LDL-Cholesterol versus Glucose in Microvascular and Macrovascular Disease

The causal relationships between increased concentrations of low density lipoprotein (LDL)-cholesterol and glucose and risk of ischemic heart disease are well established. The causal contributions of LDL-cholesterol and glucose to risk of peripheral micro- and macrovascular diseases are less studied, especially in prediabetic stages and in a general population setting.

This review summarizes the current evidence for a causal contribution of LDL-cholesterol and glucose to risk of a spectrum of peripheral micro- and macrovascular diseases and reviews possible underlying disease mechanisms, including differences between vascular compartments, and finally discusses the clinical implications of these findings, including strategies for prevention and treatment.

Combined lines of evidence suggest that LDL-cholesterol has a causal effect on risk of peripheral arterial disease and chronic kidney disease, both of which represent manifestations of macrovascular disease due to atherosclerosis and accumulation of LDL particles in the arterial wall. In contrast, there is limited evidence for a causal effect on risk of microvascular disease. Glucose has a causal effect on risk of both micro- and macrovascular disease. However, most evidence is derived from studies of individuals with diabetes. Further studies in normoglycemic and prediabetic individuals are warranted. Overall, LDL-cholesterol-lowering reduces risk of macrovascular disease, while evidence for a reduction in risk of microvascular disease is inconsistent. Glucose-lowering has a beneficial effect on risk of microvascular diseases and on risk of chronic kidney disease and estimated glomerular filtration rate (eGFR) in some studies, while results on risk of peripheral arterial disease are conflicting.