The Lancet, but the trial was only 40 weeks long and multiple endpoints including A1c, weight loss and other markers haven’t quite hit the full potential of the drug for diabetics so we’re left with questions on what happens when you take it for a longer term.
Transcending Diabetes
Starting with the diabetes data will help inform the obesity data. Transcend 1 was a 40 week double blinded trial testing 4mg, 9mg, 12mg retatrutide vs placebo. Patients had type 2 diabetes with NO other anti-diabetic agents allowed for at least 90 days prior to the trial. The intention was to see what retatrutide alone could do versus intensive diet and exercise regimen.
Average male/female ratio was 55% female 45% male, A1c was 7.9% and average BMI was just under 36. These patients had been diabetic for about 2.5 years and only about 15% of patients had ever been on a medication to treat their diabetes, these were truly treatment naive patients.
So that’s our patient demographic now let’s get into the A1c results.
No plateau!
Whoa nelly
The results were exactly in line with what we expect to see, a near 2% decrease in A1c at the highest doses!
But what is really compelling to me is that when you look at the A1c slope, you can see it hasn’t quite plateaued! That is quite odd as time after time with incretin therapy, usually by about 24 weeks the A1c reduction flattens out, but that is not at all what we see here. Only the 4mg group flattens out at the end of the trial. There is still a negative deflection for 9/12mg arms suggesting we have not reached max reduction in A1c and keep in mind this is retatrutide alone, with no other medications allowed!
Looking at glucose, we saw something similar. It’s harder to tease out because the data is a little noisier, but it appears the glucose reduction was also not quite at a plateau, suggesting further improvements may be forthcoming in longer term trials, especially if other anti-diabetic medications are on board.
And of course, the weight loss. So much weight loss.
No plateau part 2!
In fact, the most weight loss ever seen in a diabetes trial in only 40 weeks. There was no plateau, and in fact it appears longer term trials will probably easily clear 20% weight loss, especially if metformin and/or SGLT2i medications are added on as these can both add another 2-3% extra weight loss when combined with a GLP-1 medication.
Diabetics notoriously cannot lose weight compared to non-diabetics, so this is genuinely an exciting development for them, especially when you combine this data with the side effect profile.
That alot of zeros and ones
Or should I say lack of side effects, and lack of discontinuations. The 4mg arm discontinuations were from…death…and cancer. Only 5 patients stopped the trial from gastrointestinal side effects and only 5% of the 9mg and 12mg arms had to stop the trial for any adverse events. I’m not sure if that’s the drug or the trial sites encouraging patients, but it’s great to see this!
Going back to the benefits to wrap this article up, looking at weight loss by percentage lost is equally impressive. 55% of patients on the high doses lost >15% of their body weight and about 1 in 3 lost >20% in just 40 weeks.
And the cardiometabolic benefits were equally impressive.
An 11-13% drop in LDL cholesterol is really strong in diabetes, especially considering average LDL was already 97mg/dl while triglycerides reductions ranged from 30-40% reduction with a baseline triglyceride level of 150mg/dl. That means for most of these folks their ending triglycerides were about 100mg/dl and LDL dropped to about 85mg/dl. Both of those reductions are meaningful, triglycerides for insulin resistance and LDL for cardiac risk. In addition, Apolipoprotein B, or ApoB was reduced by 15-17%
This atherogenic particle is sort of the main driver of cardiovascular disease, and that level of reduction should absolutely provide meaningful benefits in cardiovascular disease. Further driving risk reduction was about a 30% decrease in hsCRP in these patients as well. Blood pressure was also modestly reduced, average baseline blood pressure was 125mmHg, it reduces this by about 6mmHg, in line with other GLP1 medications and again this is beneficial for long term health.
Diving into the supplementary appendix and related to blood pressure is eGFR. I’ve been yammering on for months(years??) Now it seems like retatrutide seems to increase GFR in patients. We again see that here. The 9mg and 12mg doses both increased GFR by about 4ml/min. Lilly made no note of this in the presentation. But here it is in the appendix. I guess we’re just going to be here waiting for an answer for a little while longer. But again, if true, would be a shock to the nephrology world and a huge benefit for the treatment or perhaps prevention of diabetic kidney disease.
We need details Lilly!
And that’s the partial picture we’re left with. A1c, glucose and weight are still trending down, vast improvements in cardiometabolic markers. Triumph 2 which is an 80 week trial in diabetics should have a fully data release this fall. Our patience shall be rewarded.
Triumphing over adioposity
Moving onto the obesity trial, Triumph-1. These results were almost unbelievable, lets just get the weight loss and tolerability out of the way first, because again it’s the other benefits that are honestly more exciting to me. Now keep in mind the presenters cautioned us that the data set was only obtained about 2 weeks ago and therefore not all data was available or fully processed yet. The trial was about 65% female, average BMI was 40, and 77% of patients had a BMI>35 indicating most of these patients fall into the severe or morbid obesity stage.
The trial was about 65% female, average BMI was 40, and 77% of patients had a BMI>35 indicating most of these patients fall into the severe or morbid obesity stage. It also included a sleep apnea ‘basket’ and knee osteoarthritis ‘basket’ Basically these were studies within the larger Triumph-1 trial looking at those co-morbid conditions.
Onto the weight loss results
That folks, is what bariatric surgery outcomes look like with a MEDICATION on the 9mg and 12mg. 26-30% weight loss across the board between 80 and 104 weeks. What's really remarkable to me is the extension trial data. As Lilly explained in the presentation, a decision was made to extend the trial to 104 weeks for about 500 patients. These patients could be in any treatment arm, including placebo, had to be on tolerating their dose and had a starting BMI >35 at time of trial enrollment. All patients were titrated up to a maximum tolerated dose of 9mg or 12mg including placebo patients.
What happened was rather remarkable, the placebo arm lost nearly 20% of their body weight in just SIX MONTHS. Even more remarkable is that the 4mg arm, starting losing weight again as well! And not just a little bit more weight, they lost another 10% of their body weight. In the end all 3 arms that were originally on retatrutide from the beginning were tightly clustered between 28 and 30% body weight loss.
But that’s the extent of data we have for the 104 week arm, everything else is 80 week data, so let’s look at differences in weight loss in male vs female patients. We know that men tend to lose 7-8% LESS weight than women on incretin therapy and we again see that here.
Lilly removed this from the slide deck, but I managed to snag a picture at the presentation
We can see the women in the trial were already at 30.8% weight loss at 80 weeks on the max dose with the 9mg dose only 2% behind and both still losing weight. The 4mg arm coming in at 21% is equally impressive! For men it was exactly as expected, 7-8% less, so 20.5% and 23.2% for 9 & 12mg and about 15% for 4mg with all of them at a plateau. Why does this happen? We still don’t have a clear understanding. But still fascinating to see.
Pulling back for a moment to just the 4mg arm overall, they lost 19% of their body weight with only ONE dose titration step. That is better than semaglutide 2.4mg, matches semaglutide 7.2mg and nearly matches 10/15mg tirzepatide. That is quite impressive and speaks to the power of this drug. Indeed, when we look at weight over by percentage lost and patients with BMI <30 and BMI <25(aka, ‘normal’ weight) we see that about 2 out of 3 patients in the higher dose arms reached a BMI<30 which is at least a 10-point drop in BMI given the starting BMI was 40 and 25% of patients reached a ‘normal weight’ aka a BMI of 25 or less.
The presenters suggested and I agree this means for the first time we really have an obesity medication that allows us to use a treat-to-target approach for obesity management instead of just aiming for a relative percent change in weight. What they note is that we need data on the health benefits of a treat-to-target approach with retatrutide, but fortunately and conveniently for us, we have multiple other trials of retatrutide that should help give us those answers including the Triumph-Outcomes trial.
The treat-to-target approach is suggested simply because >85% of patients on the two highest doses were able to lose at least 15% of their body weight and about 75% lost >20%. Even the 4mg dose saw 61% and 44% losing 15 and 20% body weight respectively. Even more is that ~40-45% of patients lost at least 30% of their body weight and about 1 in 4 lost more than 35% of their body weight. Those ranges were previously only reliably achievable with bariatric surgery. All this suggests one could titrate to the weight loss and cardiometabolic benefit needed and then either maintain at that dose or possibly dose reduce down if needed or desired.
We’ll get to the other benefits of retatrutide in a moment but let’s discuss the safety and tolerability here as well. It’s not as good as the diabetic data, partially because it’s a much larger trial and partially because diabetics just seem to tolerate these medications better.
That being said the usual big 4 of nausea, vomiting, diarrhea and constipation lead the charge here as usual. The 4mg dose had the least side effects as we’d expect, and in general has a tolerability profile of tirzepatide with the caveat of a little bit more diarrhea. That being said only 4.1 % of patients stopped the 4mg dose which is less than the placebo arm!
The 9mg and 12mg dose had a profile more consistent with semaglutide but again with more diarrhea. I suspect this is from the glucagon agonism of the drug as glucagon stimulates the formation of extra bile acids/bile salts in the liver which can be very irritating to the intestinal lining causing diarrhea. This can also be seen after gall bladder removal surgery and I wonder if patients with diarrhea on retatrutide wouldn’t benefit from psyllium husk fiber(aka Metamucil in the USA) or taking low doses of drugs called bile acid sequestrants until their GI can adjust to the retatrutide. Both these things can trap and bind up bile acids and reduce diarrhea.
Ketoacidosis while on placebo is interesting
Outside of that there were a couple new signals in the side effects, one was an increase in UTI, which was primarily in women. The cause at this point is unknown, more to come on that I’m sure. The other is dysesthesia or skin sensitivity/discomfort issues. This was seen in a roughly dose dependent manner but only led to 3 patients dropping out because of it.
Finally, the last was dizziness/hypotension. The presenters noted this was more common in the higher doses of retatrutide and more common in patients already on anti-hypertension medications and tended to resolve after stopping the blood pressure medication or increasing fluid intake. This sounds like a bit of a mixed signal in terms of some of it related to dehydration and some of it actual low blood pressure, which is the perfect segue into the cardiometabolic benefits starting with blood pressure reductions.
Up to 12mmHg systolic blood pressure reduction is a pretty profound drop in blood pressure especially when the average blood pressure was 127mmHg. That is on par with a reduction seen with a dedicated anti-hypertensive medication and does probably explain some of the complaints of dizziness and hypotension. It also calls back to a subgroup analysis from the phase 2 obesity data that showed patients with existing hypertension with a BP >140mmHg saw a sustained 30mmHg drop in blood pressure while on retatrutide. Moreover, patients losing 20-30% of their body weight also contributes to blood pressure lowering effects as well and going back to the earlier graph with 2 out of 3 patients not even being in the obese BMI category, suggests a large number of patients were probably able to reduce dose or stop their blood pressure medicine entirely but since they only had the data for a couple weeks we have to wait for confirmation on that.
Of particular note, as someone at the conference asked about the cardiac side effects reported in both trials, the presenters were quick to note the cardiac events were sinus tachycardia, ventricular extrasystoles noted on EKG(aka PVCs, something common and usually of no concern) and a couple patients reporting palpitations. Nothing to be concerned about it seems.
Other benefits found were in the sleep apnea basket, a >60% decrease in apnea-hypopnea index(AHI) this is even MORE than the benefit seen from the tirzepatide OSA trial and these patients had worse sleep apnea and a higher BMI.
Then there was the knee osteoarthritis basket, which saw a roughly 70% decrease in osteoarthritis pain.
Both of these subsets need a ton more data such as patients who stopped using CPAP machines due to sleep apnea resolution, change in amount of daily pain medication taken in the arthritis basket, etc. However, we know both of these diseases are related to inflammatory markers and the presenters did have data on high-sensitivity C-reactive protein or hsCRP.
That’s a massive drop in inflammation. And it’s not even necessarily dose dependent as the 4mg arm was only a few points behind the high doses. hsCRP is associated with an increased risk of cardiovascular disease as well, so what about lipids??
When this cardiometabolic benefit slide was shown there was audible murmuring and comments. A 40% reduction in triglycerides is what we’d expect with a class of medications called fibrates. A 20% reduction in LDL cholesterol is staggering for an incretin-based medication and matches the reductions seen with low dose statins such as the 10mg dose of simvastatin or 10-20mg dose of pravastatin.
Baseline LDL was 112.8mg/dl for the trial and doing the math, that means by the end of the trial the average LDL was 90mg/dl. The American Heart Association recommends an LDL <100mg/dl for the general population. Retatrutide got the average trial patient well below that number. Remarkable stuff. While we don't know the exact ApoB numbers from Triumph, if we look back at the Transcend 1 data showing that retatrutide was reducing ApoB at about a 1:1 rate as the LDL and we can presume a 20% drop in ApoB as well here? That’s gets us easily into the territory where would expect to see less cardiovascular events and disease.
Keep in mind semaglutide and tirzepatide have shown a clear benefit for reducing cardiovascular disease including heart attack and stroke and they usually only lower LDL cholesterol by 4-8% This is more than double that reduction. This is also probably a combination of glucagon and GIP agonism contributing to changes in certain background proteins, specifically lipoprotein lipase, ANGPTL 3 / 8 complexes and ApoC3 as shown in other studies.
And finally, prediabetic patients, regardless of the dose you essentially had about a 90-95% chance of reverting to normoglycemia with retatrutide, this is in line with tirzepatide and is just further proof that glucagon agonism isn’t adding anything deleterious to blood glucose control in these patients.
Fixing…everything?
To wrap all this up, we’re still left with so many questions. What did the liver and kidney data look like for the Triumph trial, what about the rest of the lipids including ApoB? In diabetics, where is the floor for weight and A1c? Do they see further lipid reductions at 80 weeks vs 40 weeks? What about ANY of the cardiometabolic data for the 104 week extension arm, especially the 4mg → max tolerated dose and the placebo arm → MTD. Does the lipid benefit appear in the first 12-24 weeks? What is the glucose and A1c reduction in non-diabetics & prediabetics? How many patients were able to stop blood pressure medications or alter or stop their lipid lowering therapies? What is the GFR change for non-diabetics?! We’re on one hand left with so many questions, but the answers we have point to a revolution in medicine. Yes, other incretins have some of these effects, but it’s the magnitude of the effect that is so profound, especially looking at weight loss and lipids for example. I was making a point to rattle off medication classes in this article just to point out that retatrutide could potentially replace ALOT of them. I mentioned statins, fibrates, and dedicated high blood pressure medications. It probably is powerful enough on its own to replace most oral anti-diabetic medications for a large chunk of diabetics.
The question becomes, who gets access to it? Who is safe to take this medication? For obese patients I think the initial focus should be on the patients with severe and morbid obesity first. Clearly, it gives people bariatric surgery type outcomes, and those folks stand to benefit. For more run of the mill obesity, I will defer back to the treat-to-target I mentioned earlier but also will await the Triumph-8 trial which is specifically using the 2mg and 4mg doses in patients with lower levels of obesity aka BMI <35 to see if there’s a place for it there. I imagine the answer is yes, especially if they have high blood pressure or elevated lipids but again with close monitoring as the weight loss is clearly extremely potent.
For diabetics, I am going to make a bold prediction that this drug becomes the standard of care for most Type 2 diabetics. It matches the A1c reduction of tirzepatide but contains renal and lipid benefits that tirzepatide cannot match. While we didn’t see phase 3 insulin sensitivity data, it’s clear that it profoundly reduces that just based on phase 2 data. Again, some level of consideration will have to be made for initial starting BMI, but just like the obese patients, a treat-to-target dose that considers weight + A1c goals should be the aim going forward.
I am still somewhat in shock from this data and know that even more shocking results await in the full data of Triumph 1, 2 and 3. I’ll be here to report on it when I have it.
Next article will be CagriSema and Survodutide results from ADA 2026, stay tuned!
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