HDL cholesterol and cardiovascular risk 18/09/2018 HDL cholesterol and cardiovascular risk Epidemiological evidence

FRAMINGHAM: LDL, HDL AND CHD RISK 18/09/2018 FRAMINGHAM: LDL, HDL AND CHD RISK Independent risk associated with low HDL-C * Men aged 50-70 3 2 CHD risk 25 1 45 The Framingham heart study demonstrated that there was a statistically significant increase in the number of cardiovascular (CV) events in patients with low high-density lipoprotein cholesterol (HDL-C, <34 mg/dL), especially in women (p<.01).1,2 As HDL cholesterol decreases, it contributes significantly to CHD risk at all levels of low-density lipoprotein cholesterol (LDL-C).3 References 1. Kannel WB. High-density lipoproteins: epidemiologic profile and risks of coronary artery disease Am J Cardiol. 1983;52:9B-12B. 2. Wilson PWF, et al. Prediction of coronary heart disease using risk factor categories Circulation. 1998;97:1837-1847. 3. Gordon T et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62:707-714. 65 HDL-C (mg/dL) 85 100 160 220 LDL- cholesterol (mg/dL) Gordon T et al. Am J Med 1977;62:707-714.

Meta-analysis: Predictive Value of HDL Cholesterol 18/09/2018 Meta-analysis: Predictive Value of HDL Cholesterol CPPT: Coronary Primary Prevention Trial LRCF: Lipid Research Clinics Prevalence Mortality Follow-up Study MRFIT: Multiple Risk Factor Intervention Trial FHS: Framingham Heart Study 2% risk in men 3% risk in women Meta-analysis of four large prospective studies (the Framingham Study, Lipid Research Clinics Prevalence Mortality Follow-up Study, Coronary Primary Prevention Trial and Multiple Risk Factor Intervention Trial) consistently showed that for every 1 mg/dL (0.026 mmol/L) decrease in plasma levels of HDL-C there was a 2-3% increase in the risk of CHD, independent of other risk factors, including plasma LDL‑C.1 Reference 1. Gordon DJ, Probstfield JL, Garrison RJ et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8-15. 1 mg/dl decrease in HDL-C FHS, CPPT, MRFIT FHS

InterHEART: Association of AMI with Risk Factors in the World 18/09/2018 % Cont % Cases OR adj for age, sex, smoking OR adj for all ApoB/ApoA-1 20.0 33.5 3.87 3.25 Curr smoking 26.8 45.2 2.95 2.87 Diabetes 7.5 18.4 3.08 2.37 Hypertension 21.9 39.0 2.48 1.91 Abdominal obesity 33.3 46.3 2.22 1.62 Psychosocial - 2.51 2.67 Veg & fruits daily 42.4 35.8 0.70 Exercise 19.3 14.3 0.72 0.86 Alcohol Intake 24.5 24.0 0.79 0.91 All combined 129 All combined (extremes) 334 333 Findings from INTERHEART, a global case control study of heart attack involving 52 countries, imply that even in patients with low levels of LDL cholesterol, if the level of HDL cholesterol is not sufficiently high, there remains an increased risk of further cardiovascular events. This scenario can be explained on the basis of an imbalance between the deposition and removal of cholesterol in the arterial wall. Maintaining high levels of HDL cholesterol in the plasma ensures that the HDL can counter the effects of atherogenic lipoproteins and prevent or even reduce progression of atherosclerosis. Reference Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937-52. Yusuf S et al ; Lancet 2004; 364: 937

18/09/2018 Emerging Risk Factors Collaboration: first-ever outcomes, 2.79 million person-years The Emerging Risk Factors Collaboration provides the largest body of evidence supportive of HDL cholesterol as a cardiovascular risk factor. This analysis included data from 302,430 subjects without known history of coronary heart disease (CHD) from 68 prospective population-based studies. Over 2.79 million person-years of follow-up, there were 18,368 first-ever outcomes (12,785 CHD events). Reference The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993-2000 * 2,534 ischemic stroke, 513 hemorrhagic stroke and 2536 unclassified stroke ERFC. JAMA 2009;302:1993-2000

18/09/2018 Emerging Risk Factors Collaboration: Adjusted* hazard ratios for CHD risk Lipid Hazard ratio (95% CI) HDL-C 0.78 (0.74-0.82) Non-HDL-C 1.50 (1.39-1.61) TG 0.99 (0.94-1.05) Hazard ratios were calculated for 1 standard deviation higher values of triglycerides (1 SD = 0.52 loge), HDL cholesterol (15 mg/dL), non-HDL cholesterol (43 mg/dL), apolipoproteins (apo) AI or B (29 mg/dL each) and directly measured LDL cholesterol (33 mg/dL). Adjustment was made for age, sex, systolic blood pressure, smoking status, diabetes history, body mass index and lipid measures. HDL cholesterol and non-HDL cholesterol levels were strongly associated with CHD risk, albeit in opposite directions, with risk increasing in a log-linear manner, independently of each other. An increase in HDL cholesterol by 15 mg/dL was associated with 22% reduction in CHD risk. Triglyceride levels did not impact on CHD risk (hazard ratio 0.99, 95% CI 0.94-1.05). Similar associations were shown for ischaemic stroke. Reference The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993-2000 * Adjusted for age, sex, SBP, smoking, history of diabetes , BMI and lipid measures ERFC. JAMA 2009;302:1993-2000

18/09/2018 Emerging Risk Factors Collaboration: Adjusted* hazard ratios for CHD risk HDL-C Hazard ratio (95% CI) fasting 0.79 (0.74-0.84) non-fasting 0.75 (0.68-0.83) Adjusted for non-lipid factors 0.71 (0.68-0.75) Adjusted for Non-HDL-C, TG 0.78 (0.74-0.82) *Adjusted for age, sex, SBP, smoking, history of diabetes , BMI Hazard ratios were at least as strong in individuals who fasted compared with those who did not. Adjustment for lipid or non-lipid risk factors did not appear to influence hazard ratios for CHD risk. Reference The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993-2000 ERFC. JAMA 2009;302:1993-2000

Low HDL-C increases cardiovascular risk in statin-treated patients 18/09/2018 Risk of major cardiovascular events over five years (%) Meta-analysis of 14 statin studies showed that patients with a low level of HDL cholesterol (35 mg/dL or 0.9 mmol/L) had a higher risk of further cardiovascular events than control patients with high HDL cholesterol levels (42.5 mg/dL or 1.1 mmol/L). Statin treatment did not affect this excess risk.1 The CTT have recently reported an updated meta-analysis to evaluate the effect of intensive LDL cholesterol lowering on this association. Data from 170,000 individuals involved in 26 randomised trials, five which compared more versus less intensive statin treatment (n=39 612 patients), were included. In a planned subgroup analysis, the CTT showed that the risk reduction for upper versus lower HDL tertiles (>1.3 mmol/L versus 1.0 mmol/L) was similar in individuals treated with more or less intensive statin therapy. Cardiovascular risk was always lower at higher levels of achieved HDL cholesterol concentration irrespective of the level of achieved LDL-C or the intensity of statin therapy. There was no evidence of attenuation of this relationship at low LDL-C levels.2 References 1. Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78. 2. Cholesterol Treatment Trialists' Ctt 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 Nov 8. [Epub ahead of print]. HDL cholesterol (mg/dL) Baigent et al. Lancet 2005;366;1267-78

Risk of major cardiovascular events HDL cholesterol (mg/dL) 18/09/2018 High HDL-C decreases cardiovascular risk at low LDL-C (<70 mg/dL) – TNT study 39% lower risk Risk of major cardiovascular events over 5 years (%) The TNT study was designed to investigate the effect on cardiovascular risk of lowering LDL cholesterol levels to <70 mg/dL (<1.8 mmol/L). The study included 10,001 patients with stable CHD, who were randomized to either atorvastatin 80 mg/day or 10 mg/day. Patients were followed-up for a median of 4.9 years. The primary study endpoint was major cardiovascular events, defined as CHD death, non-fatal, non-procedural myocardial infarction, resuscitation after cardiac arrest or fatal or nonfatal stroke. Subgroup analyses showed that even at low levels of LDL cholesterol (<70 mg/dL), patients with HDL cholesterol levels >55 mg/dL (>1.42 mmol/L) had a 39% lower risk of major cardiovascular events than those with levels <37 mg/dL (<0.96 mmol/L) (Hazard ratio 0.61, 95%CI 0.38 to 0.97). Reference Barter PJ, Gotto AM, LaRosa JC et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-1310. _ HDL cholesterol (mg/dL) Barter P et al. N Engl J Med 2007;357:1301-1310

Major cardiovascular event frequency by LDL and HDL levels - TNT study 18/09/2018 Major cardiovascular event frequency by LDL and HDL levels - TNT study MCVE frequency (%) * The predictive power of a low HDL cholesterol in people with very low levels of LDL cholesterol remained significant even after adjusting for age and gender, smoking, hypertension, body mass index, fasting glucose, presence of diabetes, prior cardiovascular disease, on-treatment triglyceride concentration and baseline level of LDL cholesterol (p=0.03). Reference Barter PJ, Gotto AM, LaRosa JC et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007; 357:1301-1310. >100 70-100 <70 LDL-C (mg/dL) HDL-C quintile (mg/dL) * Men 50 to 70 years of age, unadjusted data Barter P et al. N Engl J Med 2007;357:1301-1310