Macrovascular Residual Risk Studies

COMMENT

Following much speculation, IMPROVE-IT showed that compared with statin therapy alone, the addition of non-statin therapy (ezetimibe) further lowered LDL-C levels and reduced CVD events in patients with a recent ACS. It is, however, recognised that the incremental benefit was modest (6.4% reduction over a mean of 6 years follow-up). Additionally, despite the fact that the combination of simvastatin plus ezetimibe arm achieved a 50% reduction in LDL-C levels (versus 35% reduction with simvastatin alone), there was no benefit during the first year of the trial. This contrasts with the findings from PROVE-IT, which compared the effect of high-dose versus low-dose statin treatment in ACS patients, where a similar difference in the percent change from baseline in LDL-C levels resulted in a significant benefit within 30 days.(1) Thus, it is likely that the early and strong beneficial effects of statins are derived in large part from their many pleiotropic actions beyond simple reduction in LDL?C. These effects are not shared by ezetimibe, which acts mainly by further reducing LDL-C, contributing only a small incremental effect on CVD risk reduction. Furthermore, the delay in benefit with ezetimibe supports the notion that an important time factor is needed for evidence of benefit on event rates with LDL-C reduction alone, without the added modulation of triglycerides, high-density lipoprotein cholesterol, inflammation, vascular function and oxidation. In this respect, it is relevant that short term trials which evaluated the effects of adding ezetimibe to statin therapy on carotid intima-media thickness, such as ENHANCE (18 months)(2) or ARBITER 6-HALTS (24 months)(3) were negative, whereas SANDS, which was of longer duration (36 months), was not.(4)

Moreover, it is evident that patients in IMPROVE-IT still remained at high residual risk of CVD events; about one-third of patients in the ezetimibe/simvastatin group continued to experience a CVD event despite attaining LDL-C levels below current targets and while receiving best standards of care. Thus, while IMPROVE-IT provides support for the central role of LDL-C lowering in CVD prevention, there remain unanswered questions. First, should there be a lower limit for LDL-C levels in this very high risk group? Second, would effective targeting of additional risk factors offer further benefit? So far studies that have attempted to address this have failed to show definitive answers with other non-statin treatments, although flaws in the trial design or limits to the potency/selectivity of currently available therapeutic options may have been responsible for negative/neutral findings.

Ultimately, while IMPROVE-IT provides timely support for the LDL hypothesis,(5) it also highlights the unmet need for additional interventional approaches to reduce the high residual risk that persists in such patients despite best evidence-based treatment. Addressing this unmet need is a key mission of the Residual Risk Reduction Initiative.(6)