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

#210

No. PushHealth is via text only. I recommend getting oral Semaglutide from India. Just as effective if you take in a completely empty stomach with very litttle water for 30 minutes

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#211

Thanks for the suggestions. Is there are particular pharmacy in India you recommend?

#212

I am not taking it currently. And, when I was it was only once a month (ish) in very low dose. I did check my insulin during that time and it didn’t increase.

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#213

I just ordered some Rybelsus (oral semaglutide 7mg and 14mg tablets), which hopefully should be here in a few weeks. Will be interesting to see if it cuts my appetite and has any effect on body fat loss given the lower potency vs injectable semaglutide. I’ll post my results here.

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#214

Definitely seeing an appetite suppressing effect from 7mg daily. I take it when I get up to go to the bathroom in middle of the night so that my stomach is completely empty and I won’t have to worry about waiting to eat or take other meds/supplements. Zero side effects so far.

#215

I’m considering taking semaglutide in addition to dapagliflozin 10 mg to decrease further my HOMA-IR (from 1.4 to below 1).

Does this make sense?

I saw that others considered or tried GLP1RA + SGLT2 (poke @shc & @AlexKChen ):

A paper published 2 days ago found that “GLT2is + GLP-1RAs combinations were associated with significantly lower all-cause mortality when compared with individual therapies (odds ratio [95% confidence interval [CI] 0.49 [0.41, 0.60]; p < 0.00001).” (Effectiveness and safety of the combination of sodium–glucose transport protein 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of observational studies 2024)

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If true, that’s massive. But it’s based on retrospective studies and not RCTs.

Novo Nordisk ran a phase 1 trial of a fixed-dose combination tablet (oral semaglutide + dapagliflozin): A Research Study Investigating How Semaglutide and Dapagliflozin Act in Your Body When Dosed in One Tablet

The trial ended last year. The results haven’t been published. But Novo Nordisk’s Annual Report 2023 says: “Phase 1 trial investigating the effects of the combination of semaglutide and SGLT2i inhibitor dapagliflozin in people with T2D was completed. The project was terminated.” :thinking:

Phase 1 is normally for safety and pharmacokinetics. I think that companies are required to report serious and unexpected adverse reactions to the regulatory authorities immediately. So I assume that the project was not terminated due to safety reasons but for commercial reasons? Dapagliflozin was developed by Bristol-Myers Squibb in partnership with AstraZeneca. So maybe Novo Nordisk didn’t want to work with its competitors? :man_shrugging:

On the other hand, Novo Nordisk’s FLOW trial of semaglutide in people with T2D and CKD ended early due to efficacy in October 2023, and they’ve just reported “a statistically significant and superior reduction in kidney disease progression as well as cardiovascular and kidney death of 24% for people treated with semaglutide 1.0 mg compared to placebo”. Given that many people with T2D and CKD are already on SGLT2i (and they were not excluded from the trial), I assume that many in this trial were on semaglutide + SGLT2i. Unfortunately, “The detailed results from FLOW will be presented at a scientific conference in 2024.” :roll_eyes: As noted by a practician here: “Clinically I cannot wait to see what combination therapy with SGLT2 inhibitors and/or Kerendia will demonstrate.”

There’s also this observational study in a very specific population: GLP-1 receptor agonists-SGLT-2 inhibitors combination therapy and cardiovascular events after acute myocardial infarction: an observational study in patients with type 2 diabetes 2024

The combination of SGLT-2i and GLP-1RA is associated with a reduced incidence of cardiovascular events in patients with T2D and AMI compared with either drug used alone, with a significant effect also on peri-infarcted myocardial rescue in patients without a second event.

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The only potential issue (already discussed with @Neo here: New Paper: Summary of the top FDA-approved Drugs that can be Repurposed as Gerotherapeutics / Geroprotectors - #27 by adssx ) is that GLP1-RAs increase insulin secretion, which isn’t great. But do they still increase it significantly in non-diabetics?

(Regarding the cancer risk, this India paper concluded: “Semaglutide use in RCTs and real-world studies was not associated with an increased risk of any types of cancer, and this conclusion is supported by a high grade of evidence.”, Semaglutide and cancer: A systematic review and meta-analysis 2023)

Alternatives don’t seem great:

Are there any other options?

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#216

Did you experience muscle loss yourself or did you make your decision based on research such as that summarized in Attia’s Lean mass loss on GLP-1 receptor agonists: a downside of the “miracle drugs”.

#217

What is impressive is that even non-overweight people lose significant weight, even on 0.5 mg:

“Clinically relevant weight-loss differences were observed across all BMI subgroups, with a trend towards higher absolute weight loss with higher baseline BMI. […] Significantly greater proportions of subjects achieved weight loss ≥5% and ≥10% with both semaglutide doses versus comparators across all BMI subgroups (P < .05; Figure S1, Supporting Information). This effect was more marked with semaglutide 1.0 mg than with 0.5 mg.” (Semaglutide induces weight loss in subjects with type 2 diabetes regardless of baseline BMI or gastrointestinal adverse events in the SUSTAIN 1 to 5 trials 2018)

Is lean mass loss on GLP-1 RAs really a problem, though? I found the following papers:

Also, as noted by people on Twitter, most of the weight loss is fat loss: https://twitter.com/fipco/status/1627339223459045378

Is Attia wrong? (to be fair, he published his article in February 2023, while most of the above articles were published later in the same year)

Novo Nordisk is conducting trials on semaglutide for nonalcoholic fatty liver disease (NAFLD) in non-obese and non-diabetic people so we’ll soon know how good semaglutide is in this context.

#218

Thanks for sharing this!

I think that semaglutide + SGLT2 together can be very powerful, wrt health benefits

However, I currently use semaglutide but very intermittently (one 7mg tablet every three weeks). This is for multiple reasons:

  1. I still observe subtle noticeable effects .
  2. I did not want to develop tolerance by taking the high recommended dose
  3. I feel fatigue and loss of motivation if I am on a higher or a more continuous dose — even here I try to make sure that I don’t take it immediately before a deadline for example.

With respect to SGLT2 + Semaglutide:

  1. Combining them increased my fatigue / led to slight hypoglyceamic feeling, which is not only not fun, but also makes me want to go eat a bunch to feel better.

  2. I now look to use SGLT2 during the trough of semaglutide, and trough of rapamycin (especially if I’m taking a larger 25mg dose of empagliflozin), and when I am having carby and sugary meals (happens mostly while traveling, where I lean into being a ‘foodie’)

I feel like I’m in a good zone with this protocol.
Another reason for my intermittent dosing is because I’m conserving my current stack lol.
I have acarbose every day before starchy meals.
And metformin occasionally with rapamycin.

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#219

Thanks for sharing your experience!

Have you tried the lowest dose instead (oral semaglutide 3 mg)? And why don’t you abandon acarbose and metformin for just daily SGLT2i + semaglutide 3 mg?

Also: which SGLT2i are you using? Which dose?

#220

Ah yeah I used to use 3mg. I might have continued but I don’t have access to it now.

I don’t see a reason to abandon acarbose.

Maybe low dose daily SGLT2i once I have access to enough. But I hesitate during peak semaglutide because of what I mentioned, and also around peak rapa, because I do want to minimize any potential UTI.

I’ve mostly used 25mg empagliflozin, which I’ve occassionally halved (e.g. if I’ve taken 25 consecutive days in a row). I’ve tried cana before, but mostly empa.

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#221

Nice chart on the synergies: Combining glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM) 2023

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#222

From your reading, do you know if it’s only reabsorption of glucose that is inhibited by SGLT2is or are there other compounds too? Albuminuria is suggested in the diagram, I see. I wish somebody also measured the amount of plastics and PFAS that are eliminated due to SGLT2is (if any).

I do wonder if their oppositive effects on insulin are synergestic or cancel out some effects (for e.g. on appetite supression).

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#223

I don’t think anyone really knows how they work. Here are a few other good charts and papers: Acarbose - Details On Another Top Anti-Aging Drug - #448 by adssx

I don’t know, but you might like this: SGLT2 inhibition ameliorates nano plastics-induced premature endothelial senescence and dysfunction 2023

From what I read, effects are additive for weight loss, synergistic for blood pressure lowering, and complementary but non additive for Hb A1C reduction:

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#224

Thanks! This is useful.

It’s interesting that they’re additive for several health benefits, but not for diabetes (based on HbA1C), given that they’re both originally diabetes medications!

#225

Some experts have said that we may also look back on GLP-1 drugs as one of the greatest modern advancements in the treatment of chronic conditions. They’ve already shown promise for cardiovascular, liver and kidney disease, and some are now being tested on Alzheimer’s, sleep apnea, PCOS—even addictive behaviours, like gambling. That is a huge scope.

Are these drugs going to help all of these different conditions in a meaningful way? That’s unlikely. We don’t yet have enough data to say we should put this stuff in the drinking water, but there are encouraging signs of their benefits. Right now, we have excellent data for Type 2 diabetes, heart disease and obesity. We’re gonna get some excellent data for kidney disease in the next few months, then heart failure in the summer. We’ll have to wait a year or two for Parkinson’s and Alzheimer’s.

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#226

Phase 3 trial of exenatide (the first approved GLP1RA) for Parkinson’s ended last month. So we’ll get data way sooner for PD.

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#227

I lost 65 lbs of scale weight and gained 1kg of lean mass while on tirzepatide (Mounjaro). I got DEXA scans. If one gets adequate protein and lifts heavy weights at least 2x a week (I was doing 3-4, progressive overload), one does not have to lose muscle. There are many similar anecdotes online. Judging by the online forum participants, most people on these drugs are obese women who don’t lift weights. Of course they lose muscle. These are the people who are letting the drug do all the work for them (not even tracking calories and macros, etc.)

Btw, tirzepatide is generally regarded by those who have tried both to be vastly superior to semaglutide in terms of effectiveness and the side effect profile. Retatrutide is even better in some respects because one tends to have more energy (less fatigue) on it. Tirz usually begins working within a couple days of the initial injection, but with sema you have to slowly increase the dose because the side effects are otherwise often intolerable. Reta usually takes 2-4 weeks to kick in, but when it does, you simply have zero appetite. I wouldn’t waste time with semaglutide.

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#228

@AgentSmith How did you personally counteract fatigue while on it?

#229

I think the fatigue comes from allowing caloric intake to drop too low. It’s easy to not eat enough and especially not eat enough carbs when you’re trying to prioritize hitting a protein target, because after protein and fat, you might not have a lot of room left in your energy budget for carbs. I suppose the keto people wouldn’t have this issue, but I don’t function well on a keto diet and needed some carbs.

I tracked calories in Cronometer, weighing and measuring everything, and tried to not let my deficit get too low.

The other thing was to exercise daily no matter what (well, sometimes Sunday off). I mostly just alternated cardio with weights, and I didn’t slack off in terms of intensity with either.

Now with retatrutide things are a little different because the glucagon receptor agonist activity seems to provide an energy boost (a common anecdote and my experience). Retatrutide feels better than tirzepatide, I think, partially because of this. You can eat more on reta but the pounds just fall off as if they’re getting torched in a metabolic furnace.

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