Intermittent (oral) Rybelsus / Semaglutide use in healthy individuals?

I forgot to answer this. As always, thanks a lot for your help!

Good paper published last week: Glucagon-like peptide 1 receptor agonist use and risk of thyroid cancer: Scandinavian cohort study 2024

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 −0.13, 95% confidence interval −0.61 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).

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They didn’t post it on clinicaltrials.gov, so I’ve just discovered it, but a trial of oral semaglutide for PD started a few months ago in Japan: Phase 2 study of oral semaglutide tablet for patients with Parkinson’s disease (funded by the Japan Agency for Medical Research and Development)

Also, I was told that although semaglutide doesn’t cross the BBB at all (contrary to exenatide and lixisenatide, which cross it very well), it’s 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
I’m not sure if this article has been viewed. Brain activation by area - Semaglutide (and others)
For an agent that doesn’t 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.

I’m 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.

It’s 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-1’s. Surprisingly with even the ones that don’t 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. It’s 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.

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I’ve stopped Rybelsus aka oral semaglutide. I lost 10 pounds, but the side effects of elevated HR, sharply decreased HRV, constipation and fatigue just weren’t 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, I’m 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 isn’t enough to blunt the increase in autophagy which is one of the main reasons for doing the FMD in the first place (!)

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Do they have exenatide (Byetta, Bydureon)? It’s THE best for brain levels.

Interesting fact: in the lixisenatide trial people with Parkinson’s 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?

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In regard to the compounders - I was shocked to find the Liraglutide as the focus with them isn’t to replace meds for people who have T2DM, as they are usually eligible for insurance coverage. It is for meds that people wouldn’t 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 wouldn’t usually be taking Exenatide off label - as it isn’t much good for weight loss comparatively; there just isn’t demand for it.

Certainly with meds like Semaglutide (Ozempic/Wegovy) and Tirzepatide (Mounjaro, Zepbound) it really doesn’t 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 … 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 don’t 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-1’s 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.

Discussion of Brain Levels of GLP-1’s and SGLT2-i

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 … I suspect the potency of the drug will end up being the active ingredient. Just can’t prove it today.

I have patients pursuing GLP-1’s 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 one’s 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.

That’s 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.

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On oral vs injectable semaglutide, I’ve just read this: Assessing glycemic and weight-lowering potential of oral semaglutide in type 2 diabetes compared to other GLP-1 receptor agonists in Indian context 2024

Collectively, the HbA1c and weight-lowering potential of oral semaglutide (7–14 mg) appear to be nearly similar to injectable semaglutide (0.5–1.0 mg) and larger than other GLP-1RAs, currently approved in people with T2D. […] 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.

Let’s pray for SOUL :pray: :slight_smile:

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Seems like the first post here may have been prescient. This may get interesting as the research progresses:

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Anyone have experience with Retatrutide?

I’ve experimented with it. My wife is on it now.

How does it compare to the others? Side effects?

It’s 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. That’s 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 didn’t need to eat and I’d feel full quickly. It didn’t 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 it’s so powerful.

A 2mg dose goes a very long way, so it’s actually quite inexpensive if sourced from overseas.

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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?

It’s 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 that’s the one medication that I don’t 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 couldn’t measure it (<25). Truly excellent.

Not long after those tests I began lowering my tirzepatide dose and increasing calories dramatically. I’m now eating about 50% more an an attempt to gain weight back (muscle).

I’ll 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 I’m healthier than I’ve 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 haven’t been trying that for years without success. Without this medication, I’m hungry all the time no matter what kind of diet I’m on or how much I eat. People who don’t have that problem cannot comprehend it but should be humble enough to consider that the phenomenon is real.

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