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

[Davin8r]

I hope we’ll soon get some data on retatrutide and BBB. I wonder why we haven’t seen anything yet?

[DrFraser]

Interesting - so delivery is simple, you use a device called an atomizer on a syringe. We do this in the ER for intranasal lidocaine, fentanyl or ketamine.

The way this is done - is first blow the nose thoroughly as having a bunch of mucous will impair absorption. Generally, whatever the dose is you want it in a small volume (typically I use a 1 mL syringe). You lose 0.1 mL in the typical atomizer. So if you dilute your dulaglutide dose into 0.5 mL with bacteriostatic water, you’d actually need 0.6 mL of that same concentration to deliver the dose due to this loss.

Last rule is no more than 0.25 mL per dose spray. Probably better to do lower than this - but would be within standard protocol to just do 0.25 mL up the left side, wait for 3-4 minutes and do the other 0.25 mL up the right side.

Have no idea on dosing, but know lots about nasal atomized medications.

BTW interesting study.

Yes, agree the dulaglutide is looking good.

@Steve_Combi do you have a source for compounded dulaglutide? I have patients on this for PD, and have patients on other GLPs/GIPs with goal of both weight optimization, improve metabolic health and diminish dementia/pd risk. It would be nice to have a mixture of tirzepatide or retatrutide with dulaglutide so we don’t put all our eggs in one basket. The indirect signally through the vagus nerve with semaglutide and tirzepatide looks potent - it would be less with dulaglutide as it is less potent. Hitting both pathways would seem a good insurance policy.

[Steve_Combi]

It’s not an approved drug yet. Once it clears FDA for it’s intended use I’d expect to see more studies

[Davin8r]

@Steve_Combi

It’s not an approved drug yet

Right, but neither are DA4-JC or DA5-CH. Since retatrutide is the next big blockbuster GLP expected to come out, I’d think there would be more interest in the research community.

[adssx]

I think the DAx drugs are versions found by researchers specifically for neuroprotection. It seems to be an academic effort, there might be a small biotech behind but that’s it. Retatrutide being a big pharma drug, they carefully filter what they publish or not. And I’m not sure they allow other researchers to use it. There are many articles on semaglutide and tirzepatide so I think as soon as retatrutide is approved these researchers will look at its brain penetrance (let’s hope!).

[Steve_Combi]

As adssx is noting, because of what these DA’s do they may be working towards getting them approved for a different purpose than Reta. AD is a huge market.

Also these results are in mice and as we’ve seen time and again, with respect to AD, is that mice are a very poor substitute for humans for this condition

It’s not cost effective to get a drug approved for multiple targets so they pick one target as the primary to move it forward. Once it is approved for “something” it’s easier to use it off-label and get it into trials for other uses. I don’t know much about these DA’s yet

None of the current GLP1’s were initially approved as weight loss drugs. That came after and now they can be prescribed specifically for weight loss as opposed to T2D. Novo even came up with a new name to be used when Tz is prescribed for weight loss.

Took a quick look at the Vetrans study on mice and while it is intra-nasal, it’s still an injection… not a spray.

And they had the 2 DA compounds custom made, so there amy not be a ready supply of these.

[adssx]

Assessment of Changes in Body Composition After 3 Months of Dulaglutide Treatment 2024

The results showed that body weight (BW), VFA, body fat (BF), lean body mass (LBM), skeletal muscle mass (SMM) and water content were reduced after 3 months dulaglutide intervention. The lean body mass percentage (LBMP) and skeletal muscle mass percentage (SMMP) significantly increased. Moreover, there was no significant difference in bone mineral quality (BMQ) after the intervention.

[Davin8r]

“These results indicate that dulaglutide intervention does not cause muscle and bone mass loss while inducing weight loss”

Not sure why they claim that muscle mass was not decreased while at the same time stating that muscle mass was reduced (?). (I know the % muscle mass increased, but of course that’s because of the weight loss). Still, these subjects weren’t doing resistance training, so it would be really nice to see a GLP study with even just a basic RT protocol because I imagine the results would be truly impressive (significantly more fat loss, no muscle loss). It’s good to see no bone density loss despite the weight loss and no RT, although 3 months may be too short to see changes in BMD(?)

[adssx]

@Davin8r

“These results indicate that dulaglutide intervention does not cause muscle and bone mass loss while inducing weight loss”

Yes they should have added “relative” before “muscle and bone mass loss”. So yes you lose mass but proportionally less than fat so your mass % increases. And that’s all what matters no?

[Davin8r]

Ideally there is no muscle mass loss (since we want to preserve as much as possible as we age).

[AgentSmith]

@adssx

And that’s all what matters no?

I think focusing on body composition is not quite the right way to think about this. Absolute strength is what I want to preserve in old age, because that’s what enables us to engage in activities and remain independent.

[Davin8r]

Functionally speaking, yes strength is most important, but I also like the aesthetic aspect of muscle mass, so I’m going for both.

[AgentSmith]

Same. But ofc more mass is a prerequisite for strength once you get to a certain strength level. So let’s get big and strong.

Size vs. Strength

People also overlook the fact that the frail man is not treated with as much respect as the strong man. This impacts quality of life every day, and I think it may impact treatment by doctors. Being strong matters.

[CronosTempi]

Some people believe that maintaining muscle mass is metabolically useful, muscles can function as glucose disposal reserves etc. Others dispute this importance (Valter Longo). Mostly it seems muscle is important in ADL and preventing falls.

[RapMet]

All good, but you you’ve really made me think since you mentioned that we need solutions for:

1. thymus
2. Elastin

I’m afraid that unless we find a way to tackle those two, we would still be looking at best maybe 110.

[adssx]

GLP-1 Receptor Agonist Treatment Improves Fasting and Postprandial Lipidomic Profiles Independently of Diabetes and Weight Loss 2024

In adults without diabetes but with severe obesity, 3-month treatment with exenatide improved fasting and postprandial lipidomic profiles associated with cardiometabolic risk by decreasing saturated species (triacylglycerols [TAGs], ceramides, lysophosphatidylcholines) while increasing seven unsaturated phospholipid species (phosphatidylcholine, lysophosphatidylcholine) with protective effects on cardiometabolic risk compared with control.
Exenatide blunted the rise in postprandial triglycerides, especially saturated TAGs.
Postprandial triglyceride reduction was associated to decreased postprandial free fatty acid clearance, with lower saturated free fatty acid incorporation into newly synthesized lipids (TAGs and ceramides).

[Steve_Combi]

I thought size mattered?? LoL!

I do agree that strength not mass is the better indicator.

I had posted on this muscle loss thing a while ago.

I lost 50lbs over 14 months. My Withings scale indicated I had 121lb muscle when I weighed 199lbs = 60% muscle. At 140lb it indicates my muscle mass is 109lb now - 78% muscle. So did I actually lose 12lb of muscle? or did the muscle mass/volume decrease as a result of the loss of inter-muscle fat? As indicated my body weight to muscle mass has improved significantly.

Knowing that there is inter-muscle fat (having been a butcher as a kid) my “beef” with this muscle loss distraction is that anyone who loses a significant amount of weight via pretty much any method is going to experience muscle “shrinkage” as the inter-muscle fat decreases. I don’t think enough people understand this aspect of weight loss.

Also I’m quite a bit stronger today than I was 14 months ago and my muscles have gained some “body” over the past 7 weeks of working out. The transformation is pretty cool

[RapMet]

@Steve_Combi

At 140lb it indicates my muscle mass is 109lb now

Something is not jiving here. So, you weigh 140lbs and 109lbs of that is muscle? Well unless your bones are the size of a pencil, your brain the size of a bird brain and your skin and organs that of a cat, I can’t see how all those will only weigh 30lbs together, not even including your fat which it has to be at least 10% or 14 lbs. Long story short most likely you have nowhere near 109lbs of muscle mass if you weigh 140lbs.

I thought size mattered?? LoL! - YES it does matter but NOT if you measure it wrong

You may want to look at this : ≡ 20 Important Organs of the Human Body List + Size & Weight (adducation.info)

for reference and to make it easy an average human has 11lbs of blood, 20lbs of bones, 15lbs of skin, 15-30lbs of fat, and then another 10-15lbs of other organs. Consider yourself lucky if you have 70lbs muscle mass.

[Steve_Combi]

In Europe the Withings Body Cardio scale is an approved medical device that provides accurate data for PWV - Pulse Wave Velocity. This measures arterial elasticity. They achieved their approval through several studies comparing it to PWV devices used in the medical field. They have a newer model called the Body Segment (shows where the fat is) which is more accurate and one with 6 lead ECG. Withings is developing some of the best in class consumer monitoring and measuring devices.

While the absolute numbers are most likely not perfect, the trend is what I usually look at.

Also what is fat? the brain is mostly fat, not all tissues are measured separately with this scale. My brain is “lumped” in the fat catagory

Various organs have a fat content, muscle content and their own tissue signature. Since this model scale doesn’t separate out where the water, fat and muscle reside, there is a good chance these measurements are a composite.

As you can see from these charts, the bone content has not changed over 4 years. Since bone is very localized, that measurement is probably reasonably accurate.

Screen shot with Muscle - Fat - Bone - as a percent

Screen shot with Muscle - Fat - Bone - as a weight

[RapMet]

I hear you, but even if we say ok blood and some fat (not all) are a composite of other organs, only skin and bones are over 30lbs for an average person. I think @Davin8r is right it depends on what method or what device is being used to measure muscle mass. But even without looking at any info on specific weight of different organs, or body parts I know that MOST animal dressing weight is 55%-60% of live weight and that includes even the bones and some marble fat, and I know for sure some animals have bigger muscles than humans. , so no neither you nor I have anywhere near 109lbs of muscle mass (and I do weigh quite a bit more than you do).

However I have to assume that in the measurements above I guess everything is lumped in only two categories muscle and fat. So, in muscle probably they include the bones, heart and other muscle organs. either way it is a bit misleading.