Davin8r
#302
Is there reason to believe that there would be negative effects from going straight from one to the other rather than doing the phase-in?
All these type of drugs have a 1 month acclimation period. They also have different dosing regimens, based on their formulation. Semaglutide is different from tirzepatide, which is different again from retatrutide.
Just because they all have as their base a GLP1-R component doesn’t mean they are the same as noted by Dr Fraser.
I had the ability to do that, so I did. I knew the RT was more effective at weight loss and had the added GCGR aspect. The dosing between the 2 is slightly different so I want to err on the side of caution. It was a smooth an uneventful transition. I would probably have been just as smooth without my cautionary approach.
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Beth
#304
@Steve_Combi @DrFraser
Something I’ve been wondering….
I understand they these compounds are all a little different, but in which ways are they different that might prove to be beneficial, if weight loss is not part of the equation?
My goal would be to minimize weight loss, but to have a slight glucose benefit (I say slight because my blood work is fine, but I have a lot of spikes) and to have the health benefits that are independent of weight loss, such as neurodegenerative disease prevention (runs strong in my family, so this is of great interest to me).
Is what make tirzepatide and retatrutide potentially better just their enhanced weight loss capabilities, or is there something else? I am assuming there is something else in one of these other compounds, in addition to just glp-1?
And if so, would a micro dose (micro to minimize weight loss) of that compound have more of a positive health effect than a larger dose of one that is less potent for weight loss, like semaglutide?
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Davin8r
#305
Each drug is just a single active molecule, but each one (at least in the case of tirzepatide and retatrutide) can hit multiple targets in addition to GLP-1 (GIP in the case of tirzepatide and GIP+glucagon receptors in the case of retatrutide).
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I know this article has been put up here before - but will do it again Brain Uptake of GLP/GIP agents
For individuals who have symptomatic PD or AD, I might slightly favor going with Trulicity (dulaglutide) as it looks solid on brain uptake and better than exenatide, which has been the most investigated for PD.
I’m not at all convinced that these weaker GLPs are going to be superior to stronger ones (like semaglutide) or GLP/GIP agents which get no brain levels but have marked impacts on brain function, presumably through signaling from the vagus nerve.
There is an economic issue with the GLPs that cross the BBB - and this is the relative cost of these due to lack of compounding - but you can get Trulicity from Canada reasonably priced.
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adssx
#307
Brain uptake pharmacokinetics of albiglutide, dulaglutide, tirzepatide, and DA5-CH in the search for new treatments of Alzheimer’s and Parkinson’s diseases 2023
We investigated the BBB transport rate of IRAs within 1 h (Ki), total accumulation of brain uptake over 1 h (AUC), and the ability of longer-lasting IRAs to enter the brain over a 6 h period. The rate of transport specifies how quickly the IRA enters the brain, while %Inj/g levels specify the amount of IRA reaching the brain with the AUC specifying the %Inj/g integrated over time.
There was more than a 15-fold difference in brain entry rates (Ki) among the 13 IRAs studied, which shows the great variability in BBB transport rates of these drugs. The rank order of IRAs with significant BBB transport within 1 h of iv injections was: DA5-CH, Model 2 >> albiglutide > dulaglutide >> DA4-JC > exenatide > DA3-CH (Peptide 18) > Peptide 17 > lixisenatide > DA5-CH, Model 1 ≫ DA2 (Peptide 21). Our protocol did not detect brain influx within 1 h of iv injections of radiolabeled DA1-JC, liraglutide, semaglutide, or tirzepatide, which indicates that these IRAs do not cross the BBB within this time frame.
Our results and the LC-MS/MS study just described are nevertheless consistent with the view that IRAs like liraglutide, semaglutide, and tirzepatide can slowly enter the brain by the extracellular pathways traversing cranial tissues where the BBB is weak or absent (e.g., circumventricular organs, nasal epithelium, and large subarachnoid blood vessels). Such extracellular pathways are used by intravenously administered antibodies, erythropoietin, and soluble receptors entering the brain in amounts able to exert biological effects.
These results suggest that longer-lasting IRAs such as semaglutide and tirzepatide can enter the brain slowly and in relatively small amounts through the extracellular pathways, while liraglutide appears to remain adhered to or sequestered by the brain endothelial cells comprising the BBB.
Due to the ability to cross the BBB, albiglutide, dulaglutide, exenatide, DA4-JC and possibly DA5-CH are higher priority IRAs for testing as AD and PD therapeutics.
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Beth
#308
Do you feel semaglutide is equal to tirzepatide for the potential protection against neurodegenerative diseases? Meaning, is there something about GIP that would make me want to consider that one over just glp-1, or is that just for enhanced weight loss? (or glucagons of retatrutide… i haven’t heard of this one before today!)
Ty!
I don’t know for sure if any of them protect the brain - but it looks likely from what data we have. There is evidence GIP activity is beneficial to the brain also - but Tirzepatide and Semaglutide don’t get into the brain - but on functional brain MRI’s it looks like these agents have potent effects on the brain.
I guess if I were highly worried, I might go for the Trulicity option - but at a bit of a cost … and if there is weight to lose, mix in a little semaglutide or Tirzepatide.
My suspicion is that we’ll find the newer agents through signalling achieve the same or better outcomes as they are more potent - but I could be completely wrong.
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Beth
#310
Thanks for that. Because I don’t have it and may never get so unlucky, I don’t want to spend that much extra for something only potentially preventive.
You have shared you feel it may eventually be discovered that semaglutide and tirzepatide might turn out to be helpful, and @adssx also shared that they probably get into the brain slowly, so I guess where I’m going with my question is:
And I realize it’s all a guess right now, but…
Do you feel for that particular goal (and not weight loss), is there an advantage of glp-1 with the addition of GIP (tirzepatide) vs just glp-1 (semaglutide)
I guess I’m not sure what role GIP plays and if it might be additionally protective, or maybe it just makes weight loss greater
Did that make sense?
Nicholls needed to lose weight, so he began taking tirzepatide (the active ingredient in the medications Mounjaro and Zepbound), one of the newer injectable drugs that suppress appetite by stimulating hormones that control blood sugar levels.
https://www.sciencedirect.com/science/article/pii/S1568163723001381
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Davin8r
#312
Will be interesting to see if retatrutide crosses the BBB directly or indirectly (if BBB penetration matters).
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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.
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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.
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AnUser
#315
I stole the picture of a monkey drinking a coke.
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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?
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Ironic, given the much higher need for these drugs in the US vs. other countries of the world:
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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.
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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…
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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?
