Macrovascular Residual Risk Studies

COMMENT

The ACCORD Lipid trial failed to show a statistically significant benefit with fenofibrate-simvastatin combination therapy versus simvastatin monotherapy for the total study population. However, a pre-defined subgroup analysis showed clinical benefit in high-risk patients with atherogenic dyslipidaemia (baseline triglycerides ≥204 mg/dL or 2.3 mmol/L and baseline HDL cholesterol levels ≤34 mg/dL or 0.88 mmol/L). In this group, adding fenofibrate to simvastatin resulted in a 31% reduction in cardiovascular events (from 17.3% to 12.4%, absolute risk reduction 4.9%).(1)

Consistent with other fibrate trials, patients in ACCORD Lipid were categorised on the basis of fasting blood lipids. However, there is increasing evidence that nonfasting triglycerides may be of greater relevance. Studies have shown that nonfasting triglycerides are independently predictive of cardiovascular disease events, even after adjustment for other factors including HDL cholesterol.(2,3)

This ancillary ACCORD Lipid study showed that although PP triglycerides were consistently reduced by fenofibrate irrespective of baseline fasting triglycerides, fenofibrate only reduced PP apoB48 levels in patients with elevated triglycerides (³130 mg/dL). In patients with fasting triglycerides ³the 75th percentile (³139 mg/dL or 1.8 mmol/L), fenofibrate treatment was associated with almost 50% reduction in the apoB48 AUC. From a mechanistic perspective, these findings suggest that fenofibrate promotes lipolysis and release of triglycerides from chylomicrons leading in turn to improved clearance of atherogenic triglyceride-rich remnant lipoproteins, only if fasting levels are sufficiently increased at baseline. Thus, it would be expected that the greatest benefits with fenofibrate would be observed in those patients with the highest levels of triglyceride-rich remnant lipoproteins at baseline, consistent with findings of the main ACCORD Lipid trial. Indeed, a critical appraisal of evidence,(4) supports the view that increased levels of remnant triglyceride-rich lipoproteins in type 2 diabetes is a key factor contributing to increased atherogenicity, and therefore a preferable therapeutic target for reducing residual macrovascular risk in type 2 diabetes.

The authors acknowledge that this ancillary study included only ~2.5% of the total ACCORD Lipid population. Despite this limitation, the data provide an explanation of why the benefit of fenofibrate was specific to the subgroup of patients with atherogenic dyslipidaemia.