Subject: Massive GLP-1 Data From ECO 2026
From: Dave Knapp from On The Pen <[email-masked]>
To: [email-masked]
Date: Wed, 13 May 2026 14:52:49 +0000
List-Id: <onthepen.substack.com>

View this post on the web at https://onthepen.substack.com/p/massive-glp-1-data-from-eco-2026

We spent time on the podcast last week walking through what the European Congress on Obesity was likely to bring. The maintenance question was the one we flagged as most important -- not whether these drugs work, but what “staying on them” actually looks like for people navigating real lives, real costs, and real preferences about needles versus pills.
Today, on the first day of the congress in Istanbul, that question got some answers. Two major studies published simultaneously, a high-dose semaglutide sub-analysis dropped from the STEPUP trial, and Viking Therapeutics presented phase 2 oral data. It was a full day.
Here is what came back, and what it means if you are on one of these medications or thinking about it.
1. If you got to the higher doses of tirzepatide, you will likely need tirzepatide, the higher doses give you a greater “shot” at successful maintenance
SURMOUNT-MAINTAIN is the study Zepbound users have been waiting for. The question it asked: if you spent over a year losing weight on tirzepatide at your maximum dose, what happens when you step down?
Participants spent 60 weeks losing weight on tirzepatide at their maximum tolerated dose (10 or 15mg, depending on what each person could handle), then split into three groups for 52 weeks of maintenance. One group stayed on their maximum tolerated dose. One dropped to 5mg. One switched to placebo.
At week 112, measured from where everyone started:
Tirzepatide maximum tolerated dose: -21.9% body weight
Reduced to 5mg: -16.6%
Switched to placebo: -9.9%
The gap between maximum tolerated dose and 5mg is real, about 5 percentage points. For some people that will matter a lot, and for others it will not. The number that matters most for patients considering a step-down is this: roughly one in three people on 5mg maintenance retained 85% or more of their initial weight loss. That is not everyone. But it is a real and meaningful subset. If you lost 50 lbs on your highest tolerated dose and are wondering whether dropping to 5mg is workable, the data says that for about a third of people in that situation, it largely holds. That conversation with your doctor just got more grounded in evidence.
The headline, though, is that the maximum tolerated dose performed best. If keeping as much of your loss as possible is the priority, the data says staying on your highest tolerated dose is still your best bet.
The placebo arm tells a story this community already knows, stop the medication and the weight starts coming back. Not because of willpower. Because obesity is a chronic disease and the biology does not stop just because the prescription does. The data keeps confirming this, and it keeps mattering that we say it clearly.
One design detail worth noting: patients on placebo who regained more than half of their initial weight loss could restart tirzepatide. That rescue protocol is why the placebo arm did not regain everything, and it reflects a shift in how researchers are approaching these trials. They are increasingly unwilling to simply watch patients regain weight in the name of clean data. That’s news worth celebrating.
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2. Orforglipron is likely best suited to maintain weight loss from a GLP-1 agonist like semaglutide: around 85% for Wegovy users, around 74% for Zepbound users
ATTAIN-MAINTAIN is the study that deserves the most attention out of yesterday’s news, because the question it is asking is genuinely new. And the answer matters directly for a lot of people in this community.
Here is the scenario it tested: you spent 72 weeks on Wegovy or Zepbound, lost a meaningful amount of weight, and plateaued. Now you want to switch to a daily pill (Foundayo) instead of a weekly injection. Maybe you are tired of injecting. Maybe access or cost is changing. Maybe you just want a different option. Can orforglipron (Lilly’s once-daily oral GLP-1), hold what you built on an injectable?
Participants who completed the SURMOUNT-5 head-to-head trial were re-randomized to orforglipron or placebo for 52 weeks. Two cohorts: those coming off Zepbound and those coming off Wegovy. 376 participants total. They started orforglipron at 12mg and titrated up every four weeks, targeting a maximum of 36mg. A rescue protocol allowed escalation or a switch from placebo to orforglipron after week 24 for anyone who regained more than half their original loss. One detail to keep in mind: there was a two-week screening gap between studies, so some regain occurred before orforglipron began.
The results split cleanly by which injectable you came from. The Wegovy cohort on orforglipron maintained 85.9% of their body weight reduction at 52 weeks, compared to 40.2% on placebo. The Zepbound cohort maintained 74.4%, compared to 49.7% on placebo.
The weight trajectories in pounds make it concrete. The Wegovy cohort started SURMOUNT-5 at an average of 250 lbs, got down to 209 lbs on injections, and finished ATTAIN-MAINTAIN at 211 lbs on orforglipron. Essentially flat for a full year on a daily pill. The Zepbound cohort started at 255 lbs, got down to 200 lbs on their highest tolerated dose of injections, and ended at 211 lbs, or an 11 lb regain from their injectable low point, though still 44 lbs below where they started.
Lilly’s press release leaned into the fact that both cohorts ended at the same weight, 211 lbs, framing it as a unified success. That convergence is technically accurate, but it tells a more complicated story: the people who lost more on the more powerful drug gave back more when they stepped down to a GLP-1 pill. That is not a reason to panic. A 74.4% maintenance rate after switching off a dual agonist injection to a once-daily pill is a genuinely good outcome. It just deserves to be seen clearly, not averaged away.
The reason for the gap comes down to mechanism. Switching from Wegovy to orforglipron is a like-for-like swap, GLP-1 to GLP-1. Switching from Zepbound to orforglipron means losing the GIP component, which is part of what makes tirzepatide more potent. Some of that potency goes with it.
The practical takeaway: if you are on Wegovy and thinking about switching to Foundayo, the data is quite encouraging. If you are on Zepbound, the picture is still positive, but expect some drift and definitely factor that into the conversation with your doctor.
On tolerability, the transition went relatively smoothly. GI effects were mild to moderate, discontinuation rates were low across all arms, and (perhaps most importantly) no liver safety concerns emerged.
3. When measured by MRI, the gold standard for body composition, semaglutide does not come close to decimating muscle: around 16% of weight lost was lean mass
The muscle loss argument against GLP-1 medications has been circulating for years. Today’s STEPUP sub-analysis adds the most rigorous data yet to the rebuttal.
The sub-analysis looked at semaglutide at 7.2mg, three times the currently approved Wegovy dose, in 1,407 adults with obesity over 72 weeks. Nested within it was an MRI body composition sub-study of 55 participants. MRI is the gold standard for measuring body composition, more precise than the DEXA scans more commonly cited in this debate.
The findings: 84% of the weight lost was fat mass. Around 16% was lean mass. Visceral fat dropped more than 30%. And muscle function as measured by sit-to-stand testing was unchanged.
Yes, 16% of lost weight being lean mass is a real number and worth acknowledging honestly. But functional muscle preservation, the thing that actually determines whether your body works well, held up. Why? It’s pretty simple. A 300 pound man doesn’t require the same amount of muscle to move functionally as a 200 pound man. When it came to function, the data held up. Critics of GLP-1s on the muscle loss question have been working with increasingly thin evidence, and MRI data showing preserved function at a higher semaglutide dose is another data point they will need to reckon with.
The broader efficacy picture from the STEPUP sub-analysis is also worth noting. At 7.2mg overall, patients lost 20.7% of their body weight versus 17.5% at the currently approved 2.4mg dose. And early responders (those who lost 15% or more in the first 24 weeks, about one in four patients) reached 27.7% total body weight loss by week 72. Even the slower responders averaged 15.4%, which means the floor is higher than what most people experience at the current approved dose.
Wegovy at 7.2mg is now approved in the US for prescription, and it was recently announced that it would be included in the medicare BRIDGE program beginning on July 1 of this year.
4. Viking’s dual agonist pill could be among the strongest oral options on the market -- 12% weight loss after just 13 weeks, though the 120mg dose raises real questions
Viking Therapeutics presented phase 2 results from their VENTURE-Oral study, a dose-finding trial of the oral version of VK2735, a dual GLP-1/GIP agonist similar in mechanism to Zepbound.
At the highest dose tested, 120mg once daily over 13 weeks, participants lost 12.2% of body weight. GI side effects were mild to moderate and largely resolved as doses were titrated up.
Thirteen weeks is a short window, and dose-finding studies are designed to map the dose-response curve, not to show peak efficacy. But 12.2% at 13 weeks puts oral VK2735 in serious company. For context, most injectable trials at similar timepoints are not showing numbers that much higher. The phase 3 for the oral formulation is expected to read out next year.
The caveat worth sitting with: 120mg is a very large amount of active pharmaceutical ingredient for a daily pill. Viking Therapeutics has publically aknowledged that they only intend to bring the 75mg version to market, which will undoubtedly bring these numbers back down to earth. But for our community, the broader point is simple: the oral pipeline is thickening. More options with strong efficacy profiles means more competition, and more competition is good for access and affordability over time.
What It All Means
Four datasets, one day. The throughline across all of them is the same question this community has been asking for years: what does long-term treatment actually look like, and what options do people have when circumstances change?
SURMOUNT-MAINTAIN says staying on your full tirzepatide dose gives you the best shot at keeping what you lost, but stepping down to 5mg is viable for a meaningful subset. ATTAIN-MAINTAIN says switching from an injectable to a daily pill is a real option, not a theoretical one -- with results that vary depending on which injectable you came from and deserve to be understood on their own terms. The STEPUP sub-analysis says there is more efficacy headroom above the current Wegovy dose, and the body composition data from MRI continues to undercut the muscle loss argument. And VENTURE-Oral says the oral pipeline is filling in, with real numbers to back it up.
We will unpack this all on today’s live at 12PM eastern on Youtube/X/Linkedin. A a reminder, we are live every M/W/F at the same time, on the same platforms!
ATTAIN/SURMOUNT-MAINTAIN PRESS RELEASE: https://investor.lilly.com/news-releases/news-release-details/lillys-foundayo-and-lower-dose-zepbound-helped-people-maintain
STEP UP PRESS RELEASE: https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916545
VENTURE-ORAL PRESS RELEASE: https://ir.vikingtherapeutics.com/2026-05-12-Viking-Therapeutics-Presents-Data-from-its-13-Week-Phase-2-VENTURE-Oral-Dosing-Trial-of-VK2735-at-European-Congress-on-Obesity-ECO-2026

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