Residual macrovascular risk in 2013: what have we learned?

Abstract

Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptorα agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.

Figure 1

Population-attributable coronary risk due to dyslipidaemia across different regions in the INTERHEART study [5]. Dyslipidaemia was defined as the ratio of apolipoprotein B-containing lipoproteins to apolipoprotein A-I lipoproteins.

Figure 2

Remnant cholesterol, estimated indirectly as total cholesterol minus the cholesterol contents of LDL and HDL, was shown to be causal for ischaemic heart disease, independent of HDL cholesterol. Reproduced with permission from Varbo et al. [34].

Figure 3

Meta-analysis of major fibrate outcomes studies, showing the impact of fibrate treatment on residual CV risk in patients with atherogenic dyslipidaemia. An odds ratio <1 indicated a beneficial therapeutic effect. The two panels show data from subgroups of patients with dyslipidaemia i.e., high levels of triglycerides and low levels of high-density lipoprotein [HDL] cholesterol, Panel A; or from the complementary subgroups without this dyslipidaemia, Panel B. Subgroups with dyslipidaemia defined according to the ACCORD Lipid trial (triglycerides ≥204 mg/dL or 2.3 mmol/L and HDL cholesterol ≤34 mg/dL or 0.9 mmol/L) or closest to these lipid criteria in each of the other trials were used in this analysis. The outcome defined for each individual trial was used. A total of 2,428 fibrate-treated subjects (302 events) and 2,298 placebo-treated subjects (408 events) with dyslipidaemia were included in the analysis reported in A. Reproduced with permission from Sacks et al. [47].