Zepbound vs. New Obesity Drugs: Why Wave-007 Is Stealing the Spotlight
- Ann Metz
- 2 hours ago
- 6 min read
Original posted at obesity.news/ on Dec 09, 2025
Hey OTP friends, it’s Ann again. This episode is a bit of a milestone: it’s the first Tuesday “Weekly Dose” podcast we’ve done live since moving to a full live schedule on Mondays, Wednesdays, and Fridays, because Dave has officially gone full-time with On The Pen. That leap is only possible because of this community: your attention, your comments, your shares, and your trust. This rundown is my way of helping you see the through-line in a very big week for obesity medicine.
This article is reader-supported on Substack.
To receive new posts and support my work,
consider becoming a free or paid subscriber.
A New Frontier: Wave Life Sciences’ “James Bond” One-and-Done Drug (WVE-007)
Dave walks through brand-new phase 1 data from Wave Life Sciences on WVE-007, a single injection obesity drug with 85 day follow up.
In the early data, patients saw about 9.4% reduction in visceral fat, 4.5% reduction in total body fat, and a 3.2% increase in lean muscle mass—a pattern we simply do not see with current GLP-1–based therapies.
Unlike GLP-1/GIP/glucagon agonists, this drug silences the INHBE gene, lowering activin E and directly reshaping body composition rather than just dialing down appetite.
The safety profile so far looks unusually clean, minimal GI issues and no obvious lab or liver red flags, raising the possibility of a once-yearly (or twice-yearly) shot that targets fat biology upstream of appetite.
From “Eating Less” to “Body Composition”: Quality of Weight Loss Takes Center Stage
Dave contrasts today’s nutrient-stimulated hormone drugs (GLP-1, GIP, glucagon, amylin) with this new generation that targets body composition rather than just calories in.
Current workhorse drugs (Ozempic/Wegovy, Mounjaro/Zepbound, etc.) primarily reduce weight by lowering caloric intake, even though they also improve insulin sensitivity and inflammation.
Trials with semaglutide show that up to ~30% of weight lost can come from lean mass, which raises concerns about sarcopenia, metabolic health, and long-term function, especially in vulnerable populations.
The thread Dave keeps pulling on: the field is shifting from “How much weight did you lose?” to “What kind of weight did you lose?” Fat vs muscle is becoming just as important as the number on the scale.
Women, Muscle Loss, and Who Gets Enrolled in Trials
Dave circles back to amylin trials where ~78% of participants were women and asks a hard question: why do so many of these obesity medication trials lean heavily female?
He floats a hypothesis: because women, on average, start with less lean muscle mass, companies may be able to show more fat loss and less alarming absolute muscle loss, potentially softening how “bad” the lean-mass signal looks.
He’s not attacking GLP-1s; he’s flagging a potential data transparency issue and a potential blind spot: if we’re going to put tens of millions of people (including men and older adults) on these drugs, we need to understand who’s in the trials and what’s actually being lost.
T
Medicare, Seniors, and Why Muscle Matters Even More Now
With Medicare poised to open up GLP-1 coverage for obesity, Dave stresses that “quality of weight loss” becomes a patient-safety issue, not just an aesthetic one.
Older adults are already at higher risk for frailty, falls, and sarcopenia; losing an extra chunk of muscle on top of fat could have serious downstream consequences.
That’s part of why the Wave-007 data, visceral fat down, lean mass up, lands as such a big deal in this conversation.
Maintenance is the Next Battleground: Holding the Line After GLP-1s
Dave highlights that one of the largest future markets in obesity medicine will be maintenance, what happens after the big GLP-1 weight-loss phase.
He walks through Fractyl Health’s Revita data: in patients coming off GLP-1s after ~24% weight loss, those getting Revita stayed within ~1.5% of their end weight at 6 months, while the control group regained ~10% of their body weight.
Lilly’s orforglipron trials are also running weight maintenance trials, people reach goal weight on semaglutide or tirzepatide, then transition to orforglipron vs placebo, with a built-in rescue if they start regaining.
Wave-007 is already being planned not only as monotherapy but as an add-on or maintenance agent after GLP-1s, directly addressing the widespread fear of regain in this community.
Amylin Comes of Age: Cagrelintide vs Eloralintide
Dave updates where amylin agonists sit in the pipeline: Novo Nordisk with cagrelintide (and the combo CagriSema) and Eli Lilly with eloralintide.
CagriSema now looks delayed to ~2027, likely because Novo wants to fully monetize:
the Wegovy pill,
the new 7.2 mg high-dose Wegovy (roughly triple the current top dose),before risking cannibalization from the amylin combos and wrangling complex dual-chamber pens.
Lilly’s eloralintide has quietly turned from “side project” to potential star: up to
~20% weight loss at 48 weeks with curves still trending downward, compared with
~12% at 68 weeks for cagrelintide alone.
Mechanistically, eloralintide is engineered for selective AMY-1 receptor binding, with a long half-life via albumin binding and encouraging signals in lipids, blood pressure, and CRP, making it a serious contender for both monotherapy and combination therapy with tirzepatide or retatrutide.
Trial Timelines and an FDA That May Shorten the Runway
Dave notes that the FDA is signaling a move toward larger phase 2 trials that double as pivotal data, potentially trimming or eliminating traditional phase 3 programs for some obesity drugs.
That shift could accelerate timelines for promising molecules like eloralintide, retatrutide, and future combos, bringing more options to patients faster, but also raising questions about long-term safety follow-up.
The overarching message: we’re only a few years away from a world where there’s a relatively tailored pharmacologic option for almost every phenotype of obesity.
Oral Small-Molecule GLP-1s: Structure Therapeutics and the Hype Machine
Dave then pivots to Structure Therapeutics, whose stock spiked ~150% on data for their oral small-molecule GLP-1, alaniglipron (a direct rival to Lilly’s orforglipron).
The trial showed about 11.3% weight loss at 36 weeks with no plateau, using high doses (>100 mg daily) and, crucially, no liver toxicity signals like those that doomed Pfizer’s danuglipron.
He acknowledges why Wall Street is obsessed with oral GLP-1s: cleaner manufacturing, easier scaling, and once-daily pills without peptide-delivery gymnastics.
But he’s openly skeptical of the stock market euphoria: oral small molecules may be valuable options and maintenance tools, yet the real leap in efficacy and body-composition quality still seems to be coming from injectable biologics and next-gen injectables.
Counterfeit Ozempic in U.S. Pharmacies: A Three-Year Story That Won’t Die
Dave revisits a story he’s been tracking for three years: counterfeit Ozempic pens making their way into legitimate pharmacy supply chains via gray-market distributors.
He walks listeners through how to spot the current fake lot (PNT12129), specifically the placement of the EXP/LOT imprint on the pen, and urges anyone who suspects they have a fake pen to stop using it and contact their pharmacy, Novo Nordisk, and the FDA.
The deeper concern is systemic: if fakes can slip through for a high-profile injectable like Ozempic, what else might be compromised, cancer drugs, other biologics, high-cost orals?
He calls out the disconnect between the aggressive messaging against compounders (“unsafe, unregulated”) and the reality that even traditional pharmacy supply chains are vulnerable, yet this story is barely on the evening news.
His message to the community: patients deserve transparent oversight and a “sacred” pharmacy experience where what’s on the label is what’s in the pen, and we should be demanding that from regulators and the media.
Where All of This Leaves Us: Closer Than Ever to Eradicating Obesity as a Disease
Dave closes by zooming out: in just over a decade we’ve gone from bariatric surgery as the only serious medical option to a pipeline where:
GLP-1s and GIP agonists normalize physiology,
amylin and glucagon components refine efficacy,
once-or-twice-yearly injections like Wave-007 reshape body composition, and
maintenance strategies are finally being built into trial design.
The through-line of the episode is simple but profound: we’re moving from “how fast can we shrink the number?” to “how safely and durably can we restore healthy biology?”
And he ends where we started, by thanking you: this community is the reason he can now do this work full time, and the reason these complex science stories get translated into everyday language that people can actually take into the exam room.
If you become a paid subscriber to our Substack, now through the end of the this year, we will send you a free signed book and some OTP swag! Just send us your name and address at ann@onthepen.com with “NEW SUBSTACK SUB” in the subject line, so we don’t miss it!
This article is reader-supported on Substack.
To receive new posts and support my work,
consider becoming a free or paid subscriber.
