In this episode of the Ask Me Anything (AMA) podcast, Dr. Nick Stenson and I discuss the relationship between statins and insulin resistance, and the potential geroprotective benefits of SGLT2 inhibitors, metformin glp1 agonists, and other drugs that can improve metabolic health.
00:02:10.400peter welcome to another ama how you doing doing very well how's that toothpick treating you very well
00:02:21.640love me some toothpicks do you ever tell the story about how you ended up with so many i think i have
00:02:27.020shared that story in fact i know i've shared that story because when i meet strangers sometimes they've
00:02:32.840asked me if they can have some of those toothpicks are they still to the state the best toothpicks you've
00:02:38.360ever had no i would actually say my toothpick game has evolved a little bit and i have started to like
00:02:44.500other types of toothpicks those toothpicks are still remarkable but i don't think i could call them the
00:02:49.120single best toothpick in the history of dentition well maybe a future ama if there's enough demand we can
00:02:56.760break out the different types of toothpicks and pros and cons of each but not today so
00:03:02.820today we are going to talk kind of in follow-up for the first part to ama 51 which was on metabolic
00:03:11.300disease and metabolic disease is one of your four horsemen that you talk about in the book and talk
00:03:16.900about on podcasts the other three being cardiovascular disease neurodegenerative disease cancer in that ama
00:03:23.700we talked about how metabolic disease feeds those other types of diseases we went into insane detail and
00:03:30.580how to measure and know where you're at and how your metabolic health is and then we talked about some
00:03:36.100lifestyle factors that you can do to improve your metabolic health the one thing that was missing from
00:03:42.020that ama which we get a lot of questions on is what about the pharmacological options for people to
00:03:49.060improve their metabolic health so the first part of this ama we'll talk about that that will include
00:03:54.340sgl t2 inhibitors metformin glp1 and a few others and on some of those drugs such as sgl t2 inhibitors
00:04:03.380we'll also cover if there's potentially a geroprotective benefit to those because we also see questions from
00:04:09.220people who may be in good metabolic health but based on some study results are curious on that part two
00:04:16.100we're going to cover something we get asked about an insane amount and that is the relationship between
00:04:21.380statins and insulin resistance and we see a lot of questions come through and so we pulled all of
00:04:27.620them for that we'll get to those here all that said before we get started anything you want to add
00:04:33.220no i think that's a great synopsis of our very ambitious goals today we'll see what we can do
00:04:38.980the first one sgl t2 inhibitors this is something that you and rich miller talked about on the podcast
00:04:46.020where rich dove into the itp we're going to have rich miller back on again but we receive a lot of
00:04:51.940questions on sgl t2 inhibitors and it would be helpful i just think to just cover the basics of
00:04:58.180what are they and how are they initially developed i guess we could sort of demystify the acronym a
00:05:02.980little bit so sgl t2 is kind of a crappy way to abbreviate sodium glucose co-transporter protein
00:05:14.820two i know what someone's thinking which is but where's the l and where's the p don't ask that's
00:05:20.500just the way it works in biology we come up with really really bad acronyms sodium glucose co-transporter
00:05:25.540protein two is sgl t2 and honestly this is a great example of where a picture is going to be more
00:05:33.540valuable than just me rambling so for those of you that are just listening to us i'm going to do my best
00:05:39.540to try to explain this but anyone who can watch this on video be it on youtube or on our channel please
00:05:44.820do that okay so nick please pull up said figure of a nephron got it okay so the nephron is the
00:05:53.380functional cellular unit of the kidney and in the proximal tubule so i don't want to overwhelm us with
00:06:01.860renal physiology here but the kidney is kind of a unique organ in that it's really a tiny organ but it
00:06:07.940is overrun with blood so there's lots of plasma that's passing through the renal arteries and the
00:06:14.900reason for that is of course the importance of filtration so in a nutshell this is the way the
00:06:19.460kidney works and this was explained by one of my professors in medical school i never forgot this and
00:06:23.860i found it to be a very valuable way to think about it you know if you were a kid and your mom said i
00:06:28.260want you to go into your room and clean your dresser out where you have your socks you want to wear your
00:06:32.180t-shirts your shorts and all that stuff it's tempting to sort of go in there and while everything
00:06:37.140is in the dresser try to organize it and pull things out that you don't need and keep what you do need
00:06:43.060the kidney doesn't work that way the kidney has one way of filtering which is it goes to the dresser0.91
00:06:47.860and takes every single thing out and then it simply pulls back in what it wants to keep that's very
00:06:54.900different than the kidney saying i'm going to go and identify things that we don't need or we don't
00:06:59.140want and pull them out why because in the case of the latter it assumes evolutionarily that the
00:07:06.580kidney will forever be able to recognize bad things but in the former it assumes evolutionarily
00:07:14.420that the only thing the kidney needs to understand is what is good and obviously that's a much better
00:07:19.540strategy because that's a finite set of things as opposed to an infinite set of things so the way this
00:07:26.020works at the cellular level is as plasma rolls through the kidney it pulls everything out it0.81
00:07:33.540just completely dumps everything out glucose sodium potassium magnesium chloride you name it as the
00:07:42.500filtrate runs through the kidney it selectively pulls back into the circulation the things that it
00:07:48.500knows we need and that's why the kidney is the most important organ in the body for regulating our
00:07:53.860electrolytes so there's an interesting opportunity here because one of those things that happens to
00:07:58.180get filtered is glucose and even though the kidney's job is not really managing glucose concentration
00:08:04.980there's an interesting opportunity to prevent the kidney from reabsorbing all of the glucose that
00:08:13.540it immediately shunted out when the plasma came through the kidney in the first place so in other words
00:08:17.780even though the kidney's goal is not interfering with glucose concentration the way it is doing
00:08:24.100deliberately with sodium potassium chloride etc there's an opportunity so if you look at this figure now
00:08:29.060you'll see on the left hand side of it a little purple box and that's called sgl t1 and 2 there are
00:08:35.780two of them but obviously we're talking about the sodium co-transporter 2 here and you can see that it pulls
00:08:42.980sodium and glucose into the cell together by the way as an aside people who may remember the
00:08:49.460podcast we did on hydration might recall that we talked about how mixtures of glucose and sodium
00:08:56.180are the best ways to hydrate cells if you're really optimizing for water movement this kind of is a bit
00:09:01.700of a reminder why sodium and glucose move together very efficiently but let's put that aside for a moment
00:09:07.060as you can see looking at this diagram if you had a way to block that purple thing
00:09:11.140you would be able to keep more glucose in the urine on this graph this figure rather the right hand
00:09:17.220side is where things are returning to the plasma going back to the body the left hand side is things that
00:09:24.020will be excreted in the urine so when you block sgl t2 you prevent sodium and glucose from being reabsorbed
00:09:33.780by the cell to then be put back into the plasma and therefore you will pee out more sodium and glucose
00:09:42.660and therefore this has become a very attractive solution for people whose blood glucose is too high
00:09:48.820taking a very big step back how do we manage the problem of type 2 diabetes that's really what we're
00:09:54.740talking about today you can manage it by reducing glucose you can manage it by increasing insulin
00:10:00.420sensitivity you can manage it by increasing insulin itself this is a strategy that says here's how
00:10:06.900we're going to lower glucose metformin which we'll talk about as well is also a glucose lowering strategy
00:10:12.980whereas glp1 tends to be probably more of an insulin sensitizing strategy coupled with to some
00:10:19.940extent a glucose lowering strategy by the fact that you simply eat less so with that said any other
00:10:26.180questions on sgl t2 inhibitors that is to say the class of drugs that block this protein no i think
00:10:32.740that's a good overview of what they do i think some other people reached out and a good follow-up to that
00:10:38.420is how were they developed initially in the first place to solve this problem yeah so it's not an uncommon
00:10:44.660story in pharmacotherapy where there is a naturally occurring substance that sort of does this and then
00:10:52.820a drug company will come in or the scientist will come in and figure out a way to make a better
00:10:58.500version of the molecule that occurs in nature by the way metformin is a naturally occurring molecule
00:11:04.740statins are naturally occurring molecules so the naturally occurring molecules have pros and cons but
00:11:10.820that's an impetus for further development and the same is true here so there's a chemical called
00:11:15.780fluorazine primarily found in apples i think it's found in the skin of a few other fruits in relatively
00:11:23.380small quantities and was originally isolated if i'm not mistaken in the 17th century and it was part
00:11:30.580of the botanical solutions to people with various infectious diseases malaria things of that nature to
00:11:36.180be completely honest with you i don't actually know how efficacious it was however it started to become
00:11:41.940clear and this is the important point of course is that when people were given fluorazine they developed
00:11:47.620glucose urea they developed glucose in their urine and this became a very important early diagnostic
00:11:55.540step in the treatment of type 2 diabetes in other words sir william osler who's the father of modern
00:12:02.020medicine in this country and canada for that matter osler was a canadian used to actually taste his
00:12:07.540patient's urine to determine if they had type 2 diabetes so here you took patients who didn't have
00:12:12.260diabetes and you could induce this idea that we saw in people with diabetes which they're peeing out
00:12:16.980glucose so people put two and two together and said well wait a minute if we're giving this drug to
00:12:21.700people and they're peeing out glucose and they're not diabetic to begin with then this drug is doing
00:12:27.700something that is impacting that pathway and that's effectively what led to the development of these
00:12:32.180drugs in fact if you pull up a photo i think we have a picture of fluorazine
00:12:36.340fluorazine next to a modern day sgl t2 inhibitor you can see the similarity
00:12:43.380just pulled it up so there you go fluorazine naturally occurring on the left and an sgl t2
00:12:49.460inhibitor on the right and you don't have to be a biochemist to recognize that there are some
00:12:55.460similarities here now there are far fewer similarities between these two molecules than there are between
00:13:02.900the existing batch of sgl t2 inhibitors and there are currently four of them out there and they all
00:13:09.220have really really unpleasant names that are not necessarily that important but they all end in
00:13:15.060flozen not surprisingly their names will come up as we go along and we'll probably talk maybe a little
00:13:21.060bit more about kinagaflozin in a minute because it ties into the itp study but the point here is all of
00:13:28.500these giflozins if you will or glyphlozins have kind of a similar structure which is this glucose
00:13:34.820ring with an aromatic group and then they differ basically around that and these differences
00:13:41.060obviously allow you to have drug companies to make different versions of drugs from an ip
00:13:44.980perspective but they also tend to be dosed differently and that reflects a very different
00:13:49.540potency of the drugs as well although we're not talking about it today you mentioned
00:13:53.780statins and metformin which we'll cover are naturally occurring rapamycin is also naturally
00:13:59.940occurring correct that's right yeah and rapamycin interestingly is given basically in the format in
00:14:06.580which it was discovered whereas sgl t2 inhibitors are not they're now basically derivatives of what
00:14:12.260exists in nature metformin is actually pretty close to the original molecule that was discovered in the
00:14:18.660lilac lilies the very very weakest of all statins which is pravacol or pravastatin is closer to the
00:14:26.260most naturally occurring statins that are found in red yeast rice so it is really interesting that
00:14:32.500nature's given pharmacologists a head start on drug development in many cases the other follow-up is
00:14:39.380push came to shove would you be tasting your patients urine to help diagnose anything yeah i mean push
00:14:47.700comes to shove the world has run out of glucose dipsticks and we have all of the exact same
00:14:54.500technology we have today except we somehow have lost the ability to determine if there's glucose in
00:15:00.340urine so we can still split atoms and do all those other things but we just can't do that one thing is
00:15:05.460that what you're saying yes yeah just really trying to understand if your patients are listening how
00:15:10.420dedicated are you you know to their health i'm gonna go with a yes on that and i'm not gonna do it alone
00:15:16.020i'm gonna enlist the help of my entire clinical team that's right i'm sure they're very happy to
00:15:20.820hear that as well so the follow-up which hints at what you talked about there is the next question we
00:15:26.580get a ton of is what are the different sgl t2 inhibitors and what do we know about the differences
00:15:32.420between them i think anyone who's thinking about potentially taking these or is taking these
00:15:36.980will be interested in that and so maybe we can just run through that quick as it sets the stage going
00:15:41.300forward i think i already alluded to one of them caniga flows and i think it's probably the one
00:15:45.620for which we have the most data it was approved exactly 10 years ago so in 2013 and was looked at
00:15:52.660both in isolation and in combination with metformin which was obviously the standard of care for
00:15:59.940initiation therapy in many ways still is so two things were observed so the first was that in a dose
00:16:06.900dependent manner meaning more drug more response if i'm not mistaken canagaflozin is dosed i want to
00:16:14.420say between 100 and 300 milligrams daily but as the dose went up you saw a greater increase in hemoglobin
00:16:20.100a1c reduction and the results were reasonable so somewhere between a point seven and one percent
00:16:25.700reduction in hemoglobin a1c and by the way what i mean when i say point seven to one percent i mean
00:16:30.420absolute reduction in a1c not relative so if your hemoglobin a1c was 6.1 you would expect it to go
00:16:39.060down to as much as 5.1 that's a very big reduction in hemoglobin a1c and interestingly when a second
00:16:47.300trial was done that looked at metformin plus canagaflozin it found an average reduction in the
00:16:52.900in the hemoglobin a1c of 1.8 that's really significant so somebody shows up at 7.8 percent
00:17:00.660hemoglobin a1c so they're clearly and well into the territory of type 2 diabetes where that threshold
00:17:06.020is 6.5 and that person is going to come down to 6.0 so they're going to go from being in a state of
00:17:11.380raging type 2 diabetes to being pre-diabetic metformin is typically first line i suspect
00:17:16.980part of that has to do with cost but i also believe it has to do with efficacy i mean metformin
00:17:21.140monotherapy is pretty robust depends on the study but it's up to 1.3 percent reduction
00:17:28.500in hemoglobin a1c after about six months so sizable benefits again we've talked about
00:17:34.340metformin a lot on this podcast you know and i forgot to look for this earlier and i should have
00:17:38.500i don't believe that we see the same amount of weight loss with canagaflozin that we see with0.56
00:17:42.820metformin so metformin is if i had to guess and someone will check me on this i'm sure if i had to guess
00:17:48.100i would say monotherapy metformin would be associated with slightly more weight loss than monotherapy
00:17:54.420sgl t2 inhibitor but again that's something worth understanding now we're going to talk about this
00:17:59.220in more detail but the other important question here is are there other benefits associated with
00:18:05.060be it canagaflozin or other sgl t2 inhibitors that go beyond the glycemic control and again in
00:18:10.580addition to weight loss we're also seeing a greater reduction in blood pressure i've always wondered
00:18:16.340with the blood pressure improvement if it's because of if you go back to what we talked
00:18:20.660about earlier remember when you block sgl t2 you're preventing the kidney from reabsorbing
00:18:26.660not just glucose but sodium so as a patient is excreting more glucose and sodium in their urine
00:18:33.460you would think they have obviously less sodium within their plasma that may explain the benefits
00:18:38.580we see on the blood pressure front as well i guess maybe just to round this out nick there are as i
00:18:43.780said four of these drugs that are approved the three others and you'll have to bear with me for
00:18:48.340whatever reason i just have a complete brain thing that does not work when it comes to pronouncing
00:18:53.780the syllables in proximity of these things but you have dapa dapagliflozin and pegaflozin and
00:19:04.580urtugaflozin as the other three and they were approved anywhere from 2013 2014 actually up until
00:19:14.660the most recent one in 2017 if i'm not mistaken why is it that drugs have such confusing names like that
00:19:23.940why do they purposely try and make it where any human can't pronounce it yeah it's actually a great
00:19:30.500point and it's a very deliberate point the reason that if you're a drug company and you're developing
00:19:35.780a drug you really like it when it has an awful awful name is that the generic name the molecule name
00:19:44.580is free for anybody to use so when the drug goes off patent anybody can sell that drug but it's the
00:19:52.100trade name so for example for empegaflozin it's jardians that's way easier to remember so if you're the
00:19:59.540company that's making that you want everybody to forever remember jardians you want people to
00:20:06.100remember crestor not rezuvastatin you want them to remember lipitor not atorvastatin so it's just
00:20:15.300classic pharma chicanery which is let's make sure that doctors and patients alike are associating the
00:20:21.780brand name with it and presumably there's some belief that that translates to a longer tale of sales
00:20:28.340anyway i could be speculating on all of that but that's sort of my two cents the next follow-up
00:20:33.060here is something you hinted at earlier which is what do we know about other effects for sgl t2s
00:20:39.860outside of just the glycemic control yeah i think this is where things do get a little bit interesting
00:20:46.020because we've talked about metformin i think people are already familiar with the idea that
00:20:50.500okay metformin is kind of like bread and butter early intervention type 2 diabetes but that's not
00:20:56.100really the reason people are excited about it people are excited about metformin and people
00:20:59.220talk about it and people ask me about it because the belief is that it's doing something beyond
00:21:04.820regulating blood sugar and i think to a lesser extent in the public's eye but probably to a
00:21:11.940greater extent in the scientific eye the excitement is the same for sgl t2 inhibitors that's interesting
00:21:17.940isn't it right the public is way more interested about metformin i think the scientific community
00:21:22.820sees much more promise in sgl t2 inhibitors at least on average and that's based on my very
00:21:27.540unofficial survey of this why is that one of the things is that the itp the interventions testing
00:21:33.060program has found a clear difference between them we'll talk about that in a second i'm sure
00:21:37.460but the other one is just looking at the really clear differences in human clinical trials for the
00:21:44.660advantages associated with sgl t2 inhibitors in terms of major adverse cardiac events what are called
00:21:51.700mace so if you look at people with or without this is the big point without t2d sgl t2 inhibitors
00:22:00.900have been shown to decrease the risk of hospitalization and death for heart failure patients with reduced
00:22:06.660ejection fraction and improve basically all cardiovascular outcomes in patients with heart
00:22:10.580failure who have preserved ef so you take people who have reduced ejection fraction so what does that mean
00:22:16.180so the heart pumps and we can measure with an ultrasound how much blood comes out of the heart
00:22:22.180with each pump so if you're at rest that number might be 40 percent 50 percent and if you're under
00:22:27.220great stressor when you're exercising one of the tools that the body has to increase cardiac output is
00:22:31.940not just to beat faster but also to beat with greater contractility and get more ejection of blood
00:22:36.660volume well heart failure is basically a condition in which ejection fraction goes down and when ejection
00:22:41.380fraction gets low enough 20 percent 15 percent you're in a lot of difficulty and what's been
00:22:47.780demonstrated and this has been demonstrated repeatedly is that when patients have heart
00:22:52.260failure with or without reduction in ef outcomes are better if they're taking sgl t2 inhibitor even if
00:22:58.420they are not patients with type 2 diabetes again i think there are lots of potential reasons why we might
00:23:04.900see that i think it probably has to do with the reduction in blood pressure but it may have to do with
00:23:09.940other things as well which we could explore you also hinted at where we're going next there which is
00:23:15.860a lot of people when they talk about sgl t2s and a lot of questions we get it's much like metformin it's
00:23:21.700not diabetics kind of wondering about metformin it's people who are interested in the geoprotective
00:23:26.900side of it and it's the same with sgl t2s and so i think now would be a good time to just say
00:23:32.420what do we know about sgl t2s as a potential geoprotective molecule
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00:27:08.340community 2015 michael michael michael michael michael michael michael michael michael michael michael michael michael i
00:27:19.540should be a country into my school anymore in Madisonville michael michael michael michael michael michael michael michael michael michael michael al
00:27:23.940my at-terr034 amici helver okei ho a country in in southwestern in mil