Modern longevity is crowded with promises, but the useful conversations stay close to biology. This discussion on GLP-1 drug risks and benefits points to a steadier truth: healthspan is shaped by the signals we repeat, the capacity we preserve, and the recovery (our guide to recovery) we protect.
Full transcript with timestamped links back to the original YouTube conversation.
do you have any concerns with long-term safety or anything other than simply the economics of the glp ones in this current generation again huge huge leap forward between liraglutide and semaglutide yeah and uh I've discussed briefly Elsewhere on the podcast what the road map looks like for how many of these drugs are in the pipeline yeah there seems to be no end in sight and we're going to look back at semaglutide and say God thing was pedestrian that's what's going to happen so what give us the bare case what should we be concerned with what should be at least looking out for yeah I would say overall at the present time uh I would consider these drugs to be quite safe the the major issue is you have to go slow because of the GI toxicity where is the controversy involved and it's something that I'm involved with myself uh when you lose 20 or 30% of your body weight you lose muscle mass okay uh now uh I just gave a talk on this to one of the pharmaceutical companies that are involved in this area I'm not going to name the name of the the pharmaceutical company uh but I started off uh by saying look here is now a study with real data this is a gastric bypass surgery study Ry bypass and the people lost I think it was 33% of their body weight and their lean body mass came down quite significantly one of the problems is people may measure lean body mass and that's not a real measure of muscle mass in fact it's can be a very bad measure you should measure muscle mass but let's assume that the lean body mass largely reflects it's reasonable assumption muscle mass so muscle mass came down okay so why is that so bad but how much did it come down because if your total body mass came down by 33% but 34 of that mass was fat and only
33% but 34 of that mass was fat and only one quarter of that was lean we would consider that acceptable and this is where the controversy is cuz no one has really measured muscle mass that's right we're doing it okay we we will have a definitive answer you're doing that with Mr MRI yeah okay so it's it's gold stand okay but now I said look in this study they they measured absolute strength you can do grip strength or leg strength and absolute strength went down a little bit okay maybe 25% were these patients exercising During the period of the weight loss no okay no no then they said let's Express strength as for weight loss yeah up by 50% per appendicular goes up by 50% and then they said how far can they walk they went from walking 200 yards two miles and then say one of the things is how many times can you get up out of a chair in a certain period perod of time it increased like three or four fold and and they measured your V2 Max how yeah of course which is heavily dependent on weight as well yeah it all got better but in absolute terms did V2 Max get better not necessarily yeah the total V2 not normalized per kilogram no everything got better okay so so I said so why you guys that's counterintuitive by the way normally when you lose weight yeah V2 Max in liters per minute does not improve because you have less metabolic tissue but but uh here for whatever the reasons are maybe all of the fat that's pushing on your lungs so you can't oxygenate the epicardial fat uh that not allowing your heart to contract the fat that's in the heart that's causing myocardial lipotoxicity which I believe is real these things are all changing in a positive way uh so again it's a balance of yeah so uh of course they don't like this because if the people and they had all kinds of psychological questionnaires wait why weren't they
questionnaires wait why weren't they happy with these results well because uh they now the companies are all looking at developing drugs that will preserve the muscle mass or increase the muscle mass but basically what I'm saying is that look there's a huge it's lean body mass but we have to say it's reflecting muscle mass uh everything gets better the patient feels better they can walk better they feel stronger etc etc why are you so worried about muscle mass like I look all these gloomy faces because they're all developing myostatin Inhibitors or event and and so then the next slide comes up and says retort here's a good thing okay so now uh if you uh lose all of this body weight and you improve insulin sensitivity in muscle uh and you improve it in the heart uh and there are cardiovascular benefits and you correct the uh Improvement in all of the cardiovascular risk factors now even though uh you've lost musle Mass if you've improved insulin sensitivity there may be an enormous benefit of seeing the Improvement in the muscle insulin sensitivity even though you've lost muscle mass uh and they do have some concerns about these drugs these myat inhibites that actually may have some negative effects on the heart and my suggestion is actually you may find a big Improvement in myocardial function uh from uh these uh how where are myostatin Inhibitors in their development right now phase two yeah yeah and um of course I think we've talked about myostatin before on the podcast when you inhibit myostatin you increase the expression of striad muscle yeah of which cardiac is striad through the event in uh 2 a and 2B system uh um do you think that's a more promising pathway than the fallatin pathway where ftin yes I increasing increasing fallatin inhibits myostatin but this is a more direct way to go about it this a
a more direct way to go about it this a more direct way to do it so you can either have their their antibodies uh by guab uh to uh myostatin or you can interfere with the signaling uh receptor itself and we think that this can still be effective in a fully developed and mature adult I mean clearly this would be effective during development and we see that in the animal work is it how effective is it CU a lot of the animal work is sort of a character stuff it's Knockouts right they take mil Staten Knockouts and look like bodybuilders yeah but if you take a mature chicken or a mouse that's 2 years old and you give it a myostatin antibody how robust is the response even more so what about in a human exact we don't know the answer to that so what the phase two studies obviously the toxicity passed in F in Phase One yes yeah I I I'm not concerned there doesn't seem to be any adverse effect of these drugs or they wouldn't got through phase two and they actually some Philly what's the indication the indic sarcopenia I I don't know I'm uh you know the uh uh the FDA if you have a sarcopenic disease there are criteria that the FDA has established if you want to develop a drug that you have to meet certain criteria I'm not an expert in this so I I can't tell you exactly what these criteria are but they are pretty well established okay uh let's say I put you on a glp1 receptor Agonist and you lost 25% of your body weight and I put you on a my Statin inhibitor and that prevented the muscle loss didn't increase it but just prevented it so relatively but that would be ridiculous I mean if you took a 200b individual yeah who's 30% body fat yeah so they're they've they've got 60 lbs of adapost tissue on them y if you took 25% of their body weight off you take them down to 150 lb but you're
take them down to 150 lb but you're telling me potentially we prevent any deterioration of lean mass y that means they're down to 10 lb of fat Mass on 150 lb frame so I'm making an assumption this pretty radic this is remarkable right so let's say that happened okay what would be the fda's criteria I'm going to give you approval for this drug I think the FDA would ask that you've also improved function in some way yes and the function would probably be H have to be determined through absolute strength not relative strength would be my guess so I I don't know the answer to this question CU that's because because the way I think about these drugs is less about that situation uh it's more in the sarcopenic adult this is the lean particularly the older person that's right this the elderly individual who's sarcopenic and who fall risk is enormous yes and their risk of fall and uh morbidity and mortality is very high yeah and in that individual I don't think the FDA will be satisfied with simply an increase in lean body mass unless it is accompanied by strength now I think that some of the tests that are used here are silly I think the six-minute walk test should be folded up discarded put in the waist basket and never discust again it is such a stupid test they do it all the time do just makes me want to scream we need much more rigorous tests than a six-minute walk test we need a test that is actually uh more of a submaximal test so if we're testing cardiorespiratory Fitness or some sort of peak aerobic fitness we have to do more than walking and if we're testing strength I much prefer grip strength leg extension bench press uh yeah again these can be done with machines they can be done very safely but we really need to test strength well see you're raising very
strength well see you're raising very important and critical issues because there are many many companies that are going ahead with these drugs that increased muscle mass but to me okay increasing muscle mass what does that mean there needs to be some functional translation of that and and by the way there could be other functional benefits that exceed strength for example glucose disposal could be a functional sensitivity that's the one I put at the top of the list for get rid of the insulin resistance that the FDA won't give them credit for that I don't think yeah but but I think that again it's harder to tease out because there's more moving pieces and they might argue there are easier ways to increase insulin sensitivity and glucose disposal but you know one way to think about this is to go back to what if you did it the oldfashioned way what if you got in the gym and lifted a bunch of Weights that's been done yeah and it increases insulin sensitivity and functional strength and so the question is can we replicate that pharmacologically uh and that is actually exactly the way I ended my discussion to these people I show them what resistance training did and if you could show what resistance training did uh with your muscle mass uh increase then you'd have something but you need to design the studies appropriately and as I said and as you said I don't know what the criteria are going to be that the FDA uses to judge these things they do have a sarcopenia set of criteria but that's a very different group of people that we're talking about but this comes uh and hits home to one of the things you asked me earlier what about the lean person who's 80 years of age is this the right drug for that person I don't know uh maybe not but now let's say you have a healthy 80y old person and everybody in the family lives to be 105 and they have diabetes Well they're at risk to you know uh the toxic effects of hypoglycemia uh would it be reasonable to treat uh that that person
reasonable to treat uh that that person we know there powerful effects on the beta cell I would say it would be quite reasonable but I think you need to monitor what's happening to their weight and other features
Transcript auto-generated by YouTube. Verbatim — duplicates intentionally preserved.
GLP-1 medicines can improve appetite regulation, weight loss, and markers tied to cardiometabolic risk. For people living with obesity or diabetes, that can be clinically meaningful.
Good medicine starts by acknowledging benefit without turning it into a universal answer.
Nausea, nutrition gaps, lean mass loss, cost, long-term dependence, and individual response all matter. A smaller body is not automatically a healthier body if strength, nourishment, and function decline.
This is why monitoring matters. The protocol has to protect the person, not just move the metric.
Food quality, protein, resistance training, sleep, and daily movement shape the outcome around the medication. They help preserve muscle and improve metabolic flexibility.
Medication may open the door. Daily practice determines what gets built.
The best metabolic strategy protects the body’s capacity while it changes the body’s weight.
Consider GLP-1 medicines through an individualized clinical lens, not as a general wellness trend.
Protect lean mass with resistance training, adequate protein, and regular body-composition monitoring.
Pair appetite changes with better food quality and recovery so metabolic health improves alongside weight.
