1. Lipid Disorder Management - Evidence Based Approach…. Dr Gaurav Chaudhary MD,DM Cardiology Assistant Professsor Department of Cardiology

2. Global Health Estimates: Key figures and tables June 2014 Department of Health Statistics and Information Systems June 2014 Department of Health Statistics and Information Systems

3. Burden of CVD Is Enormous

4. Comparison of leading causes of deaths, Global, 2000 and 2012

5. The 10 Leading Causes of Death, Global, 2000 and 2012 NoCauses of death, 2000Deaths (million ) % of deaths NoCauses of death, 2012Deaths (million) % of deaths 1Ischaemic heart disease6.011.31Ischaemic heart disease7.413.2 2Stroke5.710.72Stroke6.711.9 3Lower respiratory infections3.56.63COPD3.15.6 4COPD3.15.84Lower respiratory infections3.15.5 5Diarrhoeal diseases2.24.15Trachea, bronchus, lung cancers 1.62.9 6HIV/AIDS1.73.26HIV/AIDS1.52.8 7Tuberculosis1.32.57Diarrhoeal diseases1.52.7 8Prematurity1.32.58Diabetes mellitus1.52.7 9Trachea, bronchus, lung cancers 1.22.29Road injury1.32.3 10Diabetes mellitus1.02.010Hypertensive heart disease1.12.0 11Prematurity1.12.0 12Road injury1.01.9 13 Tuberculosis0.91.7 16Hypertensive heart disease0.81.6 1.4 crore deaths due to CVD

6. How was correlation established between dyslipidemia and CAD  The German Pathologist Rudolf Virchow described lipid accumulation in arterial wall (1910 )  Nikolai Anitschkow showed that rabbits fed on cholesterol developed lesions in their arteries similar to atherogenesis in 1913

7. Thirteen Nobel Prizes have been awarded to scientists who devoted major parts of their careers to cholesterol research.

8. Doi H et al. Circulation 2000;102:670-676 Colome C et al. Atherosclerosis 2000;149:295-302 Cockerill GW et al. Arterioscler Thromb Vasc Biol 1995;15:1987-1994 HDLLDL Chylomicrons, VLDL, and their catabolic remnants > 30 nm20–22 nm Potentially pro-inflammatory 9–15 nm Potentially anti-inflammatory Lipoprotein Classes Bad Good

10. Penicillium citrinum 1976 Mevastatin from Penicillinum citrinum

11. Management of lipids :chronology SHORT HISTORY 1965 -74– CDP – Niacin was used 1973- CPPT - Cholestyramine was used 1976 Mevastatin from Penicillinum citrinum 1980 Mevinolin from Aspergillus terreus 1987 FDA approves Lovastatin 1988 Lovastatin not effective in FH homozygotes 1995 Pravastatin decreases heart transplant rejection and mortality independently of lowering cholesterol levels

12. 12 What was the approach till 2 year back …….

13. 13 Risk CategoryLDL-C GoalInitiate TLC Consider Drug Therapy High risk: CHD or CHD risk equivalents (10-year risk >20%) <100 mg/dL (optional goal: <70)  100 mg/dL >100 mg/dL (<100 mg/dL: consider drug options) Moderately high risk: 2+ risk factors* (10-year risk 10% to 20%) <130 mg/dL (optional goal: <100)  130 mg/dL >130 mg/dL (100-129 mg/dL: consider drug options) Moderate risk: 2+ risk factors* (10 year risk <10%) <130 mg/dL  130 mg/dL >160 mg/dL Lower risk: 0-1 risk factor* <160 mg/dL  160 mg/dL >190 mg/dL (160-189 mg/dL: LDL- lowering drug optional) Grundy S et al. Circulation 2004;110:227-39 ATP III LDL-C Goals and Cut-points for Drug Therapy ATP=Adult Treatment Panel, CHD=Coronary heart disease, LDL-C=Low-density lipoprotein cholesterol, TLC=Therapeutic lifestyle changes *Risk factors for CHD include: cigarette smoking, hypertension (blood pressure >140/90 mmHg or on antihypertensive medication, HDL-C 60 mg/dl is a negative risk factor), family history of premature CHD, age >45 years in men or >55 years in women

14. 14 YearsPoints 20-34-9 35-39-4 40-440 45-493 50-546 55-598 60-6410 65-6911 70-7412 75-7913 Step 1: Age Points TC (mg/dl) Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 <16000000 160-19943210 200-23975310 240-27996421 >280118531 Framingham Risk Score: Men Step 2: Total Cholesterol Points HDL-C (mg/dl)Points >60 50-590 40-491 <402 Step 3: HDL-C Points SBP (mmHg) If untreated If treated <12000 120-12901 130-13912 140-15912 >16023 Step 4: SBP Points Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 Nonsmoker00000 Smoker85311 Step 5: Smoking Status Points Age Total Cholesterol HDL-C Systolic Blood Pressure Smoking Status Point Total Step 6: Sum of Points Point Total 10-year Risk Point Total 10-year Risk Point Total 10-year Risk <0<1%62%1312% 01%73%1416% 11%84%1520% 21%95%1625% 31%106%>17>30% 41%118% 52%1210% Step 7: 10-year CHD Risk

15. 15 Level (mg/dl)Classification <200Desirable 200-239Borderline High >240High Level (mg/dl)Classification <40Desirable 40-50Borderline High >50High Level (mg/dl)Classification <150Normal 150-199Borderline High 200-499High >500Very High ATP III Classification of Other Lipoprotein Levels Total CholesterolHDL-Cholesterol Triglyceride Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-97

16. FOCUS ON LDL GOALS Management of hyperlipedemia - Till 2013

17. Drammatic change in New guidelines ….

18. 2001 -----------------------------------------------------------2013

19. What is new in this guideline  Do not recommend targeting LDL goals or non-HDL goals (secondary as well as primary prevention)  Suggest and specified groups who benefit from either high or moderate intensity statin therapy  Non statin therapies( Ezetimibe,fibrates,Niacin) do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD

20. Four statin groups: The ASCVD risk reduction clearly outweighs the risk of adverse events in individuals 1) With Clinical ASCVD (ACS; history of MI, stable or unstable angina, coronary revascularization, stroke, or TIA presumed to be of atherosclerotic origin, and peripheral arterial disease or revascularization) 2 ) Primary elevations of LDL–C >190 mg/dL 3) Diabetes aged 40 to 75 years with LDL–C 70 to 189 mg/dL and without clinical ASCVD 4) Without clinical ASCVD or diabetes with LDL–C 70 to 189 mg/dL and estimated 10-year ASCVD risk >7.5%

21. What is Clinical ASCVD Defined by the inclusion criteria for the secondary prevention statin RCTs  Acute coronary syndromes  History of MI,  Stable or unstable angina,  Coronary or other arterial revascularization  Stroke  TIA  Peripheral arterial disease presumed to be of atherosclerotic origin).

22. Primary and Secondary prevention trials reducing CV events by fix dose combinations irrespective of LDL levels

23. Primary prevention trials :  The Expert Panel did not find any RCTs that evaluated titration of all individuals in a treatment group to specific LDL–C targets <100 mg/dL or <70 mg/dL  Nor were any RCTs comparing 2 LDL–C treatment targets identified. No trials reported on-treatment non-HDL–C levels

24. Years Major CV Event* (%) 0123456 P<0.001 22% RRR Treating to New Targets (TNT) Trial Atorvastatin (10 mg) Atorvastatin (80 mg) CHD=Coronary heart disease, CV=Cardiovascular, MI=Myocardial infarction, RRR=Relative risk reduction HMG-CoA Reductase Inhibitor: Secondary Prevention LaRosa JC et al. NEJM 2005;352:1425-35 *Includes CHD death, nonfatal MI, resuscitation after cardiac arrest, or stroke 0.00 0.05 0.10 0.15 10,001 patients with stable CHD randomized to atorvastatin (80 mg) or atorvastatin (10 mg) for 4.9 years High-dose statins provide benefit in chronic CHD

25. CTT 2010 — Meta analysis of secondary prevention 26 trials  Statin therapy reduced the RR for CVD events by approximately 21% per 1 mmol/L (38.7 mg/dL) LDL–C reduction  This relationship was similar for more intensive compared with less intensive statin therapy and for statin therapy compared with placebo/control

26. Primary Prevention in Individuals with Diabetes  In adults aged 40 to 75 years with diabetes and >1 risk factor  Fixed moderate-dose statin therapy that achieved a mean LDL–C 72 mg/Dl  Reduced the RR for CVD by 37% (in this trial LDL– C was reduced by 46 mg/dL or 39%) CARDS trial, multicentre randomised placebo-controlled trial. Lancet 2004;364:685–96.

27. Meta analysis ( primary and secondary prevention trials)  CTT meta-analyses have shown that each 39 mg/dL reduction in LDL–C with statin therapy  Reduced ASCVD events by 22%  The relative reductions in ASCVD events were consistent across the range of LDL–C levels Cholesterol Treatment Trialists Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta- analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670–1681.

30. How to assess risk score … Global Risk Assessment for Primary Prevention This guideline recommends use of the new Pooled Cohort Equations to estimate 10-year ASCVD risk in both white and black men and women By more accurately identifying higher risk individuals for statin therapy, the guideline focuses statin therapy on those most likely to benefit Before initiating statin therapy, this guideline recommends a discussion by clinician and patients.

31. How to calculate 10-year and lifetime risk for ASCVD  Not a difficult job !!!  A downloadable spreadsheet enabling estimation of 10-year and lifetime risk for ASCVD and a web- based calculator from My.americanheart.org/cvriskcalculator and http://www.cardiosource.org/science-and- quality/practice-guidelines-and-quality- standards/2013-prevention-guideline-tools.aspx.

32. Variables in new pooled cohort equations

34. Case Based Approach …….

35. Case 1  50 yr female, house wife,lipid parameters  Total chol 260  LDL 160  HDL 42  TG 180  10 Yr risk ---------1.8 %

36. Case 2  71 yr male,retired executive,Non hypertensive,lipid parameters  Total chol 170  HDL 50  TG 146  Risk sore 10 yr ----------14.3 %

37. Case 3  55 yr male,hypertensive controlled on treatment,lipid parameters  Total chol 150  HDL 40  TG 168  10 YR risk score ------- 5.9 %

38. Case 4  64 yr male,retired executive,smoker hypertensive,lipid parameters  Total chol 240  HDL 38  TG 146  Risk sore 10 yr ----------26. %

39.  60 yr male,Buisnessman, hypertensive uncontrolled on treatment,lipid parameters  Total chol 178  HDL 42  TG 110  Risk sore 10 yr ----------19.7 %

40. Safety................ Dr.Sarma@works40 Monitoring and Safety concerns …

41. Monitoring  Recommends the use of an initial fasting lipid panel (total cholesterol, triglycerides, HDL–C, and calculated LDL–C)  Followed by a second lipid panel 4 to 12 weeks after initiation of statin therapy, to determine a patient’s adherence.  Thereafter, assessments should be performed every 3 to 12 months as clinically indicated

42. Statin induced Diabetes mellitus  Statins use is associated with an excess risk of new onset diabetes in RCTs and meta- analyses of RCTs (i.e., 0.1 excess case per 100 individuals treated 1 year with moderate-intensity statin therapy  And 0.3 excess cases per 100 individuals treated for 1 year with high-intensity statin therapy.

43. Conclusion..  These recommendations arose from careful consideration of an extensive body of higher quality evidence derived from RCTs and systematic reviews and meta-analyses of RCTs.  Rather than LDL–C or non-HDL– C targets, this guideline used the intensity of statin therapy as the goal of treatment.  Through a rigorous process, 4 groups of individuals were identified for whom an extensive body of RCT evidence demonstrated a reduction in ASCVD events with a good margin of safety from moderate- or high-intensity statin therapy:

44. Four statin groups: The ASCVD risk reduction clearly outweighs the risk of adverse events in individuals 1) With Clinical ASCVD (ACS; history of MI, stable or unstable angina, coronary revascularization, stroke, or TIA presumed to be of atherosclerotic origin, and peripheral arterial disease or revascularization) 2 ) Primary elevations of LDL–C >190 mg/dL 3) Diabetes aged 40 to 75 years with LDL–C 70 to 189 mg/dL and without clinical ASCVD 4) Without clinical ASCVD or diabetes with LDL–C 70 to 189 mg/dL and estimated 10-year ASCVD risk >7.5%

45. Recommended Schedule for Screening Tests Recommended Screenings  Blood pressure 20 yrs of age Each regular healthcare visit or at least once every 2 years if blood pressure is less than 120/80 mm Hg  Serum Cholesterol 20 yrs of age  Blood glucose test 45 yrs of age Every 3 years Age 45  Discuss smoking, physical activity, diet Each regular healthcare visit - Age 20 AHA 2013 screening recommendations

46. Thank you …… Thank You