I figured molecular weight would be key to BBB … but not here …
Dulaglutide passes BBB well 59,669 Daltons
Tirzepatide doesn’t and it is 4813.53 Daltons
Retatrutide probably doesn’t - but hard to find data, as is 4845 Daltons
Semaglutide doesn’s and is 4113 daltons
Exenatide does and is 4186 daltons …
I suspect the nature of the chemical and being transported into the brain or failing to will be a structural, not a size issue as all are actually big molecules - but Dulaglutide (Trulicity) is huge … and gets among the best brain levels.
4 Likes
Davin8r
#314
Here’s a quote from the article posted by @adssx : (note IRA stands for incretin receptor agonists and Ki is the rate of transport across the BBB)
"Upon correlating the Ki values with physical properties of the IRAs (lipid solubility, molecular weight, and charge), we identified that absolute charge is the best predictor of Ki. The greater the charge of the IRA, the faster the rate of transport.
The correlation with absolute net charge is suggestive of adsorptive transcytosis as the mechanism of BBB transfer."
I wasn’t even familiar with adsorptive trancytosis, and I still don’t know how/why having a high charge would make it happen for one molecule vs another.
3 Likes
AnUser
#315
I stole the picture of a monkey drinking a coke.
2 Likes
AnUser
#316
A tidbit from the article:
Some of those explanations will be evolutionary. GLP-1 is a master signal for the starving vs. well-fed state. Lots of bodily processes change based on whether you’re starving vs. well-fed. Naively you’d expect that there would be as many side effects as positive effects (wouldn’t some conditions be better in the starving state?), but maybe that’s not true. In particular, maybe the inflammatory nature of the starving state really hurts a lot of systems. Maybe we’ll manage to trace everything back to various food-related pathways, until all of GLP-1’s effects feel natural and satisfying.
So Rapamycin emulate a part of the starving state. GLP-1 the well-fed state.
What happens when you combine both?
3 Likes
Ironic, given the much higher need for these drugs in the US vs. other countries of the world:
4 Likes
adssx
#318
Regarding dulaglutide, this recent paper makes a very bold claim: All GLP-1 Agonists Should, Theoretically, Cure Alzheimer’s Dementia but Dulaglutide Might Be More Effective Than the Others 2024
There is only one study of dulaglutide and cognition in humans, but it was a very large study and produced convincing results. Those results are possibly due to dulaglutide’s excellent uptake in brain, which was 61.8%, compared with which the brain uptake was only 28% for exenatide, 14% for lixisinatide, and virtually zero for liraglutide, semaglutide, and tirzepatide. That very large study of dulaglutide was a randomized, double-blind placebo-controlled trial of subjects aged ≥50 years, with either established or newly diagnosed type 2 diabetes and additional cardiovascular risk factors; cognitive function was assessed at baseline and during follow-up using the Montreal Cognitive Assessment (MoCA) and Digit Symbol Substitution Test (DSST). During a median follow-up of 5.4 years, 8828 participants provided a baseline and one or more follow-up MoCA or DSST scores, of whom 4456 had been assigned dulaglutide and 4372 assigned placebo. The cognitive outcome was the first occurrence of a follow-up score in the MoCA or DSST that was ≥1.5 standard deviations below the baseline mean score in the participants’ country; that occurred in 4.05/100 patient-years in those assigned dulaglutide and in 4.35/100 patient years in those assigned placebo. After adjustment for individual, standardized baseline scores, the hazard of substantive cognitive impairment was reduced by 14% in those assigned dulaglutide (HR 0.86, p = 0.0018). The mechanism for this benefit may be because dulaglutide reduced the disadvantageous, hyperphosphorylation of tau and neurofibrillary tangles, via improving the PI3K/AKT/GSK3β signaling pathway.
It seems that exenatide (Byetta, Bydureon) is being withdrawn from the market all around the world. So dulaglutide might be an alternative. What’s more, dulaglutide seems safer than exenatide: “When dulaglutide’s initiation in patients was compared to exenatide once weekly and liraglutide, dulaglutide had a higher adherence rate and lower discontinuation rates within 6 months.” (Compare and Contrast the Glucagon-Like Peptide-1 Receptor Agonists (GLP1RAs) 2024)
These certainly continue to look like great drugs for longevity and for staying neurocognitively intact. The lack of a cost effective option for dulaglutide remains a problem for my patients who take this off label.
2 Likes
adssx
#320
It costs less than 90 USD for 1 month supply in the EU so if they travel to Europe they could buy about one year supply for the price of 1 month. Still expensive but already better…
2 Likes
From Canada it is a bit cheaper than U.S., but not anywhere near this. Are there Pharmacies in Europe willing to send to the U.S. with a U.S. Physician’s Rx?
Davin8r
#322
I read this paper a while back and it’s intriguing, but whoever wrote it apparently doesn’t understand the difference between “cure” and “treat” a disease. Or more likely, he’s being deliberately misleading in order to grab attention. His repeated use of the term “cure” throughout the paper comes across as extremely disingenuous.
2 Likes
AnUser
#323
Well it’s MDPI, it never disappoints.
2 Likes
adssx
#324
I’m afraid most EU pharmacies are either not allowed or not willing to send to the US. What about buying from Mexico or other LatAm countries?
Regarding the above paper: yes I should have added that it’s a single author paper in an okay-ish journal published by MDPI. So not high-quality (Although the evidence cited is often of high quality.)
Also worth noting that the exenatide trial in mild cognitive impairment failed: Long-acting exenatide does not prevent cognitive decline in mild cognitive impairment: a proof-of-concept clinical trial | Journal of Endocrinological Investigation
It was a tiny trial though, over less than 1y. Could dulaglutide do better? 
1 Like
Pat25
#325
This to me seems to be one of the most important questions asked in the entire thread, but it seems so scarcely discussed. How do we know if using GLP-1 inhibitors may not counteract one or more pathways of Rapa?
Admittedly I’m not at all up to date on the latest research in this area, but to just list a minor example, I remember reading multiple studies years ago about the importance and effects of an increase in grehlin in caloric restriction.
You know your drug is selling well when its significantly boosting the GDP growth of the country…
4 Likes
adssx
#327
Very interesting comment here: Comments - The Compounding Loophole - by Scott Alexander
- 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.
- 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 
Did I make a mistake in my reasoning? Do you need to do something special to use the pills sublingually?
4 Likes
Davin8r
#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
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
Davin8r
#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?
adssx
#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. 
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…
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
adssx
#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
