identification of high-risk dyslipidemias: from screening...

www.medscape.org/viewarticle/886183

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Identification of High-Risk Dyslipidemias: From Screening to Effect of Treatment


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Target AudienceThis educational activity is intended for an international audience of Asia-Pacific healthcare professionals, specifically cardiologists, diabetologists, endocrinologists, and primary care physicians involved in the management of patients with high-risk dyslipidemia

GoalThe goal of this activity is to present new data on available and upcoming treatments for high-risk dyslipidemia and to improve physicians’ education regarding the management of patients with high cardiovascular risk.

Learning ObjectivesUpon completion of this activity, participants will:

• Challenges associated with identification and management of patients with familial hypercholesterolemia and well as those with mixed hyperlipidemia

• Identification of patients with statin intolerance who would benefit from additional nonstatin therapies to lower their risk for cardiovascular events

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Posted: 28/9/2017

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Disclosures

FacultyWei Chieh Jack Tan, MDAdjunct Assistant Professor; Deputy Head; Senior Consultant, Department of Cardiology; Director, Coronary Care Unit, National Heart Centre Singapore, Singapore, Singapore

Disclosure: Wei Chieh Jack Tan, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Elixir

Served as a speaker or a member of a speakers bureau for: Abbott Laboratories; Medtronic, Inc.; Obus Neich; Sanofi

Received grants for clinical research from: Abbott Laboratories; Beckman Coulter, Inc. Atsushi Hirayama, MD, PhDProfessor; Director, Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan

Disclosure: Atsushi Hirayama, MD, PhD, has disclosed the following relevant financial relationships:

Served as a speaker or a member of a speakers bureau for: Astellas Pharma Inc.; AstraZeneca Pharmaceuticals LP; Bayer HealthCare Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals, Inc.; Chugai Pharma USA, LLC; Daiichi Sankyo, Inc.; Eisai Inc.; Kissei Pharmaceutical Co. Ltd.; Kowa Company Ltd.; Kyowa Hakko Co., Ltd.; Merck Sharp & Dohme Corp.; Novartis Pharmaceutical Corporation; Otsuka Pharmaceutical Co. Ltd.; Pfizer Inc.; Sanofi; Sanwa Kagaku Kenkyusho Co., Ltd.; Shionogi & Co., Ltd.; Takeda Pharmaceuticals North America, Inc.; Tanabe Mitsubishi Pharmaceutical Co.

Received grants for clinical research from: Astellas Pharma Inc.; AstraZeneca Pharmaceuticals LP; Boehringer Ingelheim Pharmaceuticals, Inc.; Chugai Pharma USA, LLC; Daiichi Sankyo, Inc. Dainippon Sumitomo Pharma America; Eisai Inc.; Genzyme Corporation; Goodman Co. Ltd.; Kissei Pharmaceutical Co. Ltd.; Kowa Company Ltd.; Kyowa Hakko Co., Ltd.; Medtronic, Inc.; Merck Sharpe & Dohme Corp.; Mitsubishi Tanabe Pharma Corporation; Mochida; Nihon Medi-Physics Co. Ltd.; Novartis Pharmaceuticals Corporation; Ono Pharmaceutical Co., Ltd.; Otsuka Pharmaceutical Co. Ltd.; Pfizer Inc.; Sanofi; Shionogi & Co. Ltd., Takeda Pharmaceuticals North America, Inc.; Toa Eiyo Ltd.; Zeon Medical Inc.

Brian Tomlinson, MDProfessor, The Chinese University of Hong Kong, Shatin, Hong Kong

Disclosure: Brian Tomlinson, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Amgen Inc.; EMD Serono, Inc.; Sanofi

Served as a speaker or a member of a speakers bureau for: Amgen Inc.; EMD Serono, Inc.; Sanofi

Received grants for clinical research from: Amgen Inc.; AstraZeneca Pharmaceuticals LP; Merck Sharp & Dohme Corp.; Novartis Pharmaceuticals Corporation; Roche

Sam Mirzaee, MD, MPH, FRACPConsultant cardiologist, Research Fellow, MonashHeart, Monash University, Melbourne, Australia

Disclosure: Sam Mirzaee, MD, MPH, FRACP, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: Amgen Inc.; SCM


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Editor

Walid Amara, MDScientific Director, WebMD Global, LLC

Disclosure: Walid Amara, MD, has disclosed the following relevant financial relationships:

Served as an advisor or consultant for: BIOTRONIK; Servier

Served as a speaker or a member of a speakers bureau for: Bayer HealthCare Pharmaceuticals; Boehringer Ingelheim Pharmaceuticals, Inc.; Boston Scientific; Bristol-Myers Squibb Company; Daiichi Sankyo, Inc.; Livanova; MEDA; Medtronic, Inc.; MSD; Novartis; Pfizer Inc.; Physiomed; St. Jude, Servier

Content Reviewer

Nafeez Zawahir, MDAssociate CME Clinical Director, Medscape, LLC

Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.

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Dyslipidemia is a very important risk factor for cardiovascular (CV) disease in Asia, and is often underdiagnosed and undertreated in the Asia Pacific region. In my country alone, patients who present with an acute coronary syndrome (ACS) have a prevalence of dyslipidemia up to above 70%, which is a very high prevalence.

Familial hypercholesterolemia (FH), in particular, is an under-recognized disorder in our region. Although statins are the first-line therapy, a significantly high proportion of patients do not achieve their low-density lipoprotein cholesterol (LDL-C) targets or do not tolerate the treatment well.

Recently proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors demonstrated consistent and highly effective reduction of LDL-C in patients taking maximally tolerated statins.

Wei Chieh Jack Tan, MD: Hello, my name is Jack Tan. I am the deputy of cardiology at The National Heart Centre, Singapore and the current president of the Singapore Cardiac Society. I am also the president elect of the Asian-Pacific Society of Cardiology. Welcome to this session in collaboration with Medscape. This program is titled “Identification of High-Risk Dyslipidemia: From Screening to Effect of Treatments.”


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A recent analysis of the FOURIER trial demonstrated that LDL-C can be reduced to unprecedented low levels on top of statin maximum treatment. A strong relationship between achieved LDL-C levels and CV event rates was also seen in the study.

This reduction in LDL-C was associated with a good safety profile, even in patients with very low achieved LDL-C levels, down all the way to less than 10 mg/dL.

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In this program, we will first present how to identify and manage patients with FH. This topic will be presented by professor Atsushi Hirayama from Tokyo, Japan. Second, we will present the identification and optimal therapeutic management strategies in mixed hyperlipidemia. This topic will be presented by Dr Brian Tomlinson from Hong Kong. Last, we will discuss the management of patients with a common situation of statin intolerance and this topic will be covered by Dr Sam Mirzaee from Melbourne, Australia.

I am now going to pass over to professor Hirayama from Tokyo, who will now address the identification and management of patients with FH.


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Screening, Identification, and Management of Patients With FH

This slide shows the cause of death in heterozygous FH in Japan. Sixty-six thousand men and 55,000 women with FH died because of myocardial infarction (MI) or sudden cardiac death (SCD). The mean age of patients who died from FH is 63 years in men and 72 years in women, which is significantly younger than the mean average age of death in Japan.

Atsushi Hirayama, MD: Hello, I am Atsushi Hirayama from the Division of Cardiology, Department of Medicine, Nihon University School of Medicine in Tokyo, Japan. Welcome to this presentation titled “Screening, Identification, and Management of Patients With FH.”

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This is a case of a young, 30-year-old average patient who suffered from acute coronary infarction. Coronary angiogram showed the occlusion of the proximal left anterior descending artery (LAD) and intravascular ultrasound (IVUS) of the proximal lesion showed a large thrombus. His LDL-C was 398 mg/dL and his Achilles tendon measured 9.5 mm wide.

FH is an autosomal dominant genetic cause of premature coronary heart disease (CHD) as shown previously. This slide shows the prevalence of FH among genetic disorders. FH is more common than other genetic disorders.


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The prevalence of FH globally is estimated between 1/500 and 1/200. Based on this estimation, 3.6 to 9 million patients are in Southeast Asia.

This graph shows the relationship between the accumulation of LDL-C and the threshold of coronary artery disease (CAD). The threshold is modified by sex and several other risk factors. However, LDL-C is a main risk factor.

In homozygous patients, FH exceeds the threshold at a young age. In heterozygous FH patients, the onset of CAD is a little bit greater and modified by statin treatment. Thus, LDL-C lowering therapies should be implemented as early as possible to avoid cardiac events.

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The reason for the necessity of early diagnosis of FH is the high risk for atherosclerotic CV disease due to the long-term, high LDL-C exposure after birth. CV events could be prevented by early discovery followed by an appropriate treatment.

Thus, screening should be performed as early as possible. Less than 1% of patients with FH are diagnosed in the Asia region because most countries in Asia do not have nationwide registries for FH. Another reason underlying the difficulty in diagnosing FH is the wide range of LDL-C levels of patients with FH.


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This Japanese study shows that LDL-C levels range from 450 to 130 mg/dL in patients with FH, indicating that it is very difficult to diagnose FH based only on the LDL-C level.

Although FH is known as an autosomal dominant genetic disorder, there are many known mechanisms causing FH linked to LDL-C receptor function as shown in this slide.

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This slide shows the genetic variance among Japanese patients with FH in the Hokuriku district; 72.6% of patients present low-density lipoprotein receptor (LDL-R) abnormalities and 6.6% have PCSK9 abnormalities. Based on the population, about 1/293 people have LDL-R abnormalities and well over 1/622 have PCSK9 abnormalities. No patients with apolipoprotein B (ApoB) abnormalities were found.

The Dutch Lipid Clinic Network criteria are used widely for systematic diagnosis of heterozygous FH (HeFH). These criteria use a score based on familial history, clinical history, physical examination, LDL-C levels, and DNA analysis. These criteria are widely used in Europe.


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Different diagnostic criteria are used in Asia. Some countries use the Simon Broome FH register diagnostic criteria. Others use the Dutch Lipid Clinic Network criteria or the MedPed criteria. A few countries such as Japan use their own criteria.

According to the Japanese Atherosclerotic Society (JAS) 2017 guideline, HeFH is diagnosed if ≥2 of 3 criteria are identified. These criteria are first, LDL-C level ≥180 mg/dL; second, tendon xanthoma; and third, family history. It is very difficult to measure exact tendon xanthoma according to the standard method. It is difficult for generalized screening in clinical practice.

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We focused on patients with ACS. Among these patients, 5.7% meet the criteria of FH. In patients under 60 years old, 7.8% present with FH. The prevalence of FH among patients with ACS is not low and these patients should be treated by intensive LDL-C-lowering therapy in secondary prevention. Cascade screening also should be done to prevent CV events.

The treatment strategy recommended by the Japanese guidelines is shown in this slide. Patients with FH who are ≥15 years old should be treated and the target LDL-C level is different depending on the patient’s condition. They should receive a statin at the maximum-tolerated dose with or without ezetimibe. If LDL-C targets are not achieved, a PCSK9 inhibitor should be applied to reach the target LDL-C level.


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The diagnosis of FH remains low in Asians countries. Despite the expansive use of statin treatment in Japan and Singapore, the prevalence of well-controlled patients is still low. Thus, the treatment of FH with statins alone is not enough. PCSK9 inhibitors should be used widely for the prevention of CV events in patients with FH.

FH-I and FH-II are 2 randomized, double-blind studies that assessed 78 weeks of remote treatment in patients with HeFH and inadequate LDL-C control on maximally titrated lipid-lowering therapy. After 78 weeks of treatment, the reduction in LDL-C level from baseline was 51.8% in FH-I and 52.1% in FH-II in patients taking alirocumab.

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RUTHERFORD-2, a randomized, double-blind vs placebo-controlled trial, evaluated the effect of evolocumab on LDL-C level in pa-tients with HeFH treated with lipid-lowering therapy. Evolocumab, either 140 mg weekly or 420 mg bimonthly, led to a significant reduction in mean LDL-C at the end of the study by 60.2% to 65.6%.

The effect of evolocumab on LDL-C was also shown in the YUKAWA-2 study. Although the number of patients with FH is low in each group, a significant reduction in LDL-C level by evolocumab was observed in Japanese patients with FH treated by statins. The reason for the significant reduction by evolocumab is due to the increased PCSK9 production after statin treatment.


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I would try to give this message to general practitioners. FH is a common genetic disorder. Patients with FH suffer atherosclerotic CV disease in premature age. We should suspect FH when the LDL-C level is over 180 mg/dL. Family medical interview including family history is important. Careful physical examination should be done, for example, the measurement of tendon xanthoma. Cascade screening should be tried to identify another candidate. Early appropriate LDL lowering is required to achieve the target LDL-C as early as possible by using statins and PCSK9 inhibitors.

Now, please answer the questions to evaluate your learning. Thank you for participating in this Medscape activity. Please continue to follow for the other video presentations.

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Mixed Hyperlipidemia: From Identification to Impact on Prognosis

Mixed hyperlipidemia can be defined by elevated total cholesterol, or perhaps more accurately LDL-C and elevated triglycerides (TGs). It occurs in familial combined hyperlipidemia, type 2B hyperlipoproteinemia, and it is very common in patients who are overweight or obese, as well as in those with metabolic syndrome and type 2 diabetes.

Brian Tomlinson, MD: Hello, I am Brian Tomlinson from the department of medicine and therapeutics at the Chinese University of Hong Kong. Welcome to this presentation titled “Mixed Hyperlipidemia: From Identification to Impact on Prognosis.”


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The numerical cutoff values for LDL-C are shown here according to the level of CV risk. TG is generally regarded as high if it is above 1.7 mmol/L and we can calculate the cholesterol which is associated with those levels of TGs using the Friedwald formula. Then, we can produce non-high density lipoprotein (HDL) cholesterol targets and the values are shown here.

Familial combined hyperlipidemia has been recognized for a long time. It was first described by Goldstein in 1973 at the time that he described FH. It is not so clearly defined, and involves a variation over time in the patients and a variation between family members. The consensus definition of familial combined hyperlipidemia is shown here, and it is thought to be a polygenic rather than a monogenic condition. It can be related to various genetic changes.

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The prevalence of mixed hyperlipidemia in Asia is not clearly known from the data that we have, but we think that it is probably increasing in recent years, largely because LDL-C levels are increasing. Familial combined hyperlipidemia was thought to affect 1 in 100 people, but may be more common. In fact, type 2 diabetes and metabolic syndrome are extremely common now in most Asian countries, affecting 10% or 20% of the adult population.

Some data from Hong Kong and Shanghai showed that combined hyperlipidemia is relatively common, particularly in women over 55 years of age, and the prevalence of raised non-HDL cholesterol was also very high in Hong Kong. Looking at an elderly group in Shanghai, TG levels tended to decline with age after 65 years, so non-HDL cholesterol was not as commonly high as LDL-C, and this group does have high levels of LDL-C quite frequently.


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If we think about how mixed hyperlipidemia affects CV prognosis, LDL-C, of course, is a well-established risk factor, but the role of TGs has been more controversial.

Recent data suggest that TGs contribute to CV risk and we can see that with Mendelian randomization studies.

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Here is a study looking at changes in TGs with a genetic variant in APOA5, and the increases in TG match the increase in CV risk. We can also see that with genetic variants in APOC3, other variants in APOA5, and variants in lipoprotein lipase. This slide shows the effects of genetic variants in 3 different genes: APOC3, APOA5, and lipoprotein lipase. The variants associated with lower levels of TGs here are also associated with lower levels of CV risk.

Variants associated with decreased function of the angiopoietin-related proteins type 4 and 3 (ANGPTL4 and ANGPTL3) have, as a consequence, lower levels of TGs and lower CV risk. This has become a target for new treatments for the management of hypertriglyceridemia.


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If we think about the optional therapeutic strategies for mixed hyperlipidemia, the first thing to do is to improve lifestyle, and then next, we should try to intensify statin treatment. We should avoid the highest doses of rosuvastatin and simvastatin in East Asian patients. The other treatments we can consider for high levels of LDL-C in particular are ezetimibe, bile acid sequestrants, and the PCSK9 monoclonal antibodies. For patients with predominantly high TGs, the treatments maybe fibrates, niacin, and omega-3 fatty acids.

Ezetimibe works on the intestinal uptake of cholesterol and reduces LDL by about 18% to 20%. It is a well-tolerated treatment and there is evidence that it reduces CV events from the IMPROVE-IT study. It also may work better in patients with diabetes.

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The ACCORD study showed that patients with diabetes, elevated TGs, and low HDL-C already on simvastatin alone had a higher level of CV risk. These patients benefited from treatment with fenofibrate. The overall cohort did not show any benefit, particularly if they did not have this atherogenic dyslipidemia. Perhaps fenofibrate has this very specific indication.

Niacin improves all of the different lipid profiles, and it might be a useful treatment for mixed hyperlipidemia, but the 2 large studies that recently have looked at it in patients with very low levels of LDL-C and without high levels of TG didn’t evaluate the effect of this treatment in mixed dyslipidemia.


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The PCSK9 monoclonal antibodies, again, have not been studied very widely in patients with mixed dyslipidemia, but there is this analysis looking back at the phase 3 studies with evolocumab. This slide shows the levels of LDL and non-HDL before and after treatment in the placebo group and the evolocumab-treated group. The effects in terms of changes in LDL and non-HDL are very similar whether the initial TG levels were <1.7 mmol/L or >1.7 mmol/L.

There is also an analysis looking at patients with type 2 diabetes treated with evolocumab. These are the changes in the different lipid fractions and you can see that the reductions in LDL-C and non-HDL-C are very similar in patients with and without diabetes. The TG reduction is a little bit more in people with diabetes, partly because they had a slightly higher level of TG at inclusion.

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There is a study looking specifically at patients who have mixed dyslipidemia and diabetes, the ODYSSEY-DM dyslipidemia study with alirocumab. This study identified patients with diabetes and mixed dyslipidemia defined by a non-HDL-C >100 mg/dL and TG >150 mg/dL. The response to alirocumab in these patients was that the non-HDL was decreased by 37.3% compared with 4.7% in the usual care group. Alirocumab also decreased LDL-C by 43.3%.


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In conclusion, mixed hyperlipidemia, including the polygenic familial combined hyperlipidemia, is quite common in Asian countries, particularly because of the increase in insulin-resistant conditions of obesity, metabolic syndrome, and type 2 diabetes. Also, there is a gradual increase in many Asian countries in LDL-C levels, so these things are combining together.

I think we have good evidence now that increased TG levels are associated with increased CV risk. The treatments that we might have to give are to intensify lifestyle measures and statin treatment, and then we may think about adding other treatments. Fenofibrate may be useful in patients, particularly in those with high TGs and low HDL. If we want to reduce LDL-C, we have ezetimibe, which can reduce LDL-C about 20%, and then the PCSK9 monoclonal antibodies, which can reduce LDL-C by at least 60% in many of the studies, providing a very effective treatment. There are new treatments under development which target APOC3 or the angiopoietin-related proteins and various other lipid mediators.

Now, please answer this question to evaluate your learning. Thank you for participating in this Medscape activity. Please continue to follow the other video presentations.

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Statin Intolerance: What It Means and Why These Patients Are at High Risk

Sam Mirzaee, MD, MPH, FRACP: Hello, my name is Sam Mirzaee and I am a cardiologist and research fellow at Monash Heart Cardiovascular Research Centre in Melbourne, Australia. Welcome to this presentation titled “Statin Intolerance: What It Means and Why These Patients Are at High Risk.”

Statin is the mainstay of treatment of dyslipidemia and the large body of evidence shows that statins can reduce LDL-C and subsequent CV events and mortality. I would like to draw your attention to statin intolerance during the next 10 minutes. A broad range of symptoms has been reported by patients in real-world practice, and also, in literature. The spectrum is from very non-specific symptoms, such as headache, dizziness, and sleep disorder, to very severe symptoms of rhabdomyolysis, leading to debilitating myalgia and muscle pain.


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Recently, an international lipid expert panel tried to unify the definition of statin intolerance. When we talk about statin intolerance, we are basically addressing statin-associated muscle symptoms (SAMS). The most important symptoms of statin intolerance are defined as muscle ache, weakness, soreness, stiffness, cramping, tenderness, or general fatigue. Statin intolerance is the inability to tolerate 2 or more statins because of unexplained musculoskeletal symptoms; 1 of the 2 statins should be below the recommended statin dose, such as atorvastatin or rosuvastatin 5 mg or 10 mg, which is below the recommended guideline dose. It is good to know that 90% of statin intolerance happens in the first 6 months of initiation of the treatment, and the majority of cases are between 10 to 12 weeks of treatments, so we do not expect to see statin intolerance long after starting medication.

In terms of the frequency rate of statin intolerance, the graph on the left-hand side shows the frequency rate of about 20% to 30%; 5% of them have increased creatine kinase (CK). There are about 70% to 80% of patients who can tolerate a statin well. What we can see with statin intolerance is that there is a big selection bias in the literature, mainly due to exclusion of patients with previous statin intolerance, patients with high-risk organ damage and advanced age in previous landmark trials. What we see in real-world practice is more frequent compared with the literature. There are a few demographic factors that can affect the frequency rate, such as advanced age above 85 years, female gender, Asian ethnicity, and of course genetic variance.

I would like to explain a little about Asian ethnicity and why they are at higher risk of having statin intolerance. Generally speaking, Asians can tolerate Western medicine less than the Western population. This is due to the different pharmacogenetics and pharmacokinetics of this population. The other thing is related to smaller body size and smaller muscle mass index, as well as different lifestyles.

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This graph is basically confirming what I explained in the previous slide. This is a summary of multiple Asian studies which have been done in China, Japan, Taiwan, Hong Kong, and a few of them are in multiple centers in South Asia. As you can see on the right-hand side of the graph, the mean LDL reduction is comparative with the landmark trials done in the Western population, but if you look at the statin dose, it is less than half of the recommended dose by European and American guidelines, and some of them are even less. This is basically confirming that in this population, with a lower dose of statin, we can achieve the same LDL reduction. We know that in statin intolerance, the dose is very important because it is completely dose related.

Until recently, we did not have much information about patients with statin intolerance or any studies designed specifically for this sub-group. One of the recent publications is the GAUSS-3 trial, which evaluated the efficacy of evolocumab compared with ezetimibe for the reduction of LDL-C. The study included patients with statin intolerance. After a washout period, in part A, patients were randomized into 2 groups: 1 group received a statin and the other group received a placebo. After 10 weeks and a second 2-week washout period, patients were crossed over to receive the other therapeutic option. All of the patients in this group received 1 period of a statin and 1 period of placebo.


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A substantial number of patients reported muscle pain on placebo, 43 patients in the statin group and 27 patients in the placebo group, which is basically highlighting the placebo effect of statin intolerance. On top of that, I am not surprised that we saw the substantial reduction in LDL-C in patients on evolocumab with a statistically significant P <.001.

The other recent study is the ODYSSEY ALTERNATIVE, which is basically designed in the same population with statin intolerance. They included about 360 patients with a previous history of a statin intolerance as defined in the first slide, and then gave those patients 4 weeks of placebo run. About 50 patients reported muscle pain during this period of time, which is basically highlighting again the placebo effect of statin intolerance.

After this period of time, they divided the population into 3 groups in a 2:1 manner: 1 group received alirocumab and the other groups received ezetimibe or a statin. They looked at the LDL reduction, which was significantly lower in the alirocumab group. At the same time, a substantial number of patients receiving placebo reported muscle pain.

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Why is statin intolerance important in high-risk patients? This is another study recently published looking at the retrospective information about high-risk patients with previous MI on a statin. About 1.6% of the patients reported a statin intolerance, and they looked at CV events, MI, and mortality in this group. As you can see on the right side of the graph, there is a statically significant difference between these 2 groups. The group with statin intolerance had higher risks of CV events and MI. Numerically, it sounds like a higher rate of mortality in those who tolerated the statin well, but when you adjust it with the other, they found that the mortality rate was similar and not significant statistically.

It is good to know the multiple risk factors for statin intolerance as it helps us to tackle the problem in the future. First are the demographics that I briefly mentioned in the previous slides. The second is medication, which is very important. There is a long list of medications that can interfere with cytochrome oxidation in the liver. I just highlighted a few medications we commonly use in clinical practice, such as diltiazem, verapamil, and warfarin, and of course there is a common genetic disposition in CYP isoenzymes and comorbidities; on top of them is hypothyroidism.


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This means that everyone we want to start on a statin should have a baseline thyroid function test. Vitamin D deficiency is the other factor that needs to be checked, and then any other causes for systematic musculoskeletal disease, such as autoimmune disease, rheumatic arthritis, dermatomyositis, etc. Alcohol abuse is the other problem, as well as major surgery and genetic myopathies. Other factors can be important, such as exercise and trauma. It would not be a good time to prescribe a statin, and at the same time, ask patients for exercise and lifestyle changes.

This is a simplified algorithm for statin-induced myopathy proposed by the Canadian Society of Atherosclerosis. As you can see on the right-hand side, we basically take symptoms after a few weeks and use CK as a biomarker of statin intolerance after initiation of a statin. If the patient does not report any symptoms and CK is within normal (usually we do not check CK commonly), then the treatment is continued. However, if there is any evidence of muscle symptoms and CK is within normal range, we suggest stopping the statin for a few weeks, giving a washout period, and then restarting the statin with a lower dose and less frequency.

In the middle line is a CK level that is <10-fold the upper limit of normal (ULN) with symptoms. For this group of patients, we will stop the statin and check it after 4 to 6 weeks and then restart with a different type of statin, either with the low or medium intensity and more hydrophilic statins, such as rosuvastatin, fluvastatin, or pravastatin, at the lower dose and re-challenge them again.

On the right-hand side is the worst-case scenario when the CK is >10-fold ULN with muscle pain. We then consider stopping the statin immediately and treat these patients as they need hydration and their kidneys need to be looked after, with renal function needing to be checked serially. After a few weeks, they need to be reviewed by other specialists or experts to make sure to weigh the risks and benefits of restarting statins in this group. At the same time, we should consider all non-statin options and lifestyle changes in all of these patients.

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There are some emerging therapeutic strategies to assist patients who are statin intolerant. First, which is most important, is risk stratifying patients with a high predisposition to statin intolerance as already mentioned. For this group, we need to use a lower dose and also less frequent statin. The other thing is coenzyme Q10; we do not have evidence-based data for these patients, but it has been shown that it is useful and beneficial to give coenzyme Q10 in this sub-group. The next is vitamin D replacement; in patients with lower vitamin D levels, it has been shown that there are some benefits of giving it at the same time. Using non-statin lipid-lowering is another option, such as ezetimibe, fibrates, niacin, bile acid sequestrants, and PCSK9 inhibitors, which is topical at the moment.

Nutraceutical medication is the other emerging field, with supplements such as red yeast rice and beer brine. There is limited evidence about this group of medications, but they are evolving.


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In conclusion, I would like to draw your attention to a few points. Statin intolerance is real and relatively common in clinical practice. This is the most important cause of poor adherence to statin in high-risk patients. Statin intolerance is mainly defined as statin-associated muscle symptoms and it can occur without elevated CK. Risk factors for statin intolerance should be assessed prior to starting statin. In terms of management, we should think about re-challenging with the treatment after a washout period and also using non-statin agents along with lifestyle changes.

Now, please answer these questions to evaluate your learning. Thank you for participating in this Medscape activity and I hope that you found it useful for your practice. Thank you again.

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From Screening to Effect of Treatments: Keys Messages

Dr Tan: In this program, in summary, professor Hirayama addressed the key messages on screening of FH, which remains an undiagnosed and perhaps undertreated condition in many Asian countries; Dr Tomlinson then addressed the frequent situation of mixed hyperlipidemia and how we classify, diagnose, and manage this condition; finally, Dr Mirzaee presented the consequences of statin intolerance and how to manage this very challenging situation, particularly for patients requiring adequate LDL-C reduction and secondary prevention.

These different patients with high-risk dyslipidemia frequently have LDL-C levels that do not reach their intended targets and are frequently associated with an increase in CV risk. This is particularly so for the subgroup of patients presenting with an ACS. For example, in my country, in Singapore, after an ACS, 20% of patients present with another major adverse cardiac event within 1 year.


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Lipid-lowering therapy should be tailored in this situation to hit LDL-C targets, hopefully without causing excessive side effects. Novel agents such as PCSK9 inhibitors are highly effective agents that have been studied in these situations and can be considered for use. PCSK9 inhibitors have demonstrated a significant reduction in LDL-C.

This is actually demonstrated with outcome trials. The FOURIER outcome trial demonstrated a significant reduction of CV events with evolocumab.

The ongoing ODYSSEY outcome study will also give us much more information about the CV effects of alirocumab in this high-risk population with much longer follow-up.

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I want to end by thanking all of the faculty and participants for staying to the end of this Medscape activity. We hope to hear from you and see you in the next Asian Pacific Society of Cardiology (APSC)-Medscape collaboration. Thank you very much.


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AbbreviationsAdd abbreviations below:Adj = adjustedAE = adverse eventANGPTL = angiopoietin-like ApoB = apolipoprotein BARR = absolute risk reductionASCVD = atherosclerotic cardiovascular diseaseBAS = bile acid sequestrantCAD = coronary artery diseaseCHD = congenital heart diseaseCI = confidence intervalCK = creatine kinaseCoQ10 = coenzyme Q10CV = cardiovascularDHA = docosahexaenoic acidEPA = eicosapentaenoic acidFCHL = familial combined hyperlipidemiaFH = familial hypercholesterolemiaHbA1c = glycated hemoglobinHDL-C = high-density lipoprotein cholesterolHe = heterozygousHR = hazard ratioJAS = Japanese Atherosclerosis SocietyLCAT = lecithin-cholesterol acyltransferaseLDL-C = low-density lipoprotein cholesterolLDL-R = LDL-receptorLLT = lipid-lowering therapyLP(a) = lipolipoprotein aLPL = lipoprotein lipaseMI = myocardial infarctionMS = metabolic syndromeMSK = musculoskeletal disordersNNT = number needed to treatNPC1L1 = niemann–Pick C1-like 1 PCKD = polycystic kidney diseasePCSK9 = proprotein convertase subtilisin/kexin type 9 q2w = every 2 weeksR = randomizedRRR = relative risk reductionSAMS = statin associated muscle symptoms SC = subcutaneousSD = standard deviationSI = statin intoleranceT2DM = type-2 diabetesTC = total cholesterolTG = triglycerideTNFRSF1B = tumor necrosis factor receptor superfamily member 1BUA = unstable anginaULN = upper-limit normalUSF1 = upstream transcription factor 1VLDL-C = very low-density lipoprotein cholesterol

identification of high-risk dyslipidemias: from screening...

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