Macrovascular Residual Risk Studies

COMMENT

Despite attainment of guideline-recommended LDL-C targets with statin therapy, individuals with cardiovascular disease continue to be at risk of (recurrent) events. To reduce this risk, it has been proposed that LDL-C levels should be lowered below these targets. This approach is supported by evidence from the Cholesterol Treatment Trialists’ Collaboration, which showed greater reduction in cardiovascular events with greater absolute reduction in LDL-C levels with more intensive statin therapy.1 Additionally, results from the IMPROVE-IT study2 showed modest benefit (reduction by 6.4%) for the risk of recurrent cardiovascular events, predominantly myocardial infarction and ischaemic stroke, in individuals with acute coronary syndromes, with further lowering of LDL-C levels with the addition of ezetimibe to statin therapy (1 year mean LDL-C levels 53.2 mg/dl versus 69.9 mg/dl with simvastatin 40 mg monotherapy). In IMPROVE-IT, the reduction in CV events was essentially derived from a relatively large subgroup with diabetes at baseline, suggesting that patients with type 2 diabetes may derive more benefit that nondiabetic patients from achieving very low LDL-C levels. However, the overall modest treatment benefit with ezetimibe plus statin has led some to question a ‘lower is better’ approach in the general population. Moreover, while post hoc and exploratory analyses from PCSK9 inhibitor trials are encouraging for this approach,3,4 these are based on few absolute events and definitive evidence is needed from ongoing cardiovascular outcome studies.

 The ‘lower LDL-C is better’ approach supports LDL-C as the predominant contributor to lipid-related residual cardiovascular risk in high risk patients. Yet there is accumulating evidence for the atherogenicity of other cholesterol-rich apolipoprotein-B containing lipoproteins, notably triglyceride-rich lipoproteins and their remnants, especially in individuals with metabolic disease such as type 2 diabetes.5 Indeed, analysis of data from the Danish general population showed that while increasing plasma levels of nonfasting LDL-C or remnant cholesterol were associated equally with risk of cardiovascular events (ischaemic heart disease events and myocardial infarction), only nonfasting remnant cholesterol was associated with overall mortality risk.6

 These findings need to be borne in mind when considering the results of the current cohort study, which failed to show any significant benefit of further lowering LDL-C (beyond the recommended target for high risk patients of 70 mg/dl or 1.8 mmol/L) in patients with stable ischaemic heart disease. The findings from this study are robust, as shown by consistency in secondary and sensitivity analyses that adjust for differences in baseline characteristics between the groups, and strengthened by taking account of adequate adherence (at least 80%) and polypharmacy among the subjects. Consideration of other cholesterol-rich apolipoprotein-B containing lipoproteins as potential contributors to lipid-related residual cardiovascular risk is therefore warranted, a view consistent with the Residual Risk Reduction Initiative.