Table 5.

Evidence supporting the contention that elevated LDL-C, elevated fasting or non-fasting TRL and their remnants, and subnormal HDL-C alone and/or together play causal roles in CVD

Type of evidence	Elevated LDL-C	Elevated TRL, their remnants or low HDL-C
Human epidemiology	Direct association between LDL-C and CVD in numerous studies	Direct association between TG and CVD in numerous studies; association lost on correction for non-HDL-C and HDL-C in ERFC93
		Strong inverse association between low HDL-C and CVD in numerous studies; association maintained after correction for TG and non-HDL-C in ERFC93
Mechanistic studies	Definitive mechanistic evidence; LDL accumulate in arterial intima and promote atherosclerosis	Arterial accumulation of TRL and their remnants to promote atherosclerosis like LDL, with potential pro-inflammatory and pro-thrombotic/anti-fibrinolytic effects
		In vitro and ex vivo evidence for potential anti-inflammatory vasculoprotective, anti-thrombotic and cytoprotective effects of HDL particles; central implication of cholesterol acceptor activity
Animal models	Pro-atherogenic effect in numerous studies	Pro-atherogenic and pro-inflammatory effects for TRL and their remnants
		Atheroprotection exerted by elevated HDL or apo A-I levels
Human genetic studies	Direct causal association in numerous studies, and notably in familial hypercholesterolaemia	Dysbetalipoproteinaemia (remnant hyperlipidaemia , apo E2/E2) provides causal evidence for the atherogenicity of elevated TRL and their remnants
		Lack of definitive insight for HDL-C, potentially due to the complexity of HDL metabolism
Human intervention studies	Statin trials provided conclusive proof of causality	Imaging trials reveal that fibrate therapy may impact atherosclerosis progression but fails to slow intima–media thickening; see Supplementary material online, Table S2
		Meta-analysis of fibrate trials (+statin) show clinical benefit limited to non-fatal CV events.208 Subgroup analyses reveal major reduction in CV events in patients with high TG and low HDL-C211
		Niacin imaging trials showed consistent stabilization and/or regression of atherosclerosis or intima–media thickening in monotherapy or in combination; see Supplementary material online, Table S1
		Reduction in CV events and total mortality with niacin monotherapy183,184
Interpretation 2010a	Definite causality	Evidence suggestive of a strong causal association of atherogenic dyslipidaemia, i.e. elevated TRL and their remnants combined with low HDL-C
		Insufficient evidence for TRL and their remnants alone
		Insufficient evidence for low HDL-C alone

^aFor an interpretation of causality given the data available in 2010, all five types of evidence should favour causality and all three types of human studies (epidemiology, genetics, and intervention trials) must be consistent; this is clearly the case for elevated LDL-C.