st st 8 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Lipid Association of India Expert Consensus Statement on Management of Dyslipidemia in Indians 2020: Part III

Expert Consensus Panel: Raman Puri, Chairman1, Vimal Mehta, Co-Chair2, SS Iyengar, Co-Chair3, SN Narasingan, Co-Chair4, P Barton Duell5, GB Sattur6, Krishnaswami Vijayaraghavan7, JC Mohan8, SK Wangnoo9, Jamshed Dalal10, D Prabhakar11, Rajeev Agarwal12, Manish Bansal13, Jamal Yusuf2, Saibal Mukhopadhyay2, Sadanand Shetty14, Prabhash Chand Manoria15, Avishkar Sabharwal16, Akshayaya Pradhan17, Rahul Mehrotra18, Sundeep Mishra19, Sonika Puri20, A Muruganathan21, Abdul Hamid Zargar22, Rashida Melinkari Patanwala23, Soumitra Kumar24, Neil Bardoloi25, KK Pareek26, Aditya Kapoor27, Ashu Rastogi28, Devaki R Nair29, Altamash Shaikh30, Chandra Mani Adhikari31, Muhammad Shoaib Momen Majumder32, Dheeraj Kapoor33, Madhur Yadav34, MR Mubarak35, AK Pancholia36, Rakesh Kumar Sahay37, Rashmi Nanda38, Nathan D Wong39

Introduction proposed by Lipid Association of India regarding various interventions based (LAI),8 identification and application on scientific evidence. The section on ndia is in the middle of an epidemic of lipid markers like lipoprotein (a) low LDL-C levels sums the evidence to Iof atherosclerotic cardiovascular [Lp(a)] and apolipoprotein B (apo the present date and gives justification disease (ASCVD) which is showing B) for risk stratification and control for lower proposed LDL-C goals. Since no signs of abating.1,2 Coronary artery of vascular inflammation. Since hypertriglyceridemia as a component disease (CAD) manifests almost a significant residual risk persists even of atherogenic dyslipidemia is highly decade earlier in India than in Western after high-intensity statin therapy9 and prevalent, a section on triglycerides countries.3 Further, the incidence further lowering of LDL-C beyond that discusses the evidence and gives of CAD is increasing most rapidly achieved by statins has been shown recommendations for approach to among patients younger than 40 years to further reduce CV risk by addition patients with hypertriglyceridemia. of age. About 10%-25% of myocardial of non-statin lipid-lowering drugs in Increased Lp(a) levels are also highly 10-12 infarctions (MI) in India occur before recent large randomized trials, LAI prevalent but are a neglected entity. 4,5 13 the age of 40 years and more than proposes lower LDL-C goals. Hence, the section on Lp(a) deliberates 50% of CAD-associated deaths in India The foundation for prevention on the evidence and recommends 3-5 occur before the age of 50 years. of ASCVD is appropriate lifestyle universal screening of Lp(a) to estimate Although multiple risk factors changes. The section on lifestyle CV risk. The section on C-reactive including smoking, sedentary lifestyle, changes guides the physicians protein discusses the current evidence obesity, hypertension and diabetes are all important contributors to ASCVD, dyslipidemia is the major condition 1Chairman, Sr. Consultant Cardiologist, Indraprastha Apollo Hospitals, New Delhi; 2Co-Chair, Professor Department of Cardiology, necessary for the atherosclerotic GB Pant Hospital, New Delhi; 3Co-Chair, Sr. Consultant and Head, Department of Cardiology, Manipal Hospital, Bangalore, 4 process. Alarmingly, the prevalence Karnataka; Co-Chair, Former Adjunct Professor of medicine, The Tamil Nadu Dr MGR Medical University and Managing Director, SNN Specialities Clinic, Chennai, Tamil Nadu; 5Professor of Medicine, Knight Cardiovascular Institute and Division of Endocrinology, of dyslipidemia [defined according Diabetes and Clinical Nutrition, Oregon Health & Science University, Portland, OR, USA; 6Sr. Consultant Physician and Diabetologist, to National Cholesterol Education Sattur Medical Care, Hubli, Karnataka; 7Clinical Professor of Medicine, University of Arizona and Adjunct Professor of Medicine, Programme (NCEP) guidelines]6 in Midwestern University, Glendale, Arizona, USA; 8Consultant Cardiologist, Fortis Hospital, New Delhi; 9Consultant Endocrinologist, Indians is very high with 79% of subjects Indraprastha Apollo Hospitals, New Delhi; 10Consultant Cardiologist, Kolilaben Ambani Hospital, Mumbai, Maharashtra; 11Sr. 12 having at least one lipid abnormality, Consultant, Department of Cardiology, Apollo Hospitals, Chennai, Tamil Nadu; Sr. Consultant Cardiologist, Jaswant Rai Speciality Hospital, Meerut, Uttar Pradesh; 13Associate Director, Department of Cardiology, Medanta Hospital, Gurugram, Haryana; 14Head with decreased high density lipoprotein of Department of Cardiology, K.J. Somaiya Super-speciality Institute, Mumbai, Maharashtra; 15Director, Heart and Critical Care cholesterol (HDL-C) levels in 72.3% Hospital, Bhopal, Madhya Pradesh; 16Division of Geriatrics, Hackensack University Medical Centre, USA; 17Sr. Consultant, Department subjects, hypertriglyceridemia in 29.5% of Cardiology King George’s Medical University, Lucknow, Uttar Pradesh; 18Director and Head Non-Invasive Cardiology, Max Super 19 20 subjects and elevated low density speciality Hospital, Saket, New Delhi; Professor of Cardiology, AIIMS, New Delhi; Assistant Professor, Dept. of Nephrology/ Transplant, Rutgers Robert wood Johnson University, USA; 21Sr. Consultant Internal Medicine, AG Hospital, Tirupur, Tamil Nadu; lipoprotein cholesterol (LDL-C) levels 22Medical Director, Center for Diabetes & Endocrine Care, National Highway, Gulshan Nagar, Srinagar, Jammu and Kashmir; 23Sr. 7 in 11.8% of subjects. Hence, optimal Consultant, Department of Internal Medicine, Sahyadri Speciality Hospital, Pune, Maharashtra; 24Prof. and Head, Department of management of dyslipidemia is key Cardiology, Vivekananda Institute of Medical Sciences, Kolkata, West Bengal; 25Managing Director and HOD, Cardiology, Excel Care to stem the epidemic of ASCVD along Hospital, Guwahati, Assam; 26Head of Department of Medicine, SN Pareek Hospital, Kota, Rajasthan; 27Professor of Cardiology, Sanjay 28 with control of other risk factors. Gandhi PGIMS, Lucknow, Uttar Pradesh; Assistant Professor, Department of Endocrinology & Metabolism, PGIMER Chandigarh, Punjab; 29Sr. Consultant Department of Lipidology and Chemical pathologist, Royal Free Hospital, London, UK; 30Sr. Consultant, The appropriate approach to Endocrinology, Diabetology and Metabolic Physician, Mumbai, Maharashtra; 31Consultant Cardiologist, Shahid Gangalal National management of dyslipidemia includes Heart Centre, Kathmandu, Nepal; 32Consultant, Dept. of Rheumatology & Medicine, Bangabandhu Shiekh Mujib Medical University, 33 34 identification of subjects with Bangladesh; Head of Department of Endocrinology, Artemis Hospital, Gurgaon, Haryana; Director Professor of Medicine, Lady Harding Medical College, New Delhi; 35Consultant Cardiologist, Lanka Hospital, Colombo, Sri Lanka; 36Head of Department of dyslipidemia, increasing the usage and Medicine, Clinical and Preventive Cardiology, Arihant Hospital and Research Center, Indore, Madhya Pradesh; 37Professor and adherence of statins in suitable subjects, Head of Department of Endocrinology, Osmania Medical College, Hyderabad; 38Consultant, Cardiac Care Centre, South Extension, focus on achievement of LDL-C goals New Delhi; 39Professor and Director, Heart Disease Prevention Program, Division of Cardiology, University of California Irvine, USA st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 9 on the role of inflammation in ASCVD validation cohort was taken comprising 3. Prabhakaran D, Jeemon P, Roy A. Cardiovascular diseases in India: Current epidemiology and future directions. and gives criteria for its use in clinical physicians from across the country Circulation 2016; 133:1605-20. practice. Most importantly, the risk of (May 2020 and July 2020). To ensure 4. Yusuf S, Hawken S, Ounpuu S, et al, for the INTERHEART ASCVD events may be underestimated that the recommendations in this Investigators. Effect of potentially modifiable risk factors by use of LDL-C alone to estimate statement reflected expert opinion associated with myocardial infarction in 52 countries (the INTERHEART study): case control study. Lancet 2004; CV risk especially in subjects with among lipid specialists throughout 364:937-52. atherogenic dyslipidemia. Normal India, a series of 19 meetings were 5. Ardeshna DR, Bob-Manuel T, Nanda A, Sharma A, Skelton or mildly elevated LDL-C levels may conducted in 13 cities involving 162 IV WP, Skelton M, Khouzam RN. Asian-Indians: a review of give a sense of complacency regarding expert health care providers over 11 coronary artery disease in this understudied cohort in the United States. Ann Transl Med 2018; 6:12. doi: 10.21037/ estimation and management of lipid months. Subsequently a total of 55 atm.2017.10.18. risk. Hence LAI proposes that apo B webinars (duration 150 minutes each) 6. Executive summary of the Third Report of the National be universally measured to estimate were held across the country over 3 Cholesterol Education Program (NCEP). Expert Panel the true risk. Because one molecule months period between May 2020 and on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; of apo B is present on all atherogenic July 2020 involving local physicians 285:2486-97. lipoprotein particles, apo B levels will where new Indian guidelines were 7. Joshi SR, Anjana RM, Deepa M, Pradeepa R, Bhansali A, et clearly categorize these patients. In the presented and discussed and comments al. Prevalence of dyslipidemia in urban and rural India: The section on apo B, LAI has given cut-offs recorded. The recommendations ICMR–INDIAB Study. PLoS ONE 2014; 9:e96808. for risk stratification. presented in this document represent 8. Iyengar SS, Puri R, Narasingan SN, et al. Lipid Association of India expert consensus statement on management of Finally, the LAI recommends information collected during these dyslipidemia in Indians. Part 1. J Assoc Physicians India 2016; non-HDL-C as a co-primary target, series of meetings and summarized 64:S7‐52. as important as LDL-C (a position here in this consensus document. These 9. Heart Protection Study Collaborative Group. MRC/BHF Heart recommendations are not binding and Protection Study of cholesterol lowering with simvastatin endorsed by LAI since 2016), for lipid in 20536 high-risk individuals: a randomised placebo lowering therapy. The monitoring of are aimed to provide general guidance controlled trial. Lancet 2002; 360:7-22. non-HDL-C is a simple, practical tool regarding dyslipidemia management 10. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, for treatment decisions relating to to clinicians. The clinical judgment is Theroux P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372:2387-97. lipid-lowering therapy since it does of paramount importance in individual cases and all decisions must be taken 11. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and not require a fasting blood sample clinical outcomes in patients with cardiovascular disease. N and takes care of both LDL-C and after counseling and informing the Engl J Med 2017; 376:1713-22. triglyceride targets. patient in detail (shared decision). 12. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. The Lipid Association of India References N Engl J Med 2018; 379:2097-107. started the process of developing 13. Puri R, Mehta V, Duell PB, Nair D, et al. Proposed low-density this updated consensus statement 1. Duell PB, Mehta V, Nair D, et al. The epidemic of lipoprotein cholesterol goals for secondary prevention atherosclerotic cardiovascular disease in India- Editorial. J in August 2018. It was a two step and familial hypercholesterolemia in India with focus on Clin Lipidol 2020; 14:170-2. PCSK9 inhibitor monoclonal antibodies: Expert consensus process. In the first phase we developed 2. Kalra DK, Sikand G, Vijayaraghavan K, Guyton JR. JCL statement from Lipid Association of India. J Clin Lipidol 2020; the recommendations (August 2018 roundtable: South Asian atherosclerotic risk. J Clin Lipidol 14:e1-e13. to June 2019). In the second phase 2020; 14:161-9. st st 10 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Lifestyle Modification in the Prevention of Atherosclerotic Cardiovascular Disease

ifestyle modification plays an community-based study- The Indian for achieving and maintaining weight Lenormously important role in the diabetic prevention program (IDPP- loss.5 While no specific limitation in reduction of risk of MI and stroke, two 1),3 the progression of DM and effects total fat from calories is specified, a major cardiovascular killers globally. of interventions were studied in native recommendation to keep saturated Lifestyle modification is the cornerstone Indians who were younger, leaner and fat intake to under 7% of calories and of ASCVD prevention. Lifestyle more insulin resistant, with impaired avoidance of trans-fats is noted. modification includes attention to diet, glucose tolerance (IGT). Compared Evidence related to diet and CHD physical activity, alcohol consumption, to the control group, the relative risk A number of studies indicate tobacco usage and stress management. reduction was 28.5% with lifestyle that diets using whole grains as the modification, 26.4% with metformin The importance of lifestyle-related main form of carbohydrates, non- alone and 28.2% with lifestyle risk factors and their role in ASCVD hydrogenated unsaturated fats as a modification with metformin, clearly were clearly highlighted by two predominant form of dietary fat and 1 delineating the key role of life style in landmark studies-the INTERHEART abundance of fruits and vegetables with 2 diabetes progression and prevention. and the INTERSTROKE study. The adequate omega-3 fatty acids can offer INTERHEART study, which was a In the subsequent sections, we significant protection against CAD.6 large, standardized, case-control describe the various components of In the Indo-Mediterranean study, the study of acute myocardial infarction lifestyle management and propose LAI intervention groups consumed more (MI) patients in 52 countries, showed recommendations. fruits, vegetables, legumes, walnuts that the two risk factors, smoking 1. Dietary changes and almonds than did controls with and abnormal lipids, accounted for There can be no single diet which reduction in CHD events in Asian about two-thirds of the population 7 can be prescribed to everyone. Diet Indians. attributable risk (PAR) of an acute prescription should be “individualized” The Lyon Diet Heart Study8 was a myocardial infarction and both showed based on the metabolic status, body randomized single blind secondary a graded relationship with the odds of a mass index (BMI), age and should prevention trial aimed at testing a myocardial infarction. Besides, regular accommodate patient’s lifestyle, eating Mediterranean-type diet vs. a prudent consumption of fruits and vegetables habits, concurrent diseases, financial western diet. It showed nearly 70% were associated with 30% risk status, along with cultural and ethnic reduction in cardiac events with the reduction. In addition, it demonstrated background. For instance, the American Mediterranean type of diet. Various that eating fruits and vegetables, Diabetes Association (ADA) in 2019 other dietary interventional studies undertaking regular physical activity noted that there is no single ideal have also shown similar reduction and avoiding tobacco usage (smoking) dietary distribution of calories among in cardiac events with diets rich in could lead to about 80% lower relative carbohydrates, fats, and proteins, omega-3 fatty acids.9-11 The PREDIMED risk for MI. The study also found which can be prescribed for people (Prevention Con Delta Mediterranean) markedly lower prevalence of physical with diabetes. The macronutrient Study was a primary prevention activity and regular intake of fruits and distribution, should be individualized dietary intervention trial and showed vegetables in South Asians than the while keeping total calorie and that among persons at high risk of western population. Besides, regular metabolic goals in mind.4 cardiovascular disease (CVD), a alcohol consumption was not found to Mediterranean diet supplemented with be protective among south Asians. The More important than a specific extra virgin olive oil or nuts reduced INTERSTROKE study complimented distribution of carbohydrates, fats, the incidence of major CV events.12 the above observations and concluded and proteins is the overall dietary The AHA Guidelines subsequently that 5 risk factors (hypertension, pattern. The 2019 American College of also favored a Mediterranean type of abdominal obesity, diet, physical cardiology/American heart association dietary pattern.13 inactivity and current smoking) (ACC/AHA) Guidelines on the accounted for >80% of global risk of Primary Prevention of Cardiovascular However, after the Prospective all strokes. In terms of prevention, it Disease, effectively summarized Urban Rural Epidemiology (PURE) was demonstrated that intake of fish the recommended diet pattern: ‘all study,14 several controversial findings and fruits (Mediterranean pattern adults should consume a healthy emerged although many experts have diet) was associated with greatest risk diet that emphasizes the intake of raised concerns because of many reduction. It was thus concluded that vegetables, fruits, nuts, whole grains, methodological issues concerning this modifications in BP, physical activity, lean vegetable or animal protein, and study. In this study, 135,335 people smoking, and diet could substantially fish and minimizes the intake of trans from 18 countries were followed up reduce the burden of stroke worldwide. fats, red meat and processed meats, for 7.4 years. The main findings from refined carbohydrates, and sugar- the PURE study were: higher intake Regarding obesity and diabetes sweetened beverages. For adults with of fat (saturated and unsaturated) mellitus (DM), which are closely linked overweight/obesity, counseling and was associated with a lower risk of with ASCVD, the role of lifestyle cannot caloric restriction are recommended mortality, higher carbohydrate intake be underscored. In a prospective st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 11

(>60% of diet) was associated with fats, low in saturated fats, has a high Dietary Approaches to Stop Hypertension a higher risk of mortality, with no fibre content and high PUFA (omega-3). (DASH) diet association between demonstrated Its constituents are fruits, vegetables, This is a dietary pattern similar with intake of total fat or types of fat fatty fish, whole grains, low amounts to the Mediterranean diet that also on CV mortality. This study has been of red meat, lower fat or fat free dairy advocates intake of fruits, vegetables, criticized by many experts in nutrition, products, nuts, olive or canola oil and whole grains, low fat dairy products, in part, due to the limited range of moderate amounts of red wine. It is legumes, poultry, fish, nuts and non- fat intake among the populations proposed that Mediterranean diet when tropical oils. It limits the intake of studied. The recommendation of the combined with regular physical activity sweets, sugar sweetened beverages guidelines restricting total fat to <30% and no smoking, can help avoid 90% of and red meat. Sodium intake in DASH rd or saturated fat to <10% total fat was type 2 DM, 80% of CAD, 1/3 acute MI diet is limited to no more than 2400 17 not supported by this study. In general, and 70% of strokes. mg of sodium/day. In patients with raw vegetables appeared to be more To summarize, the protective effect hypertension, DASH diet has proven to protective than cooked vegetables and of the Mediterranean diet on chronic be effective in reducing BP even more a balanced diet of >3-4 daily servings diseases is provided by antioxidants, than a sodium restricted diet alone. of fruit, vegetables and legumes was anti-inflammatory agents and bioactive In a meta-analysis which included associated with lower mortality. components found in the nutrient seventeen trials on the effect of diet on 1a. Diet Patterns: contents. The diet has a protective effect BP, found that DASH diet, Nordic diet, It is now understood that the dietary against obesity due to the high fibre and Mediterranean diet significantly pattern rather than individual nutrient content which requires increased time lowered systolic and diastolic BP by components are a better approach to in chewing thereby enhancing satiety 4.26 and 2.38 mmHg, respectively. study and recommend to the patients. and also facilitates the secretion of These diets are rich in fruit, vegetables, As a result, several diet patterns cholecystokinin, a known anorexigenic whole grains, legumes, seeds, nuts, fish, are promoted as heart healthy dietary factor. These effects also reduce the risk and dairy and low in meat, sweets, and patterns. The most relevant ones are of developing chronic diseases caused alcohol. Further research is needed to briefly discussed below: by obesity. establish the effect of dietary patterns on BP in different cultures other than Bergeron et al (2019) conducted Indo-Mediterranean Diet those identified in this review.20 a study to test whether levels of For Indians with typically different atherogenic lipids and lipoproteins patterns which also varies by region, Emerging Diet trends differed significantly following a single dietary recommendation is Ketogenic diet consumption of diets with high red difficult to implement. However, an The ketogenic diet encourages meat content compared with diets with Indo-Mediterranean diet is proposed high fat and protein intake, while similar amounts of protein derived from that focuses on consumption of restricting carbohydrate consumption white meat or non-meat sources, and fruits, vegetables, whole grains like to as low as 20-50 g daily.21,22 The diet whether these effects were modified by unpolished rice, whole wheat and is intended to induce a state of ketosis concomitant intake of high compared millets; fatty fish for non-vegetarians in the body, promoting fat loss. The with low SFAs. Subjects were healthy and fenugreek seeds, mustard seeds, high fat and protein content of the diet men and women, 21-65 years, BMI 20-35 flax seeds, soya bean oil, mustard oil for may decrease hunger and promote 2 kg/m , were randomly assigned to 1 of vegetarians (as sources of omega-3 fatty satiety and several meta-analyses have 2 parallel arms (high or low SFA) and acids); and nuts to work as a cardio- produced contrasting results of weight within each, allocated to red meat, protective diet. Extra-virgin olive loss, cardiovascular health benefits, and white meat, and non-meat protein diets oil (an unrefined oil) can be used for long-term mortality.23 The impact of the consumed for 4 weeks each in random cooking but it has a lower smoke point ketogenic diet on cardiovascular health order. LDL-C and apo B were higher than many other oils, which means it remains unclear and does not appear in with red and white meat than with burns at a lower temperature. Besides recommendations by any major society. non-meat, independent of SFA content cooking and baking, it is recommended Intermittent Fasting (P <0.0001 for all, except apo B: red meat that it be used for dipping bread, compared with non-meat [P =0.0004]). dressing, dips, cold dishes. However, Intermittent fasting is the practice This was due primarily to increases this diet pattern has been criticized of alternating periods of normal food in large LDL particles, whereas small for not adequately being supported intake with periods of little to no caloric LDL-C and HDL-C were unaffected by robust data.18 It has recently been intake. A popular weekly regimen is 5 by protein source. The findings were suggested that adherence to the intake days of normal eating with 2 days of in keeping with recommendations of Indo-Mediterranean style diets could restricted eating (about 400 calories per promoting diets with a high proportion markedly reduce the incidence of heart day). Initial results have been promising, of plant-based food.15 failure as well as cardiac arrhythmias. with several studies showing reduced Mediterranean Diet The cardioprotective effects of diets LDL-C levels, decreased systolic and rich in flavonoids and long-chain diastolic blood pressure, decreased The Mediterranean diet has been omega-3fatty acids (PUFA) are most systemic inflammatory biomarkers, and shown to reduce CV morbidity 21 likely associated with their potent improved glycaemic profile. However, and mortality in both primary and antioxidant and anti-inflammatory this diet may be challenging or even secondary prevention.16 A typical actions.19 dangerous for those with pregnancy, Mediterranean diet is moderate in total diabetes or eating disorders. st st 12 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Apart from diet patterns, oils as edible oil in many countries, and there of Clinical Trials showed that coconut cooking media and as dressings has is mixed evidence for its effects on oil consumption results in significantly always attracted much attention. There lipid profiles and CVD risk. CO has higher LDL-cholesterol than non- has been lot of information about the generated discussions about its possible tropical vegetable oils.31 The AHA had various types of oils available and their effects on health, especially for being oil issued a scientific advisory statement in merits/demerits. rich in saturated fat, which is known 2017 to replace saturated fats (including 1b. Oils to contribute to the development coconut and other tropical oils) with of atherosclerosis and CVD. On the unsaturated fats. The AHA advised Since no single oil is ideal, combining other hand, CO contains high levels against the use of CO, and suggested various oils is recommended so that a of lauric acid that is directly absorbed limiting all saturated fat. For those at balance of different fatty acids can by enterocytes and may prevent the risk for or who have heart disease, they be maintained. Coconut oil (CO) and fat deposition in blood vessels. In advise no more than 6% of total calories ghee need special mention as their addition, flavonoids and polyphenols from saturated fat, or about 13 g based use is significantly prevalent in India present in CO may be beneficial in on a 2000-calorie diet. One tablespoon and continues to be hotly debated reducing the oxidative stress involved of CO comes close to that limit at about regarding CV risk. Ghee, also known in the etiology of various diseases, like 12 g of saturated fat.32 Despite the rising as clarified butter, has been utilized CVD and cancer. CO is predominantly popularity of coconut oil because of its for thousands of years in Ayurveda as a composed of saturated fatty acids purported health benefits, Coconut oil therapeutic agent and in ancient India; (SFA), corresponding to approximately should not be viewed as healthy oil for ghee was the preferred cooking oil. In 90% of its total composition. In cardiovascular disease risk reduction the last several decades, ghee has been nutritional terms, a tablespoon of and limiting coconut oil consumption implicated in the increased prevalence CO (13 g) contains about 120 kcal, 12 because of its high saturated fat content of CHD in Asian Indians due to its g of total fats, 11.2 g of SFA, 0.7 g of is warranted. content of saturated fatty acids and monounsaturated fatty acids (MUFA) cholesterol. Ghee (clarified butter) is Key points on oils and 0.2 g of polyunsaturated fatty acids rich in conjugated linoleic acid, a fatty • Smoke point has to be considered (PUFA). The main fatty acids (FA) found acid known to be protective against when choosing oils for frying. in CO are the lauric (12:0), myristic carcinogens, artery plaque formation (14:0) and palmitic (16:0) acids, which • Mustard and Canola oil appear and DM. One tablespoon of ghee has represent 46%, 17% and 9% of the FA, to be most heart healthy as they are approximately 135 calories, all of which respectively. Unlike the long-chain FAs, low in saturated fat, high in MUFA come from fat. It also has a higher which require the aid of lipoproteins and PUFA and they have the highest smoking point and a more complex that can be deposited in various organs, N-3/N-6 ratio. flavor profile.24 CO mostly consists of medium chain • To achieve best health benefits, As of now, there are no large FAs, which are directly absorbed by oils rich in PUFA should be used in randomized controlled trials on ghee the intestine and sent to the liver to be combination with those rich in MUFA consumption. It is another matter that used as energy source.27 like olive oil, mustard oil or groundnut in India, ghee is commonly used in A study to examine the association oil. many households as daily ritual. There between CO consumption and • A combination of oils may be are few small studies in humans in this lipid profiles in a cohort of 1,839 better rather than relying on single oil. regard. A study in a rural population Filipino women (age 35-69 years) Use of both MUFA (Mustard) and PUFA in India showed a significantly lower provided one of the earliest evidence (Sunflower) oils. prevalence of CHD in men who for a relationship between high CO consumed higher amounts of ghee.25 • Trans fats (hydrogenated consumption and beneficial lipid In a study conducted to assess serum fat): Trans fats are produced when profiles in the Philippines.28 However, lipid response to introducing ghee as a polyunsaturated vegetable fats are no convincing evidence exists that partial replacement for mustard oil in artificially hydrogenated, a process that consumption of CO, as opposed to the diet of healthy young Indians (63 increases both their firmness and their consumption of unsaturated oils, led healthy, young, physically active adult resistance to oxidative spoilage. TFA to a decreased risk of CVD.29 A meta- volunteers (52 male, 11 female) showed are present in vanaspati, and reused analysis of 60 controlled trials showed that serum total cholesterol level rose oil that crosses the “smoke point”. that the main fatty acid in coconut fat, significantly in the experimental group Trans fats can be found in many foods lauric acid has the greatest cholesterol at 4 weeks; the rise persisted at 8 weeks. – including fried foods like doughnuts, raising effect of all FAs, but much A similar rise was also seen in HDL-C. and baked goods including cakes, pie of this is due to HDL-C. As a result, Hence the total cholesterol/HDL-C ratio crusts, biscuits, frozen pizza, cookies, lauric acid had a more favorable did not change significantly. The study crackers, and stick margarines and effect on total: HDL-C than any other did not indicate any adverse effect other spreads. The amount of trans fats FA, either saturated or unsaturated. of ghee on the lipoprotein profile.26 in a particular packaged food is LDL-C/HDL-C ratio among CO users is The large amounts of saturated fat mentioned on the packaging. However, significantly lower than the same ratio contained in ghee, however, makes it products can be listed as “0 grams in Palm oil (monounsaturated fatty acid non-ideal and not recommended for of trans fats” if they contain less than 0.5 rich) and corn oil (polyunsaturated grams of trans fat per serving. Current heart health. 30 fatty acid rich) consumers. A recent US recommendations support the Coconut oil (CO) is commonly used systematic Review and Meta-Analysis avoidance of trans fats in any amount. st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 13

• Cooking oils should never be to Indian Council of Medical Research oleic acid. Magnesium and copper re-used as they turn rancid and increase ICMR 2018 guidelines, carbohydrate present in the nut may protect against the trans-fatty acids.4 content should be 55-60%. However, CHD. Since they are rich in calories • Ordinary home cooking does not the consensus statement from lipid and fat, nuts should be consumed lead to a significant production of association of India (LAI) restricts in small quantities. Almonds are trans fats but avoid reaching a point carbohydrate consumption between the best source of alpha-tocopherol 34 where oils starts to smoke, the “Smoke 50-60%. form of vitamin-E and among the Point.” The recommendations for best whole food sources. 70% of fats in almonds is MUFA which helps A brief list of various cooking oils macronutrient intake are summarized 35-36 reduce cholesterol. Eating almonds according to the types of fatty acids in table 3. consistently lowers total cholesterol present in them is mentioned in Table 1. Excessive intake of salt or sodium and LDL-C, respectively by 4-5%. chloride can accentuate hypertension Refined versus unrefined oils Walnuts contain high concentration and also cause water retention. Limit Unrefined oil is processed with of omega-3 fatty acids, alpha linolenic the use of salt to no more than 6g/day minimal or no heat. They are usually acid. Walnuts have highest antioxidant which is equivalent to 2.4g sodium. referred to as cold pressed or expeller activity. Processed (canned and frozen) foods pressed oil. These are also labeled as tend to be the major source of sodium Fibre: Beneficial effects of fibre raw, pure or virgin oils. Refined oils, in the diet; however, use of salt at the operate via different mechanisms on the other hand, have been bleached table should of course be limited. throughout the digestive system or deodorized to extract the maximum including the mouth, stomach and Tips to reduce sodium in diet amount of oil. It can be as simple as small and large intestine; some of which include: Avoid adding table salt on top filtration to more complex processes are still not completely understood. of prepared food. Always wash canned like degumming or acid refining. This Insoluble fibres include cellulose, foods to remove excess salts. Limit process reduces the nutrients in the hemi-celluloses and lignin and soluble the intake of high salt foods such as oil and compromises its effectiveness. fibres include pectins, β-glucan and processed foods (pickles, chutneys and Some oils, like coconut oil, do not hydro-colloids. Systematic reviews of preserved foods), salted nuts. To limit require any refining and can be used trials and cohorts support that high salt intake, add lemon juice for flavor. as such while some, like palm oil, need fibre consumption is associated with refining. Some examples of unrefined Fruit and Vegetable intake: these reductions in the risk for cardiovascular oils are extra virgin olive oil, avocado reduce incidence of stroke, CHD and disease (both heart disease and stroke) oil, sesame oil and macadamia oil. DM. They also result in substantial and lower risk of type 2 diabetes, Some examples of refined oils include improvement in BP, lipid levels, insulin lower LDL-cholesterol, lower blood canola oil, rice bran oil, soya oil and resistance, adiposity and endothelial pressure, and some cancers.37 However, sunflower oil. function. Flavonols, powerful health- consumption of fibres is far less than It is advisable to avoid refined giving chemicals which can protect what is recommended. The average oils, since during the refining process; against heart disease, are found in fruits American gets about 16 grams of fibre oils are heated to high temperatures and vegetables. Red onions are full of a day38 as opposed to the recommended resulting in their degradation and flavonols whereas white onions have 30 grams.39 practically none. Unlike many vitamins generation of toxic substances. Refined Fish and fish oils: Modest flavonols are not easily destroyed by oils, particularly high in PUFAs, consumption, particularly, non-fried, cooking; 4 to 5 servings of fruits and degrade easily and therefore, should oily fish, (2 servings/week) lowers vegetables daily are recommended. be avoided for frying. In contrast, oils CHD mortality. Omega-3 FAs are the Fruits and vegetables are also the high in saturated fats (like ghee) can key beneficial component responsible richest source of fibre. Raw foods be used for Indian cooking, as they are for this benefit. Fish oils contain the 33 contain more fibre than the processed comparatively stable during frying. omega-3 PUFAs- eicosapentaenoic ones. Choose fresh, colorful fruits Key Points on diet acid (EPA) and docosahexaenoic acid rather than canned fruits or juices. Have (DHA) which has pleiotropic, anti- • Dietary patterns are more a salad every day. important rather than individual inflammatory, antioxidant, and anti- Seeds and Beans: They lower the dietary components hence adopt a platelet properties. Fish oil causes a incidence of CHD and DM, lower dietary pattern that emphasizes intake decline in hepatic VLDL production LDL-C, inflammation and improve of vegetables, fruits, whole grains, and increase VLDL clearance. By endothelial dysfunction. low fat dairy products, poultry, fish, increasing LPL activity, it enhances legumes, non-tropical vegetable oils Nuts: Modest nut consumption clearance of TG rich lipoproteins. At and nuts etc. lowers cardio metabolic risk. Active a dose of fish oil of 3-4g/day, plasma components are fibre, folate, phenols, TG levels are reduced by about 25-50% • Carbohydrates (table 2) can be tocopherols and plant proteins. A after 1 month of treatment. Higher simple and complex. Examples of growing body of scientific evidence consumption of fish and n-3 fatty simple are Maida, sugar, honey, fruit suggests potential beneficial effects acids were associated with multiple juice and cola. Simple carbohydrates from the ingestion of tree nuts such measures of lipoproteins that were are sugars that should largely be as walnuts, almonds and pecans. mostly consistent with cardiovascular avoided. Complex ones are cereals, They contain high amount of prevention, (reduced total cholesterol, pulses, vegetables and fruits. According monounsaturated fat in the form of LDL cholesterol, apolipoprotein B, and st st 14 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Table 1: Brief list of various cooking oils Table 2: Complex carbohydrate and fiber content of cereals which are commonly used in used in India according to the different parts of India. types of fatty acids (% of total fatty acids)41 Geographic Region High Carbohydrate High Carbohydrate Low Carbohydrate in India Less Fibre Moderate Fibre High Fibre Fats/oil SFA MUFA LA ALA South Maida Finger millet Green gram whole/Muttar Black High (Medium Chain) SFAs Red rice gram whole/Kali Urad Parboiled rice Bengal gram whole/Chole Coconut 92 6 2 - Brown Rice Black Kidney beans/Rajma Palm Kernel 83 15 2 - North Maida Jawar / Sorghum Black Kidney beans Butter/Ghee 68 29 2 1 Buckwheat/Kuttu Green gram whole High SFAs and MUFAs Whole wheat flour Red gram Barley Bengal gram whole Palmolein 39 46 11 <0.5 West Maida Brown Rice Red gram High MUFAs and Moderate LA Buckwheat/Kuttu Chole /Bengal gram whole Groundnut 19 41 32 <0.5 Whole wheat flour Muttar/Green gram whole Rice bran 17 43 38 1 Maize Kali /Black gram whole Sesame 16 41 42 <0.5 East Maida Brown Rice Rajma/Black Kidney beans/Green High LA Buckwheat/Kuttu gram whole Whole wheat flour Kali Urad/Black gram whole Cotton seed 24 29 4 1 Maize Chole/Bengal gram whole Corn 12 35 50 1 Safflower 9 13 75 - Table 3: LAI Recommendations for daily intakes of macronutrients: Sunflower 12 22 62 - Carbohydrates Proteins Fats Fruits, fibres and sodium LA and ALA 50-60% energy intake/day 10-15% energy/day 15-30% energy/day Soya bean 14 24 53 7 Prefer complex Sources- Components: 4-5 servings of fruits and Canola 6 60 22 10 carbohydrates. Low Non-vegetarian: fsh, lean - Saturated fats: 10% vegetables daily of 100 g Mustard/rape seed 4 65 15 14 glycemic index and low meat, egg whites, low fat - Trans fats: nil each/day Flax seed 10 21 16 53 glycaemic load foods are dairy products - MUFA:10% preferable Vegetarian: Pulses, - PUFA:8-10% (omega-6: High TFAs legumes, whole grams etc. 5-8%, omega-3: 1-2%, Vanaspati 46 49 4 - omega-6/omega-3 ratio: SFA=Saturated Fatty Acids, TFAs=Trans Fatty 5-10) Acids, MUFA=Monounsaturated Fatty Acids, More than 50% grains Sources of PUFA Higher intake of fbres LA=Linoleic Acid, ALA=Alpha Linolenic Acid should be whole grains - Omega-6/Linoleic acid (25-40 g/day) daily (LA): most vegetable larger LDL size.40 oils, except coconut oil - omega-3: Meat: Red meat such as from beef * Alpha-linolenic acid and lamb is a major source of saturated (ALA, the parent fat in the diet, which can significantly compound of omega 3): e.g.soyabean/mustard/ raise blood cholesterol levels. Processed canola oils, flax seeds, meats more than unprocessed meats fenugreek seeds, increase the risk of diabetes and green leafy vegetables, walnuts etc. coronary heart disease (CHD). * Eicosapentaenoic acid Dairy: Consumption of low and (EPA)/docosahexaenoic acid (DHA)-oily fsh especially fat-free dairy products * Cholesterol 200-300 mg/ (like skimmed milk and yoghurt) is day associated with lower CHD/DM/stroke. Sugars- Reduce sodium intake <10% of total calories from <2400 mg/day • Tea/Coffee: There is little evidence sugar. related to the beneficial effect of these Minimize sucrose intake beverages. It is however believed when substituting for starch that green tea (>2 servings/d) lowers Avoid sugar-sweetened CHD, stroke and diabetes risk. Green beverages and sweets tea lowers LDL-C, and it contains Substitute with water, more polyphenols than black tea. The buttermilk, tender coconut water, green polyphenols present in tea prevent the tea etc. oxidation of low-density lipoprotein by effects of exercise,42 including skeletal damage.41 Intervention studies have inhibiting formation of atherosclerotic muscle growth, vascular remodeling, reported that both aerobic and strength plaques. Frequent (>2 servings/day) and beneficial effects on metabolism. training have favorable effects on CV coffee intake also reduces risk of CVD: A number of studies have risk factors in individuals at high risk diabetes. 45-47 shown a strong inverse relationship for CVD. 2. Physical Activity: between habitual exercise and the Diabetes: Aerobic exercise may 2a. Benefits of exercise risk of CHD, cardiac events, and CV improve glycemic control and insulin Exercise has always been highlighted death for both primary and secondary sensitivity and may prevent the as a cost-effective prevention strategy prevention.43,44 Exercise also induces development of T2DM in high-risk for CVD. Both human and animal studies structural changes in cardiac muscle, groups. have demonstrated multifactorial which helps to protect against ischemic Cancer prevention and st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 15 treatment: Exercise may provide particular importance to Indians, who in greater oxygen consumption by the modest protection against breast, have increased proportions of small, body than it would do while resting. intestinal, bladder, kidney, lung, dense LDL particles. However, the benefits of exercises stomach, esophageal, prostate, A Longitudinal Analyses in the are related to the “dose” – which 44,48 endometrial, and pancreatic cancers. UK Biobank Study involving a large encompasses its duration, intensity Obesity: Compared with a weight cohort of 502, 635 individuals, 40 to 69 and frequency. The intensity of exercise loss diet alone, diet coupled with either years of age, analyzed the associations is generally categorized as either exercise or exercise and resistance of objective and subjective measures moderate- intensity dynamic aerobic training is associated with a greater of fitness and physical activity with exercise or vigorous- intensity dynamic reduction in body fat and enhanced 6 CV outcomes and total mortality, aerobic exercise. When using absolute preservation of body lean mass, and explored these associations in terms, exercise can be categorized compared with weight loss diet alone. individuals with different genetic as- Light intensity activities: 1.1 to 2.9 METs of energy expended during an Osteoporosis: Weight bearing burden for CVD. Study revealed that activity, Moderate-intensity activities: exercise is associated with an increase Fitness and physical activity has 3.0 to 5.9 METs of energy expended in bone mineral density in men and inverse associations with incident CVD during an activity, and Vigorous- women. in the general population, as well as in individuals with elevated genetic intensity activities: ≥6.0 METs of energy Gallstones: Physical activity is risk for these diseases.59 Among those expended during an activity. associated with a decreased risk of at high, intermediate, or low genetic There is no single exercise cholelithiasis. predisposition for CHD and AF, there prescription for all adults; exercise Cognition: Exercise has been was a graded inverse association with should be individualized to suit the associated with improved cognitive these parameters among each stratum patient’s capabilities and to prevent function in both young and older of genetic risk. UK Biobank Study also injuries and to maximize incentives adults.49 suggested that in the longer term, for maintaining a consistent regimen. Psychological: Regular exercise identifying subgroups based on genetic In general, reasonable weekly goals is associated with improved sleep, risk that benefit most from lifestyle for dynamic aerobic exercise are at reduced stress and anxiety, and a lower interventions could help personalize least, 150 min of moderate-intensity risk of depression.50 prevention strategies of chronic physical activity (approximately 30 Physical activity thus has linear diseases. Furthermore, personalized min/day, ≥5 days/week) or at least, 75 relation with multiple health prevention and treatment strategies min of vigorous- intensity physical benefits.51,52 It increases left ventricular could help motivate individuals more activity (approximately 30 min/day, ejection fraction, arrhythmia threshold, efficiently compared with general ≥3 days/week). For additional or more HDL-C, promotes fibrinolytic activity, guidelines. extensive health benefits, adults should insulin sensitivity and psychological Physical inactivity - Indian scenario increase their aerobic physical activity to 300 min/week of moderate intensity wellbeing.53 It decreases non-HDL-C, The World Health Organization or 150 min/week of vigorous intensity TG, LDL-C, total cholesterol, platelet (WHO) in 2010 stated that physical activity. A combination of moderate aggregation, abdominal obesity and inactivity was the fourth leading cause and vigorous intensity activity can also body weight. Further exercise has also of mortality globally.57 been shown to reduce PCSK-9 levels. be implemented. According to ICMR in 201460, 392 The most extensively studied form In the HERITAGE family study, million people were inactive in India of exercise is dynamic aerobic exercise the largest published interventional representing nearly one third of our which is regular and purposeful study, 675 normo-lipidemic subjects population. There was high prevalence movement of large muscle groups in were given 20 weeks of supervised of obesity, T2DM, metabolic syndrome moderate and/or vigorous activity exercise. Their HDL-C concentration and CHD in India. The Indian diet that places stress on the CV system. increased by 3.6 ± 11 % in both males and lifestyle were the main reason for Examples include: brisk walking, and females compared to baseline premature CHD and also early onset of jogging, dancing, cycling, swimming but with significant inter-individual type-2 diabetes.61-63 variability. A significant reduction and using certain exercise equipment. The evidence-based Guidelines on (p<0.01) from baseline levels in plasma The evidence on dynamic resistance physical activity have been proposed by total and VLDL was also observed only exercise is limited. Common type of the WHO57, AHA64 and US department in the 24h post training specimens dynamic resistance exercise is weight of health and Human services.65 reflecting a response to the last bout lifting often with the use of exercise of exercise.54 As for LDL-C physical 2b. Classification of exercise equipment. These types of exercises activity alone has shown no significant Exercise has been classified as are typically performed with a goal effect as shown in several systemic isotonic, isometric and aerobic.65 of progressively increasing muscle reviews.55,56 Nevertheless, resistance Dynamic (isotonic) refers to regular, strength. training over longer periods may purposeful movement of joints and 2c. Risks of Exercise reduce LDL-C also. 57 Physical activity large muscle groups. Isometric exercise In the majority of patients, the appears to increase the average size of involves the static contraction of benefits of physical activity far LDL particles and reduce the number muscles without joint movement while outweigh the possible associated of more atherogenic, small, dense aerobic exercise is any activity which risks. Musculoskeletal injury is the LDL particles.58 This observation is of uses large muscle groups and results st st 16 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Table 4: Salient points from relevant guidelines on physical activity. document.71

US Department of Health WHO AHA Indian Consensus Ideal Body Weight and Human Services Document Maintaining an ideal body weight is Avoid inactivity - - Physical inactivity should be avoided as much as essentially related to diet and physical possible activity. The cut-off of increased Aerobic Physical Activity BMI for Indians is 23 kg/m2. The Adults should do at least Adults aged 18-64 should Adults should do at least A total of 60 min of Asian Indian-specific guidelines for 150 min/week of moderate do at least 150 min of 150 min/week of moderate physical activity daily, defining and managing overweight intensity activity moderate intensity intensity activity which includes aerobic and obesity have defined normal BMI aerobic physical activity activity, and muscle- 2 throughout the week. strengthening activity. as 18.0–22.9 kg/m , overweight as those 2 OR 75 min/week of vigorous At least 30 min of with BMI between 23.0–24.9 kg/m and intensity aerobic exercises moderate- intensity obesity as those having BMI ≥25.0 kg/ aerobic activity (e.g. brisk m2.72 walking, jogging, hiking, gardening, bicycling etc.), While BMI remains the most widely 15 min of work – related used clinical method of measuring activity (e.g. carrying heavy loads, climbing obesity, in the case of the Indian stairs etc.) and 15 min population, the measurement of waist of muscle strengthening circumference (WC), should also be exercises considered as important as BMI, if 75 min/week of vigorous At least 75 min of intensity aerobic exercises vigorous intensity not more. The recommended waist aerobic physical activity circumference for Indian men is 90 throughout the week cm or 35.4 inch (it is 102 cm/40.1 inch OR globally) and 80 cm or 31.5 inch for An equivalent An equivalent A combination of Aerobic activity should be Indian women (as opposed to 88 combination of moderate combination of moderate moderate and vigorous performed in bouts of at and vigorous intensity and vigorous intensity intensity aerobic activity least 10 min duration cm/34.6 inch globally). Asians and aerobic exercises activity South Asians in particular, have more Aerobic activity should Aerobic activity should be Aerobic activity should severe inflammation, insulin resistance, be performed in episodes performed in bouts of a be performed in episodes of 10 min and be spread least 10 min duration. of 10 min and be spread and liver fat even when non-obese by throughout the week throughout the week BMI standards used for Caucasians.72,73 AND In addition to increasing the risk of Muscle strengthening Muscle – strengthening For lowering blood Adults should increase hypertension, overweight and obesity Adults should do muscle activities should be done pressure and cholesterol, their moderate- intensity increase CV risk through adverse effects strengthening activities involving major muscle an average 40 min of aerobic physical activity to on lipids, insulin resistance, and other that are moderate or high groups on ≥2 days/week moderate- to vigorous 300 min/week, intensity and involve all intensity aerobic activity, cardio-metabolic processes. major muscle groups on Adults should increase 3 or 4 times/week Engage in 150 min of 3. Alcohol ≥2 days/week their moderate – intensity vigorous intensity aerobic For additional health aerobic physical activity physical activity/week An updated meta-analysis of 34 benefts 300 min/week to 300 min/week, or prospective studies showed a J-shaped of moderate intensity activity. Engage in 150 min of relationship between alcohol and total 150 min/week of vigorous vigorous-intensity aerobic mortality in both men and women.74 intensity aerobic exercises physical activity/week Consumption of alcohol up to 4 drinks/ OR day in men and 2 drinks/day in women An equivalent An equivalent An equivalent was inversely associated with total combination of moderate combination of moderate- combination of moderate- and vigorous intensity and vigorous- intensity and vigorous intensity mortality in western population. aerobic exercises activity. activity. Heavy drinking was associated with most common risk of exercise. More elevation of creatine kinase (CK) are an increase in mortality, hypertension, serious but much less common risks common following physical exertion. alcoholic cardiomyopathy, cancer include arrhythmia, sudden cardiac The CK levels can rise several-fold, and cerebrovascular events including arrest and MI. Those who engage in particularly after intense exercise for cerebrovascular hemorrhage. A host sports activities run a higher risk of extended periods of time (e.g. marathon of mechanisms have been postulated incurring minor injury but people running).68 to explain the benefit that light to moderate alcohol intake has on the who do not participate in regular Bronchoconstriction — Exercise- heart, including an increasing HDL-C, exercise are more likely to incur more induced bronchoconstriction occurs in increase in fibrinolysis, reduction severe injuries when engaging in such the majority of patients with current in plasma viscosity and fibrinogen activity. Myocardial infarction or symptomatic asthma.69 Other effects — concentration, decrease in platelet Sudden cardiac death (SCD) is rare but Hypothermia, hyperthermia, and aggregation, reduction of inflammation, may occur during physical activity, dehydration are potential preventable improvement in endothelial function particularly among those with multiple risks associated with physical activity.70 and promotion of antioxidant effects.75 cardiac risk factors and those who Table 4 summarizes the salient features 66,67 exercise infrequently. from the recommendations of the Observational studies provide Rhabdomyolysis — Subclinical major organizations for physical strong evidence that moderate amounts myoglobinemia, myoglobinuria, and activity, including the Indian consensus of all alcoholic drinks are linked with st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 17 lower risk. Thus, the substantial portion lowering the maximum HR that can Healthcare professionals play an of benefit is from alcohol rather than be achieved. Smoking and tobacco important role in tobacco cessation other components of each type of chewing have equal and comparable interventions; in fact, advice from a drink (e.g. beer, wine or spirits).76 adverse effects on the lipid profile and physician increases by 66% the chance However, it is important to note that therefore raise the CV risk in same that a smoker will make a successful most of the benefits of moderate alcohol proportion. Smoking cigarettes with quit attempt.84 Smokers who quit start consumption apply to the Western lower levels of tar or nicotine does not to improve their heart health and population. In the INTERHEART study, reduce the risk for CVD. reduce their risk for CVD immediately. regular alcohol consumption did not Besides, exposure to second hand Within a year, the risk of heart attack demonstrate protective effect on CHD smoke causes heart disease and stroke drops dramatically, and even people 77 among South Asians. Hence, alcohol even in nonsmokers.81 There is no safe who have already had an MI can cut intake even in moderation should be lower limit of exposure to secondhand their risk of having another if they quit avoided by Indians, since it has no smoke.82 More than 41,000 preventable smoking. Within 5 years of quitting, virtues to offer. However, the per capita deaths occur in United States from smokers lower their risk of stroke to alcohol consumption in India increased CHD caused by exposure to second about that of a person who has never from 2.4 liters in 2005 to 4.3 liters in hand smoke. Therefore, 2019 AHA/ACC smoked. 78 2010 and 5.7 litres in 2016. guidelines on the primary prevention The 5A’s strategy is suggested Patients with ASCVD who have of CVD recommend that patients be for achieving avoidance of tobacco never tasted alcohol should not be advised to take precautions against products in clinical practice.85 encouraged to take up regular alcohol exposure to secondhand smoke and Ask: systematically identify all consumption. However, for patients aerosol from all tobacco products. tobacco users at every visit. who drink, alcohol should not exceed Electronic Nicotine Delivery Systems Advise: strongly urge all tobacco up to 2 drinks /day for men and Electronic nicotine delivery systems users to quit. 1drink/day for women. (1 drink =1.5 oz (electronic cigarettes, e-cigarettes or distilled spirits, 5 oz wine, 12 oz beer. Assess: determine willingness to vaping devices) deliver nicotine by A standard drink is equal to 14.0 grams make a quitting attempt. heating a solution, called e-liquid, that (0.6 ounces) of pure alcohol. Assist: aid every willing patient in contains nicotine, propylene glycol and quitting by behavioral counseling and 4. Tobacco a wide range of additives and flavoring pharmacotherapy Smoking is a major cause of CVD agents. Because they do not burn and an independent risk factor for tobacco, e-cigarettes expose the user to Arrange: schedule for follow-ups atherosclerosis, CHD and peripheral fewer and lower levels of the harmful For those requiring pharmacotherapy artery disease. It causes approximately chemicals found in cigarette smoke. to aid in quitting, nicotine gums, 1of every 4 deaths from CVD, according Therefore, they are likely to be less lozenges, patches, inhalers, nasal spray to the 2014 US Surgeon General’s Report harmful than continuing to smoke, even are available.86 Nicotine replacement on smoking and health.79 Globally, though they are not harmless because therapy (NRT) is available even without cigarette smoking is a predominant users are exposed to nicotine and other a doctor’s prescription. Medicines form of tobacco consumption whereas chemicals. According to a white paper for which a prescription is needed in India, Beedi and tobacco chewing on e-cigarettes by the Indian Council of are bupropion and varenicline. are widely prevalent. There is a dose- Medical Research (ICMR), depending Pharmacotherapy is generally safe, response relationship between the on the battery output voltage used and is clearly safer than continuing number of cigarettes smoked/day nicotine solvents can release in varying to use tobacco products. Despite and CV mortality and morbidity.80 amounts, potential carcinogens such some controversy regarding the Cigarette smoke contains more than as acetaldehyde, formaldehyde safety of bupropion and varenicline, 4000 chemical substances, including and acetone. The liquid-vaporizing regulatory agencies consider these nicotine and carbon monoxide (CO) solutions also contain “toxic chemicals drugs as having a favorable benefit/ that can have harmful effects on and metals that can cause several risk profile. However, given the high cardiovascular function. These adverse health effects including cancers rate of psychiatric comorbidity in basic ingredients of tobacco smoke and diseases of the heart, lungs and dependent smokers, practitioners cause an increase in oxidative stress, brain”. E-cigarettes also contain volatile should closely monitor patients for endothelial damage and dysfunction, organic compounds, heavy metals, such neuropsychiatric symptoms. Second- and are associated with significantly as nickel, tin and lead. E-cigarettes are line pharmacotherapies include higher serum concentrations of total increasingly popular among youth and nortriptyline and clonidine. 83 cholesterol and TG, and lower levels dual use with cigarettes is often seen. A recent study among the general of the cardio protective HDL. By E-cigarettes are however, banned in public showed that tobacco cessation causing intravascular inflammation, India. therapy did not increase the risk of smoking promotes the development The consumption of tobacco serious CV events.86 of atherosclerosis and cardiovascular products in any form, including 5. Stress management disease. Nicotine deregulates cardiac flavored or unflavored E-cigarettes autonomic function, boosts sympathetic should be avoided completely. Since According to the INTERHEART activity, and increases heart rate (HR) nicotine is a highly addictive substance, study stressful life events were more at rest, while blunting HR elevation quitting tobacco use can be challenging. common within the prior year in during progressive exercise and patients with MI than among controls. st st 18 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Psychological stress is also a predictor practitioners. Stress is a powerful However, the reported studies have of fatal ischemic strokes. Most of risk factor for CVD which largely several limitations and larger studies the associations can be explained goes undetected, is not managed are needed to confirm these findings. by behavioral changes such as lack appropriately and is thus increasing to Even then, meditation is widely being of physical activity, diet, smoking epidemic proportions. Antidepressants/ accepted as a safe and effective tool for etc., which are commonly associated anxiolytics have multiple, bothersome CVD risk reduction that can be easily with altered psychological states.87 side effects and interactions-owing incorporated in the daily routine. Depression is among the most to which they are not preferred by Summary and LAI recommendations common psychosocial issues among the patients as well as physicians, Diet patients with a prevalence of up to particularly for long-term use. Several 30% in those with cardiovascular studies have been published regarding • The overall dietary pattern is disease, roughly 2-3-fold greater the role of meditation in stress more important for cardiovascular than those without cardiovascular management. A meta-analysis of 47 health than the specific composition disease. Simple screening tools such studies in >3000 subjects demonstrated of individual macronutrients. Thus, as the Patient Health Questionnaire-9 that the effect size of meditation we recommend the adoption of a (PHQ-9), are recommended in clinical was comparable to anti-depressant DASH-like or Mediterranean dietary practice, especially in those with medications without any attendant side pattern that emphasizes intake of known cardiovascular disease. A effects.45 Meditation is thus an integral vegetables, fruits, and whole grains, simple algorithm for management of part of stress management programs low-fat dairy products, poultry, fish, depression has been recommended by and is being encouraged at all levels legumes, non-tropical vegetable the American Heart Association based by governments, corporate sector for oils, nuts, etc. A combination of on scores obtained from the PHQ-9.88 its employees, in the armed forces, monounsaturated and polyunsaturated oils may be considered. Oils rich in Several different stress management educational institutions, as well as in PUFA should be used in combination and reduction approaches are available. hospital settings for the patients as well with those rich in MUFA like olive These include advice related to proper as physicians and nurses. oil, mustard oil or groundnut oil. It is sleep, changes in behavior (behavior Several studies have also evaluated advisable to avoid refined oils, since therapy) and advice against use of the role of meditation in impacting during the refining process; oils are harmful substances like alcohol or other risk factors like elevated BP, heated to high temperatures resulting narcotic drugs as a remedy to manage blood sugar and dyslipidaemia.89-92 in their degradation and generation of stress. Meditation has been considered Acknowledging these findings, the toxic substances. We do not recommend as a useful stress management and AHA recommends meditation as a use of coconut oil, and suggest limiting CV risk reduction tool in recent years life-style intervention for overall CV all saturated fats. We also recommend and has been systematically studied risk reduction.61 However, not all limiting intake of sweets, sugar for its various psychological and meditation practices are equal. Some sweetened beverages and meat. This physiological benefits. are quite cumbersome, not widely above can be achieved by adopting a available, require considerable training, 5a. Role of meditation in stress diet pattern such as Mediterranean or involve expense and are not widely management and CV risk reduction Indo-Mediterranean diet as described available. Meditation is an ancient Indian above. Heartfulness is a heart-centered discipline which has been practiced for Incorporating dietitians into clinical system of practices, based on the several hundred years as an approach practices can provide a valuable ancient raja yoga (yoga of the mind) to attaining union with the ultimate resource for patients and healthcare which originated in India more than a (yoga). Several different types of providers alike. Multiple sessions with century ago. Currently being practiced meditation have been prevalent with the such trained lifestyle interventionalists in >150 countries of the world, it is common features being contemplative over several months are often needed to widely being practiced in India too. It inward attention, leading to a state of achieve adequate adherence to dietary is offered free of cost, is undemanding absorption. Recently, lot of attention recommendations. has been garnered by the meditation and can be incorporated in the daily Physical activity for adults practices owing to the corollary health life quite easily by everybody. This benefits that accrue in those who simple but effective system has also • Physical inactivity is harmful and practice it. Systematic studies with been explored for its scientific benefits should be avoided. For substantial different types of meditation have and has demonstrated consistent health health benefits adults should do demonstrated that it is an active process benefits. In a study on heartfulness at least 150 min/week of moderate that results in significant short- and and heart rate variability, it was intensity, or 75 min/week of vigorous- long-term physiological alterations, all shown that the practice resulted in intensity aerobic physical activity, or of which are favorable for overall health beneficial alteration of sympatho- an equivalent combination of moderate- and well-being. The greatest advantage vagal balance, reduction in heart rate, and vigorous intensity aerobic activity. 93 is that all these benefits are obtained as well as BP. In another study, a Aerobic activity should preferably be without any harmful side effects. short duration of heartfulness practice spread throughout the week. Aerobic resulted in positive psychological activity can also be performed in As expected, the maximal benefit changes, reduced burnout, as well as episodes of at least 10 min, 3 times/day. has been on the ability of meditation impacted the telomere length of the • For additional and more extensive to reduce perceived stress in the 94 practitioners in a healthcare setting. health benefits, adults should increase st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 19 their aerobic physical activity to 300 over several months. Incorporating 15. Bergeron N, Chiu S, Williams PT, King SM, Krauss RM. Effects of red meat, white meat, and nonmeat protein sources on min / week of moderate-intensity, or 150 dietitians and exercise physiologists atherogenic lipoprotein measures in the context of low min / week of vigorous-intensity aerobic into medical practices throughout India compared with high saturated fat intake: a randomized physical activity, or an equivalent will be important to accomplish this. controlled trial. Am J Clin Nutr 2019; 110:24-33. combination of moderate-and vigorous Indians are at increased risk of ASCVD 16. Eilat-Adar S, Sinai T, Yosefy C, Henkin Y. Nutritional recommendations for cardiovascular disease prevention. intensity activity. Additional health primarily owing to the composition of Nutrients 2013; 5:3646-83. benefits are gained by engaging in the native diet and inadequate physical 17. Willett WC. The Mediterranean diet: Science and practice. physical activity beyond this amount. activity. Evidence based interventions Public Health Nutrition 2006; 9:105-10. • Adults are also advised to do which are also easily followed and 18. Horton R. Expression of concern: Indo-Mediterranean Diet Heart Study. Lancet 2005; 366:354-6. muscle strengthening activities that are tailored to local needs should be implemented. These guidelines are 19. Singh RB, Takahashi T, Fatima G, et al. Effects of antioxidant- moderate or high intensity and involve rich Indo-Mediterranean foods on pre-heart failure: Results all major muscle groups on ≥2 days/ a step in this direction and aim to from the meta-analysis of randomized controlled trials. week. However, time spent in muscle- reduce the risk of ASCVD in the Indian The Open Inflammation Journal 2020; Volume 8:1-10. DOI: 10.2174/1875041902008010001. strengthening activities does not count population. Widespread availability and awareness about these will go a 20. 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Effects of ketogenic diets on cardiovascular risk factors: evidence from animal and human 2. Donnell OMJ, Xavier D, Liu L, et al. Risk factors for ischaemic adequate adherence to physical activity studies. Nutrients 2017; 9:517. recommendations. and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): A case-control study. Lancet 2010; 23. Naude CE, Schoonees A, Senekal M, et al. Low carbohydrate Alcohol 376:112-23. versus isoenergetic balanced diets for reducing weight and cardiovascular risk: a systematic review and meta-analysis. 3. Ramachandran A, Snehalatha C, Mary S, et al. The Indian • Alcohol intake should preferably PloS One 2014; 9:e100652. diabetes prevention programme shows that lifestyle be avoided by Indians, or whenever modification and metformin prevent type 2 diabetes in 24. Rama Murthy MK. factors affecting the composition, flavour possible kept to a maximum of one Asian Indian subjects with impaired glucose tolerance and textural properties of ghee. Indian Dairyman 1980; (idpp-1). Diabetologia 2006; 49:289-97. 32:765-8. drink daily for women and two drinks 4. American Diabetes Association. Cardiovascular disease and 25. Gupta R, Prakash H. Association of dietary ghee intake with daily for men. One drink is considered risk management: Standards of medical care in diabetes- coronary heart disease and risk factor prevalence in rural to be 1 oz of spirits, 4 oz of wine, or 12 2019. Diabetes Care 2019; 42:S103. males. J Indian Med Assoc 1997; 95:67-9. oz of beer. 5. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA 26. Shankar SR, Yadav RK, Ray RB. Serum lipid response to guideline on the primary prevention of cardiovascular introducing ghee as a partial replacement for mustard oil in • Patients with who do not consume disease: A report of the American College of Cardiology/ the diet of healthy young Indians. Indian J Physiol Pharmacol alcohol should never be encouraged to American Heart Association Task Force on Clinical Practice 2005; 49:49-56. start drinking it. Guidelines. Circulation 2019; 140:e596-e646. 27. Boemeke L, Marcadenti A, Busnello F, et al. Effects of 6. Hu FB, Willett WC. Optimal diets for prevention of coronary coconut oil on human health. Open Journal of Endocrine Tobacco products heart disease. JAMA 2002; 288:2569-78. and Metabolic Diseases 2015; 5:84-7. • Complete abstinence from tobacco 7. Singh RB, Dubnov G, Niaz MA, et al. Effect of an Indo- 28. Feranil AB, Paulita L. Coconut oil is associated with a products, including all vaping products Mediterranean diet on progression of coronary artery beneficial lipid profile in pre-menopausal women in the disease in high risk patients (Indo-Mediterranean diet Philippines. Asia Pac J Clin Nutr 2011; 20:190-5. and exposure to secondhand smoking heart study): A randomised single-blind trial. Lancet 2002; 29. Eyres L, Eyres MF, Chisholm A, et al. Coconut oil consumption is recommended. Healthcare providers 360:1455-61. and cardiovascular risk factors in humans. Nutr Rev 2016; should incorporate the five A’s as 8. Lorgeril MD, Salen P, Martin JL, et al. Mediterranean diet, 74:267-80. described above when counseling traditional risk factors, and the rate of cardiovascular 30. Mensink RP, Zock PL, Kester AD, Katan MB. Effect of dietary complications after myocardial infarction final report of the patients with tobacco use. fatty acids and carbohydrate on the ratio of serum total to Lyon Diet Heart Study. Circulation 1999; 99:779-85. HDL cholesterol and on serum lipids and apolipoproteins: Stress management 9. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, a meta-analysis of 60 controlled trials. American Journal of fish, and fibre intakes on death and myocardial reinfarction: Clinical Nutrition 2003; 77:1146-55. • In view of the widespread Diet and reinfarction trial (DART). Lancet 1989; 2:757-61. 31. Neelakantan N, Seah JYH, van Dam RM. The effect of coconut availability in rural as well as urban 10. Hopper L, Ness A, Higgins JP, et al. GISSI-Prevenzione trial. oil consumption on cardiovascular risk factors: A systematic areas of the country, its simple and Lancet 1999; 354:1557. review and meta-analysis of clinical trials. Circulation 2020; 141:803-14. secular nature and availability of studies 11. Singh RB, Niaz MA, Sharma JP, et al. Randomized, double- demonstrating its salutary effects, LAI blind, placebo controlled trial of fish oil and mustard oil in 32. Sacks FM, Lichtenstein AH, Wu JH, et al. Dietary fats and patients with suspected acute myocardial infarction: The cardiovascular disease: a presidential advisory from the recommends that heartfulness practices Indian experiment of infarct survival-4. Cardiovasc Drugs American Heart Association. Circulation 2017; 136:e1-e23. be included in the daily routine of all Ther 1997; 11:485-91. 33. Manchanda SC, Passi SJ. Selecting healthy edible oil in the individuals. Adequate sleep should 12. Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention Indian context. Indian Heart J 2016; 68:447-44. also be encouraged. of cardiovascular disease with a mediterranean diet. N Engl 34. Iyengar SS, Puri R, Narasingan SN, et al. Lipid Association J Med 2013; 368:1279-90. of India Expert Consensus Statement on Management of Conclusions 13. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline Dyslipidemia in Indians 2016: Part 1. Supplement to Journal of The Association of Physicians of India 1st March, 2016:7-51. Lifestyle management forms the on lifestyle management to reduce cardiovascular risk: A report of the American College of Cardiology/American 35. Iqbal R, Anand S, Ounpuu S, et al. Dietary patterns and the foundation of ASCVD risk reduction Heart Association task force on practice guidelines. risk of acute myocardial infarction in 52 countries: Results and should be implemented in all Circulation 2014;129:S76-S99. of the INTERHEART study. Circulation 2008; 118:1929-37. patients with the appropriate guidance 14. Dehgan M, Mente A, Zhang X, et al., Association of fats 36. Misra A, Sharma R, Gulati S, et al. Consensus dietary from lifestyle interventionalists such as and carbohydrate intake with cardiovascular disease and guidelines for healthy living and prevention of obesity, the mortality in 18 countries from 5 continents (PURE): A metabolic syndrome, diabetes, and related disorders in dietitians and exercise physiologists, prospective cohort study. Lancet 2017; 390:2050-62. Asian Indians. Diabetes Technol Ther 2011; 13:683-94. ideally in multiple sessions done st st 20 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

37. Charlotte Elizabeth Louise Evans. Dietary fibre and 2010. World Health Organization. Available at http://www. 77. Ajay VS, Prabhakaran D. Coronary heart disease in Indians: cardiovascular health: A review of current evidence and who.int/dietphysicalactivity/global-PA-recs-2010.pdf. Implications of the INTERHEART study. Indian J Med Res 2010; policy. Proc Nutr Soc 2020; 79:61-7. 132:561-6. 58. Kraus WE, Houmard JA, Duscha BD, et al. Effects of the 38. Hoy MK, Goldman JD. Fiber intake of the U.S. population: amount and intensity of exercise on plasma lipoproteins. 78. Neetu Chandra Sharma. Alcohol consumption in India what we eat in America, NHANES 2009-2010. Food Surveys N Engl J Med 2002; 347:1483-92. doubled in 11 years: WHO report. 2018. livemint. https://www. Research Group Dietary Data Brief No. 12. September 2014. livemint.com/Industry/0PBqBWHOYz8msKWSD6a84H/ 59. Tikkanen E, Gustafsson S, Ingelsson E. Associations of Alcohol-consumption-in-India-doubled-in-11-years-WHO- 39. Institute of Medicine 2005. Dietary reference intakes for fitness, physical activity, strength, and genetic risk with report.html energy, carbohydrate, fiber, fat, fatty acids, cholesterol, cardiovascular disease. Longitudinal analyses in the UK protein, and amino acids. Washington, DC: The National Biobank Study. Circulation 2018; 137:2583-91. 79. Smoking and cardiovascular disease. CDC. https://www. Academies Press. https://doi. org/10.17226/10490. cdc.gov/tobacco/data_statistics/sgr/50thanniversary/pdfs/ 60. Anjana RM, Pradeepa R, Das AK, et al. Physical activity and fs_smoking_CVD_508.pdf. 40. Amigo N, Akinkuolie AO, Chiuve SE, Correig X, Cook NR, Mora inactivity patterns in India- results from the ICMR-INDIAB S. Habitual fish consumption, n-3 fatty acids, and nuclear study (phase-1) [ICMR-INDIAB-5]. Int J Behav Nutr Phys Act 80. Devaranavadgi BB, Aski BS, Kashinath RT, Hundekari IA. magnetic resonance lipoprotein subfractions in women. J 2014; 11:26. Effect of cigarette smoking on blood lipids– a study in Am Heart Assoc 2020; 9:e014963. Belgaum, northern Karnataka, India. Global Journal of 61. Tang YY, Tang R, Posner MI. Brief meditation training induces Medical Research 2012;12:57-61. 41. Srilakshmi B. Dietetics. New Age International (P) Limited, smoking reduction. Proc Natl Acad Sci USA 2013; 110:13971- Publishers. 8th edition, 2019. 5. 81. Lv X, Sun J, Bi Y, et al. Risk of all-cause mortality and cardiovascular disease associated with secondhand smoke 42. Mann N, Rosenzweig A. Can exercise teach us how to treat 62. Levine GN, Lange RA, Bairey-Merz CN, et al. American exposure: a systematic review and meta-analysis. Int J heart disease? Circulation 2012; 126:2625-35. Heart Association Council on Clinical Cardiology; Council Cardiol 2015; 199:106-15. on Cardiovascular and Stroke Nursing; and Council on 43. Kodama S, Saito K, Tanaka S, et al. Cardiorespiratory fitness Hypertension. J Am Heart Assoc 2017; 6:e002218. 82. Oono IP, Mackay DF, Pell JP. Meta-analysis of the association as a quantitative predictor of all-cause mortality and between second hand smoke exposure and stroke. J Public cardiovascular events in healthy men and women: a meta- 63. Misra A, Khurana L. Obesity and the metabolic syndrome in Health (Oxf) 2011; 33:496-502. analysis. JAMA 2009; 301:2024-35. developing countries. J Clin Endocrinol Metab 2008; 93:S9-30. 83. Grana R, et al. E-cigarettes: A scientific review. Circulation 44. Kyu HH, Bachman VF, Alexander LT, et al. Physical activity 64. Thompson PD, Buchner D, Piña IL, et al. Exercise and 2014; 129:1972-86. and risk of breast cancer, colon cancer, diabetes, ischemic physical activity in the prevention and treatment of heart disease, and ischemic stroke events: systematic review atherosclerotic cardiovascular disease: A statement from 84. WHO Tobacco Free Initiative. Summary of effectiveness data and dose-response meta-analysis for the Global Burden of the council on clinical cardiology (subcommittee on for smoking cessation interventions. http://www.who.int/ Disease Study 2013. BMJ 2016; 354:i3857. exercise, rehabilitation, and prevention) and the council on tobacco/quitting/summary_data/en/. nutrition, physical activity, and metabolism (subcommittee 45. Martins RA, Neves AP, Coelho-Silva MJ, et al. The effect of 85. Tobacco dependence treatment guidelines. National on physical activity). Circulation 2003; 107:3109-16. aerobic versus strength-based training on high-sensitivity tobacco control programme, directorate general of health C-reactive protein in older adults. Eur J Appl Physiol 2010; 65. Physical activity guidelines for Americans. U.S. Department services, ministry of health and family welfare, government 110:161-9. of health and human services 2008. Available at http:// of India 2011. https://ntcp.nhp.gov.in/assets/document/ health.Gov/paguidelines. Guideline-manuals/Tobacco-Dependence-Treatment- 46. Cauza E, Hanusch-Enserer U, Strasser B, et al. The relative Guidelines.pdf benefits of endurance and strength training on the 66. Corrado D, Migliore F, Basso C, Thiene G. Exercise and the metabolic factors and muscle function of people with type risk of sudden cardiac death. Herz 2006; 31:553. 86. Benowitz NL, Pipe A, West R, et al. Cardiovascular safety of 2 diabetes mellitus. Arch Phys Med Rehabil 2005; 86:1527-33. varenicline, bupropion, and nicotine patch in smokers: A 67. Willich SN, Lewis M, Lowel H, et al. Physical exertion as randomized clinical trial. JAMA Intern Med 2018; 178:622-31. 47. Kraus WE, Houmard JA, Duscha BD, et al. Effects of the a trigger of acute myocardial infarction. Triggers and amount and intensity of exercise on plasma lipoproteins. Mechanisms of Myocardial Infarction Study Group. N Engl 87. Bairey Merz CN, Dwyer J, Nordstrom CK, Walton KG, Salerno N Engl J Med 2002; 347:1483-92. J Med 1993; 329:1684. JW, Schneider RH. Psychosocial stress and cardiovascular disease: Pathophysiological links. Behav Med 2002; 27:141-7. 48. Kushi LH, Doyle C, McCullough M, et al. American Cancer 68. Anonymous, Physical activity guidelines for Americans. Society Guidelines on nutrition and physical activity for US Department of Health and Human Services 2008.1-61. 88. Lichtman JH, Bigger JT Jr, Blumenthal JA, et al. Depression cancer prevention: reducing the risk of cancer with healthy https://health.gov/paguidelines/2008/pdf/paguide.pdf and coronary heart disease: recommendations for food choices and physical activity. CA Cancer J Clin 2012; screening, referral, and treatment: a science advisory from 69. Periard JD, Caillaud C, Thompson MW. Central and peripheral 62:30. the American Heart Association Prevention Committee of fatigue during passive and exercise-induced hyperthermia. the Council on Cardiovascular Nursing, Council on Clinical 49. Stern Y, MacKay-Brandt A, Lee S, et al. Effect of aerobic Med Sci Sports Exerc 2011; 43:1657-65. Cardiology, Council on Epidemiology and Prevention, exercise on cognition in younger adults: A randomized 70. Randolph C. An update on exercise-induced and Interdisciplinary Council on Quality of Care and clinical trial. Neurology 2019; 92:e905. bronchoconstriction with and without asthma. Curr Allergy Outcomes Research: endorsed by the American Psychiatric 50. Gordon BR, McDowell CP, Hallgren M, et al. Association Asthma Rep 2009; 9:433. Association. Circulation 2008; 118:1768-75. of efficacy of resistance exercise training with depressive 71. Misra A, Nigam P, Hills AP, et al. Consensus physical 89. Anderson JW, Liu C, Kryscio RJ. Blood pressure response to symptoms. JAMA Psychiatry 2018; 75:566-76. activity guidelines for Asian Indians. Diabetes Technol Ther transcendental meditation: A meta-analysis. Am J Hypertens 51. Bays HE, Jones PH, Brown WV, Jacobson TA. National Lipid 2012;14:83-98. 2008; 21:310-16. Association annual summary of clinical lipidology 2015. J 72. Misra A, Chowbey P, Makkar BM, et al. Consensus 90. Raub JA, Psychophysiologic effects of hatha yoga on Clin Lipidol 2014; 8:S1-36. statement for diagnosis of obesity, abdominal obesity musculoskeletal and cardiopulmonary function: A literature 52. Warburton DE, Nicol CW, Bredin SS. Health benefits of and the metabolic syndrome for Asian Indians and review. J Altern Complement Med 2002; 8:797812. physical activity: The evidence. CMAJ 2006; 174:801809. recommendations for physical activity, medical and surgical 91. Mahajan AS, Reddy KS, Sachdeva U. Lipid profile of coronary management. J Assoc Physicians India 2009;57:163-70. 53. 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Low Density Lipoprotein Cholesterol Targets in Secondary Prevention of Atherosclerotic Cardiovascular Disease

Background and Introduction Society of Cardiology), CCS (Canadian during treatment with a statin started Cardiovascular Society), and NLA later in life.16 German pathologist, Rudolf 5-9 (National Lipid Association). These Recently, European Atherosclerosis Virchow in 1856 suggested that A organizations recommended an LDL-C Society assessed meta-analyses of blood lipids accumulate in arterial wall.1 less than 70 mg/dl in very high risk over 200 prospective cohort studies, In 1977, the Framingham study showed persons or for secondary prevention. Mendelian randomization studies, that elevated low density lipoprotein- A lower treatment goal of and randomized trials of more than cholesterol (LDL-C) and reduced LDL‐C <50 mg/dl for very high‐risk 2 million participants with over 20 high density lipoprotein-cholesterol Indians was recommended by the million person-years of follow-up and (HDL-C) levels independently predict Lipid Association of India (LAI) over 150,000 cardiovascular events risk for developing atherosclerotic in March, 2016.10 Subsequently in and stated that irrespective of any cardiovascular disease (ASCVD). 2017, a goal of LDL-C <55 mg/dl in mechanism of lowering LDL-C, there is LDL-C contributes significantly to patients with extreme risk and ACS a positive linear relationship between the initiation and progression of patients with DM was put forward risk of ASCVD reduction and absolute atherosclerosis through a pathway by AACE (American Association reduction in LDL-C. The risk of ASCVD involving endothelial cell dysfunction, of Clinical Endocrinologists) and is also directly related to cumulative formation of oxidized LDL, foam cell Taiwan guidelines respectively.11,12 duration in reduction of LDL-C. There formation and inflammation.2 The LAI subsequently in December is a consistent dose-dependent log- In 2001, ATP III guidelines focused 2017 published dyslipidemia linear association between magnitude on intensive treatment of patients management guidelines in special of exposure of the vasculature to LDL-C with coronary heart disease (CHD) patient populations.13 Most recently, the and the risk of ASCVD; and this effect and recognized significant ‘CHD risk’ ESC (European Society of Cardiology) appears to increase with increasing in persons with multiple risk factors. has recommended a treatment goal duration of exposure to LDL-C.17 LDL-C <100 mg/dl was identified as of <55 mg/dl for LDL-C for those A meta-analysis of nearly 175,000 optimal and LDL-C was considered the patients at very high risk, including participants in 27 randomized trials primary target of therapy with non– all patients with ASCVD, with optional of statins including 22 trials of statin HDL-C <130 mg/dl as a secondary target consideration of an LDL-C <40 mg/ versus control (n=134,537; mean LDL-C in patients with hypertriglyceridemia.3 dl for those who have had a recurrent difference 1.08 mmol/L; 4.8 years) and 14 event within the past two years. five trials of intensive versus moderate The 2004 update of ATP III considered Indians develop ASCVD at a younger statin therapy (n=39,612; mean LDL-C 5 major clinical outcome trials- HPS, age, have malignant disease and high difference 0.51 mmol/L; 5.1 years) PROSPER, ALLHAT-LLT, ASCOT-LLA case fatality rates.15 Hence, the ever- was carried out by the Cholesterol and PROVE-IT TIMI 22 published expanding epidemic of ASCVD among Treatment Trialists (CTT) collaborators. between 2001 and 2004, that addressed Indians warrants further lowering It concluded that a reduction of 1 issues not previously focused upon in of LDL-C especially in patients with mmol/L (38.7 mg/dl) in LDL-C levels clinical trials of cholesterol lowering. It extreme risk of recurrence of CV events. brings about a 21% reduction in the risk recognized the following- diabetes as a Linear correlation between LDL-C of major vascular events over 5 years, CHD risk equivalent, an optional goal lowering and risk of ASCVD irrespective of age, sex, baseline LDL-C of LDL-C less than 70 mg/dl in very levels and previous vascular disease. A series of meta-analyses calculated high-risk patients, and combination An additional 15% reduction in ASCVD the effect of long-term exposure to therapy of statins with non-statins in risk was noted in the intensive statin lower levels of LDL-C on the risk of patients with hypertriglyceridemia or trials following lowering of LDL-C by CHD mediated by 9 polymorphisms in low HDL.4 an additional 0.5 mmol/L.18 6 different genes. All 9 polymorphisms These goals served as the standard were associated with significant Magnitude of ASCVD problem in India of care for patients with dyslipidemia reduction in the risk of CHD per unit Cardiovascular diseases have for more than a decade. LDL-C lower LDL-C. Non-overlapping data attained epidemic proportions continues to be the lipoprotein of from 312,321 participants in a meta- worldwide with mortality declining interest as recommended by ATP III analysis with natural random allocation in developed nations while rising (Adult Treatment Panel III), AHA/ to long-term exposure to lower LDL-C in the developing nations due to ACC (American Heart Association/ was associated with 54.5% reduction epidemiological transition.19 Mortality American College of Cardiology), in the risk of CHD per mmol/L lower rates from CHD and stroke have shown IAS (International atherosclerosis LDL-C. This correlates to nearly a 3-fold an obvious decline in the western society), EAS/ESC (European greater reduction in the risk of CHD per world, with age-adjusted mortality Atherosclerosis Society/European mmol/L lower LDL-C than that noted rates having dropped by one-third from st st 22 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Table 1: The achieved LDL-C levels on moderate versus high intensity statins to New Targets), IDEAL (Incremental

Trial Number of patients LDL-C achieved LDL-C achieved Percent of patients Decrease in Endpoints Through on moderate dose on intensive dose suffering events on aggressive Lipid Lowering), JUPITER statins statins intensive doses (Justification for the Use of Statins 26 PROVE IT-TIMI 22 4162 95 mg/dl 62 mg/dl 22.4% in Prevention: an Intervention Trial 27 IDEAL 8888 104 mg/dl 81 mg/dl 12.0% Evaluating Rosuvastatin), SPARCL TNT28 10,001 101 mg/dl 77 mg/dl 8.7% (Stroke Prevention by Aggressive Table 2: The adjusted hazard ratios based on achieved LDL-C levels in a meta-analysis of eight Reduction in Cholesterol Levels) and 31 major trials CARDS (the Collaborative Atorvastatin LDL-C | <50 mg/dl 50-75 mg/dl 75-100 mg/dl 100-125 125-150 150-175 >175 mg/dl Diabetes Study)- with determination of (mg/dl) (n=4375) (n=10,375) (n=10,091) mg/dl mg/dl mg/dl (n=375) lipids and apolipoproteins at baseline (n=8953) (n=3128) (n=836) and at 1-year follow-up, revealed Major CV 0.44 0.51 0.56 0.58 0.64 0.71 1.00 (ref) events (0.35-0.55) (0.42- 0.62) (0.46-0.67) (0.48- 0.69) (0.53- 0.79) (0.56- 0.89) 54% reduction in major CV events. It included 38,153 patients allocated 1960 to 2000.20 The Global Burden of therapy significant residual risk to statin therapy and a total of 6,286 Disease Study of 2016 for India reported contributes to future adverse CV cardiovascular events occurred in 5,387 an estimated 32.7% increase in years events. Further aggressive lowering study participants during follow-up. of life lost (YLL) from 1990 until 2016 of LDL-C along with more intensive Compared to patients who achieved whereas YLL declined in United States control of other risk factors may prove an LDL-C >175 mg/dl, it was noted by 62.4% and in European countries beneficial to reduction of recurrent that those who achieved an LDL-C of by 72.2%. Disability adjusted life years events and mortality. 75-100 mg/dl, 50-75 mg/dl and <50 mg/ (DALYs) for ischemic heart disease in Does further LDL-C lowering dl had adjusted hazard ratios for major India doubled from 19.77 million/year from 70 mg/dl to 30 mg/dl reduce CV events of 0.56 (95% CI 0.46-0.67), in 1990 to 40.29 million in 2016.21 cardiovascular events? 0.51 (95% CI 0.42-0.62) and 0.44 (95% Ischemic heart disease is the leading Evidence from randomized trials and meta- CI 0.35-0.55), respectively. There was cause of premature deaths with a 53% analysis for LDL-C lowering from 70 mg/dl a 19% relative risk reduction (adjusted rise from 2005 to 2016 as per India to 50 mg/dl hazard ratio 0.81; 95% CI 0.70-0.95) in Health Metrics.22 The prevalence of 4162 patients with a median MACE in the group with LDL-C less dyslipidemia is 79% among Indians LDL-C of 102 mg/dl were enrolled than 50 mg/dl compared to LDL-C which is higher than 53% reported in the PROVE-IT TIMI 22 study. It of 75-100 mg/dl. No increase in the among the US population.23,24 compared intensive therapy (80 mg of adverse effects was noted (Table 2).31 A study from India, providing atorvastatin) versus moderate therapy The landmark IMPROVE-IT trial estimates of 333 diseases and 84 risk (40 mg of pravastatin) in patients (15281 participants) concluded that 30 factors from different states, covering following acute coronary event. The in post-acute coronary syndrome the period from 1990 to 2016 reported safety and efficacy of achieving very patients (within 10 days of index event), that CVD and diabetes accounted for low LDL-C levels with intensive statin ezetimibe 10 mg/simvastatin 40 mg was 15.9 and 8.9% of the disability-adjusted therapy was evaluated by a sub study of superior to simvastatin 40 mg alone life years respectively. Change in PROVE IT-TIMI 22. The median LDL-C in reducing CV events in long term DALYs and percent change in rates achieved in the atorvastatin group was at follow up of 7 years. Baseline LDL for the leading 30 causes during the 62 mg/dl. The distribution of LDL-C cholesterol levels was 95 mg/dl in the period 1990–2016 in India showed that levels after 4 months was divided into 4 participants of both groups. The median ischemic heart disease has moved up to groups- <40 mg/dl (11%), >40-60 mg/dl follow-up levels were 53.7 mg/dl versus the first position.25 (34%), >60-80 mg/dl (31%) and >80-100 69.5 mg/dl in the ezetimibe/simvastatin Residual risk following intensive statin mg/dl (14%). There were 193 patients and simvastatin arms, respectively therapy: LDL cholesterol in the group that achieved an LDL-C of at the end of one month.73 No rise in less than 40 mg/dl. The hazard ratio was Three trials26-28 compared higher muscle complaints, liver enzymes, lowest in this group with fewer cardiac cancer, cataract, neurocognitive defects vs. lower intensity statin therapy 30 events. No significant increase in 73 resulting in lower achieved LDL-C to and diabetes was noted. The results of adverse effects was observed while 39% prevent major events in patients with this study supported LDL-C lowering RR reduction in MACE was recorded in history of CHD or ACS. There were down to around 55 mg/dl. the group with achieving LDL-C less statistically significant reductions In the ODYSSEY LONG TERM than 40 mg/dl as compared to those in LDL-C but a significant quantity study- 2341 high risk patients on with LDL-C levels >80-100mg/dl. of residual risk was noted (Table 1). statins were administered alirocumab Superko mentioned that while 22.4% of A meta-analysis of 8 major trials- 4S subcutaneously in a dose of 150 mg subjects in the intensively treated group (Scandinavian Simvastatin Survival once every two weeks and compared in the PROVE-IT TIMI 22 achieved an Study), AFCAPS/TexCAPS (Air Force/ to placebo in a 2:1 ratio. The mean LDL LDL-C<70 mg/dl, they still experienced Texas Coronary Atherosclerosis at baseline was 120 mg/dl. The mean a clinical event.29 Prevention study), LIPID (Long- percentage change in LDL cholesterol Term Intervention with Pravastatin Hence, despite intensive statin level from baseline to week 24 was in Ischemic Disease), TNT (Treating st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 23

Table 3: Lipid Association of India 2016 LDL-C and non-HDL-C goals IMPROVE-IT trial

Treatment goals and statin initiation thresholds according to ASCVD risk categories (2016) 40% <30 30-49 50-69 ≥70 (Lipid Association of India) 35% 36% Risk category Treatment goals Consider drug therapy 30% 31% 25% LDL-C (mg/dL) Non-HDL-C (mg/dL) LDL-C (mg/dL) Non-HDL-C (mg/dL) 26% Very high risk <50 <80 ≥50 (preferably in all) ≥80 (preferably in all) (%) patients 20% High risk <70 <100 ≥70 (preferably in all) ≥100 (preferably in all) 15% 10% Moderate risk <100 <130 ≥100 ≥130 Number of 5% Low risk <100 <130 ≥130* ≥160* 6% 0% *After an initial adequate non-pharmacological intervention for at least 3 months Achieved LDL-C levels (mg/dL) at 1 month Giugliano RP et al. JAMA Cardiol 2017;2:547-55. −61.0% with alirocumab versus 0.8% The ODYSSEY OUTCOMES study Fig. 1: The distribution of achieved with placebo. The mean absolute LDL compared the safety and efficacy LDL-C levels at one month in cholesterol level at week 24 was 48 mg/ of alirocumab with placebo among 15,281 patients in the IMPROVE- dl and 119 mg/dl in the alirocumab patients with recent acute coronary IT trial and placebo groups respectively. After syndrome (ACS) already on intensive The FOURIER study randomized 78 weeks treatment with alirocumab, statin therapy. Participants were 27,564 patients with ASCVD and LDL-C LDL-C levels were 53.1 mg/dL resulting enrolled to receive either alirocumab (n ≥70 mg/dl on maximally tolerated in 48% relative risk reduction of CV =9,462) every 2 weeks subcutaneously statin therapy to receive evolocumab events as compared to the placebo. The or placebo (n =9,462). The dose was (either 140 mg every 2 weeks or 420 mg number of participants with adverse titrated between 75 and 150 mg to keep monthly) or placebo as subcutaneous events was similar in the 2 groups.33 LDL-C between 25 and 50 mg/dl, but injections. At 48 weeks, the mean above 15 mg/dl. The duration of follow Similar results were noted with percentage reduction in LDL-C levels up was 2.8 years.36 The mean LDL-C evolocumab in the OSLER trial. It with evolocumab was 59%, from a was 87 mg/dl at baseline and 53.3 mg/ included two extension studies with median baseline value of 92 mg/dl dl on treatment at 44 months. LDL-C 4465 patients on standard therapy and to 30 mg/dl. Significant reduction in reduction in alirocumab vs. placebo evolocumab or standard therapy alone the risk of the primary and secondary was 62.7% (37.6 mg/dl vs 93.3 mg/dl) in a 2:1 ratio. Evolocumab reduced the end points was noted. LDL-C values at 4 months; 50% (48 mg/dl vs 96.4 LDL-C levels by 61%, from a median reduced to ≤70 mg/dl in 87% versus mg/dl) at 12 months and 54.7% (53.3 of 120 mg/dl to 48 mg/dl contributing 18%, to ≤40 mg/dl in 67% versus 0.5% mg/dl vs 101.4 mg/dl) at 2.8 years.37 In to 53% reduction in CV outcomes and to ≤25 mg/dl in 42% versus less than patients on alirocumab, 15% reduction when compared to the placebo group 0.1% in the evolocumab versus placebo in CV events and all cause deaths was at the end of approximately 1 year of groups respectively. The event rates of 34 noted. Non-fatal MI reduced by 14%, treatment. primary end point and secondary end stroke by 27% and unstable angina The post hoc analysis of 10 Odyssey point were 11.3% and 7.4% in placebo by 39%. The primary endpoint of trials including 4974 patients (3182 on group while they were 9.8% and 5.9% MACE was significantly lower in the alirocumab, 1174 on placebo, 618 on in the evolocumab group respectively at alirocumab group versus the placebo ezetimibe) evaluated the relationship the end of 2.2 years.37 This contributed group (9.5% vs 11.1%).36 No effect between on-treatment LDL-C levels to ARR of 1.5% and NNT of 67 for on CV death was observed. Adverse and percent reductions in LDL-C from primary endpoint. No significant effects were comparable in both groups baseline with MACE (coronary heart effect on CV death was observed. except minor injection-site reactions disease death, non-fatal myocardial No significant difference in the rates in the alirocumab group. This trial too infarction, ischemic stroke, or unstable of muscle-related events, cataract, supported benefit of lowering LDL-C angina) in multivariate analyses. neurocognition and hemorrhagic to levels around 50 mg/dl. Almost 33.1% of the pooled cohort stroke was observed between the two Benefit of further lowering of LDL-C to 30 achieved average LDL-C <50 mg/dl: groups. Injection-site reactions though mg/dl and below 44.7% to 52.6% allocated to alirocumab, rare, were more frequent with injection 6.5% allocated to ezetimibe, and 0% Only more recently, however, has evolocumab. New binding antibodies allocated to placebo. MACE was evidence accumulated to support the developed in 43 patients (0.3%) but no inversely correlated to the percent benefit of attaining levels of LDL-C neutralizing antibodies were noted.38 even below 50 mg/dl. In the IMPROVE- reductions in LDL-C down to 25 mg/ A risk reduction of 17% was noted in IT trial of patients with an acute dl. MACE appeared to be 24% lower for key secondary endpoint among patients 35 coronary syndrome within 10 days, every 39 mg/dl lower achieved LDL-C. in the top quartile for baseline LDL-C, 6.4% (971) patients achieved LDL-C <30 Based upon these data from RCTs in whom evolocumab lowered LDL-C mg/dl (Figure 1). There were significant and meta-analysis, LAI released its level from 126 mg/dl to 43 mg/dl and a 21% relative risk reduction as compared first expert consensus statement on 22% risk reduction was noted in the key to those who achieved LDL-C ≥70 mg/dl management of dyslipidemia in Indian secondary endpoint among the patients (adjusted HR 0.79; P =0.001). There were population in March 2016 (Table 3).10 in the lowest quartile for baseline no significant adverse events in those LDL-C was the primary target with LDL, in whom evolocumab lowered with achieved LDL-C below 30 mg/dl.32 non-HDL-C as co-primary target. LDL-C from 73 mg/dl to 22 mg/dl.37 A st st 24 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Table 4: Relationship between achieved LDL-C levels, CV events and relative risk reduction in FOURIER Study38

Patients Achieved Kaplan Relative risk LDL-C levels Meier reduction at 4 weeks Event rates (RRR) 2669 <0.5 mmol/l 10.3% 24% (10%) (<20mg/dl) 8003 0.5 to <1.3 12.4% 15% (31%) mmol/l (20 mg/dl to <50 mg/dl) 3444 1.3 to <1.8 13.6% 6% (13%) mmol/l (50 mg/dl to <70 mg/dl) 7471 1.8 to <2.6 13.7% 3% (29%) mmol/l (70 mg/dl to <100 mg/dl) 4395 ≥2.6 mmol/L 15.5% - (17%) (≥100 mg/dl) Table 5: Meta-analysis of statin and non- statin data in populations with baseline LDL-C values of ≤70 mg/ dl41

Groups Baseline Vascular Risk Ratio mean Events per 38.7 mg/ Fig. 2: The incremental benefit for reduction of primary endpoint according to achieved LDL-C dl (1 mmol/l) LDL-C levels at 4 weeks. A: The percentage of patients with different levels of mg/dl reduction of achieved LDL-C levels in the two study groups; B: Mean reduction in LDL-C levels LDL-C in the evolocumab group compared to placebo; C: The relative risk reduction (RRR) Statins only 65.7 1922 0.78 with evolocumab based on the achieved LDL-C levels; D: The relationship between mg/dl (0.65-0.94) achieved LDL-C levels and adjusted event rates showing significantly decreased Non-statins 63-70 9570 0.79 event rates with further lowering of LDL-C levels down to <20 mg/dL added to statins mg/dl (0.70-0.88) Statins only 0.79 second year of the trial reduced the risk benefits with no observed adverse + Non-statins (0.71-0.87) of multiple cardiovascular outcomes effects.41 added to statins combined by 18–23% per mmol/L reduction in Evidence from Imaging Trials LDL-C, which is very similar to the linear relationship was noted between Multiple imaging trials have proven 22–25% reduction in risk for these same achieved LDL and CV outcomes in a that aggressive lowering of LDL-C outcomes observed during the second pre-specified secondary analysis of level to 50 mg/dl or less contributes year of treatment in the statin trials.40 FOURIER trial (Fig. 2). Approximately to significant reduction of progression 504 patients achieved median LDL-C A meta-analysis of Cholesterol of atherosclerotic plaques and CV levels of 7 mg/dl at 4 weeks with Treatment Trialists Collaboration events.42-48 Patients who underwent more cardiovascular efficacy and no (CTTC) for statin data and Medline PCI were randomly assigned to 20 mg worsening of adverse effects (Table 4).39 database for non-statin data was carried atorvastatin monotherapy versus 20 mg out to evaluate safety and efficacy A post-hoc analysis of ODYSSEY atorvastatin plus 10 mg of ezetimibe of further lowering LDL-C levels in 46 OUTCOME study concluded that the daily in PRECISE-IVUS study. Serial populations with average LDL-C levels hazard ratio for all-cause death by volumetric IVUS was performed at of 70 mg/dl (1.8 mmol/L) or below. The baseline LDL subgroups was the lowest baseline and again at 9 to 12 months to non-statin trials include Improved in the group with baseline LDL-C of quantify the coronary plaque response Reduction of Outcomes: Vytorin at least 100 mg/dl with absolute risk in 202 patients. Combination therapy Efficacy International Trial (IMPROVE- reduction of 1.6% (relative RR of 29%) resulted in lower levels of LDL-C than IT), Further Cardiovascular Outcomes in this group and 3.4% absolute risk monotherapy (63.2 ± 16.3 mg/dl vs 73.3 Research with PCSK9 Inhibition in reduction (relative RR of 24%) for CV ± 20.3 mg/dl; p <0.001). Coronary plaque Patients With Elevated Risk (FOURIER) events.36 regression on IVUS was achieved in and Randomized Evaluation of the more patients on combination therapy An analysis of FOURIER, SPIRE, Effects of Anacetrapib through Lipid than those who received monotherapy and the Cholesterol Treatment Trialists Modification (REVEAL) (Table 5). The (78% vs 58%; P=0.004). Side-effect Collaboration concluded that lowering data suggests treating patients with profiles were similar in both groups.46 LDL-C with a PCSK9 inhibitor reduces mean LDL-C level of 65 mg/dl (1.7 In Yellow trial there was significant the risk of major events by the same mmol/L) and achieving LDL as low reduction in LCBI (lipid core burden amount as statins per mmol/L reduction as a median of 21 mg/dl (0.5 mmol/L) index) using Near infrared spectroscopy in LDL-C. In the FOURIER trial, achieved further cardiovascular treatment with evolocumab during the (NIRS) with short duration (6 to st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 25

8 weeks) intensive statin therapy calcification and reductions in the size suggests that benefits are higher in (Rosuvastatin) as compared to standard of all other plaque components.49 patients with higher baseline LDL-C.51,52 therapy. Mean achieved LDL-C level Hence, it can be presumed that The ODYSSEY OUTCOMES study with rosuvastatin 40 mg/d was 60 mg/ LDL-C level of 30 mg/dl is safe, at least concluded that MACE benefit was dl compared to 82 mg/dl with standard within the duration of follow-up time largely driven by patients with LDL-C 47 therapy. available from the supporting clinical values of 100 mg/dl or more. The hazard Recently, GLAGOV trial48 evaluated trials, and there is also evidence of ratio for primary outcome was 0.91 the effect of evolocumab on progression further significant reduction in ASCVD (0.81-1.02) in those with LDL less than of coronary atherosclerosis in statin events as compared to LDL-C of 50 mg/ 100 mg/dl as compared to 0.76 (0.65- treated patients. 968 participants on dl with no increase in adverse effects. 0.87) in those with higher LDL-C (≥100 statins with angiographic coronary Which group of patients would benefit mg/dl) values. Absolute risk reduction artery disease were randomized to from aggressive LDL-C lowering? due to CHD, CV death and all cause receive monthly evolocumab (420 death was 1.0%, 1.3% and 1.7% in those Based on available data and mg) (n = 484) or placebo (n = 484) via with LDL-C less than 100 mg/dl as evidence, the benefit from aggressive subcutaneous injections for 76 weeks. compared to 1%, 4% and 6% in those LDL-C lowering therapies depends on Mean baseline LDL-C level was 92.5 with LDL-C ≥100 mg/dl.37 the following: mg/dl. The LDL cholesterol at 76 weeks In SPIRE-1 and SPIRE-2 studies, 1. Absolute reduction in LDL-C was 36.6 mg/dl in the evolocumab patients with elevated cardiovascular levels group versus 93.0 mg/dl in the placebo risk with two varying baseline levels group. Change in percent atheroma 2. Baseline LDL-C cholesterol levels of LDL-C were assigned to either volume (PAV) from baseline to week 3. Baseline cardiovascular risk the PCSK9 inhibitor bococizumab or 78, measured by serial intravascular placebo. In the lower-risk arm, patients 4. Duration of LDL-C lowering ultrasonography (IVUS) imaging was had a baseline LDL-C of ≥70 mg/dl. Absolute reduction in LDL cholesterol the primary efficacy endpoint. Change At median follow-up of 7 months, in total atheroma volume (TAV) and As discussed previously reducing major events occurred in 173 patients demonstration of plaque regression was LDL-C down to 30 mg/dl or below has each in the bococizumab group and secondary efficacy endpoint. been shown to significantly reduce the placebo group (hazard ratio, 0.99; Compared with placebo, the ASCVD events.36-41 Further in the 95% confidence interval [CI], 0.80 to evolocumab group achieved lower ODYSSEY OUTCOMES trial, of the 1.22; P =0.94). In the higher-risk arm, mean LDL-C levels (93.0 vs 36.6 mg/ 9462 patients randomized to receive patients had baseline LDL-C ≥100 dl; difference, -56.5 mg/dl; P <0.001). alirocumab, 730 (7.7%) patients reached mg/dl. At median follow-up of 12 PAV increased by 0.05% with placebo very low LDL-C (<15 mg/dl) and were months, major cardiovascular events versus decrease by 0.95% with switched to placebo after a median 8.3 occurred in 179 and 224 patients in the evolocumab, while TAV decreased 0.9 months after randomization. Using bococizumab group and the placebo mm3 with placebo and 5.8 mm3 with propensity score matching, they were group, respectively (HR 0.79; P =0.02). evolocumab (difference, -4.9 mm3; compared (3:1) with 2152 patients Thus, the benefit was seen only in P <0.001). Plaque regression was noted initially assigned to placebo. Despite patients with higher baseline LDL-C in a greater percentage of patients on being switched to placebo, patients levels.53 evolocumab than placebo (64.3% vs with very low LDL-C on alirocumab Baseline cardiovascular risk 47.3%; difference, 17.0%; P <0.001 for had fewer MACE than matched patients Baseline cardiovascular risk is a PAV). A LOESS plot showed a linear from the placebo group (6.4% vs major determinant of risk of future relationship between achieved LDL-C 8.5%; HR 0.71, P=0.039). The very low adverse ASCVD events in patients level and PAV for LDL-C levels ranging LDL-C levels on alirocumab were with CAD. In secondary prevention from 110 mg/dl to as low as 20 mg/dl.48 not associated with risk of new-onset setting, the risk is predominantly diabetes, neurocognitive events or Plaque composition changes defined by number, type and severity of haemorrhagic stroke. This clearly were determined in 331 patients baseline risk factors like older age ≥75 demonstrates the extended benefit of with radiofrequency analysis of the years, diabetes mellitus, hypertension, very low levels of LDL-C even after the ultrasound backscatter signal. No smoking, eGFR <60 ml/min, peripheral discontinuation of pharmacotherapy.50 changes were observed between the artery disease, prior stroke, prior Baseline LDL cholesterol levels evolocumab and placebo groups in CABG and CHF.64 FOURIER study changes in calcium, fibrous, fibrofatty In the 4S study, the mean LDL-C was showed those with a recent MI (<2 and necrotic volumes. Hence, 190 mg/dl. Treatment with simvastatin years), multiple MIs, multivessel evaluation of plaque morphology using resulted in 34% RRR in CHD death or CAD, or PAD benefited the most.54 virtual histology imaging may provide nonfatal MI and 30% reduction in total The Odyssey Outcomes study showed no additional information about the mortality. In the CARE study, mean those with disease in multiple vascular plaque effects of evolocumab beyond LDL-C was 139 mg/dl and treatment beds or defined as “very high risk” 49 measurement of plaque burden. with 40 mg pravastatin resulted in 24% benefitted the most.55,56 The absolute However, LDL-C lowering was RRR in CHD death or non-fatal MI and risk reduction (ARR) was 1.4, NNT =71 associated with an increase in plaque 8.3% reduction in total mortality. This for patients with arterial disease in one st st 26 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Table 6: Subgroup analysis of 4S study: Table 7: Absolute risk reduction (ARR) in In a Korean study, 2438 patients post Relative risk of major endpoints diabetics versus non-diabetics PCI following myocardial infarction in simvastatin treated diabetics were stratified to four groups according versus non-diabetics63 Trial Absolute Risk Absolute Risk Reduction Reduction to the presence of DM or hypertension Endpoints Diabetics Non-Diabetics (ARR) in (ARR) in Non- Diabetics Diabetics and followed up for 1 year. MACE was Total Mortality 0.57 0.71 Fourier38 2.7% (NNT 37) 1.6% (NNT 62) 15.9% in non-diabetic/non-hypertensive Atherosclerotic Event 0.63 0.74 Odyssey 2.3% (NNT 43) 1.2% (NNT 83) vs 22.9% in hypertensives vs 28.8% in CHD Event 0.45 0.68 outcomes36,37 diabetics vs 37.0% in hypertensive and vascular bed versus ARR of 13.0, NNT Improve-IT32,73 5.5% (NNT 18) 0.6% (NNT 166) DM group. The combination of DM and =8 for patients with arterial disease in NNT: number needed to treat hypertension had higher mortality than three vascular beds, suggesting that coronary calcium in adults with DM or either alone.64 alirocumab was 9 times more beneficial metabolic syndrome shows a 10-fold Further, the ARR was higher 55 in patients with polyvascular disease. variation in event rates. For example in amongst the diabetics as compared to In primary prevention, persons with those with DM with a 0 calcium score, the non-diabetics in the 3 major trials homozygous or heterozygous familial CHD event rates were 0.4% per year, as shown in table. It can be concluded hypercholesterolemia are at substantial compared to 4% per year in those with that patients with higher baseline risk 60 baseline risk due to their lifetime of calcium scores of 400 or greater. Most derive higher benefits from further elevated LDL-C levels. In addition, recently, Rana and colleagues showed aggressive LDL-C reduction (Table 7). those with diabetes, especially when among a large registry of DM patients LDL-C risk curve concept accompanied with multiple risk factors from Kaiser Permanente pointed that are at high or very high risk.57,58 The those DM patients with a duration of The concept of a “risk curve” aim of determining baseline CV risk DM of 10 years or more have a risk correlates to the absolute risk of a patient is to identify patients who require similar to those with pre-existing for future CV events over a varying more intensive risk factor control and CHD.61 These studies support the more range of LDL-C levels. An analysis to management. contemporary concept that not all with probe the relationship between LDL-C Diabetes- From CHD risk equivalent to DM are CHD risk equivalents, but that and CVD risk for the placebo and extremely high-risk category risk assessment is important in those active-controlled trials was done and at DM to identify those at highest risk the risk curves were constructed. The In a Finnish population-based who need even more intensive therapy. rationale was to identify patients who study, the incidence of myocardial require aggressive LDL cholesterol- infarction among 1373 non-diabetics Similar conclusions were derived lowering therapy. The position on the was compared to 1059 diabetic subjects from the data collected in 6 different curve is based not only on the baseline over 7-year period. The incidence in countries for the Organization to Assess LDL-C levels but also on the presence non-diabetic subjects was 18.8% and Strategies for Ischemic Syndromes or absence of diabetes, metabolic 3.5% versus 45.0% and 20.2% in diabetic (OASIS) registry. In the registry, syndrome and IFG. Patients who are subjects with and without previous 21% of 1718 were diabetic patients. high risk based on their position on myocardial infarction respectively. The mortality was highest amongst the risk curve require further LDL-C In an 18-year follow-up study of diabetics. Diabetes independently reduction as well as aggressive risk Finnish subjects, type 2 diabetes is a predicted mortality, CV death, new factor control to shift their position “CHD equivalent” if prior myocardial myocardial infarction, stroke, and downwards on the risk curve.65 infarction was used to define CHD. congestive heart failure.62 A post-hoc When less stringent criteria for prior subgroup analysis of 4S study including In LDL-C and CVD risk curve, when CHD were used (myocardial infarction 202 diabetic patients and 4,242 non- LDL-C is reduced from 100 to 70 mg/ or ischemic ECG changes or angina diabetic patients with previous dl, the absolute risk reduction is 6% in pectoris), type 2 diabetes carried a cardiac event, elevated cholesterol and patients of CHD plus diabetes compared larger risk than prior CHD, especially in triglycerides analysis was carried out. to 3% in those with CHD without women.57 Hence, it can be concluded that Patients were assigned to double-blind diabetes or metabolic syndrome or cardiovascular risk factors in diabetic treatment with 20 mg simvastatin with impaired glucose tolerance over period patients must be treated as aggressively dose titration to 40 mg daily, according of 5 years. Residual risk for 5 years, as non-diabetic patients with prior to cholesterol response during the at an LDL level of 40 mg/dl for CHD myocardial infarction.58 However, first 6-18 weeks, or placebo. The subjects with and without diabetes is several years later a meta-analysis of relative risk (RR) of major endpoints 10 % and 8% respectively. The number- over a dozen studies examining this in simvastatin-treated diabetic vs non- needed-to prevent an event at LDL-C issue showed overall that those with diabetic patients as shown in table 6.63 40 mg/dl is 23 in patients with CAD and DM which is lower than NNT of DM without a prior MI had a 43% lower Higher absolute risk of recurrent 45 for patients with CAD without DM, risk of future CHD compared to those CV and other atherosclerotic events 59 metabolic syndrome or IFG. Hence, with a prior MI without DM. Finally, in diabetics corresponds to greater aggressive therapy is reserved for those data from the Multiethnic Study of absolute clinical benefit achieved by at the highest risk.65 Atherosclerosis examining CHD and cholesterol lowering in diabetics than CVD event rates according to levels of in nondiabetics.63 st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 27

Table 8: Reduction in primary endpoint in With Metabolic Syndrome Without Metabolic Syndrome the evolocumab group based on 1 the presence or absence of high- risk features 0.9 Presence or Evolocumab Primary absence of group- endpoint 0.8 high-risk features Number needed RRR ARR to treat (NNT) 0.7 Multivessel Disease 28 21% 3.6 No multi-vessel 83 7% 1.2 0.6 HR 0.83 HR 0.89 HR 0.76 HR 0.86 disease (0.76-0.91) (0.79-1.01) (0.68-0.86) (0.74-1.01) 0.5 Qualifying MI < 2 30 20% 3.4 P <0.001 P=0.069 P<0.001 P=0.07 years

Qualifying MI > 2 125 5% 0.8 Ratio Hazard 0.4 years 2 or more prior MIs 27 18% 3.7 0.3 1 prior MI 77 8% 1.3 0.2 Efficient risk stratification to identify high risk groups for secondary prevention 0.1

The TIMI Risk score identified 9 0 independent clinical indicators in TRA 2°P-TIMI 50 [Thrombin Receptor Primary Outcome Key Secondary Outcome Antagonist in Secondary Prevention Fig. 3: Effect of evolocumab treatment in patients with and without the metabolic of Atherothrombotic Ischemic Events- syndrome (Fourier Trial) TIMI 50]- age, diabetes mellitus, hypertension, smoking, peripheral risk patients who will benefit most in the simvastatin treatment group with arterial disease, previous stroke, from additional lipid lowering with zero score and 2% had a score of ≥5. previous coronary bypass grafting, non-statin therapy (ezetimibe) over and The event rate would have been higher heart failure, and impaired renal above statin treatment for secondary for the DYSIS II patients observed function. In this study, 8598 placebo prevention. This benefit was seen by extrapolating the event rate of patients with a prior MI were followed without any increase in adverse events IMPROVE-IT. MACE were noted in 67 for 2.5 years. High-risk patients (≥3 risk over 7-year period. 68% of the simvastatin-treated patients indicators) had a 3.2% absolute risk Similarly, TIMI Risk Score for in IMPROVE-IT with a TRS 2°P of ≥5. reduction in cardiovascular disease/MI/ Secondary Prevention (TRS 2°P) The benefits of ezetimibe addition to ischemic stroke (NNT-31) as compared showed a strong graded relationship the statin therapy were observed in the to intermediate-risk patients (1-2 risk with the rate of CV death, MI or patients with higher TRS 2°P values, indicators) who had a 2.1% absolute stroke when applied to 27,564 patients which indicates that use of ezetimibe risk reduction (P<0.001) with NNT of with atherosclerotic heart disease would have even greater benefits 48. Higher the number of risk factors, and LDL-C ≥70 mg/dl randomized to for the higher risk DYSIS II CHD 69 greater was the number of MACE-3.5% evolocumab or placebo in FOURIER population. Thus in real world patient in those with no risk factors and 58.6% study. Intermediate risk patients population significant proportion of in presence of 7 or more risk factors. demonstrated a 1.9% ARR (NNT 53) in patients are very high risk suggesting The greater reduction in ARR in cardiac CV death, MI or stroke at 3 years with that additional LDL-C lowering with events with vorapaxar in high risk evolocumab while high-risk patients non-statin therapies is likely to confer patients as compared to the intermediate had a 3.6% ARR (NNT 28).68 further risk reduction. risk concludes that stratification of The Dyslipidemia International In an analysis of FOURIER study, baseline atherothrombotic risk can Study (DYSIS II) CHD study was a 22,351 post-MI patients were grouped assist with therapeutic decision making cross-sectional observational study of based on presence of high-risk features 66 for secondary prevention post MI. 3,867 ACS and 6794 patients with stable following myocardial infarction. The Another study applied this score to coronary heart disease (CHD) across 18 high-risk features were <2 years from 17,717 post-ACS patients randomized countries including India. Hypertension qualifying MI, ≥2 prior MIs or residual either to ezetimibe and simvastatin (96.0%) and diabetes mellitus (40.3%) multivessel disease. The 8343 patients or to placebo and simvastatin in were the most common risk factors (37% of prior MI population) had zero IMPROVE-IT study. High-risk patients noted in the DYSIS II population and risk features and demonstrated 6% RRR with ≥3 risk indicators, had a 6.3% ARR 2.0% of patients had a TIMI risk score and 0.5% ARR with the NNT being as in events at 7 years with ezetimibe/ for secondary prevention (TRS 2°P high as 200. The remaining 13,973 (63% simvastatin, thus translating to a score) of zero and 3.7% had a score of prior MI population) showed at least number-needed-to-treat (NNT) of 16. of ≥5. The DYSIS II CHD population a single risk feature and showed 22% Intermediate-risk patients with 2 risk displayed a greater number of TRS 2°P RRR and 2.5% ARR with the NNT of 54 factors had a 2.2% ARR with NNR =45. risk factors as compared to IMPROVE- 41. The detailed analysis of each risk Thus, risk stratification identifies high IT study which had 12% of the patients feature is mentioned in the Table 8. st st 28 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Benefits in peripheral artery disease was noted in an analysis of data from ESC 2019 guidelines advocated that 3642 patients (13.2%) had PAD (1505 FOURIER study in adults with/without very high-risk patients should achieve 72 with no prior myocardial infarction or metabolic syndrome (Fig. 3). a goal LDL-C level of <55 mg/dl. It stroke) in the FOURIER study.70 Patients Duration of LDL-C Lowering recognized that ACS patients are at very high risk of recurrent events and those with PAD had much higher ARR for A series of meta-analyses were who experience a second vascular event the primary end point (3.5% with PAD, carried out to quantify the effect of within 2 years on maximally tolerated 1.6% without PAD) and secondary end long-term exposure to lower LDL-C statin therapy, an LDL-C goal of <40 point (3.5% with PAD, 1.4% without on the risk of CHD mediated by 9 mg/dL be considered.14 PAD) with evolocumab due to higher polymorphisms. These Mendelian attributable risk. There was significant studies were combined in a meta- Recently Polish Cardiac Society reduction (42% RRR) in major adverse analysis to compare it with the clinical Working Group on Cardiovascular limb events in the evolocumab group benefit associated with the same Pharmacotherapy endorsed as compared to placebo. A consistent magnitude of LDL-C reduction with Interdisciplinary Expert Position relationship between lower achieved statin treatment. Statement Recommendation for the LDL-C and reduced risk of limb events management of dyslipidemia in Poland. These polymorphisms were (P=0.026 for the beta coefficient) that This document recommended LDL-C associated with consistent reduction extended down to <10 mg/dl was of less than 35 mg/dl in extreme risk in the risk of CHD per unit lower noted.70 group patients.74 LDL-C. In a meta-analysis of 312,321 The long-term cardiovascular risk participants, naturally random Newer lipid-lowering drugs associated with polyvascular disease, allocation to long-term exposure to PCSK 9 inhibitors in high-risk patients type II diabetes, and their combination lower LDL-C led to 54.5% reduction in Although various guidelines in patients with CAD was assessed in the risk of CHD for each mmol/l (38.7 suggest the use of PCSK9 inhibitors an exploratory analysis of IMPROVE- mg/dl) lower LDL-C. This represents is appropriate in indicated patients, IT study. Patients in the IMPROVE-IT nearly 3-fold greater reduction in the the use is minimal due the perceived trial with polyvascular disease with risk of CHD than that observed during expense. Various models focusing concomitant type 2 diabetes were at very treatment with a statin started later on cost-effectiveness analyses have high risk (60% MACE rate at 7 years) 16 in life. produced widely varying and confusing compared to those without diabetes and Evidence from Guidelines results.75,76 The ‘highest risk–highest polyvascular disease (29.6% MACE rate benefit’ concept has been recommended at 7 years), P <0.0001. The absolute risk Various international bodies have by Annemans et al as a strategy to reduction with ezetimibe 10 mg/d on also recognized the impact of lowering assist in the identification of patients the background of simvastatin 40 mg/d LDL to less than 50 mg/dl in patients who will derive maximum benefit from was 9.1% in polyvascular disease with with very high risk of events in the PCSK9 therapy.77 The former part is to concomitant type 2 diabetes compared future. In 2016, Lipid Association of identify those with the ‘highest baseline to 1.7% in those without diabetes and India (LAI) brought out a consensus event rate’ primarily for secondary polyvascular disease over 7 years, P document which set lower, stricter prevention- polyvascular disease, <0.0001.71 treatment goals of LDL‐C <50 mg/dl and non-HDL‐C <80 mg/dl- for very ASCVD with co-morbidities such as The ODYSSEY Outcomes Trial also high‐risk Indians. The very high-risk chronic kidney disease or diabetes showed that patients with recent ACS category included patients with pre- with end-organ damage or FH patients and dyslipidemia despite being on existing ASCVD, diabetics with 2 or with a CVD event. FH with high LDL-C intensive statin therapy, polyvascular more major risk factors or evidence of despite statin therapy is the only disease (concurrent peripheral artery end-organ damage and homozygous criteria for primary prevention. The disease, cerebrovascular disease, or familial hypercholesterolemia.10 latter part is to identify patients who both), carry a higher risk of MACE and would get ‘highest benefit’. The RRR is This was soon followed by AACE death, and alirocumab leads to large proportionate to the absolute decrease 55 recommending an LDL-C goal of less absolute reductions in the risk. in LDL-C. Estimated NNT is lower in than 55 mg/dl in patients at extreme Benefits in metabolic syndrome patients with the highest CVD risk and risk. This group included progressive largest absolute LDL-C reduction.77 Participants with metabolic ASCVD, established clinical ASCVD syndrome achieved a greater risk with diabetes, CKD stage 3 or 4, and/or Robinson and Watson proposed reduction for the primary endpoint HeFH, or individuals with premature that NNT can provide the basis for (HR = 0.83; 95% CI, 0.76-0.91) vs. those ASCVD (<55 years of age in males shared decision making by patients without metabolic syndrome (HR =0.89; or <65 years of age in females).11 In and clinicians. They identified three 95% CI, 0.79-1.01). Similarly, 24% risk 2017, Taiwan lipid guidelines for high phenotypes- extremely high risk, very reduction for secondary endpoints in risk patients recommended that a high risk and high risk and LDL-C those with metabolic syndrome (HR = lower target of LDL-C <55 mg/dl can thresholds for each group that would 0.76; 95% CI, 0.68-0.86) versus 14% risk be considered in ACS patients with aid in the identification of patients most reduction for those without metabolic DM.12 This was based on the findings likely to benefit from adding ezetimibe syndrome (HR = 0.86; 95% CI, 0.74-1.01) of IMPROVE IT study.73 Recent EAS/ or a PCSK9 inhibitor. An NNT of less than 25 for PCSK9 inhibitors and st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 29

Fig. 4: Risk stratification approach previously recommended by the Lipid Association of India in 2016

NNT less than 30 for ezetimibe were of 56 patients hypercholesterolemic levels ≥70 mg/dl to bempedoic acid or considered to make these cost-effective patients with statin intolerance, placebo while receiving maximally in deserving candidates.78 bempedoic acid has been studied four tolerated lipid lowering therapy. The Bempedoic Acid phase III clinical trials representing addition of bempedoic acid (180 mg) more than 3,600 patients.80 The CLEAR to maximally tolerated lipid-lowering Bempedoic acid (ETC-1002) is a Harmony trial randomized 2230 patients therapy significantly lowered LDL-C prodrug that requires conversion by (2:1) with ASCVD, heterozygous levels compared with placebo (-15.1 acyl-CoA synthease-1 to its active familial hypercholesterolemia, or both vs. 2.4%, P <0.01) at 12 weeks. The moiety, ETC-1002-coenzyme A on maximally tolerated statin with bempedoic acid also significantly (ETC-1002-CoA). The active form LDL-C levels ≥70 mg/dl to bempedoic decreased non-HDL-C (-10.8% vs. of bempedoic acid is a competitive acid or placebo. The mean LDL-C 2.3%), total cholesterol (-9.9% vs. 1.3%), inhibitor of the enzyme adenosine level decreased by 19.2 mg/dl (16.5% apolipoprotein B (-9.3% vs. 3.7%) and triphosphate (ATP)-citrate lyase (ACL) decrease from baseline levels, P <0.001) high-sensitivity CRP (-18.7% vs. -9.4%) and reduces the production of cytosolic at 12 weeks. The overall incidence of compared to placebo.82 acetyl coenzyme A (acetyl-CoA), the adverse events (78.5% patients) in the final substrate for both fatty acid and In a pooled analysis of 3623 patients bempedoic acid group compared to sterol synthesis, located upstream included in four randomized trials with with placebo group (78.7% patients) of HMG-CoA in the cholesterol ASCVD or HeFH or both, the mean was similar. However the incidence of biosynthesis pathway. It is an oral, baseline LDL-C level was 107.6 mg/dL. gout (18 patients [1.2%] vs. 2 [0.3%]) once-daily, non-statin LDL-C lowering At week 12, the LDL-C level change from was higher with bempedoic acid.81 drug.79 baseline was −16.0% with bempedoic The CLEAR Wisdom trial acid vs 1.8% with placebo (P <0.001). After small studies including by randomized 779 patients (2:1) with Patients with statin intolerance had Thompson et al who reported that ASCVD, heterozygous familial a mean baseline LDL-C level of 144.4 bempedoic acid reduced LDL-C levels hypercholesterolemia, or both on mg/dL. The changes in LDL-C levels at by 28.7% more than placebo in a maximally tolerated statin with LDL-C week 12 were −23.0% in the bempedoic randomized, placebo-controlled study st st 30 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Updated Risk Stratification Approach Recommended by Lipid Association of India 2020 Risk factors/markers Major ASCVD risk factors Other high-risk features Moderate risk non-conventional risk factors 1. Age ≥45 years in males and ≥55 1. Diabetes with 0-1 other major ASCVD risk factors and 1. Coronary calcium score 100-299 HU years in females no evidence of target organ damage 2. Increased carotid IMT 2. Family history of premature ASCVD 2. CKD stage 3B or 4 3. Lipoprotein (a) 20-49 mg/dL 3. Current cigarette smoking or 3. Familial hypercholesterolemia (other than familial 4. Impaired fasting glucose* tobacco use homozygous hypercholesterolemia) 5. Increased waist circumference** 4. High blood pressure 4. Extreme of a single risk factor 6. ApoIipoprotein B ≥110 mg/dL 5. Low HDL-C 5. Coronary calcium score >300 HU 7. hsCRP ≥2 mg/L*** 6. Non-stenotic carotid plaque 7. Lipoprotein (a) ≥50 mg/dL Risk Group Low risk Moderate risk High risk Very High risk Extreme Risk 0-1 major ASCVD risk • 2 major ASCVD risk • ≥3 major ASCVD • Pre existing ASCVD Category A Category B factor And Life-time factors risk factors • Diabetics with 2 CVD risk <30 % • Low risk group with • 2 major ASCVD risk other major ASCVD ≥1 moderate risk factors with ≥I risk factors or CAD with ≥1 feature CAD with ≥1 feature of non- conventional moderate risk non- evidence of target of high risk group very high risk group or risk factor conventional risk organ damage recurrent ACS (within • Life-time CVD risk factor • Familial homozygous one year) despite LDL-C ≥30% • ≥1 other high-risk hypercholesterolemia  50 mg/dL or features polyvascular decease Clinical judgment to be used if the patient has atherosclerotic peripheral arterial disease instead of coronary artery disease; *A fasting blood sugar level from 100 to 125 mg/dl. It should be confirmed by repeat testing; **Waist circumference is to be measured at the superior border of the iliac crest just after expiration. Increased waist circumference is defined as >90 cm in men and >80 cm in women. If increased waist circumference is the only risk factor, it should again be measured after 6 months after initiating heart healthy lifestyle measures; ***On two occasions at least 2 weeks apart. For reclassifying moderate risk group only

Fig. 5: Updated 2020 risk stratification approach recommended by the Lipid Association of India

acid group and 1.5% in the placebo useful option for additional LDL-C the body cells with cholesterol.87 group (P <0.001). The decrease in lowering beyond maximally tolerable In a prospective cohort study of LDL-C levels with bempedoic acid was statin. 27,937 women from Women’s Health sustained during long-term follow-up Although the LDL-C lowering effects Study (primary prevention study) in both groups (patients with ASCVD and safety profile of bempedoic acid followed up for a mean period of 19.3 or HeFH or both receiving a maximally are encouraging, it’s effect on clinical years it was found that LDL-C of less tolerated statin, LDL-C change of endpoints are yet to be determined. than 70 mg/dl and low triglyceride −12.7% at week 52; patients with statin CLEAR Outcomes trial is an ongoing levels were associated with increased intolerance, LDL-C change of −22.2% at study to assess major adverse risk of hemorrhagic stroke. One should week 24). Treatment-emergent adverse cardiovascular events in patients appreciate that this is a primary events associated more frequently with with, or at high risk for cardiovascular prevention study restricted to female bempedoic acid than with placebo disease who are statin intolerant treated gender and study had limited power included increased blood uric acid with bempedoic acid or placebo.79 of determining hemorrhagic stroke level (2.1% vs 0.5%), gout (1.4% vs Physiological levels of LDL-C subtype and, other confounding 0.4%), decreased glomerular filtration variables were menopausal status, Experimentally, healthy baboons rate (0.7% vs <0.1%), and increased availability of only baseline lipid values show LDL-C levels of approximately of hepatic enzyme levels s (2.8% vs and low statin usage.88 1.3%).83 40 to 80 mg/dl.84 There is evidence from hunter-gatherer populations Hence, based on the above data there The US Food and Drug Administration demonstrating no evidence of is no evidence at present to suggest any approved bempedoic acid for the atherosclerosis, even in individuals safety concern with pharmacologically treatment of adults with heterozygous living into the seventh and eighth achieved LDL-C levels less than 30 mg/ familial hypercholesterolemia (HeFH) decades of life.85 Their total cholesterol dl in extremely high-risk individuals. or established ASCVD who require levels are approximately 100 to 150 Updated Recommendations by LAI additional lowering of LDL-C on mg/dl with estimated LDL cholesterol February 21, 2020. On February 26, The Lipid Association of India levels of about 50 to 75 mg/dl. Neonates the FDA also cleared a fixed-dose published a practical algorithm for are born with LDL values in the range risk evaluation amongst Indians in combination containing bempedoic 86 of 30-70 mg/dl. A theory suggests that 10 acid and ezetimibe.79 This combination 2016 (Figure 4). It included four risk an LDL value of 25 mg/dl in the plasma therapy provides LDL-C reductions in categories- Very high, High, Moderate is enough to provide nourishment to the range of 35%, making this a very and Low risk. st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 31

Table 9: Proposed LDL-C goals in very high risk and extreme risk group patients ≤30 mg/dl is recommended for those in

Risk group category B. Very High Risk group (VHRG) Extreme Risk group Justification for Extreme Risk Group Category A Category B CAD is designated as very high-risk LDL-C goal category in 2016 LAI consensus statement ∆ LDL-C goal of <50 mg/dl LDL-C goal of <50 mg/dl LDL-C goal of ≤30 mg/dl 10 (Indispensable) on management of dyslipidemia. LDL-C goal of ≤30 mg/dl However, all CAD patients do not (optional)∆ have the same prognosis. Selected High-risk conditions CAD patients have higher risk of future Any one of following: CAD° with ≥1 of following: CAD° with ≥1 of following: adverse CV events because of presence ASCVD (CAD/PAD/TIA or stroke) Diabetes without target organ Diabetes + polyvascular disease/≥3 of risk factors, comorbidities and extent damage/0-2 major ASCVD risk major ASCVD risk factors*/target Homozygous familial of atherosclerosis. The number, type hypercholesterolemia factors organ damage and severity of risk factors determine Diabetes with ≥3 major ASCVD Familial hypercholesterolemia ≥3 Recurrent ACS (within 12 months) risk factors*/target organ damage major ASCVD risk factors CKD despite on LDL-C goal the risk of subsequent adverse CV stage 3B and 4 Homozygous familial events. This has been discussed in ≥2 major ASCVD risk factors with hypercholesterolemia detail above. To adequately manage ≥1 moderate non-conventional risk factor# the risk in patients with increased risk, Lp(a) ≥50 mg/dl LAI proposes a new category- Extreme Coronary calcium score ≥300 HU risk. These “Extreme risk” patients Extreme of a single risk factor require aggressive management to PAD decrease future ASCVD events (Table H/o TIA or stroke 9). Further, more aggressive LDL-C ∆The LDL-C goal of ≤30 mg/dl must be pursued after detailed risk-benefit discussion between physician and goals in Indians are needed compared patient to the western countries as prevalence °Clinical judgment to be used in decision making if the patient has disease/risk factors not covered in the of coronary artery disease as well as table, eg. PAD or cerebrovascular disease cardiovascular events in south Asians Abbreviations: ACS: acute coronary syndrome; ASCVD: atherosclerotic cardiovascular disease; polyvascular disease: evidence of atherosclerotic disease in at least two vascular territories: coronary artery is 1.5- to 2-fold higher compared to disease (CAD), peripheral arterial disease (PAD) and history of (H/o) transient ischemic attack (TIA) or native US population.89 Besides CAD is stroke, CKD: chronic kidney disease; Lp(a): lipoprotein(a) malignant in Indian subcontinent with * Major ASCVD risk factors: 1. Age- male ≥45 years, female ≥55 years, 2. Family h/o premature CAD- male more than 50% of CAD associated death <55 years, female <65 years, 3. Smoking/tobacco use, 4. Systemic hypertension, 5. Low HDL (males <40 mg/ dl and females <50 mg/dl) in India occurring before the patient #Moderate non-conventional risk factors: 1. Coronary calcium score 100-299 HU, 2. Increased carotid reaches the age of 50 years and 25% of intima-media thickness, 3. Lp(a) ≥20-49 mg/dl, 4. Impaired fasting glucose, 5. Increased waist circumference, myocardial infarctions occur before the 6. Apolipoprotein B ≥110 mg/dl, 7. hsCRP ≥2 mg/L age of 40 years15 necessitating vigorous Table 10: Newer treatment goals and statin initiation thresholds based on the risk categories and determined measures to stem the proposed by LAI in 2020 ASCVD epidemic. Risk group Treatment Goals Consider Drug Therapy Statins are the mainstay of treatment LDL-C (mg/dl) Non-HDL (mg/dl) LDL-C (mg/dl) Non-HDL (mg/dl) to prevent future CV events. However Extreme Risk Group <50 (Optional goal ≤30) <80 (Optional goal ≤60) ≥50 ≥80 Category A significant residual risk persists despite Extreme Risk Group ≤30 ≤60 >30 >60 statin therapy. This risk is significantly Category B more in patients with additional risk Very High Risk <50 <80 ≥50 ≥80 factors. Recent non-statin trials have High Risk <70 <100 ≥70 ≥100 shown that further risk reduction Moderate Risk <100 <130 ≥100 ≥130 can be achieved by LDL-C lowering Low Risk <100 <130 ≥130* ≥160* regardless of means of LDL-C lowering. * After an adequate non-pharmacological intervention for at least 3 months We have recently proposed aggressive Additional Category in the Risk group (Extreme risk group category A) lowering of LDL-C for secondary Stratification Algorithm 2. CAD with features of very prevention through improved usage of Considering the elevated risk of high-risk group or recurrent ACS high-intensity statins with ezetimibe, malignant nature of ASCVD in Indians (within one year) even after LDL-C possibly in combination with PCSK9 90,91 and availability of evidence supporting target of less than 50 mg/dl is achieved inhibitor monoclonal antibodies. the benefits and safety of lowering (Extreme risk group category B) Bempedoic acid has been recently LDL below 30 mg/dl, an Extreme Risk approved by US FDA for LDL-C The Extreme Risk Group category is Category has been incorporated in the lowering in HeFH and established divided into category A and category 79 existing risk stratification algorithm ASCVD. It can be considered on the B depending on the underlying risk by Lipid Association of India (Fig. 5). background of other lipid lowering conditions. An optional LDL-C of ≤30 agents prior to addition of PCSK9 Extreme Risk category includes: mg/dl is proposed for Category A while inhibitors. 1. CAD with features of high-risk st st 32 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Algorithm for treatment to achieve LDL cholesterol goals in very high risk • The calculated LDL-C includes and extreme risk group patients the cholesterol contained in Lp(a). The Lp(a) cholesterol is not reduced by statins. Hence individuals with elevated Optimal control: Reinforce lifestyle + High-intensity statin + Lp(a) may have a less-than-anticipated Diabetes and measures: response in LDL-C reduction on statin hypertension as Diet therapy. This should raise the suspicion per respective Regular exercise of a markedly elevated Lp(a). guidelines Weight reduction LDL-C level ≥50 mg/dL • Identification of highest risk (where appropriate) groups who would benefit maximally Quit smoking with efficient drug therapy is probably Alcohol restriction Add ezetimibe the missing key. LDL-C Goal However, the final decision should LDL-C level ≥50 mg/dL Very High Risk Group: follow a detailed discussion between <50 mg/dL the patient and treating physician (shared decision). Consider Bempedoic acid/ Extreme Risk Group: Category A: <50 mg/dL References PCSK9 inhibitor (Optional goal ≤30 mg/dL) 1. Cullen P, Rauterberg J, Lorkowski S. The Pathogenesis of monoclonal antibodies Category B: ≤30 mg/dL Atherosclerosis. In: von Eckardstein A. (eds) Atherosclerosis: Diet and Drugs. Handbook of Experimental Pharmacology, Fig. 6: Algorithm for treatment in very high risk and extreme risk group patients to vol 170. Springer, Berlin, Heidelberg. 2005. achieve LDL-C goals. Refer to table 9 for criteria of very high risk and extreme risk 2. Berliner JA, Navab M, Fogelman AM, et al. Atherosclerosis: group basic mechanisms. Oxidation, inflammation, and genetics. Circulation 1995; 91:2488-96.

Treatment Goals Conclusions 3. National Cholesterol Education Program. Third report of The different treatment goals and • Children are born with an LDL-C the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood statin initiation thresholds based on level of about 30 mg/dl. Cholesterol in Adults (Adult Treatment Panel III): final report. Circulation 2002; 106:3149-421. the risk categories are proposed in the • Hunter gatherers had low table. cholesterol with a very low prevalence 4. Grundy S, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Recommended Treatment Protocol of CAD. Program Adult Treatment Panel III guidelines. Circulation 2004; 110:227-39. The 2020 Lipid Association of India • The Extreme risk group is an LDL-C and non-HDL-C treatment goals additional ASCVD risk category 5. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce and algorithm are given in Table 10 and indicating greater atheroma load and atherosclerotic cardiovascular risk in Adults: a report of the Figure 6. greater risk of MACE. American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2014;129:S1- Shared decision-making • The Extreme risk group is divided S45.

As highlighted above, there is in two categories: 6. Grundy SM. An International Atherosclerosis Society Position ample evidence to justify aggressive Paper: Global recommendations for the management of • Category A- CAD with ≥1 high-risk dyslipidemia. J Clin Lipidol 2006; 7:561-5. LDL-C lowering to very low levels group feature with LDL-C goal of <50 in patients with “extreme risk” for 7. Perk J, De Backer G, et al. European Guidelines on mg/dl (recommended) and ≤30 mg/dl cardiovascular disease prevention in clinical practice ASCVD. However, such intensive (optional) (version 2012). The Fifth Joint Task Force of the European LDL-C lowering involves use of high- Society of Cardiology and other societies on cardiovascular • Category B- CAD with ≥1 very intensity statin therapy combined often disease prevention in clinical practice (constituted by high-risk group features with LDL-C representatives of nine societies and by invited experts). with ezetimibe and/or PCSK9 inhibitors European Association for Cardiovascular Prevention goal of ≤30 mg/dl (recommended). leading to issues related to cost and & Rehabilitation (EACPR), ESC committee for practice guidelines (CPG). Eur Heart J 2012; 33:1635-701. patients’ concerns about side-effects • Extreme low levels of LDL-C (≤30 of medications as well as of very low mg/dl) can be achieved with newer 8. Andersen TJ, Gregoire J, Pearson GJ, et al. 2016 Canadian Cardiovascular Society guidelines for the management of LDL-C levels. Recognizing this, the LAI drugs and should be considered as dyslipidemia for the prevention of cardiovascular disease strongly emphasizes the role of shared an option in patients at extreme risk in the adult. Can J Cardiol 2016; 1263-82. decision-making when recommending to further reduce ASCVD events (MI/ 9. Jacobson TA, Ito MK, Maki KC, et al. National Lipid treatment to this group of patients. stroke/ revascularization) Association recommendations for patient-centered management of dyslipidemia: Part 1-full report. J Clin Lipidol Moreover, a comprehensive discussion • Maximal tolerated doses of 2015; 9:129-69. about lifestyle management should statins with or without ezetimibe, 10. Iyengar SS, Puri R, Narasingan SN, et al. Lipid Association always be central to the patient-clinician adequate lifestyle interventions and of India expert consensus statement on management of discussion. All the benefits and risks of treatment of all modifiable factors dyslipidemia in Indians. Part 1. J Assoc Physicians India 2016; 64:S7‐52. therapy should be discussed with the must be investigated carefully prior to patient and the patient family before 11. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American addition of newer drugs such as PCSK9 Association of Clinical Endocrinologists and American reaching a joint decision about further inhibitors. College of Endocrinology guidelines for management of lipid-lowering in any given patient. st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 33

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Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol lowering 45. Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two 27. Pedersen TR, Faergeman O, Kastelein JJP, Olsson AG, with simvastatin improves prognosis of diabetic patients intensive statin regimens on progression of coronary Tikkanen MJ, Holme I, et al. High-dose atorvastatin vs usual- with coronary heart disease. A subgroup analysis of the disease. N Engl J Med 2011; 365:2078-87. dose simvastatin for secondary prevention after myocardial Scandinavian Simvastatin Survival Study (4S). Diabetes Care infarction: the IDEAL study: a randomized controlled trial. 46. Tsujita K, Sugiyama S, Sumida H, et al. Impact of dual 1997; 20:614-20. JAMA 2005; 294:2437-45. lipid-lowering strategy with ezetimibe and atorvastatin on 64. Lee MG, Jeong MH, Lee KH, et al. Prognostic impact of coronary plaque regression in patients with percutaneous 28. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid diabetes mellitus and hypertension for mid-term outcome coronary intervention: The multicenter randomized lowering with atorvastatin in patients with stable coronary of patients with acute myocardial infarction who underwent controlled PRECISE-IVUS trial. J Am Coll Cardiol 2015; 66:495- disease. N Engl J Med 2005; 352:1425-35. percutaneous coronary intervention. J Cardiol 2012; 60:257- 507. 63. 29. Superko HR, King III S. Lipid management to reduce 47. Kini AS, Baber U, Kovacic JC, et al. Changes in plaque lipid cardiovascular risk: a new strategy is required. Circulation 65. Robinson JG, Stone NJ. Identifying patients for aggressive content after short-term intensive versus standard statin 2008; 117:560-8. cholesterol lowering: the risk curve concept. Am J Card 2006; therapy: The yellow trial (reduction in yellow plaque by 98:1405-8. st st 34 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

66. Bohula EA, Bonaca MP, Braunwald E, et al. Atherothrombotic Statement endorsed by the Polish Cardiac Society Working 83. Banach M, Duell PB, Gotto Jr AM, et al. Association of risk stratification and the efficacy and safety of vorapaxar Group on cardiovascular pharmacotherapy. Cardiology bempedoic acid administration with atherogenic lipid in patients with stable ischemic heart disease and previous Journal 2018; 25:655-65. levels in phase 3 randomized clinical trials of patients with myocardial infarction. Circulation 2016; 134:304-13. hypercholesterolemia. JAMA Cardiol 2020. doi:10.1001/ 75. Gandra SR, Villa G, Fonarow GC, Lothgren M, Lindgren jamacardio.2020.2314. 67. Bohula EA, Morrow DA, Giugliano RP, et al. Atherothrombotic P, Somaratne R, van Hout B. Cost-effectiveness of risk stratification and ezetimibe for secondary prevention. J LDL-C lowering with evolocumab in patients with high 84. Kemnitz W, Sapolsky RM, Altmann J, et al. Effects of food Am Coll Cardiol 2017; 69:911-21. cardiovascular risk in the United States. Clin Cardiol 2016; availability on serum insulin and lipid concentrations in 39:313-20. free-ranging baboons. Am J Primatol 2002; 57:13-19. 68. Bohula EA, Morrow DA, et al. Atherothrombotic Risk Stratification and magnitude of benefit of evolocumab in 76. Kazi DS, Moran AE, Coxson PG, Penko J, Ollendorf DA, 85. Cordain L, Eaton SB, Miller JB, Mann N, Hill K. The paradoxical FOURIER. Abstract 20183. Circulation 2018; 136:A20183. Pearson SD, Tice JA, Guzman D, Bibbins-Domingo K. nature of hunter-gatherer diets: meat based, yet non- Cost-effectiveness of PCSK9 inhibitor therapy in patients atherogenic. Eur J Clin Nutr 2002; 56(Suppl 1):S42-52. 69. Bonaca MP, De Ferrari GM, Atar D, et al. How does the TRS with heterozygous familial hypercholesterolemia or 2°P score relate to real-world patients? Eur Heart J Cardiovasc 86. O’Keefe Jr JH, Cordain L, Harris WH, et al. Optimal low- atherosclerotic cardiovascular disease. JAMA 2016; 316:743- Pharmacother 2018; 4:72-4. density lipoprotein is 50 to 70 mg/dl: Lower is better and 53. physiologically normal. J Am Coll Cardiol 2004; 43:2142-6. 70. Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, 77. Annemans L, Packard CJ, Briggs A, Ray KK. ‘Highest Kanevsky E. Low-density lipoprotein cholesterol lowering 87. Brown MS, Goldstein JL. A receptor mediated pathway for risk–highest benefit’ strategy: a pragmatic, cost-effective with evolocumab and outcomes in patients with peripheral cholesterol homeostasis. Science 1986; 232:34-47. approach to targeting use of PCSK9 inhibitor therapies. Eur artery disease: Insights from the FOURIER Trial (Further Heart J 2018; 39:2546-50. 88. Rist PM, Buring JE, Ridker PM, Kase CS, Kurth T, Rexrode KM. Cardiovascular Outcomes Research With PCSK9 Inhibition in Lipid levels and risk of hemorrhagic stroke among women. Subjects With Elevated Risk). Circulation 2018; 137:338-350. 78. Robinson JG, Watson KE. Identifying patients for non-statin Neurology 2019; 92:1-9. therapy. Rev Cardiovasc Med 2018; 19:S1-S8. 71. Bonaca MP, Gutierrez JA, Cannon C, Giugliano R, Blazing M, 89. Kalra DK, Sikand G, Vijayaraghavan K, Guyton JR. JCL Park JG, White J, Tershakovec A, Braunwald E. Polyvascular 79. Markham A. Bempedoic acid: first approval. Drugs 2020; roundtable: South Asian atherosclerotic risk. J Clin Lipidol disease, type 2 diabetes, and long-term vascular risk: a 80:747-53. 2020; 14:161-9. secondary analysis of the IMPROVE-IT trial. Lancet Diabetes 80. Thompson PD, Rubino J, Janik MJ, et al. Use of ETC-1002 Endocrinol 2018; 6:934-43. 90. Puri R, Mehta V, Duell PB, Nair D, et al. Proposed low-density to treat hypercholesterolemia in patients with statin lipoprotein cholesterol goals for secondary prevention 72. Deedwania P, et al. Late-Breaking Pharmacological Science. intolerance. J Clin Lipidol 2015; 9:295-304. and familial hypercholesterolemia in India with focus on Presented at: European Society of Cardiology Congress; Aug. 81. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of PCSK9 inhibitor monoclonal antibodies: Expert consensus 25-29, 2018; Munich, Germany. bempedoic acid to reduce LDL cholesterol. N Engl J Med statement from Lipid Association of India. J Clin Lipidol 2020; 73. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, 2019; 380:1022-32. 14:e1-e13. Theroux P, et al. Ezetimibe added to statin therapy after 82. Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of bempedoic 91. Duell PB, Mehta V, Nair D, et al. The epidemic of acute coronary syndromes. N Engl J Med 2015; 372:2387-97. acid vs placebo added to maximally tolerated statins on atherosclerotic cardiovascular disease in India- Editorial. J 74. Szymanski FM, Barylski M, Cybulska B, et al. Recommendation low-density lipoprotein cholesterol in patients at high risk Clin Lipidol 2020; 14:170-2. for the management of dyslipidemia in Poland- Third for cardiovascular disease: the CLEAR wisdom randomized Declaration of Sopot. Interdisciplinary Expert Position clinical trial. JAMA 2019; 322:1780-8. st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 35

Triglycerides and Atherosclerotic Cardiovascular Disease

pidemiologic studies have TG (≥200 mg/dl) and elevated LDL-C follow up compared to those with TG Esuggested that triglycerides (TGs) in the Helsinki Heart Study and <150 mg/dl (HR 0.72) despite patients are a significant factor in evaluating Bezafibrate Infarction Program carried having achieved a LDL-C goal of <70 coronary heart disease (CHD) risk.1-3 the highest risk of CHD events.8,9 This mg/dl with high dose of atorvastatin.18 However, the extent to which TG serves emphasizes the importance of elevated In dal-OUTCOMES, long-term risk as an independent CHD risk factor TG in determining CHD risk, thereby increased across quintiles of baseline has proved elusive because of its close suggesting that high TGs potentiate the triglycerides, highest/lowest quintile association with other covariates. In the risk of elevated LDL-C levels. (>175/≤80 mg/dl) with hazard ratio largest population-based prospective The meta-analysis of 5 landmark 1.61 (P <0.001). In the atorvastatin study of nearly 300,000 men and trials (ACCORD, FIELD, BIP, HHS group of MIRACL, short-term risk women, linear association between TG and VA-HIT) which included 4726 increased across tertiles of baseline levels and CHD risk was noted until patients proved that PPAR-α agonists triglycerides (HR 1.50, P =0.03) in adjustments are made for non-HDL-C reduced CV events by 35% in patients highest/lowest tertiles (>195/≤135 mg/ 4 and HDLC. Compared with cholesterol, with high TG ≥204 mg/dl and low dl). The relationship of triglycerides to TG is readily metabolized to free fatty HDL ≤34 mg/dl.10,11 The Fenofibrate risk was independent of LDL-C levels acids which serve as a source of energy. Intervention and Event Lowering in both studies.19 The free fatty acids activate pro- in Diabetes (FIELD) study aimed at TGs and CVD inflammatory pathways which possibly assessing the effect of fenofibrate on Twenty two year follow up of the contribute to insulin resistance and cardiac events in diabetics. A reduction 5 Bezafibrate Infarction Prevention (BIP) atherogenicity. TGs are metabolized of total CV disease events from 13.9- study and registry concluded that in by most cells, are not taken up by the 12.5% was noted though it did not patients with established CHD, higher macrophages and do not contribute reduce the risk of the primary outcome TGs levels are independently associated directly to the plaque formation. of coronary events.12 However, no with increased 22-year mortality. Current evidence benefit was noted and the combination Mortality increased by 68% in those of fenofibrate and simvastatin did not Available evidence points towards with TGs ≥500 mg/dl compared with reduce the rate of CV events in the remnant cholesterol, marked by raised patients with TGs <100 mg/dl.20 TG, as an additional causal risk factor Action to Control Cardiovascular Risk 13 3216 American Indians with no for ASCVD and all-cause mortality.2,3 in Diabetes (ACCORD) Lipid trial. CVD at baseline were followed for 17.7 Mutations that disrupt apo C3 function These findings are relevant for years. Subjects with high TG and low were associated with lower levels of Indians as atherogenic dyslipidaemia is HDL-C levels had a 1.32-fold higher plasma TG and apo C3.6 Subjects with highly prevalent. Globally, every 3 out HR (95% CI 1.06-1.64) for CHD than these mutations were found to have of 4 diabetic suffers from dyslipidaemia. those with normal TG and normal a reduced risk of ischaemic cardiac However, almost 9 out of 10 diabetics HDL-C levels.21 Among diabetics, HR events. Genome Wide Association have dyslipidaemia in India.14,15 An for CHD with high TG (>150 mg/dl) and Studies (GWAS) have found a causal epidemiological study, ICMR INDIAB low HDL-C (<40 mg/dl) was 1.54 fold association of raised TGs with CHD. study across 15 states of India revealed higher compared with those without Nearly 30 gene variants can modestly that the prevalence of dyslipidaemia, high TG and low HDL-C indicating a increase TG. Of these, 6 different hypertriglyceridemia and low HDL-C relative risk of 54% for CHD. Similarly, genes- Lipoprotein lipase (LPL), apo as 79.6%, 29.5% and 72%, respectively.16 the HR for stroke was 2.13 fold higher C2, apo A5, lipase maturation factor TGs in stable CHD among diabetics with high TG and low (LMF1), glycosylphosphatidylinositol- The Cholesterol and Recurrent HDL-C values.21 anchored HDL-binding protein-1 Events trial (CARE) and the Long-term (GPIHBP1), and glycerol-3-phosphate Hypertriglyceridaemia and Intervention with Pravastatin in dehydrogenase 1A (GPD1A) can atherogenesis Ischemic Disease study (LIPID) trials increase TG substantially. These are The plasma TG level represents the were secondary prevention trials monogenic disorders and numerous concentration of TG-rich lipoproteins: evaluating pravastatin. Both concluded studies have linked high TG with VLDL, chylomicrons and their remnants that TG levels remain a CVD risk factor increased CV risk.7 Lipoprotein lipase is (Figure 1). Although chylomicrons are in patients treated with statins. There the principal TG-metabolizing enzyme too large to penetrate the arterial wall, was a consistent rise in CVD event rates and its action is modulated by various VLDL and remnants (chylomicron in those with TG levels ≥150 mg/dl in proteins like apo C3 and apo A5. Hence remnants, VLDL remnants, and the pravastatin groups in both studies targeting these proteins may yield intermediate-density lipoproteins) are compared with placebo.17 reduced CV risk.7 small enough to enter the arterial wall, TG in acute coronary syndrome Data from randomized trials have and have been identified in human (ACS) consistently shown that individuals and animal atherosclerotic plaques. with mixed hyperlipidaemia, defined In PROVE IT-TIMI 22 study, elevated Because of the strong association by either the lipid triad (elevated TGs ≥150 mg/dl increased the risk of between plasma TG and remnant LDL-C, elevated TG, and low HDL-C) myocardial infarction, ACS or death lipoprotein concentration, high TG in the 4S or the combination of high (HR 0.84) within 30 days to 2 years of levels serve as a biomarker for the st st 36 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Hepatocyte Enterocyte endothelium derived lipoprotein lipase (LPL) to form VLDL remnants. VLDL Free fatty acids Free fatty acids remnants are hydrolysed to form IDL, Glycerol DGAT Glycerol DGAT which are further hydrolysed to form LDL. The chylomicrons are hydrolysed Triglycerides Triglycerides by lipoprotein lipase resulting in Apo B 100 MTP Apo B 48 MTP formation of chylomicron remnants. Lipoprotein lipase hydrolyses VLDL Chylomicrons triglycerides thereby releasing free Blood vessel fatty acids which are taken up by the myocytes and adipocytes (Figure 1). Apo B 100 Apo B 100 Apo B 48 Apo CIII inhibits LPL activity. VLDL IDL LDL Chylomicron Chylomicrons TG stimulates the production of remnants proinflammatory cytokines, fibrinogen VLDL and coagulation factors and impairs remnants LPL LPL LPL of fibrinolysis.28 The combination of elevated TG and elevated LDL-C × contributes to elevated CHD risk vs LDL-C elevation alone. Conversely, Apo CIII Free fatty acids individuals who live in regions of the world that maintain low lipid levels Myocyte/Adipocyte retain an overall low risk of CHD.29-32 Figure 1: Triglyceride metabolism. Fig. 1: Triglyceride metabolism. Abbreviations: Apo CIII: Apolipoprotein CIII, DGAT: The blood samples of 523 healthy Abbreviations: diacylglycerolApo CIII: Apolipoprotein acyltransferase, CIII, IDL: DGAT: Intermediate Diacylglycerol density lipoprotein,acyltransferase LDL: Low, Tarahumaras Indians of Mexico (ages IDL: Intermediatedensity density lipoprotein, lipoprotein, LPL: Lipoprotein LDL: Low lipase,density MTP: lipoprotein, Microsomal LPL: triglyceride Lipoprotein transfer lipase, 5-70 years) were surveyed for lipids MTP: Microsomalprotein,triglyceride VLDL: Very transfer low density protein, lipoprotein VLDL: Very low density lipoprotein and lipoproteins. All atherogenic presence of atherogenic circulating is associated with the diminished lipoproteins including TGs were below remnant particles.22 activity of adipocyte lipoprotein lipase, normal range. Particularly notable was the virtual absence of the hypertension, A second consequence of leading to free fatty acid mobilization, hepatic VLDL overproduction, and up- obesity, and the usual age related hypertriglyceridemia is a relative increase of the serum cholesterol change in the composition of LDL and regulation of cholesteryl ester transfer protein (CETP). Increased CETP activity in adults. Hence, the regular diet HDL particles. The small, dense LDL of the Tarahumaras is adequate in particles share a linear relation with facilitates the transfer of TG to LDL and HDL in exchange for cholesteryl ester. all nutrients, low in lipids and is the levels of circulating TG and are presumably antiatherogenic.29 more atherogenic than large buoyant TG-enriched LDL particles are further LDL.23 Above a threshold of fasting acted upon by hepatic lipase, resulting Though previous studies in TG concentration, there will be a in small, dense LDL particles that are Melanesians of Papua New Guinea have predominance of small, dense LDL subjected to oxidative modification documented low serum cholesterol particles (phenotype B) and below the as compared with the larger, buoyant concentrations and a virtual absence threshold large, more buoyant particles LDL particles. This is followed by of CHD, modernization has brought will predominate (phenotype A).23,24 increased uptake of LDL particles in dyslipidaemia and unless effective and their incorporation by scavenger preventative strategies can be developed, The TG concentration that produces receptors on the surface of the arterial one can expect an increasing incidence a shift from one subclass pattern to 30 wall.25,26 Further TG-enriched HDL of CHD. Consumption of freshwater another varies with each patient. A particles may be less efficient in reverse fish (300-600 g daily) was associated fasting TG concentration of <100 mg/ cholesterol transport.27 with raised plasma concentrations of dl favors pattern A in 85% of the Triglyceride metabolism. The free omega-3 polyunsaturated fatty acids, population whereas a fasting TG lower blood pressure, and lower plasma concentration ≥250 mg/dl favors pattern fatty acids are esterified with glycerol in a multistep process involving lipid concentrations in a village in B in 85% of the population. Therefore, Tanzania.31 maintaining TGs at 200-250 mg/dl diacylglycerol acyltransferase (DGAT) in Classification of fasting TG Levels may not be optimal for regression of the hepatocyte and enterocyte resulting atherosclerosis.25 Most patients have in the formation of triglycerides. The The generally followed classification a threshold of 100 to 250 mg/dl for apolipoproteins and phospholipids are for TG values based on fasting lipid shifting LDL-C subclass pattern and added to triglycerides in the process profile is tabulated.1 involving microsomal triglyceride since small, dense LDL-C is more • Optimal <100 mg/dl (<1.1 mmol/l) transfer protein (MTP) with apo B100 atherogenic, keeping TG even at • Normal <150 mg/dl (<1.7 mmol/l) added in the liver and apo B48 added 200-250 may not reduce atherosclerosis • Borderline high 150-199 mg/dl (1.8-2.2 mmol/l) in the intestine resulting in formation completely. A target of TG <100 mg/dl • High 200-499 mg/dl (2.3-5.6 mmol/l) of VLDL in the liver and chylomicrons may be preferable. • Very High >500 mg/dl (>5.65 mmol/l) in the intestine. VLDL produced from A classical hypertriglyceridaemic liver enters the circulation where state is insulin resistance which triglycerides are hydrolysed by st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 37

Non-fasting vs fasting TG drugs known to increase TG levels the Friedewald equation leads to more concentrations • Additional laboratory tests errors in non-fasting samples compared Although traditionally a blood requested that require fasting or with fasting ones. The maximal errors sample for lipid profile is taken in the morning samples (e.g. fasting glucose, are observed at LDL-C <70 mg/dl which fasting state, recent studies have not therapeutic drug monitoring) is most significant in those at very high risk.41 shown any advantage of performing a • To confirm adherence to therapy fasting lipid profile, unless obtaining The Martin-Hopkins LDL-C method • To estimate residual risk in an LDL-C requires use of the Friedwald has converted the LDL-C measurement patients on maximal intensity statin formula (when TG <400 mg/dl). Rather, to a more individualized approach. It therapy there is an advantage of non-fasting has replaced the fixed factor of 5 used fasting lipid profile measurements • To judge effectiveness of treatment for the triglyceride to VLDL-C ratio by 1 in that the blood sampling process is on LDL-C or need for additional LDL-C of 180 patient-specific variables.42 These simplified for patients, doctors and lowering, a fasting lipid profile or direct variables are calculated based on serum hence increases adherence to drug LDL-C measurement is recommended TG and non-HDL-C concentrations. therapy and monitoring. (Figure 2). More than 97% of patients have errors In most patients, there is usually Situations where a non-fasting lipid <10 mg/dl, even in the non-fasting 40 a clinically unimportant increase in profile may be done state. TG concentrations, by 18-36 mg/dl • In primary prevention setting, e.g. How does the Martin-Hopkins (0.2-0.4 mmol/L) on average, 2-6 hours mass screening of a community calculation differ from the Friedewald 33-35 calculation for LDL-C after eating normal meals. Even • Initial lipid profile testing in any a non-fasting concentration predicts patient, especially those who have not It provides greater customization increased CV risk. Most people eat been fasting to a patient’s specific TG level by regularly throughout the day and are • For CV risk assessment using a more “personalized” factor usually fasting (defined as at least 8 h to calculate VLDL-C from TG. The since the last meal) only for a few hours •Emergency assessment of adjustable factor ranges from 3.1 to in the morning. For all these reasons, pancreatitis patient 11.9. It is derived from an analysis of non-fasting lipid concentrations might • Patients admitted with ACS TG -to-VLDL-C ratios in more than 1.3 be a better indicator of average lipid • In children million people. The factor is lowest concentrations in the blood rather than for patients with very low levels of 36,37 • If preferred by the patient fasting concentrations. TG and high levels of non-HDL-C and Fasting and post-prandial TG and CV • In diabetic patients [due to highest for those with very high levels risk hypoglycemia risk] of TG and low levels of non-HDL-C. Some studies support the hypothesis • In the elderly It correlates better with direct LDL-C that non-fasting TG levels may be more • When extreme levels are observed, measurements. The primary advantage significant predictors of CVD risk than for example approximately ≥500 mg/dl, of the Martin-Hopkins equation is that fasting levels. The increasing levels treatment may be started immediately it is applicable to low LDL-C levels of non-fasting TGs were associated with repeat fasting lipids done after even in the presence of elevated TG 42 with increased risk in the Copenhagen initiation of treatment concentrations. City Heart Study and Copenhagen Significance of methods of estimation Secondary causes of Population Study, with TG of 585 Hypertriglyceridemia The Friedewald LDL-C equation mg/dl (6.6 mmol/l) versus 71 mg/dl was originally derived in fasting There are numerous conditions (0.8 mmol/l), the age-adjusted and patients. Now it is increasingly utilized that can result in increase in serum TG sex-adjusted hazard ratios [HR] were 43 in the non-fasting setting to guide levels. 5.1 (95% CI 3.5–7.2) for myocardial management to lower LDL-C. However, 1. Diabetes infarction, 3.2 (2.5–4.1) for ischaemic it cannot be used if TGs are >400 mg/dl heart disease, 3.2 (2.2–4.7) for ischaemic 2. Obesity and in rare type III lipid abnormality. stroke, and 2.2 (1.8–2.7) for all-cause 3. Metabolic syndrome Martin et al analysed samples of mortality.3 1 million patients to compare the 4. Alcohol consumption Indications for fasting lipid profile Friedewald-estimated and directly 5. Insufficient physical activity testing measured LDL-C. Among patients 6. Acute pancreatitis • Non-fasting TGs ≥400 mg/dl (4.5 with Friedewald-estimated LDL-C 7. Hypothyroidism mmol/l) <70 mg/dl, nearly 23% had LDL-C 8. Pregnancy • Familial dyslipidemia ≥70 mg/dl by direct measurement (39% when concurrent TG values 9. Nephrotic syndrome • Follow up patient with were 150 to 199 mg/dl and 59% when hypertriglyceridemia 10. Chronic renal failure concurrent TG values were 200 to 399 • Recovering from mg/dl). The authors concluded that the 11. Obstructive liver disease hypertriglyceridemia-related acute Friedewald equation underestimated 12. Autoimmune disorders pancreatitis LDL-C when TG levels were ≥150 mg/ 13. Drugs such as steroids, beta- • Patients with premature ASCVD dl and especially, at TG levels >200 mg/ blockers, protease inhibitors for 38 39,40 • Baseline TG levels before start of dl. A recent analysis showed that treatment of HIV infections, steroids, st st 38 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Lipid Association of India: Lipid Profile assessment for Indian the remainder with diabetes and multiple risk factors) were on stable population statin therapy and were followed for a median of 4.9 years and the median LDL-C was 75 mg/dl. The triglyceride FIRST VISIT levels decreased from baseline to one year by 18.3% (39 mg/dL decrease) and non-HDL-C decreased by 12.2%. The primary end-point event occurred in FASTING LIPID NON-FASTING LIPID 17.2% of those in the icosapent ethyl PROFILE PROFILE group vs 22.0% of those in the placebo group (P <0.001); the corresponding SECOND VISIT rates of the key secondary end point were 11.2% and 14.8% (P <0.001), respectively.47 The dose of purified eicosapentaenoic acid (EPA) (4 g/day) NON-FASTING LIPID PROFILE FASTING LIPID PROFILE was higher than what was tested in other clinical trials. The rates of the Fig. 2: In Indian subjects with dyslipidemia, both the fasting and non-fasting lipid Figure: In Indian subjects with dyslipidaemia, both the fasting and non-fasting lipid primary and secondary composite profile should be known. A fasting lipid profile or direct LDL-C measurement is profile shouldrecommendedbe known to judge. To whetherjudge whether LDL-C goalsLDL have-C goals been achievedhave been andachieved to determineand to CVD endpoints were reduced by 25% determinethethe needneed for additionalfor additional LDL-CLDL lowering.-C lowering, Non-fastinga fasting lipid lipidprofileprofile is requiredor direct to LDL-C and 30%, respectively, as well as all measurementdetermineis recommended post-prandial .hypertriglyceridemiaNon-fasting lipid profile is required to determine post- individual secondary endpoints except prandial hypertriglyceridaemia. for all-cause mortality in the icosapent estrogens, tamoxifen, retinoic acid, activity and are more readily absorbed. ethyl group.47 This is one of the first certain drugs used in chemotherapy In Japan the average fish intake non-LDL-C targeted trials to show a CV and anti-psychotic medications is about 5 times higher than other benefit. As similar benefit was found Pharmacological agents for managing countries. The Japan eicosapentaenoic in those who attained on-treatment TG hypertriglyceridemia acid (EPA) Lipid Intervention levels of <150 mg/dl versus ≥150 mg/ The conventional medications for Study (JELIS) randomized 18,645 dl, the CV benefits of icosapent ethyl lowering of triglycerides (TGs) are hypercholesterolaemic patients to 1800 may be due to other mechanisms such tabulated.43 mg of EPA (EPA ethyl ester is purified as anti-inflammatory or anti-oxidant from n-3 polyunsaturated fatty acids activity present in the product. Medication Reduction of TG levels present in fish oil) daily combined The hypothesis of EVAPORATE trial Fibrates 30 - 50% with statin or statin only. The primary is that icosapent ethyl 4 g/d in addition Niacin 20 - 50% endpoint of any major coronary event to statin therapy would reduce the Omega-3 fatty acids 20 - 50% was reduced from 3.5% in the statin progression of plaque volume over 9 Statins* 10 - 30% alone group to 2.8% in the combination to 18 months compared with the use of Ezetimibe 5 - 10% group on five years follow-up, a statin therapy alone on a multidetector *High potency statins and higher doses of statins result in greater triglyceride reduction. Patients 19% relative risk reduction (p=0.01). computed tomography angiography with higher baseline triglyceride levels achieve Unstable angina and non-fatal coronary (MDCTA) population of statin‐treated greater reduction with same dose of statin. events were also significantly reduced patients with elevated TG levels of While statins can lower TG levels in the EPA group.45 Of note, in the pre- 200-499 mg/dl.48 Patients with known modestly, recent data show that among specified subgroup with TG >150 mg/ angiographic disease on statins (n=80) US adults on statin therapy, one-fourth dl and HDL-C <40 mg/dl, there was a were randomized to either icosapent still have borderline or elevated levels 53% risk reduction associated with the ethyl (IPE) 4 g/day or placebo. The final of TG (≥150 mg/dl), even when LDL-C EPA treatment.46 results after 18 months of follow-up is <100 mg/d, indicating the need for But given the statin dosages used in showed a significant difference in the additional lifestyle and where indicated, JELIS were lower and baseline plasma change in the primary endpoint of low pharmacologic therapies to address this EPA levels much higher than in the US attenuation plaque volume, which was residual hypertriglyceridemia.44 and Europe, a large multinational trial reduced by IPE by 17%, but increased Available Data on Newer Drugs was needed to further confirm these by 109% in the placebo group (p <0.01); significant differences in rates of 1. Eicosapentaenoic acid (EPA)- results. progression between IPE and placebo Icosapent ethyl ester The REDUCE-IT trial was a at study end were also seen for fibrous, multinational double-blind, placebo- Eicosapentaenoic acid (EPA) is an and fibrofatty (FF) plaque volumes controlled study designed to evaluate omega‐3 polyunsaturated fatty acid which regressed in the IPE group and whether treatment with icosapent ethyl, that is incorporated into membrane progressed in the placebo group (P < a highly purified eicosapentaenoic phospholipids and atherosclerotic 0.01 for all).49 plaques. The EE (ethyl ester) form of acid ethyl ester 4 g/day vs placebo 2. Epanova (Omega-3 carboxylic omega-3 fatty acids must be converted reduces CV events in patients who acids) into FFA (free fatty acids) by pancreatic despite statin therapy had elevated lipase while the FFA forms are not TGs and other CV risk factors. Patients Epanova is a combination of omega-3 dependent on pancreatic enzyme (n =8179; 70% with previous CVD, free fatty acids and can lower TGs by up st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 39 to 31%. The STRENGTH Study evaluated lipase, the enzyme that breaks down patients with familial chylomicronemia the efficacy of epanova (omega 3 triglycerides. Participants with syndrome with fasting TG ≥750 mg/ carboxylic acids) 4 grams daily as an heterozygous loss-of-function variants dL (mean TG levels: 2209 mg/dL) adjunct to statin therapy in high-risk in ANGPTL3 had lower levels of TG, to 300 mg of volanesorsen injected subjects with hypertriglyceridemia and HDL-C and LDL-C than participants subcutaneously weekly for 52 weeks low HDL-C levels in the prevention and without these variants in the DiscovEHR or placebo. Volanesorsen reduced reduction of major CV events.50 The study.53 Further the loss-of-function triglycerides by a mean of 77% and study had enrolled 13,086 patients, but variants in ANGPTL3 were associated reduced recurrence of pancreatitis. was prematurely terminated on Jan. 13th with reduced risk of CHD with an Thrombocytopenia was observed 2020 as preliminary analysis showed odds ratio for CHD of 0.61 (95% CI, in 5 patients.58 The COMPASS trial that Epanova had a low likelihood of 0.45 to 0.81) among patients with such randomized 75 patients with fasting showing benefit. variants, as compared with patients triglyceride values ≥500 mg/dl to 53 3. PPAR alpha agonist- Pemafibrate without them. weekly subcutaneous injections of 300 mg of volanesorsen or placebo for 26 Pemafibrate is a PPARα agonist Antisense oligonucleotides (ASO) weeks. Treatment with volanesorsen and is >2500-fold more potent than targeting mouse ANGPTL3 retarded yielded 72.7% reduction in triglycerides fenofibric acid, the active metabolite the progression of atherosclerosis at 3 months, and significantly reduced of fenofibrate, for human PPARα with and reduced levels of atherogenic pancreatitis compared with placebo >5000-fold activity for PPARα than lipoproteins in mice. Similar (0 vs. 6 cases, P <0.01).59 In May 2019, either PPARγ or δ. The PROMINENT strategy was applied to target volanesorsen was approved in the EU Study is evaluating of Pemafibrate human ANGPTL3 reduced levels of 54 for the treatment of adult patients with to reduce CV outcomes by reducing atherogenic lipoproteins in humans. familial chylomicronemia syndrome.57 TGs in diabetics with atherogenic Human participants (n=44) with dyslipidaemia despite statin therapy. TG levels 90 to 150 or >150 mg/dl 6. Gene therapy It includes 10,000 participants depending on the dose group received Alipogene tiparvovec is LPL and expected to complete in 2022. subcutaneous injections of placebo or gene therapy that utilizes adeno- Pemafibrate leads to marked reduction an antisense oligonucleotide targeting associated viral vector 1 (AAV1) of TGs, non-HDL-C, VLDL, apo B100, ANGPTL3 mRNA in a single dose (20, combined with a gain-of-function LPL apo B48, remnant cholesterol and apo 40 or 80 mg) or multiple doses (10, 20, variant, which encodes the protein, CIII and increase in HDL-C.51 40 or 60 mg/week for 6 weeks). After LPLS447X. It is used for patients with 6 weeks of treatment, subjects in the 4. Dual PPAR agonists hyperchylomicronemia syndrome multiple dose groups had reductions due to lipoprotein lipase deficiency. Saroglitazar is a novel non- in levels of ANGPTL3 protein (-46.6 It was approved in Europe in 2012. thiazolidinedione, dual peroxisome to -84.5%, P<0.01), triglycerides (-33.2 However high cost and rarity of disease proliferator activated receptor (PPAR) to -63.1%), LDL-C (-1.3 to -32.9%), resulted in premature withdrawal from agonist which shows an improvement VLDL-C (-27.9 to -60.0%), non-HDL-C market.60 in lipid and glycaemic parameters (-10.0 to -36.6%), apo B (-3.4 to -25.7%), 7. MTTP (Microsomal triglyceride through the PPAR-α and γ agonist and apo C-III (-18.9 to -58.8%).54 transfer protein) inhibitor actions, respectively. A consistent Recently, Evinacumab, a fully human reduction in TG levels (up to ~45% to anti-ANGPTL3 monoclonal antibody, Lomitapide, a microsomal 62%), non-HDL-C levels (up to ~21% caused a dose-dependent placebo- triglyceride transfer protein [MTP] to 36%) and glycosylated hemoglobin adjusted decrease in fasting TG levels inhibitor is also available and FDA levels (up to ~0.7% to 1.6%) with an of up to 76% and LDL-C levels of up to approved for homozygous familial increase in mean HDL-C levels (up 23%.53 New approaches that increase hypercholesterolemia. In addition to to 9%) was reported in an analysis of lipoprotein lipase activity, including LDL-C lowering properties, trials have 18 studies enrolling 5824 patients in ANGPTL3 inhibition, represent a shown up to a 45% reduction in plasma India.52 The Drug Controller General fresh frontier in the treatment of TG levels.61 The common side-effects of India (DCGI) approved the drug for hypertriglyceridemia and CHD.55 are nausea, vomiting and diarrhea the treatment of diabetic dyslipidemia Similarly ANGPTL4 is an inhibitor of which necessitate slow upward dose and hypertriglyceridemia in patients LPL and a potential novel therapeutic titration. Hepatic steatosis is more with type 2 diabetes not controlled by target for reducing triglycerides and serious side-effect. However it is not statins alone in 25 Feb 2013. In January treatment of metabolic syndrome.56 yet approved for hypertriglyceridemia 2020, saroglitazar got approval for the and has been used for this indication Another target of therapy is treatment of type-2 diabetes mellitus on compassionate grounds. inhibition of apo C3. Loss of function and on 5th March 2020 DCGI has granted mutations in the gene encoding apo C3 8. Diacyl glycerol acyl transferase approval for saroglitazar to treat non- leads to low TG levels and a decreased (DGAT) inhibitors cirrhotic non-alcoholic steatohepatitis risk for CVD and overexpression The synthesis and metabolism of (NASH) in India. However, no large of apo C3 is associated with cardiac triglyceride play a pivotal role CV outcome studies are available at hypertriglyceridemia. Volanesorsen in the regulation of lipid metabolism present. is an antisense oligonucleotide against and function of the heart. The last step 5. Antisense oligonucleotides apo C3 mRNA and reduces apo C3 in TG synthesis is catalyzed by diacyl Angiopoietin-like protein 3 production and TG concentration.57 glycerol acyl transferase (DGAT). There (ANGPTL3) inhibits lipoprotein The APPROACH trial randomized 66 are two DGAT isoforms, DGAT1 and st st 40 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

fenofibrate) and then add statin to TG 150-199 TG 200-499 TG 500-999 TG ≥1000 achieve LDL-C and non-HDL-C goals. mg/dl mg/dl mg/dl mg/dl 12. Among non-statin drugs, omega-3 fatty acids especially icosapent • Measure LDL-C levels Increased risk of Markedly increased ethyl in dose of 4 grams per day is • Calculate non-HDL-C pancreatitis/ASCVD risk of pancreatitis preferred as it has been shown to • Assess ASCVD risk reduce adverse CV events in patients Aggressive lifestyle interventions with ASCVD or diabetes and multiple Lifestyle interventions • Very low fat diet, Avoid refined carbohydrates risk factors. In subjects with very high • Low fat diet, Avoid refined carbohydrates • Weight reduction, Exercise TG levels, fibrates are to be initiated • Weight reduction, Exercise • Avoid alcohol, No smoking • Avoid alcohol, No smoking • Control secondary causes, eg. diabetes first with simultaneous identification • Control secondary causes, eg. diabetes + and control of secondary causes. Fibrate, Omega-3 fatty acids References • Increased LDL-C levels • Increased non-HDL-C Consider statin ± If TG levels still very 1. Third report of the National Cholesterol Education Program • High ASCVD risk (NCEP) expert panel on detection, evaluation, and treatment ezetimibe to high, consult lipid of high blood cholesterol in adults (Adult Treatment Panel achieve LDL-C specialist. Genetic III) final report. Circulation 2002; 106:3143-421. Add statin ± Add statin ± ezetimibe; testing and newer ezetimibe to If TG/ Non-HDL-C still high targets if High 2. Schwartz GG, Abt M, Bao W, et al. Fasting triglycerides achieve LDL-C consider omega-3 fatty LDL-C levels/High drugs may be predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. J Am Coll Cardiol targets acids/fibrate ASCVD risk required 2015; 65:2267-75. Aim is to achieve LDL-C, Non-HDL-C and Apo B targets as per LAI recommendations 3. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014; 384:626-35. Fig. 3: Treatment algorithm for hypertriglyceridemia based on baseline triglyceride levels 4. Sarwar N, Sandhu MS, Ricketts SL, et al. Triglyceride mediated pathways and coronary disease: Collaborative DGAT2, in the mammalian heart but 6. In patients with elevated TG analysis of 101 studies. Lancet 2010; 375:1634-9. their roles are poorly defined. A study levels, rule out secondary causes for 5. McArdle MA, Finucane OM, Connaughton RM, et al. showed that inhibition of DGAT1 or hypertriglyceridemia. Mechanisms of obesity induced inflammation and insulin resistance: Insights into the emerging role of nutritional DGAT2 in adult mouse heart results 7. Lifestyle changes are strategies. Frontiers in Endocrinology 2013; 4:52. in a suppression of TG synthesis recommended for all patients with 6. Crosby J, Peloso GM, Auer PL, et al. Loss-of-function and turnover. This protects the heart hypertriglyceridemia: Regular exercise, mutations in Apo C3, triglycerides, and coronary disease. N Engl J Med 2014; 371:22-31. against high fat diet-induced lipid maintenance of appropriate body accumulation.62 7. Singh AK, Singh R. Triglyceride and cardiovascular risk. A weight, avoidance of alcohol and critical appraisal. Indian J Endocrine Metab 2016; 20:418-28. LAI recommendations smoking, eating a diet with reduced 8. Ballantyne CM, Olsson AG, Cook TJ, et al. Influence of Both fasting and non-fasting lipid saturated fat and refined carbohydrates. low high-density lipoprotein cholesterol and elevated Lifestyle modification can reduce TG by triglyceride on coronary heart disease events and response profiles are important for managing to simvastatin therapy in 4S. Circulation 2001; 104:3046-51. as much as 50% (Figure 3). Indian patients with dyslipidemia. For 9. Barter PJ, Rye KA. Is there a role for fibrates in the routine screening, a fasting lipid profile 8. Adequate glycaemic control in management of dyslipidemia in the metabolic syndrome? is not mandatory. DM will result in substantial fall in Arterioscler Thromb Vasc Biol 2008; 28:39-46. triglyceride levels. 10. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy 1. Direct LDL-C measurement is in type 2 diabetes. N Engl J Med 2010; 363:692-4. preferred if TG is ≥200 mg/dl or LDL-C 9. If TG is ≥150 mg/dl but <500 mg/ 11. Scott R, O’Brien R, Fulcher G, et al. Effects of fenofibrate is <70 mg/dl. dl: consider statin ± ezetimibe as the treatment on cardiovascular disease risk in 9,795 individuals first line drug therapy. First priority is with type 2 diabetes and various components of the 2. There is substantial evidence that metabolic syndrome (FIELD Study). Diabetes Care 2009; triglyceride rich lipoproteins play a achievement of LDL-C target to reduce 32:493-8. causative role in atherosclerosis and ASCVD risk; if TG remains ≥200 mg/ 12. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of CHD. TG levels remain a significant dl calculate non-HDL-C level, if above combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362:1563-74. predictor of residual risk and focus goal, a non-statin drug can be added to achieve the non-HDL-C goal. For those 13. Keech A, Simes RJ, Barter P, et al. Effects of long-term on non-HDL-C after control of LDL-C fenofibrate therapy on Cardiovascular events in 9795 people levels is recommended. A combination with ASCVD or diabetes and multiple with type 2 diabetes mellitus (the FIELD study): Randomised of high TG and LDL-C imparts even risk factors IPE can be considered in controlled trial. Lancet 2005; 366:1849-61. greater CV risk. those with TG of 150 mg/dL or higher to 14. Selby JV, Peng T, Karter AJ, et al. High rates of co-occurrence provide further risk reduction benefit of hypertension, elevated low-density lipoprotein 3. All patients with cholesterol, and diabetes mellitus in a large managed care beyond a statin. hypertriglyceridemia should be population. Am J Manag Care 2004; 10:163-70. evaluated for ASCVD risk. 10. Unless TG is very high, ≥500 mg/ 15. Manoria PC, Chopra HK, Parashar SK, et al. The nuances of dl, a statin ± ezetimibe, with the option atherogenic dyslipidemia in diabetes: Focus on triglycerides 4. High TG is often accompanied and current management strategies. Indian Heart J 2013; to consider IPE for those with TG of 150 by low HDL-C levels and increased 65:683-90. mg/dL is preferred before considering a proportion of small dense LDL-C, 16. Joshi SR, Anjana RM, Deepa M, Pradeepa R, Bhansali A, et fibrate or other non-statin drug. al. Prevalence of dyslipidemia in urban and rural India: The a pattern known as atherogenic ICMR–INDIAB Study. PLoS ONE 2014; 9:e96808. 11. If TG is ≥500 mg/dl the primary dyslipidemia. 17. Sacks FM, Tonkin AM, Shepherd, et al. Effect of pravastatin on objective is to reduce the risk of acute 5. Maintain TG <150 mg/dl, coronary disease events in subgroups defined by coronary pancreatitis by lowering TG first. Start risk factors. The Prospective Pravastatin Pooling Project. preferably <100 mg/dl. Circulation 2000; 102:1893-1900. treatment with a non-statin drug (e.g., st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 41

18. Miller M, Cannon CP, Murphy SA, et al, PROVE IT-TIMI community-based population: A cross-sectional study. Arch (icosapent ethyl) on progression of coronary atherosclerosis 22 Investigators. Impact of triglyceride levels beyond Intern Med 2012;172:1707-10. in patients with elevated triglycerides (200–499 mg/dl) on low-density lipoprotein cholesterol after acute coronary statin therapy: Rationale and design of the EVAPORATE 34. Langsted A, Nordestgaard BG. Nonfasting lipids, syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol study. Clin Cardiol 2018; 41:13-9. lipoproteins, and apolipoproteins in individuals with and 2008; 51:724-30. without diabetes: 58 434 individuals from the Copenhagen 49. Budoff MJ, Bhatt DL, Kinninger A, et al. Effect of icosapent 19. Schwartz GG, Abt M, Bao W, et al. Fasting triglycerides general population study. Clin Chem 2011; 57:482-9. ethyl on progression of coronary atherosclerosis in patients predict recurrent ischemic events in patients with acute with elevated triglycerides on statin therapy: final results of 35. Langsted A, Freiberg JJ, Nordestgaard BG. Fasting and coronary syndrome treated with statins. J Am Coll Cardiol the EVAPORATE trial [published online ahead of print, 2020 nonfasting lipid levels: Influence of normal food intake on 2015; 65:2267-75. Aug 29]. Eur Heart J 2020; ehaa652. doi:10.1093/eurheartj/ lipids, lipoproteins, apolipoproteins, and cardiovascular risk ehaa652 20. Klempfner R, Erez A, Sagit BZ, et al. Elevated triglyceride prediction. Circulation 2008;118:2047-56 level is independently associated with increased all-cause 50. Nicholls SJ , Lincoff AM, Bash D, et al. Assessment of omega-3 36. Kolovou GD, Mikhailidis DP, Kovar J, et al. Assessment mortality in patients with established coronary heart carboxylic acids in statin-treated patients with high levels and clinical relevance of non-fasting and postprandial disease: Twenty-Two-year follow-up of the bezafibrate of triglycerides and low levels of high-density lipoprotein triglycerides: An expert panel statement. Curr Vasc infarction prevention study and registry. Circ Cardiovasc cholesterol: Rationale and design of the STRENGTH trial. Clin Pharmacol 2011; 9:258-70. Qual Outcomes 2016; 9:100-8. Cardiol 2018; 41:1281-8. 37. Mihas C, Kolovou GD, Mikhailidis DP, et al. Diagnostic value 21. Lee JS, Chang PY, Zhang Y, et al. Triglyceride and HDL-C 51. Fruchart JC. Pemafibrate (K-877), a novel selective of postprandial triglyceride testing in healthy subjects: A dyslipidemia and risks of coronary heart disease and peroxisome proliferator-activated receptor alpha modulator meta-analysis. Curr Vasc Pharmacol 2011; 9:271-80. ischemic stroke by glycemic dysregulation status: the Strong for management of atherogenic dyslipidaemia. Cardiovasc Heart Study. Diabetes Care 2017; 40:529-37. 38. Martin SS, Blaha MJ, Elshazly MB, et al. Friedewald- Diabetol 2017; 16:124. estimated versus directly measured low-density lipoprotein 22. Imke C, Rodriguez BL, Grove JS, et al. Are remnant like 52. Kaul U, Parmar D, Manjunath K. New dual peroxisome cholesterol and treatment implications. J Am Coll Cardiol particles independent predictors of Coronary heart disease proliferator activated receptor agonist- Saroglitazar 2013; 62:732-9. incidence? The Honolulu Heart Study. Arterioscler Thromb in diabetic dyslipidemia and non-alcoholic fatty liver Vasc Biol 2005; 25:1718-22. 39. Pallazola V, Sathiyakumar V, Martin SS, et al. Optimizing disease: integrated analysis of the real world evidence. non-fasting lipid analysis in the era of precision medicine. Cardiovascular Diabetology 2019; 18:80. 23. Maki KC, Bays HE, Dicklin MR. Treatment options for the Expert analysis Mar 21, 2018. https://www.acc.org/latest- management of hypertriglyceridemia: Strategies based on 53. Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and in-cardiology/articles/2018/03/21/08/51/optimizing-non- the best-available evidence. J Clin Lipidol 2012; 6:413-26. pharmacologic inactivation of ANGPTL3 and cardiovascular fasting-lipid-analysis-in-the-era-of-precision-medicine. disease. N Engl J Med 2017; 377:211-21. 24. Brewer HB, Jr. Hypertriglyceridemia: Changes in the 40. Sathiyakumar V, Park J, Golozar A, et al. Fasting versus plasma lipoproteins associated with an increased risk of 54. Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and nonfasting and low-density lipoprotein cholesterol cardiovascular disease. Am J Cardiol 1999; 83:3F-12F. metabolic effects of ANGPTL3 antisense oligonucleotides. accuracy. Circulation 2018; 137:10-19. N Engl J Med 2017; 377:222-32. 25. Austin MA, King MC, Vranizan KM, Krauss RM. Atherogenic 41. Scharnagl H, Nauck M, Wieland H, et al. The Friedewald lipoprotein phenotype. A proposed genetic marker for 55. Tall AR. Increasing lipolysis and reducing atherosclerosis. N formula underestimates LDL cholesterol at low coronary heart disease risk. Circulation 1990; 82:495-506. Engl J Med 2017; 377:280-3. concentrations. Clin Chem Lab Med 2001;39:426-31. 26. Kwiterovich PO, Jr. Clinical relevance of the biochemical, 56. Nagaike H, Hayashi T, Nakanishi N, et al. Increased 42. Martin SS, Blaha MJ, Elshazly MB, et al. Comparison of a metabolic, and genetic factors that influence low density angiopoietin like proteins 4 (ANGPTL4) is associated with novel method vs the Friedewald equation for estimating lipoprotein heterogeneity. Am J Cardiol 2002; 90:30i-47i. higher concentration of LDL-triglycerides in type 2 diabetes. low-density lipoprotein cholesterol levels from the standard Diabetes 2018;67 (Supplement 1):619-P. 27. Greene DJ, Skeggs JW, Morton RE. Elevated triglyceride lipid profile. JAMA 2013; 310:2061-8. content diminishes the capacity of high density lipoprotein 57. Paik J, Duggan S. Volanesorsen: first global approval. Drugs 43. George Y, Khalid ZA, Robert AH. Hypertriglyceridemia: its to deliver cholesteryl esters via the scavenger receptor class 2019; 79:1349-54. etiology, effects and treatment. CMAJ 2007;176(8):1113-20. B type I (SR-BI). J Biol Chem 2001; 276:4804-11. 58. Gaudet D, Digenio A, Alexander VJ, et al. The APPROACH 44. Fan W, Philip S, Granowitz C, Toth PP, Wong ND. 28. Tenenbaum A, Klempfner R, Fisman EZ. Hypertriglyceridemia: study: a randomized, double-blind, placebo-controlled, Hypertriglyceridemia in statin-treated US adults: the A too long unfairly neglected major cardiovascular risk phase 3 study of volanesorsen administered subcutaneously National Health and Nutrition Examination Survey. J Clin factor. Cardiovasc Diabetol 2014; 13:159. to patients with familial chylomicronemia syndrome (FCS). Lipidol 2019; 13:100-8. J Clin Lipidol 2017; 11:814-5. 29. Connor WE, Cerqueira MT, Connor RW, et al. The plasma 45. Yokoyama M, Origasa H, Matsuzaki M, et al. Japan EPA lipids, lipoproteins, and diet of the tarahumara Indians of 59. Gouni-Berthold I, et al. Apolipoprotein C-III inhibition Lipid Intervention Study (JELIS) investigators. Effects Mexico. Am J Clin Nutr 1978; 31:1131-42. with volanesorsen in patients with hypertriglyceridemia of eicosapentaenoic acid on major coronary events in (COMPASS): a randomized, double-blind, placebo- 30. Hodge AM, Dowse GK, Erasmus RT, et al. Serum lipids and hypercholesterolaemic patients (JELIS): a randomised open- controlled trial. J. Clin Lipidol 2017; 11:794-5. modernization in coastal and highland Papua New Guinea. label, blinded endpoint analysis. Lancet 2007; 369:1090-8. Am J Epidemiol 1996; 144:1129-42. 60. Scott LJ. Alipogene tiparvovec: a review of its use in adults 46. Saito Y, Yokoyama M, Origasa H, et al. Effects of EPA on with familial lipoprotein lipase deficiency. Drugs 2015; 31. Pauletto P, Puato M, Caroli MG, et al. Blood pressure and coronary artery disease in hypercholesterolemic patients 75:175-82. atherogenic lipoprotein profiles of fish- diet and vegetarian with multiple risk factors: sub-analysis of primary prevention villagers in Tanzania: The lugalawa study. Lancet 1996; cases from the Japan EPA Lipid Intervention Study (JELIS). 61. Brahm AJ, Hegele RA. Lomitapide for the treatment of 348:784-8. Atherosclerosis 2008; 200:135-40. hypertriglyceridemia. Expert Opin Investig Drugs 2016; 25:1457-63. 32. Robinson D, Williams P, Day J. High-density-lipoprotein 47. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk cholesterol in the maasai of East Africa: A cautionary note. reduction with icosapent Ethyl for hypertriglyceridemia. 62. Roe ND, Handzlik MK, Li T, Tian R. The role of diacylglycerol Br Med J 1979; 1:1249. REDUCE-IT investigators. N Engl J Med 2019; 380:11-22. acyltransferase (DGAT) 1 and 2 in cardiac metabolism and function. Sci Rep 2018; 8:4983. 33. Sidhu D, Naugler C. Fasting time and lipid levels in a 48. Budoff M, Muhlestein JB, Le VT, et al. Effect of Vascepa st st 42 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Lipoprotein(a) and ASCVD risk

ipoprotein(a) [Lp(a)] was Lp(a) levels. It is possible that the further supports a causal role of Lp(a) Ldiscovered in 1963 by Kare Berg proportion of the isoforms of Lp(a) lipoprotein in CHD. as a new antigen associated with LDL. which are less atherogenic are elevated In a meta-analysis of 36 prospective The new antigen was called Lp(a) after by therapeutic life style changes.3 studies, involving a total of 126,634 lipoprotein, and (a) as this was the Clinical Studies (Epidemiology and individuals who had no known prior accepted terminology to name antigens Genetics) history of CHD, the relationship of in human immunogenetics.1 The LPA Mendelian randomization data Lp(a) concentration with risk of major gene is located on chromosome 6q26-27 support a causal role for Lp(a) in vascular and non-vascular outcomes region encoding the apo(a) component CAD.4 In this analysis, three studies was analysed.6 The study concluded that of Lp(a). from Denmark were included: the there were continuous, independent, Lp(a) is an LDL like particle with Copenhagen City Heart Study with 16 and modest associations of Lp(a) a molecule of apo B-100 linked to years of follow-up (total number 8637 concentration with risk of vascular apo(a) by a disulphide bridge (Figure and MI events 599); the Copenhagen outcomes (CHD and stroke). 1). The apo(a) component shares General Population Study (total In the INTERHEART-Lp(a) study7, structural homology to plasminogen number 29,388 and MI events 994); 6086 cases of first myocardial infarction and competes with plasminogen and the Copenhagen Ischemic Heart (MI) and 6857 controls were included in binding sites– resulting in reduced Disease Study (total number 2461 and the analysis of 7 ethnic groups. There fibrinolysis.2 Lp(a) is also thought to MI events 1231). Genetically elevated were 775 Africans, 4443 Chinese, 1352 speed up the process of atherosclerosis Lp(a) was associated with an HR of Arabs, 1856 Europeans, 1469 Latin by binding to LDL, calcium and other 4 1.22 per doubling of the Lp(a) level. Americans, 1829 South Asians, and components into the blood vessel wall These data support causal association 1221 Southeast Asians. Serum Lp(a) in an atherosclerotic plaque. Lp(a) has between elevated Lp(a) levels and levels were measured using an isoform proinflammatory properties too. increased risk of MI. insensitive assay. Lp(a) concentration The serum Lp(a) levels are reported In a genome wide association ≥50 mg/dL was associated with an to remain same throughout life without study, 3145 patients with CHD and increased risk of MI (odds ratio, intervention. However, in women, 3352 control subjects were studied.5 1.48; 95% CI, 1.32-1.67; p<0.001). This estrogen therapy decreases Lp(a), It identified two LPA variants that association was independent of other while after the menopause Lp(a) levels showed strong association with an ASCVD risk factors (diabetes mellitus, increase. Growth hormone increases increased level of Lp(a) lipoprotein smoking, high BP, and apo B and apo Lp(a) levels. Surprisingly, exercise and and an increased risk of CHD. This A ratio). The population-attributable dieting have been shown to increase risk of high Lp(a) for MI varied from 0% in Africans to 9.5% in South Asians (Table 1). Indian studies Lp(a) may have particular relevance for Indians in causing ASCVD. The coronary artery disease in Asian Indians (CADI) study showed that levels of Lp(a) are significantly elevated among Indians.8 Approximately 25% of Indians and other South Asians have elevated

Table 1: Prevalence, odds ratio, and population-attributable risk (PAR) for acute myocardial infarction in South Asians in the INTERHEART Study7

Risk factors Prevalence Odds ratio PAR% % (OR) High apoB/ 44 2.57 47% apoA1 ratio Current 41 2.57 38% smoking Hypertension 13 2.92 19% Diabetes 10 2.52 12% mellitus Fig. 1: Structural characteristics of Lp(a) and structural homology between Lp(a) and Lipoprotein(a) 9 2.14 10% plasminogen (from Disease Markers 2013; 35:551-559, an open access article) >50 mg/dL st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 43

Table 2: Lipoprotein(a) levels in Indians with CAD or stroke compared to age-matched control LDL-C lowering. However, when (Age group 45 years or less) (9-13) baseline Lp(a) was >50 mg%, the Author Number Mean Lp(a) level P value association between Lp(a) reduction Cases Control Cases Control and MACE remained significant in Christopher R9 50 stroke 50 23.1 ± 24.3 11.7 ± 11 <0.001 a fully adjusted model.27 In a pre- Gambhir JK12 50 CAD 50 35.0 ± 32.4 20.3 ± 17.0 <0.002 specified analysis of the ODYSSEY Isser HS13 50 AMI 50 22.28 ± 5.4 9.28 ± 22.59 <0.002 Outcomes trial in patients with recent Angeline T10 65 AMI 50 58.6 ± 3.20 19.70 ± 0.18 <0.05 acute coronary syndrome (ACS)28 to Wadhwa A11 40 AMI 40 38.74 ± 26.15 20.54 ± 16.27 <0.05 evaluate whether alirocumab-induced Lp(a) levels (≥50 mg/dL), rendering dL) in patients undergoing transcatheter changes in lipoprotein(a) and LDL-C it a highly prevalent risk factor in aortic valve replacement (TAVR) independently predicted major adverse the population. Numerous studies was 35%; these patients more often cardiovascular events (MACE), it was have shown that elevated Lp(a) is had coronary artery disease (CAD) found that lipoprotein(a) and corrected significantly associated with premature requiring revascularization compared LDL-C levels and their reductions by and malignant CHD among Indians9-13 with patients with normal Lp(a) (65% alirocumab predicted the risk of MACE (Table 2). vs 47%; p=0.047). Patients with Lp(a) after recent ACS. The authors concluded ≥30 mg/dL also had higher incidence that “Lipoprotein(a) lowering by The recently published of paravalvular leak compared with alirocumab is an independent INTERHEART-Lp(a) also demonstrated those with normal Lp(a) (13% vs 4%; contributor to MACE reduction, which that South Asians (including Indians) p=0.04).18 suggests that lipoprotein(a) should be had the second highest Lp(a) levels an independent treatment target after after Africans among various ethnic Lp(a) and stroke ACS”. In another study, anacetrapib, groups and had the highest risk of In a meta-analysis of 31 studies 7 a CETP inhibitor, reduced Lp(a) by MI from elevated Lp(a). Enas et comprising of 56,010 subjects and 14 36.4% and the best outcome results al emphasized the importance and >4609 stroke events, it was concluded were achieved with the lowest achieved usefulness of estimating Lp(a) levels in that elevated Lp(a) was a risk factor LDL-C and the lowest achieved Lp(a).29 assessing the risk of acute MI in South for incident stroke.19 Lp(a) amplifies Asians who, as shown in the study by the impact of high LDL-C, low HDL-C, Although it is indisputable that 7 Pare et al have the highest risk and systemic hypertension, DM and elevated Lp(a) is a strong risk factor population attributable risk. hyperhomocysteinemia.20,21 The risk of for ASCVD, only PCSK9 inhibitors Lp(a) and calcific aortic valve disease recurrent events doubles when Lp(a) are currently available for lowering 24-28 (CAVD) levels are high as compared to low Lp(a) Lp(a) Therefore, at present, LDL-C reduction and effective control of other Lp(a) may also predispose to levels. Further, the levels correlate with 21 risk factors remain the primary goals aortic valve calcification in familial the severity of the disease. of therapy. When Lp(a) is >50 mg/ hypercholesterolemia (FH) patients.15 Therapeutics dl, aggressive LDL-C lowering with CAVD remains the leading cause Among various lipid-lowering statins should be achieved to reduce of aortic valve replacement in the agents, statins have negligible effect on the multiplicative effect of LDL-C and developed world, yet there is no drug Lp(a) but niacin significantly reduces it. Lp(a). With PCSK9 inhibitors showing therapy to slow the disease progression. Unfortunately, two major studies with reduction of Lp(a), further data showing In the ASTRONOMER (Aortic niacin- AIM-HIGH and HPS-THRIVE the clinical impact of Lp(a) reduction is Stenosis Progression Observation: showed no significant clinical benefit now eagerly awaited.30 Measuring Effects of Rosuvastatin) and hence, niacin is no longer used as New therapeutic agents trial, elevated Lp(a) levels were linked a lipid-lowering agent for the purposes to echocardiographically measured of cardiovascular risk reduction.22,23 APO(a)-LRx, an oligonucleotide progression of aortic stenosis, as well However, recently, the interest in targeting apo(a), is a novel therapy as the need for aortic valve replacement Lp(a) has received a positive thrust by to reduce Lp(a) concentrations and 15 (AVR). The patients with elevated the finding of nearly 25% reduction in Lp(a)-mediated CV risk. A phase II 31 Lp(a) and oxidized phospholipids Lp(a) with PCSK-9 inhibitors.24 One of trial assessed the effect of IONIS- (OxPL) on apo B-100 (OxPL-apoB) the proposed mechanisms of action of APO(a)Rx, a ligand-conjugated levels had the fastest progression rate PCSK-9 inhibitors is that the increased antisense oligonucleotide designed 15 and higher need for AVR. number of LDL-C receptors also bind to be highly and selectively taken up Torzewski et al17 demonstrated the to Lp(a) particles and remove them by hepatocytes, in participants with presence of Lp(a)-associated molecules from circulation.25 In the FOURIER elevated Lp(a) levels. It was a dose in plasma and in aortic valve leaflets trial, the patients with higher baseline ranging study with administration of of patients with calcific aortic valve Lp(a) exhibited greater lowering of the drug once a week, for 12 weeks. stenosis. These data support the Lp(a) with evolocumab and derived IONIS-APO(a)-LRx reduced Lp(a) by hypothesis that Lp(a) is a key etiologic greater coronary benefit.26 Alirocumab, 66% to 92%, with no serious side effects. factor in patients with calcific aortic another PCSK9 inhibitor, reduced The study also showed a significant valve stenosis. In another study, the Lp(a) by 23% but did not significantly reduction in LDL-C, apo B and oxidised prevalence of elevated Lp(a) (≥30 mg/ reduce MACE when adjusted for phospholipids (OxPL) associated with st st 44 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

apoB and apo(a). The lowering of Lp(a) initiating LA, incidence of MACEs has when Lp(a) is >50 mg/dl or125 nmol/L. and associated OxPL led to reduced decreased by 78% during two years of The recommendations for measuring monocyte inflammatory activation LA treatment.35 Lp(a) are: supporting the hypothesis that Lp(a) Lipoprotein apheresis is generally 1. Family history of premature is proinflammatory. well tolerated and safe, but cost and ASCVD , or A double-blind, placebo-controlled, accessibility are the constraints. An 2. Personal history of ASCVD not dose-ranging trial randomized 286 interesting clinical point is that ACE- explained by major risk factors patients with established CV disease inhibitors are contraindicated in and lipoprotein(a) levels of ≥60 mg/dL patients undergoing apheresis, since They recommend it to be to the hepatocyte-directed antisense they could cause a bradykinin reaction. considered in women only in the presence of hypercholesterolemia since oligonucleotide APO(a)-LRx, in 5 Lp(a) lowering vs LDL-C lowering different dosing regimens (20, 40, or 60 improvement in risk prediction in adult A Mendelian randomization mg every 4 weeks; 20 mg every 2 weeks; women was minimal. analysis36 compared Lp(a) and LDL-C or 20 mg every week), or saline placebo European Society of cardiology in >62,000 patients with CHD and subcutaneously for 6 to 12 months.32 (ESC)/European Atherosclerosis >127,000 controls. The conclusion was The primary end point was the percent Society (EAS)42 recommend that Lp(a) that for each 10 mg/dL reduction in change in isoform-independent assay measurement should be done at least Lp(a), the CHD risk decreased by 5.8%. measured lipoprotein(a) level from once in each adult’s lifetime to identify In contrast, a 10 mg/dL reduction in baseline to sixth month of exposure. those with very high Lp(a) levels, LDL-C would reduce the CHD risk by The median baseline Lp(a) levels in especially in patients with family 14.5%. Thus, for CHD risk reduction the six groups ranged from 81.8 to 98.6 history of premature CVD. Lp(a) >180 equivalent to reducing LDL-C by mg/dL. Administration of APO(a)-LRx mg/dL has a lifetime risk of ASCVD 38.67 mg/dL is 101.5 mg/dL for Lp(a), resulted in dose-dependent decreases equivalent to the risk associated with which is a daunting task. However, it in lipoprotein(a) levels, with mean HeFH.42 is likely that it is an overestimation, as percent decreases of 35% at a dose of 20 Lp(a) also has proinflammatory and Enas et al43 have suggested that mg every 4 weeks, 56% at 40 mg every 4 prothrombotic actions. Lp(a) can be measured any time beyond weeks, 58% at 20 mg every 2 weeks, 72% age of 2 years after which the levels at 60 mg every 4 weeks, and 80% at 20 Laboratory estimation of Lp(a) do not change, and recommended mg every week, as compared with 6% Lp(a) particle sizes differ and has Lp(a) estimation in subjects with a) with placebo (P values 0.003 to <0.001). more than 40 isoforms. Small isoforms personal history of premature CVD, There were no significant differences of Lp(a) are associated with high b) family history of premature CVD between any APO(a)-LRx dose and Lp(a) levels and high risk of ASCVD and/or elevated lipoprotein(a) levels placebo with respect to platelet counts, while large isoforms are associated c) familial hypercholesterolemia d) liver and renal measures, or influenza- with low Lp(a) levels and low ASCVD recurrent CVD events despite high- like symptoms. The most common risk. An isoform-insensitive enzyme- intensity statin treatment e) statin adverse events were injection-site linked immunosorbent assay (ELISA) resistance (<50% reduction in LDL-C, reactions.32 is the reference standard for measuring in spite of high intensity statin therapy) Plasma Lp(a) Apheresis Lp(a) levels. As small Lp(a) isoforms and f) unclear about indications and/ deteriorate significantly than larger There are no drugs available or intensity of statin therapy. Mora44 isoforms in specimens stored over now for clinical use to lower Lp(a) recommends that it is preferable to a period of time. Lp(a), should be effectively, and thus lipid apheresis has do one-time measurement of Lp(a) measured in fresh plasma.37 Measures an important role to play. Lipoprotein in patients after ACS. This would be of Lp(a) in nmols/l can be roughly apheresis decreases LDL-C and Lp(a) useful for risk stratification, in selecting translated into mg/dL using the by about 60-70%. There is a rebound, higher risk patients for novel therapies, conversion factor of 2.4.38 necessitating weekly apheresis. including PCSK9 inhibitors, and for Apheresis has shown to improve Guidelines and Recommendations: cascade screening of families with endothelial function and myocardial The LAI in 2016 recommended40 inherited Lp(a) disorders. Treatment perfusion in patients with high Lp(a). estimation of Lp(a) levels by isoform with a PCSK9 inhibitor antibody may be considered in FH patients with CVD The German Lipoprotein insensitive assay for ASCVD risk or with other factors putting them at Apheresis Registry (GLAR) data stratification in Indian subjects, very high risk for CHD, such as other showed that ASCVD events were particularly in those who have family CV risk factors, family history, and reduced significantly.33 A significant history or premature CAD. A level ≥20 high Lp(a).39 However, neither PCSK9 regression of coronary atherosclerosis mg/dL indicates increased ASCVD risk inhibitors or any other therapies are by angiography was seen with in in Indians, Lipoprotein (a) ≥50 mg/ currently indicated for lowering Lp(a) the selective Lp(a) apheresis group dL is a high-risk feature. Lipoprotein for the purposes of reducing CVD risk. compared to atorvastatin in an open (a) 20-49 mg/dL is a moderate risk label prospective study of 18 months.34 nonconventional risk factor. ACC/AHA A recent international consensus 41 Shettler et al from Germany report 2018 guidelines consider an elevation statement45 recommended that Lp(a)- that relative to the two years before of Lp(a) as a risk-enhancing factor, corrected LDL-C should be assessed at st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 45 least once in patients with high Lp(a) could be assessed in such patients). lipoprotein(a), and progression of calcific aortic valve stenosis. J Am Coll Cardiol 2015; 66:1236-46. or if the patient shows a poor response If LDL-C is at goal and Lp(a) is high, to LDL-lowering therapy. Peter Libby PCSK9 inhibitors may be used. 17. Torzewski M, Ravandi A, Yeang C, et al. Lipoprotein(a)- associated molecules are prominent components in plasma once commented “Lp(a)– a frustrating v. It is preferable to estimate in and valve leaflets in calcific aortic valve stenosis. JACC Basic final frontier in lipid management?”46 Trans Sci 2017; 2:229-40. patients However, with vigorous research 18. Ma GS, Wilkinson MJ, Reeves RR, et al. Lipoprotein(a) in activities being witnessed in the field a. Who sustain ischemic stroke of patients undergoing transcatheter aortic valve replacement. currently, it may not remain so for long. uncertain etiology Angiology 2019; 70:332-6. b. Who have calcific aortic valve 19. Smolders B, Lemmens R, Thijs V. Lipoprotein(a) and stroke. A LAI Recommendations - 2020 meta-analysis of observational studies. Stroke 2007; 38:1959- stenosis 1. Use an assay for Lp(a) measurement 66. that is unaffected by the isoform size. c. Who are undergoing transcatheter 20. Hopkins PN, Wu LL, Hunt SC et al. Lipoprotein interactions aortic valve replacement (TAVR) with lipid and nonlipid risk factors in early familial coronary 2. Lp(a) multiples the risk of other artery disease. Arterioscl Throm Vasc Biol 1997; 17:2783-92. ASCVD risk factors like high LDL-C, References 21. Enas EA, Chacko V, Senthilkumar A, et al. Elevated low HDL-C, systemic hypertension, lipoprotein(a)- a genetic risk factor for premature vascular diabetes and hyperhomocysteinemia. 1. Witztum JL Ginsberg HN.Lipoprotein(a):coming of age at disease in people with and without standard risk factors: a last. J Lipid Res 2016; 57:336-9. review. Dis Mon 2006; 52:5-50. With only PCSK9 inhibitors being 22. The AIM High investigators. Niacin in patients with low HDL available as effective pharmacotherapy 2. Cai A, Li L, Zhang Y, et al. Lipoprotein(a): A promising marker for residual cardiovascular risk assessment. Disease Markers cholesterol levels receiving intensive statin therapy. N Engl at present, other risk factors must 2013; 35:551-9. J Med 2011; 365:2255-67. be treated optimally to counter 3. Randall OS, Feseha HB, Illoh K, et al. Response of 23. The HPS-2 Thrive Collaborative Group. Effects of extended- multiplicative risk of raised Lp(a). lipoprotein(a) levels to therapeutic life-style change in release niacin with laropiprant in high risk patients. N Engl J obese African–Americans. Atherosclerosis 2004; 172:155- Med 2014; 317:203-12. 3. Lp(a) ≥20 mg/dL indicates 160. 24. Toth PP. PCSK(9) and lipoprotein(a): the plot thickens. Circ increased ASCVD risk in Indians. 4. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard Res 2016; 119:3-6. Lp(a) 20-49 mg/dL is a moderate risk BG. Genetically elevated lipoprotein(a) and increased risk of 25. Raal FJ, Giugliano RP, Sabatine MS, et al. PCSK9 inhibition- myocardial infarction. JAMA 2009; 301:2331-9. non-conventional risk factor, whereas mediated reduction in Lp(a) with evolocumab: an analysis Lp(a) ≥50 mg/dL is a high-risk feature. 5. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants of 10 clinical trials and the LDL receptor’s role. J Lipid Res associated with Lp(a) lipoprotein level and coronary disease. 2016; 57:1086-96. 4. In view of the high prevalence N Engl J Med 2009; 361:2518-28. 26. O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), of raised Lp(a) in Indian population 6. The Emerging Risk Factors Collaboration. Lipoprotein(a) PCSK9 Inhibition, and cardiovascular risk. Insights from the its routine assessment will help in concentration and the risk of coronary heart disease, stroke, FOURIER Trial. Circulation 2019; 139:1483-92. and nonvascular mortality. JAMA 2009; 302:412-23. detecting high risk individuals (Lp(a) 27. Ray KK, Vallejo-Vaz AJ, Ginsberg HN, et al. Lipoprotein(a) ≥50 mg/dL) and as non-conventional 7. Pare G, Caku A, McQueen M, et al. Lipoprotein(a) levels and reductions from PCSK9 inhibition and major adverse cardiovascular events: Pooled analysis of alirocumab phase risk marker for further risk stratification the risk of myocardial infarction among seven ethnic groups. Circulation 2019; 139:1472-82. 3 trials. Atherosclerosis 2019; 288:194-202. in low and moderate-risk individuals 28. Bittner VA, Szarek M, Aylward PE, et al. Effect of alirocumab (Lp(a) 20-49 mg/dL). 8. Enas EA. The coronary artery disease in Asian Indians (CADI) study. Asian Am Pac Isl J Health 1993; 1:161-2. on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol 2020; 75:133–44. 5. Lp(a) measurement is strongly 9. Christopher R, Kailasanatha KM, Nagaraja D, Tripathi M. Case- recommended: control study of serum lipoprotein(a) and apolipoproteins 29. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib A-I and B in stroke in the young. Acta Neurol Scand 1996; in patients with or at high risk for coronary heart disease. N i. At the time of initial screening of 94:127e130. Engl J Med 2010; 363:2406-15. all subjects (18 years of age in adults 10. Angeline T, Aruna R, Ramadevi K et al. Serum lipoprotein 30. Saeedi R, Frohlich J. Lipoprotein (a), an independent and at the age of 2 years in subjects with (a) and lipid profile in young South Indian patients cardiovascular risk marker. Clin Diabetes Endocrinol 2016; 2:7. family history of FH and premature with myocardial infarction. Indian J Clin Biochem 2003; 18:103e106. 120. ASCVD) 31. Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense 11. Wadhwa A, Avasthi R, Ghambhir JK et al. To study the oligonucleotides targeting apolipoprotein(a) in people ii. In patients with: prevalence and profile of metabolic syndrome, levels of with raised lipoprotein(a): two randomised, double-blind, hs-CRP, Lp(a) and serum ferritin in young Indian patients placebo-controlled, dose-ranging trials. Lancet 2016; a. Premature ASCVD (<55 years in (45 years or less) with acute myocardial infarction. J Assoc 388:2239-53. Phys India 2013; 61:384e386 men, <65 years in women) 32. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular b. Familial hypercholesterolemia 12. Gambhir JK, Kaur H, Gambhir DS, Prabhu KM. Lipoprotein(a) as an independent risk factor for coronary artery disease disease. N Engl J Med 2020; 382:244-55. in patients below 40 years of age. Indian Heart J 2000; c. A family history of premature 33. Schettler VJ, Neumann CL, Peter C et al. First data from the 52:411e415. CVD and/or elevated Lp(a) German lipoprotein apheresis registry (GLAR). Atheroscler 13. Isser HS, Puri VK, Narain VS et al. Lipoprotein (a) and lipid Suppl 2015; 18:41e4. levels in young patients with myocardial infarction and their d. Recurrent ASCVD despite optimal 34. Safarova MS, Ezhov MV, Afanasieva OI et al. Effect of specific first degree relatives. Indian Heart J 2001; 53:463e466. lipid lowering treatment lipoprotein(a) apheresis on coronary atherosclerosis 14. Enas EA, Varkey B, Dharmarajan TS, et al. Lipoprotein(a): An regression assessed by quantitative coronary angiography. iii. In patients after an ACS: This underrecognized genetic risk factor for malignant coronary Atheroscler Suppl 2013; 14:93e9 artery disease in young Indians. Indian Heart J 2019; 71:99- helps in risk stratification, selection of 35. VJJ Schettler, J Ringel, S Jacob et al. Current insights into the 112. higher risk patients for novel therapies German lipoprotein apheresis standard:PCSK9-inhibitors, and for cascade screening of families. 15. Vongpromek R, Bos S, Ten Kate GJR, et al. Lipoprotein(a) lipoprotein apheresis or both. Atherosclerosis supplements levels are associated with aortic valve calcification in 2017; 30:44-49. asymptomatic patients with familial hypercholesterolaemia. iv. In patients showing poor 36. Burgess S, Ference BA, Staley JR, et al. Association of LPA J Intern Med 2015; 278:166-73. response to maximum lipid lowering variants with risk of coronary disease and the implications therapy (and Lp(a) corrected LDL-C 16. Capoulade R, Chan KL, Yeang C, et al. Oxidized phospholipids, for lipoprotein(a)-lowering therapies: a Mendelian st st 46 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

randomization analysis. JAMA Cardiol 2018; 3:619-27. 2016; 64:S7-S52. independent, genetic, and causal factor for cardiovascular disease and acute myocardial infarction. Indian Heart Journal 37. Kronenberg F, Trenkwalder E, Dieplinger H, Utermann G. 41. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, 2019; 71:99e112. Lipoprotein(a) in stored plasma samples and the ravages Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ of time. Why epidemiological studies might fail. Arterioscler ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the 44. Mora S. Lp(a)’s Odyssey. Should we measure Lp(a) post-ACS Thromb Vasc Biol 1996; 16:1568-72. management of blood cholesterol: A report of the American and what should we do with the results?. JACC 2020; College of Cardiology/American Heart Association Task 75:145-7. 38. Marcovina SM, Albers JJ. Lipoprotein (a) measurements for Force on clinical practice guidelines. Circulation 2019; clinical application. J Lipid Res 2016; 57:526-37. 45. Langlois MR, M Chapman MJ, Cobbaert C, et al. Quantifying 139:e1082–e1143. atherogenic lipoproteins: current and future challenges 39. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) 42. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS in the era of personalized medicine and very low as a cardiovascular risk factor: current status. Eur Heart J Guidelines for the management of dyslipidaemias: lipid concentrations of LDL Cholesterol. A consensus statement 2010; 31:2844-53. modification to reduce cardiovascular risk.Eur Heart J 2020; from EAS and EFLM. Clinical Chemistry 2018; 64:1006-33. 40. Iyengar SS, Puri R, Narasingan SN, et al. Lipid Association 41:111-188. 46. Libby P. Lipoprotein (a): A frustrating final frontier in lipid of India expert consensus statement on management of 43. Enas EA , Verkey B, Dharmarajan TS et al. Lipoprotein(a): An management? JACC Basic Transl Sci 2016; 1:428-31. dyslipidemia in Indians 2016: Part 1. J Assoc Physicians India st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 47

High Sensitivity C-Reactive Protein

n many patients ASCVD events occur with age and are also elevated in Secondary prevention Iin individuals with none or only one metabolic syndrome, mediated by The data regarding the role of CRP risk factor. Hence newer biomarkers are inflammatory cytokines released from in patients with risk factors for CVD needed to identify individuals at risk visceral fat. Women compared to and those with established CVD is of future adverse CV events especially men have higher levels of hsCRP and divisive. In the PROVE IT-TIMI 22 in those individuals who have no or certain ethnic groups such as African- trial9 and REVERSAL trial10, greater 1 minimal conventional risk factors. Americans have lower levels. There are reduction in LDL-C and hsCRP levels Biomarkers are naturally occurring several studies correlating the role of together was associated with a greater molecules, genes, or characteristics hsCRP with CV events. They support a reduction in the number of clinical by which a particular pathological or role of hsCRP as a risk marker and not events and progression of the plaque. 5 physiological process, disease, etc. as a risk factor. In contrast, in the HPS trial, simvastatin can be identified. There are three Clinical evidence of utility of CRP 40 mg resulted in CV risk reduction types of biomarkers for ASCVD, the Primary prevention in proportion to LDL-C lowering, genetic biomarkers, serum circulating irrespective of hsCRP levels.11 In this The inclusion criteria of LDL-C biomarkers and the imaging biomarkers. study the patients (n=20,536) were level of <130 mg/dL with hsCRP level The genetic biomarkers may be useful divided into six groups based on ≥2.0 mg/L in healthy men and women in predicting genetic susceptibility to baseline CRP levels and the proportional was used in the primary prevention disease and for detecting subclinical reduction in primary endpoint was JUPITER trial in which rosuvastatin 20 disease. Serum circulating biomarkers similar regardless of the baseline CRP mg/d reduced LDL cholesterol levels may be most informative in detecting levels.11 The authors concluded that by 50% and hsCRP levels by 37%. This earlier stages of disease, whereas baseline CRP levels had no bearing on resulted in 44% relative risk reduction imaging biomarkers directly detect the magnitude of vascular benefit with in CV events (P <0.00001) and 20% subclinical disease. statins. Similarly, in the ASCOT trial, relative risk reduction in all-cause atorvastatin decreased CRP levels by Inflammation is an integral mortality (P =0.02).6 Lowest event 27.4%.12 Although baseline CRP levels component of atherosclerosis and rates were seen in individuals with correlated with baseline LDL-C levels acute coronary syndromes, being both low achieved LDL-C (<70 mg/dl) and showed a direct linear association involved in initiation, development and low achieved hs-CRP levels (<2 with the risk of CHD, the statin effect and progression of atherosclerosis. mg/L).7 It should be noted that hsCRP did not differ according to the tertile High sensitivity C-reactive protein is related to event rates rather than of baseline CRP levels. Further, there (hsCRP) is one of the serum circulating atherosclerosis. Since hsCRP levels was no significant difference in the biomarkers that has been shown to increase with age, the JUPITER study 2 area under ROC curve in the modified predict ASCVD in patients. It has the data may be applicable to primary Framingham model after addition of most clinical evidence as a marker prevention in adults as studied in CRP.12 of cardiovascular risk, and recently JUPITER trial i.e. men ≥50 years and evidence of its reduction (and other women ≥60 years. In the Framingham In the in the Multi-Ethnic Study inflammatory measures) linked to Heart study 3006 subjects free of CV of Atherosclerosis (MESA) 1330 reductions in cardiovascular disease disease were followed up for 12 years.8 intermediate risk participants (median risk. The net reclassification improvement Framingham Risk Score 8.8%) without C-reactive protein (CRP) is an acute (NRI) with hsCRP in the Framingham diabetes mellitus were followed up for phase reactant and nonspecific marker Heart study was 11.8% for CHD and a median of 7.6 years. The prevalence of inflammation. It is mainly produced 5.6% for CVD.8 The above studies of hypertension was 38.2% and 14.1% in the hepatocytes as a pentamer suggest that the circulating levels of patients were taking statins. For of identical subunits.3 One of the CRP are helpful in estimating the risk prediction of CHD/CVD events, the most potent drivers of production of of first adverse CV event and that this addition of 6 risk markers to the CRP is interleuin-6 which is released risk can be mitigated by statin therapy baseline model improved the AUC from activated leukocytes. The initiated on the basis of elevated CRP significantly. Of these, coronary artery leukocytes are activated in response levels in select group of patients. calcium showed the highest increment to trauma, infection or cytokines However, since statins lower both for incident CHD and CVD whereas released from vascular smooth muscle hsCRP as well as LDL-C, whether the high-sensitivity CRP showed modest cells in response to atherosclerosis. reduction in CVD risk was due mainly improvement for incident CHD and CRP binds to oxidized LDL which or exclusively to LDL-C reduction or brachial flow mediated dilation showed is atherogenic.4 Persistent low-grade partly from reductions in hs-CRP is the least increment for incident CVD. inflammation in atherosclerosis is not clear, and the actual contribution The NRI was 7.9% for CHD for hsCRP, detected during health as low levels of reductions in hsCRP to the observed whereas the corresponding NRI values of hsCRP (levels <10 mg/L). A serum reduction in CVD risk in JUPITER was for coronary artery calcium (CAC) hsCRP >2 mg/L is considered elevated, not described. Hence, the JUPITER trial score was 65.9%, suggesting small but in the absence of infection, arthritis, did not provide conclusive evidence for significant incremental value of hsCRP chronic inflammatory disorders or the inflammatory hypothesis. in risk prediction in intermediate risk 13 recent trauma. hsCRP levels increase individuals. Significantly, in persons st st 48 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 who had low 10-year risk, an elevated a specific group of responders can 95% CI, 1.31-1.53) during a median hsCRP did not significantly increase be identified by checking hsCRP follow up of 3.2 years. The relationship the CV risk above that predicted by levels one month following initiation between the hsCRP and outcomes was conventional risk factors. Conversely, of canakinumab. Canakinumab was linear until hsCRP >5 mg/L.20 a low hsCRP in high risk individuals associated with a higher incidence Colchicine is an oral drug which 14 did not significantly reduce the risk. neutropenia, thrombocytopenia and has potent anti-inflammatory effects This leaves us with the intermediate fatal infections than was placebo. and is an accepted treatment for risk patients (Framingham Risk Score There was no significant difference pericarditis. In the COLCOT study, >5% to <20%) only in whom hsCRP in all-cause mortality (HR for all 4745 post myocardial infarction 14 may have clinical utility. In the canakinumab doses vs. placebo, 0.94; patients were randomized to low dose 17 WOSCOPS Heart Study, 26% men P =0.31). In a subgroup analysis of colchicine (0.5 mg daily) or placebo with metabolic syndrome had high CANTOS study, subjects with on- within 30 days of index event. The CRP levels as compared to those treatment hsCRP levels <2 mg/L had primary endpoint occurred in 5.5% without metabolic syndrome despite a 25% reduction in primary endpoint of patients in the colchicine group as similar LDL-C levels. The elevated (P <0.0001) compared to only 5% compared to 7.1% in the placebo group CRP increased the risk of future CHD among those with on-treatment hsCRP (P =0.02) over a median follow up of events and had similar predictive value levels ≥2 mg/L. Similarly, reduction 22.6 months.21 When colchicine (0.5 as presence of metabolic syndrome in hsCRP <2 mg/L also led to a 31% mg) was administered in the chronic for CHD events (HR=1.6) with risk reduction in CV death (P =0.0004) coronary artery disease patients in increasing markedly with both high and all-cause mortality (P <0.0001) the LODOCO2 trial, primary endpoint CRP levels and metabolic syndrome compared to non-significant reductions occurred in 6.8% compared to 9.6% in 18 being present (HR=2.75) compared to with achieved hsCRP levels ≥2 mg/L. the placebo group (P <0.001). However both low CRP levels and absence of While these adverse effects were in an increase in the incidence of non- 15 metabolic syndrome. part responsible for the drug not being cardiovascular deaths with colchicine In addition to using hsCRP for approved in the US for CVD event (0.7 vs 0.5 events per 100 patient years, ASCVD risk prediction, inflammation reduction, the CANTOS trial is the hazard ratio, 1.51; 95% CI, 0.99 to 2.31) has been explored as a direct therapeutic first clear proof of the inflammatory was an area of concern.22 16 hypothesis demonstrating reduction target also. Interleukin-1β is a In a recent review, Indian data from of inflammation to reduce CVD events. cytokine that drives the interleukin-6 various published studies on hsCRP signalling pathway and is pivotal to the To pursue this inflammatory was analysed. Multiple techniques inflammatory response. In the CANTOS theory further and to find a less were used for estimation of hsCRP trial, canakinumab, a high-affinity fully expensive alternative to canakinumab, (33% ELISA, 25% nephelometry, 29% human monoclonal antibody against the US National Institutes of Health turbidimetry, 8.3% chemiluminescence, interleukin-1β (IL-1β) was used to sponsored CIRT trial was performed and one study with latex agglutination address residual inflammatory risk in with methotrexate at multiple sites test) which could have contributed to 17 a secondary prevention setting. The throughout the US and Canada. varying values across the studies. The study enrolled 10061 patients with Methotrexate produces adenosine basal concentration of hsCRP in Indians history of myocardial infarction and mediated anti-inflammatory effect and was high with a mean hsCRP of 1.88 elevated hsCRP >2 mg/L. Canakinumab is used for the treatment of rheumatoid mg/L in the control arm and 2.46-9.3 (150 mg administered subcutaneously arthritis. However, in 2018 the trial was mg/L in patients having established every 3 months) decreased hsCRP levels terminated prematurely due to futility. CVD. The high prevalence of obesity by 37% and showed a significant 15% There was no significant reduction in and metabolic syndrome in India could reduction in the primary outcome of MACE (HR 0.96, 95% CI, 0.79-1.16, P be one of the contributors of high basal nonfatal MI, nonfatal stroke and CV =0.67) and neither LDL-C, nor hsCRP or hsCRP in India. This increased basal death (P =0.02) at 48 months. The key IL-1β showed any significant reduction inflammation among Indians, in turn, secondary endpoint which included with methotrexate. The probable reason could be the reason for the higher the components of primary endpoint for the failure of methotrexate is that prevalence of premature CHD disease plus hospitalization for unstable angina adenosine mediated anti-inflammatory in India. The hsCRP was found to be that led to urgent revascularization was effects are not beneficial in CV risk an independent predictor of diverse significantly decreased in canakinumab reduction, and only the IL-1 blocking end points ranging from obesity, 19 150 mg dose group, HR =0.83, P =0.005). drugs are effective. type 2 diabetes mellitus, metabolic There was nominally significant In another study of 17,464 patients, syndrome, increased carotid intima- reduction in MI and hospitalization when hsCRP was studied among MI media thickness, stable CAD, first acute for unstable angina that led to urgent survivors (>30 days after MI), previous coronary event, and recurrent CVD revascularization in canakinumab percutaneous coronary intervention, events among Indian patients.23 150 mg dose group. However, when ongoing renin angiotensin receptor LAI 2019 Recommendations the persons who achieved hsCRP blockade and statin therapy were 1. HsCRP is not directly involved <2.0 mg/L were compared to those associated with low hsCRP. High in atherosclerosis but is a risk marker who did not, a significant reduction values of hsCRP ≥2 mg/L seen in 66% for adverse cardiac events. It is not in CV mortality was found (HR 0.69, of patients were associated with major a replacement for conventional risk p=0.004) without any significant adverse coronary events (HR 1.28; factors like serum LDL-C levels but may reduction in LDL-C. This shows that 95% CI, 1.18-1.38) and death (HR 1.42; st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 49 be used as an adjunct to further risk C-reactive protein prior to and on-treatment as a predictor References of benefit from atorvastatin: observations from the Anglo- stratify select individuals. However, Scandinavian Cardiac Outcomes Trial. Eur Heart J 2012; 1. Khot UN, Khot MB, Bajzer CT, et al. Prevalence of conventional lower levels (hsCRP <2 mg/L) are 33:486-94. risk factors in patients with coronary heart disease. JAMA associated with improved CVD-event 2003; 290:898-904. 13. Yeboah J, McClelland RL, Polonsky TS, et al. Comparison of novel risk markers for improvement in cardiovascular risk free prognosis and there is now clinical 2. Yousuf O, Mohanty BD, Martin SS, Joshi PH, Blaha MJ, Nasir assessment in intermediate-risk individuals. JAMA 2012; K, Blumenthal RS, Budoff MJ. High-sensitivity C-reactive trial evidence that lowering the levels 308:788-95. of hsCRP lowers CVD events. protein and cardiovascular disease. A resolute belief or an elusive link? J Am Coll Cardiol 2013; 62:397-408. 14. Musunuru K, Kral BG, Blumenthal RS, et al. The use of high sensitivity C-reactive protein in clinical practice. Nat Clin 2. For using hsCRP as a risk 3. Norata GD, Marchesi P, Venu VKP, et al. Deficiency of the Pract Cardiovasc Med 2008; 5:621-35. stratification tool, at least 2 readings long pentraxin PTX3 promotes vascular inflammation and atherosclerosis. Circulation 2009; 120:699-708. 15. Sattar N, Gaw A, Scherbakova O, Ford I, O’Reilly DS, Haffner 2-3 weeks apart must be obtained. If SM, Isles C, Macfarlane PW, Packard CJ, Cobbe SM, Shepherd 4. Ridker PM. A test in context. High-sensitivity C-reactive the second reading is also ≥2 mg/L then J. Metabolic syndrome with and without C-reactive protein protein. J Am Coll Cardiol 2016; 67:712-23. it can be used for risk stratification. as a predictor of coronary heart disease and diabetes in the 5. Mehta V, Sukhija R, Mehra P, et al. Multimarker risk West of Scotland Coronary Prevention Study. Circulation If readings are very high, i.e. >10 stratification approach and cardiovascular outcomes in 2003; 108:414-9. patients with stable coronary artery disease undergoing mg/L, they may suggest acute phase 16. Ridker PM. From C-reactive protein to interleukin-6 to elective percutaneous coronary intervention. Indian Heart response to underlying subclinical or interleukin-1: Moving upstream to identify novel targets J 2016; 168:57-62. clinical infection or other inflammatory for atheroprotection. Circ Res 2016; 118:145-56. 6. Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to 17. Ridker PM, Everett BM, Thuren T, et al. CANTOS Trial disorder. They should be repeated after prevent vascular events in men and women with elevated Group. Antiinflammatory therapy with canakinumab for C-reactive protein. N Engl J Med 2008; 359:2195-2207. 4 weeks and the initial strategy of 2 atherosclerotic disease. N Engl J Med 2017; 377:1119-31. 7. Ridker PM. The JUPITER trial: Results, controversies, and consecutive readings must be fulfilled. 18. Aday AW, Ridker PM. Targeting residual inflammatory implications for prevention. Circ Cardiovasc Qual Outcomes risk: A shifting paradigm for atherosclerotic disease. Front 3. The hsCRP has modest benefits 2009; 2:279-85. Cardiovasc Med 2019; 6:16. in reclassifying moderate risk persons 8. Wilson PWF, Pencina M, Jacques P, et al. C-reactive protein 19. Ridker PM, Everett BM, Pradhan A, et al, for the CIRT and reclassification of cardiovascular risk in the Framingham in primary prevention, whereas its investigators. Low-dose methotrexate for the prevention Heart Study. Circ Cardiovasc Qual Outcomes 2008; 1:92-7. utility in low- and high-risk individuals of atherosclerotic events. N Engl J Med 2019; 380:752-62. 9. Ray KK, Cannon CP, Cairns R, Morrow DA, Ridker PM, is limited. Therefore, hsCRP may 20. Carrero JJ, Franko MA, Obergfell A, et al. HsCRP level and the Braunwald E. Prognostic utility of apoB/AI, total cholesterol/ risk of death or recurrent cardiovascular events in patients be used as a marker for further risk HDL, non-HDL cholesterol, or hs-CRP as predictors of clinical with myocardial infarction: a healthcare based study. J Am risk in patients receiving statin therapy after acute coronary stratification in intermediate-risk Heart Assoc 2019; 8:e012638. syndromes: results from PROVE-IT TIMI 22. Arterioscler individuals, provided there is no Thromb Vasc Biol 2009; 29:424-30. 21. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of alternate cause for elevated hsCRP. low-dose colchicine after myocardial infarction. N Engl J 10. Nissen SE, Tuzcu EM, Schoenhagen P, et al. for the REVERSAL Med 2019; 381:2497-505. 4. In the post-ACS setting, hsCRP Investigators. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary 22. Nidorf SM, Fiolet ATL, Mosterd A, et al. Colchicine in patients may be useful in identifying patients atherosclerosis: a randomized controlled trial. JAMA 2004; with chronic coronary disease. N Engl J Med DOI: 10.1056/ at high risk for future adverse cardiac 291:1071-80. NEJMoa2021372 events who may warrant more 11. Heart Protection Study Collaborative Group. C-reactive 23. Kamath DY, Xavier D, Sigamani A, Pais P. High sensitive aggressive management of risk factors. protein concentration and the vascular benefits of C-Reactive protein (hsCRP) and cardiovascular disease: An statin therapy: an analysis of 20536 patients in the Heart Indian perspective. Indian J Med Res 2015; 142:261-8. For this purpose, hsCRP readings at Protection Study. Lancet 2011; 377:469-76. least 4 weeks after ACS should be 12. Sever PS, Poulter NR, Chang CL, et al. Evaluation of considered. st st 50 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Apolipoprotein B as a Predictor of CVD

“Apolipoprotein B unifies, amplifies, VLDL to LDL conversion takes containing VLDL and IDL particles, and simplifies the information from the six hours, and LDL remains in the though rich in cholesterol can not conventional lipid markers as to the circulation for 48 hours. Thus apo B penetrate into the arterial subintimal atherogenic risk attributable to the apo spends 90% of its lifespan as an LDL.6 space.16,17,21 Because Apo B provides B lipoproteins”. The principal event in the an accurate estimate of the total -Sniderman et al1 pathogenesis of atherosclerotic disease concentration of atherogenic particles under all circumstances, it is the Apolipoproteins, the protein is the retention of apo B containing preferred measurement to further components of lipoproteins have the particles within the arterial vessel wall. refine the estimate of ASCVD risk. following functions:2,3 Most Apo B containing lipoproteins (up to 70 nm in diameter), except for LDL-C is the predominant cholesterol 1. They modulate the enzymatic fully formed chylomicrons and large carrying apo B among the non-HDL-C activity on lipoproteins, VLDL promote plaque formation.7 particles and has 70% of cholesterol. 2. They are responsible for The concentration of apo B containing The remaining 25% is present in maintaining the structural integrity of particles in the blood, the permeability TG-rich VLDL, IDL, Chylomicrons and the lipoproteins, and, of the vascular endothelium and the their remnants as well as Lp(a). Most 3. They facilitate the uptake of binding affinity of the apo B particles of the clinical laboratories calculate lipoproteins through a receptor to the collagen and elastin of the arterial LDL-C using the Friedewald equation mediated mechanism. wall determine the rate and extent of (LDL-C = Total Cholesterol–HDL-C– Apolipoprotein B (Apo B) is the this retention of apo B in the vessel VLDL-C), VLDL-C being calculated as 5 carrier for chylomicrons, low-density wall. triglycerides/5 in mg/dl, as long as the lipoprotein (LDL), very low-density Plasma LDL-C is a measure of triglyceride value is <400 mg/dl. This lipoprotein (VLDL), intermediate the cholesterol mass carried by LDL calculated value includes the LDL-C as density lipoprotein (IDL), and particles, by far the most numerous well as the IDL-C and the cholesterol 9 lipoprotein (a). There are two circulating of the Apo B-containing lipoproteins, carried by Lp(a). forms of apo B: apo B48 (from the and is an estimate of the concentration LDL-C measures the cholesterol small intestine) and apo B100 (from of circulating LDL. In general, LDL-C, content of LDL. Non-HDL-C the liver). Intestinal Apo B present in non-HDL-C, and apo B concentrations measures the cholesterol content of all chylomicrons has a molecular mass 48% are very highly correlated. As a result, atherogenic lipoprotein particles. Apo of that of hepatic apo B. The same gene under most circumstances, they B concentration measures the number codes for both apo B48 and apo B 100. A provide very similar information of all atherogenic particles.10 8 genetic mutation in apo B that prevents about ASCVD risk. However, under Statin therapy reduces the LDL-C binding of the defective apo B to the certain circumstances—including more than apo B. The decrease in LDL-C LDL receptor is an autosomal dominant among people with elevated TG is greater than the apo B lowering by disorder and leads to classical familial levels, DM, obesity, or very low 15%.11 Hence on-treatment apo B is a hypercholesterolemia. achieved LDL-C levels—the calculated more reliable index of the residual risk. Apo B-100 is necessary for assembling or directly measured LDL-C level The 4S, LIPID, AFCAPS/TexCAPS, and VLDL in the liver and also serves as a may underestimate both the total the Leiden Heart Study showed that apo ligand for LDL receptor-mediated concentration of cholesterol carried B was more predictive of the residual clearance. Apo B-48 is essential for the by LDL and, more importantly, risk of vascular events.10 The Air formation of chylomicrons and serves underestimate the total concentration Force/Texas Coronary Atherosclerosis in the absorption of dietary fats from of apo B containing lipoproteins, thus Prevention Study (AFCAPS/TexCAPS), the intestine.4 underestimating the risk of ASCVD. In is a primary prevention study of 6605 around 20% of patients there may be asymptomatic individuals with average One molecule of apo B48 is found discordance between measured LDL-C in each chylomicron and chylomicron LDL-C and below-average HDL-C. The and Apo B levels. Considering these levels of LDL-C, HDL-C and apo B were remnant. One molecule of apo B100 potential inaccuracies in measuring is found in each LDL, IDL and VLDL significant predictors of a first acute LDL-C in dyslipidemia among patients coronary event; however, only on- and Lp(a) particle. However, 85-90% with DM or high TG levels, and in of apo B100 is found in LDL-C. Many treatment apo B and apo B/apo A-I ratio patients with very low LDL-C levels, was predictive of subsequent risk.12 methods for apo B measure total apo B measurement of both Apo B and The Long-Term Intervention with or apo B100. non-HDL-C is recommended as part of Pravastatin in Ischemic Disease (LIPID) Apo B envelops the surface of a routine lipid panel for risk evaluation Trial studied 9014 CHD patients with atherogenic lipoproteins as a in patients with elevated plasma TGs. pravastatin for 1 year. Baseline apo B macromolecular scaffold and provides When there is high non-HDL-C due and apo A-I were stronger predictors of structural integrity.5 to high VLDL-C and high buoyant CHD events than LDL-C and HDL-C. LDL-C, the small dense LDL particles Total apo B concentration = apo B in The unadjusted on treatment apo B may be low in numbers, indicating chylomicron + apo B in VLDL + apo B and apo A-I levels were predictive comparatively low numbers of apo in VLDL remnant + apo in IDL + apo in of a subsequent coronary event, LDL + apo B in Lp(a). B particles. These larger cholesterol st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 51

apo B in young adulthood (mean: 25 Low apo B/ Low apo B/ High apo B/ High apo B/ years) and coronary calcification in Low LDL-C High LDL-C Low LDL-C High LDL-C middle age (mean: 50 years). In the big (Low Non-HDL-C) (High Non-HDL-C) (Low Non-HDL-C) (High Non-HDL-C) contest between non-HDL-C which measures the cholesterol payload and apo B measuring the number of atherogenic particles, apo B is superior to LDL-C.22 The risk of coronary artery calcification was more influenced by Concordant Discordant Discordant Concordant apo B than by LDL-C and non–HDL-C lowest risk low risk high risk highest risk in early adulthood. The subjects with the high LDL-C or non–HDL-C and high apo B had the highest risks for In discordant groups, the risk for subclinical atherosclerosis appears subclinical atherosclerosis (coronary more strongly associated with apoB than with LDL-C or non–HDL-C artery calcification) in midlife. In fact, Apo B is also recommended to assess Fig. 1: Apo B, LDL-C Discordance/Concordance and risk of subclinical atherosclerosis CV risk, particularly in patients with hypertriglyceridemia, diabetes, obesity, whereas on-treatment concentrations analysis showed that apo B was a more metabolic syndrome and very low 13 of LDL-C or HDL-C were not. The accurate marker of cardiovascular risk LDL-C levels, and it can be used as 17 Scandinavian Simvastatin Survival than non-HDL-C. The Framingham an alternative to LDL-c for screening, 18 Study (4S) included 4444 CHD patients Heart Study showed that apo B had diagnosis and management.9,23 randomized to receive simvastatin or a greater predictive ability for CHD placebo and were followed up for 5 events than LDL-C and non-HDL-C. In It has been demonstrated that in years. Baseline apo B was significant the Women’s Health Study, non-HDL- metabolic syndrome patients or in those predictor of CHD for patients in the C, apo B, and LDL particle number had with evidence of insulin resistance, a placebo and treatment groups, but greater predictive value than LDL-C for discordance between apo B and LDL-C LDL-C only predicted CHD risk for CHD events.19 is more evident and apo B appears to patients in the placebo group.14 The be superior to LDL-C in predicting CV Although of apparently similar risk (Figure 1).24 Leiden Heart Study had 848 patients significance, measurement of the (675 men, 173 women) with proven number of atherogenic particles Type III hyperlipoproteinemia CAD who received effective statin may be more meaningful than the (remnant lipoprotein disorder or familial treatment. The study found that apo measurement of the cholesterol content dysbetalipoproteinemia), a highly B and apo A-I were superior to LDL-C alone. Calculation of non-HDL-C and atherogenic dyslipidemic disorder is for predicting vascular events. In apo B are highly correlated but only common and is a less recognised entity. multivariate analysis, on-treatment apo moderately concordant.20 Measurement of apo B makes possible B and apo A-I were the only significant the diagnosis of all the atherogenic In a meta-analysis21 based on all the predictors for subsequent MI and apo B dyslipoproteinemias, including published epidemiological studies that 25 all-cause mortality, after adjusting type III hyperlipoproteinemia. This contained estimates of the relative risks for total cholesterol, triglycerides, is another strong justification to of non-HDL-C and apo B of fatal or gender, diabetes, age and smoking. In include apo B in the assessment of nonfatal ischemic CV events, there were a meta-analysis of prospective studies dyslipoproteintemia. Otherwise, the 233,455 subjects and 22,950 events. Apo of apo B,15 it was seen that apo B was a diagnosis may be missed in routine B was the most potent marker of CV significant predictor of CHD, with an clinical care. In fact, Sniderman et al risk. The authors calculated the number overall relative risk of about 2.0 for the state emphatically that “Indeed, except of clinical events prevented. Over a upper versus the lower tertile. for Lp(a), diagnosis of all the apo B 10-year period, a non-HDL-C strategy atherogenic dyslipoproteinemias is In the AMORIS (Apolipoprotein- would prevent 3,00,000 more events Related Mortality Risk Study) study,16 possible based on the plasma levels of than a LDL-C strategy, whereas an apo triglyceride, cholesterol, and apo B.26 >1,75,000 men and women over the B strategy would prevent 5,00,000 more age of 60 were followed for about events than a non-HDL-C strategy. Statin therapy usually increases 5 years. After adjusting for age and These results further strengthen the discordance between apo B and the traditional lipid risk factors, including value of apo B in clinical care. cholesterol markers as LDL-C and LDL-C, apo B remained a significant non-HDL-C are lowered more than The levels of LDL-C and apo B can predictor of MI for both men and apo B.27 Thus apo B is a more accurate be used to reclassify risk as elegantly women. From the INTERHEART study, measure of the response to statin described by Wilkins et al.22 They also a case control study of myocardial therapy and benefit due to statin suggest a dose–response association infarction in 52 countries (15152 cases therapy than either LDL-C or non- between apo B in young adults and the 27 and 14820 controls), blood samples of HDL-C. Two transformational studies presence of midlife CAC independent of 9345 cases and 12,120 controls were by Ference et al clearly showed that baseline traditional CVD risk factors.22 tested for discordance analysis of clinical benefit correlated with apo This study demonstrates a strong non-HDL-C and apo B. Discordance B, not LDL-C and measuring apo B association between plasma levels of st st 52 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Table 1: Effectiveness of statin treatment Table 2: The treatment goal of apo B and Table 3: The treatment goals of Apo B and at reducing LDL-C, non–HDL-C, their corresponding LDL-C and their corresponding LDL-C and apo B in Apo B studies of 17,035 non-HDL-C goal in the AACE non-HDL-C goals recommended by participants26 guidelines35 Lipid Association of India

Reduction on Mean on- Risk Goal Goal Goal Risk category Goal Goal Goal Apo therapy treatment category LDL-C Non-HDL-C Apo B LDL-C Non-HDL-C B (mg/dL) concentration (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) LDL-C 42.1 % 99.2 mg/dL High Risk <100 <130 <90 High Risk <70 <100 <80 Non–HDL-C 39.6 % 127.0 mg/dL Very high <70 <100 <80 group Apo B 33.1 % 101.6 mg/dL risk Very high risk <50 <80 <65 Extreme <55 <80 <70 group provides all the information necessary risk Extreme <50 <80 <65 to assess the adequacy of a lipid- risk group- From all the studies available, it lowering therapy.28,29 Category A may be surmised that at a population Extreme ≤30 <60 <50 Multiple discordance analyses have level, apo B is a superior analytic tool risk group- shown that when non–HDL-C was high to LDL-C or non-HDL-C. In patients Category B but apo B was normal, cardiovascular in whom LDL composition is normal, concentration or very low LDL-C risk was not high, whereas when non– the cholesterol markers and apo B are levels, non-HDL-C and apo B could be HDL-C was normal but apo B was high, equivalent markers of risk. But, when preferred in order to estimate CV risk. cardiovascular risk was high.6 Apo B, the markers are discordant, that is, The LAI recommended apo B goals therefore, is superior to non–HDL-C as when LDL-C is normal but LDL-P is for Indians in high risk, very high risk a marker of cardiovascular risk.30 high or, alternatively, when LDL-C and extreme risk groups are listed in Apo B and CKD : Serum Apo B, is high but LDL-P is normal, there is Table 3. ApoA1, conventional lipid parameters evidence that risk follows apo B and The use of LDL-C to assess and lipid subfractions were analyzed in LDL-P, not LDL-C.33 cardiovascular risk and guide therapy 9403 subjects and were followed up for Once apo B gets into the sub is firmly established and entrenched in 10 years. Even after adjusting for other endothelial space in the vessel wall, the minds of clinicians and in routine risk factors, high Apo B concentrations smaller cholesterol-depleted apo B practice. Replacing LDL-C with apo B had an association with the risk of particles get trapped more avidly is likely to take time and is not easy, end stage renal disease (ESRD). Apo B than larger cholesterol-enriched apo since physicians and patients are levels may be helpful for the predicting B particles to the glycosaminoglycans. accustomed to LDL-C. Efforts should the risk of ESRD. Probably glomerular Cholesterol-enriched particle would be made to change perceptions and endothelial cells and kidney vessels contribute more cholesterol than a practice gradually.33 can become sites of oxidation and cholesterol-depleted apo B particle. LAI Recommendations inflammation secondary to high Apo B Thus, all apo B particles are equally 1. Apo B is moderate non- concentrations, leading to progression atherogenic.1 conventional risk factor (a level ≥110 of CKD.31 ApoB Measurement mg/dl of apo B corresponds to an LDL-C Apo B or LDL-P measurement Measurement of apo B can be done ≥130 mg/dl) in low and moderate risk to assess CHD risk is becoming directly from the non-fasting serum. groups increasingly important in the present Measurements of apolipoproteins are 2. To assess ASCVD risk, It is scenario of a rapidly growing subset internationally standardized (Table 2), preferable to estimate serum apo B in of the population with prediabetes, automated, cost-effective in many areas patients with diabetes and metabolic syndrome. and more convenient and precise than Individuals with metabolic syndrome i. diabetes, those for LDL cholesterol.34 or diabetes tend to have an increased ii. metabolic syndrome, number of small, dense LDL particles The goal Apo B is <80/dL in iii. obesity, but relatively normal LDL-C very high-risk individuals whereas concentrations. Because statin therapy the LDL-C goal is <70 mg/dL and iv. high triglyceride concentration or reduces LDL-C to a greater extent non-HDL-C is <100 mg/dl. The AACE v. very low LDL-C levels 26 guidelines equate an LDL-C <55 mg/dl than they do LDL particles, apo B 3. Apo B measurement is to an Apo B <70 mg/dl. or LDL-particles (LDL-P) appear to recommended in high-risk subjects, provide a better assessment of on- The 2018 ACC/AHA guidelines after LDL-C and non-HDL-C goals have treatment residual risk than LDL-C mention apo B, stating that an been achieved. Discordant elevated apo 32 measurement. apo B greater than 130 mg/dl is a B levels may identify individuals who The reduction in serum apo B risk-enhancing factor and requires have high residual cholesterol risk. This or LDL-P concentration is not as measurement in primary prevention may warrant intensive statin therapy dramatic as the reduction in LDL-C or treatment protocols and this is an and use of non-statin drugs. essential step towards the analysis of non-HDL-C (Table 1). So, the patients 4. Recommended for diagnosis of apo B for cardiovascular risk.36 treated to goal for LDL-C may not Type III hyperlipoproteinemia. have achieved optimal LDL particle In 2019, the ESC/EAS Guidelines37 5. Efforts should be made to bring concentrations or apo B levels, leaving recommended that when evaluating in gradual change in perception of them with residual risk.26,32 patients with diabetes, metabolic the importance of apo B amongst syndrome, obesity, high triglyceride st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 53 physicians, patients and laboratories. HDL to VLDL1 particles. Arterioscler Thromb Vasc Biol 2000; and low-density lipoprotein particle number is associated 20:189-97. with insulin resistance in clinical practice. J Clin Lipidol 2015; Laboratories should standardise their 9:247-55. 12. Gotto AM, Whitney E, Stein EA, Shapiro DR, Clearfield M, methods. Weis S. Relation between baseline and on-treatment lipid 25. Sniderman A, Couture P, de Graaf J. Diagnosis and treatment 6. Apo B estimation should be parameters and first acute major coronary events in the of apolipoprotein B dyslipoproteinemias. 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Sniderman A. Targets for LDL-lowering therapy. Curr Opin lipoproteins and atherosclerotic cardiovascular disease. HDL-C. Eur J Prev Cardiol 2015; 22:1321-7. Lipidol 2009; 20:282-7. F1000Research 2017;6(F1000 Faculty Rev):134. 19. Mora S, Buring JE, Ridker PM. Discordance of LDL cholesterol 34. Contois JH, McConnell JP, Sethi AA, Csako G, Devaraj 6. Ference BA, Kastelein JJP, Catapano AL. Lipids and with alternative LDL-related measures and future coronary S, Hoefner DM, Warnick GR. Apolipoprotein B and lipoproteins in 2020. JAMA 2020; 324:595-6. events. Circulation 2014; 129:553-61. cardiovascular disease Risk: Position statement from the AACC Lipoproteins and Vascular Diseases Division Working 7. Boren J, Williams KJ. The central role of arterial retention of 20. Sniderman AD, St-Pierre A, Cantin B, et al. Concordance/ Group on best practices. Clinical Chemistry 2009; 55:407-19. cholesterol-rich apolipoprotein-B-containing lipoproteins in discordance between plasma apolipoprotein B levels and the pathogenesis of atherosclerosis: a triumph of simplicity. the cholesterol indexes of atherosclerotic risk. Am J Cardiol 35. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Curr Opin Lipidol 2016; 27:473-83. 2003; 91:1173-7. Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of 8. Emerging Risk Factors Collaboration, Di Angelantonio E, Gao 21. Sniderman AD, Williams K, Contois JH, et al. A meta-analysis dyslipidemia and prevention of cardiovascular disease. P, Pennells L, et al. Lipid-related markers and cardiovascular of low-density lipoprotein cholesterol, non-high-density Endocr Pract 2017; 23(Suppl 2):1-87. disease prediction. JAMA 2012; 307:2499-2506. lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes 2011; 36. Wilson PWF, Polonsky TS, Miedema MD, et al. Systematic 9. Jacobson TA, Ito MK, Maki KC, et al. National Lipid 4:337-45. Review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ Association recommendations for patient-centered ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA. Guideline on management of dyslipidemia: Part 1– full report. J Clin 22. Wilkins JT, Li RC, Sniderman A, et al. Discordance between the management of blood cholesterol: A Report of the Lipidol 2015; 9:129-69. Apolipoprotein B and LDL cholesterol in young adults American College of Cardiology/American Heart Association predicts coronary artery calcification. The CARDIA study. J 10. Barter PJ, Ballantyne CM, Carmena R, et al. Apo B versus Task Force on Clinical Practice Guidelines. Circulation 2019; Am Coll Cardiol 2016; 67:193-201. cholesterol in estimating cardiovascular risk and in guiding 139:e1144-e1161. therapy: report of the thirty-person/ten country panel. 23. Paredes S, Fonseca L, Ribeiro L, Ramos H, Oliveira JC, Palma 37. Mach F, Baigent C, Catapano AL, Koskina KC, Casula M, Journal of Internal Medicine 2006; 259:247-58. I. Novel and traditional lipid profiles in metabolic syndrome Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference reveal a high atherogenicity. Sci Rep 2019; 9:1-7. 11. Guerin M, Lassel TS, Le Goff W, Farnier MA, Chapman BA. 2019 ESC/EAS guidelines for the management of MJ. Action of atorvastatin in combined hyperlipidemia: 24. Varvel, S. A. et al. Discordance between apolipoprotein B dyslipidaemias: lipid modification to reduce cardiovascular preferential reduction of cholesteryl ester transfer from risk. Eur Heart J 2020; 41:111-8. st st 54 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

Non-HDL Cholesterol and Atherosclerotic Cardiovascular Disease

ow density lipoprotein cholesterol necessity of patients to return on a separate may not be required to obtain a valid L(LDL-C) plays a key role in fasting visit for assessment of calculated sample. There is also evidence showing atherogenesis from initiation (e.g. LDL-C. Non-high density lipoprotein- that D-LDL-C correlates well with beta endothelial dysfunction) to eventual cholesterol (non-HDL-C) has already quantifcation of LDL-C. Although in the clinically evident atherosclerotic been included as a co-primary target in original paper by Friedewald, calculated cardiovascular disease (ASCVD).1 the previous Expert Consensus of the LAI. LDL-C was shown to correlate with Hence, lowering LDL-C levels results in Calculated LDL-C: Almost all beta quantification, in patients with 1 substantial reduction of ASCVD risk. laboratories report a calculated LDL-C moderate increase in TG levels it showed Large scale randomized clinical trials of based on the Friedewald equation. There discordant calculated LDL-C compared statins support this conclusion. Numerous are several issues with using this equation, with beta quantifcation even between TG primary and secondary prevention trials, especially in patients with combined concentration 200 and 499 mg/dl. Here especially trials conducted in high risk hyperlipidemia which is not uncommon apolipoprotein B (apo B) or non-HDL-C populations, have clearly proven the in patients with diabetes mellitus (DM) and perhaps D-LDL-C, if available, are beneft of statins in decreasing ASCVD risk or those with insulin resistance. When superior to calculated LDL-C. The lack of 2-6 by reducing LDL-C levels. The dominant the TG concentration is >400 mg/dl, standardization of D-LDL-C continues to 15 role of LDL-C is further exemplifed by calculating the LDL-C concentration be an issue. people with familial hypercholesterolemia using Friedewald equation becomes Non HDL-C and ASCVD risk (FH), who commonly develop premature invalid. Even at TG levels of 200-400 Non-HDL-C is calculated as total atherosclerosis and clinical ASCVD even mg/dl, there are data showing LDL-C is cholesterol minus HDL-C. Since HDL-C in the absence of other risk factors.7 Based underestimated when the Friedewald is the only anti-atherogenic lipoprotein, on these evidences, the prime focus equation is used, hence questioning the non-HDL-C effectively measures all for prevention of ASCVD has been on validity of calculated LDL-C even in this atherogenic (apo B carrying) lipoproteins lowering LDL-C levels and maintaining ranges of TGs. In an Indian population, in the circulation, including LDL, this throughout life. such moderately elevated TG levels are VLDL, IDL and Lp(a) (Figure 1). Hence, However, large scale statin trials have highly prevalent and pose challenge in non-HDL-C is accepted as a more accurate shown that despite marked ASCVD risk using and achieving target LDL-C levels. predictor of ASCVD risk compared with reduction, the residual risk of ASCVD in Further, when the calculated LDL-C LDL-C. Several large scale studies have statin-treated patients remains as high levels are low (<70 mg/dl), this may often proven this hypothesis5-9, showing that 8-12 as 55-70%. Further with the advent of be a result of underestimation by the non-HDL-C levels are stronger predictors 14 newer lipid lowering therapies, that help Friedewald equation. of all-cause and ASCVD mortality when to achieve very low LDL- C levels, focus on Direct LDL-C (D-LDL-C): Clinical compared with LDL-C levels. For example, other lipoproteins to reduce the residual laboratories are increasingly able to in the Lipid Research Clinics Program, risk has gained recognition. There are provide a direct LDL-C estimation method, 4462 middle aged individuals, free from several other atherogenic lipoproteins in because it offers the advantage that fasting ASCVD, were followed up for an average the circulation that contribute to ASCVD risk including triglyceride (TG)-rich lipoprotein remnants [very low-density Plasma lipoproteins lipoprotein (VLDL) and intermediate density lipoprotein (IDL)] and lipoprotein (a) [Lp(a)]. These lipoproteins may account for a signifcant proportion of ASCVD risk, Chylomicrons VLDL IDL LDL Lp(a) HDL particularly in those with elevated TG Remnants (Apo B100) (Apo B100) (Apo B100) (Apo B100) (Apo A I) levels or where LDL-C has already been (Apo B48) lowered with statins.8 It seems prudent that in order to reduce ASCVD risk effectively, all atherogenic lipoproteins Triglyceride rich should be targeted and not just LDL-C lipoproteins alone. While the clinical trial evidenced has Non-HDL-C focused on LDL-C as the target of therapy, meta-analyses13 show non-HDL-C to be at least as strong if not a strong predictor Non-HDL-C = total cholesterol – HDL-C of CHD risk than LDL-C, suggesting Remnant cholesterol = total cholesterol – HDL-C – LDL-C the appropriateness of non-high density lipoprotein-cholesterol (non-HDL-C) as a Fig. 1: Plasma lipoproteins and non-HDL-C. CM- chylomicrons, VLDL- very low density co-primary or secondary target of therapy. lipoprotein, IDL- intermediate density lipoprotein, LDL- low density lipoprotein, Importantly, non-HDL-C can be estimated HDL- high density lipoprotein, Lp(a)- lipoprotein(a), Apo B- apolipoprotein B, Apo in the non-fasting state, eliminating the A1- apolipoprotein A1 st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 55 of 19 years.5 Non-HDL-C was a stronger It showed that a reduction in non-HDL-C risk of future CV events, even if LDL-C predictor of ASCVD outcomes compared strategy are likely to avoid 300,000 events is under control with statins. A meta- with LDL-C. A 30 mg/dl (0.78 mmol/l) more than an LDL-C strategy, while an analysis of 8 statin trials which focused on increase in non-HDL-C resulted in a 19% apo B strategy is likely to avoid 500,000 LDL-C and non-HDL-C levels, the HR for increase in CV mortality in men and 11% events more than a non- HDL-C strategy.21 major CV events revealed continuous and increase in women compared with 15% and This study concluded that apo B was progressive reduction in HR for MACE 8%, respectively for LDL-C concentration.5 superior in clinical care. However, the with lower achieved levels of LDL-C and In other studies, non-HDL-C has correlated performance of non-HDL-C compared non-HDL-C. The HR for LDL-C was 0.44 well with subclinical atherosclerosis with apo B, continues to be a point of and for non- HDL-C 0.57 for achieved assessed either by imaging studies10,11 or on-going debate. Non-HDL-C is more LDL-C levels <50 mg/dl (achieved by 4375 at autopsy.12 a practical marker of choice due to ease patients of 38,153 patients) and achieved 22 Non-HDL-C levels predict ASCVD of calculation and no added cost. The non-HDL-C levels <75 mg/dl, respectively. risk irrespective of TG concentration. calculation uses parameters such as total There was large inter-individual variation Thus, while EPIC-Norfolk (European cholesterol and HDL-C measurements in achieved LDL-C and non-HDL-C Prospective Investigation into Cancer which have already been standardized. levels with only 13.8% patients on statins 26 and nutrition- Norfolk) study16 confrmed An elevation in non-HDL-C, apo B100 or achieving non-HDL-C of <75 mg/dl. predictive accuracy of non-HDL-C in LDL particle concentrations puts a patient A retrospective study attempted patients with relatively low TG (<200 mg/ at an increased risk and aggressive lipid to predict the association of attaining 23 dl), the SHEP (Systolic Hypertension in lowering is recommended in this case. non-HDL-C goals as compared to attaining the Elderly Program) study17 documented A large multinational cardiovascular LDL-C goals with long-term major that non-HDL-C predicted ASCVD risk in risk consortium data from 19 countries adverse CV events (MACE) in patients those with elevated TG (>400 mg/dl). In involving 524,444 individuals with a who presented with acute MI (AMI). the SHEP study, LDL-C lost its predictive median follow up of 13.5 years showed Patients (n=868) were followed post- AMI value when TG levels exceeded 400 mg/dl. a progressively higher CV event rates for 2.6 years. Of these, 34.4% reached Non-HDL-C has also been compared with increasing non-HDL-C levels from non-HDL-C target <100 mg/dl while 23.7% with apo B for its ability to predict <2.6 mmol/L to ≥5.7 mmol/L (7.7% to reached LDL-C target <70 mg/dl and ASCVD risk. Since all the atherogenic 33.7% in women and from 12.8% to 43.6% 21.2% experienced MACE. The incidence lipoproteins, whether LDL, VLDL or in men; P <0.0001). The multivariable of MACE was higher in patients with Lp(a), contain one apo B molecule, apo adjusted Cox models showed an increase non-HDL-C of >130 mg/dl compared with B may be a more accurate predictor of in association between non-HDL-C and non-HDL-C <100 mg/dl. The conclusion ASCVD risk. This was indeed confrmed cardiovascular risk with HR 1.1 to 1.9 was that if non-HDL-C goals were not by the INTERHEART case-control study in women and 1.1 to 2.3 in men with achieved, the risk at long-term follow up 24 of acute myocardial infarction (MI) in 52 increasing non-HDL-C lvevls. Hence, it for MACE after AMI was higher while countries in which 15,152 cases and 14,820 is pertinent that all laboratories should not attaining the LDL-C goal was not controls were enrolled. It showed that the report non-HDL-C levels in addition to associated with a similar increased risk. ratio of apo B to apo A-I was the strongest conventional reporting of LDL-C and Hence, non-HDL-C may be considered a determinant of myocardial infarction TG for better characterization of residual better target for treatment than LDL-C in 27 risk with population attributable risk of ASCVD risk and treatment targets. post-AMI patients. 49·2% for top four quintiles versus lowest Non HDL-C and statin treatment The Very Large Database of Lipids 18 quintile. Since non-HDL-C measures all There is reasonable evidence in favour (VLDL-2) examined patient-level the apo B containing lipoproteins, it also of non-HDL-C for an accurate prediction of discordance between population correlates withthe circulating levels of residual ASCVD risk in patients on statin percentiles of LDL-C and non-HDL-C in apo B. In the Women’s Heart Study, the therapy. A meta-analysis of 62,154 statin- 1,310,440 adults. LDL-C cut offs of 70, 100, highest quintile of non-HDL-C had similar treated patients in 8 trials (4S, AFCAPS, 130, 160, and 190 mg/dl were in the same relative risk for major ASCVD events as the LIPID, CARDS, TNT, IDEAL, SPARCL, population percentiles as non–HDL-C 9 highest quintile of apo B. However, in JUPITER) published between 1994 and values of 93, 125, 157, 190, and 223 mg/dl, the Health Professionals Follow-up study, 2008 revealed that 1 SD increase in LDL-C, respectively. Among those with LDL-C non-HDL-C was found to be an inferior apo B and non-HDL-C increased the risk <70 mg/dl, 15% had a non-HDL-C level predictor of CV events compared with of CV events by 13%, 14%, and 16%, of ≥100 mg/dl (guideline-based cut point) 19 apo B. Nevertheless, it is important to respectively indicating that the strength and 25% had a non-HDL-C value of 93 mg/ note that in both these studies, non-HDL-C of association with ASCVD was greater dl (percentile-based cut point). However was a better predictor of ASCVD risk for non-HDL-C than for LDL-C or apo concurrent higher TG levels of 150 to 199 than LDL-C. A meta-analysis of 25 trials B.25 Compared with the patients who had mg/dl altered these values to 22% and 50%, (1,31,134 participants) on lipid lowering LDL-C <100 mg/dl and non-HDL-C <130 respectively meaning that discordance therapy concluded that non-HDL-C mg/dl, those who had elevated non-HDL-C between LDL-C and non-HDL-C 20 outperforms apo B for prediction of CVD. >130 mg/dl but low LDL-C levels <100 increased with higher TG levels. This has A number of studies have found that mg/dL the hazard ratio (HR) was 1.32 implications in the treatment of high-risk non-HDL-C and apo B are better than indicating 32% excess ASCVD. In contrast, individuals as there is signifcant patient- LDL-C in CVD risk prediction. A meta- the HR was only 1.02 when LDL-C was level discordance between non-HDL-C analysis of LDL-C, non-HDL-C and apo elevated but non-HDL-C was low. These and LDL-C percentiles at lower LDL-C B as markers of CV risk including 233,455 fndings strongly suggest that increased and higher triglyceride levels. The subjects and 22,950 events, was carried out. non-HDL-C is associated with increased recommended non-HDL-C cut points for st st 56 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 high risk patients need to be lowered to but not LDL-C on multivariate analysis.7 Practical advantages of non-HDL-C match percentiles of LDL-C cut points. In fact, the calculated LDL-C excludes the Besides being an important ASCVD risk Small absolute changes in non-HDL-C cut cholesterol of triglyceride-rich lipoproteins marker, non-HDL-C offers several other offs will result in substantial reclassifcation (TGRLs) which are proatherogenic. Thus, advantages that are relevant to clinical of patients to higher risk categories with for diabetic patients with the combined practice: potential implications for risk assessment dyslipidemia, calculated LDL-C fails to • Estimation of non-HDL-C adds no and treatment.28 be an adequate index of overall lipid- extra cost; it can be easily calculated by associated risk. Data of 4957 patients with coronary subtracting HDL-C from total cholesterol. heart disease (CHD) from 9 clinical trials A recent observational study in India of • Calculation of non-HDL-C includes who underwent serial intravascular 808 patients with DM showed that elevated total cholesterol and HDL-C measurements ultrasonography to assess changes non- HDL-C was the second commonest that are standardized. Therefore, it is in percent atheroma volume (ΔPAV) lipid abnormality after low HDL-C levels considered superior to D-LDL-C or apo B was evaluated against on-treatment among type 2 DM patients. The prevalence since both these measurements have not non-HDL-C levels (<100 mg/dl/≥100 mg/ of elevated non-HDL-C was 21.6% among undergone the rigorous standardization. dl) and TG levels (<200 mg/dl/≥200 mg/dl). patients who were on statin therapy with This evaluation was carried out in patients optimal LDL-C levels although the authors • Measurement of non-HDL-C does with variable on-treatment LDL-C 400 mg/dl. was found to have stronger association predictor of CV disease than LDL-C or with achieved non-HDL-C than LDL- C in TGs as it represents the majority of all • Non-HDL-C measures all the this analysis. TG values >200 mg/dl were circulating atherogenic lipoproteins. atherogenic lipoproteins including LDL-C 29 associated with plaque progression. This Under-treatment of patients may arise as a and the TG-rich lipoprotein remnants. strengthens the fact that non-HDL-C (and result of not considering the signifcance of Furthermore, as LDL-C is the major possibly TG) lowering is essential to reduce non-HDL-C among people with diabetes.32 component of non-HDL-C, non-HDL-C residual CV risk. The use of non-HDL-C as a screening tool maintains focus on LDL-C, currently the Although most patients with to identify individuals with clustering primary target for ASCVD risk reduction. non-HDL-C ≥160 mg/dl show elevations metabolic abnormalities and increased • Non-HDL-C also equates to the excess in LDL-C and/or TG, a disproportionate predisposition to coronary artery disease ASCVD risk imparted by the small dense elevation in non-HDL-C that coincides with has been highlighted in a study conducted form of LDL that is more atherogenic low to normal levels of LDL-C (<100 mg/ in a North Indian population with and than the normal large buoyant particles. dl) may occur in some patients. Familial without CAD.33 Small dense LDL is the dominant form dysbetalipoproteinemia is characterized Non-HDL-C as a predictor of future risk of LDL particles in patients with elevated by elevation in remnant particles (i.e. IDL) TG levels.23,35-37 An elevated non-HDL- In the Framingham Offspring study of due to mutation(s) in the apoE gene that C, being a surrogate for elevated TG, 2,516 subjects aged 25-40 years, free of CVD encodes a defective apoE ligand (i.e. E2/ indirectly represents the presence of and DM were divided into 2 groups based E2 rather than the normal E3/E3 isoform), greater proportion of small, dense LDL on non-HDL-C levels: non-HDL-C ≥160 resulting in impaired hepatic clearance of particles in contrast to LDL-C levels that mg/dl (“high”) and <130 mg/dl (“low”) TG rich remnants, elevated TG levels and fail to provide any information about LDL at the first 2 examinations. The mean premature CVD.30 High non-HDL-C can particle size. non-HDL-C levels measured in young also result from elevations in Lp(a).30 adulthood were highly predictive of levels International guidelines and non- Non-HDL-C in DM later in life at a mean follow-up of 32.6 HDL-C Non-HDL-C is particularly informative years, with later values remaining close Based on accumulated evidence, in diabetic patients who tend to have to initial values in most subjects. Those non-HDL-C is being increasingly higher TG levels, and thus a greater with high non-HDL-C in young adulthood recognized by most experts worldwide to difference is observed between LDL-C had a 22.6% risk of CVD in the next 25 be a better target for lipid lowering therapy and non-HDL-C. A post-hoc analysis of years compared with a 6.4% risk in those than LDL- C alone. Most of the current 4 large prospective studies- The Lipid with low non-HDL-C. Thus, non- HDL-C guidelines have incorporated non-HDL-C Research Clinics Program follow up study, levels in younger healthy individuals may in their recommendations. Multiple Risk factor intervention trial, identify those at increased risk of future The Third Adult Treatment Panel (ATP The Framingham Cohort Study and The adverse CV events.35 This may even be III) of the National Cholesterol Education Framingham offspring study included more important for the Indian population Program (NCEP) recommended the use 19381 participants and demonstrated who develop vascular disease 10 years of non-HDL-C as a secondary target of that diabetic patients had significantly earlier than their western counterparts and lipid lowering, after achieving adequate higher non-HDL-C levels compared with have a high prevalence of DM.33 control of LDL-C and if TGs are elevated non-diabetic patients (194.1 and 176.7 Also, it is recently observed that the (≥200 mg/dl). mg/dl, respectively) but almost identical ratio of non-HDL-C to TC signifcantly The JBS3 consensus recommendations LDL-C levels (148.6 and 148.0 mg/dl, predicts the severity of coronary lesion in for the prevention of ASCVD state that respectively). The CV risk in diabetics statin treated patients and the occurrence non- HDL-C should be used in preference increased with increase in non-HDL-C of MACE [RR 1.9 (95% CI; 1.2-3.4)].34 to LDL-C as the treatment goal for lipid st st Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020 57 lowering therapy.38 In 2014, the National What should be recommended for References Institute for Health and Care Executive Indians? (NICE) lipid management guidelines 1. Davidson MH. Reducing residual risk for patients on statin Several studies have shown that Indians therapy: the potential role of combination therapy. Am J recommended the measurement of total have high prevalence of T2DM, obesity Cardiol 2005; 96:3K-13K; discussion 34K-35K. cholesterol, HDL-C, non-HDL-C, and and metabolic syndrome, all of which 2. Kastelein JJP, van der Steeg WA, Holme I, et al. Lipids, TG concentrations. It also recommended apolipoproteins, and their ratios in relation to cardiovascular are characterized by high TG levels, low events with statin treatment. Circulation 2008; 117:3002-9. to lower non-HDL-C by 40% in patients HDL-C and higher prevalence of small on lipid lowering drugs for secondary 3. Lloyd-Jones D, Adams RJ, Brown TM, et al. Executive dense LDL particles, which is also known summary: Heart disease and stroke statistics-2010 update: 39 prevention. Similarly, the U.S. National as atherogenic dyslipidaemia. Accordingly, A report from the American Heart Association. Circulation Lipid Association guidelines have placed as discussed in relevant sections in this 2010; 121:948-54. a greater emphasis on non-HDL-C than document, a high prevalence of elevated 4. Libby P. The forgotten majority: Unfinished business in LDL-C.40 The International Atherosclerosis cardiovascular risk reduction. J Am Coll Cardiol 2005; TG and low HDL-C has been highlighted in 46:1225-8. 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Joint distribution of dl for very high risk individuals not very therapy in Indians. In all individuals, the non-HDL and LDL cholesterol and coronary heart disease different from the LAI target of <50 mg/dl risk prediction among individuals with and without non-HDL-C level should be kept not any diabetes. Diabetes Care 2005; 28:1916-21. published in 2016 as part of their guideline. higher than 30 mg/dl of LDL-C goals. 8. Bittner V, Hardison R, Kelsey SF, et al. Non-high-density However, they defined non-HDL-C Summary and recommendations: lipoprotein cholesterol levels predict five-year outcome levels as a secondary target but they did in the bypass angioplasty revascularization investigation not reflect the differential importance of • Non-HDL-C, which is equal to total (BARI). Circulation 2002; 106:2537-42. non-HDL-C especially those with high TG. cholesterol minus HDL-C, includes all 9. Ridker PM, Rifai N, Cook NR, et al. Non-HDL cholesterol, apolipoproteins A1 and B100, standard lipid measures, lipid The levels recommended were 30 mg/dl circulating atherogenic lipoproteins and ratios, and CRP as risk factors for cardiovascular disease in higher for each risk group as <85, 100 and is therefore a more accurate predictor of women. JAMA 2005; 294:326-33. 135 mg/dl of non-HDL-C and these levels ASCVD risk, particularly in patients who 10. Orakzai SH, Nasir K, Blaha M, et al. Non-HDL cholesterol is are more conservative for population that have elevated TG (e.g. diabetics, obese strongly associated with coronary artery calcification in asymptomatic individuals. Atherosclerosis 2009;202:289-95. have a very high risk. persons, those with metabolic syndrome) 11. Kawamoto R, Oka Y, Tomita H, et al. Non-HDL cholesterol and those already on statin therapy. In view of high prevalence of as a predictor of carotid atherosclerosis in the elderly. J atherogenic dyslipidaemia in Indians, LAI • The LAI recommends non-HDL-C AtherosclerThromb 2005; 12:143-8. recommends non-HDL-C as a co-primary as a co-primary target, as important as 12. Rainwater DL, McMahan CA, Malcom GT, et al. Lipid and apolipoprotein predictors of atherosclerosis in youth: target which is as important as LDL-C LDL-C, for lipid lowering therapy. Apolipoprotein concentrations do not materially improve target. It can be concluded that non-HDL-C • Monitoring of non-HDL-C will prediction of arterial lesions in PDAY subjects. The PDAY research group. Arterioscler Thromb Vasc Biol 1999;19:753-61. is a metric of good quality of care for provide a simple, practical tool for 43 13. Robinson JG, Wang S, Smith BJ, Jacobson TA. Meta-analysis CVD prevention. However, reaching to treatment decisions relating to lipid- of the relationship between non-high-density lipoprotein non-HDL-C goals has been inadequate. lowering therapy since it does not require cholesterol reduction and coronary heart disease risk. J Am Various reasons can explain this: (1) a fasting blood sample and takes care of Coll Cardiol 2009; 53:316-22. Lack of knowledge among practitioners both LDL-C and TG targets. 14. Martin SS, Blaha MJ, Elshazly MB, et al. Friedewald- estimated versus directly measured low-density lipoprotein of the importance of non-HDL- C, (2) • In all individuals, the non-HDL-C cholesterol and treatment implications. J Am Coll Cardiol Laboratories not providing automatically level should be kept within 30 mg/dl of 2013; 62:732-9. calculated non-HDL-C levels. Ignorance LDL-C levels. 15. Nauck M, Warnick GR, Rifai N. Methods for measurement regarding the simple math required to of LDL-cholesterol: A critical assessment of direct Statins remain the frst line agent for measurement by homogeneous assays versus calculation. calculate non-HDL-C, (3) Unawareness Clinical Chemistry 2002; 48:236-54. about the treatment goals for non-HDL-C, lipid lowering, regardless of whether LDL-C is the target for therapy or non- 16. Arsenault BJ, Rana JS, Stroes ESG, et al. Beyond low-density (4) Patients related issues like intolerance lipoprotein cholesterol: Respective contributions of non- to statins or lack of adherence to statin or HDL-C. Increasing the dosage of statin high-density lipoprotein cholesterol levels, triglycerides, or switching to a more potent statin and and the total cholesterol/high-density lipoprotein non-statin treatment which are required to cholesterol ratio to coronary heart disease risk in apparently intensifying lifestyle measures should be achieve non- HDL-C goals. healthy men and women. J Am Coll Cardiol 2009; 55:35-41. the frst step to achieve further non-HDL-C Providing non-HDL-C as part of a 17. Frost PH, Davis BR, Burlando AJ, et al. Serum lipids and lowering when LDL-C target has already incidence of coronary heart disease. Findings from the routine lipid profle from laboratories may been reached. Adding ezetimibe should systolic hypertension in the elderly program (SHEP). Circulation 1996; 94:2381-2388. improve the existing lack of awareness be considered when the above measures among practitioners. Goal attainment prove inadequate. Icosapent ethyl, once 18. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially for non-HDL-C will probably require modifiable risk factors associated with myocardial infarction available in India, may also be a useful in 52 countries (the INTERHEART study): Case-control study. interventions that incorporate measures alternative as in higher doses of 4 g/day, Lancet 2004; 364:937-52. geared towards better dissemination of it lowers triglycerides. It also reduces 19. Pischon T, Girman CJ, Sacks FM, et al. Non-high-density lipoprotein cholesterol and apolipoprotein B in the cholesterol-management guidelines to ASCVD risk beyond statin therapy in the providers, together with continual prediction of coronary heart disease in men. Circulation persons with LDL-C 41-100 mg/dl and 2005; 112:3375-83. feedback on their performance.43 known ASCVD or diabetes and multiple 20. Robinson JG, Wang S, Jacobson TA. Meta-analysis of risk factors.44 comparison of effectiveness of lowering apolipoprotein st st 58 Supplement to Journal of The Association of Physicians of India ■ Published on 1 of Every Month 1 November, 2020

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Conflict of Interest The following authors declare conflict of interest

Raman Puri : Boehringer Ingelheim, Novartis Vimal Mehta : Participated as principal investigator from GIPMER in FOURIER, Evolocumab in Homozygous Hypercholesterolemia, THEMIS, DAPA-HF and EMPEROR studies SS Iyengar : Reddy’s Lab, Amgen, Emcure, Glenmark, Boehringer Ingelheim, Pfzer, Mankind P Barton Duell : Esperion, Regeneron, Regenxbio, Retrophin Krishnaswami Vijayaraghavan : Amgen, Amarin, Esperion SN Narasingan : USV, Novo Nordisk, ERIS, Glenmark, Torrent, Boehringer Ingelheim, J.B. chemicals and Pharmaceuticals Devaki Nair: : Abbott Diagnostics Nathan D Wong : Research funding through institution from Amgen and Amarin, Speakers bureau for Esperion and Amarin, Research funding through institution from Novo Nordisk, Boehringer-Ingelheim, and Novartis, Consultant, Novartis and I-Health Other authors have no conflict of interest.