Davin8r
#374
There’s no reason to believe other GLP-1s are more immunogenic at higher dosing frequencies (if anything, the opposite given the study w/exenatide).
The drug companies use once weekly dosing because it is the least frequent regimen that still works and because the less frequent the dose, the better for sales. There’s no incentive for them to test 2x or 3x weekly doses (even if it were to work better and cause less side effects) because it would be a disaster for marketing.
If using a compounded version and self-dosing, lots of people do lower doses multiple times per week and have great results and less rebound hunger or other side effects. Others prefer the convenience of once weekly and tolerate the side effects well enough to do it that way.
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Yikes. This feels like fearmongering, and really hurts his credibility for me.
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KarlT
#376
I don’t think he is in agreement with the majority of physicians who would start GLP1’s with life style changes, rather than waiting 3-6 months.
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In a few years the primary treatment for obesity will become glp1s with the recommendation of eating more protein and fiber instead of telling people for decades to “just move more and eat less bro”.
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Agreed, in the long run, that only works for about 10% of the population.
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I am very intrigued by this new GLP1 agonist on trial, which only requires 1 shot a month.
Months after posting weight loss of 7.5% at 36 days for patients taking MET-097i, Metsera releases mid-stage results of just over 11% average body weight reduction at 12 weeks, with no plateau and a promising safety profile.
Just over three months after it commanded the industry’s attention with impressive Phase I data, Metsera is back with more promising findings for its investigational subcutaneous GLP-1 therapy MET-097i, which in a Phase IIa readout on Tuesday showed strong weight reduction and an encouraging tolerability profile.
After 12 weekly doses, patients on MET-097i lost 11.3% of their body weight on average, as compared with placebo. In the 1.2-mg dose group, individual responses reached as high as 20% in some cases. According to the biotech, all patients treated with MET-097i, regardless of dose, achieved “clinically meaningful and statistically significant weight loss” after 12 weeks.
Notably, Metsera had not yet detected a plateau effect at the time of the readout, indicating that MET-097i could elicit even greater weight-loss with longer dosing, the company said.
More on the trial here https://www.clinicaltrialsarena.com/news/metsera-announces-positive-results-in-newest-phase-iia-glp-1ra/
The randomised, double-blind, placebo-controlled trial enrolled five cohorts of 120 obese patients who are not type 2 diabetic. In all five cohorts, 20 patients received the active drug while four patients were given a placebo. Four of the five cohorts received 0.6mg, 0.8mg, 1.0mg, or 1.2mg, weekly, without titration, for 12 weeks. Patients in the fifth cohort were also given weekly doses but instead received escalated doses of 0.4mg for four weeks, then 0.8mg for a further four weeks, then 1.2mg for another four weeks.
John Buse, director of the University of North Carolina Diabetes Center, said: “Taken together, this data suggests that MET-097i has the potential to be a foundational therapy for people with obesity and overweight, by virtue of its effectiveness, compelling tolerability profile and flexible options for dosing, including titration-free weekly dosing and monthly dosing.”
Looks like weekly dosing to me?
The relevant quote in Metsera Touts ‘Powerful’ Weight Loss Results—Again - BioSpace
Additionally, pharmacological exposure to MET-097i accumulated over the study’s 12-week period, hitting a four-fold increase in concentration in patients who were dosed without titration. According to Metsera, this prolonged exposure to the drug is driven by its 15- to 16-day half-life and ultra-long-acting profile, which in turn could support monthly dosing.
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OK, weght loss in the obese. Fantastic news for the obese. I think? But I’m like the window shopper behind the glass - I see it, but how does this fit me? I am not obese. I do not need to lose weight. Will this drug prolong my life? Will it prolong the life of the obese person - I know they’ll lose weght, but prolonging life needs to be shown. Understandably we cannot know. Same as with rapamycin - we cannot know. Might it improve health in the obese? In the nonobese - will it improve my health?
Has this drug - or drugs in the same class - extended lifespan in mice the way rapamycin has, or canagliflozin (in males)?
If you want to lose weight for whatever reason, tune in. If you are looking for lifespan/healthspan, your heels are getting cool, and will stay cool for a long while yet. YMMV.
Since the trial was done with weekly dosing, they will need to do another trial with monthly dosing to be able to remove the word “could” 
That will be a great advance for weight loss.
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Yes, of course, if you don’t need to lose weight, then this is probably not for you. That’s a given.
I suppose there’s been interest in what BJ does, because historically this site has followed what he’s been up to. So, no question there is historical interest!
But speaking just for myself, after seeing his justifications for taking a drug/supplement or intervention, I’ve lost interest in what it is that he’s doing or not doing. I have no faith in his approach or methodology.
Again, that’s just me, and I’m sure many others have a different view, and without a doubt, he’s a high profile life extension advocate, so what he does resonates with the public.
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adssx
#387
It’s one data point. Like anyone else here. I also stopped Rybelsus last month for similar reasons.
From what I read, he did only 3 weeks? Maybe it would have been more informative if he followed the protocol : 4 weeks at the initial dose, followed by 4 weeks at weight loss dose (whatever that’s defined as) . Elevated heart trate could be transient.
But anyway, not everyone has to be on every drug to extend longevity, and he doesn’t seem to be overweight.
Of course, completely understandable. My unease is from the fact that I don’t know what these small changes in RHR and HRV mean - is this temporary? Apparently BJ didn’t take it for long. I’m thinking about the effect od SGLT2i on egfr kidney. There is the initial dip in the egfr number, but longer term there is a recovery - however, the recovery can take up to a year! And when netted out, SGLT2i generally are beneficial to the kidney (at least if the drug is used before the egfr number gets below 30 or so). What if the Rybelsus agent follows a similar path?
Ultimately of course, the bigger question is how meaningful is the RHR and HRV change if netted out to other benefits. I don’t know. Perhaps, it’s worth the slightly worse numbers in exchange for neurological protection? I don’t know. Longitudinal studies would be nice, but I guess there hasn’t been enough time.
Anyhow, a decision about starting or stopping a drug is individual. I never jumped on this particular class of drugs, because I don’t have enough information about concrete benefits and the reading that I have done (and also the papers cited on this board), have not made a compelling enough case for me. Unlike SGLT2i - I have read up on these and ultimately decided that empagliflozin is worth the gamble. YMMV.
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Another once a month glp agonist in the works https://www.nytimes.com/2024/11/26/health/weight-loss-drug-maritide-amgen.html
The pharmaceutical manufacturer Amgen announced on Tuesday that an experimental obesity drug helped patients lose up to 20 percent of their weight in a year. The drug, MariTide, is given by injection once a month, compared with once a week for other obesity drugs like Wegovy and Zepbound that are already on the market.
Dr. Jay Bradner, the company’s chief scientific officer, noted a surprising effect of the drug: When the trial ended, many participants maintained their weight loss for as long as 150 days. That means that less frequent injections could be possible or even that patients may not need to stay on the drug permanently. The company said it was studying quarterly injections.
And this drug actually inhibits GIP, instead of activating it. Fascinating.
Dr. Bradner said the company decided to block GIP because it had genetic data from Iceland indicating that people who had a variant that stops GIP from working were naturally thinner
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I’ve heard about it a few months ago on meso-Rx:
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I took another look at the article and it’s actually quite interesting. The authors found that, at least in pigs, the autonomic nervous system is not involved at all in the change in heart rate. This is in contrast to mice and rats where the autonomic nervous system IS involved. So it could be a rather benign increase via direct action on GLP-1 receptors on the heart.
