A preprint out of China, so take it with a grain of salt. Also - given most of the people taking GLP agonist drugs are overweight, how much of the benefit is simply them getting more healthy (slowing the accelerated aging of obesity) vs. actual age mitigation.
Functional & multi-omic aging rejuvenation with GLP-1R agonism: GLP-1R agonists not only help manage diabetes but also show promise in rejuvenating aging processes at cellular and molecular levels. They target key pathways to enhance longevity and…”
Related:
Aging Mice Treated With A GLP-1 Agonist That Is Commonly Used In Weight Loss Drugs Start Exhibiting “Age-Counteracting Effects”
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adssx
#287
Glucagon-like peptide-1 receptor agonist semaglutide reduces atrial fibrillation incidence: A systematic review and meta-analysis 2024
Semaglutide reduces the risk of AF by 42% (RR .58, 95% CI .40-.85), with low heterogeneity across the studies (I2 0%). At subgroup analysis, no differences emerged between oral and subcutaneous administration (oral: RR .53, 95% CI .23-1.24, I2 0%; subcutaneous: RR .59, 95% CI .39-.91, I2 0%; p-value .83). In addition, meta-regression analyses did not show any potential influence of baseline study covariates, in particular the proportion of diabetic patients (p-value .14) and body mass index (BMI) (p-value .60).
Semaglutide significantly reduces the occurrence of incident AF by 42% as compared to placebo in individuals at high CV risk, mainly affected by type 2 diabetes mellitus. This effect appears to be consistent independently of the route of administration of the drug (oral or subcutaneous), the presence of underlying diabetes and BMI.
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This is great to see reduced afib risk with semaglutide! Just started tirzepatide 3 days ago (compounded injectible from Olympia Pharmaceuticals in Orlando, FL) and the very next day started getting strong appetite suppression at just the 2.5 mg dose with essentially no side effects (a far, far cry from the oral semaglutide (Rybelsus) tablets I tried last year, which caused appetite suppression but intolerable side effects, mainly increased heart rate, decreased heart rate variability and significant daytime fatigue). Tirzepatide appears to be not only more effective, but just a better drug in every conceivable way.
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adssx
#289
Less great: Prescribing semaglutide for weight loss in non-diabetic, obese patients is associated with an increased risk of erectile dysfunction: a TriNetX database study 2024
Non-diabetic men prescribed semaglutide were significantly more likely to develop erectile dysfunction and/or were prescribed phosphodiesterase type 5 inhibitors (1.47% vs 0.32%; RR: 4.5; 95% CI [2.3, 9.0]) and testosterone deficiency (1.53% vs 0.80%; RR: 1.9; 95% CI [1.2, 3.1]) when compared to the control cohort of non-diabetic men who never received a semaglutide prescription.
It’s a longitudinal study. So the link might not be causal. For instance, men on semaglutide might lose weight and gain self-confidence, and have more sexual intercourses, and then they might need PDE5i more. @DrFraser do you have any experience of ED post GLP-1 treatment?
On the other hand, this industry-funded RCT for another GLP-1RA found a slight protective effect on ED: Erectile function in men with type 2 diabetes treated with dulaglutide: an exploratory analysis of the REWIND placebo-controlled randomised trial 2021
The incidence of erectile dysfunction following randomisation was 21·3 per 100 person-years in the dulaglutide group and 22·0 per 100 person-years in the placebo group (HR 0·92, 95% CI 0·85–0·99, p=0·021).
Long-term use of dulaglutide might reduce the incidence of moderate or severe erectile dysfunction in men with type 2 diabetes.
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The devil is in the details. If one loses muscle mass as part of their journey as a % of body composition, then I expect some untoward issues to come up. The critical issue is no more than 1 lb wt loss per week initially, and after a few months, try to slow to 0.5-0.75 lb/week loss. If you lose too fast, and aren’t doing some weights and solid aerobic activity, you’ll preferentially lose muscle and I’d expect testosterone to drop.
They need to add a DEXA and see what happened to body composition - and I’d propose that everything will be explained by worsening body composition with use of these drugs in a way that worsens this.
The absolute numbers are really small however … so I’m just not that excited by this.
No I’ve not seen issues with this, but I also try to make sure my patients are carefully advised on not losing too fast.
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AnUser
#291
The study, of 204 people with Alzheimer’s disease in the United Kingdom, found that those taking the diabetes drug liraglutide – an earlier medication in Ozempic’s class, which are known as GLP-1 receptor agonists – had 18% slower cognitive decline over the course of a year compared with those taking a placebo.
The trial’s main goal, though – changing the rate at which the brain metabolizes glucose – was not met, which researchers suggested could have been a result of its small size. The findings were shared Tuesday at the Alzheimer’s Association International Conference in Philadelphia and haven’t yet been published in a peer-reviewed journal.
Bagsværd, Denmark, 16 December 2020 – Novo Nordisk today announced the decision to enter phase 3 development in Alzheimer’s disease with 14 mg oral semaglutide, a once-daily oral formulation of the long-acting GLP-1 analogue semaglutide. The decision follows evaluation of GLP-1 data from preclinical models, real-world evidence studies, post-hoc analysis of data from large cardiovascular outcomes trials, as well as discussions with regulatory authorities.
They’re testing oral semaglutide rather than injectable for Alzheimer’s?
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adssx
#292
They’re also running a small study with injectable semaglutide: ClinicalTrials.gov
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The big question is whether the GLPs that don’t cross the BBB, but have very powerful effects on the brain end up decreasing neurocognitive decline? This also furthermore brings in the much less potent GLP-1 agonist tirzepatide which is much more powerful on weight loss, but due to GIP activity. Then enter Retatrutide with triple agonism. It seems like the more potent the weight loss effect - which is driven substantially by effects on the brain - possibly correlates well with the degree of of neurocognitive protection and improvement in brain insulin resistance? Then along with this - the favorable research on PD is focused on agents that cross the BBB … which none of these do.
It’ll be interesting to see how this all pans out, as I’d like to see the injectable be the standard for investigation right now to make sure we have a good consistent level and sort out, is the indirect signally with the vagus nerve the active ingredient, or is a brain level actually needed.
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adssx
#294
Indeed, liraglutide (tried in the paper posted by @AnUser) barely crosses the BBB. Semaglutide suffers from the same problem. Exenatide and lixisenatide cross the BBB well (and both got good results in phase 2 trials for PD, phase 3 results expected in the next 12 months for exenatide…): x.com
Time will tell if BBB crossing is what matters. Unfortunately, no one is testing exenatide or lixisenatide for AD now.
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Maybe the internasal route is the solution to work around the BBB situation
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I wonder if rectal administration of the compounded tablet form of tirzepatide would be absorbed? I thought about trying it since I have months of tablets left over (combined from me and my wife) that are otherwise worthless because they caused zero effect, which I equate to zero sublingual absorption. I decided it’s not worth the uncertainty of the pharmacokinetics nor the unpleasantness of the route of administration.
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Davin8r
#298
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Started our Tirzepatide journey Aug 2023 at a weight of 190lb. Not diabetic but “borderline” for 3 years.
I had plateaued at a satisfactory weight of 155 after losing 35lb in 7 months with a 3.0mg dose of TZ. Stayed around that for 3 months with a slow loss over those 3 months of another 3 lb.
We switched from TZ to Retatrutide about 3 months ago. Did a phase in initially with 50/50 TZ/RT mix for 4 weeks prior to the complete switch over. Lost a couple more lb during that process
RT is amazing for weight loss, at the 3.0 dose I lost another 6lb in 8 weeks. Will probably drop the dose to 2.5mg and see if that will be our maintenance dose. I have not been this weight (143) since high school 
a life changing process.
I’ve not had any issues with respect to ED keeping my wife alive it my top priority
Have not noticed muscle mass loss but got motivated to start resistance and cardio training 3 weeks ago after 10 years of moderate activity.
With all the additional benefits being studied with GLP1-r+GIP+GCGR, I feel that these drugs are going to be in my life for the duration.
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This class of drugs appear to improve health in multiple domains, used long term - with some items probably being independent to some degree from the weight loss. Retatrutide is certainly more potent mg for mg with Tirzepatide.
The main issue is slow weight loss and some weight training and cardio … it sounds like you are approaching it sensibly, and will, on average gain years of healthspan from this!
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Davin8r
#302
Is there reason to believe that there would be negative effects from going straight from one to the other rather than doing the phase-in?
All these type of drugs have a 1 month acclimation period. They also have different dosing regimens, based on their formulation. Semaglutide is different from tirzepatide, which is different again from retatrutide.
Just because they all have as their base a GLP1-R component doesn’t mean they are the same as noted by Dr Fraser.
I had the ability to do that, so I did. I knew the RT was more effective at weight loss and had the added GCGR aspect. The dosing between the 2 is slightly different so I want to err on the side of caution. It was a smooth an uneventful transition. I would probably have been just as smooth without my cautionary approach.
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Beth
#304
@Steve_Combi @DrFraser
Something I’ve been wondering….
I understand they these compounds are all a little different, but in which ways are they different that might prove to be beneficial, if weight loss is not part of the equation?
My goal would be to minimize weight loss, but to have a slight glucose benefit (I say slight because my blood work is fine, but I have a lot of spikes) and to have the health benefits that are independent of weight loss, such as neurodegenerative disease prevention (runs strong in my family, so this is of great interest to me).
Is what make tirzepatide and retatrutide potentially better just their enhanced weight loss capabilities, or is there something else? I am assuming there is something else in one of these other compounds, in addition to just glp-1?
And if so, would a micro dose (micro to minimize weight loss) of that compound have more of a positive health effect than a larger dose of one that is less potent for weight loss, like semaglutide?
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Davin8r
#305
Each drug is just a single active molecule, but each one (at least in the case of tirzepatide and retatrutide) can hit multiple targets in addition to GLP-1 (GIP in the case of tirzepatide and GIP+glucagon receptors in the case of retatrutide).
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I know this article has been put up here before - but will do it again Brain Uptake of GLP/GIP agents
For individuals who have symptomatic PD or AD, I might slightly favor going with Trulicity (dulaglutide) as it looks solid on brain uptake and better than exenatide, which has been the most investigated for PD.
I’m not at all convinced that these weaker GLPs are going to be superior to stronger ones (like semaglutide) or GLP/GIP agents which get no brain levels but have marked impacts on brain function, presumably through signaling from the vagus nerve.
There is an economic issue with the GLPs that cross the BBB - and this is the relative cost of these due to lack of compounding - but you can get Trulicity from Canada reasonably priced.
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