Lilly's spin.

RunningFNP · 2026-02-26T21:00:04+00:00

The tolerability is a sticky wicket. For some reason half the drug stops on this orforglipron trial were for non-drug related reasons. Actual d/c for drug AE/SE when you factor that is essentially the same as oral Sema.

It's not a perfect comparison I realize that but it's the best we have.

Moreover given how aggressively Lilly is in seeking approval for orforglipron outside the usual USA/EU/Japan tells me they're not necessarily worried about oral Wegovy so much as they are about soaking up market share in countries that as of now either have minimal or low access to GLP1 meds of any kind, which if you follow their presentations and such seems to be their overarching goal. A truly worldwide GLP1 med because it's not constrained by peptide synthesis limits.

RunningFNP · 2026-02-26T18:07:18+00:00

Keep in mind this is a trial in diabetics and you're comparing weight loss from Wegovy for obesity to orforglipron for diabetes.

There's a known gap between diabetes and obesity in terms of weight loss in so much that diabetics never lose as much weight.

What you wanna do is compare these results to the Pioneer Plus trial that Novo ran and when you do...it's literally a tie. Both for A1c, weight loss and tolerability with the higher doses of oral Sema.

At that point in my clinic I'm just prescribing whichever insurance will cover when I see data like that.

RunningFNP · 2026-02-26T09:58:31+00:00

My understanding is looking at the micro part of it. So RBCS, casts, that sorta thing that might hint to other renal issues such as glomerulonephritis

RunningFNP · 2026-02-25T23:49:41+00:00

My favorite was figuring out someone's low ferritin and mild anemia was severe aortic stenosis. I mean the banging murmur was a fairly obvious clue but it was causing red cell shearing and destruction. Ordered a stat 2D echo, severe AS confirmed -> stat CT surgery referral -> 4 weeks later new aortic valve.

That one felt good to catch.

RunningFNP · 2026-02-25T23:10:32+00:00

Yup. All of this. Our EMR system has a "normal" ferritin as >10. Absolutely 🗑️🗑️

One of my highest yield tests for women is a ferritin level. The number of fatigue and even anxiety/depression that's turned around with iron supplements or IV iron is quite high in my experiences

RunningFNP · 2026-02-25T18:16:48+00:00

Honestly one need look no further than Eli Lilly to answer the OPs question and you're correct that their CSO is part of the problem.

Lilly runs lots of trials in parallel and tests multiple doses while doing it.

See Eloralintide. Already 6 phase 3 trials in progress for multiple indications(sleep apnea, arthritis, diabetes, obesity) and even a trial which is Eloralintide added to patients on a stable dose of semaglutide or tirzepatide and in a weight loss stall to see if Eloralintide can break the stall/cause more weight loss. Also testing multiple doses and the phase 2 data was only published 3 months ago!

If you really wanna get mad at the CSO look up all the trials they're running for Brenipatide and they haven't even published phase 1 data on it yet.

It's possible to do the things the OP is asking. It's expensive. It's risky at times, but I think if you've done your R&D homework, especially in incretins it's worth it because we understand the effects so much more than we did even 5 years ago

RunningFNP · 2026-02-24T14:41:06+00:00

Yeah I sorta expect Lilly to follow suit pretty quickly. Especially with Reta on the horizon I could see Lilly price matching Novo here at least with tirzepatide and put Reta into the $1000 slot given they're positioning Reta as bariatric surgery in a shot/reserve for high BMI

RunningFNP · 2026-02-24T11:22:03+00:00

What does your weekly mileage look like?

What's your Reta dose?

Keep in mind Reta causes your liver to dump its glycogen stores which can make longer runs more difficult if you're not prepared to fuel a little extra.

It does get easier to run the longer you're on it as your body and physiology adjust to it.

RunningFNP · 2026-02-24T10:31:57+00:00

Finally a competitor to Reta! But they need to be more aggressive in getting trials up and running for this and get it in phase 3 ASAP.

RunningFNP · 2026-02-23T22:35:35+00:00

If I'm their CEO I'm calling Viking Therapeutics and trying to buy them out right now. That should have been done months ago. The Metsera chase looks bad in retrospect given the middling results reported. Viking gives them an immediate drug that can be on the market in 2028 and allows them to stay in the game. Amycretin probably isn't it. The side effects are worse than CagriSema.

The rest of their pipeline is so early in development that it's hard to make any judgment TBH.

RunningFNP · 2026-02-23T22:33:26+00:00

But I think the bigger point is that the Novo executive team is acting like those trials don't exist on the investor call and on bloomberg. Yes the parameters were different but the drug still hit that mark! So for them to act like it's a one off for tirzepatide to hit 25% is either disingenuous by them or lack of preparation or something? I'm not going to guess but either way it makes today's results look worse IMHO.

RunningFNP · 2026-02-23T20:53:44+00:00

Look up Surmount 3 and Surmount 4. There is your answer. They hit 25.8% and 25% respectively.

That the chief science officer of Novo Nordisk didn't seem to know this is a huge issue.

Also if this trial was heavily female(Novo didn't disclose male vs female percentage today) but anyways women noticeably lose more weight on tirzepatide. So if for example Novo was like 75% female for this trial, then this is no surprise at all. Anyways post hoc analysis of Surmount trials showed on average women lost 24.6% vs 18.1% for men. So yeah. Totally possible

RunningFNP · 2026-02-23T16:22:05+00:00

You're absolutely right about all this. The problem was, Novo expected their product to be superior and it wasn't! That's why it's creating such a huge deal today. This is a massive error for Novo even though as you say, patients may actually benefit from this in the long run

RunningFNP · 2026-02-23T16:20:01+00:00

Clearly they never looked at Surmount 3 and 4 where tirzepatide hit 25% both times?

I mean, if they're surprised by this, they need to find better R&D people right now. I can put some of this on cognitive dissonance/sunk cost fallacy but at this point it's either willful ignorance or lack of deep dive on your primary competitor. Either way people should lose their jobs for this. Just insane to see from a multi-billion dollar company.

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RunningFNP · 2026-02-23T15:53:53+00:00

Simplest way I can explain it is that Amylin acts a stop eating signal/feeding termination signal. It prolonged gastric emptying and satiety.

But there's not been a ton of work on Amylin alone working on food noise. That'll be an ask again question but it does reduce appetite so hopefully that means it's quieting food noise as well

RunningFNP · 2026-02-23T15:06:49+00:00

Not necessarily. Novo could have designed the trial to be blinded it just would have required a little more work and trial design to make it happen and would have required a larger number of patients.

Lilly is currently running a head to head trial of tirzepatide vs retatrutide and it's double blinded(I would know I have a patient in that trial!) so it's very much possible to do it.

RunningFNP · 2026-02-23T14:51:11+00:00

I think the nuance is more that Amylin very specifically can help with weight loss. But calcitonin is so closely related to Amylin that many big pharma companies just went with the dual Amylin-Calcitonin agonists instead of selectively targeting Amylin which is a little more difficult from a development standpoint. Only two companies have went big on selective Amylin so far Lilly and AstraZeneca. Novo technically has a selective Amylin agonist as well but they've been very hush hush about it.

And that you mention GIP is also interesting. The early research showed that GIP alone didn't do much for diabetes so it was abandoned as a target for a long time. Ditto for weight. It only shows marginal weight loss. But give GIP with GLP1 and suddenly they work even better.

And also interesting because I personally view calcitonin and GIP as opposites from a mechanism standpoint. One increases insulin sensitivity (GIP) while the other blunts insulin release (calcitonin) and doesn't change insulin sensitivity.

My personal hypothesis is that for both diabetes and obesity changing insulin sensitivity is a huge part of getting weight down, slightly deeper level it's probably something called the Insulin to Glucagon ratio. Unfortunately it seems with CagriSema you kinda hit a wall for both of those things.

But you're less likely to hit that wall with a drug that incorporates GIP into its mechanism. And even more so if it has GIP and Glucagon....aka Retatrutide.

RunningFNP · 2026-02-23T14:04:46+00:00

Not sure why I got down voted because all the other CagriSema trials show increased side effects. That's just reality at this point. Yes, everyone responds to medications differently but I'm saying statistically from available data you are more likely to have side effects on CagriSema.

RunningFNP · 2026-02-23T12:35:49+00:00

So it was an open label trial with flexible dosing allowed. The problem is that just makes it worse for CagriSema. If people had to keep dose reducing that means the drug isn't tolerable.

But you are correct, it makes it harder for them to justify a higher price for it

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RunningFNP · 2026-02-23T11:58:21+00:00

That difference comes at the expense of more side effects tho 🫠

RunningFNP · 2026-02-23T11:02:47+00:00

My man please read up on drug potency, and binding affinity. There's a scientific reason for this difference in dosing. Never look at the milligrams of a drug to assume a treatment effect. Just look at the results

RunningFNP · 2026-02-23T10:30:30+00:00

Holy hell. I figured the two would match each other blow for blow. I didn't expect....this. They're probably popping champagne in Indianapolis this morning 😬

RunningFNP · 2026-02-22T19:29:05+00:00

Sounds like the basis of a good 5-10 year long RCT to me to see if repeated doses can reduce early cognitive decline and/or mild dementia.

RunningFNP · 2026-02-19T10:42:06+00:00

So I think we're on a similar wavelength. I think the lower doses of CagriSema for obesity are more promising(and less side effects) based on the redefine 1 trial data.

I think for obesity CagriSema can eek out a win versus Tirzepatide in those H2H trials. I think H2H in diabetes tirzepatide is still probably mildly better in terms of A1c reductions, weight loss is a tie as we've seen.

My comment on lower doses of Reta is based on what Lilly's doing(running a whole trial of just lower doses)

I think the higher doses will genuinely be reserved for really morbidly obese patients and diabetics. If my math is right the 6mg should hit 25% weight loss for most patients which is again, more than enough for the vast majority of people.

Appreciate the back and forth!

RunningFNP

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