Rethinking good cholesterol: a clinicians' guide to understanding HDL

Abstract

Low HDL cholesterol dyslipidaemia affects about half of people with type 2 diabetes and represents a major independent risk factor for atherosclerotic cardiovascular disease. The "good cholesterol" label was coined decades ago on the basis of a presumed causal role of HDL cholesterol in atherosclerotic cardiovascular disease. However, this view has been challenged by the negative results of several studies of HDL cholesterol-raising drugs, creating a paradox for clinicians regarding the value of HDL cholesterol as a risk biomarker and therapeutic target, and seemingly contradicting decades of evidence substantiating an inverse relation between HDL cholesterol and cardiovascular disease risk. We seek to resolve this issue by revisiting the history of the HDL hypothesis, chronicling how this paradox is ultimately rooted in the progressive erroneous blurring of the distinction between HDL and HDL cholesterol. We describe the compositional complexity of HDL particles beyond their cholesterol cargo and focus on their role in lipid transport. We discuss the evidence regarding novel HDL functions, including effects on glucose metabolism, and speculate on the implications for type 2 diabetes. HDL cholesterol is an imperfect biomarker of a highly complex and multifunctional lipid transport system, and we should now consider how new HDL markers more causally linked to cardiovascular complications could be adapted for clinical use. In the absence of a superior alternative, HDL cholesterol generally has value as a component of primary cardiovascular disease risk prediction models, including in people with type 2 diabetes. However, to avoid prognostic overgeneralisations, it is high time that the good cholesterol label is dropped.