#327

Very interesting comment here: Comments - The Compounding Loophole - by Scott Alexander

  1. Oral semaglutide is an available Novo Nordisk product called Rybelsus, indicated for diabetes. It costs ~ the same for 30 tablets as for a month’s worth of Ozempic. It contains a fun “absorption enhancer” called SNAC. That basically means it punches little tiny holes in your stomach lining to let the semaglutide get across the stomach lining into your blood. Even with the SNAC, only about 1% of the semaglutide that you swallow gets into your blood. (source, see the PI for it here: https://www.novo-pi.com/rybelsus.pdf ). This is because semaglutide is a peptide - i.e. basically meat so far as your digestion is concerned - your gut is great at cutting up peptides into constituent amino acids. As a result, the dose of oral semaglutide is dramatically larger than the dose when it’s injected - for diabetes it tops out at 14 mg/day or 98 mg/week, vs. injected for diabetes it tops out at 2 mg/week.
  2. As it turns out, probably the cheapest source of semaglutide available on a per mg is… rybelsus tablets, but you can’t put that into an injectable product. We generally prepare it into a sublingual formulation, but figuring out the appropriate dose is tricky. It absorbs really well across the blood vessels under the tongue, but I’m not sure what % of a given dose does get across there, but my current guess is that ~8-14% of a dose gets across the sublingual mucosa if its held there long enough (2-5 minutes). That’s really hard to get people to actually do though. But this method feels extremely useful to me for a number of reasons: a) it is NOT “essentially a copy” of any currently existing formulation from Novo, so the “shortage loophole” is not an issue - this type of compounding is still very doable legally even if there’s no shortage. b) Novo gets a cut of the price because I’m literally using their tablets. c) it’s super cheap comparatively - we can get 14 mg of semaglutide from a single tablet - the cost is ~$43/tablet if you use the $1300/month divide by 30. Even if the absorption is only 8%, then you can still get basically a week’s worth of semaglutide out of a $43 tablet.

So if you buy one month of Rybelsus 14 mg in Europe or India for ~$100 and if the sublingual absorption is 10x greater than the normal oral absorption, does it mean you can crush the pills and use them sublingually and save 10x on semaglutide? Actually, if what you want is the equivalent of the lowest semaglutide dose (3 mg oral), with this strategy you can divide costs by 50 and get the equivalent of Ozempic for $2 per month :smiley: Did I make a mistake in my reasoning? Do you need to do something special to use the pills sublingually?

4 Likes
#328

My wife and I tried the HenryMeds version of sublingual tirzepatide and got absolutely no effect from it. They probably are not using any kind of special delivery system (liposomes, etc).

1 Like
#329

I have been taking 3 mg Rybelsus for a couple of weeks. It is the most strongly bitter obnoxious medication – you have to really concentrate hard to get it swallowed fast to minimize the obnoxious taste. I cannot imagine holding any of this under your tongue. What am I missing?

3 Likes
#330

You make a really good point, @Deborah_Hall . I remember that nasty taste when I was on Rybelsus. Maybe some strong counter-flavor added to the sublingual pill could help?

#331

Confirmation by this pharmacist that my reasoning is correct: Comments - The Compounding Loophole - by Scott Alexander

So anyone buying Rybelsus 14 mg for ~$100 from Europe, India or Latin America could theoretically get the equivalent of the lowest Ozempic dose for $2/month. :warning: I don’t think anyone should do this, but it just shows how insane the pharma margins are before generic entry and how cheap generic Ozempic will be in 2031… :warning:

Regarding the taste: I tried Rybelsus twice and didn’t notice anything particular. If the taste is terrible you could block your nose? Or add some food for taste?

By the way in the US there’s now generic liraglutide as an alternative: Victoza: Generic Ozempic-Like GLP-1 Drug Now Available in U.S.

4 Likes
#332

SGLT2i seem to be as good (if not better?) as dulaglutide in this emulated trial: Sodium–Glucose Cotransporter-2 Inhibitors, Dulaglutide, and Risk for Dementia: A Population-Based Cohort Study 2024

Results: Overall, 12 489 patients initiating SGLT2 inhibitor treatment (51.9% dapagliflozin and 48.1% empagliflozin) and 1075 patients initiating dulaglutide treatment were included. In the matched cohort, over a median follow-up of 4.4 years, the primary outcome event occurred in 69 participants in the SGLT2 inhibitor group and 43 in the dulaglutide group. The estimated risk difference was −0.91 percentage point (95% CI, −2.45 to 0.63 percentage point), and the estimated risk ratio was 0.81 (CI, 0.56 to 1.16).
Limitation: Residual confounding is possible; there was no adjustment for hemoglobin A1c levels or duration of diabetes; the study is not representative of newer drugs, including more effective GLP-1 RAs; and the onset of dementia was not measured directly.

3 Likes
#333

I don’t know how you knew about the generic liraglutide before I did!

So with a GoodRx coupon, 3 pens 18 mg/3mL at Walgreens is $334.29. So at full dose of 1.8 mg per day, that would be a 30 day supply.

Not cheap, but is much better than the usual $1000 monthly.

4 Likes
#334

In addition to the awful taste, there are the gastro effects. You are not “supposed” to feel much at this non-therapeutic starter dose but I am here to report that indeed you do. Have been on the starter 3 mg tabs 2+weeks and really feeling it. Have stepped back to every other day – need recovery days and also stretching supply til I can see the endocrinologist. But GLP’s are not approved or covered for Type1 DM so I will most likely continue to buy from India.

But – the price is pretty great. $5 for a 7 mg and $5.50 for a 14 mg. If you stay on the 7 mg which compares to lowest dose of injectable sema, and split the 14 mg pills, – as adssx said --about $2/month. per adssx “I don’t think anyone should do this . . . .” ----why not? what am I missing? I would rather have the injectable but if ordering from India, thinking of transit, refrigeration requirements ?, shortages —

#335

Interesting that you’re using it for T1D. This paper from 2 days ago shows potential: Liraglutide enhances insulin secretion and prolongs the remission period in adults with newly diagnosed type 1 diabetes (the NewLira study): A randomized, double-blind, placebo-controlled trial

I said this because I don’t want to imply that it’s safe. I think no one knows.

#336

I like that paper.

“There is only one study of dulaglutide and cognition in humans, but it was a very large study and produced convincing results.” “That very large study of dulaglutide was a randomized, double-blind placebo-controlled trial of subjects aged ≥50 years”

What do you think?

Questions: If used as a prophylactic, do you have to take dulaglutide forever or is one several-month course adequate?

Trulicity dulaglutide by Eli Lilly is available at a reasonable price from India. Since dulaglutide is a peptide do you think it might not travel well from India?

#337

Thank you @DrFraser . Anyone interested in Monjuaro (or other fixed dose GLP1 pen like semaglutide, etc.) should check this out. Please note the amount drawn up in the syringe was 0.1 mL which is 3 mg when using the 15 mg pen.

2 Likes
#338

Interesting, I wonder if that’s why my estradiol has been coming back high for awhile now. I’ve been using GLP1’s for the last couple years on and off. SHBG slightly high too, but all other markers and hormones look same or improved.

#339

In rodent models of AD so not sure it’s worth much but… The GLP-1 medicines semaglutide and tirzepatide do not alter disease-related pathology, behaviour or cognitive function in 5XFAD and APP/PS1 mice 2024

1 Like
#340

This paper is a few years old, but it makes sense that combining SGLT2i with GLP-1 agonists would be at least additive in their potential weight loss and health benefits:

After starting tirzepatide 2.5 mg weekly in early August, I stopped my empagliflozin since I’d expected the empa to be superfluous, but now I’m going to try “micro dosing” the tirz (1mg weekly) and going back on empagliflozin 25mg daily. This should minimize side effects from the tirzepatide (increased heart rate, lowered HRV, sleep disruption).

I never really lost any weight from empa because my appetite simply increased to compensate for the glucose excretion. The low dose tirzepatide should take care of that.

Benefits of this approach: dramatically decreased cost of GLP agonist therapy due to low doses (while SGLT2i drugs are cheap from India), greatly decreased risk of side effects, additive/synergistic health and weight loss benefits.

3 Likes
#341

The scientists I’ve seen say its still too early to tell this (slowing aging):

4 Likes
#342

Yes I think the SGLT2i + GLP-1RA combo is the way, check the ORs here it’s very impressive: Intermittent (oral) Rybelsus / Semaglutide use in healthy individuals? - #215 by adssx

Unfortunately, Novo Nordisk stopped its single pill dapagliflozin + oral semaglutide…

In terms of effects:

image
image2144×452 91 KB

  • Subadditive for HbA1C
  • Additive for weight loss
  • Synergistic (i.e. supra-additive) for BP

Paper just published suggests additive effects for eGFR: Cardiovascular, Kidney and Safety Outcomes with GLP-1 Receptor Agonists Alone and in Combination with SGLT2 Inhibitors in Type 2 Diabetes: A Systematic Review and Meta-Analysis

Open questions:

  • Lipids
  • Liver
  • Neuroprotection
  • Muscle mass
  • Mood disorders
  • Arrhythmia

And as you said, can you increase the safety with a low-dose combination? :person_shrugging:

3 Likes
#343

On the same topic: Effects of the glucagon-like peptide-1 receptor agonist dulaglutide on sexuality in healthy men: a randomised, double-blind, placebo-controlled crossover study 2024

24 out of 26 randomised participants completed the study (13 participants randomised to dulaglutide first and 13 to placebo first). No change in the MGH-SFQ was observed after four weeks of dulaglutide versus placebo (estimated difference 0.58 [95% CI −0.83 to 2.00], p-value = 0.402). Hormones of the hypothalamic-pituitary-gonadal axis (estimated differences: total testosterone (nmol/l) 0.9 [95% CI −1.5 to 3.3], FSH (IU/l) −0.2 [95% CI −0.3 to 0.0] and LH (IU/l) −0.8 [95% CI −1.5 to 0.0]) as well as sperm parameters all remained in the normal range without significant differences between the treatments. No severe adverse events occurred.
In this study of healthy men, we found no evidence of negative impacts of a four-week treatment with the widely used GLP-1 receptor agonist dulaglutide on sexual desire, hypothalamic-pituitary-gonadal axis hormones or sperm parameters.

1 Like
#344

Thanks for seeing my friend, who successfully used CVS coupon for rapamycin for prices much better than shipped from India!

3 Likes
#345

No problem - it was a pleasure, and thank you for the referral.
It’s usually a nice experience for someone who is used to feeling a little on the fringe to meet with someone who is completely used to all the things they do and can do, and is supportive.
Interestingly, I had someone go to CVS with a GoodRx coupon which I think was going to be about $45 for 30 mg, and they had an “internal” CVS coupon that put it down to $27. This is my first time seeing a U.S. pharmacy sell at <$1/mg.

4 Likes
#346

The GLP-1 medicines semaglutide and tirzepatide do not alter disease-related pathology, behaviour or cognitive function in 5XFAD and APP/PS1 mice 2024

It’s an animal model (actually two) and we know that these models are not great at representing neurodegenerative diseases. Still, despite robust glucose control and weight loss, neither semaglutide nor tirzepatide improved cognition, behavioral testing, plaque burden or neuroinflammation in these mice.

Is BBB crossing needed (e.g. exenatide or dulaglutide)? Are the models bad? :man_shrugging: