Blood cholesterol is a well-recognised risk factor for the development and progression of atherosclerosis. Consistent evidence from genetic studies, epidemiologic observations, and randomised controlled trials (RCT) has unequivocally shown that elevated plasma concentrations of atherogenic lipid, particularly low-density lipoprotein cholesterol (LDL-C), are causally linked to atherosclerotic cardiovascular disease (ASCVD).(1) Conversely, for higher-density lipoprotein cholesterol (HDL-C), higher levels are associated with a lower ASCVD risk.
In their recent article, Kim and all analyzed coronary computed tomography angiography (CCTA) data from 5,130 non-diabetic Korean patients without known coronary artery disease in relation to HDL-C and LDL-C levels.(2) Imaging outcomes included any obstructive plaque; presence of obstructive plaques in clinically most relevant locations (i.e. left-main or proximal left anterior descending artery); and multivessel obstructive lesions. The authors found that patients with low levels (< 40 mg/dL) of HDL-C, as compared with those with higher levels (≥ 40 mg/dL), had a higher prevalence of obstructive plaques (by any of the aforementioned three definitions), but only in the subgroup of patients with LDL-C levels <130 mg/dL. In contrast, there was no difference in the prevalence of obstructive plaques in relation to HDL-C in the context of higher (≥ 130 mg/dL) LDL-C levels.(2)
Some aspects of the study methodology deserve consideration in interpreting these results. First, thresholds for considering LDL-C levels as “normal” or “elevated” are not the same for all individuals, but rather depend on each individual’s cardiovascular risk: for patients with established ASCVD or at higher risk of developing ASCVD, lower LDL-C levels are generally recommenced.(3) In the study by Kim et al, about 26% had a high ASCVD risk score, whereby recommended LDL goals according to current guidelines are not <130 mg/dL but lower.(3) It would be of interest to explore whether favorable (high) HDL-C levels remain to be predictive of less advanced coronary atherosclerosis in the context of lower LDL-C levels (< 100 mg/dL) in these higher-risk primary-prevention individuals. Second, the long-established concept “the higher, the better” for HDL-C might may not apply for the entire spectrum of HDL-C levels, since extremely high HDL-C was paradoxically associated with high mortality in recent observational studies.(4) With respect to coronary atherosclerosis by CCTA, this aspect cannot be addressed by applying a dichotomous approach for HDL-C (< vs. ≥40 mg/dL). Notwithstanding these considerations, and taking into account the observational, cross-sectional study design (thus showing associations but precluding any inference on causality), Kim et al. provide interesting data that add to the evidence base of HDL-C and its relation to ASCVD risk.(2)
The inverse association between plasma HDL-C and the risk of ASCVD has been consistently shown in numerous epidemiological studies.(5) In contrast, a causal role of HDL-C in ASCVD was not confirmed in Mendelian randomisation studies (6), although the latter evidence requires cautious interpretation given that most genetic variants associated with lower HDL-C are also associated with higher LDL-C and triglyceride levels. Importantly, RCTs of medications that increase plasma HDL-C levels, e.g. cholesteryl ester transfer protein (CETP) inhibitors, failed to show a reduction in the risk of CV events.(7,8) Along the same lines, directly infused HDL mimetics that raise HDL-C plasma level did not reduce the progression of atherosclerosis as measured by intravascular ultrasound.(9)
Taken together, elevated HDL-C levels do associate with a lower risk of CVD in epidemiological studies, and consistently with fewer obstructive lesions in the CCTA study by Kim et al (2), but there is currently no RCT or genetic evidence that raising plasma levels of HDL-C effectively reduces ASCVD risk. In contrast, lowering LDL-C level by 1.0 mmol/l (38.7 mg/dL) reduces the risk of major cardiovascular event by about 20%.(10,11) Accordingly, current guidelines recommend LDL-C as the primary lipid analysis for screening, diagnosis, and management; HDL-C analysis is recommended to refine risk estimation.(3) With respect to physician-patient communication, it is essential to explain to our patients that high levels of their “good” (HDL) cholesterol may indeed be protective, but this does not compensate for the adverse, pro-atherogenic effects of elevated levels of “bad” (LDL) cholesterol.