Hello, my name is Dan Hurley, the current Chancellor of ACE, and I have the pleasure of introducing our next speaker. Dr. Dennis Brumer is a Staff Cardiologist and Director of Cardiometabolic Health in the Preventive and Rehabilitation section of Cardiovascular Medicine at the Sedell and Arnold Miller Family Heart and Vascular Institute at Cleveland Clinic. Dr. Brumer specializes in the comprehensive management of cardiovascular risk and metabolic control of patients with diabetes, and he is board-certified in internal medicine, endocrinology, cardiovascular disease, and comprehensive echocardiography. He received his MD-PhD from the University of Hamburg in Germany and then went on to residency training in internal medicine and cardiology in Germany to include the German Heart Institute in Berlin. He was relocated to the United States in 2001 for a research fellowship in molecular biology at the University of California, and after completion of that research, Dr. Brumer joined the faculty at UCLA and was subsequently recruited further to the University of Kentucky, where he served as faculty member and clinician investigator at the University of Kentucky to include Associate Director of the Saha Cardiovascular Research Center at the University of Kentucky. Dr. Brumer's research is focused on the mechanism of atherosclerosis and risk factor intervention for the prevention of coronary disease, and he's been supported by grants from the NIH, the American Heart Association, and the ADA to include others. He has published over 200 manuscripts, review articles, and abstracts, which have been cited over 6,000 times. Dr. Brumer is a frequent lecturer at national and international conferences, and he's been honored with numerous awards to include the Young Scholars Award of the American Society of Hypertension, the Young Investigator Award in Basic Sciences of the European Society of Cardiology, the Endocrine Society Young Investigator Award, a Career Development Award from the ADA, among others. Dr. Brumer serves on various national and international review committees and as a reviewer for leading manuscripts to include Science, Cell, Proceedings of the National Academy of Sciences, Circulation, Hypertension, Diabetes, among others as well. It's my pleasure to welcome Dr. Brumer to present to us his presentation titled, Hyperlipidemia in Young Patients with Type 1 Diabetes, a Review of Current Guidelines and Evidence. Yes, good afternoon. My name is Dennis Brumer, and first of all, I would like to thank the organizers of the ACE meeting for inviting me, for allowing me to present some of our views, and we will be discussing this afternoon the role of dyslipidemia in young patients and type 2 diabetes. We will be reviewing current guidelines and the evidence to support these guidelines and to support, in particular, early management of dyslipidemia. So I have no relevant disclosures for this presentation. Just briefly, the overview of today's presentation here, we will be, as I alluded to, we will be discussing the evidence for increased cardiovascular risk and mortality in patients with type 1 diabetes. We will be reviewing cardiovascular disease in patients with type 1 diabetes, discuss dyslipidemia and the evidence to support its early treatment. And then we will finally close with a brief review of the pediatric and adult guidelines for the management of LDL cholesterol in type 1 diabetes. I think before we start, I would like to disclose that there's really a paucity of clinical trial evidence for lipid-lowering therapy in patients with type 1 diabetes, in fact, at any age. So much of our current treatment recommendations and guidelines really derives from management of type 2 diabetic patients, which were mostly included in the vast majority of clinical trials. I'd also like to point out there's neither long-term safety nor cardiovascular outcome data for efficacy and statin therapy that has been established for the pediatric population. So with that in mind, we will start, and I will first remind everyone about the main concern that we will be discussing, which on this slide you will basically see the mortality of patients with type 1 diabetes in one of the largest registries, the Swedish National Diabetes Register, which really followed type 1 diabetic patients from 1998 to 2012 through 2014 and included over 30,000 patients with type 1 diabetes and about 180,000 controlled. So it is one of the largest patient cohorts that includes patients specifically only for type 1 diabetes. So as you can see in this slide, that during the years from 1998 to 2014, all-cause mortality and cardiovascular mortality, hospitalization from cardiovascular disease, all have notably declined over the course of these years. However, I think it is important to note that there remains a considerable amount of excess overall cardiovascular mortality and outcomes that are associated with type 1 diabetes and match controls. And this is really what we will be focusing today in our discussion. Now as does not come to much of a surprise to us, there are some factors that are associated with excess mortality in patients with type 1 diabetes. And among those, one of the major factors is obviously glycemic control. It is age at the time of the diagnosis and the time the patient had type 1 diabetes. So in this Swedish registry, as shown, patients with poor glycemic control, as shown on the bottom, of above 9.7% really had an 8 to 10 times higher risk for death from any cause as compared to the general population. Now patients with type 1 diabetes and a hemoglobin A1C, there was control that 6.9% had a lower risk of death from any cause and from cardiovascular cause, but it was still twice as high as compared to the risk for a matched control cohort. So clearly, glycemic control, as we all are quite aware, is a major risk factor for excess mortality in patients with type 1 diabetes. Now as I mentioned, age at the onset of type 1 diabetes is an important determinant of survival, as well as cardiovascular outcomes, with the highest excess risk actually being in women. Being diagnosed with type 1 diabetes before the age of 10 years of age resulted in an average loss of life expectancy of 16 years compared to matched controls. Among patients that were diagnosed later in life, between 26 to 30 years, women lost about 10 years of life, whereas men lost about 9.4 years. So on average, about 10 years of life expectancy lost with a later diagnosis and about 16 years lost at a young age of diagnosis. And this is really what we try to meaningfully, meaningful effect in the care of our patients in managing type 1 diabetic patients. Now cardiovascular risk is considerably higher and strongly related to age of the time of diabetes onset, but there are notable differences between males and females, such that the females actually display greater risk, greater excess risk throughout. Now women who were diagnosed with type 1 diabetes at an age of 10 years had a hazard ratio of 91, for example, here shown for acute myocardial infarction in type 1 diabetes. So really, at 10 years of a diagnosis, females have a risk that's 90-fold higher compared to the general population for experiencing a myocardial infarction. Similarly, in other cohorts, here is a large Scottish cohort that included about 24,000 patients with type 1 diabetes. And shown you here on the bottom is the age, to the left is the surviving population, men and women. And as you can see that in this population, at age 20 years, followed throughout life, men experienced an approximately 11 years loss of life expectancy, whereas compared to women, we experienced an average loss of about 13 years of life expectancy. So fairly consistent in two independent large cohorts with type 1 diabetic patients. Now as we're quite all aware, one of the major causes of death in patients with type 1 diabetes is actually ischemic heart disease, and the largest percentage of estimated loss of life expectancy was really related in the Scottish cohort to cardiovascular disease. Mostly ischemic heart disease, circulatory disease is shown here in about 40% on the right and 26% ischemic heart disease. So this is really what we like to affect, and this is what we will continue to discuss. Now you're all familiar with the DCCT trial. I think this trial does not need much introduction to the endocrinologist in this audience. But just briefly to remind you, the DCCT randomly assigned 1,400 patients with type 1 diabetes to either intensive versus conventional therapy and followed these patients in the intervention time in the DCCT trial for a time of 6.5 years. And after this, about 93% were then followed ultimately in the observational aspect, the EDIC trial. Now cardiovascular outcomes were adjudicated and were followed over time. And as you can see here, this is the latest data of about 30 years of follow-up. There was really a sustained legacy effect of early intervention with intensive therapy in these patients. So let's look at some of the factors that were really important for cardiovascular outcomes. As I had mentioned, baseline age at the time of diagnosis was associated with a 50% increase, with a hazard ratio of 1.5, a 50-fold higher risk for adverse cardiovascular outcomes. In hemoglobin A1c, systolic blood pressure, the traditional risk factors. But as you can see also at the bottom, mean LDL cholesterol was a significant factor contributing to cardiovascular event rates in the DCCT trial. So time of diagnosis, glycemic control, and the traditional cardiovascular risk factors. Now similarly in other cohorts, similar observations were noted. This is the Prospective Observational Pittsburgh Epidemiology Childhood Onset Diabetes Complication Study run in Pittsburgh by Dr. Trevor Orchard that basically followed outcomes in patients with type 1 diabetes longitudinally and looked at about 906 subjects in this study which were stratified into five cohorts as seen on the right, dependent on the year of diagnosis. And in this study, basically looking at cohorts stratified by time, 20 years, 25 years, and 30 years, you can see that the coronary event rates in these patients really did not decrease over the years. So there's still about a 15% risk in these cohorts, cumulative risk for coronary events over 30 years after a diagnosis. So cardiovascular disease, again, is a major determinant of outcomes in patients with type 1 diabetes. Now in addition to following these patients, the relative risk of mortality in coronary artery disease were determined using grouping for traditional risk factors. Here shown you the grouping for LDL cholesterol by cohorts of an LDL cholesterol less than 100, 100 to 129, 130 to 159, and above 160 on the left at the lower. You can see the LDL cholesterol numbers. And then you can see the risk ratio for mortality on the left and for coronary artery disease on the right. And as you probably would expect, the least risk was really with an LDL cholesterol of less than 100. And there was a near linear increase in risk associated with increasing LDL cholesterol levels. So really, LDL cholesterol is an important contributor to mortality and cardiovascular event rates in patients with type 1 diabetes. Now following up, again, traditional risk factors were assessed in patients that had ultimately experienced coronary artery disease in this cohort. You can see 44 patients had coronary artery disease, and the majority did not have coronary artery disease. And you can see that, as in the general population, risk factors were associated with cardiovascular disease, age, diabetes duration, total cholesterol, and LDL cholesterol increased in the coronary artery disease group, although non-significantly. You can see further down at the bottom that LDL particle size was one of the important factors that was actually smaller, which is associated with increased cardiovascular risk in those patients that experienced coronary artery disease. So many of the traditional risk factors are associated with adverse outcomes in patients with type 1 diabetes. Now going back to the aforementioned Swedish National Diabetes Register cohort that followed patients from 1998 to 2014, again, these were over 30,000 patients with type 1 diabetes. And you can see in looking at what is the prognostic importance of risk factors for type 1 diabetes. And these are stratified by all-cause mortality on the left and for acute myocardial infarction on the right. And you can see that in this cohort, the strongest predictors for all-cause mortality were, again, age, duration of diabetes, hemoglobin A1c, and now microvascular complications, including microalbuminuria. For cardiovascular outcomes, as you can see on the right, again, age, duration of diabetes, and actually LDL cholesterol were the most important predictors of myocardial infarction. So it is the glycemic control, the age of diagnosis, and the LDL cholesterol that predicts acute myocardial infarction and cardiovascular outcomes in cardiovascular death in patients with type 1 diabetes. So looking at this a little bit more in fine print, here is shown, again, similar as coming out of the Swedish National Diabetes Register, looking at the contribution of glycemic control, blood pressure, and LDL cholesterol to the hazard ratio for myocardial infarction. And as you can see, LDL cholesterol was a very strong predictor for myocardial infarction in this large patient cohort, and demonstrating a 47% higher relative risk for each 39 milligram per deciliter increase in LDL cholesterol levels. So therefore, really, in patients with type 1 diabetes who have not developed cardiovascular disease, specifically in younger patients, these might benefit from more aggressive primary cardiovascular prevention efforts, and perhaps an earlier initiation of lipid-lowering therapy. Now again, looking at the same cohort, now stratified by patients according to the number of risk factors that are controlled. As shown on the upper right, risk factors included blood pressure, LDL cholesterol, smoking, albuminuria, and a hemoglobin A1C above 6.9. So looking at these five risk factors, which we know very well are associated with poor outcomes. If mortality rates among patients with type 1 diabetes were the lowest for those with all these risk factors, a target, having a hazard ratio of 1.31. Now, the adjusted hazard ratio for acute myocardial infarction as shown on the bottom versus control with all risk factors at target was 1.82. So having none of the five risk factors at target yielded a hazard ratio for patients with type 1 diabetes versus matched control of 12.3 for acute myocardial infarction. So really this highlights, similarly as we know for patients with type 2 diabetes, this really highlights the importance of a comprehensive approach in patients with type 1 diabetes, focusing on microvascular complications, glycemic control, and LDL cholesterol, as well as blood pressure reduction. Now, I'm briefly going back to the Scottish population that we had already looked at earlier. So what is the prevalence of risk factors in patients with type 1 diabetes? In other words, how often do we see patients with type 1 diabetes and associated risk factors? Or maybe even how well do we do in treating those risk factors? So I think it is clear that risk factor treatment for patients with type 1 diabetes has much room for improvement. In this Scottish cohort, only 13% of the patient cohort achieved a hemoglobin A1c of less than 7%. The majority of patients with type 1 diabetes actually had poor control. In fact, over 37% of patients in this population had a hemoglobin A1c of above 9%. Now, looking at other risk factors, this is showing you the data for blood pressure in this cohort. Again, 20,000 patients with type 1 diabetes followed. Among those above age 40, about one third of patients had a blood pressure above 130 over 80 millimeter mercury on medication. And another third had a blood pressure of about 130 over 80 who were on no medication at all. Overall, among those aged above 40, 37% had blood pressures that were even more increased above very conservative targets of 140 over 90. So clearly, blood pressure is highly prevalent. Hypertension is highly prevalent in patients with type 2 diabetes and frequently has notable room for improvement in care. Now, finally, looking at hyperlipidemia in this patient cohort, some of the recommendations overseas are to target a total cholesterol of 174 milligrams per deciliter. This is where on the right, this is given here in millimole per liters. So slightly different numbers here, but just briefly, two thirds of patients in this population had a total cholesterol that was above the recommended target. And if we are looking at patients above 40 years, which are our treatment recommendations over here, 39% of patients were actually not treated with a statin. So overall, traditional risk factors like hypertension and hypercholesterolemia are frequent and frequently undertreated in patients with type 1 diabetes. Similarly, as we know in this country, frequently have poor glycemic control that is not on target. Now, in another cohort, this is looking at children, adolescent and young adults with type 1 diabetes in Germany, looking at the prevalence of risk factors in particular hyperlipidemia in 27,000 children, adolescents and young adults. So a very large group. And in this group overall, the vast majority, in fact, 53% of the adolescent had at least one cardiovascular risk factors. 70% of the adolescents in the age group, 17 to 26 years, had a hemoglobin A1C of above 7.5%. 35% had a hemoglobin A1C above 9% in this population. Now, looking at dyslipidemia shown on this slide here, 28% of patients had dyslipidemia, 36% in the female and 23% in males. And merely, in this analysis, nearly 0.4% of patients were actually treated with statin therapy. Although, as you can see on this slide here in the middle, although about 15% had an LDL, 15% of females and about 8% of males had an LDL cholesterol that was above 130. And about 7% of females and about 4% of males had an LDL cholesterol that was, in fact, above 160 milligrams per deciliter. So clearly dyslipidemia is common in young adults with type 1 diabetes. Now, if we look at data from the DCCT trial again, which looked at, here in this analysis, looked at the DCCT patient population and compared those with a comparative group coming out of the Lipid Research Clinic analysis, looking at non-diabetic individuals and really looking at different age groups, females on the left and males on the right, and following LDL cholesterol levels in these patient groups, you can see that in females, was a slightly higher LDL cholesterol levels at younger age. This was not seen in males. So overall lipid panels are fairly comparable, but it is evident from the DCCT trial that younger females may have a more elevated LDL cholesterol, at least in this patient cohort. Now, on standard lipid testing, differences in lipoprotein particle distribution may not be immediately apparent. In order to identify subtle changes in patients with type 1 diabetes, lipoprotein fractionation studies have been done and looked at this in more detail. So while individuals with type 1 diabetes may initially have similar standard lipid panel testing as HSACs and BMI matched controls, differences in lipoprotein particle distribution may be subtle. This is looking at adult patients with type 1 diabetes in a sub-study of the coronary artery calcification and type 1 diabetes study, which included 82 subjects with age 46 and 52 in females and included 49% with type 1 diabetes. So looking at their lipoprotein fractionation, you can see that in adults, patients with type 1 diabetes here in the dashed lines have lower VLDL. This is mostly due to the treatment effect of insulin and increased fatty acid uptake into the adipocytes. Seem to have lower VLDL fraction and higher HDL fraction, whereas in adults, there's little change in actually LDL particle fractionation. Now, if we look specifically at sex differences by lipoprotein sub-fractionation studies, among men, as you can see on the left, type 1 diabetics have less VLDL and more HDL as I had just shown. You can see here, this is basically fraction number on the bottom and cholesterol percent on the left. And this is basically FPLC cholesterol content in type 1 diabetic divided by non-diabetic. So you can see the shift. You can see on the left, as indicated by the arrow, lower VLDL and higher HDL in males. Similarly, trends seen in females, but among women, those with type 1 diabetes actually have a shift in their LDL particle size towards a more LDL-dense particle. And those are particularly those LDL particles that have been associated with an increased risk for coronary artery disease. Now, lipoprotein profiles here, again, shown in young with and without type 1 diabetes, you can see that the prevalence of abnormal lipid concentration is fairly similar between control type 1s and type 1 diabetic patients and healthy subjects. However, in young adults with suboptimal glycemic control, there's a much higher prevalence of abnormal lipid composition shown in the black bars here with higher total cholesterol, higher LDL cholesterol, lower HDL cholesterol. Now, again, looking at adolescents, in earlier type 1 diabetic patients, those going through puberty and adolescence, changes in lipoprotein distribution may become more prevalent and actually are frequently associated with insulin resistance, as shown on this slide, despite there not being any overt differences in their standard lipoprotein measurements that we get on standard protein lipid profiles. This study actually looked at, again, lipoprotein fractionation and included particularly those patients that were insulin resistant as assessed by hyperinsulinemic euglycemic clamp studies. So these are insulin resistant young type 1 diabetic females and males. And as you can see, actually, on the LDL distribution, adolescents with type 1 diabetic had multiple fractionations that were significantly higher in the LDL particle range compared to their respective controls. Now, in addition, these patients had a higher, had an increased shift towards small dense LDL. Now, we had mentioned that patients with type 1 diabetes frequently actually have an increased HDL levels, but it has been shown that this HDL level is likely dysfunctional and does not confer the usual protective cardiovascular benefit that we see in healthy subjects. High HDL is associated with inflammation, as shown, summarized in the summary slide from a large study that was done, published in European Heart Journal in 2019, including adolescents with type 1 diabetes, age 10 to 17 and matched to controls and looking at endothelial dysfunction, actually, and looking at the functionality of HDL. And as you can see on the right, if we just focus on the right, those subject that actually had high inflammatory markers in these patients, HDL had more HDL-mediated superoxide production, so increased reactive oxygen species, decreased NO bioavailability, and this was associated with endothelial dysfunction in these patients. So it is pretty well established now that the increased HDL that we see in patients with type 1 diabetes is dysfunctional and does not confer the usual benefit that we see. Now, this is another study, the Adolescent Type 1 Diabetes Cardiovenal Intervention Trial, which looked at 406 adolescent patients with type 1 diabetes. These were about 14 years in average and had diabetes for about six years and compared to 57 age-matched controls. And as you can see, clinical and biochemical data were shown here. Obviously, as you can see, hemoglobin A1C was higher in the type 1 diabetic patients as we would expect. Blood pressure levels were higher. We discussed the LDL cholesterol levels that were higher, shown at the bottom, and HDL cholesterol was also slightly higher in these patients. Now, in this study, these parameters, these metabolic baseline characteristics were assessed in multivariable models for aortic intima media thickening, which has been suggested to be more sensitive for detection of vascular remodeling in patients with type 1 diabetes. And in type 1 diabetic patients, this increase in aortic intima media thickening was related mostly to two factors. It was related to microvascular complications, including the urinary albumin to creatinine ratio, but it was also highly associated to LDL cholesterol levels. So again, LDL cholesterol playing a major role in vascular remodeling of patients with type 1 diabetes. Now, in this study, 443 adults were then assigned to a placebo-controlled trial using an ACE inhibitor or a statin in a two-by-two factorial design to look at a primary outcome for both interventions, which was a change in albumin secretion. Secondary outcomes in this trial were microvascular complications and measurements of carotid artery intima media thickening. As you can see here, so these are adolescent subjects treated with either a statin or treated with an ACE inhibitor. And you can see the LDL cholesterol with statin treatment dropped significantly on the left, but with statin, there was no effect on the cumulative probability of microalbuminuria. And there was also in this trial no significant effect on carotid artery intima media thickening. The reason why I present this trial because the study showed that it was safe to use statins in this particular population. Now, another study that used cholesterol-lowering medication atorvastatin was a pediatric atorvastatin in diabetes trial, the PATIT trial, which included 51 patients between age 10 and 21 of age with type 1 diabetes. And treated with atorvastatin 20 milligrams for 12 weeks. This was a study that mostly was a proof of concept, mostly a safety trial, because much of the statin safety data really comes from adolescents with familiar hypercholesterolemia, where really statin therapy is one of the mainstream of therapy. So in this cohort with type 1 diabetes, atorvastatin had an excellent short-term safety profile, reduction in LDL cholesterol of 29 milligrams per deciliter over a 12-week period. And there was a non-significant reduction in arterial stiffness in the group treated with atorvastatin. So a positive signal for vascular modeling and excellent safety data. Now, so what do we know about treatment with statins in type 1 diabetic patients? Well, as I had mentioned earlier, much of our knowledge is really extrapolated from trials with type 2 diabetes or studies that included small cohorts of type 1 diabetes in their patient population. Now, this is the heart protection study, which included 5,900 subjects who either were having diabetes, known to have diabetes, and an additional 14,000 patients with occlusive artery disease. And in this trial, you can see, this is a subgroup analysis, and you can see that essentially in every group, simvastatin seemed to be better than placebo. I'd like to point out here that this was even the case in type 1 diabetic patients. In this trial, there were 615 patients, about 10% of the patients in the study were classified as having type 1 diabetes, whereas 5,400 patients had type 2 diabetes. So there were highly significant reduction of events seen in this study, major coronary events for strokes and for revascularization. And the proportional reduction, proportional benefit in patient groups seemed to be extended to the patient population with type 1 diabetes. Now, another analysis is from the cholesterol treatment trialists, the CTTT collaborator, a large meta-analysis, which included data from 18,000 people with diabetes, and this out of 14 randomized trials on statins. And this study included 1,400 subjects with type 1 diabetes. And again, this slide shows the proportional effect across all groups favoring statin treatment. And this benefit for cardiovascular outcomes was also conferred to patients with type 1 diabetes. So in general there was a 21 proportional reduction in major cardiovascular event per millimole per liter reduction in LDL cholesterol in patients with diabetes and that signal was similar versus similar in type 1 diabetic patients versus type 2 diabetic patients. And so looking at an additional cohort, this is again going back to the Swedish registry that I had discussed earlier. In this Swedish national diabetes registry there were about 24,000 patients with type 1 diabetes. And out of those, in looking at those that were treated, 5,000 out of those were actually treated with lipid lowering medication versus untreated. And you can see that there was a clear survival benefit in those patients that were treated actually with statin therapy. Now the association in this observational study, it was clearly shown that lipid lowering therapy was associated with a 22 to 44 percent risk reduction in the risk for cardiovascular disease and cardiovascular death among patients with type 1 diabetes. So a clear benefit in those patients that were actually on statin therapy. So what do the guidelines say? In the last couple minutes I will just briefly review the current treatment guidelines for patients with diabetes. I would particularly focus on those patients with type 1 diabetes. Now in looking at our American Diabetes Association standards of medical care, just published 2021, it is recommended that after the age of 10 years, addition of statin therapy is suggested in patients after medical nutrition therapy and lifestyle changes who continue to have an LDL cholesterol of above 160 or above 130 and one or more cardiovascular risk factors. The goal of therapy is less than 100 milligrams per deciliter. Now this is fairly consistent with the 2018 American Heart Association ACC ADA guidelines on the management of blood cholesterol in patients with diabetes, of which all of you are familiar. Looking just here on the left, this is the age group where we don't distinguish between type 1 and type 2 diabetes. In patients that have no overt clinical atherosclerotic cardiovascular disease, the age group of age 40 to 75 should be considered for moderate to intense statin therapy, high-intensity statin therapy. Now in the age group younger than 40, 20 to 39, therapy can be considered. And this is the specific detail. Again, in adults age 40 to 75 years of age with diabetes, that being either type 1 diabetes or type 2 diabetes, moderate to high-intensity statin therapy is recommended. In adults age 20 to 39 of age with diabetes of long duration or one or more complications or cardiac risk factors, it may be reasonable to initiate statin therapy. And the point I would like to make here, long duration is, with respect to type 1 diabetes, above 20 years of having had type 1 diabetes. Diabetes complications are those that we're familiar with, and the standard atherosclerotic cardiovascular risk factors are also those that we're all very familiar with. Now probably the most updated guidelines are those that are provided by the European Society for Cardiology. And this is a little bit more intense therapy, lower threshold for treatment, and more aggressive treatment. And I would just briefly go through some of the key aspects of these treatment guidelines. Now you can see here that there is clear differentiation between risk, low risk, moderate risk, high risk, and very high risk. And those that are moderate risk are those young patients that are less than 35. High risk are patients with type 1 diabetes without target organ damage with type 1 diabetes of a duration of above 10 years or an additional risk factors. Very high risk are any diabetic patients with atherosclerotic cardiovascular disease, diabetes with target organ damage, more than three risk factors, or early onset of type 1 diabetes. So specifically, in more detail, statins are recommended in patients with type 1 diabetes who are at high or very high risk. And this is a class 1 recommendation. Statin therapy may be recommended in patients with type 1 diabetes less than 30 age of age with evidence of end organ damage and or an LDL cholesterol of above 100. Now in the next slide, I will crystallize these recommendations, which I think are the ones that provide the most aggressive and most consense treatment recommendation for dyslipidemia in patients with type 1 diabetes. And personally, I think those are the straightforward recommendations that we really should be following based on the evidence that I have just highlighted. So let's look at moderate risk patients. In moderate risk patients, the LDL cholesterol goal is less than 100 milligrams per deciliter. In moderate risk, those are those patients with type 1 diabetes of less than 35 years of age and a duration of less than 10 years and no additional risk factors. I had shown you the evidence to support the goal of LDL cholesterol of less than 100 milligrams per deciliter coming out of the Pittsburgh observational type 1 diabetic study. Those patients high risk, an LDL cholesterol goal would be less than 70 milligrams per deciliter. And those would be patients with type 1 diabetes without target organ damage with a duration of above 10 years or additional risk factors. Very high risk patients would be patients with type 1 diabetes with target organ damage or more than three risk factors or a duration of above 20 years. I'd also like to point out that per those guidelines, fairly consistent with our endocrinology with our ACE and endocrinology guidelines, a very high risk patient includes those that have any history of atherosclerotic cardiovascular disease. So any type 1 diabetic patient with a history of atherosclerotic cardiovascular disease, the goal of treatment would be less than 55 milligrams. In addition for primary prevention, type 1 diabetic patients with target organ damage or more than three risk factors or a duration of above 20 years should have an LDL cholesterol goal of less than 55 milligrams per deciliter. And I think this is a very aggressive goal, but I think based on what I had discussed and based on some of the extrapolation that we do with patient groups, including type 2 diabetic patients, these target goals and these recommendations are well justified. So I will stop here and I will be delighted to entertain any questions and to follow up with a discussion among us on this topic. Thank you very much. Dr. Brumer, thank you for just a delightful and excellent talk on risk of cardiovascular disease and patients with type 1 diabetes focusing on dyslipidemia. Let me, as prerogative of the moderator, ask you the first question, and that would have to do with lipoprotein subfraction analysis. You mentioned that HDL may be dysfunctional in patients with type 1 diabetes, that there may be a different subfraction in patients with type 1 diabetes versus controls. When should I consider maybe getting a lipoprotein subfraction? So first of all, Dr. Hurley, let me thank you and the ACE for inviting me to present and to share some of our views and discussion of the current guidelines. It's really a privilege for me to be here. So to jump right in, I think what we really want to do if we discuss additional testing, we want to look at whether we can reclassify a patient that maybe seems to be at an intermediate risk to a low-risk patient or vice versa, low risk to an intermediate risk patient, where we ultimately then make a decision to treat with statins. So I think with respect to lipoprotein subfractionation, in general, I usually do not find that there is any additional value to obtain this testing beyond a standard lipid panel because, well, we know the patient with type 1 diabetes has an increased risk, as I had discussed. We know that the patient, if there's not a large number of small dense LDL particle, would that really differ from statin therapy treatment or not? I don't think that this information adds value to our clinical history looking at the age of the patient, looking at the duration of the patient. But I will say that overall I think I've reviewed that cardiovascular risk factor treatment in general is insufficient in patients with type 1 diabetes. And that does not just apply for lipids, it's also for hypertension. And I think we have a lot of low-hanging fruits to prevent cardiovascular disease and to treat risk factors. So I think we should be focusing on those in sort of a comprehensive fashion. And oftentimes, I don't really think we need to get additional testing. We have a question here from a participant, Meneghini, asking about coronary calcification scores. Do you use them? When should we get them? And particularly for someone who may be in the 40 years category that may have a low score, if you do a test and they have a low score, would you treat them with high-dose statins? What would be your LDL goal at that point? So first of all, as I said, we use testing to re-stratify patients, maybe from an intermediate risk category to low risk category. In general, coronary calcium scanning is not recommended in patients that are at an age of 40 to 75 years old with diabetes. So it's only recommended in those patient population without diabetes. Guidelines specifically state to treat with statin therapy even in the absence of an increased coronary calcium score. The reason for this is if we understand vascular pathology and vascular disease and coronary calcification, yes, it's a risk factor. But really, what causes acute plaque rupture are the small plaques that we often can't even detect on a coronary calcium scan. So to answer this question directly, I would treat with statin, regardless as to whether the patient has a coronary calcium scan of zero. I was struck by the data from the DCCT and the EDIC as well as the beautiful Swedish National Diabetes Registry, focusing on age and time of diagnosis, A1c and LDL as risk factors. I'm curious if we're waiting too long to use a statin for those patients that may have diabetes beyond 10 years, but no other traditional risk. What are your thoughts about that? I think we're waiting too long with everything, because this is prevention. And we know that exposure time to hypercholesterolemia, to hyperglycemia, and to hypertension plays a major role in all of the cardiovascular events that we're discussing. And I think from all the studies that we've been discussing and looked at, usually, and we know this also, of course, best from patients with type 2 diabetes or in general cardiovascular disease, there is really hardly any condition or any subgroup that had been looked at where not high intensity or higher dose statin therapy is in favor of cardiovascular outcomes. So I think if in doubt, I would always treat the patient. And yes, I absolutely agree. I think we need to start to treat these patients early. And this is now for the first time, actually, clearly becomes part of all guideline recommendations to put an age in the equation. And it probably makes a difference if someone had a hemoglobin A1C of 6.5 for 10 years, or hemoglobin A1C of 9.8 for eight years. So I think we have to still individualize patients. But I think in doubt, we always favor statin therapy. And if we're not sure, I would probably look at the overall spectrum. Is the patient hypertensive? Do we have renal disease? So these factors all add to the equation. And now that's exactly part of the ESC guidelines. There's a question from Dr. Shiraz. Do you manage patients, younger patients, particularly who are female patients, screening or statin therapy? And how do you recommend statin therapy in their reproductive age? Concerns there. Well, I think in their reproductive age, I mean, certainly that's a concern, statins. I mean, there has to be birth control or a clear discussion as to when do we use statins. As I indicated, and as I had alluded to, females are a particular risk. And in females, I would go along with what we have discussed. And we look at the risk factors. We look at the guideline recommendations and we treat appropriately. I think the question comes down to what are the targets? What targets would we use? I think that in general, if we test patients with type 1 diabetes, drug naive, a lipid panel, the vast majority of patients that I, maybe from personal experience, most of these patients do have an LDL cholesterol above 100. And these patients should be treated. A follow-up question by Dr. Sudhu. You know, in these patients that may have had diabetes for a long period of time, maybe younger, under 35 years of age, but have had diabetes for, you know, five to 10 years, no other risk. What's your goal LDL? Do you shoot for 100? Do you go lower since you're on a statin? I think if the patient has a short history of less than 10 years, I would shoot for less than 100. And I may say, well, if the LDL is 130, which is very common in this country, in type 1 diabetic college kids, for example. So I think using a low-dose statin, and even if it's just reservoir statin, five milligrams at that time would be not unreasonable. Now, I would definitely do that if the time for time exposure time, if the diabetes has been present for more than 10 years. Shorter than that, I would test and I would still treat with statin at a lower dose. What about the other end of the spectrum? Swarna Campbell asks, you know, a patient who has high risk, maybe not at goal with LDL. Do you use another agent? Maybe, when do you go to PCSK9? So we here go to PCSK9 inhibitors very quickly, very early. I mean, yes, based on the IMPROVER trial, you could argue that statin with maybe even a moderate intensity statin with azetamide might be appropriate to get to goal. But I think if patients are statin intolerant, we have now very powerful alternative treatment possibilities. And in the PCSK9 inhibitor trials, keeping in mind Fourier and Odyssey, the patient population with diabetes now, given that was mostly type 2 diabetic patients, was about 40%. So we have a large number of diabetic patients that had been treated with PCSK9 inhibitor. And if you look at the outcome, it was much driven by the benefits seen, and particularly in the diabetic population. We have about 20% of our diabetic population patients here on PCSK9 inhibitors. So we're out of time. We'll try and get to some of these questions by email if possible. Just would like to thank Dr. Brumer for a wonderful discussion as well as presentation. Thank you again for presenting at ACE InVision for 2021. Thank you, Dennis. Thank you very much for having me. Thank you. I appreciate it.

dyslipidemia

type 1 diabetes

early management

cardiovascular risk factors

glycemic control

LDL cholesterol

statin therapy

cardiovascular events

treatment guidelines