1. HDL cholesterol and cardiovascular risk Epidemiological evidence

2. FRAMINGHAM: LDL, HDL AND CHD RISK Independent risk associated with low HDL-C
The Framingham heart study demonstrated that there was a statistically significant increase in the number of coronary heart disease (CHD) events in individuals with low high-density lipoprotein cholesterol (HDL-C, <34 mg/dL). This was especially evident in women (p<.01).1,2 As HDL-C 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:
3. Gordon T et al. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62:
Men aged years
Gordon T et al. Am J Med 1977;62:

3. 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.
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.
2%  in risk for men
1 mg/dL  in HDL-C
3%  in risk for women

4. InterHEART: Global Study Association of AMI with Risk Factors
% Cont % Cases
OR adj for age, sex, smoking
OR adj for all
ApoB/ApoA-1
20.0
33.5
3.87
3.25
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:
Yusuf S et al ; Lancet 2004; 364: 937

5. Total cases (n=18,368) Non-fatal MI (n=8,857) CHD Death (n=3,928)
Emerging Risk Factors Collaboration: First-ever outcomes, million person-years
Total cases (n=18,368)
Non-fatal MI (n=8,857)
CHD Death (n=3,928)
Stroke* (n=5,583)
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:
*2,534 ischemic stroke, 513 hemorrhagic stroke and 2,536 unclassified stroke.
ERFC. JAMA 2009;302:

6. Emerging Risk Factors Collaboration: Adjusted
Emerging Risk Factors Collaboration: Adjusted* hazard ratios for CHD risk
Lipid
Hazard ratio
(95% CI)
HDL-C
0.78
( )
Non-HDL-C
1.50
( ) TG
0.99
( )
Hazard ratios were calculated per 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 ) after adjustment.
Similar associations were shown for ischaemic stroke.
Reference
The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:
* Adjusted for age, sex, systolic BP, smoking, history of diabetes, BMI and lipids
ERFC. JAMA 2009;302:

7. Emerging Risk Factors Collaboration: Adjusted
Emerging Risk Factors Collaboration: Adjusted* hazard ratios for CHD risk
HDL-C
Hazard ratio
(95% CI)
fasting
0.79
( )
non-fasting
0.75
( )
Adjusted for non-lipid factors
0.71
( )
Adjusted for Non-HDL-C, TG
0.78
( )
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:
* Adjusted for age, sex, SBP, smoking, history of diabetes, BMI and lipid measures.
ERFC. JAMA 2009;302:

8. Low HDL-C increases cardiovascular risk in high-risk statin-treated patients
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= 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 participants in 14 randomised trials of statins. Lancet 2005;366:
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;376:
Baigent et al. Lancet 2005;366;

9. High HDL-C decreases cardiovascular risk at low LDL-C (<70 mg/dL) – TNT study
39% lower risk
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:
Barter P et al. N Engl J Med 2007;357:

10. Major cardiovascular event frequency by LDL and HDL levels - TNT study
The predictive power of a low HDL cholesterol plasma level 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:
* Men 50 to 70 years of age, unadjusted data.
Barter P et al. N Engl J Med 2007;357: