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The Curbsiders Internal Medicine Podcast
REBOOT: #481 Prediabetes and Diabetes Prevention with Dr. Scott Isaacs
01:33:35
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- [00:00]
A
Hey, listeners, you're about to hear a Curbsiders classic episode. If you heard it the first time, listen again for that space learning. But if you haven't heard it yet, then you are in for a treat. So without further ado, enjoy and don't forget to check out our patreon@patreon.com curbsiders if you want ad free episodes, bonus episodes, and a whole bunch of other cool stuff. Patreon.com curbsiders you know, Paul, I found a rock yesterday which measured 1,760 yards in length. Must be some kind of milestone.
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B
I would have gotten there. All right, Matt, you ready?
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A
Sure.
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B
I already filled with shame. So, Matt, jokes about white sugar, they're rare, but jokes about brown sugar. Demerara.
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A
What?
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B
Yeah, Demerara is a type of brown sugar. So that's a requisite part for you to actually appreciate that joke.
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A
I am not familiar with that. Okay,
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C
the Curbsiders podcast is for entertainment, education and information purposes only. And the topics discussed should not be used solely to diagnose, treat, cure or prevent any diseases or conditions. Furthermore, the views and statements expressed on this podcast are solely those of those and should not be interpreted for the official policy or position of any entity. Aside from possibly cash, like more hospital and affiliate outreach programs, if indeed there are any. In fact, there are none. Pretty much. We are responsible if you screw up. You should always do your own homework and let us know when we're wrong.
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A
Welcome back to the curbsiders. I'm Dr. Matthew Frank Watto, here with my great friend and America's primary care physician, Dr. Paul Nelson Williams. Paul, how's your shame?
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B
It's all. It's bad. It's real bad. I hate that this is even on film.
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A
All right, well, we have a great episode tonight with a great guest. We're talking about pre diabetes and diabetes prevention with Dr. Scott Isaacs. Thanks to the American association of Clinical Endocrinology for hooking us up with Dr. Isaacs. We'll tell you more about him in a second. But Paul, what is it that we do on Curbsiders?
- [02:11]
B
Sure, Matt. As a reminder to our audience, we are the internal medicine podcast. We use expert interviews to bring you clinical pearls and practice changing knowledge. We should also mention that tonight we are joined by Malini Gandhi, super producer, wunderkind, future boss. All the things I've been on the show multiple times before. Malini, always lovely to see you.
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D
How are you doing?
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E
Doing well.
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A
Yeah. Malini, many of our greatest hits. I don't know, Molly. You've done like, adrenal, you've done some hypertension episodes. There's a lot more. But this is great. This, this is an instant classic as well. So thank you for producing this.
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E
No. We had a Wonderful guest tonight, Dr. Scott Isaacs, who I can tell you about. He is an endocrinologist and obesity medicine specialist at Emory University School of Medicine, and he's president of the American association of Clinical Endocrinology. His practice focuses on cardiometabolic disease, obesity, diabetes, prediabetes, and general endocrinology. He's involved in algorithm and guideline development, including the ACE type 2 diabetes algorithm. And he co chaired the ACE guideline for the management of metabolic fatty liver disease in the primary care and endocrinology settings. And today he provided us with a lot of wonderful pearls on prediabetes and diabetes prevention. He taught us about different screening tests for prediabetes and diabetes, really wonderful pearls on identifying cases of atypical non type 2 pre diabetes, and then provided really thoughtful guidance on how to individualize management strategies related to both lifestyle changes and medications in the setting of diabetes prevention.
- [03:51]
A
All right, And a reminder that this and most episodes will be available for CME credit for all health professionals through VCU Health at curbsiders.vcuhealth.org well, Scott, we've been talking for a while. I'm excited for the audience to meet you. And as a way of doing that, how about you tell them a hobby or interest that you have outside of medicine?
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F
Well, one thing I like to do is I like to grow vegetables. And so I like to do it from seed. And I use raised beds. And so it's like going through for months and months till I finally get something that I can actually eat. But then I like to cook things from what I've grown. So I like to make caprese salad, I like to make stuffed peppers, and I like to make eggplant parmesan.
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A
Speaking my language, Paul, yet another guest who is better than us because they're a gardener and.
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B
Or at least almost certainly better adjusted because that seems to be the larger theme.
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A
Yeah, absolutely. Paul, I know we got a lot to get to, but what else do you want to know?
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B
Yeah, I mean, I always love the advice or feedback question, so I'll default to that one. Scott, can you tell us a piece of advice or feedback that you either received or that you frequently give that has been helpful throughout the course of your career?
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F
Well, one thing I've received and I give is from an attending When I was a fellow in endocrinology is that all patients, they have either one of two focuses, they're either minimalist or maximalist, and that's really how they want to be treated. And so that's your job as their doctor, is to figure out which one they are, a minimalist or a maximalist. And once you figure that out, it really makes the approach towards their management much easier and much more specific. And it helps you kind of direct where to go.
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B
I love that I just inherited a chunk of patients from someone whose practice style was completely the opposite of mine. And some of them were. I'd be like, I'd like to do these, these things. And this person was much less aggressive than I am. And God bless, because the patients are doing great. And some of the patients are like, oh, wonderful. I'm so glad we're finally looking at that. And others I'm like, I'd like you to see back in three months. They're like, no, no, I'll see you back in a year. Oh, okay, fair enough. So just trying to figure that out with folks has been. I've never heard you said explicitly, but I love that feedback.
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A
Yeah, I like that too. So, Malini, anything you'd like to ask before we get to the first case?
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E
Yeah, one other thing we love to ask is favorite failure and what you learned from it. And it can be related to medicine, not related to medicine.
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F
Okay, well, we'll go back to my gardening and I'll tell you a failure. Like I was saying, two years ago, I spent all winter growing my seedlings from seed. And it was also the year I decided I was going to be an organic gardener. So I got this organic fertilizer and I planted everything. But it turned out the fertilizer smelled a lot like my dog's dog treats. And so after I got everything planted, later on that day, the dog came. His face was just covered in mud, and all my seedlings had been eaten by the dog. So that was my one year that I actually had to go to the plant store and buy some baby plants.
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A
Well, lesson learned. I mean, I'm sure you still love your dog. This is why Paul's a cat person. For this reason, exclusively for this.
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F
Well, I'm not an organic gardener anymore.
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A
Well, we have a lot to get to. So, Malini, would you do us the honors of reading our first case from Cash? Like, sure.
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E
All right. So our case from Cash today is, is a case of Ms. Dulce Sugarman. A 48 year old woman has a History of hypertension, hyperlipidemia, and obesity. A BMI of 36. And she's presenting to your primary care clinic for an annual physical. Overall, feeling well, you can an A1C to screen for diabetes, and it returns at 6.1%. So to start us off, we'd like to ask, generally, why do we screen for prediabetes and diabetes?
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F
Well, first of all, I just want to say my initial thoughts about this case is that this is a very typical case. This is something someone that I would see almost every day, probably you as well. And she has the classic features of metabolic syndrome. And although they weren't really described exactly that way, I think that she fits. So metabolic syndrome is where you have at least three of the components, which are elevated blood pressure, elevated glucose, elevated waist circumference, elevated triglycerides or HDL cholesterol. And just in this initial history, she's got the A1C that's elevated. So we know she has Pre diabetes. Her BMI is elevated, and it's over 35. So we know she has an elevated waist circumference and her blood pressure is elevated. So right there, we don't even have to know her lipids. We know she has metabolic syndrome. So thinking about that, it helps us to put this whole patient into perspective. Now, why do we screen for diabetes and Prediabetes? Well over 800 million adults in the world have diabetes, which is about 14% of the global population. In the U.S. that's about 15% of adults, which is about 38 million people. And of those, about 3.5%, or 9 million Americans have undiagnosed diabetes. And prediabetes is even more common. It's about 100 million adults, about 38% of the U.S. population. And the vast majority of people with prediabetes don't know they have it. So that's why it's so important to do screening.
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A
I find in my clinic that it's almost more common to see abnormal testing than it is to see normal testing. When I'm checking metabolic parameters, you know, it just is.
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F
Yeah, I mean, you're going to see it a lot, especially if you look for it. It's just one of these things. And the prevalence is rising.
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A
Okay, so I get this question a lot. Like, and this comes up on our boards, and I think it trips people up because, you know, you see so much abnormal testing, and then you're like, okay, so who are. What do the guidelines recommend? Like, who should we be testing? And I think a Lot of people don't really know what that is offhand. They're just like, no, I just test everyone because it seems like I have a pretty high hit rate with that, which I can't really argue with. But what should, what do officially the guidelines say?
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F
Well, first of all, I agree with you. You feel like you're going to have to test everybody, and it basically is almost everyone. But there's two sets of guidelines. There's the U.S. preventative Services Task Force, and they recommend adults age 35 to 70 who are overweight or who have obesity be tested. So all adult overweight or obesity. The American Diabetes association also has guidelines and they recommend screening all adults over the age of 35, period. And then also adults under the age of 35 if they have risk factors. And so the risk factors that they mention, if you're under the age of 35, you'd screen patients that have obesity, plus any other risk factors, such as a family history, first degree, relative high risk ethnicity, like African American, Latino, Native American, Asian Pacific Islander, history of cardiovascular disease, hypertension, metabolic dyslipidemia with low HDL or high triglycerides, a history of gestational diabetes or PCOS or physical inactivity. So if they have any of these risk factors, you want to screen folks at an earlier age.
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A
Paul, is that a long enough list of risk factors for you?
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B
Well, it's really uncommon stuff, so, yeah, I'm not sure how that is particularly germane to the patients that we see, but yeah, no, it's to your point, Scott. It does seem like we're gonna be with those parameters screening almost anyone anyway.
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A
Yeah. So the age limit cutoff of 70, why do you think that is? Do they think it's that if they haven't been diagnosed by age 70, is it like with prostate cancer? Like, if you haven't died by. If you haven't been diagnosed or died by it by age 70, you're not gonna die from it. Just don't even anymore.
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F
I think that's a good thought. I don't know why they have that. I don't use that guideline. And the ADA doesn't have an upper limit, but the US Preventative Services Task Force recommends screening up to age 70. I've diagnosed new diabetes in patients in their 90s, and so it's not that difficult to check a fasting blood sugar every once in a while. So I think it's a good idea just to keep it, keep it in mind all the time.
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A
Paul, are you going to say something or is that just your face?
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B
Yeah. This ties into a question that probably is best served for later in the episode. But I'm just going to throw it out there now because I did want to ask about the idea of pathologizing prediabetes in older patients specifically. And I think this is maybe a conversation for someplace else on the show, but since we're all on the topic, I'm just going to bring it up here. There's that paper that came out, I want to say, in JAMA Internal Medicine, that showed that the risk of becoming diabetic was less than the risk of becoming euglycemic or even dying if you're over the age of 65 in the prediabetes range. And the authors made the argument that maybe we were pathologizing prediabetes a little bit too much. I wondered what your thoughts were about that, since statistically they were much more likely just to actually go back to regress to the mean than they were to actually regress to diabetes.
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F
That's a very interesting concept, and I think part of it goes to complications also. And the diabetes complications are related to duration of exposure. So if someone's diagnosed at an early age, they're gonna be much more likely to develop complications. But maybe if they get this at an older age, it gives them less time to develop complications.
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A
Yeah, yeah, that's a, that's, that's a good point. So maybe, maybe that's it. So maybe that is kind of like the, like the prostate cancer thing. I was saying with the PSA testing, like, you know, it has such, it needs, there's such a long lead time before people get sick from it. So maybe that's what that's about. You mentioned the screening. Like you mentioned a fasting glucose. There's the A1C, there's the two hour postprandial glucose. So when we're screening people, do you recommend using one or all of these tests? How do you like to do it?
- [14:21]
F
Well, the ADA says that you can screen with either the fasting plasma glucose, the A1C, or the 2 hour plasma glucose during an oral glucose tolerance test. But most people are either going to do the fasting glucose or the A1C. You can do either one, but I usually do both because they're not that expensive and they're easy to do. And if you do simultaneous testing of the fasting plasma glucose and the A1C, it may facilitate a diagnosis because then you don't have to have a second patient visit to confirm the abnormal results. You've got both test right there and so especially patients that are at really high risk and you think they're likely to have prediabetes or diabetes, go ahead and just do do both at the same time. But if you only use one test, the A1C is the best test to screen for diabetes because it correlates best with the rate of incident diabetes, diabetes complications and all cause mortality.
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D
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A
and the cutoffs for this differ a little bit too, right? Between like the W, the WHO and the ada. I I think they're just slight. Like with if you're looking at A1C, there's some have like the stricter range, 5.7 to 6.4 is prediabetes and some say just 6% to 6.4 is prediabilities for the A1C and the fasting plasma glucose I think is like one has a cutoff of 100 or higher and the other is 100 or 10 or higher, 110 or higher. Which ones do you follow or do you recommend we just follow the more inclusive ones?
- [19:24]
F
You know, I think most people are going to use the ADA numbers, so they're going to use the 5.7 to 6.4 for prediabetes and then 6.5 and above for diabetes and then for impaired fasting glucose it's 100 to 125 and then 126 and above is diabetes. But I think the other important point to make is that this is a continuous spectrum, that the risk is continuous and the risk for comorbidities is continuous. And so the cut points are really, they're arbitrary. They're based on percentages and they're based on mathematical values. But it's not like if you have a glucose of 99, you're safe and 100, you're at risk. And so we have to look at it as a continuous spectrum.
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A
Yeah. Nowadays more and more people are getting exposed to like the continuous glucose monitors because you can get them over the counter. So I think it is worth saying, like, what's a normal two hour plasma glucose after, like that oral glucose tolerance test, which is like a 75 gram glucose load. Right. It's just like a simple sugar that they're giving to people and they're checking to at two hours later.
- [20:44]
F
Yeah, so. So that's exactly right. So it's 75 grams of glucose. And, and you know, it comes in a bottle of like 100 grams. So you pour out 25 grams of glucose and you have them drink that on an empty stomach. Usually get the fasting glucose first and then you do the two hour glucose. And a two hour glucose level above 200 diagnoses diabetes, but then a level between 140 and 199 is impaired glucose tolerance. And that's one of the types of prediabetes.
- [21:22]
A
Yeah. Outside of obgyn, I don't think many doctors are using that test anymore. Though I have heard some people that if it was easier to get that test. I think some people really like that. At least I've heard some experts say that. I'm not sure how you feel about it.
- [21:39]
F
I like it. Endocrinologists like the test. It's different than fasting glucose. And so it's actually giving you different information. When you have impaired fasting glucose, that's primarily associated with reduced first phase insulin secretion. But the second phase insulin secretion remains normal. And impaired fasting glucose is also associated with hepatic insulin resistance, where insulin doesn't adequately suppress glucose production by the liver at night. That's called gluconeogenesis. So the liver is overproducing glucose in the fasting state. But with postprandial hyperglycemia, which is impaired glucose tolerance, this is a result of both defective first phase and second phase insulin release. And it's also combined with muscle insulin resistance, peripheral insulin resistance. And so the peripheral glucose uptake is impaired and that leads to that later postprandial hyperglycemia. And so you can have either impaired fasting glucose or impaired glucose tolerance, or you can have both. You don't necessarily have both, but you can have both. And both conditions increase the risk of developing diabetes and cardiovascular complications. Although the impaired glucose tolerance is a stronger Predictor of type 2 diabetes and cardiovascular complications.
- [23:04]
A
Yeah, and so it's interesting. It's like the stronger predictor is the one that we're not getting as often, just because it's a harder test to get. And I guess it's just kind of like for patients, when you're talking to them about these tests, how do you talk to them about, like, the significance of this, of this risk you just mentioned, cardiovascular risk or prediction of progressing to diabetes, Is there, I don't know, is there a rule? Like if based on, based on their A1C or based on their fasting glucose, how do you talk to them about their risk of progression?
- [23:38]
F
Well, first of all, we try to have what we call complication centric approach. So the idea is that when we identify people with undiagnosed progress prediabetes, we want to be able to intervene earlier to prevent or delay the onset of diabetes, but also diabetes complications. And so we're not just looking at it from a glucose centric perspective. We want to look at the comorbidities or the multimorbidities associated with insulin resistance in the metabolic syndrome. So kind of, you know, think about cardiovascular disease, coronary artery disease, carotid artery disease, peripheral vascular disease, HFpEF, steatotic liver disease, or metabolic dysfunction associated steatotic liver disease, which, by the way, the prevalence is the same as prediabetes. It's about 38% of the US population, and then also chronic kidney disease. So really trying to think about the big picture and not just the glucose levels, but when they ask about progression to diabetes, probably about 5 to 10% per year would be the risk.
- [24:49]
A
Paul, any. Anything there surprise you about, like the oral impaired glucose tolerance is like a bigger predictor of progression, but we're not really checking that for most people.
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B
No, no, I, it's, it's interesting. There's, I was thinking there's an ophthalmologist they used to work with that would just tell patients like, oh, you don't want a 1C, you need the glucose tolerance test. Like, he would just order it, like he loved it and we all thought he was a maniac. So it's, it's so apologies, apologies, wherever you might be at this point,
- [25:14]
A
the research, when I was kind of reviewing for this, it seems like they're mostly checking for fasting glucose, for impaired fasting glucose, and they're checking for the impaired glucose tolerance. They're not necessarily a lot of Them going by the A1C in studies of prediabetes. At least that was my impression from my reading.
- [25:36]
F
I think the glucose tolerance test is like, very important for clinical research in all the studies. It's a great test clinically, but the problem is that it's not as easy to do as the A1C or the fasting glucose. And so I don't do it in everybody, but I do it when I feel like I need it, especially if I have questions about the accuracy of the A1C and the fasting glucose is kind of borderline and I need a confirmatory test. I think the OGTT is helpful in that situation.
- [26:13]
A
I haven't tried to order one from one of the big commercial labs, which is what in my area. That's where most people are going to get their labs done now. So can you order them from those big commercial labs? We don't have to say their names. Or do you do them in your clinic? At Endocrinology Clinic?
- [26:31]
F
We do them ourselves. I mean, we just keep the glucose in there. But I'm pretty sure you can get them from the big labs because that's where we get our glucose from. Our. They call it Glucola, the glucose drink. So they, they give it to us and we draw the blood and then we send it back to them to analyze. But it's, it's really. If you talk about doing, you know, tests, it's not just a simple blood test. It's one of the easiest things you can do, but it still takes time. And, you know, the patients don't always want to spend two hours in the office. I tell them they can leave, they can come back, as long as they come back in time to get their blood drawn.
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A
Yeah, they probably shouldn't eat anything while they're gone either.
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D
Yeah.
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B
I have two errant thoughts. Like, I think diabetes, from a pathophysiology standpoint, like, it's, it's intuitive in terms of like high sugar bad and lower the. You need to lower the sugar. Like, I think that's understandable. The complications, I don't think are necessarily intuitive. And then prediabetes, you're at risk for this thing where the complications are not intuitive, I think is less impactful. So I can't help but wonder if being sent for a glucose tolerance test kind of underscores the importance that you're concerned about it. Because I think a lot of the times it's sort of ordered, you pick it up, incidentally, you're like, well, make sure you Diet and exercise, and we'll see you in six months. And that's kind of the extent of the conversation. I wonder if more patients were sent for a process. And this is not putting the onus on the patients. This is also, I think, coming from the side of the clinicians, if that wouldn't sort of underscore that this is a serious marker of potential cardiometabolic disease. But that was a lot of words without a lot of content. So just spitballing here.
- [28:02]
F
Well, I think that, you know, they go through the process and they think about it the whole time they're doing it. And if it's an abnormal test, I think it does have an impact on how they think about it.
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A
Can we talk about the pitfalls of A1C testing?
- [28:18]
F
Yes. So I mentioned that sometimes you don't trust the A1C. And the point about it is that it's hemoglobin A1C. So anything that affects the hemoglobin is going to affect the accuracy of the hemoglobin A1C. You can either have a falsely low or falsely high a 1C. When you have increased red blood cell turnover, you get a falsely low A1C. So that would be like chronic hemolysis, thalassemia, G6PD deficiency, treatment with EPO or hemodialysis. Also advanced chronic kidney disease will give you A falsely low A1C. Blood transfusion, HIV infection, treatment for anemia will also falsely lower the A1C. But anemia itself, like iron deficiency anemia, B12 or folate deficiency anemia, they'll actually give you A falsely elevated A1C because there's low red blood cell turnover in anemia.
- [29:27]
A
Yeah, And I've definitely seen that. I guess I've definitely had some patients with a 1C like 6.3, and maybe this isn't your typical person that looks like they would have metabolic syndrome. And to my knowledge, they don't have thalassemia, they don't have sickle cell, something like that. And we're trying to figure out, like, they don't have anemia of any kind. And we're trying to figure out, like, why, like, do they really have. Is the A1C really elevated? So other than getting the. I guess we could get the oral glucose tolerance test, which is not something I usually think to do, and a fasting glucose. What do you think about these other ones? Fructosamine is one I've. I've sent sometimes, although I'm not as confident in my interpretation of that test as I am as other ones. Do you use any of these other, other markers or do you calculate any of these insulin resistance equations like the quickie or the homa ir?
- [30:20]
F
Yeah, I do. I order Fruitosamine. But I'm like you, I'm not sure it's really helpful. But you know, fructosamine measures the level of glycated proteins in the blood, primarily albumin. So this reflects an average glucose over about one to three weeks. It's not used to diagnose diabetes or pre diabetes. It's sort of used to maybe give you a general sense of glucose levels, but it's really, it's hard to interpret. There's no universally accepted reference range for fructosamine levels and it can vary depending on the laboratory. You know, interestingly, you know, fructosamine is the main way of measuring long term glucose control in animals. So, Paul, if your cat gets diabetes, they might need a fructosamine.
- [31:10]
B
Entirely possible, unfortunately.
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A
Yeah. Knowing Paul's cats a. Well, his current cat is getting older and your previous cats had a lot of medical problems, Paul. So I wouldn't put diabetes past it.
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B
Yes, thank you for that, wado. Yeah, I've already had to deal with hokum and ibs or ibd, I should say. So. Yeah. Diabetes is probably not far behind.
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F
Well, hopefully not. But pets do get diabetes, dogs and cats. It's so common in humans, you imagine it's common in pets too.
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A
Okay, so it sounds like the Fruitosamine test is not, you know, if we can get an oral glucose tolerance test, that's probably a better place to put our money because we at least know how to interpret that and we have good guidance and a lot of data behind that test.
- [31:54]
F
Exactly, yes. And then the other test that you could do is give somebody a CGM continuous glucose monitor. And there's no, it's not used to diagnose, but if you really want to know, they can wear it. And you get different glucose measurements, but you can get something called the EAG or estimated average glucose. And this is basically, it's a number that's like the A1C that's based on the glucose data. And so it's just another piece of information that you can get.
- [32:26]
A
Yeah. And for the audience, we had the great Dr. Jeff Colburn on. We talked about CGMS and the time and range. Usually they give you like this stoplight type thing. It's like sort of the red is the lows, the green is the time that they're in the range, which is usually 80 to 180 or something like that. And then the yellow is if it's above 180, so when they're high and then they give you that estimated average glucose. So they're really useful. And I've started to have more people get them. So I'm getting more and more used to looking at them. And now there's that over the counter version. We won't say the brand name, but there is an over the counter one that people can wear as well, correct?
- [33:03]
F
Yes. And with prediabetes, you know, most of the time they're gonna be like 98, 99% time and range, but you can still get that EAG. And it's really helpful.
- [33:15]
A
Yeah. Okay, that's a good tip.
- [33:18]
B
Yeah.
- [33:19]
F
And getting to your other question though, about calculations, the homa and the quickie, I don't use them a lot. These are calculations that use fasting glucose and insulin in different ways to estimate both insulin resistance and beta cell function. And they're mainly used in research settings. I just, I don't use them. They're time consuming. And I find that if I want to know about a patient's insulin resistance or beta cell function, I use other tests. I'll either use the fasting insulin and see peptide levels or for insulin resistance. Really the best thing is the physical exam.
- [33:57]
B
If we could take it back to the case, this has been phenomenal. But let's go back to Ms. Sugarman as a reminder. So she's our 48 year old woman. High blood pressure, dyslipidemia, a BMI of 36. And now we have this, this A1C of 6.1%. When you're looking at young Ms. Sugarman, like what, what things are gonna be important to your examination when you're having this conversation about prediabetes, what do you kind of hone in on? I have to imagine the, the waist circumference. But there's gotta be other good stuff you'd like to share with us.
- [34:21]
F
Absolutely. But so with the waist circumference, I do wanna make a point about that because central adiposity, central obesity is really what's associated with insulin resistance. And so we always talk about a waist circumference greater than 35 inches in a female or greater than 40 inches in a male is going to be suggestive of insulin resistance, central obesity. But if you have a BMI above 35, your waist circumference is going to be in that category, most likely. And so I usually don't measure a waist circumference in somebody with a BMI over 35, like Ms. Sugarman, she's 36, but if you did, it probably would be greater than 35 inches. And, you know, it's really important to do this in our patients because if they have that lower bmi, but they have an elevated waist circumference, that's equally high risk for pre diabetes for insulin resistance. You know, measuring the waist circumference, it's not always the easiest thing to do in the office. It's probably easier said than done. But one tip that I learned that I think is a good way to do it is you hand the patient the tape measure and you ask them to turn around. So it kind of wraps around their waist, and then you have both ends of it after they've kind of done a little spin in front of you. And that way you're not like passing your arm around them, basically giving them a hug, trying to put the tape measure around them. So I just feel like it's a more convenient way. And then you want to try to. The standardized way is to try to measure at the iliac crest. The belly button is not good because it's highly variable, especially someone with a panis. The belly button may be much lower than the actual where the waist circumference is. So using the iliac crest is going to be much more accurate. The other thing about this is, though, is just when you just look at the patient, so not even measuring anything, but if they have central adiposity, you can see by their body habitus, they have that apple shaped body where the weight is concentrated in the midsection and the hips and the thighs are generally going to be leaner compared to the upper body. So just you can kind of look at them as they walk in the room and sometimes make that diagnosis. The other thing on physical exam for insulin resistance is you want to pay close attention to the skin. And one of the most common findings in insulin resistance is going to be acanthosis nigricans. And this is where the patients will have these dark, velvety patches of skin that commonly appear on the neck. But also it can be on the face, the armpits, the umbilicus, the groin, the hands, the knuckles. A really commonplace look on their knuckles, elbows, knees. And so this is a good indicator of insulin resistance. When you see it, People that have darker skin tend to have more acanthosis nigricans, but you can see it in people with any skin color. The other thing is looking for skin tags which are called acrocordons and these are small growths of skin on the neck, sometimes in the groin. And really, acanthosis nigricans and skin tags are the same thing. It's just acanthosis are little, tiny, miniature skin tags, like a whole carpet of them. And then that's what gives that dark appearance. The other thing to look for in the skin is in women looking for acne and hirsutism and hair loss. Thinking about how insulin resistance may be associated with pcos, but this is less specific than acanthosis nigricans.
- [38:02]
A
I knew the relationship with skin tags, but I had no idea how they were related to acanthosis nigricans. And I guess I also didn't know that the acanthosis could be instrumental. So many different spots. Like, usually you're taught to classically look for it in the back of the neck. All right, so we gotta look pretty much everywhere.
- [38:20]
F
Yeah, well, the knuckles are great because before you do the exam, and they're just kind of sitting there and you can kind of glance down and see it on their knuckles. And so that always clues me in pretty early.
- [38:31]
A
All right, Paul, are you satisfied?
- [38:33]
D
Yeah.
- [38:34]
B
You can get a good look at the neck while you're going in for the hug, while you're measuring the waist, if you want to do it the
- [38:37]
D
old fashioned way, too.
- [38:38]
B
So there's a lot of options in the physical examination.
- [38:42]
A
All right, Malini, what should we get to next?
- [38:46]
E
Yeah, I think so. Thinking about. Would love to hear a little bit about how you talk to patients about this result. And I know you already started to touch on this a little bit with thinking about a complication centered approach. But what's your initial spiel typically look like when talking to patients? How do you describe these kind of more conceptual ideas of insulin resistance and beta cell dysfunction to a patient that's sitting in front of you?
- [39:14]
F
Wow. Well, you know, some of these are pretty complicated concepts, and so you really have to kind of meet the patient on. On where they are. But the first thing that I try to do is, you know, first of all, I should say patients can be. They have a different variety of reactions to a diagnosis of pre diabetes. Some people just completely brush it off. They don't care. It's no big deal. And other people, it's extremely serious. They're worried, they're nervous. And so just kind of trying to assess where they are, I think is really helpful. The other thing I do is what I mentioned earlier about viewing the glucose as a continuous spectrum of risk. So I talk to the patients about it's not like overnight your risk change. This is a gradual and continuous spectrum of risk rather than distinct conditions with clear boundaries. And I try to explain that the progression from normal blood sugars to pre diabetes and eventually diabetes is a process influenced by many factors including their lifestyle, their genetics and their overall metabolic health. And so there's a lot that they can do to prevent the progression of prediabetes to diabetes, but then also a lot that they can do to prevent these other complications of diabetes or pre diabetes. And I also, I come back to the ACE guidelines. We are, we have ACE diabetes guidelines and an ACE diabetes and prediabetes algorithm and we have goals for the management of prediabetes. So I tried to bring these up pretty early with the patient and we talk about the five goals are diabetes prevention, improving cardiovascular risk factors, preventing the progression of mastle d metabolic steatotic liver disease, weight loss or preventing weight gain. And then the fifth is improving functionality and quality of life. So trying to stay away from just being glucose centric and trying to look at the big picture and being more of a complication centric approach. And these are usually issues that I've already been working on with the patients.
- [41:24]
A
Anyway, love that and
- [41:30]
D
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- [41:51]
B
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- [41:52]
D
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- [42:09]
B
That's it.
- [42:10]
D
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- [43:28]
A
Do you talk to them about this being reversible at the point of prediabetes? Do you consider it to be reversible? I think with type 2 diabetes, I guess from what I've read, you can go into remission, but I don't know that we've got. We're calling it a cure at this point.
- [43:45]
F
That is a really good point. And I treat prediabetes diabetes the same. As far as reversibility. I talk to patients about they can make it go away, they can go into remission, but if they do that through weight loss and then they gain the weight back, it's still going to be there. So it's not really gone. It's controlled diet control. There's so many different words that you can use, but I think remission is a pretty good word. I think reverse is probably more the word that they like to use on the Internet and on social media. But I just, I worry about that because then you kind of think it's a permanent cure and then you stop doing all those things that you did to make it go away.
- [44:30]
A
Oh yeah, I think that's probably important that you can telling them that like they're always going to be at risk if they sort of slack off and let things go back to where they were when they originally developed a condition. So, okay, are we ready to talk about treatment, Paul? Am I jumping the gun here or are we?
- [44:49]
B
So I did just in terms of sort of pre gaming for the show and you're nice enough to provide a lot of notes and sort of thoughts and stuff. When we're talking about prediabetes in this context, it's like the pre type 2 diabetes is kind of the discussion that we seem to be having, I'm not sure if now is the time to talk about the other types of prediabetes, like the pre type 1 diabetes or sort of like the pancreatogenic. Are there other cases or do you think about prediabetes differently in different circumstances and is this the place to talk about that or should we bring that up at a different time?
- [45:18]
F
I think this is a great time to talk about it. I think the important thing is you want to make sure when you have a patient with prediabetes that they have pre type 2 diabetes or you want to screen for the atypical types of prediabetes because although most are going to have the insulin resistance and pre type 2, some of them are not. And you hate to miss someone that has atypical prediabetes. And so you mentioned the types, but I just want to kind of go through them real quickly and just make sure that everybody knows to think about other types of prediabetes other than insulin resistance. So the first one is that pre type 1 or LADA, latent autoimmune diabetes in the adult. The other name for that is stage two type one diabetes, because there are three stages of type one diabetes and stage two is like that pre diabetes stage. But one of the things is, one of the clinical pearls is to look for signs of autoimmune disease. And for example, any patient with prediabetes and vitiligo you should screen for pre type 1 diabetes. But the other one would be a goiter. And then also looking at their medical history, if they have a history of autoimmune disease, if they have Hashimoto's or other celiac, rheumatoid arthritis, lupus, inflammatory bowel disease, psoriasis, anything like that, you want to think about autoimmune prediabetes. Even if they have signs of insulin resistance, you can have double diabetes or double pre diabetes and that's where you have insulin deficiency plus insulin resistance. You also want to think about pre type 1 in younger people that are younger, people that have lower body weight, people that have a family history of type 1 diabetes or insulin dependent diabetes. So those are all areas where you want to think about pre type one.
- [47:23]
A
Okay, and for this, what are we going to do if we consider, let's say it's a person who, they're not our typical metabolic syndrome. Like to look at them and they're younger and their body weight's on the lower side. Are we just checking the GAD65 antibodies, auto insulin antibodies, that sort of thing. What else would we do here?
- [47:45]
F
That's a good, good place to start. So I like to do some sort of assessment of insulin production. So I usually get a fasting insulin or a C peptide. It's not always helpful because in prediabetes they can have normal insulin and C peptide levels. But if someone has an overtly low insulin or a C peptide level in the setting of an elevated fasting glucose, that's a pretty good indicator that they have insulin deficiency and they have pre type 1 diabetes. But the diabetes antibodies are also a very good way to screen for pre type 1 diabetes. And the GAD65 is the most prevalent. So ideally it'd be good to get multiple antibodies. There are several that you can get, and the laboratories have packages that contain. You can have three or four antibodies like IAA, which is insulin autoantibody, Ia2a, which is insulinoma associated protein autoantibody, and then there's ZNT8, which is zinc transporter 8, and then islet cell antibodies. And so the more you have, the more likely you are to have pre type 1. But if you can only get one, it's going to be the GAD 65. It's found in about 80% of patients with type 1 diabetes. At clinical presentation, it can go negative later on in the course of diabetes. So if you test someone who's had diabetes for a long time, they may not have GAD antibodies. But, you know, an interesting aside about the GAD antibodies is GAD antibodies are responsible for the disease stiff person syndrome, which has become famous because of Celine Dion, who has this condition. And she's been very public about it. And that's because the GAD autoantibodies target glutamic acid decarboxylase, which is an enzyme that converts glutamate to gaba, aminobutyric acid, which is gaba. And that's the primary inhibitory neurotransmitter in the brain. So when GABA levels are low, the nerve cells are hyperexcitable, there's excessive muscle activity, muscle stiffness and spasm. The muscles don't relax. And so that's what is stiff person syndrome. And all people with stiff person syndrome also have type 1 diabetes. And so this was the model for us understanding that type 1 diabetes is an autoimmune disease.
- [50:19]
A
You knew that, right, Paul?
- [50:21]
B
Yeah, no, of course. It's nice to have a refresher every once in a while, but, yeah, that was Pretty much what I thought.
- [50:26]
A
Okay, so we're gonna look out for this LADA, this kind of pre type 1 diabetes. And we can order the antibodies that we just talked about, Gad65 being most important, but the insulin autoantibodies or the IA2A, the zinc transporter 8. And the islet cell antibodies.
- [50:49]
F
Yes, and the islet cell antibodies aren't being done as much as the other antibodies as they used to be.
- [50:56]
A
Okay, and then what other types of prediabetes should we think about or other atypical presentations should we think about?
- [51:06]
F
So the other one to think about is pancreatic prediabetes. So that's pretty straightforward. But that's anybody with a history of pancreatitis. Sometimes you could think about it with a history of gallstones or gallstone pancreatitis or a history of pancreatic exocrine insufficiency, if they have diarrhea, steatorrhea, if they need to take pancreatic enzymes, or, you know, thinking about it. Also, usually someone who's normal body weight doesn't have other signs of insulin resistance. So, you know, it's usually pretty straightforward when they have a history of pancreatitis, it's something you want to think about. And again, it's important to differentiate this from other types of prediabetes because you may want to treat them differently as well as far as maybe starting insulin a little bit earlier because they have insulin deficiency. But it's something that's usually pretty easy to pick out of your practice. Now, the other point that I would make is that 80% of newly diagnosed pancreatic cancer cases have prediabetes or diabetes. But it's very rare for this to be a cause of prediabetes. So even though it's common within pancreatic cancer, it's not recommended to go and screen everybody with prediabetes or diabetes for pancreatic cancer. I do every once in a while if I have a patient that I see is something about them makes me suspect it, a family history, a history of other cancers, a lot of weight loss, things like that. And I've done a few CTs in my patients. I've never found a case of pancreatic cancer, but I think it's just something
- [52:47]
B
to point out that's a paraneoplastic phenomenon, which is something I feel like I learned relatively recently. I think I used to assume that the pancreatic cancer just ate up all the. The eyelid cells, but I think in actuality, it's actually paraneoplastic that causes the diabetes, which is just wild to me. There's no other point to make there, though. I just thought that was interesting.
- [53:07]
F
It is interesting. The other area that, as internal medicine doctors, especially, you do not want to miss are Cushing's and acromegaly, especially the obvious cases. So you always want to think about patients with dysglycemia with elevated glucose. Could they have an endocrine cause? And so Cushing's and acromegaly are the ones to think about. So a couple of considerations for Cushing's syndrome. Early on, Cushing's can look just like obesity and insulin resistance, and it's very hard to tell the difference, and vice versa. A lot of patients with obesity may look like they have Cushing's. They have facial rounding, they have other features. So there's this overlap, but most patients obviously don't have Cushing. The second thing is there's a condition called mild autonomous cortisol secretion, or max. So MAX is kind of common, but it's hard to diagnose if you don't already have an adrenal something. So endocrinologists get a lot of these cases because we're referred to patients that have adrenal incidentalomas. And we test everybody for Cushing's, and we find that about a fair number of patients who have adrenal incidentalomas have max. Also, we look for it in patients that have, like, resistant diabetes. If someone is on three or more medications for diabetes and they're uncontrolled, then that would be someone you'd want to screen for Max. So you can't screen every case of prediabetes for max, but it's just something you want to think about, especially if they have anything going on with their adrenal gland. The other point, and I'm going to talk about screening for Cushing's, but for max, the only test that really works is the dexamethasone suppression test, the 1mg overnight DST. The other tests are just not sensitive enough to pick it up.
- [55:05]
A
This is something that was on our radar. We talked about this. We did an adrenal incidentaloma episode, and we talked about it. And I had never heard about it before.
- [55:14]
F
So, you know, it's out there. And there's controversy also about should it be treated, does it cause problems? But I think there's enough evidence to say that people that have MAX get elevated glucose, they get hypertension, they get these. They get increased cardiovascular risk. So if you have Max and you have an adrenal adenoma, that it needs to come out.
- [55:36]
A
Yeah.
- [55:37]
F
So, but really what I also want to make sure is that we don't miss the really obvious cases of Cushing's because they will walk through your door. And so thinking about the Cushingoid body habitus, the central obesity, the round face, moon face, super, superclavicular fat pads, also the dorso cervical fat pad on the back of the neck. Sometimes it's called the buffalo hump. Patients don't like being told they have a buffalo hump. So I think it's better to use the term dorso cervical fat pad. Also pro tip.
- [56:11]
B
Yes.
- [56:13]
F
Also stretch marks. So the, the key with Cushing's is the type of stretch marks because a lot of people have stretch marks, but it's the wide purple or red striae, the ones that are more than 1cm, those are the ones that are more likely to be Cushing's. Also something to think about though is any, any new stretch mark is going to be red or dark pink and then they fade with time. But it's the ones that don't fade, the ones that stay red or purple, those are very sensitive for Cushing's. The other thing to think about is thin skin in a young person, easy bruising and then proximal muscle weakness, you know, getting them to stand up from a chair, proximal, that's a very concerning sign for possible, possible Cushing syndrome. So the screening test, if you think your patient might have Cushing's, I mentioned the 1mg dexamethasone suppression test, but it's, you know, it's difficult because you got to give them a pill and they have to take a blood test at 8 o' clock the next morning. So I'll usually either do 24 hour urine free cortisol or late night salivary cortisol, which is where they collect their saliva at basically at bedtime. And there's pearls and pitfalls to all these tests. None of them are perfect tests, but usually if someone has these high risk symptoms or signs, I should say for Cushing's, it's reasonable to do at least one of these tests.
- [57:50]
A
Yeah. Paul, I don't know. Are you just like rifling through your panel in your head right now thinking about if you're missing anything here?
- [57:56]
B
I mean, every single episode. Matt, that's just kind of.
- [58:01]
A
This is a great discussion of this. Yeah. And Max is just particularly interesting. I feel like that's going to be More and more common and more and more taught. Now it seems like I've been hearing about it from multiple sources recently. Yes, because there's so many people in our panels with incidentalomas, and I don't think people are necessarily doing the full workup and trying to figure out if they have that or not.
- [58:29]
F
That's the point, is that people are getting scans, they're getting CTs for kidney stones and for all kinds of different things. And then we find all these incidental illness and we work them up and then we find stuff. And a lot of times they don't have a lot of symptoms, but it's something that's there.
- [58:48]
A
Yeah.
- [58:50]
F
So the other one, the last one that I just wanted to talk about is acromegaly. So even though it's kind of rare, it's another one you don't want to miss. The average person with acromegaly, it takes four to 10 years to be diagnosed from the time they first report having symptoms. Sometimes it's called a handshake diagnosis because they have swelling of the hands and feet. And the old time endocrinologist was, would brag about making the diagnosis with a handshake. I had an attending when I was, when I was a fellow and he would brag that the patient came in to see him and he shook the husband's hand and he said, he started talking about his diagnosis. He said, no, I'm the husband. He said, no, you're going to be my patient as well. And it turned out he actually did have acromegaly. So it does happen. But the pearl, the thing to do is ask patients about a change in ring size or, or shoe size. Weight gain can do that too. But you might want to just raise some eyebrows if they say that and start thinking about acromegaly. The other one is facial changes. They get these acromegaloid facial changes with thickening of facial features, the jaw, the protruding jaw, the thick, broad nose, thick lips, increased space between the teeth. The dentists are all trained to look for acromegaly in patients that have wide spaces between their teeth. Also, like a deepening of the voice, thickening of the skin, oily skin, excessive sweating and body odor, arthritis and headaches. And so most people have real subtle symptoms if you catch them early. But the longer they go, the more severe they become. And the most famous case of acromegaly was Andre the Giant, who is a professional wrestler. He was 7 foot 4. If you get acromegaly before puberty, you get gigantism so you also grow taller. If you get it after puberty. You don't grow anymore, just the hands and feet and facial features. But Andre the giant weighed 500 pounds. He was also in the Princess Bride. He was Fezzik in the Princess Bride.
- [60:58]
A
Amazing movie.
- [61:01]
F
Yes. So that's where he's famous for a lot of people, too. But he was never treated. He died at the age of 46, basically from congestive heart failure and from untreated acromegaly.
- [61:12]
A
I think he drank like 100 beers a day, too, from what I hear.
- [61:15]
F
Something like that. Yeah. Like 20 bottles of wine. There's a great documentary about his life. I think it's on. Maybe I shouldn't say the name of the channel, but he's on one of the pay channels. And if you're really an endocrine geek, you'll love to watch this documentary about Andre the Giant's life.
- [61:35]
A
Yeah, we could say that. Was it hbo?
- [61:38]
F
I think it was, yeah.
- [61:39]
A
And Max, I'm gonna have to look for that.
- [61:41]
F
Okay, so the screening test, you know, it's pretty much. It's an IGF1 level insulin, like growth factor one. You might want to get a prolactin. Some people are co secretors. And if that's elevated, there's more tests. You can do a growth hormone suppression test, which is kind of like an oral glucose tolerance test with growth hormone. And then eventually you might want to get an mri. But that's kind of the lowdown for diagnosing the rare endocrine diseases.
- [62:10]
A
Probably going to send them to you. If I think someone has acromegaly, I think we should definitely get to treatment now, just with the time we have left. So, Malini, you want to. Do we have any more of the case before to set that up, or are we just jumping right in?
- [62:29]
E
Yeah. So going back to Ms. Sugarman, so we think she most likely has kind of classic pre type 2 diabetes. Don't have anything that's tipping us off for pre type 1 diabetes. We shook her hand. We didn't see any signs of acromegaly. Nothing. Cushing's on exam. So she's asking you, what can I do to prevent my progression to diabetes? What can I do day to day? So starting out, wanted to start out with kind of lifestyle changes. How do you counsel patients on both diet, exercise in modifying their risk of progression to diabetes?
- [63:08]
F
So, you know, with Ms. Sugarman in particular, you know, she's got an A1C of 6.1%. And I usually would start off with saying something like, your risk of progressing to diabetes is about 5 to 10% per year, but this is your risk only if nothing is done. And there's a lot that you can do to prevent diabetes. And then we'll talk about different approaches. A lot of times I do mention the Diabetes Prevention Program because it's like this classic study. And just the name of the study, Diabetes Prevention Program, it just kind of rings home with patients. And so I don't always mention studies, but this is a good one to kind of say the name of the study. And you talk about how with lifestyle change that resulted in a 7% weight loss, I didn't have to lose a lot of weight. There was a 58% reduction in progression to diabetes. So that right there, just kind of laying that groundwork that it's not inevitable that they're going to get diabetes and that there's a lot that they can do to prevent diabetes. I think is a really good start.
- [64:22]
A
Yeah, I wish it was easier for patients to like. I feel like the things, when I talk to people about this, I say, well, there are a lot of things you can do. They're kind of simple things, but they're not easy to. To do. If they were, everyone would be doing them. It is what it is in that case. But do you have any favorite eating pattern, diet, if you want to call it a diet or eating style that you recommend to patients?
- [64:49]
F
Yeah. So, first of all, this is where I'll also sort of go back to my advice that I gave in the very beginning of the show about, you know, trying to assess is. Is my patient a minimalist or a maximalist, and where do they want to go? So if there's someone that's a maximalist, you know, we talk about the diet and the eating, but a lot of times this is already someone that's got a good knowledge of nutrition. They're not coming to me for nutrition. They're coming to the endocrinologist for meds. And we kind of skip. We make sure that they're doing the diet, but then we kind of go to meds. But for others, you know, I think it is important to have a conversation about diet and lifestyle and exercise. And it's just you cannot spend. You could actually spend all day in your office talking to patients about different kinds of diets and what they can do. So you have to develop a strategy of what you can say, sort of like a quick message, and if they need more counseling, that's where I'm going to Refer them to a dietitian for, for longer counseling. So I'll talk about the easy wins and you know, if they're drinking a lot of sodas or in the south, it's a lot of sweet tea, or if they're eating a lot of processed foods, you know, we talk about, you know, easy things that they can cut off, cut out to make a difference. Sometimes in some patients are drinking, literally drinking five sodas a day, they do that and their blood sugar just drops. We also talk about the thing I always mention is the calories and that in order to lose weight you have to have a caloric deficit. And like you were just saying, it's easier said than done. You know, say cut the calories and people sometimes get, get upset with you if you tell them to eat less and exercise more. But you also have to face the reality that that's what it takes to lose weight. And then how do you get to that place where your body's in a caloric deficit is what differs for different people? When patients start to talk to ask me about, you know, what diet should I go on? Should I do the dash diet, diabetes diet, Mediterranean diet, a keto diet? I mentioned there's several studies out there where they looked at, they varied the micronutrients, they varied the, excuse me, the macronutrients. So the percentages of protein, carbohydrates and fats and all those different diets had the same amount of weight loss. So the macronutrients really didn't matter. It was the calories that made the difference in the end. So I tell patients, do what works for you. I want you to avoid the obviously unhealthy foods and I want you to avoid the extremes like don't eat all carbs or all protein and fat. Maybe you want to have a balance, but the exact percentage of macronutrients, of carbohydrates, protein and fat, you know, it can be customized. And so you want to do what works best for you that's going to be effective for a long term. Because, you know, I consider a diet where you, a short term diet where you lose weight and gain it back. I consider that to be a failure. And really what we want to have is long term lifestyle change where they have more sustained weight loss. And that really means making those permanent changes.
- [68:09]
A
Well, let's list the medications that are in play. When someone's coming to see you, a maximalist is coming to see you for medication. How do you talk to them about what's available and then we can maybe dig into each of the classes.
- [68:23]
F
Okay, well, with medications, one of the things that you could do is follow the ACE pre diabetes algorithm, which mentions a few, or you can kind of talk to patients about the individual medications, risk, benefits, side effects, and then also taking cost into consideration. But for most, metformin is going to be the first medication recommended for diabetes prevention for prediabetes. And that's because it's been around for a long time, it's inexpensive. There's data in the DPP that it reduces the risk for diabetes by approximately 30%. So not as good as lifestyle, but it does work and it's in all the guidelines or a lot of the guidelines as first line treatment.
- [69:20]
A
And that's regardless of if they have impaired fasting glucose or if you happen to know if they have impaired glucose tolerance. Right. Like the impaired fasting glucose. It seems like metformin would work more directly towards that mechanism of helping shut down hepatic gluconeogenesis and that mechanism.
- [69:39]
F
You know, that is a great point and it probably does work more in that way. However, the main benefit of metformin really is the weight loss. And so you get about 3 to 5% weight loss. You don't get a huge amount, but you do get some weight loss. So I think that makes a, a difference. But as far as in practical sense, I will use metformin whether they have IGT IfG elevated A1C, I don't think it matters at a clinical level.
- [70:12]
A
And what doses are we talking about here? Are you pushing it to 2000mg a day? If people can tolerate it, yes.
- [70:20]
F
I try to get the dose exactly to two grams a day. So not everybody tolerates that. Metformin comes in either immediate release pills or extended release. You need to start a low dose for the immediate release. It comes in 500s, 850s and thousand milligram pills. I usually start at 500 milligrams once a day and then work up to twice a day for the immediate release. You have to take it with food. If you take it on an empty stomach. I tell the patients, if you take it on an empty stomach, it will give you an upset stomach. So take it. And they usually say take it right in the middle of the meal. That's, that's like the time to the best way to reduce side effects. So generally with titrate it up to the 2 grams a day over a couple of months. The extended release, the ER comes in 500 milligram pills, 750 milligram pills. It also comes in 1000s, but they're huge. Patients don't like to swallow them and they're for some reason very expensive. So I usually stick with the 500s and the 750s. To start the patient, I usually just write a prescription for two pills, but I tell them to start with one and do that for a week until they make sure they're not having side effects and then they can increase it to two pills a day. I always tell them you can take the two pills once a day, you don't have to take it to twice a day. For some reason, when you tell patients two pills a day in their brain, they always think twice a day. If you tell them four pills a day, they think four times a day. So I try to make that emphasis. It's once a day because if they go to twice a day, the compliance goes way down.
- [72:00]
A
Yeah.
- [72:01]
F
So I try to stick with that and that's why I prefer the er. Even though there's not quite as much weight loss with the ER as with the immediate release, it's still pretty, pretty good weight loss. And although the average is 3 to 5%, some patients will lose a lot of weight with Metformin. And so it's definitely worth a try. If they take the er, they don't have to take it with food. They can take it any time of the day. Some like it bid, but really once a day is fine. And then one other thing for, for everybody to know about is Metformin Ghosts. So I don't warn patients about ghosts in advance, but if they ask you, you need to know that ghost tablets are the remnants of the Metformin, er, tablets that can appear in the stool. And they'll see these in the toilet. And the remnants, they can be mistaken for undigested medication or sometimes they think it's a parasite. They basically look like pills in their stools, so they will tell you about them. It happens a lot, so it's just something to be aware of.
- [73:05]
A
I didn't know they were called ghosts, but Paul, I had a patient 10 years ago who swore to me that he was seeing. He's like that Metformin he made. We switched him off, extended release because it freaked him out so much. He's like, I see like this shell of the pill in the toilet. Like, that's what he was telling me.
- [73:23]
F
Well, that's it.
- [73:24]
B
So, yeah, the case has been cracked wide open.
- [73:27]
D
Yeah.
- [73:28]
F
But the medicine is gone, so it's not a problem. You know, if it really freaks him Out. You could switch them to the immediate release, but. But I usually just tell them not to worry about it. It's just a normal thing, and they're usually fine with that.
- [73:40]
A
All right, well, metformin ghosts, maybe. I got an idea for the COVID
- [73:44]
B
image here for the post hardcore band that I'm gonna start one of these days.
- [73:51]
A
Okay, what about GLP1 agonists, or are there any other older medications before we talk about GLP1 agonists that you think are worthwhile for this?
- [74:00]
F
Sure. Yeah. Well, okay, we'll save the GLPs for last. There's two.
- [74:04]
A
Two others.
- [74:06]
F
But one I like to talk about is pioglitazone. A lot of people may not like pioglitazone, but I love it. You know, it has a lot of benefits. But there are two major trials that show that pioglitazone reduces the risk for type 2 diabetes. One was an older trial called the Act now trial. And in that study, pioglitazone resulted in a 70% reduction in the risk of diabetes in patients with impaired glucose tolerance. And then there's another, more recent trial called the IRIS trial, which is for insulin resistance intervention after stroke. And in that study, not only did it show that pioglitazone reduced the risk of another stroke, but it reduced the risk of developing diabetes by about 52% over about a five year follow up. So both of these showed, you know, pioglitazone is obviously better than metformin as far as diabetes prevention. And, you know, the benefit of pioglitazone is that it's actually the only drug that we know of that works by lowering insulin resistance. Other drugs lower insulin resistance through weight loss, but this is the only one that directly lowers insulin resistance and it reduces the risk of a heart attack, of a stroke. It reduces inflammation, it reduces liver fat and mash hepatic steatosis and steatohepatitis. It improves the lipid panel, it reduces triglycerides, it raises hdl, and it's inexpensive. So it's really, it's a good drug. It does. You know, people complain about the risks, like weight gain, but really the weight gain is minimal. It's only 1 to 2% on the 15 milligram dose, which is what I usually use. The higher dose doses, the 45 milligram dose, you can get up to a 5% weight loss. But if you stick with the lower dose and if you combine it with metformin or SGLT2 inhibitors or GLP1 medications, there's no weight gain with pioglitazone. So don't worry about the weight. This other side effects edema. I just listened to your both of yours podcast on lower extremity edema, which I thought was fantastic. And I know you mentioned pyoglitazone, but it's definitely worse if you combine pyoglitazone and amlodipine, which I'm sure you know that that's a pretty bad combination. Also insulin, that's a, that can give you some edema, but it does. Pioglisone does not cause heart failure. It actually can improve heart failure. The problem is it can cause some fluid retention. And so if you have heart failure, if you have class three or four, New York Heart association class three or four, you don't want to use pioglitazone. There are concerns with bone loss. So if someone's like at risk for bone loss, postmenopausal may want to get a DEXA scan. The other concern people had was bladder cancer, but I think that's pretty much been discounted at this point that it doesn't cause bladder cancer.
- [77:18]
A
I think I'm going to have to relook at pioglitazone because there's very few patients in my panel that still take it. But I also heard Dr. DeFronzo, who you might know, talking about this recently, how thinking about like, he thinks that when patients are newly diagnosed with diabetes they should be put on multiple drug therapy right from the start and that, that over time you'll get better results. Rather than do like metformin, see if they fail, if they fail, add another drug. He's saying right from the start we should do be doing multiple therapies. And this was one of the ones he liked. And like you said, the weight gain, which is the big sticking point now with the newer drugs that, that help mitigate weight gain, you know, it might be back in play as part of like a multi drug therapy. So I think it's interesting.
- [78:09]
F
Yeah, yeah, that's true. Yeah. Dr. DeFronzo, he really likes that combo of pioglitazone, SGLT2 inhibitor and GLP1 receptor agonist. And you know, it makes sense that if you can preserve people's beta cells early on that they're going to have less severe diabetes as time goes on. So I like that too. It's just, it's an expensive combination of medicines. Except for the pioglitazone.
- [78:36]
A
Yeah.
- [78:37]
F
But yeah, I think it's a good approach.
- [78:41]
B
There was a little bit of enthusiasm for pioglitazone, I think in the setting of the metabolic dysfunction associated with steatotic liver disease, which is still a mouthful and they should still be ashamed of the name change. But I. And I'm with you, Matt. I feel like when we're talking about treatment options, it's almost like, well, of course you're not going to do a glitazone. It's almost sort of discounted out of hand. So it's just they've. But with both that one and even Tametformin, I think to some extent I feel like they've become the bridesmaids in the era of GLP1 agonists. Because if someone has all the dysmetabolic stuff and then also pre diabetes, I feel like that's the medication you're just fighting tooth and nail to get. For a bunch of reasons, I think people just forget that these medications even exist anymore as a way to prevent diabetes.
- [79:17]
F
Yes. I mean, it's always good to have options, that's for sure. And there's patients that can't take one or the other and it's just good to have something else.
- [79:26]
A
So is acarbose the other older drug that you wanted to mention?
- [79:30]
F
Sure, yeah. So acarbose. There is a study called the Stop Nidum trial, Niddm. And it showed that acarbose reduced the risk by about 25%. I rarely use acarbose. The side effects are intolerable GI side effects. And really 25% is not a great risk. So it's listed in the diet in the ACE algorithm. So I mention it, but it's. I don't use it very much.
- [80:00]
A
Yeah, it's like someone needs to figure out a way to make the side effects of that tolerable. But it's because it's like if you, if you took a carbos and had a pack of like Sour Patch Kids or something like that, would you just be like in agony for. I'm just trying to think of a high sugar. A high sugar delivery system.
- [80:16]
F
Yeah, yeah. I mean, it's, it's, it has limited use, but, you know, for interest sake, it's there. The one other drug I would mention though is phentermine topiramate, er, which is, you know, it's a weight, it's sold as a weight loss medication, but the average weight loss at the highest dose is 10 to 12%. So anything that gives you weight loss can be effective for diabetes prevention, especially if you're over that 7% weight loss. And so this is also a medication that's listed in the ACE algorithm for diabetes prevention.
- [80:48]
A
And we've been taught how to prescribe that sort of like, you know, phentermine separate from topiramate. And you kind of try to approximate what you'd be getting with the combination pill. And in that way it is actually very affordable compared to the brand, the branded drug, which is still, I think on patent or it still seems to be expensive the last few times I've looked it up.
- [81:09]
F
Yeah, I mean, it's definitely. You can use the components and get the same effect. Sometimes there's less tolerability because of it not being time released. Sometimes what I do is I start them off on the branded drug so they get used to it and then I switch into the generics after they've gotten used to it.
- [81:28]
A
Okay. All right, so should we get. I know we have limited time left. So the GLP1 agonists, I think what's been studied so far there are there certain agents. Have we got it up to tirzepatide yet? Being studied for this?
- [81:44]
F
Yeah. So there's. In general, the GLP medications reduce the risk of diabetes by 75 to 95%. So they're very effective in reducing diabetes. And we, you know, I'll just talk about some trials with liraglutide, semaglutide and tirzepatide. There was liraglutide. Paul, I know you like the names of trials and the liraglutide trial.
- [82:10]
A
Wow, you really did your homework. This is impressive.
- [82:14]
F
Well, the liraglutide is called the scale obesity and pre diabetes trial. So in the scale trial, there was a really good reduction in the risk of diabetes. Liraglutide group only had 2% of people converted to diabetes after two years and that was compared to 6% on the placebo. The semaglutide trials were called the step trials. And there were several step trials that looked at pre diabetes. But on average, that higher dose of semaglutide 2.4 milligram dose reduced the risk by about 85%. What was interesting in the step trials was the placebo group had a 50 to 70% reduction in diabetes risk as well. And that's because even in the placebo group they got intensive lifestyle intervention with counseling and diet and physical activity. So in all of these trials, there's a huge reduction in the placebo group as well. There's also another semaglutide trial called the select trial, which was a large cardiovascular trial that had 17,000 participants and that showed about 73% relative risk reduction over about a three year period. And then with tirzepatide, there was a trial called Surmount 1, which was one of the phase three trials for tirzepatide. And this was an analysis of over 1,000 patients. And this showed that tirzepatide reduced the risk of type 2 diabetes by about 94%. And with that one, the number needed to prevent one case of diabetes was nine. So that was a pretty good, pretty good result. To treat nine people and prevent one case of diabetes.
- [84:03]
A
Do we think this is all mitigated by weight loss or most of it is mitigated by weight loss? Like, I guess if you compare the group that wasn't on a GLP1 versus the group that was 30% difference or something you said.
- [84:15]
F
Yeah, I mean, a lot of it is weight loss, but you know, these drugs do lower glucose. I mean, they increase insulin secretion and they reduce glucagon secretion. And they're used, you know, they're also used as diabetes medications. But I think the primary thing that we're looking at is the weight loss itself.
- [84:35]
A
Yeah, we've talked a lot. We've covered so much. Malini, is there anything we're missing that you, that you had planned for us to cover today?
- [84:46]
E
Yeah, no, this has been absolutely fantastic. Thank you so much. One follow up question to the kind of GLP1 world data on kind of combinations of metformin and GLP1s compared to one alone, or is that data still to come?
- [85:05]
F
So that's a great question. And so we have that data for diabetes because Most of the GLP1 trials with diabetes, the patients are either on background metformin therapy or they're on it in the placebo group. But for these pre diabetes studies, they are not allowed in the study if they're taking metformin. So they can be put on metformin if they develop diabetes in the study, but that was obviously only a small percentage of people, so we don't have good data in that way. However, that's what I do in my practice. Every day I combine GLP1s and metformin in patients with prediabetes. Sometimes it's about tolerability because they have overlapping side effects. Sometimes that can be an issue. But I think it's a pretty good way to go, especially if your patient is a maximalist.
- [86:01]
A
Okay. And you're targeting both weight loss for a lot of these. The reason to combine the two because, I mean, it sounds like GLP1s alone would work really well, is the combination just you get better weight Loss, just smoother glucose control or.
- [86:18]
F
Yeah, I mean, all of the above. And just some patients don't respond as well as others. And you add the metformin and I'd say that's probably not, that's outside of the guidelines, but it's something that I do that I find effective, especially in a patient that's, you know, not responding as well as you'd like. You add something and they do a little better. But, you know, it's not just for their blood sugar, it's for all the other. You know, we talked about the complication centric approach to treating prediabetes. So we want to reduce their cardiovascular risk. They want to help their kidney and their liver. And if they have sleep apnea, we're going to help their sleep apnea. If they have arthritis, it's going to help their arthritis. And so it's really like treating the whole patient with these medications.
- [87:02]
A
Yeah. Well, now I'm thinking I might pioglitazone 15 milligrams with a GLP1 if the patient gets, can get it. If they have like MASLD and they have pre diabetes. And, you know, these would all be things that I'd be thinking about. So lots of options here. Well, I think, Paul, are we ready for take home points, Paul, or you have other stuff you want to ask?
- [87:28]
B
I think so. I mean, I think this kind of touches on the broader question. Is your approach just to follow up in general for these patients, like, how often are you seeing them and how often are you repeating the A1C? And it sounds like focusing more on the cardiometabolic stuff, but at least in terms of lab parameters and just sort of the practicalities of office visits, I feel like this is something that is often like, oh, phew, one less thing I have to worry about because they don't have diabetes and you sort of park it until next year. But for you, for someone who worries about this stuff professionally, what does the interval look like and how do you think about following up with these patients?
- [87:59]
F
Well, if you screen them and they don't have pre diabetes, the recommendation is to screen every three years, which I think is kind of long, and I'll usually do it more frequently. I usually see my patients at least once a year. So that's what I do. But for patients that already have prediabetes, I'm going to, I'm going to recheck their A1C at least once a year. And usually more than once a year, they want that feedback. They want to see if they're making those lifestyle changes, they want to see the improvement and so it gives them that positive feedback to keep going. It gets them motivated. So I guess I'm a maximalist as far as checking glucose and A1C because I just find it to be helpful and not that difficult to do.
- [88:45]
A
Yeah, because you do find that patient once in a While where their A1C was 6% and then you check it a year later and it's 9% or even it's gone double digits on you. So the more frequent checking, if the patient's game, it helps. And I think just the accountability, seeing them more frequently helps them with their lifestyle changes too.
- [89:04]
F
Absolutely, that's a really good point. I mean that's like the primary factor that determines how well someone does on some of these diets is if the frequency that you see them back.
- [89:17]
A
Okay, well let's go to take home points and we're also going to give you a chance to plug anything but take home points. First, what are some important things you want people to remember from this conversation?
- [89:29]
F
Okay, so the first one is I want everybody to remember that 1 in 3 adults or more than 1 in 3 adults in the US have prediabetes. It's extremely prevalent, but most people don't know they have it. So we need to do the screening. My second point is that not all prediabetes is from insulin resistance, although insulin resistance is the most common cause. Think about atypical prediabetes. So think about pre type 1 or LADA. Think about pancreatic diabetes. Think about Cushing's syndrome and acromegaly. The next point is about treatments. Remember, lifestyle and a 7% weight loss can reduce diabetes by about 60%. Metformin works best if you have a BMI over 35 or a family history of gestational diabetes. And the GLP medications reduce the risk of diabetes by 75 to 95%. And then my final take home point I want everybody to think about is not to have a purely glucocentric view of prediabetes and to focus on a complication centric view looking at total cardiometabolic risk.
- [90:43]
A
Love it. And would you like to plug anything? Maybe an upcoming meeting, maybe society or organization you're a part of?
- [90:52]
F
Well, yeah, I guess I would since I'm president of ace. I guess I have to plug ace, the American association of of Clinical Endocrinology. And you know what I would say is I've been involved with ACE for like 17 years and I've seen a lot of changes, but we have changed the organization to become much more inclusive and we actually changed the name of the organization from Endocrinologists to Endocrinology. And so we are open to internal medicine, family practice, primary care, advanced care providers. And so I would invite everybody to check out our website, ace.com, our educational offerings, our CME, our programs. Our annual meeting is coming up. It's in Orlando this year, May 15th through 17th. So that should be a great meeting if anybody's in the area. So I just invite everybody to just check out ace.
- [91:46]
A
Yeah, I've been to the meeting before. It was a really great time and so much great stuff and actually like a lot has changed since then too. So I think I need to get to another ACE meeting. I took this year off from conferences, but maybe next, maybe next year. Scott, thank you so much. This was really fantastic. Definitely very high yield. It's going to be hugely helpful to the audience. So thanks for all your time.
- [92:11]
F
Thank you.
- [92:17]
B
This has been another episode of the Curbsiders, bringing you a little knowledge food
- [92:20]
D
for your brain hole.
- [92:21]
E
Yummy.
- [92:23]
A
See?
- [92:24]
B
So much better. Matt, why can't you be more like Melanie? Still hungry for more? Join our Patreon and get all of our episodes, ad free monthly bonus episodes@patreon.com curbsiders. You can find our show notes at the curbsiders.com and sign up for our mailing list to get our weekly show notes in your inbox. This includes our Curbsiders Digest, which recaps the latest practice, changing articles, guidelines and news in internal medicine.
- [92:42]
A
And we're committed to high value practices, changing knowledge and we want your feedback. So email us@askcurbsidersgmail.com and a reminder that this and most episodes are available for CME credit for all health professionals through VCU healthurbsiders.vcuhealth.org Special thanks to our writer and producer for this episode, Dr. Malini Gandhi, and to our whole Curbsiders team. Our technical production is done by Podpaste. Elizabeth Proto does our social media. Jen Watto runs our Patreon, Kristen the Chew Manchu moderates our discord. Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Watto.
- [93:17]
E
I've been Malini Ganby and as always,
- [93:19]
B
our main doctor, Paul Nelson Williams. Thank you and goodbye.
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F
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