#184

Yes, long term studies and observations would be helpful.

In my own experience, mental fatigue was the major issue when I was on regular semaglutide. I wonder if my body was beginning to develop tolerance to it because I needed to up the dose to keep the same benefits.

After a couple month break from semaglutide however, I have found that just one 7mg Rybelsus dose every three weeks keeps my overeating impulses at bay, with minimal fatigue and that’s the regimen that I currently am on.

The point about influencers bringing up aspects like muscle loss without getting to the underlying mechanisms however seems like fearmongering to me to preserve their relevance. I highly doubt that there would be any significant muscle loss compared to any other weight loss program, if one kept exercise levels and protein consumption fixed.

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#185

Weight loss drug Wegovy improves function in people with common type of heart failure.

The results, published Friday in the New England Journal of Medicine, found that among people with obesity and heart failure with preserved ejection fraction, or HFpEF, those taking Wegovy experienced greater improvements in symptoms and physical function compared with those on placebo. The improvements were greater than what’s been seen in trials of some other HFpEF treatments.

Paper:

http://www.nejm.org/doi/full/10.1056/NEJMoa2306963

1 Like
#186

For me key questions re longevity value (in non-obese individuals) are as follows - what are peoples’ thoughts?

Potential pro longevity

  • helps people achieve Calorie Restriction (and perhaps also more/longer fasts and shorter feeding windows in intermittent fasting)

  • helps lower blood glucose

Potential ANTI-longevity

  • a big part of the mechanism seems to be to INCREASE insulin secretion, while most longevity literature seems to suggest we want insulin down (as long as glucose is not high)

  • risk of cancer? (Thyroid, pancreatic, other?)

—-

www.nature.com/articles/s41598-023-27509-3

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#187
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#188

Besides Alzheimer’s, GLP1 agonists are also promising as potential disease-modifying treatments for Parkinson’s disease: Preliminary phase 2 trial results of lixisenatide presented (August 2023):

  • “A one-year, phase 2 clinical trial of Type 2 diabetes drug lixisenatide has reported positive early results, which indicate that the treatment may slow the progression of motor (or movement) symptoms.”
  • “These preliminary results are important because they represent the second clinical trial of GLP-1R agonists in people with Parkinson’s to have demonstrated a positive result. The results of a previous small clinical ‘pilot’ trial of another GLP-1R agonist called exenatide suggested that those people with moderate Parkinson’s treated with exenatide for 12 months showed improvement in their motor symptoms. The recent LixiPark study was much larger than the exenatide pilot study and involved 21 research centres across France; the LixiPark study results replicate the earlier exenatide results. There is now a large, multicentre phase 3 clinical trial of exenatide for Parkinson’s being run across the UK, and the top-line results are due to be reported in the second half of 2024.”

Of note: not all GLP-1R agonists cross the blood-brain barrier.

Exenatide, the first GLP1 agonist on the market, is available in twice-daily (potentially better for non-motor symptoms) or once-weekly (potentially better for motor symptoms) versions, see: Exenatide — the latest trial results explained | by Claire Bale | Parkinson’s UK | Medium

Even though it was FDA-approved in 2005, there’s still no generic exenatide in the US (Generic Byetta Availability - Drugs.com). It’s only available as an injection: it may be impractical for an ITP protocol on mice. It would be super interesting, though. I wouldn’t be surprised if it performed even better than acarbose given its weight-loss and neuroprotective properties (in addition to glucose management).

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#189

Semaglutide ameliorates cognition and glucose metabolism dysfunction in the 3xTg mouse model of Alzheimer’s disease

Disorders of brain glucose metabolism is known to affect brain activity in neurodegenerative diseases including Alzheimer’s disease (AD). Furthermore, recent evidence has shown an association between AD and type 2 diabetes. Numerous reports have found that glucagon-like peptide-1 (GLP-1) receptor agonists improve the cognitive behavior and pathological features in AD patients and animals, which may be related to the improvement of glucose metabolism in the brain. However, the mechanism by which GLP-1 agonists improve the brain glucose metabolism in AD patients remains unclear. In this study, we found that SIRT1 is closely related to expression of GLP-1R in hippocampusof 3xTg mice. Therefore, we used semaglutide, a novel GLP-1R agonist currently undergoing two phase 3 clinical trials in AD patients, to observe the effect of SIRT1 after semaglutide treatment in 3XTg mice and HT22 cells, and to explore the mechanism of SIRT1 in the glucose metabolism disorders of AD.

https://www.sciencedirect.com/science/article/abs/pii/S0028390823003064?via%3Dihub

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#190

Sounds like a lot more research to do with the glp drugs. I would like to think we’ve found something great here but I’m not convinced.
If a 300 lb person loses 50 lbs but their ideal body weight is 150. That’s great but not a fix.
Science and education have a lot more work to do to solve the obesity problem.

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#191

It’s interesting that you feel effects for so long from the oral dose.

#192

They do have a half-life of almost a week. I am trying to ensure that I stay sensitive to it, and don’t develop tolerance.

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#193

Tolerance develops toward GLP-1 receptor agonists’ glucose-lowering effect in mice

Tolerance develops toward GLP-1 receptor agonists' glucose-lowering effect in mice - PubMed(GLP,effects%2C%20e.g.%2C%20gastric%20motility.

#194

Tolerance make sense, as folks have to ramp up their dose generally.

Do you take the pill on an empty stomach and wait a while before eating?

#195
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#196
SELECT Trial (Semaglutide)

exciting news!

~17,000 obese. Half of them on 2.4 mg Semaglutide weekly. Not diabetic. 40 months follow-up.

The primary outcome:

Composite of CV death, nonfatal MI, and nonfatal stroke, for semaglutide vs. placebo, was: 6.5% vs. 8.0% (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.72-0.90, p < 0.001).

Secondary outcomes for semaglutide vs. placebo:

  • CV death: 2.5% vs. 3.0% (HR 0.85, 95% CI 0.71-1.01, p = 0.07)

  • CV death or HF hospitalization: 3.4% vs. 4.1% (HR 0.82, 95% CI 0.71-0.96)

  • All-cause death: 4.3% vs. 5.2% (HR 0.81, 95% CI 0.71-0.93)

  • Nonfatal MI: 2.7% vs. 3.7% (HR 0.72, 95% CI 0.61-0.85)

Additional outcomes for semaglutide vs. placebo:

  • HbA1c ≥6.5%: 3.5% vs. 12.0% (HR 0.27, 95% CI 0.24-0.31)

  • Change in systolic blood pressure: –3.8 vs. –0.5 mm Hg

  • Mean change in body weight at 104 weeks: –9.4% vs. –0.9%

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#197

The case for semaglutide for those who need to lose weight keeps getting stronger and I bet the critics are becoming quieter. I wonder if Peter will still go on MSM to talk about how his anecdotes.

Even a statististically significant decrease in all cause mortality.
And it worked for those with BMI less than 30:

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#198

Just say your BMI and health is at it should be.

Just to clarify in this case does that mean a BMI of >30 ?

#199

Yes. I think CanShipMeds has stopped selling it due to demand problems. I have stopped taking it because of the muscle loss it causes.

If I were going to start again, I’d order Rybelus pills from a good Indian supplier. 30 minutes of no food or drink each morning is a small inconvenience, but much easier than hunting down the injectable.

1 Like
#200

Let’s keep in mind that it’s possible to have two things going on at the same time:

  1. fat loss and all its positive health consequences
  2. muscle loss and its negative long-term consequences (frailty, risk of falls, etc)

I’m eager to see a study where subjects have supervised resistance training and protein supplementation along with a GLP1a.

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#201

Definitely, we’ve heard the reports of muscle loss along with fat loss using these drugs, but of course most people do zero exercise, so muscle loss along with fat loss in a calorie deficit is not surprising. But still, nobody has confirmed that there isn’t something extra special catabolic about glp1 inhibitors. Hopefully not, but would be nice to confirm.

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#202

There are studies that have looked at liraglutide and muscle loss, and found that there’s no statistically significant muscle loss when under liraglutide compared to controls

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#203

To put my past posts in context (more in other threads): I finally found the injectable, did 15% of 5mg, and had heavy appetite suppressant effects for a week, and smaller ones the next one. Will continue.
The oral just didn’t work. Maybe I should have taken it longer to prevent some of my excess calorie consumption parts of this year, but it doesn’t matter that much anymore.

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