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.
Itās definitely different. Initially, I actually became slightly more hungry but also energetic, both of which are not unusual reports. After the 2nd or third dose I sometimes had to remind myself to eat because I had no appetite whatsoever. Thatās also pretty common especially as it builds up in the system. It seems to take up to a month to be felt for a lot of folks, though my wife got appetite suppression on 1mg immediately.
Unlike tirzepatide, which caused me a feeling of almost-nausea (very faint, hard to describe), reta felt great. If I wanted to eat, I could eat, but I didnāt need to eat and Iād feel full quickly. It didnāt cause side effects except for an elevated heart rate for the first couple weeks (also common). The reason I went on it was that I had stalled on tirzepatide.
I went back to tirz for maintenance because I have a large stockpile, and I want to reserve the reta for future cuts since itās so powerful.
A 2mg dose goes a very long way, so itās actually quite inexpensive if sourced from overseas.
Hi @AgentSmith - do you have any sense of what happens with insulin levels in healthy individuals when on these different GLP/GIP drugs?
From a longevity perspective that is one of my main questionmarks - are they (a) raising fasting insulin levels and (b) making insulin levels constantly revved up and not cyclically up around and then decreases, down after meals/when sleeping.
Insulin up is of course one way to lower blood glucose, but insulin up also has negative longevity effects. So in someone with good glucose control may not be net good to increase insulin.
Do you have any data from your N=1 experiments and/or see what people on your other forums and groups have experienced?
Itās true that I have done some experimentation, but I actually started tirzepatide under the supervision of a doctor, and did the semaglutide also under her supervision. When I began this process I was obese and was unable to lose more than 12 lb, even with rather significant caloric reduction and exercise. My metabolism was in bad shape because of massive weight gain after a hospitalization that significantly reduced my muscle mass and destroyed my gut microbiome. I was not yet diabetic, but the trend was troubling.
After a 20% weight loss from the peak, my HbA1c was 4.9 when on about 10mg/wk of tirzepatide. 3 months later, it was 5.3, still on about the same dose. The difference may have been my Acarbose use, but thatās the one medication that I donāt log for some reason and my memory of that is poor.
At the time of the 5.3 reading, my insulin was 4.7 for a HOMA-IR of 0.9 based on fasting glucose, or 1.2 based on an estimate of average glucose from the HbA1c. Not horrible . However, at the same time I got a LabCorp NMR Lipoprofile that put my insulin resistance score (LP-IR) so low that they couldnāt measure it (<25). Truly excellent.
Not long after those tests I began lowering my tirzepatide dose and increasing calories dramatically. Iām now eating about 50% more an an attempt to gain weight back (muscle).
Iāll get fasting glucose, insulin, and HbA1c this coming Friday. It will be interesting to see where much higher carb intake, yet more muscle and much less tirzepatide will land me. I was using Acarbose for 2 of the 3 months that this latest HbA1c will cover, but abandoned it because the sides are horrible for me. I can report back when I get the results.
Regardless of all this, I could not lose weight before the meds, and a year later I think Iām healthier than Iāve been since my mid 20s. I get really ticked off at all the pundits and influencers who just tell obese people to eat less and move more as if many of them havenāt been trying that for years without success. Without this medication, Iām hungry all the time no matter what kind of diet Iām on or how much I eat. People who donāt have that problem cannot comprehend it but should be humble enough to consider that the phenomenon is real.