Recent publications on Residual Risk

Data from the prospective Second Manifestations of ARTerial disease (SMART) cohort suggested that higher levels of high-density lipoprotein (HDL) cholesterol at baseline are associated with increased cardiovascular risk in type 2 diabetes patients with controlled low-density lipoprotein (LDL) cholesterol concentration. In total, 1,829 type 2 diabetes patients (mean age 60 years, 70% men, 60% on lipid lowering therapy) were included. Over a median follow-up of 7 years, there were 335 new cardiovascular events (myocardial infarction [MI], ischaemic stroke, vascular death) and 385 patients died. In all patients, the risk of MI decreased by 7% per 0.1 mmol/L increase in HDL cholesterol concentration (adjusted hazard ratio 0.93, 95% confidence interval 0.87–1.00); there was no association with any other endpoint. However, baseline plasma HDL cholesterol concentration was not associated with risk of cardiovascular events (hazard ratio 0.97, 95% confidence interval 0.93–1.01) or all-cause death (hazard ratio 0.99, 95% confidence interval 0.96–1.03). Subgroup analyses did suggest that LDL cholesterol concentration may modify the association between HDL cholesterol and cardiovascular events or all-cause death. Indeed, the risk of cardiovascular events was 10% higher (hazard ratio 1.10, 95% confidence interval 1.07–1.21), and all-cause mortality 14% higher (hazard ratio 1.14, 95% confidence interval 1.07–1.21), in individuals with high baseline HDL cholesterol levels and plasma LDL cholesterol concentration <2.0 mmol/L. There was no association in individuals with higher LDL cholesterol levels. These findings may lend some credence to the proposal that an increase in HDL cholesterol concentration is not always beneficial (as shown by dal-OUTCOMES), possibly attributable to modification of HDL functionality and/or distribution changes within HDL subclasses. Additionally, whereas low HDL cholesterol concentration has been shown to be a cardiovascular risk factor, supported by extensive evidence, raising HDL cholesterol levels with HDL-targeted therapies has not been shown to reduce cardiovascular events. Taken together, these findings raise questions about the relevance of HDL cholesterol to residual cardiovascular risk that persists in high-risk patients despite well controlled LDL cholesterol levels.