Newsletter · · Ashutosh Agarwal

Retatrutide Hits 28% Weight Loss and Lilly's Amylin Combo Reaches 23% - The GLP-1 Complex - Week of October 5, 2026

The GLP-1 Complex for the week of October 5, 2026. Podcast synthesis on the full retatrutide Phase 3 paper reaching 28.3% weight loss, Lilly's amylin-plus-tirzepatide combo hitting about 23%, high-dose Wegovy versus Zepbound, Novo's pill and patent moves, and the employer, hospital and snack-maker read-throughs.

The GLP-1 Complex

Week of October 5, 2026: Retatrutide Hits 28% Weight Loss and Lilly's Amylin Combo Reaches 23%

Last week the full retatrutide paper came out in the New England Journal of Medicine. Lilly's next-generation shot now has peer-reviewed data showing an average weight loss of 28.3% at the top dose.

In the same week, Lilly said that adding an amylin drug to tirzepatide took weight loss to about 23%. (Amylin is a second gut hormone that helps you feel full.) Novo, for its part, spent its week on pills and patent fights.

The debate has moved on from whether these drugs work. Now the questions are who pays for them, how much of each drug a patient really needs, and what happens to the rest of the economy when 15 million Americans eat less.

TL;DR

  • Lilly widened its lead on efficacy. The full retatrutide data reach 28.3% weight loss at 80 weeks. An amylin-plus-tirzepatide combo hit about 23% in a mid-stage trial, and Leerink puts Lilly's amylin franchise at more than $23B a year by 2035.
  • Novo's high-dose Wegovy narrows the gap but doesn't close it. Novo is also paying $300M up front for a once-weekly pill that hasn't been tested in humans yet. It is leaning hard on direct-to-consumer sales because insurance coverage has stalled.
  • The bill keeps getting bigger. Bank of America now spends $250M a year on GLP-1s, a hospital CEO says these drugs pushed pharmacy costs past plan, and a study finds each GLP-1 dollar creates about 22 cents of other medical spending. Snack makers, meanwhile, are moving toward smaller portions and premium products.

What's new

1. Retatrutide's full paper: the numbers held up, and now the question is dosing

On On The Pen GLP-1 News (They TRIPLED Wegovy Dose, Does it Beat Zepbound?, Oct 1), host Dave Knapp went through the full Phase 3 TRIUMPH results. A Phase 3 trial is the final, large study run before approval.

  • Average weight loss at 80 weeks: 19% on 4mg, 25.9% on 9mg and 28.3% on 12mg. That uses the "efficacy estimate," which counts only patients who stayed on the drug.
  • Longer run: in an extension for patients who started with a BMI of 35 or more, those on the top dose reached about 30% weight loss by week 104.
  • The low dose is already strong. Knapp pointed out that 4mg alone roughly matches today's best shots:

"If four milligrams of retitrutide gives someone enough benefit, uh, that person may never need 12 milligrams."

  • Side effects rise with the dose. Knapp said nausea and vomiting cluster around the times the dose is stepped up, more patients quit at higher doses, and heart rate rises during that step-up period.

On This Week in Cardiology (Oct 02 2026), cardiologist John Mandrola (TheHeart.org / Medscape) gave the doctor's view. The 2,400-patient trial showed 24–25% weight loss on the 9–12mg doses, against 4% on placebo:

"A 250-pound person becomes a 200-pound person in about a year. It's remarkable."

  • Other health markers: systolic blood pressure (the top number) fell about 10 points, and the share of patients with prediabetes dropped from 39% to 6%. Knee pain and sleep apnea both improved.
  • His concern: resting heart rate rose 7–9 beats per minute on the top doses. In his words, that "should give us pause" for patients with weakened heart pumping (heart failure with reduced ejection fraction).

Why it matters: if many patients do well on a lower dose, Lilly needs less drug per patient, and its factories can treat more people. The heart-rate signal is the thing regulators will watch as trials grow.

2. Lilly's amylin combo reaches 23%, and Wall Street starts to put a number on it

CNBC's Annika Kim Constantino reported the data on Squawk on the Street (10AM Hour, 9/30/26).

  • The result: in patients with both obesity and type 2 diabetes, Lilly's experimental amylin drug plus tirzepatide gave up to about 23% average weight loss at 48 weeks. Tirzepatide alone at a high dose gave nearly 15%.
  • The catch: side effects were higher on the combo. Lilly plans to fine-tune dosing in Phase 3 trials starting at the end of this year.

Two days later on Closing Bell Overtime (10/2/26), she added the first big revenue estimate:

"Drugmakers are making a big bet that the next generation of weight loss drugs will not replace the current blockbusters, but rather complement them."

  • The forecast: Leerink Partners estimates Lilly's amylin franchise could bring in more than $23 billion a year by 2035. Leerink sees a market of more than 10 million people who don't get enough benefit from GLP-1s alone.
  • First to market: Novo's CagriSema will likely be the first big test of the amylin class when it launches next year.

On Biotech Hangout (Episode 198, Oct 2), co-host Sam called the result unprecedented:

"I don't think we'd ever seen 23%, 23% weight loss at that time point. Now, obviously, your discontinuation rates was quite high."

His summary: "Lily is firing on all cylinders here." He also said "pretty much every other data point was a bit of a meh" at the conference.

3. High-dose Wegovy vs. Zepbound: the answer depends on how you count

Knapp's On The Pen episode also covered Lilly's comparison of Zepbound with Novo's new 7.2mg Wegovy, presented at the EASD diabetes conference. This was not a head-to-head trial. Lilly lined up results from two separate studies.

  • Counting everyone who started, including those who quit: Zepbound 15mg came out 4.5 percentage points ahead.
  • Counting only patients who stayed on the drug: the lead shrank to 1.8 points. That gap was not statistically significant, so it could be chance.
  • The 10mg dose: 3.2 points ahead on the first method, 0.7 on the second.
  • The one real head-to-head trial compared Zepbound with the old 2.4mg Wegovy: 20.2% vs. 13.7% at 72 weeks.

"Turning semaglutide up to 7.2 may not completely close the gap with terzepatide, but it gets pretty close."

Why it matters: the 4.5-point headline makes the gap look bigger than it may be. If high-dose Wegovy really is close to Zepbound, Novo has a better case with insurers and in pricing talks than the headline suggests.

4. Novo bets on pills and DTC, and defends its patents

On the same On The Pen episode, Knapp walked through three Novo stories:

  • A $300M bet on an untested pill. Novo licensed HRS-1596 from Hengrui, a once-weekly oral drug that hits both GLP-1 and GIP. Novo pays $300M up front, with up to $2.6B in total, for a molecule that hasn't entered Phase 1 trials. Knapp suspects Novo wants the technology for making peptide pills more than this one drug.
  • Why that technology matters. Knapp said the Wegovy pill needs far more drug than the shot:

"The Wegovi pill 25 milligrams has about the same efficacy as the 2.4 milligram shot, except the pill uses 10 times the amount of semaglutide per day."

  • Lilly's pill is easier to make. Foundayo (orforglipron) is a small-molecule drug, which means it is cheaper and simpler to scale up. In Lilly's ACHIEVE-3 trial, Foundayo 17.2mg produced 9.2% weight loss vs. 5.3% for oral semaglutide 14mg, and blood sugar (A1c) fell 2.2 points vs. 1.4. Against the newer 25mg oral semaglutide, an indirect comparison put Foundayo 1.5 to 2.4 points ahead on weight.
  • The patent fight. Viatris, through Mylan, is challenging US patent 12,551,536. That patent was issued in February 2026, covers semaglutide for weight management and runs to October 2038. Knapp said the case is less about cheap generics arriving soon and more about whether competition starts in the 2030s or much later.

Separately, Constantino reported on Squawk on the Street that Novo shared real-world data from Ro's telehealth platform. Patients who switched from injections to the Wegovy pill kept losing weight over three months.

On STAT's The Readout Loud (Ep. 415, Oct 1), reporter Elaine described a big change in how Novo sells its drugs:

"Novo explicitly calls its GLP-1 drugs weight loss drugs in its ads. It's running campaigns with the slogans like Live Lighter, Summer Glow Up."

"Because insurance coverage has stalled, they've increasingly turned to the direct-to-consumer channel where they're selling their drugs directly to patients."

Her warning: framing the drugs as lifestyle products weakens the medical argument insurers rely on when deciding to cover them. "It ultimately seems like these drugs are headed towards the over-the-counter direction."

5. The next wave: fewer shots, and "quality" of weight loss

  • Amgen's MariTide. On Back on Track (MariTide: Could the Next Generation of Weight Loss Medications Be Once a Month?, Sept 28), physician Dr. Alicia Shelley reviewed the Phase 2 data (592 adults):
    • 12–16% weight loss at 52 weeks in people without diabetes, vs. about 2.5% on placebo
    • 8–12% in people with type 2 diabetes
    • patients were still losing weight when the trial ended
    • doses given every 4 to 8 weeks, about 12 or 6 shots a year instead of 52
    • the Phase 3 program, MARITIME, includes heart disease, heart failure, sleep apnea and switching patients over from weekly drugs
  • Boehringer Ingelheim's survodutide. On Citeline Podcasts (Strategic Intent: Boehringer Ingelheim's Brian Hilberdink on Launching Into the GLP-1 Era, Sept 28), Brian Hilberdink, President of US Human Pharma at BI, said the company won't compete on raw pounds. It will focus on liver fat, belly fat and keeping muscle, rather than "the race to drop the greatest number of pounds." His sharpest line was about how patients get these drugs:

"Healthcare professionals, you know, who I think in some regards have kind of lost the obesity patient because we know a lot of obesity patients are getting their products through online pharmacies."

Mandrola's This Week in Cardiology gave the efficacy check: survodutide's 750-patient SYNCHRONIZE-2 trial showed 8–9% weight loss vs. 4% on placebo. In his words, "this wasn't as impressive."

  • Muscle drugs are struggling. On Biotech Hangout, the hosts said Regeneron's trevogrumab kept muscle on MRI scans when combined with semaglutide, but nobody knows what result the FDA would accept for approval. Roche has dropped its own muscle-preserving candidate.

The debate

The bull case (pundit and clinician voices):

  • Lilly keeps lengthening its lead. It now has a triple-acting shot at 28%, an amylin combo at 23%, and a small-molecule pill that is easier to manufacture. On Stock Club (Could Eli Lilly Become the First $10 Trillion Stock?, Oct 1), hosts Emmett Savage and Mike Mahoney cited Q2 2026 revenue of $23B (up 48%), with Mounjaro and Zepbound contributing nearly $15B, and full-year guidance of $85–87B. They note a 10x gain over 20 years would take about 12.2% a year.
  • Use is spreading well beyond obesity. On WellBuilt (Investing in the Future of Wellness, Sept 29), Rachel Hirsch of Wellness Growth Ventures raised her forecast:

"I think probably like a year ago I said 30% of Americans will be on GLP-1s by 2030. I think that was like a really low estimate. I think we'll see 40% by then at the latest."

The bear case (operators and pundits):

  • Employers are feeling the cost. On This Time Is Different (Will Healthcare Costs Take More Jobs Than AI?, Sept 29), the hosts cited:
    • Bank of America CEO Brian Moynihan saying the bank spends $250M a year on GLP-1s, more than 10% of its healthcare budget
    • a National Bureau of Economic Research study: about $60,000 over five years for someone who stays on the drug, $23,000 on average because many people quit, and 22 cents of extra non-GLP-1 medical spending for every GLP-1 dollar over five years
    • Cigna and PepsiCo, which the hosts said have scaled back or dropped GLP-1 coverage
  • Hospital systems see it too. On 13th & Park (Can a Safety Net Hospital Be the Model for American Healthcare?, Oct 2), health-system CEO Craig Wagoner said that in his diabetes program:

"Pharmacy costs did go up... However, this went up more than we thought because of the GLP-1s."

  • Safety and positioning. Mandrola's heart-rate concern and the Readout Loud worry about "lifestyle" marketing both point the same way. The more these drugs look like consumer products, the harder it gets to win insurance coverage at today's prices.

Read-throughs

Packaged food and snacks (HSY, PEP, GIS, MDLZ)

"The category has been very resilient with GLP-1 users. They're not wanting to compromise the things that they love... Now, they'll enjoy less of them."

  • More than 30% of Hershey's portfolio is already in portion-control packs.
  • Premium chocolate is "growing three times faster than the category."
  • On salty snacks: "we're building a business of permissible snacking," meaning brands like SkinnyPop and LesserEvil.
  • The data view. On The CPG Guys (Commerce Riff with Sri & PVSB, Sept 30), the hosts revisited a Cornell/Numerator study:
    • households with a GLP-1 user cut grocery spending about 6% within six months, and close to 9% in higher-income homes
    • savory snacks fell 11%; chips, baked goods and cookies fell between 6.7% and 11.1%
    • about 15 million US adults are now on these drugs
    • Conagra now labels Healthy Choice meals "GLP-1 friendly," and Nestle has launched products aimed at GLP-1 users
  • The investor view. On WellBuilt, Hirsch said General Mills "has not valued this properly."

Aesthetics and oral care

  • Hirsch said a Beverly Hills plastic surgeon she spoke to is doing ten times as many facelifts. More than 90% of his patients are on GLP-1s, up from under 10% two years ago.
  • Because the drugs reduce saliva, she sees oral care (enamel, mouthwash, breath mints) as a spillover market she is investing in.

Telehealth and behavior apps

  • On Behavioral Grooves (The Psychology of Habits | Charles Duhigg, Oct 5), author Charles Duhigg said he has used a GLP-1 for about two years and partnered with Noom, which now prescribes the drugs. He said the drugs quiet "food noise" and open a "habit window" for new routines.
  • Taken together with BI's point that doctors have "lost the obesity patient" to online pharmacies, the clear trend is more prescriptions flowing through telehealth and app platforms.

Sleep apnea (INSP, RMD)

  • Mandrola noted that retatrutide "markedly" improved sleep apnea in TRIUMPH, and MariTide's Phase 3 includes a sleep apnea study. Every new drug with sleep apnea data adds pressure on the CPAP and implant story.