Does It Matter How You Lower LDL or How You Raise HDL?

Does It Matter How You Lower LDL or How You Raise HDL? Thomas P. Bersot, M.D., Ph.D. Gladstone Institute of Cardiovascular Disease UCSF 25 th Annual Advances in Heart disease 12 December 2008 Disclosures: Research and educational grants, consulting and promotional speaking for Abbott, AstraZeneca, Merck, Merck Schering-Plough, Pfizer, GSK 2

Does It Matter How Whether You Lower LDL or How You Raise HDL? Thomas P. Bersot, M.D., Ph.D. Gladstone Institute of Cardiovascular Disease UCSF 25 th Annual Advances in Heart disease 12 December 2008 Disclosures: Research and educational grants, consulting and promotional speaking for Abbott, AstraZeneca, Merck, Merck Schering-Plough, Pfizer, GSK 3

Prevalence of Abnormal Levels of LDL-C and HDL-C in 8,500 CHD Patients* LDL-C > 130 mg/dl - 58 % HDL-C < 40 mg/dl - 67 % LDL-C < 130mg/dL & - 29 % HDL-C < 40 mg/dl * Distribution of Lipids in 8,500 Men with Coronary Artery Disease. Rubins HB et al., Am J Cardiol 75: 1196-1201 (1995) 4

Hazard Ratios of Future CHD Events in 15,652 Healthy Women (Highest vs. Lowest Quintiles of Each Variable) Ridker, P. M et al. JAMA 2005;294:326-333. Copyright restrictions may apply. 7

Relating Lipid Changes to CHD Risk Reductions Reduction in Total Cholesterol R 2 =0.55 Reduction in LDL Cholesterol R 2 =0.53 Reduction in Triglyceride R 2 =0.45 Increase in HDL Cholesterol R 2 =0.65 Reduction in Non-HDL C R 2 =0.65 Reduction in TC/HDL C R 2 =0.86 Meta-analysis by A. Alsheik-Ali, HM Abourjally, E Stanek, M McGovern, JT Kuvin, and RH Karas, Tufts-New England Medical Ctr, Boston, Abstract presented at AHA 2004, based on 3,869 CHD events occurring in 44,170 subjects participating in randomized placebo controlled lipid intervention trials-hhs, FATS, HATS, 4S, WOSCOPS, LIPID, AFCAPS/TEXCAPS, VA-HIT, BIP, DAIS, HPS, PROSPER, ALL-HAT-LLT, ASCOT-LLA 8

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159 98 28 5.6 161 mg/dl 269 189 48 5.6 12

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159 98 28 5.6 161 mg/dl 269 189-119=70 48 5.6 13

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159 99 28 5.6 161 mg/dl 269-119=150 189-119=70 48 5.6 14

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159 99 28 5.6 161 mg/dl 269-119=150 189-119=70 48 5.6 3.1 15

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159 99-29=70 28 5.6 161 mg/dl 269-119=150 189-119=70 48 5.6 3.1 16

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159-29=130 99-29=70 28 5.6 161 mg/dl 269-119=150 189-119=70 48 5.6 3.1 17

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159-29=130 99-29=70 28 5.6 4.6! 161 mg/dl 269-119=150 189-119=70 48 5.6 3.1 18

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159-29=130 99-29=70 28 5.6 4.6 3.0 161 mg/dl 269-119=150 189-119=70 48 5.6 3.1 19

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159-29=130 99-29=70 28 5.6 4.6 3.0 161 mg/dl 269-119=150 189-119=70 48 5.6 3.1 20

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159-29=13084 99-29=70 28 5.6 4.6 3.0 161 mg/dl 269-119=150 189-119=70 48 5.6 3.1 21

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159-75=13084 99-29=70 28 5.6 4.6 3.0 161 mg/dl 269-119=150 189-119=70 48 5.6 3.1 22

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159-75=13084 99-2875=24 28 5.6 4.6 3.0 161 mg/dl 269-119=150 189-119=70 48 5.6 3.1 23

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C 161 mg/dl 159-75=13084 99-2975=24 28 5.6 4.6 3.0 161 mg/dl 269-119=150 189-119=70 48 5.6 3.1 24

Two CHD Patients, 64 y.o. LDL-C Goal < 70 mg/dl Pt. 1 Pt. 2 Triglycerides Total Chol LDL-C HDL-C TC/HDL-C % LDL-C 161 mg/dl 159-75=13084 99-2875=24 28 5.6 4.6 3.0 75/99=76 % 161 mg/dl 269-119=150 189-119=70 48 5.6 3.1 119/189=63% 25

Absolute values of LDL-C and HDL-C are less important than their relationship to each other as assessed by ratios Total cholesterol/hdl-c LDL-C/HDL-C Apolipoprotein B / apolipoprotein AI 27

Does It Matter How You Lower LDL or How You Raise HDL? LDL getting to goal is important, but how you get there (i.e. which medicines you use) is not. STATIN FIRST (more evidence). HDL raising HDL-C can be dangerous (consider estrogen and the cholesterol ester transfer protein inhibitor, torcetrapib). For every new drug that raises HDL-C a mortality and morbidity outcomes trial will be required to establish efficacy and safety. 28

Pleiotropic Effects of Statins: Benefit Beyond Cholesterol Reduction?* Meta-analysis of 5 diet, 3 bile acid sequestrant, 1 partial ileal bypass surgery and 10 statin trials. 81,859 subjects 3 or more years of follow-up (most 5 years) Uniform primary outcome: CHD death or nonfatal myocardial infarction * Robinson J et al., J Am Coll Cardiol 46: 1855-1862 (2005) 29

Pleiotropic Effects of Statins: Benefit Beyond Cholesterol Reduction? * Result: no difference in the relationship of CHD event reduction and LDL-C reduction irrespective of how LDL-C was lowered. Conclusion: statin benefit is almost entirely due to lowering of LDL-C. The putative clinical benefit of the Pleiotropic effects of statins requires further study. * Robinson J et al., J Am Coll Cardiol 46: 1855-1862 (2005) 30

Raising HDL-C Niacin - up to 30% Statins, fibrates - 5-10% Exercise - dose related (HDL-C varied from 47 to 56 mg/dl in healthy men running 0 to 31 miles weekly*) Ethanol up to 20 %; dose dependent Saturated fat restriction lowers HDL-C * Miles run per week and HDL cholesterol levels in healthy, middle-aged men. Arch Int Med 155: 415-420 (1995) 32

Characteristics of People with Lowest Risk of Heart Attack (Framingham Heart Study) LDL-C= 100-129 mg/dl BP < 120/80 (no HTN rx)* HDL-C>60 mg/dl* non-diabetic* non-smoker * Not too common in the overweight or obese Wilson et. al. Circ. 97:1837-47 (1998) 34

The Singing Lipidologist 35

Scientific Sessions 05 Dallas, Texas Mammas don t let your babies grow up to be couch girls (orchow boys ) (Apologies and thanks to Waylon and Willie) 36

Couch girls like restin an takin things easy and such. They never sweat or exercise much. By the time they re fifty with knees and hips creaky, they mostly stay in one place. An when they do travel they drive the ol pickup to Walmart s closest handicapped space. 37

Mammas, don t let your babies grow up to be Couch girls. Walkin with em s better than givin em pearls. Mammas, don t let your babies grow up to be Couch girls. Give em a sports bra, sneakers an shorts and tell em about Title IX sports! 41

Chow boys ain t easy to feed right and become hard to hold. They d rather eat greasy than live to be old. Lonestar belt buckles on overstretched levis get tighter and tighter each day, til a plaque ruptures and he dies young - to boot hill you ll haul him away! 45

Mammas, don t let your babies grow up to be Chow boys, Don t feed im those steaks an burgers an chips- his belly will swell til he can t see his hips! Mammas, don t let your babies grow up to be Chow boys Before he turns fifty he ll turn in his 6- gun- for syringes and vials of ins lun. 49

Mammas, don t let your babies grow up to be Chow boys, Don t feed im those steaks an burgers an chips- his belly will swell til he can t see his hips! Mammas, don t let your babies grow up to be Chow boys! Before he turns fifty he ll turn in his 6- gun- for syringes and vials of ins lun. 51

Mammas, don t let your babies grow up to be Chow boys, Don t feed im those steaks an burgers an chips- his belly will swell til he can t see his hips! Mammas, don t let your babies grow up to be Chow boys, Before he turns fifty he ll turn in his 6- gun- for syringes and vials of ins lun. 52

Waylon, Johnny and Willie may think my song silly, but only one s alive. Waylon and Johnny, obese diabetics, aren t the ones who survive. Its 73 year old Willie, a karate black belt who s skinny, who ll see his ninth decade arrive. Farm fresh food, a slug of bourbon or two, its what makes him thrive. 53

Waylon, Johnny and Willie may think my song silly, but only one s alive. Waylon and Johnny, obese diabetics, aren t the ones who survive. Its 77 year old Willie, a karate black belt who s skinny, who ll see his ninth decade arrive. Farm fresh food, a slug of bourbon or two, its what makes him thrive. 54

Mammas, don t let your babies grow up an have MI s. Feed em veggies, fruit, chicken an fish, an don t give in to any fast food wish. Mammas, don t let your babies grow up an have MI s, Walk, swim, run with em- whatever it takes, If Dad does it, too, Viagra s a drug he can forsake! 57

Mammas, don t let your babies grow up an have MI s Feed em veggies, fruit, chicken an fish, an don t give in to any fast food wish. Mammas, don t let your babies grow up an have MI s, Walk, swim, run with em- whatever it takes, If Dad does it, too, Viagra s a drug he can forsake! 58