Good afternoon, everyone, and welcome to session 16, Lipid Management in Patients with Endocrine Disorders, the Endocrine Society's Clinical Practice Guideline. My name is Patrick McBride. I'm an emeritus professor of medicine at the University of Wisconsin School of Medicine and Public Health. And I'm excited to share with you today with a bunch of our panelists. And you can find our guideline and associated resources by going to the Endocrine Society's page or to the link you see on our page here today. Next slide. I'm joined by a number of distinguished panelists today who you'll all meet. And these are members of the Guideline Writing Committee, Dr. Newman, Dr. Goldberg, Dr. Chait, and others. But you can see the complete list on this slide here today. Next slide, please. My distinguished panel is Dr. Connie Newman, an adjunct professor from the New York University Grossman School of Medicine, Dr. Ira Goldberg, a professor also at the New York University Grossman School of Medicine, Dr. Alan Chait, professor emeritus from the University of Washington in Seattle, and Dr. Lisa Tanik, professor at the University of Kentucky in Lexington, Kentucky. Next slide, please. This is a list of the disclosures of our panel members today for your reference. Next slide, please. Our session today will be conducted in a way that I think you'll find interactive and really relevant both to the guideline and to your practice. We're first gonna cover an overall review of the guideline, and then we'll have three patient presentations. Common disorders that you see in your practice at least every week, if not every day, a patient with type 2 diabetes, a patient with severe hypertriglyceridemia, and a patient with subclinical hypothyroidism. You'll have an opportunity for review and discussion of each of these patients. Next slide. I'd like to take this opportunity to have Dr. Newman, an adjunct professor from New York University, present an overview of the guidelines. Dr. Newman. Thank you very much. First, I'd like to thank the Endocrine Society for supporting the development of this guideline. I served as the chair of the guideline writing committee, and I was fortunate to work with 10 other people who were content experts in lipid disorders, endocrinology, diabetes, cardiology, and clinical epidemiology. We commissioned two systematic reviews for this guideline, one on the effect of treatment of thyroid disease on serum lipids, and the other on the effect of weight loss on serum lipids, and these informed the recommendations in our guideline. Next slide, please. The reason that we wrote this guideline is because other guidelines of cholesterol management did not include patients with endocrine disorders, except for the patients with diabetes. One of our main objectives was to assess the lipid profile in patients with endocrine disorders, and to determine whether treatment of the endocrine disease would improve the lipid profile and or reduce cardiovascular disease risk. Next slide. The key points of our guideline are shown on this slide and the next one. It is critical to obtain a lipid panel and to also evaluate cardiovascular risk factors in adults with endocrine diseases. For patients with type 2 diabetes and risk factors for cardiovascular disease, it is important to start statins earlier than the age of 40 if that seems appropriate. For patients with type 1 diabetes who have obesity, vascular complications, or a 20-year history of type 1 diabetes, it is important to consider statin therapy at a younger age. Another key point was to rule out hypothyroidism before treatment with lipid-lowering medications, and in patients with hypothyroidism, reevaluate the lipid profile when the patient has thyroid hormone levels in the normal range. Next slide. Next slide. We recommend monitoring the lipid profile in patients with Cushing's syndrome and to consider statin treatment in addition to lifestyle modifications if Cushing's syndrome persists after treatment. In postmenopausal women, we recommend statins rather than hormone therapy to treat high cholesterol or triglycerides. And also, it is important to evaluate and treat lipids and other cardiovascular disease risk factors in women who enter menopause early before the age of 40 or 45 because these women have enhanced cardiovascular disease risk. Next slide. I now like to turn the session over to Dr. McBride. At this point, we are going to discuss patient cases, panel discussion, and have time for audience questions. Thank you very much, Dr. Newman, for a nice overview of our guidelines. Next slide. At this point, I'm going to introduce Dr. Lisa Tanik to present our first patient case, a patient with type 2 diabetes. Dr. Tanik. Thank you, Dr. McBride. So we're going to start with the first case, which is a 32-year-old woman presenting as a new patient to you. Her history is significant for gestational diabetes at her only pregnancy at age 22. She was then followed by a primary care provider who was watching progressive impaired fasting glucose and she finally reached the diagnosis of type 2 diabetes two years ago at age 30. Her history is pertinent also for hypertension on two medications. She does not smoke, but there is a family history of both type 2 diabetes in her parents and her father who had cardiovascular bypass surgery at age 48. Next slide. Her current medications at your assessment are metformin, gilagoside, and Atlantis. Her current hemoglobin A1C is 7.9%. And on review, it's not been higher than 8.6% since her diagnosis. On exam, she is obese, BMI is 36, and she has acanthosis nigrogans. Her blood pressure is reasonably well controlled on the two medications. And her fasting lipid panel is as shown. Total cholesterol is 212, HDL cholesterol is 32, LDL cholesterol is 124, and triglycerides are 278. Next slide. So this is now a chance to get the audience poll and how would you respond? So the question is, what is the next best step? A, would you do a high intensity statin? B, would you start a moderate intensity statin? C, would you wait until age 40 to start a statin? D, would you assess her atherosclerotic cardiovascular risk and start a statin only if her 10-year risk is greater than 7.5%? Or E, would you add prandial insulin? And if we're ready, we'll look at how the audience has responded. All right. So this is, the answer that we recommend in our guidelines is to start a high intensity statin now, although it looked like most individuals wanted to start a moderate intensity statin now. So here I'd like to invite our panelists to join me in discussing this particular question. So some of us would agree with the audience response, especially if our goal is the reduction of LDL. And in fact, if we're not reduced enough, we can make a good argument that using even a low dose or a low intensity statin, 10 milligrams of suvastatin or atorvastatin and adding a zetamine to it will lower LDL as much as raising that statin dose up to fourfold. And so, you know, low dose plus a zetamine is probably better than high intensity statin. Dr. Goldberg, thank you for saying that, but I just want to remind everyone here that we have much more randomized clinical trial data looking at cardiovascular outcomes with statins, which is why we recommend statins first as the first line therapy for treatment of hypercholesterolemia as adjunct to diet. We do have some data with statins and a zetamine, but not as much. What about the issue of her age? I'm curious to see how my colleagues feel about the age. This case I purposely made fairly young, she's 32 years old. Dr. Tanik, that's a really important question because some of the audience has concerns about the risk of pregnancy in this particular patient and the risk in this age group for females, if you discuss that. So I purposely selected a patient who's young because of that exact issue. And I will say, I think the data suggests that we tend to undertreat women. And what we know about type 2 diabetes is it seems to remove or reduce the female premenopausal protection against cardiovascular disease. And I think we're all as providers so concerned about the risk of statins in pregnancy that we tend not to treat women of reproductive age. Whereas the part that I always find remarkable is we'll use lisinopril and other much more clearly high-risk pregnancy drugs in the same age population. And the data with pregnancy and statins, it's still not recommended, but it does not, in the few cases that have been reported of statins exposure in early pregnancy, there does not seem to be any increased adverse risks for the baby. So just the fact that this woman is a younger woman with her other risk factors of a family history and hypertension, I do strongly feel that she is a candidate for therapy and that we should be treating her. But we should use contraception. I'll ask the patient to use contraception. If she's actively trying to get pregnant, that may be a reason to discontinue for a while. Absolutely. And, you know, can you discuss a bit about the evidence in patients with diabetes, especially younger patients with type 2 diabetes, specifically with higher dose or more intense therapy? Yeah, so this is the biggest challenge, of course, is most of the studies wanted to enroll patients at higher risk, because the studies have five term outlines. So most of the studies enrolled in older individuals. Really, I think we need to reach into some of the other literature, such as patients with familial hypercholesterolemia syndromes, where there has been shown no increased adverse effects of statins at younger age, even into children with some of these populations, and no increased risk for other developmental factors, including, and this is not a pediatric case, but including growth and development. So I think we are extrapolating from the literature, and that's obviously one of the more controversial facets of this recommendation. And certainly we have some data from diabetes trials. Isn't that correct? Mostly, we have some data from diabetes trials, but it's mostly retrospective and database studies, where we can look and see what's happened in real life studies. There's very few randomized trials that have looked at this. And certainly at younger individuals, really don't have any data looking at long-term cardiovascular outcomes. Those studies tend to be done in older individuals. But I'll remind the audience that there is such a robust literature demonstrating that patients with diabetes have a significant risk reduction for cardiovascular events with statins. And so I think that's why the recommendation is to use statins, even in younger individuals who have other risk factors for cardiovascular disease. Is there any other panelists that has a comment to make about data regarding type 2 diabetes patients and the use of LDL lowering therapy? You know, I think it's actually worth noting that actually in some of the early trials, and even some of the later trials, actually almost all the effects of statins are seen in the groups with diabetes. In fact, some of the early trials, if you take out the patients with diabetes, it's almost hard to show an effect of statins itself, because there's such a high risk group. Well, even in the IMPREVA trial with ezetimibe, had a major group that benefited with the people with diabetes. So I think collectively, that's why the writing committee did recommend that we consider using statins in patients with diabetes with other cardiovascular risk factors. Great, thank you very much. I think that's a great discussion. Any other comments? Let's move on to the next set of questions. All right, so in follow-up with this patient, you decided to start a torvastatin 40 milligrams daily. And after three months, her repeat fasting blood tests are shown here. Her total cholesterol has now dropped to 149. Her HDL cholesterol has bumped up a little bit to 34. Her LDL cholesterol has dropped to 69, and her drugless range are 227. Her hemoglobin A1C remains 7.6%. Next slide, please. And so we don't have time to do another audience response poll here, but the question that we would pose here is, is additional therapy needed to reduce her cardiovascular risk? And you can see the answer options that we recommend, including no changes, adding icosapentaenoic acid ethyl ester, adding a phenofibrate, adding prandial insulin, or adding pyoglitazone. Next slide. And based on the guidelines and evidence, we suggest that you would consider this patient for adding icosapentaenoic acid ethyl ester. Next slide. So the key recommendations for type 2 diabetes that we highlight in this guideline is to consider statin therapy for adults with type 2 diabetes and other cardiovascular risk factors in order to reduce cardiovascular risk. Next slide. In adults with type 2 diabetes and other cardiovascular risk factors, we suggest lowering LDL cholesterol to target less than 70 mgs per deciliter. Next slide. And in adults with type 2 diabetes on a statin who are at their LDL goal, but have residual triglycerides elevated over 150 mg per deciliter, as well as having two other risk factors or risk enhancing factors, this is where we suggest adding icosapentaenoic acid ethyl ester to reduce cardiovascular risk. Next slide. It's time for us to answer a number of questions from the audience now. And we have a number of excellent questions some of which you answered, but I wanna emphasize that one of the important points that you made was with high intensity statin, we wanna get to a goal of less than 70 in a high risk patient. And a high risk patient is defined by type 2 diabetes here. Would you comment further on the specific reason that this patient is being treated at a younger age? You know, the question is, is it a risk factor? Is it a risk factor to be treated at a younger age? You know, the question is, is it the combination of family history and type 2 diabetes, or just the type 2 diabetes history alone that really indicates treatment here? Yeah, so this is one of the art of medicine questions. And I think that's a really good question. You know, in this woman who's only had diabetes based on the history I provided, she's only had diabetes for two years. We don't have a long unknown pre-existing duration diabetes. And so, collectively, it's that combination of risk factors that we feel puts her at increased risk. And as the audience knows, the risk calculators generally start at age 40. And so, we can't actually use any of the available risk calculators to calculate her risk. But I personally feel that waiting another eight years just so she hits that magic age of 40 is actually withholding therapy that could help her have enjoyable quality and quantity of life in her later years. So, do you recommend the use of a risk calculator in a patient with type 2 diabetes or go straight to treatment? Yeah, so another good question. I would argue that for most of the patients with type 2 diabetes, you do not need a risk calculator. And again, it's taking into consideration the presence of other risk factors and perhaps the duration of diabetes, the control of diabetes, if known, and the presence of other diabetes complications collectively should provide most providers with enough evidence to support use of a statin. And a number of questions came up regarding the use of other measures to look at risk, such as coronary artery calcium. So, in a younger female with the use of radiation, would you recommend any other measures or is her diabetes alone enough to indicate treatment based on our guidelines and evidence? So, I think that's a great question. I would argue that in the case I presented, who is a patient with type 2 diabetes and hypertension and a premature family history, I don't really see that there's any cost effectiveness for additional therapy. However, if you didn't have those other risk factors, then that's something you might consider. And I'm gonna see if any of my panelists wanna jump in and join me on that discussion. Lisa, you forgot out an additional risk factor that you mentioned and that she's overweight. So, that again magnifies the issue. The time for measuring coronary artery calcium, as far as I'm concerned, is it's gonna, if it's going to help you make a decision about treatment. And I think in this case, you've made a very poignant argument that the patient needs statins. If you were fence-sitting and didn't know whether or not to treat, that's, I think, the time to measure a coronary artery calcium score. That's a very important point, Dr. Cheat. You know, we use lab tests like that to really help us make a decision, but the decision is already clear based on that. And you also brought up the point about a question that somebody raised is, what is a risk-enhancing factor? And you brought up the point of obesity, but are overweight. And there's also this issue of family history. So, Dr. Tanik, do you wanna say something about risk-enhancing factors related to the guideline? Yes, thank you. So, the other comment I'd make about risk-enhancing factors, she has a history of gestational diabetes, and there's an emergent literature looking at the history of complications during pregnancy as a risk factor for future cardiovascular events. And so, I would add that that's another risk-enhancing factor in this patient. So, just quickly, I wanna mention that in the guideline, there's a separate discussion of type 1 diabetes, but that came up in the discussion with the audience about is treatment similar based on patients with type 1 diabetes and type 2 diabetes? Would you like to just discuss that a little bit while we're in this discussion area? Yeah, absolutely. So, the writing group actually had a lot of fun looking through the literature on type 1 diabetes. There's very few studies that actually looked at type 1 diabetes specifically. There are some retrospective chart review studies and database studies. But in the subgroup analysis of studies that included patients with diabetes and did report on type 1 versus type 2, first, it appears that type 1 patients have the exact same benefit of statins in terms of cardiovascular outcomes. Secondly, there is a strong and growing literature looking that even though type 1 diabetes may onset at a much younger age, that collectively, the years of diabetes plus the presence of other microvascular complications indicate risk. And so, in the guideline, we actually do recommend consideration of statin therapy for patients with type 1 diabetes after 20 years duration or the presence of other risk factors. Great, thank you. I might add that many of these patients with type 1 in addition have some features of the metabolic syndrome, which again would be an additional risk enhancing factor in patients with type 1 diabetes. And this again would provide rationale for wanting to treat them earlier. You know, that's a really good point to make about not just medication treatment we're talking about, but also lifestyle treatment and its risk enhancing factors that are very important risk enhancing factor that both you and Dr. Tanik brought up. And that relates to a number of questions that came up related to the other part of the lipoprotein panel that is part of this patient's spectrum, and that's the triglycerides and the appropriate choice for management beyond lifestyle treatment for a patient like this. A number of questions were why that choice, why not things like phenofibrate, why not use pioglitazone or other forms of treatment to bring down the triglyceride level? Why the choices that you made in this particular case? So I think that's another topic that we can probably debate for much more time than we have available. But based on clinical trial evidence with the reduced trial, there is evidence for eicosapentaenoic acid, ethyl ester. I think there is evidence to consider a fibrate. I think the pioglitazone option is an interesting one. It's very much fallen out of favor, although it can reduce triglycerides and we do have cardiovascular outcome studies with it. And we didn't even get into some of the diabetes specific medications with cardiovascular benefits that we can also consider for this therapy. So I would say that the good news in 2021 is we have a large array of options to try to reduce the cardiovascular risk for our high-risk patients. Great, thank you so much. It's time for us to move on to the next patient presentation but I really wanna thank the audience for some great questions and I wanna keep us on time. So we'll move on to the next case. So patient number two is a patient with severe hypertriglyceridemia and to present the patient is Dr. Alan Chait from the University of Washington. Dr. Chait. Thank you, Dr. Fry. Can we have the next slide, please? So this patient is a 52-year-old female admitted to the hospital with acute pancreatitis. She was previously healthy other than for mild hypertension, well-controlled on thiazide. She drinks a glass of wine every night but it was her birthday just before this onset of the pancreatitis and on her birthday, she consumed at least three glasses of wine. Her BMI is 27.6. She had her onset of a menopause a year previously and since then, her weight has increased. She's had some night sweats and difficulty sleeping and her lipid panel from two years previously is shown over here. The total cholesterol was 199, triglycerides 159, an LDL cholesterol 121 and HDL cholesterol of 46. Next slide, please. Interestingly, her father and older brother both had myocardial infarctions in their 50s. Her physical examination was unremarkable other than for a blood pressure of 169 over 92, a low grade fever and a marked upper abdominal tenderness as one might expect with acute pancreatitis. Her labs were quite remarkable. Her triglycerides now were nearly 2,700. Her total cholesterol was 312. She had a very low HDL cholesterol of 22. And in addition, she now had a blood glucose of 203 and a hemoglobin A1C of 8.2. Next slide, please. So this is the poll for the audience. What is the likely cause of the dramatic increase in her triglyceride levels since it was measured two years previously? New onset diabetes, an increase in alcohol consumption the previous night, her birthday, her weight gain since the onset of her menopause or all of the above? So let's see what the audience's response is. Hmm, okay, most people think all of the above. The answer that the group came up with was new onset diabetes. So let's get the panel back because this is going to be obviously a good one for discussion. Yes, thank you, Dr. Chait. It's a fascinating patient and one, of course, that's really high risk. Can you explain to the audience how great the risk is for risks of pancreatitis and severe illness? Yeah, I'm not sure I fully understand your question, Dr. McBride, but if I understand it correctly, it really relates to people who have very high triglycerides, above 1,500 to 2,000, and the risk of pancreatitis. Very high triglycerides is about the third commonest cause of pancreatitis after alcohol and gallstones. And the interesting thing is the outcomes with triglyceride-induced pancreatitis are actually worse than acute pancreatitis from other causes. This goes as far as sort of mortality and morbidity outcomes, and this is not well appreciated. It's not even included in, triglycerides are not included in some of the Apache scores. So I think triglyceride-induced pancreatitis is an extremely serious condition. But I think we need to get back to the question that organs all seem to say all of the above, and we said diabetes, the new-onset diabetes, is the thing that precipitates this. And I'd like to see what other members of the panel think about this, because I felt fairly strongly that even though all of the above were small contributing factors, the fact that she'd moved from non-diabetes to a diabetic state, in addition to what we believe would be a genetic predisposition, is what facilitated the onset of the pancreatitis and the very high triglyceride levels. Thank you. And you addressed exactly what I was trying to get at. I wanted to make sure that everyone understood how severe an issue this is. This is a severe illness. This pancreatitis caused by this can be quite severe. The issue is also the confluence of risk that she developed. And you mentioned the family history, so there's a genetic component. And then the new-onset of diabetes really tips the scales here. So can you talk about what the new-onset of diabetes did from a metabolic point of view related to her predisposing genetic risk? Yeah, well, if you remember correctly, she started with a borderline elevated triglyceride of 159, presumably on a genetic basis. So when you get new-onset diabetes, you have a number of metabolic changes, including a reduced clearance of triglycerides through lipoprotein lipase. You also have an increased production of triglycerides, partly due to the increased level of free fatty acids that circulate in diabetes. So the net effect is you're now going to have an increased input of triglyceride into plasma, saturating the removal systems for triglycerides. When you get above 500 to 700 milligrams per deciliter, you saturate triglyceride removal systems, and then any further input, be it endogenous, such as from the diabetes, and then exogenous from your diet, is going to not be able to remove, and therefore will lead to these very high levels, as we saw in this patient. But certainly the other things that happened, you know, the alcohol consumption and other things did contribute. There's no question about it. And weight gain, they certainly would contribute. But without the diabetes, it probably would not have been enough. It's the diabetes, I think, that set the stage higher to reach the saturation level. And certainly three drinks the night before may have contributed, but it wouldn't have done it by itself. Great. Other comments from the panel? I think the other part, Alan, is she clearly had some underlying issue, even the triglycerides of 150 are somewhat elevated. And then it's, since we don't have her without the alcohol and the other things, we don't really know, but I saw a patient about six months ago who had Brewer's syndrome, who, when he ate a bagel, his triglycerides would go from 150 to 800. And that's presumably from the alcohol. Yeah, and a very informed audience member brought up the thiazide as well, so. Yeah, well, again, the thiazides are very important here in that, even though by itself, it would probably not be enough, but again, in combination with everything else, I think it is a factor. And this brings up the point that when we're trying to treat hypertension, and this will come back when we proceed with the case a little bit further, when we treat hypertension in a patient who already has a baseline elevation of triglycerides, it is best to try and choose a lipid-neutral antihypertensive, such as a calcium channel blocker, an ACE inhibitor, or an angiotensin receptor blocker. And a thiazide, yes, could be a contributing factor in a patient like this. And would we want to make sure that this patient is, of course, hospitalized and then put into a fast for a period of time? Yes, indeed. The best way of bringing down triglycerides in a patient with acute pancreatitis due to triglycerides is just get them into the hospital, put them on NPO, no calories in, and make sure that if you're going to use any supplemental nutrition, you don't use a lipid emulsion, which essentially is triglycerides and acts like a chylomicron and will increase the triglycerides even further. So just the catabolic state that occurs in a hospital when patients are admitted with acute pancreatitis and nothing by mouth, this will bring the triglycerides down rapidly and there's seldom a need for plasmapheresis or anything beyond that. Great. Let's move on to your next slide so we can move into the treatment phase of it. Sure. Okay. Great. Okay, so the question here is whether her positive family history of early onset coronary disease and a triglyceride level of 159 two years previously suggests that her offspring are at increased risk of developing pancreatitis. Being female, the risk of developing premature cardiovascular disease is low. A baseline genetic form of hypertriglyceridemia played an important role in the development of the triglyceride-induced pancreatitis or none of the above. So as we've already discussed and shown on the next slide, the baseline genetic form of hypertriglyceridemia clearly played an important role in this case. What we discovered many years ago is when we studied patients whose triglycerides were above 2,000, what we found is that when they had family members to study, there was about a 95% prevalence of high triglycerides in the family members. But the triglyceride levels in the family members were considerably lower than those in the index patients with very high triglycerides. What we then went on to show is that when we looked for secondary causes of high triglycerides in the index patients with triglycerides above 2,000, almost all of them had additional things such as diabetes, oftentimes undiagnosed or not adequately treated, or drugs such as diuretics, beta blockers and similar type of things. We think the genetics is very important over here. Can we move on to the next slide, please? With time, she improved the concept of management for the pancreatitis as we discussed, and treatment of the newly diagnosed diabetes brought her triglycerides down, and she was discharged from the hospital after a week. Her triglycerides at the time of discharge had come down from nearly 3,000 to 288. When re-evaluated four weeks later, she had lost six pounds. She had stopped drinking alcohol completely, but her blood pressure remained elevated at 151.91. She continued to be bothered by menopausal symptoms, and her triglycerides had crept up slightly to 325. Next slide, please. The question here is what the most effective way of preventing recurrent episodes of pancreatitis would be. Would it be to lose a few more times, a few more pounds and maintain your weight loss, adding a beta blocker for residual hypertension, adding a statin, or treating her diabetes and adding a phenofibrate? The correct answer, as shown on the next slide, is the bottom line, and that is treating her diabetes and adding a fibrate. And the importance here is that this will lower and keep her triglycerides down and prevent any further episodes of pancreatitis. Adding a statin would be important to prevent cardiovascular disease, for which she's also at risk, but that wouldn't help prevent the recurrent pancreatitis. And adding a beta blocker for residual hypertension would be contraindicated because it actually increases triglycerides further. So, I believe that's the last slide of these, except for the recommendations. In adults with fostering triglycerides above 500, we recommend pharmacological treatment as an adjunct to diet and exercise to prevent pancreatitis, particularly recurrent pancreatitis. In adults with type 2 diabetes and other cardiovascular risk factors, we suggest lowering LDL to achieve a goal of less than 70 for LDL cholesterol in order to reduce cardiovascular risk. Okay, thank you. Great. Thank you very much for that robust discussion. At this time, we're going to encourage questions from the audience, and there is a number of very interesting questions. One of the questions relates to the use of omega-3 fatty acids in this condition and whether or not they'd be indicated, and if they are, what dose and which specific types of omega-3s? Okay. Well, certainly high-dose omega-3 fatty acids are good for reducing triglycerides, but not as good as fibrates. So, always in this situation, my choice would be to use a fibrate rather than an omega-3 fatty acid. Nonetheless, omega-3 fatty acids can be used, and if you can't get your triglycerides down sufficiently with lifestyle measures, treatment of diabetes, and a fibrate, you can certainly add an omega-3 to this. The question is which omega-3? I think any of the non-supplemental ones and the ones that actually require a prescription would be the appropriate ones, because at least you know what's in it, you know the dose is correct, and high-dose is good in this situation. I don't know if anybody else has anything to add, particularly related to the difference between EPA, eicosapentaenoic acid, and DHA, the eicosahexaenoic acid, but it seems to be that EPA may be important for cardiovascular protection, but here we're talking about prevention of pancreatitis. Dr. Chang, just one comment about the phenol fibrate that I remind our fellows is that it also is protective against retinopathy, for example, in the ACCORD trial. Yeah, Dr. Goldberg, that's a great point, and especially if you do have retinopathy, we deal with this in the guidelines that patients with retinopathy and diabetes ought to be on a fibrate. There's sufficient evidence to support that recommendation. Some questions came up about phenofibrate and fibrates being more indicated over a statin. Can you discuss the reasons for that, and then maybe something about the interaction potential between phenofibrate and the statin class? So, in terms of prevention of pancreatitis, fibrates clearly reduce triglycerides to a far, far greater extent than to statins. So, in terms of pancreatitis prevention, fibrates and triglyceride-lowering drugs are the treatment of choice, but remember that this patient also has a family history of cardiovascular disease. She has diabetes. She's a great risk of cardiovascular disease in addition to pancreatitis. Therefore, once one has dealt with the emergency and got her triglycerides down, the next approach would be to then try and prevent cardiovascular disease, and I would then add a statin, but for that indication rather than for pancreatitis prevention. In terms of interactions, Dr. Newman, this is your area of expertise. Why don't you make a comment about this? Thank you. Yes, statins are contraindicated with fibrates. That is in many of the statin labels, but that data really comes from an interaction of gemfibrozil with statins, and we have a lot of data now showing that it is relatively safe to use phenofibrate in combination with a statin, but for gemfibrozil, there would be an increased risk of myopathy, meaning muscle symptoms and very high increases in CK, and in fact, that was the reason that one of the other earlier statins, Cerevastatin, was taken off the market because of this interaction with Cerevastatin and gemfibrozil. Great. Thank you. Just sorry to cut you off there, Dr. Newman. We just have a few seconds remaining, and there's been a number of questions asking about insulin in the acute treatment of a patient like this, so in just a few seconds, can you comment about that, please? Yeah. There's no good trials to show that it actually adds any benefit. If the patient had kind of microanemia-induced pancreatitis due to anything other than diabetes, the danger of using insulin infusions is that you can cause hypoglycemia. In a patient like this with diabetes, I think it is reasonable to use insulin, although there's no evidence that I know of that adding insulin actually will do any benefit and bring the triglycerides down more rapidly. Okay, great. Thank you so much for that excellent case. It's time for us to move on now. And for our third and final patient presentation, we're going to discuss a patient with subclinical hypothyroidism, and I'm honored to present Dr. Ira Goldberg, who's a professor at New York University, to present our patient. Thank you, Dr. McBride. So this is a situation that our panel spent a lot of time thinking about and discussing. So the case is a 62-year-old woman with no cardiovascular history. She comes to your office complaining of fatigue and weight gain. Her father had cardiovascular disease and had a bypass at age 55, so premature cardiovascular disease, but he was overweight, had type 2 diabetes, and was a cigarette smoker. She denies recent weight changes but states that she's gained 18 pounds in the last 10 years. So since her menopause, she denies changes in hair, skin, GI, response to hot or cold weather. Her blood pressure was 130 over 80. Her pulse is 80. BMI is somewhat up, 27. And the remainder of her physical exam was unremarkable. Next slide. So this is her laboratory. So her free T4 is within normal range, although on the lower side. Her TSH is 8.5, with a normal up to 4.5. Hemoglobin A1c is normal. Her total cholesterol is 250, triglyceride 125, HDL 45, and LDL elevated at 180. Her LP little a is not elevated, so it's not an extra risk. If you ran her through two different profiles, either the Reynolds score profile or the AHA ACC, she's actually at intermediate risk from her age and this lipid profile. Next slide. So here's the question. Would you take this lady, and the next thing you would do is put her on thyroid hormone replacement? I'll give you a couple of minutes, a couple of seconds, actually. So no, 28%. Yes, 72%. So this is how our panel came up with it. So yes, in most lipid clinics, she would probably be started on a thyroid replacement for an elevated TSH, and this will be our first panel discussion. So Dr. Goldberg, if I can jump in, this is a very controversial issue, because in the thyroid literature, there's actually not a lot of evidence that treating subclinical hypothyroidism with a TSH less than 10 and a normal free T4 has any benefit on quality of life on symptoms. And the other part of that is there's also pretty strong literature that many of these patients actually revert to euthyroidism in subsequent labs without treatment. So can you discuss that, how the lipid panel affects your management combined with that data? Yeah. Well, so one is a little bit of a rigor. Of course, you would repeat this to make sure that the TSH elevation occurred on the second the second reading. But if it did, yes, you would say she had subclinical hypothyroidism. You might say, well, she's older and TSH goes up with age. However, in most lipid clinics, it's pretty clear that if you put her on some thyroid supplement, and this was reviewed by our panel, her LDL cholesterol would go down. There's also a sense that if her thyroid is a little higher, her metabolism of statin that you give her may be improved. And so you don't really want to be in the situation of having her have a muscle side effect with statin and then be in the situation where her TSH is still elevated. So I think most lipid clinics would do this. And it's pretty clear that the thyroid supplement would lower her LDL before we added anything else. I just wanted to add that we commissioned a systematic review of the effects of treating thyroid disease on lipids. And what we found in the studies that treated patients with subclinical hypothyroidism, there was a significant decrease in LDL cholesterol. So that is the basis for our recommendation in the guideline. Now, this decrease in LDL cholesterol with subclinical hypothyroidism is much less than what is seen with overt hypothyroidism when that's treated. So the endocrinologists are online. If you watch LDL cholesterols on your patients with Graves' disease and Hashimoto's disease, the changes are like 100%. LDL could drop in half when you treat hypothyroidism. It could double when you treat Graves' disease. Sorry, Dr. McBride. Yes, thanks for answering that. And what I was going to ask was, before we get to treatment, were there any further diagnostic workups beyond TSH that you would do, such as other thyroid testing, thyroid antibodies? Are there other screening tests that you might do around her cardiovascular disease risk that would change your management of this patient? Yes, there are. Those are the next questions. Uh-huh. Great. Okay. Is there anything else before we get to those next questions? Great. Let's just go on to the next questions then. That'll give us more time for discussion. So this is exactly the question that Dr. McBride asked. If and when you tested her for anti-TPO antibodies or you did an ultrasound and it was indicative of autoimmune disease, would that make a difference on the way you approach her? So this is not an obvious response, but hit the next one. And so I think most endocrinologists would feel this way, that if she had antibodies or a gland that looked autoimmune, it would give you some more confidence that what you were really doing is treating a diseased gland that over time would probably get worse, and that this wasn't just age-related increases in TSH. So next slide. So this is a second question of Dr. McBride. Would a coronary calcium score alter your approach to this patient? So she's intermediate risk by both Reynolds score and the ACCHA risk scores. So if we did a coronary calcium score, would it make a difference? So these are the obvious. If zero, it might make a difference. If zero, it might alter your LDL goal. If high, it would alter my LDL goal. And if over 100 or another high, it would alter my LDL and thyroid treatments. Okay. So in an intermediate patient like this, our guidelines and the ACCHA guidelines would recommend doing a coronary score. And if the score is high, meaning over 100, yes, it would alter your LDL goal. You would view this patient as having subclinical coronary artery disease, and your LDL goal for many people would be the same goal as somebody who already has disease, to try to lower her LDL to 70 or below. Actually, some people would also say, gee, you know, she has a high score. Maybe she should also be put on some low-dose aspirin, although that also is somewhat controversial. Next slide. So recommendations from our panel were that patients with subclinical hypothyroidism, not real hypothyroidism, but subclinical with TSH below 10 and associated hyperlipidemia, we suggest considering thyroxine treatment as a means to reduce her LDL levels. And we recommend this prior to putting her on statin therapy. Next slide. Our second recommendation is that with adults with endocrine disorders who are borderline or intermediate risk, you know, 5% to 10% or greater, especially if they have other risk factors and in whom the decision about statin treatment is uncertain, we suggest sending them for a coronary artery calcium score to inform shared decision making. Next slide. If there's not another panel discussion, I'll turn this back over to Dr. McBride. DR. MCBRIDE Great. Thank you. As you can see, there are a number of other very important and valuable topics in the guideline. And that includes type 1 diabetes, which we briefly discussed. Obesity is not only a contributing but important issue. Other endocrine issues related to the use of glucocorticoids and other endocrine problems, as you can see on this slide, a number of things that you're going to see in your clinical practice, probably as common as anything, the issues around menopause and hormonal replacement, which have come up in the Q&A and which I think we should discuss, hypogonadism and testosterone replacement and the abuse of that, which is a common issue now. And there have been questions around gender-affirming hormone therapy if we get time to discuss that. So, again, I encourage you strongly to both read the guideline and go to the journal, but it's a very easy guideline to access at the Endocrine Society website. So let's go to the Q&A right now and answer a number of important questions. I'd like to have our panelists join us. So could you talk a little bit, Dr. Goldberg, about the level of TSH or other thyroid studies that push you to the point of using thyroid replacing therapy? What kind of cutoffs or clinical acumen do you use to make that decision? Yeah, so it's not so clear. I think somebody who's above, you know, the normal of TSH on multiple measurements is somebody that we would view as having subclinical hypothyroidism. And, you know, this is somewhat of a controversial area, but I do think if they have evidence of a real autoimmune gland, that really pushes you to say, oh, this really makes sense to do. But it really is repetitive TSH levels above normal and high LDL, obviously. And a question has come up regarding the use of either or both. So if you get the significant reduction in LDL cholesterol that you've mentioned when you put the patient on levothyroxine, do you need the statin on top of that? And what are the reasons for using the concurrent therapy of both levothyroxine and a statin? And how does risk assessment enter into that equation? Yeah, so it depends where they go, you know. So the last ACC AHA guidelines, because they were written by epidemiologists, they kicked the can down the road and basically didn't set up guideline goals of what the therapy should be. But I think most people who run preventive cardiology clinics or lipid clinics think somewhat differently. So depending on whether your goal is an LDL below 100 or an LDL below 70, if you achieve it, you know, if you achieve it, however you achieve it, you've hit your goal, whether it's with statins or without statins. There are those who say, well, but the data is strongest with statins, and maybe there's something, you know, magical about LDL lowering with statins. And that, to be quite honest, is controversial. There was this idea around for more than a dozen years that there are pleiotrophic effects of statins that occur elsewhere. And I think the more recent studies with PCSK9 inhibitors and with zetamide, both of which have shown benefit, I think make it clear that the, you know, the real benefit is LDL reduction. And in fact, that data goes back, you know, more than 20 years when people with familial hypercholesterolemia were treated with niacin and choastyramine and were shown to get benefit with drugs that were not statin, but that lowered LDL. And just to comment, I was on both the guidelines that put in targets, and then we took out targets. Yes. There were very few epidemiologists on the guideline, actually. The reason that the targets were softened and taken out as opposed to high intensity versus moderate intensity of treatment is because there's not a single randomized clinical trial that treated to a target, not one. So there isn't any clinical trial evidence of treating to a target. There are people that achieved certain levels, but not a trial designed to do that. That's why we made that change. And so your comment about how important it is to treat, to lower LDL cholesterol to an intensity is the important comment, I think, to make at least from our, and I'll take comments from the panel on that. You know, I won't, I have to disagree with that because the prior guidelines actually quoted the same trial of high dose atorvastatin and low dose atorvastatin, and they quoted that trial as showing that LDL, more LDL lowering was better. And then the next set of guidelines said, no, no, no, that's not what it showed. It showed that the high dose is better than the low dose. Right. Because in those trials, there was no, there was not a specific target of treatment. All they did was put people on a higher dose or a moderate dose. There was no treatment and looked at the mean levels. They didn't look, but people had an entire range of levels in those two groups. So not to belabor it, but the trial was designed to treat with a low dose or a high dose or a specific dose or placebo. Not ever was there a trial treating to a specific target. It was always based on intensity of treatment. I just want to add, this is an international society, the Endocrine Society and the European guidelines actually have goals of less than 70, less than 55, less than 40. Of course, they're in millimoles per liter. And they interpret the studies differently than the ACC AHA guidelines. We do include goals in the ACC AHA, but we just say that most important is to treat intensively or moderate. Right, but the European guidelines actually go down to like a millimole per liter in varying cases where atherosclerotic cardiovascular disease is severe. And there are current events. I just wanted to point that out. Sure, absolutely. It's a very difficult area, but when you look at evidence, that's where the evidence is. So there's a number of other questions related to the level of treatment with levothyroxine and age on both ends. If the patient were younger or older, would you do anything differently? Well, if the patient were younger and they showed up in your office and was a 25-year-old with a TSH of eight and a half, you would say she has a failing gland and you would treat her. You wouldn't have the question as much as an older person because there's not a sense their data that TSH goes up with age. So I think that would make a difference. When somebody gets quite a bit older, what you choose to treat is always something that you think about in a doctor's office and especially when you're treating prevention. So would you treat a 90-year-old with this being their major problem when they have dementia or cancer or some other kinds of issues? Those are decisions that doctors make in their office all the time. And so, yeah, age will matter. So we have very little time remaining in the session. And I just want to know if there's a final comment that any of the authors want to make about this guideline and refer people to it. If I can jump in, thank you, Dr. McBride. I want to add that I think one of the things you're going to see underlying all of the recommendations in this guideline is that we're really concerned about the cardiovascular risk. And a lot of the current guidelines focus so much on age that they miss all these other risk factors. And so the focus is we go through each of some of the major endocrine diseases and address their risk, extrapolating the data as best we can where it's limited, and recommend that instead of treating, you know, necessarily the number or the patient or being tricked by their age, it's recognizing that a lot of our endocrine disorders convey increased cardiovascular risk. And therefore, recommending that we treat patients not just for that underlying endocrine disorder, whether it's Cushing's or acromegaly or what have you, but also recognizing that it does convey increased cardiovascular risk and urging you as an endocrinologist to try to reduce their future risk. That's a really, really critical point that I think overlies this entire guideline is that these patients don't have a single issue. They have issues that precipitate other problems. And these are metabolic disorders that lead to vascular complications. So I want to take this opportunity to thank all of our panelists. I want to take the opportunity to thank the people that spent such hard work. I know how hard it is to write a guideline and look at all the evidence. I want to thank the staff that worked so hard to put on this session. And I want to thank the audience for being part of this and asking such great questions today. So thank you very much for a wonderful session. And go enjoy the rest of the great session that you're part of. Have a great day, everyone.

lipid management

endocrine disorders

Endocrine Society

Dr. Patrick McBride

clinical practice guidelines

statin therapy

type 2 diabetes

cardiovascular risk

hypertriglyceridemia

fibrates