The mean follow-up time was 3.9 years (standard deviation 3.5 years) in the GLP1 receptor agonist group and 5.4 years (standard deviation 3.5 years) in the DPP4 inhibitor group. 76 of 145 410 patients (incidence rate 1.33 events per 10 000 person years) treated with GLP1 receptor agonists and 184 of 291 667 patients (incidence rate 1.46 events per 10 000 person years) treated with DPP4 inhibitors developed thyroid cancer. GLP1 receptor agonist use was not associated with increased risk of thyroid cancer (hazard ratio 0.93, 95% confidence interval 0.66 to 1.31; rate difference ā0.13, 95% confidence interval ā0.61 to 0.36 events per 10 000 person years). The hazard ratio for medullary thyroid cancer was 1.19 (0.37 to 3.86). In the additional analysis comparing the GLP1 receptor agonist group with the SGLT2 inhibitor group, the hazard ratio for thyroid cancer was 1.16 (0.65 to 2.05).
Also, I was told that although semaglutide doesnāt cross the BBB at all (contrary to exenatide and lixisenatide, which cross it very well), itās still transmitted to the hypothalamus. Also, as the BBB in PD and AD is more porous, semaglutide might cross it in these populations. (poke @DrFraser)
@adssx
Iām not sure if this article has been viewed. Brain activation by area - Semaglutide (and others)
For an agent that doesnāt cross the blood brain barrier it certainly has some effects.
What do others make of this? The oral levels are clearly not getting anywhere near as high as the subcutaneous ones - but I appreciate the ease of giving patients something orally as in the Phase 2 study above.
Iām in a tight spot with patients financially, as we can easily and cheaply get semaglutide and tirzepatide - both of which likely have these impacts seen in this article. However, no significant brain level. Is it the brain level or is it the effect on the brain activation.
Itās a big deal to go from essentially $100/month for those agents vs. $1000/month for things like Trulicity - not even to mention the availability issues with the Rx GLP-1ās. Surprisingly with even the ones that donāt cause major weight-loss being in short supply many places.
Edit: Just found that Empower Pharmacy, the group I use for Semaglutide and Tirzepatide also compound Liraglutide. Itās about $260 per month at maximum dose. Certainly getting a little more affordable, at least for some people who have early PD and trying to stop progression. Sadly still not getting same brain levels as Trulicity.
Iāve stopped Rybelsus aka oral semaglutide. I lost 10 pounds, but the side effects of elevated HR, sharply decreased HRV, constipation and fatigue just werenāt worth it. After the fatigue finally got a bit better after about 4 weeks on the 7mg dose, the appetite suppression also seemed to go away. No WAY was I going to through another month of this (or worse) by starting the 14mg tablets.
After washout, Iām considering trying the 7mg dose for short periods of time during a 5-day Prolon fast in the hope of getting all the benefits of the fast while taking the edge off the hunger. I only hope that the mild insulin-raising effect isnāt enough to blunt the increase in autophagy which is one of the main reasons for doing the FMD in the first place (!)
Do they have exenatide (Byetta, Bydureon)? Itās THE best for brain levels.
Interesting fact: in the lixisenatide trial people with Parkinsonās did NOT lose weight. Similarly, the weight loss effect of GLP-1RAs is way lower on non obese people with T2D vs obese people. Did you notice significant weight loss in your non obese PD patients @DrFraser?
In regard to the compounders - I was shocked to find the Liraglutide as the focus with them isnāt to replace meds for people who have T2DM, as they are usually eligible for insurance coverage. It is for meds that people wouldnāt have access to via a regular Rx, and for meds that are expensive and would be cash pay. The classic example is Ozempic/Mounjaro. Given that someone wouldnāt usually be taking Exenatide off label - as it isnāt much good for weight loss comparatively; there just isnāt demand for it.
Certainly with meds like Semaglutide (Ozempic/Wegovy) and Tirzepatide (Mounjaro, Zepbound) it really doesnāt make a big difference if you are ideal body weight and not diabetic - most people will have very substantial weight loss, which is dose dependent. It can certainly be a real limiting factor for prescribing these for neurocognitive decline, as sarcopenia is an independent risk of poor outcome, especially in PD, but I also believe in AD.
Fortunately, living in America ā¦ only a small % of patients have no weight that would be beneficial to lose, so it is only occasionally a limiting factor.
The data however needs to come through on the more potent GLP-1 agonists that donāt necessarily get brain levels but have powerful effects on the brain. By choosing something like exenatide or dulaglutide which get good brain levels, but are less potent GLP-1ās than our newer agents - if the effect is a brain level - then these older drugs end up being the winner - however if GLP-1 activity ends up being the active ingredient, then we end up giving a weaker agent by chasing a brain level when this may not even be the reason for the benefit.
This article above somewhat goes through some of that discussion. Given the powerful behavioral changes which seem to correlate best with more powerful GLP-1/GIP agonists ā¦ I suspect the potency of the drug will end up being the active ingredient. Just canāt prove it today.
I have patients pursuing GLP-1ās with brain levels and others who are pursuing potency. My personal choice right now is for potency, but for neurocognitive decline/PD it seems like not putting all of oneās eggs in one basket is smart - so Rapa+SGLT2+PDE5+GLP/GIP/Telmisartan is probably a reasonable starting point (plus optimize other things like lipids/BP/Weight/Glucose/Sarcopenia). If one or more of these end up not panning out - the others will still be there.
Thatās my current approach - and it will certainly evolve as more data comes in.
As usual - no medical advice meant here to anyone - just putting forward my present thoughts.
Collectively, the HbA1c and weight-lowering potential of oral semaglutide (7ā14 mg) appear to be nearly similar to injectable semaglutide (0.5ā1.0 mg) and larger than other GLP-1RAs, currently approved in people with T2D. [ā¦] Notwithstanding, unlike injectable semaglutide which has shown a significant reduction in MACE (SUSTAIN 6) and has an additional label for cardiovascular (CV) risk reduction, oral semaglutide is yet to show CV superiority over placebo (PIONEER 6). Since PIONEER 6 was not powered to assess the CV superiority of oral semaglutide over placebo, the SOUL (Semaglutide cardiOvascular oUtcomes triaL, NCT03914326) has been specifically designed for this purpose and is estimated to be complete by July 2024.
