GAED | Management of Dyslipidemia

0:06 Good evening everybody. Welcome to the uh to this webinar. My name is Tama. I'm a consultant endocrinologist uh from Kuwait. I'm also the secretary of the uh Gulf Association of the Clinical Endocrinology and uh and diabetes. And I would really welcome you to be part of this symposium uh to deliver um scientific information about management of dyslomia. uh we've been doing this eval this management for doing these reviews uh in symposium and throughout the year and we're very delighted to hold also this um to this webinar and also plus the webinar we're doing many other activities relating to our congress every year and also our board review

0:52 that we do also every year and we really would welcome you to be part of this association please scan the barcode to become a member of gate you can enjoy many facilities ilities that we are actually providing in terms of increasing and improving your uh medical information and science and reviews for medical conditions. Uh please follow us. We have many platform for social medias. We post a lot of news, a lot of information and we would like you to be part of our community society to know more information about our activities. We would like to thanks the sponsors for our today's symposium viatric. Uh the title of our symposium today is management of dysipidemia.

1:38 This is organized by the choice and this is an CME accredited activity. Um all the people who registered will receive their and attended the the symposium will receive their CME credits uh by the email that they actually registered with starting tomorrow morning. Um we have an esteemed faculty of physicians presenting our um current and latest information about management dysipidemia. These are the presentations and the titles and also the presenters. I will be very delighted to present each uh each presenter by itself um during their uh during before their their their talk. Please this this symposium would not be

2:24 completed unless you actually join us in your questions and your queries and we would love to discuss them in the question and answer uh session at the end of the presentations. So you see the box please add your questions into that. Okay. So it'd be very delightful to uh to present my dear friend and colleague Dr. Dar Khad. Dr. He's the president of the Gulf Association of the Endocrinology and Diabetes Gate. He's a senior consultant indicronologist at Hammed Medical Corporation. Uh very esteemed physician and very well scientist as well. He's going to talk today about management of dysipidemia in type 2 diabetes. Dr. Taro, please start

3:10 your presentation. >> Thank you very much uh Dr. Samir and I apologize for this uh lapse of uh some technicality issues. Uh it gives me special pleasure to talk to you tonight on behalf of GATE and I would like to thank our sponsors as well as thank our organizers the choice and Dr. Rafett. Um uh tonight we are going to cover the uh theme of dis lipidmia and I'm going to quickly start by giving you a talk about management of disademia in type 2 diabetic patients. Um u those are my disclosure. This meeting is part of an educational series as uh my colleague

3:58 Dr. Sam has alluded to organized by gate and uh you have to keep looking out for subsequent events actually in the next few months and would like to thank our sponsor again beatatric for supporting this educational meeting. Um, of course we know that diabetes per se increases the risk of cardiovascular disease as people with diabetes have an increased risk of cardiovascular morbidity and mortality and and you could see that you know cardiovascular disease is a cause of morbidity and mortality in people with diabetes as you could see from this

4:43 cartoon where people with diabetes No matter being a male or female, they do have quite actually uh average annual incidence of cardiovascular disease amounting to up to 40% in males and just below 30% in females compared with people without diabetes. And uh those without diabetes um um in the male population they only have a risk of 19% and those who are females have a far less actually sort of risk being only uh above 10%. And uh diabetes on its own right as a

5:30 syndrome does not actually present as a solo problem. Type 2 diabetes does actually cluster with multiple comorbidities. As you could see that only around 6.6% of type 2 diabetes population do not have other comorbidities. Those who have one comorbidity like hypertension, hyper lipidmia uh um uh heart failure as well as hypermia tend to be only uh representing 14.4%. If you move to those who are harboring two coorbidities, this will rise to 27% and just below quarter of the whole type

6:17 two population might actually have three or more comorbidities. And uh among these sort of comorbidities hyper lipidmia tend to actually focus very highly um uh with a prevalence of around 80% uh shoulderto-shoulder with the prevalence actually of hypertension. And if we look at our region, um um there is a study actually uh published uh uh in plus one um uh not long time ago which actually has looked into the uh uh uh cardiovascular um uh uh sort of correlates uh risk

7:03 factors like smoking, like obesity, hypertension, abdominal obesity as well as hyper lipidmia in addition to diabetes. And uh that study actually showed that people in the Middle East do represent very high actually reponderance to develop hyper lipidmia and indeed hyper lipidmia represent around 70% of those actually risk factors when you look into the general population beyond doubt you know um uh evidence from meta analysis of various studies being Mandenial Mandelian randomization

7:48 studies or prospect cohort studies as well as randomized control studies like WO was cops, like Jupiter, like HO um uh covering whether primary privation or secondary privation um of cardiovascular disease. It has actually shown beyond doubt that low density lioprotein is a causal factor actually in development of asterosclerosis and uh higher lifelong exposure to high level of LDL cholesterol can lead actually to acute coronary syndrome early in life. As you could see in this slide to the left side of the uh uh uh

8:37 uh slide, if you have a sort of a a high level of LDL cholesterol greater than 200 mgram per DC liter, okay, you you confer actually a very significant risk even if you are at 20 years of age. And if you have you know the higher level the older you are this level actually will confer a a lifelong sort of risk and uh and then this will result actually in decrease the average age for the occurrence of acute mioardial infection uh in the age below 40.

9:23 Cardiovascular disease as we know can occur even before the diagnosis of type two diabetes. Type two diabetes does run actually a significant actually pre-clinical phase by roughly greater than 10 years and at the time of the diagnosis there is actually might be development of established microvascular complications and development of aosclerotic disease tend to actually precede that and uh the risk factor for cardiovascular disease actually tend to cluster in people with diabetes even before the diagnosis of uh the disease per se.

10:09 Having diabetes is a bad news for the subject because life expectancy is reduced by roughly around 12 years in patients with diabetes who have got established cardiovascular disease. Those who have got diabetes without established cardiovascular disease life expectancy tend to be reduced by average six years compared to those who have got no diabetes and no cardiovascular disease. There are unmet needs in treatment of dyslexidemia which as I have uh uh uh mentioned earlier that it is a major ashual risk factor for cardiovascular disease and despite all the advances in

10:56 modern health care and despite good standard of care many patients with diabetes are still actually not yet achieving the optimal LDL. we will come to what sort of optimal level and uh there is uh a fact that more than two out of three patients are not at the recommended LDL cholesterol level which is supposed to be actually standing at and the inability to achieve LDL uh cholesterol goal is multiffactorial many well-treated patients at recommended LDL goal continue to have cardiovascular events and this mean that the decrease in events due to LDL

11:44 reduction uh with a statin still leaves actually significant proportion of people who are at risk up to 20% of patient um uh with diabetes who are taking limit lowering ages do actually have issues related to tolerability and we should not forget that familial hypercoly in the diabetes population is generally actually uh underdiagnosed. So lowering LDL cholesterol has been established beyond doubt to decrease cardiovascular risk. As we know that the elevated LDL cholesterol is the first modifiable limit risk factor which you can actually

12:29 manipulate and this has been actually very much proven by meta analysis looking into many studies like 4S like it like improve it and uh this is very much actually you know uh the case that uh treatment of the LDL cholesterol control can be predict actually the clinical event rates uh of uh uh uh cardiovascular events and roughly reduction of uh 39 mill per dc um uh of the LDL cholesterol can actually decrease the relative risk of cardiovascular disease by a factor of 20

13:15 to 25%. The LDL cholesterol guidelines goals are infrequently achieved in very high-risk patients and this has been actually shown by studies that actually covered um various corners of the globe. For example, a study by Arafa Etal in the Arabian Gulf have shown that around 68% of patients who are supposed to reach the goal of the LDL cholesterol do not actually reach that target and uh this result is actually translated in other parts of the world like the study by Manawal from Indonesia and that by Wong Ital in US as well as by voters from

14:03 Canada Mexico Brazil Spain Netherland, France, Taiwan and Korea. So still we have got actually much effort to try to implement in order to reach the LDL um the LDL target and uh and you could see from this slide that actually looked into 17 guidelines as well as 42 observational studies we are far away from achieving uh such actually target. When we are talking about what sort of level of the LDL cholesterol in patients with uh type 2 diabetes we should be aiming at. We have first of all to categorize our patients as low category,

14:51 moderate category, high category and very high category. I will start with very high category and this is actually from the latest guidelines published back in 2019 by the European Society of Cardiology and European Atherosclerosis Society that actually recommended the goal for LDL reduction uh in general patients. For example, when you take the very high category, uh you could see that people with diabetes and target organ damage who have got, you know, three or more major risk factors are categorized at a very high actually risk

15:40 and those they should have the lowest as possible of LDL reduction and I will come to this again. If you move into the least sort of category and if you could just focus on people with diabetes without target organ damage and who have got diabetes duration uh greater than 10 years and no other additional factor they are placed as a sort of a high category. Uh uh uh people who have been placed in the moderate category are those young patients with type 1 diabetes who are younger than 35 years or those with type 2 diabetes who are younger than 50 years but they have

16:25 got a sort of a diabetes duration of less than 10 years. So uh we do have many drugs at our aramentarium. Recently we have got uh uh the availability of uh this drug the BCSK9 inhibitors uh which is uh stands for broine convertase subtly kein type 9 and this tend to work actually uh whenever we can we have failed actually to achieve the reduction of the LDL cholesterol by the uh uh orthodox conventional means and I will come to this when I discuss what sort of uh uh uh combination of treatment to take and of course this drug works in a

17:13 sort of a unique action and I won't go through this for the time being and of course you know the recycling of the LDR receptors uh is a determining factor actually um in development of uh the asylcotic plaques and the BCSK9 tend to work actually uh in this sort of area. So the uh most latest guidelines published by the European Society of Cardiology which was published in the European Heart Journal uh uh just over uh uh two years ago in 2023. Um they have actually uh uh published the guidelines for management of

17:58 cardiovascular disease in patients with diabetes. And here they have actually made a special focus in the LDL reduction. So the recommendation is that when you are treating distribia in diabetes you have to consider that people with type 2 diabetes who are at very high risk um the reduction of the LDL cholesterol has to be greater than 50% from baseline and uh the goal has to be 1.4 4 mill per liter which is equivalent to 55 mg per DC dill liter and those with type 2 diabetes who are at high risk I have alluded to this earlier they should be

18:43 again reduction of LDL cholesterol greater than 50% from baseline however the level could be slightly less stringent at 1.8 8 which is less than 70 migram per DC liter and here statine are recommended in patients with type 1 diabetes who are at high or very high risk. What about the uh intensification of therapy? It has been recommended that intensific intensification of statin therapy should be considered before the introduction of combination therapy and if the goal is not reached statin combination with isami should be considered. However, you know, there are

19:29 other factors to consider that you know statin therapy is not of course recommended in brieosal patients with diabetes who are considering pregnancy or are not using adequate actually contraception. So as I alluded to earlier, we have very high risk and those are patients with diabetes and established cardiovascular disease as I have alluded to or other target organ damage or those with diabetes who are having actually three or more major risk factors or those with early onset type 1 diabetes of long duration than greater than 20 years. Those who are in the high-risisk

20:15 category are those with diabetes who have got a duration greater than 10 years but without target organ damage plus any other additional risk factors. Moderate risk comprise young patients with type 1 diabetes age less than 35 years or those with type 2 diabetes who are less than 50 years with diabetes duration less than 10 years without other risk factors. So the cardiovascular risk category very high risk as I mentioned and I will reiterate again just for sake of this fact to be actually very much imprinted into our neuronal DNA that people with diabetes with target organ damage as well as those who have got three major

21:03 risk factors or early onset of type 1 diabetes of long duration greater than 20 is this patient we should aim for an LDL cholesterol less than 1.4 4 mill which is equivalent to 55 mg per dill liter. Likewise there are other categories which you have to remember in this category apart from those with diabetes. those who have got chronic kidney disease with an EGFR less than 30 as we know that most of them they do succumb due to cardiovascular events and patients with family history of asoscllorative cardiovascular disease or without another major risk factor and patients who have got a calculated score

21:50 greater than 10% for 10 years um risk of fatal uh cardiovascular disease. So the high risk the subsequent category we should aim for a level of LDL cholesterol less than 1.8 mill which is equivalent to less than 70 migram per DC liter those who are in the moderate category of moderate risk are uh patient who should have actually less stringent level. Um but we should be actually more proactive in treating uh uh patient uh even who have got low risk um uh in order to prevent future development.

22:39 What are the new recommendations? the new recommendations as stemming out from the guidelines published 2023 and I mentioned um uh the recommendation for other people who have got you know um other hyper lipidmia like patients with hypertrigidemia those who are in the high risk or above who have got a triglyceride level between 1.5 and 5.6 6 mill per liter equivalent to 135 up to 499 mg per deciliter being on statin treatment u uh uh uh uh uh essential fatty acids should be considered in

23:26 combination with the statin. The other category is treatment of people with hetererozygos familial hyper cholesterolmia and here those whom we are aiming for primary prevention uh we should uh consider them as at very high risk and the LDL reduction of 50% or more from baseline should be considered in this patient. What about treatment of distribia in older people? Okay. Treatment with a statin is recommended for primary prevention according to the level of risk in older people age less than 75. Treatment of dysipidemia in older

24:12 patient should be with initiation of statin treatment for primary prevention in older patients uh who are age greater than 75 may be considered even if at high risk or above. So again I will retitate the very low we have to be less stringent the level of LDL could well be actually sitting around 3 mm mole per DC dc liter which is acceptable for those with moderate it could actually be at 2.6 6 mill. However, when it comes to high and very high, the level we are aiming at is greater than 50% reduction from baseline

24:57 and this is equivalent to 1.8 mill uh uh as well as 1.4 mill respectively for those with high and very high risk. So the cardiovascular risk categorization in patients with type 2 diabetes is based on uh uh uh several factors. Uh asoscllorotic cardiovascular disease, severe uh actually uh peripheral arterial u peripheral arterial olusive disease or um those who have got a score of diabetes actually greater than two. So the very high risk as I mentioned and I will sum up again we should aim for a

25:42 level of 1.4 or less high risk 1.8 or less moderate risk we can actually accept level of 2.6 mill or less. This recommendation actually has been endorsed and been actually uh recommended again by other leading professional organization like the AAS. They have recommended actually using statin as a prime treatment. And if we do not achieve our target, we have to combine iside with statin. And if we are not yet receiving reaching our target,

26:28 we have to consider actually combining or using the new agent of the BSK 9 uh inhibitors. Other agents could be actually considered like bile acid sequesterant and the combination syrupy could actually comprise all these agents together. So in summary, we know that cardiovascular disease is a leading cause of mortality in patients with type 2 diabetes. We have to consider intervening early and consider intensive LDL reduction. And if the LDL cholesterol is more than 3.2 to in patients who are statin naive, we have

27:15 to consider uh BCSK in addition to statin and very low LDL cholesterol is considered to be safe and effective and it can actually uh uh augment further reduction in cardiovascular uh event rates. And we have to be very proactive using sort of agents sequentially or in combination as early as possible. And we have to aim for a sort of a very actually low level as much as we can in very high risk as well as in high risk patients. I think I will stop here. Mr. Chairman, >> thank you so much Dr. Dar. uh really appreciate this comprehensive review of the uh management steps and uh and

28:02 guidelines related managements. Really appreciate that. Before moving on to our next presenter, I would really like you to uh take a look at this activity that we're doing um which we've been doing every year after the annual congress of GATE. This is the 10th Gulf indocrine review course. Um and this is going to be updated information about management of different medical conditions in every part of endocrinology um field. Uh this is going to be online um November 5 to 5th to 7. Um excellent speakers, excellent reviews um of of many different medical condition. Please scan the code for for the registration. Um also very delighted to present our next presenter, dear colleague and friend Dr. Muhammad Bashir. Um he's a

28:50 senior um oops he's a senior indocrine consultant at medical corporation and also director of the national diabetes center at the women wellness and research center in he will talk to us today about management of disloidemia in a special populations. Dr. So one more time sent you Dr. Thmber for the um introduction and uh my I did something wrong here. So my task here is to give you to go through management of lipids in special situations and I'm going to challenge some of the um uh points that was raised in the guidelines here and bring it up for discussion. So I have no conflict of interest. So let me go by giving discussing three cases um that I've actually seen in um in my

29:35 clinic. So this is a 38 years old woman who has a history of familiar uh dysipidemia. A very strong history of premature cardiac death. Uh she had uh two uncles, one aunt and a cousin who recently died um in their late 30s or early 40s and she has been started on a tobat in 40 40 migs once per day and her LDL was about 1.9 millles per liter. She's actually currently planning for pregnancy and her family physician has advised her to stop statins uh because basically for a fear of for congenital malfformation and I'm going to uh ask the audience here of what will you advise um this patient to do so. So um should you ask her to stop the statins? Will you leave her but switch her to

30:22 reserve a statin? Will you keep her on a toast statin or will you give her phenofibrates? So, um uh would you please uh vote? Um you'll have 20 seconds to vote, please. Great. So, I'm getting about 30% stopping statins and uh the rest is divided between switching to resuba statin or continuing on a statin. So let's dig a little bit into the evidence and before we go over there let's review what happens in terms of metabolic changes during pregnancy and let's focus on the first part of pregnancy where the body is geared towards building up fat. So um the to do this the building of fat the women's are most of the time they are hungry they're eating more the

31:07 insulin sensitivity is actually increased and there is an upregulation in the lioprotein liase leading to enhanced free fatty acid uptake by adibos tissue but at the same time the peripheral uh tissue particularly muscles are using glucose less than more than free fatty acids at that point in time. So the body is geared towarding storing fat. However, as things move on and heading off from 16 weeks onwards, the body start to become more insulin resistant in order to secure glucose for the growing fetus under the effect of certain hormones. The uh insulin resistance that develops gradually over time and peaks or start to increase really above 24 weeks gestation inhibits this activity of the lipoprotein libase and rather than process of lipogenesis.

31:53 Sorry. Uh we are going through a process of lipolysis which produces various uh levels of high levels of free fatty acids and glycerol that is actually currently used by the liver to make more glucose but also says that high levels of free fatty acids are circulating into the system in a form of triglycerides and very LDL and very low density lioprotein. So what actually happens during pregnancy is a significant increase in the levels of total cholesterol uh triglycer LDL and even HDL. They usually increase by about 30 to 50% throughout pregnancy. But triglyceride levels increases two to four fold. And if you take a zoom a little bit into this, you will see this graph here. It mimics exactly what

32:38 happens in terms of insulin resistance throughout pregnancy. High level of triglycerides and high level of cholesterol. So this lady is going to face these changes or this metabolic media throughout the pregnancy and her cholesterol levels are actually distant to significantly increased throughout pregnancy. So what is the the relationship between lipids and placenta and lipids are really central to the development of the placenta because they play critical role in the process of angioenesis which is the initial process of placentation. We know that women who have very low density lipoprotein or triglycerides have tend to be have smaller placental weights and their babies could be a little bit smaller while those with a high level of triglycerides and LDL their placental words are higher and their babies could be a little bit

33:23 larger. Lipids are very important to maintain the function and the integrity of the placenta and it's also important for the transfer of nutrients. So lipids are really essential for the placenta and a healthy uh pregnancy uh per se. So let's go back to the patients who have familiar hyper cholesterolmia and let's look at the risks of cardiovascular disease in this age group. And if you look closely over here you will see that the standard incidence rate of cardiovascular disease of patient with familiar hyperlimmia is particularly high early on um compared to the general population. So it's higher under the age of 50 and that's why you can see a high rate of premature cardiac death. As time goes on, the standards incident rate of

34:08 these complications goes down. But it's also very critical to look at the difference between men and women in this disease. While you can see that there is well very little difference and a lot of overlap between women and men and women in terms of coronary heart disease, it's quite obvious that women tends to be at a little bit higher risk compared to men. And when you look at acute micardian in function, you can clearly see that the women are actually at high risk of developing uh acute micardian function in uh in among patients with familiar hyperlanmia. And when you look deeply in data that published by the United Kingdom, you can look and you can find that at the age group between 30 to 50, there is a significant increase in the risk of morbidity from cardiovascular disease

34:55 among women. at this age group which is basically childbearing age and this study tried to answer the question is why is that and what they found here is very simple that there is a significant delay in starting statins in those women the differences between men and women in this category was almost 5 years delay in starting uh statins that disadvantaged those women and increase the risk of cardiovascular disease but why is that why there is a delay in starting them ended up all to be due due to pregnancy. Women are um uh and this study which is from a Scandinavian one of the Scandinavian countries is basically showed that as the number of pregnancies and breastfeeding increases there is a significant delay in starting um the uh statins in women uh in these

35:44 countries and the median delay is about 2.3 years but it can extend up to 14 years. The more number of p babies they have, the higher is the delay in uh starting status. And as we all know that the risk of cardiovascular disease, the risk of complications is actually related to the duration of exposure to the risk factor. The longer the person is exposed to the risk factor, the higher is the complications or the shorter is going to be uh the time uh between to develop uh complications. And that applies to every known risk factor per se. And what's the why regarding statins? It's actually related to congenital mal foration and there is no evidence that statins increase the risk of congenital mal formations. There's multiple systematic reviews to came out and say well basically women exposed to

36:29 uh statins early in pregnancy there was no increase it's actually neutral uh the risk of congenital malf for another meta analysis that tried to zoom a little bit more to look at any particular at organ specific levels of congenital malfformation and it found there isn't any uh increased risk of congenital malfformation per se. So what they did found is that the there is a lower rate of having a live birth in women exposed to statins and when you zoom in in a different analysis that was actually related to a higher risk of miscarriage in those women. And if you follow with what I said earlier on that the lipids are actually really really essential for the process of angioenesis and a process of development of um of the placenta.

37:15 You will raise a questions like I will do here. Is this the effect of the statins directly medications or it this effect that those women were treated to a very low level of LDL and hence the placental process placentation process was impaired or that those women actually have a level of vasculopathy they are on statin for a reason they because they have a risk of cardiovascular disease. So maybe they have a level of vasculopathy and because of the vasculopathy process the presentation process is actually impaired or it could be the effect of the medications but it could be any of these as well. So there is a high risk of miscarriage. It's undeniable. However, is it the medications or is it other uh other factors? So let's move backward back to 2021 when the FDA

38:01 actually uh came out and they removed the blackbox warning around cholesterol use in pregnancy removing that saying based on the fact that there is no actual evidence of increased risk of congenital malfformation. However, what's really important to point out that's not a license to use statins in all pregnancies. um it's actually opening the door to consider statins in some people with high risk of our cardiovascular disease similar to the patients we have who's actually was extremely anxious uh from the idea that she can stop she's going to stop statins during pregnancy. So are all statins equals in pregnancy? Well, we don't have a lot of studies looking at different form of statins. However, the evidence we have showed us

38:48 that patients exposed to hydrophilic statins uh like pravisatin or roivatin have actually lower rate of having a low birth weight uh or a preterm delivery compared to those exposed to uh patients uh on atrovastatin. Hence in this patient what I did advise her to do is that I switch her to resatin uh and we kept her on treatment throughout the pregnancy. However, we did not particularly titrate the dose because as I said, LDL is destined to increase, but we kept her on the maximum tolerable dose of Rua Satin. Now, moving on to another scenario here. Um, this is a 46 years old man with a history of chronic kidney disease

39:35 secondary to chronic pionritis. is not known to have hypertension or diabetes with the BMI on the overweight category, blood pressure on the higher side, but has an EGFR of 40 mls per minute. The fasting cholesterol is 5.5 and LDL was 3.2, triglyceride was 2.4 and HDL was 0.9 millm moles per liter. And the question is here is what are you going to do here? Are we going to start on a statins? Are we going to measure the cardiovascular risk score first before starting on statins? Will we consider phenop fibbrates or will we start with lifestyle modification and I would please vote. Great. So 45% are going to do measure the statins start on statins and about

40:20 and 39% are actually going to measure the cardiovascular risk score first before considering statins. So let's examine the evidence see where we what are we going to do here. So let's go back to chronic kidney disease and this is the heated mouth from the giggo which shows the the risks of chronic kidney disease or endstage renal disease based on the EGFR and albimic retin ratio and as we go down this uh graph the risk of endstage renal disease is significantly increased in these group of patients however the sim this heated map can actually be represented uh and actually um replicate what we see in terms of cardiovascular mortality. So the same heated map represent endstage renal disease also represent increased risk of

41:08 cardiovascular morbidity and mortality. And we also know if you individually looked at the rate of EGFR decline, we're going to see that the higher the EGFR decline, the higher are the cardiovascular mortality uh and uh overall and cardiovascular mortality per se. So people with endstage kid or chronic kidney disease at high risk of cardiovascular disease per se and you probably have seen this graph that's been presented by my colleague Dr. HUD which basically showed that this is a graph that putting all everything we know about LDL and and cardiovascular risk together in the x-axis is showing the reduction to the uh LDL in the y-axis it is the reduction in the cardiovascular in uh cardiovascular

41:54 heart disease and as you can see as we the higher the more we reduce the LDL the higher is our reduction or the reduction in cardiovascular risk And that's regardless of which you if you looked at Mandelia randomization, prospective studies or randomized control trials. So the lower the LDL, the more is the protective effect. How about patients with cardiovascular with indicadrenal disease. A there are multiple studies that looked at that. One of them is the Aurora study which is looked at ruatin in patients with chronic kidney disease who are undergoing diialysis. And what this study showed is that well resubatin did exactly what is written on the tin. It reduced the uh LDL by 50%. And that happened within 6 months from the

42:39 exposure to the treatment. However, there was no effect on the threepoint maze at all. It was neutral. Um and h ratio was as you can see 96. What's really interesting to point out here is that by the end of the study in five years the um the incidence of um of the primary outcome occurred the primary outcome occurred in 40% of the patients. This is extremely high. This is twice maybe three times what you see in diabetes cardiovascular and uh cardiovascular studies like ember egg or leader trial for example much lower than that. So those group of patients are at extremely high risk of cardiovascular disease. Yet ruaatin didn't help much in this uh category. Well the study was

43:25 replicated in a similar way in a German study that used atvastatin in people undergoing hemodialysis. Again atvastatin did the job brought down the LDL by almost 50%. But again same scenario no benefit in terms of cardiovascular disease. What you can see also and appreciate the instance rate of um of the primary endpoint almost 50% of the patients had a cardiovascular event or died uh within 6 years uh of the expo uh of the study. So extremely high-risisk group with very little almost no benefit actually from exposure to statins. Now another study known as the sharp study which was published in 2011 and the sharp study actually decided to use a combination of simatin and isetamide and they recruited large

44:12 number of patients close to 10,000 one/ird of them on diialysis 23 of them were not on diialysis and the patients should not have history of cardiovascular disease and so it was a primary prevention and they were using simatin 20 migrams plus isetamide 10 milligrams versus a placebo And they were looking at the threepoint uh mace uh as well in addition to um hemorrhage. And what they did show that this time this combination actually worked and there was a reduction about 17% in the primary outcome in people exposed to the sastatin plus. However, there was a catch here and the catch was very simple. When you do a subgroup analysis, you can see that the benefits were only seen in those patients not analysis. But anybody in hemodilysis did

44:59 not benefit from the treatment uh or the combination therapy event rates remain unchanged. And when you put everything everything together in a uh in a meta analysis, it was very clear that the impact of statins in reducing cardiovascular disease is actually lower uh goes down as the EGFR is reduced. So um and if you look on your um on your uh relative risk reduction over here you can see that for example major coronary artery event once the EGFR is less than 40 uh between 30 to 45 sorry uh less than 45 there's no benefit in terms of major coronary events when you look at coronary vascularization again EGFR uh less than 45 there's no benefit uh from

45:44 statins in this age in these groups you look deeper a little bit on stroke and major cardiovascular event you see exactly the same as the GFR goes down the benefit from statins is actually reduced or completely lost um in terms of cardiac uh protection and why is why is that uh that benefit patients with endstage renal disease are not benefiting probably because it's already an advanced atheroscllerotic condition and the intervention is actually quite late some studies were showed but some some studies as you have seen actually stayed for about 6 years. But there's also the issue that there is other things that's increasing the risk of cardiovascular disease which is um uric millio which is you can have inflammation vascular calcification

46:30 independent of the LDL uh per se and you have high risk of mortality for other reasons apart from cardiovascular disease per se. So what do the guidelines says? So basically what the kadigo recommend is that patients not on diialysis above the age of 50 you can use statins plus isetamide. Um and that will go even in those and patients not on diialysis under the age of 50 run a risk score and if it is high then you use statins and is zetamide but those on diialysis you already on diialysis uh you don't start them on isetamide uh or um or statins and if they're already on

47:17 them leave them on the same uh statin and acetam if they're already on them and they end up into diialysis. Same similar recommendations actually from uh the European Society of Cardiology. Uh what the nice guidelines say uh it's a little bit different. They think there's no point using the uh risk engines in any of these groups. Uh they're not accurate including chronic kidney disease. And then we recommend a pragmatic um approach that if you would like to uh use um statins for primary or secondary prevention just use adorbatin 20 milligs. Uh as long as the EGFR is above 30 m per minute you can initiate the medications. Aim for a 40% reduction in primary prevention and LDL less than two for secondary prevention. And then

48:02 you might titrate up tovvisatin as long as the EGFR is above 30. However, once the AGFR goes less than 30, they would recommend that um consultation with a nephrologist, more risk assessment in order to decide should you go more higher with the dose or not. And why did they go with a toastatin? Uh basically because other agents needs adjustment. Rua statin usually maximum dose you use is 10 milligrams. Uh what's the EGFR less than 30 because of a high uh risk of muscle toxicity. Blueatin required those adjustment. Simba statin required those adjustment. Louva statatin requires those adjustment but only atrova and private statin they do not require those adjustment. So that was a pragmatic approach from uh the nice guidelines to this condition. So

48:47 currently I will agree with most of you that we will start them on statins. Um to the last case over here. So we're looking at a 75 years old uh gentleman with a history of hypertension for about 15 years. He's a non-smoker, physically active, works as a solicitor uh uh on a combination therapy of amadopine and prenopril and his home blood pressure is actually normal. HPC is about 5 is 5.9%. His LDL is 3.3 his HDL is8 triglyceride 1.9 and his cardiovascular risk score which you run is about is 10.2%. And the question here will you start on statins? You've seen the guidelines what they say. Will you discuss this with the patient? Will you start on a zetami and

49:34 will you go on a lifestyle intervention alone? Great. So 57% will start the patient on statins and 20% will discuss it with the patients and 14% will go for isettoide. Okay, let's try and dig deep here. The question here that basically are asking is do people above the age of 75 benefit from LDL reduction at all? Because you see the guidelines stopped at the age of 75. Again, I'm showing you the same thing. The lower the LDL, the lower the risk of cardiovascular disease. So, we have studies that try to answer these questions. So the card study which was a toastatin um um at a atrovisatin

50:22 prime prevention study showed that the benefit in patients who have cardiovascular disease was actually seen in patients whether they're above the age of 65 or under the age of 65 with similar benefits in these groups. It all this is it also showed this is the primary outcome of all major cardiovascular events. Same impact on uh age of 65 and under 65. However, what's been striking you can find in this graph is that people under the age of 65, the the benefit is actually seen within one year. However, age above 65, there is a little bit of a delay before we start to see the impact or the benefit uh for um major cardiovascular event using ator statin. So,

51:08 so this is though there is an interesting analysis that tried to look at the time to benefit from intensive statin therapy. How long will it take before you see the impact on cardiovascular outcomes? And this analysis examined actually that and found that when we are using statins, it takes about 15 months dosing patients with established cardiovascular disease before we start to see protection from these agents. Now when you add psychi which usually added on top of statins that will add at 17 month benefit but when you have a zettoide that will take you to a good three uh months or uh sorry a good 3 years or uh close to four years before you start to see any benefit in secondary prevention.

51:55 Now how about primary prevention? This meta analysis looked at age group between 50 to 75 years of age and looked at primary prevention uh were the use of statins and what they did show is well when you use statins there is benefit but is very small so within one year so this is a modeling for about 100 patients treated for um for 7 years one year of exposure you reduce.3 events of maze 3 years 1.3 events of mace are reduced and within 5 years 2.5 events of maze are actually reduce. So there is benefit but it's actually very modest. And when you try to look and see how long does it take before we start to see benefit from a primary prevention point of view, you can actually exa uh look at

52:41 this graph and see that there is variable u u valuable durations actually be reported as low as 1.5 years to as high as 6 years. However, the average is 2.5 years before we start to reduce one cardiovascular event. So statins seem to work. However, it seems to be delayed. So modest effect has no impact on mortality as a primary prevention and it needs 2 and a half years of treatment before you see any benefits. But mind you that the adverse event of statins that gets people to stop it a little bit uh stop it occurs very early in um in the um at the start of the of the treatment within the first few weeks per se. So putting this in mind,

53:28 statins, sorry, statins will work but have a very modest effect in primary prevention. Then there is one of the options that we just shared early on and this is a study known as well I can only read it as utopia 75. uh however this is a study that was done in Japan among Japanese uh population and the study was stopped early stopped early because of the overwhelming benefit which is huge in terms of primary prevention you're talking about 34% risk reduction in the treat in the risk of cardiovascular outcomes in this group exposed to isetami and the impact is actually seen very early on in patients with cardiovascular uh in patients as a primary prevention of cardiovascular disease. This study generated a

54:14 generated a lot of kind of discussion again to and again with supporting it or against it. It stopped early and it's only uh in the Japanese population has not been repeated uh any anywhere else. I don't see they can see a lot of 75 years old people with primary prevention other apart from Japan or uh per se. So generally speaking at this point in time your advice when you look at this gentleman is to discuss this issue with the patient knowing that you need a minimum of 2.5 years of exposure to statins knowing that the side effects is probably going to happen earlier than that knowing that uh the benefits are quite modest in a gentleman uh like him then you need to discuss it with the patient and then get decide together what does he want to do.

55:01 So uh the guidelines um or the uh recommendations in elderly patients actually are split. Some are looking at 65 but some groups are looking at 75. Our patient is represented in American Heart Association. But they basically say you need to do a a risk assessment using a coronary artery calcification score uh something else in addition to uh the clinical risk score. But they did say it is reasonable to use moderate intensity statins and it is uh uh and they reasonable to stop the statins if there is an issue of uh decline in function or reduced life expectancy uh because the there's no much benefits and the the risks of exposure and the uh

55:48 adverse events that impact the quality of life is actually higher. So it is a reasonable option to start somebody on statins. Now after discuss this with the patient he was happy to start on a tovocat in 10 milligrams. He got back in 3 months tolerating the medication although a little bit of stiffness aches and pains uh now and again. Um cholesterol uh LDL came down to 2.7 and the rest hasn't changed that much. So what is your next step here? Are you going to increase that toastatin to 20 milligrams or we're going to start a zetami keep him on change or try PCS canines? This is the last question I promise almost half between atvisatin 20 or no

56:34 change and about a third are going to go for isetamide. So let's examine the option of isetami a little bit. question here is that is it safe to titrate obstatins or we should do something else. Let's examine is because it has an interesting uh scenario in elderly patients. So isamide added to sveastatin um compared to titration of sastatin was shown to be superior to titration of sveastatin in terms of cardiovascular protection in patient who have established cardiovascular disease and this is the well-known improved trial. What I'm not showing here uh is that the benefits were actually much higher in those above the age of 75 than those under the age of 75 of the combination of svestatin plus isetami per se. So there was not a

57:21 huge difference in terms of tolerance of the medications um which is a surprise because simvestatin is notorious at higher doses of causing myopathy. However, other studies showed different things. flow studies that looked at um and this is two different studies uh at the top one which is the tempo study when we add a tovocatin 20 to iset isolite there was a 31 further reduction in LDL versus 11% reduction when we titrate up the tovoatin to 40 mig again similar study we're looking at 40 mig levels of a tovoatin adding a 10 milligs of zetamide you get much greater benefit in terms of L L reduction compared to titrating up to 80 uh milligrams at um

58:07 milligrams dose of a tobatin and this is an interesting study that I try to answer two questions. So if you have somebody on to or toatin 10 milligs not achieving target a switch them add is zetamide b increase the dose to 20 mig c switch them to ruatin 10 mig what it did show that the superior intervention is adding is zetami 10 mig more people achieving LDL less than 100 and more people achieving LDL less than 70 migs per diliter. So it seems the most reasonable option in this gentleman is actually to start a small dose of a zetami. You'll get more benefit and probably we're going to expose uh less exposure to adverse events of

58:52 I would like to thank you at this stage and I back to my colleague uh Dr. Tam. >> Thank you so much Dr. Muhammad really appreciate the excellent review different case scenarios. Uh very good examples and I liked also the enthusiasm of the audience. Very good job in answering questions and being involved in this. Um uh also again um this is our commitment to the uh to the society to deliver the best information available. Uh this is an absolute uh privilege to present the next ACE uh gate congress which will be uh from 16 17th of October in Dubai. Um please do register for this. Please show up. Um there going to be a lot of discussions, excellent u updated information about many topics

59:39 regarding um endocrinology and diabetes. So last and but not least our dear friend Dr. Dr. Ibrahim Mammoon very delighted to present him to uh into this presentation. He's a senior technic physician um and endocrinologist at Sidra Medicine. He's assistant professor of clinical medicine at will kernel medicine um college at Qatar and he's going to be presenting our sponsor symposium of the limit at the core evidence-based cardiovascular risk management. Please Dr. Imams Dr. Ibrahim sorry please start the presentation. Thank you Samir and uh thank you for the organizing committee for uh the invitation. So the uh talk of of today's is about the limits at the core

1:00:25 evidence-based cardiovascular risk management. This is my disclaimer that I receive by Varus. So hopefully by the end of this session you'll be able to understand the epidemological scale of cardiovascular mortality worldwide. recognize the unique and amplified cardiovascular risk profile in patient with diabetes and explain the mechanistic and clinical link between LDL and acidoscotic progression and hopefully apply uh some of the evidence and uh American uh 2026 liit guideline update on clinical practice. So why this matter? Now I think all of us as as practicing physician uh we see every week if not every day uh patients

1:01:10 whose first presentation of diabetes actually cardiovascular event whether it's a micardial inffection, stroke, heart failure or progression of their chronic kidney disease. So the challenge is not whether cardiovascular exists in diabetes. The challenge is whether we need to intervene early enough. I think we uh when we go back to our clinic, we need to uh just to dig deep and see how many of us still have the patient with diabetes with LDL above target despite already being on treatment. We know that the cardiovascular disease is a is a global uh crisis and this is a an old data back to 2015. That's about 18 uh million uh deaths uh due to cardiovascular disease representing one in three of all global deaths. and uh

1:01:56 four out of five of the cardiovascular deaths uh worldwide due to heart attack and and stroke. Unfortunately, uh more than 3/4 uh of these happen in in low and middle inome uh countries. However, most of the cardiovascular deaths are preventable and this is as you know could be the obesity, diabetes, hypertension, uh dysipidemia, uh smoking or sedentary lifestyle we live in. when you look at our region uh the problem is actually uh more amplified and compounded. Uh the reason behind this is that diabetes develop in younger uh patients because uh we see more prevalent obesity and the cardiovascular events appear earlier compared to the

1:02:42 western population. Again I want you when you go back to your uh clinic to to look at the what is the most uh uncontrollable risk factor in your practice. Is it the glycemic control? or is it the blood pressure or is it the uh limit profile? This was shown earlier by Dr. IC that the the uh uh multiple risk factors dramatically amplify the the cardiovascular risk. is that uh if you have uh adding each major risk factor compound to an odd ratio of cardiovascular uh uh uh increase and if you have four for example if you're diabetic hypertension and hyper lipidmia and smoker your uh uh risk factor will

1:03:27 the odd ratio will exceed 42 uh fold increase and this if you add to this any psychological uh factor the the uh odd ratio goes up to three more than 300 about 70 75% of uh attributable cardiovascular risk is accounted by the uh the cluster of the non-modifiable risk factors I alluded to previously. So we look after our patient with diabetes and uh I like to call them the vascular storm uh the the uh cardiovascular risk as you all know uh very rarely go in solo and that in patient with type two diabetes they tend to clusters patient with type two diabetes they've got in increased insulin resistance with the vascular adiposity increased hypertension low HDL

1:04:15 high LDL elevated hypertribulusmia and obviously the inducelian dysfunction and low grade uh inflammation. However, when we uh uh care after our patient with with diabetes, uh we tend to concentrate even the patient tend to concentrate more on the uh glycemic targets and a lot of our patient achieving HB1C of less than 7% but still the LDL uh remain above target and uh there is a shared responsibility between patient physician and the system. We tend to prescribe a statin but the adherence uh determine the outcome. the best drug in the world does not work if patients stop uh after few weeks of prescription of uh statin. There multiple reasons for this uh the

1:05:02 influence of the social media uh driven misconception uh to drive more discontinuation of the medication and uh this can be solved by proactive counseling at initiation of a statin and at each uh visit. also the fear of side effects as I mentioned myalgia is is uh over uh uh estimated and that the concern are frequently cited but the when we look at the evidence compared to the number of patient on a statin uh the the the uh prevalence of myalgia is not that common and I think uh a bit of reassurance with use of dose titration can improve the long-term uh tolerability between our patient we tend to fail to intensify the therapy when targets are not met and This is what we

1:05:48 call a therapeutic uh inertia which remain to be a a systemic barrier to optimal LDL control. I think uh education should be in the core and structured patient education should be at core uh with each prescription initiation and each uh clinic visit. We all know that type 2 diabetes is a major independent cardiovascular risk factor that drive vascular injury, accelerate acilloscerosis and significantly reduce life expectancy. Patient with diabetes has got more than 70% vascular disease uh uh and uh account for over 70% of the diabetic deaths. This is two to four increased

1:06:33 fold in the risk of dying from cardiovascular uh disease in patient with diabetes and about 12 years uh uh average uh reduction in life expectancy among patients with diabetes. So whether you have a prior micardary infection or not the the the risk of cardiovascular disease is high. So in patient without the prior history of micardial infection they have diabetes this increase the cardiovascular death by more than 140%. And in patient with prior micardial infection this will the uh even be more. So diabetes amplify the cardiovascular mortality independent of the schemic history. So we've got the uh uh modifiable risk factors uh but not all of them under

1:07:19 your control. Some of them under the patient control for example they can change the life style in terms of of unhealthy uh diet and uh physical activity uh stopping smoking and uh the use of alcohol. But the some are physician related or they have more control on for example we need to uh tackle their hypertension managing uh the hypertension uh uh via different combination of anti-hypertensive using uh combination uh medication tackling uh hyper cholesterolmia by using the statin and and adivant uh therapy. the new therapies evolved and uh now with the new uh treatment we have for diabetes the optimizing the glycemic control and

1:08:05 continuous monitoring and uh uh tackling the underlying problem within resistant and obesity and the the use of different pharmacoth therapy and structural weight program. You've been shown this before that cardiovascular risk are highly prevalent in patient with with type two diabetes and as you can see that about 66% of patient with diabetes has got this lipidmia and this lipidmia is cited as the most common cardiovascular risk factor in patient with type two diabetes. So the the risks tend to uh uh multiply and that the diabetic smoker with a history of hypertension and this liidmia doesn't have only four risk factors. they have uh more uh uh increased uh

1:08:53 vascular risk. So each additional cardiovascular risk factor compound the biological insult to the to the vessel wall to the incelial dysfunction to black instability accelerate the thrombonogenesis and uh for this reason we need to have a a comprehensive multiffactorial uh risk reduction rather than targeting a single biomarkers uh of blood pressure uh diabetes and uh hyper lipidmia uh in isolation. Don't need to remind you about the target in diabetic patient with different uh target with blood pressure LDL and HBO and C target. If patient doesn't have uh uh diabetes but they have hypertension. We know that hypertension especially suboptimal blood

1:09:39 pressure uh uh can lead to can be a major risk factor for eskeemic heart disease and eskeemic stroke and this is due to the mechanical sheer stress damage the arterial indicium and uh uh leading to initiating a cascade of acceleration of plaque formation. On the other hand, hyper cholesterolmia especially elevated LDL drive the lipid deposition in the arterial walls promoting uh form cell formation and plaque progression and for each 1 millol uh reduction in LDL uh this will reduce the major cardiovascular event by approximately 22%. So if you have uh both hypertension and hyper liidmia which most of the time is the case this will dramatically amplify the risk of

1:10:24 acute coronary uh syndrome and stroke. So if you look at the what we call the cardiovascular continuum that the the cardiovascular disease begin years and even decades before the first clinical event and by the time a patient uh present with angina or heart heart failure stroke or uh a ceroscotic injury has already been accumulating silently and a seroscerotic is cumulative vascular exposure over time. So the question should not be uh should we treat after the the disease abuse but the question should be how early should we intervene. So I think early intervention is the key and that the greatest mistake is a waiting for the LDL to become very high uh for the coronary event to happen for

1:11:11 the uh chronic kidney disease to progress uh for the multiple risk factor complication to occur uh because we uh basically missed the boat because the the black burden is already established in patient with type two diabetes. the risk cardiovascular risk is elevated from diagnosis and statin should be used as a preventive uh measures not as a reactive treatment. So early LDL lowering translate directly to uh few lifetime vascular event. So most of the uh modern guideline principle is that to we need to diagnose early identify patient with type 2 diabetes as a ceroscolic cardiovascular risk equivalent and diagnosis. We need to treat uh proactively by initiating statin therapy and not waiting for the LDL uh to escalate. Uh lower the LDL

1:11:59 early and intervene comprehensively uh uh uh targeting all the risk factor of blood pressure uh glucose and lifestyles simultaneously. It is shown before that LDL has a a causal relationship uh from uh decade of of genetic epidemological and and trial data confirm that LDL uh uh is causal and not just association. Uh uh there is accumulative burden matters. You can think of it the same as smoking that the burden of LDL like a smoking packs per year. How many uh uh cigarettes you smoke, how many years you've been having high LDL. So the longer the exposure the greater the arterial damage and also the risk reduction continue with every

1:12:45 increment in LDL lowering even at already low LDL at baseline. So it's uh well established that LDL uh continuously correlates and linearly correlated with uh uh C c HD or uh heart disease and uh that about uh 30% relative uh cardascular coronary heart disease risk uh for every 30 migram per deciliter increase in in in LDL. It's also important to uh note that uh the not only lower is better but earlier is better and that the evidence uh for the LDL reduction uh is very robust now

1:13:30 and the life exposure to elevated LDL drive the commumulative uh acidoscotic burden making early and sustain intervention the cornerstone of prevention. It's also uh been shown that the uh from uh uh uh B meta analysis data that 22% proportional risk reduction in major vascular event uh per 1 mill uh of LDL uh reduction uh consistent across uh statins and more intensive versus less intensive statins and this is applied to low-risk patients that even individual with the less than 10% uh five year risk uh every each 1 mill mole uh uh per liter reduction yield about 11 fewer

1:14:17 major vascular event per thousand over 5 years and obviously the the benefit is more the higher the risk and this is absolute benefit greatly exceed any known hazards of statin therapy. uh most guidelines such as the uh they recommend the use of a statin in patient with diabetes and as you can see there uh across major international guidelines the first line is statin therapy is recommended for patient with diabetes with or without uh kidney CKD regardless of baseline LDL levels reflecting the high absolute cardiovascular risk conferred by patient with diabetes. uh recommendation from the NICE and and ADA uh that uh uh the 2021 stroke

1:15:03 prevention guidelines reinforce the universal application of statin therapy across patient with diabetes including those with stroke and history of uh chronic kidney disease.

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