Lilly dropped topline Phase 3 results for Triumph-2 (Type 2 diabetes + obesity) and Triumph-3 (severe/morbid obesity + established CVD with or without diabetes) last week while I was on vacation so pardon the delay in this post. 

Both trials provide more evidence that retatrutide is the most potent single agent weight-loss molecule we've seen yet. However, Triumph-3 gave us a genuinely interesting non-signal on cardiovascular outcomes, and Triumph-2 gave us groundbreaking weight loss but a muted A1c reduction. I have feelings about all of this and can honestly say both of these trials, at least how Lilly presented this data in their press release, feels like a rare misstep for a company that is becoming the dominant force in the obesity medicine space. Read on and I’ll explain.

But not for retatrutide.

Triumph 2 showed that we can finally break 20% average weight loss!

This trial had 1,152 participants with T2D and obesity/overweight, with an average BMI of 38.2, doses tested were 4/9/12 mg vs. placebo over 80 weeks with an average hemoglobin A1c of 7.7%. 

Put this next to SURMOUNT-2 tirzepatide in essentially the same population (T2D + obesity, 72 weeks, BMI 36.1, A1c 8%) and in that trial where 15 mg topped out at 15.7% weight loss. Retatrutide's 12 mg is beating that by 5 points in a population that's the final boss for weight loss drugs. Not only that but at nearly 21% weight loss we finally can say we have a drug that at least hits the lower bound for bariatric surgery outcomes in diabetes as well. This is perhaps more critical than people realize as obese diabetics don’t have many choices outside of tirzepatide or weight loss surgery, and if they don’t respond to tirzepatide then it’s surgery. Next year they’ll have another option. But what about the A1c reduction?

A1C dropped up to -1.6% from a 7.7% baseline, with all three doses landing in a -1.4 to -1.6% range. Well, this is ODD, this is less than what we saw with Transcend 1 in June and these patients were allowed to be on metformin for this trial. So why the seemingly low reduction? The answer isn’t glucagon causing hyperglycemia, because chronic glucagon agonism doesn’t do that.

It’s that Lilly powered this trial for weight loss. Even the primary outcome was weight loss, not A1c. Moreover, with a low average A1c to begin with at 7.7% these patients didn’t have much room to go down. Keep in mind the ending A1c was on average 6.1% which is an excellent outcome by any measure. But this is misstep by Lilly and has people doubting the A1c effectiveness of this drug. To those folks I say, just wait for Transcend 2 and 3. Those trials are powered for A1c reduction, and I think we’ll see the true strength of retatrutide show up there. This trial, in my opinion, was about Lilly chasing 20% weight loss just like they chased 30% weight loss in Triumph 1.

If you’ve followed the development of retatrutide, there is a continuous thread of people who are worried that the glucagon agonism part of retatrutide is causing issues with the heart. Glucagon can acutely elevate the heart rate and is a known physiological thing that it does. This in part stems from the phase 2 data where Eli Lilly had a detailed chart of cardiovascular adverse events and a few folks have continued to use that as evidence of potential harm. I won’t get into the details here, you can look up the data, but suffice to say, there wasn’t really any signal of harm, but despite that, this idea persisted for years now.

Enter Triumph-3.

These patients could be diabetic or not, but had to have severe/morbid obesity by BMI at baseline and an established history of cardiovascular disease (stroke, heart attack etc., there were 1,949 participants, average BMI 40.4, doses were 9/12 mg vs. placebo, 1:1:2 randomization:

That's essentially SURMOUNT-1's 22.5% (15 mg tirzepatide, BMI 38, non-diabetic obesity population) except TRIUMPH-3 enrolled people with cardiovascular disease, a population that skews older, sicker, and again with generally more difficulty losing weight, especially because a large chunk of the trial population was diabetic. Both doses (9mg/12mg) were essentially the same weight loss as well, suggesting some folks may not need the full 12mg dose, but we’ll need more details to confidently say that. 

The cardiometabolic secondary data at 12 mg is also impressive:

That hsCRP and cholesterol number are the real standouts. Cutting high-sensitivity CRP in half is impressive in a population with existing CVD. In addition, that ~16% reduction in cholesterol should pay dividends over the longer term for cardiovascular outcomes as we’ve seen in the past with other cholesterol lowering medications. But those outcomes were not what Lilly expected.

TRIUMPH-3 had pre-specified MACE analyses, and this is where I want to slow down. Overall event rates were lower than expected in both arms, which is a sign a trial may be underpowered to detect what it was looking for, even if a real beneficial effect exists. Once again, this trial was powered for weight loss FIRST. Here’s what Lilly says directly from the pressor:

In the study, major adverse cardiovascular events (MACE) occurred less frequently than anticipated in both retatrutide and placebo arms. In pre-specified analyses for time to first occurrence of MACE, there were 44 MACE-5 (all-cause death, heart attack, stroke, heart failure event, or coronary revascularization) events observed in participants randomized to retatrutide (pooled 9 mg and 12 mg) and 52 events observed in those randomized to placebo, resulting in a hazard ratio of 0.82 (95.0% CI: 0.55 to 1.22). There were 27 MACE-3 (cardiovascular death, heart attack, or stroke) events in participants randomized to retatrutide and 23 in those randomized to placebo, resulting in a hazard ratio of 1.12 (95.0% CI: 0.64 to 1.96).

Both confidence intervals cross 1. Neither is statistically significant. And notice the direction: the composite that favors retatrutide (MACE-5) is probably being carried by all-cause mortality, heart failure events and revascularization while the harder atherothrombotic triad (MACE-3) numerically favors placebo, albeit with a wide, uninformative CI on 50 total events. The on-treatment analysis tightens MACE-5 to 0.73 (0.47–1.12), which is a more encouraging point estimate and suggests with longer treatment the benefit would show through, but for now it still crosses 1 and therefore is not statistically significant. All this points to a trial that was underpowered for MACE and did NOT last long enough. Keep in mind this trial was only 88 weeks (a little over 1.5 years) long, where usual CVOT trials whether for statins or GLP-1 or SGLT2i medications are usually 3-4 years and recruit far more than the 2,000 patients seen here. This feels like unforced error by Lilly.

As a contrast, look at the SELECT trial, where semaglutide's MACE-3 reduction in a similarly designed obesity/CVD population was clearly significant (HR ~0.80, CI excluding 1), because SELECT was built from the ground up as an adequately powered, dedicated CVOT. TRIUMPH-3 wasn't; it's an obesity trial with CV analyses, and the lower-than-expected event count shows as much.

Tirzepatide's own dedicated CV outcomes trial in obesity, SURMOUNT-MMO, is still pending for exactly this reason you need the time AND events to read out the answer, that trial has 15,000 patients and wraps up next year after 4.5 years. Retatrutide has its own CVOT trial, it’s called Triumph-Outcomes and won’t finish until 2029, it's 4.5 years long and includes over 10,000 patients. 

I personally think Lilly wanted to show the drug was safe in a sicker population with existing CVD and they did that. The misstep I think was having it be a shorter trial with a mixed population of diabetics and non-diabetics. Lilly has been ruthless in finding ways to shorten drug development times and get drugs to market faster, but this trial may have shown the flaws in doing that. But what about side effects?

TRIUMPH-2 (4/9/12 mg vs. placebo):

The 9 mg arm oddly discontinuing more than 12 mg, worth watching if it repeats in other trials, or perhaps just a statistical fluke? 

TRIUMPH-3 (9/12 mg vs. placebo): broadly similar GI profile, plus the now-familiar dose-dependent dysesthesia (6.4/6.4% vs. 1.3%) and a UTI signal (6.1/7.0% vs. 5.3%) that showed up in TRIUMPH-1 too. Still no mechanistic explanation for either thing that I've seen. Discontinuation rates were higher here (9.8/13.5% vs. 4.8%), which tracks with an older, sicker, higher-comorbidity population and is worth exploring the full data set to see what’s behind it. Importantly though the most common side effect was NOT nausea in either trial, it was diarrhea. 

I think this speaks to the power of GIP agonism helping to reduce nausea rates, but on the flip side the glucagon agonism aspect is probably responsible for the increased rates of diarrhea. Chronic glucagon agonism increases the production of bile acids/salts, these bile salts can be very irritating to the gut and can infamously cause something called bile acid diarrhea (BAD) It will cause frequent watery, loose bile movements and oftentimes is not helped by Imodium. The only thing that usually helps is a bile acid sequestrant drug such as WelChol. Regardless, I’ll be looking to see how many patients quit the trials from diarrhea.

With this readout we have 3 FDA indications ready to go for retatrutide, obesity, knee arthritis, and obstructive sleep apnea. Once Transcend 2 and 3 report out later this year they’ll have enough for diabetes as well. What is really fascinating is Lilly intends to file with a BLA submission targeted for Q1 2027. BLA stands for Biologics License Application. Lilly has been battling with the FDA arguing that retatrutide isn’t just a new drug, but a new BIOLOGIC drug. Without getting into the courtroom drama, if the FDA agrees that retatrutide is a biologic it would be a longer period of market exclusivity before generics could enter the market AND would be illegal for pharmacies to compound retatrutide. That would be a massive blow to compounding/online pharmacies and would keep profits solely in Lilly’s pockets. 

At this point, retatrutide is only 6 amino acids different from tirzepatide (they’re both built from the same 39 amino acid GIP backbone) and if retatrutide is a biologic and tirzepatide isn’t then I guess the sky is green.

If Lilly keeps the price in line with other GLP-1 medications then that will be useful and keep pressure on insurers to cover it, if on the other hand they use it to demand a price premium it’ll just create even deeper access issues in an area of medicine that is already deeply fraught with access and affordability issues. And perhaps the biggest unanswered question, will they offer it through LillyDirect as a cash pay drug? I hope they do, as it offers some benefits unseen in other drugs in this class.

For now, I’m left with a few other questions that should hopefully be answered when the full data is published:

Full data drops for both trials occur in the fall and should answer all these questions and more! For now, we impatiently wait. Stay tuned! 

Reference: Lilly's triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C | Eli Lilly and Company