Dr G R Letchuman. Clogged by Cholesterol

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1 Dr G R Letchuman Clogged by Cholesterol

2 Main message Cholesterol management is all about reducing risk of CV events vs the side effects, hassle and cost of drugs News that it is no longer important to avoid high cholesterol in the diet is not the same as reducing risk of CV events by drug treatment in high risk patients Every health care provider is responsible for the management of his/her unique patient based on evidence, preference, compliance, cost, side effects & respect for patient autonomy. Shared decision. Mutual respect.

4 Content 1. What is already well known? 2. Misconceptions 3. Understanding lipid metabolism 4. How low should you go? 5. Improving compliance

5 Content 1. What is already well known? 2. Misconceptions 3. Understanding lipid metabolism 4. How low should you go? 5. Improving compliance

6 What is already well known: NCVD-ACS Registry ( ) % had at least one established CV risk factor hypertension (65%), dyslipidaemia (37%) and/or diabetes (46%). National Health and Morbidity survey % of the adult population has hypercholesterolaemia. Atherosclerosis affects the entire vascular tree. However, evidence for a causal link is strongest for CVD.

7 INTERHEART Study: Case-control study by Salim Yusuf

8 INTERHEART: Focus on 9 risk or protective factors Design Participants Objective Large international case-control study 12,461 cases; 14,637 controls; 52 countries To determine association of first MI with: Smoking Lipids Hypertension Diabetes Obesity Diet Physical Alcohol Psychosocial activity consumption factors* Follow-up 4 years, February 1999 March 2003 *eg, stress, depression Yusuf S et al. Lancet. 2004;364:

9 INTERHEART: ApoB-ApoA1 ratio Graded relation to MI risk, no evidence for a threshold 8 Odds ratio for 1st MI (99% CI) ApoB-ApoA1 ratio (deciles) Number of controls Number of cases Median Note: odds ratio plotted on a doubling scale Yusuf S et al. Lancet. 2004;364:

10 INTERHEART: Impact of multiple risk factors on CV risk Odds ratio for 1st MI (99% CI) Smk (1) DM (2) Smk = smoking DM = diabetes HTN = hypertension Obes = obesity Ps = psychosocial factors Note: odds ratio plotted on a doubling scale HTN (3) ApoB- ApoA1 (4) All 4 All 4 + Obes All 4 + Ps All risk factors Yusuf S et al. Lancet. 2004;364:

11 INTERHEART: Association of risk factors with acute MI in women and men Risk factor Current smoking Diabetes Hypertension Abdominal obesity Psychosocial index Fruits/Vegetables Exercise Alcohol ApoB-ApoA1 ratio Gender F M F M F M F M F M F M F M F M F M Adjusted for age, sex, geographic region Note: odds ratio plotted on a doubling scale Odds ratio (99% CI) Yusuf S et al. Lancet. 2004;364:

12 INTERHEART: Clinical implications 9 simple and modifiable risk factors are strongly associated with acute MI worldwide. These 9 risk factors account for >90% of the PAR globally and in most regions. Abnormal ApoB-ApoA1 ratio and smoking are the 2 most important risk factors and account for over two thirds of the PAR. PAR = population attributable risk Apo = apolipoprotein Yusuf S et al. Lancet. 2004;364:

What is already well known: In a meta-analysis of 27 randomized trials and 174,000 participants, for every 1 mmol/ L (~40 mg/dl) LDL-C reduction with statin therapy, the relative risk of major

13 What is already well known: In a meta-analysis of 27 randomized trials and 174,000 participants, for every 1 mmol/ L (~40 mg/dl) LDL-C reduction with statin therapy, the relative risk of major adverse cardiovascular events is reduced by ~20-25%, and all-cause mortality is reduced by 10%. More intense statin regimens yield a 15% further proportional reduction Relative reductions are similar in primary vs. secondary prevention, lower vs. higherrisk, men vs. women Lancet. 2015;385:

Atherosclerosis Timeline 1 Foam Cells Fatty Streak Intermediate Lesion Atheroma Fibrous Plaque Complicated Lesion/Rupture From first decade Endothelial Dysfunction From third

14 Atherosclerosis Timeline 1 Foam Cells Fatty Streak Intermediate Lesion Atheroma Fibrous Plaque Complicated Lesion/Rupture From first decade Endothelial Dysfunction From third decade From fourth decade Growth mainly by lipid accumulation Smooth muscle and collagen Thrombosis, hematoma Azhari Rosman Adapted from Stary HC et al. Circulation 1995;92:

15 Comparing cost effectiveness of different interventions Measured by Quality Adjusted Life Year (QALY) Saved

18 Content 1. What is already well known? 2. Misconceptions 3. Understanding lipid metabolism 4. How low should you go? 5. Improving compliance

19 Misconception 1: Cholesterol restriction is no longer needed U.S. Department of Health and Human Services and U.S. Department of Agriculture Dietary Guidelines for Americans. 8 th Edition. December The previous restriction of 300 milligram daily limit of cholesterol was removed. This was picked upon but the following was conveniently left out

Misconception 1: Cholesterol restriction is no longer needed Eat as little dietary cholesterol as possible because food that are high in cholesterol are also high

20 Misconception 1: Cholesterol restriction is no longer needed Eat as little dietary cholesterol as possible because food that are high in cholesterol are also high in SFA (e.g. fatty meats and high-fat diary product) Limit sugar, SF, trans-fat and salt Restrict added sugar to < 10% of calories - For a 55 kg person =1 can of coke

Misconception 2: Interventional cardiology is most important to reduce morbidity in all cases In stable angina, all studies have shown that it is

21 Misconception 2: Interventional cardiology is most important to reduce morbidity in all cases In stable angina, all studies have shown that it is medical therapy that reduces CV events. Invasive intervention does not reduce mortality. For long term symptom relief & in ACS, invasive therapy is needed

Coronary Artery Disease: Nature of the Problem

lipid, Fibrosis, Ca ++ Vulnerable Plaque Minor

Thin cap Both types of lesions are inevitably

any point in time Exertional Angina, (+) ETT

22 Coronary Artery Disease: Nature of the Problem Severe Fibrotic Plaque Severe obstruction, No lipid, Fibrosis, Ca ++ Vulnerable Plaque Minor obstruction, Eccentric plaque, Lipid pool, Thin cap Both types of lesions are inevitably present within the same stable CAD patient at any point in time Exertional Angina, (+) ETT Plaque Rupture Acute MI, Unstable Angina, Sudden death

23 THE PROBLEM: Major Cardiac Events Occur in Non-Target Lesions Following Successful PCI Hazard Rate (%) Non-Target Lesion Event Rates: 12.4% Year % Year Year 1 Year 2 Year 3 Year 4 Year 5 Target Lesion Event Non-target Lesion Event (Cutlip, et al. Circulation 2004;110:1226) 5 year Followup of 1228 Patients Treated with Bare Metal Stents

24 Content 1. What is already well known? 2. Misconceptions 3. Understanding lipid metabolism 4. How low should you go? 5. Improving compliance

25 Density of lipoprotein increases with increasing protein and cholesterol content and decreasing triglyceride content Types: -Chylomicrons -VLDL -IDL -LDL -HDL

26 Lipoprotein Chylomicrons VLDL LDL HDL Function Transports dietary TG and cholesterol from intestines to tissues and liver Transports TG from liver to tissues Delivers cholesterol into cells Transports cholesterol accumulating in blood vessels to liver Apoprotein apob-100, apoa-1, etc. Function Involved in uptake of specific lipoproteins

29 Content 1. What is already well known? 2. Misconceptions 3. Understanding lipid metabolism 4. How low should you go? 5. Improving compliance

30 Misconception 3: Plasma cholesterol should not be reduced because it is an essential component of cell membrane and for production of hormones and bile acids. On the other hand, some argue that LDL-C levels of 1.3 to 1.8 mmol/l are physiologically normal in man. O Keefe Jr JH et al. J Am Coll Cardiol. 2004;43: Symptomatic CHD is uncommon in populations with very low levels of serum cholesterol throughout their life (TC < 3.9 mmol/l or LDL-C < 2.6 mmol/l). Keys ABCambridge, Mass: Harvard University Press; 1980.; Circulation. 1992;85: There is overwhelmingly good evidence that reducing plasma cholesterol levels in those with high risk of CV events saves lives.

31 How low should you go? Cholesterol Lowering Can Reduce Mortality: Results of a Meta-Analysis Karol E. Watson, MD, PhD, FACC Navarese EP et al. JAMA 2018 Apr trials of more- vs less-intensive lipidlowering All-cause mortality lower with moreintensive vs less 7.08% vs. 7.70% (rate ratio, 0.92). Lower mean baseline LDL levels were associated with a smaller magnitude Mortality improvement occurs only when baseline LDL is over 2.6 mmol/l

32 What is a high risk lipid level and what to measure? Dyslipidaemia has been well established as a CV risk factor. It refers to the following lipid levels: - TC > 5.2 mmol/l - HDL-C < 1.0 mmol/l (M), < 1.2 mmol/l (F) - TG > 1.7 mmol/l - LDL-C levels - will depend on the patient s CV risk Trials have consistently shown that reducing TC and LDL-C reduces vascular risk and prevents CVD. LDL-C is the primary target of therapy.

33 What is a high risk lipid level and what to measure? Measurement of Non-HDL-C: Non-HDL-C (mmol/l) = TC HDL-C Estimates the VLDL, VLDL remnants,idl, LDL-C and lipoprotein(a) {Lp(a)}) Used to evaluate CV risk when TG is > 4.5 mmol/ If non-hdl-c is used as a treatment target, the value is 0.8 mmol/l higher than the corresponding LDL-C target level.

34 What is severe dyslipidemia? Severe dyslipidemia - LDL cholesterol level, 5 mmol/l might have familial hypercholesterolemia (FH)

35 Secondary causes of hyperlipidemia Increased Cholesterol: Obstructive liver disease / Primary Biliary Cirrhosis Hypothyroidism Nephrotic Syndrome Increased TG: Cushing s syndrome Alcoholism Insulin resistance states - T2DM and metabolic syndrome.

36 How low to go? The 2015 edition Malaysian CPG on Management of Dyslipidaemia clearly spells out the targets for different groups of patients. For very high-risk patients target LDL should be < 1.8 and those with high risk it should be < 2.6 mmol/l.

37 Content 1. What is already well known? 2. Misconceptions 3. Understanding lipid metabolism 4. How low should you go? 5. Improving compliance

38 Improving Compliance Noncompliance usually discovered by asking patients to bring back all medications. Explain to patients the two basic mechanisms playing out in ischaemic heart disease. It is important to know that unstable plaques of all sizes can rupture and not just the bigger ones. Angioplasty is only performed on obstructive lesions but reducing LDL would stabilize throughout the arterial system. Knowing this, patients may be motivated to be compliant with their statins and antihypertensive medication.

39 Improving Compliance Common problem with statin therapy: myalgia Withhold statin for a few days to gauge resolution of symptoms and then rechallenge for recurrence of symptoms to ensure that statin is the culprit If it is - use a lower dose - use the statin on alternate days - change to different statin - change to different anti-lipid drug

40 Improving Compliance The difference in the values between a fasting and non-fasting sample is small and has been shown to have no impact on CV risk estimation. This may make it easier for patients as it would not be necessary for all of them to join long early morning queues.

41 Improving Compliance Adjust drugs to be convenient to the patient. Since cholesterol is biosynthesized in the early morning hours, statins with shorter half-lives (lovastatin 2 hours, simvastatin <5 hours, and fluvastatin <3 hours) should be administered in the evening. In contrast, statins with longer half-lives (atorvastatin 14 hours, rosuvastatin 19 hours, and pravastatin 22 hours) can be administered during the day.

42 We talked about: 1. What is already well known? 2. Misconceptions 3. Understanding lipid metabolism 4. How low should you go? 5. Improving compliance

Main message Cholesterol management is all about reducing risk of CV events vs the side effects, hassle and cost of drugs News that it is no longer important to avoid high cholesterol in the diet is

43 Main message Cholesterol management is all about reducing risk of CV events vs the side effects, hassle and cost of drugs News that it is no longer important to avoid high cholesterol in the diet is not the same as reducing risk of CV events by drug treatment in high risk patients Every health care provider is responsible for the management of his/her unique patient based on evidence, preference, compliance, cost, side effects & respect for patient autonomy. Shared decision. Mutual respect.

44 Thank you

45 Dr G R Letchuman Clogged by Cholesterol

46 HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, officially abbreviated HMGCR) is the rate-controlling enzyme (NADHdependent, EC ; NADPH-dependent, EC ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids. Normally in mammalian cells this enzyme is suppressed by cholesterol derived from the internalization and degradation of low density lipoprotein (LDL) via the LDL receptor as well as oxidized species of cholesterol. Competitive inhibitors of the reductase induce the expression of LDL receptors in the liver, which in turn increases the catabolism of plasma LDL and lowers the plasma concentration of cholesterol, which is considered, by those who accept the standard lipid hypothesis, an important determinant of atherosclerosis. [5] This enzyme is thus the target of the widely available cholesterol-lowering drugs known collectively as the statins. HMG-CoA reductase is anchored in the membrane of the endoplasmic reticulum

48 PCSK9 - Proprotein convertase subtilisin/kexin type 9 is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins.

Pathophysiology of Lipid Disorders

Pathophysiology of Lipid Disorders Henry Ginsberg, M.D. Division of Preventive Medicine and Nutrition CHD in the United States CHD is the single largest killer of men and women 12 million have history