Effect of Evolocumab on Vascular Function

The recently published IMPROVE-IT trial was the first to demonstrate that in high-risk patients, reduction of low density cholesterol (LDL-C) beyond current treatment goals by addition of ezetimibe to statin therapy leads to a further improvement of cardiovascular (CV) outcomes. The results of this study provide strong support for the concept that it is lower LDL-C levels that is key to achieving better outcomes, and that it is possible to achieve these on top of statin therapy (despite the much debated potential "pleiotropic" effects of statins). However, ezetimibe has only limited ability to reduce LCL-C further (-24% lower compared with statin alone in the IMPROVE-IT trial). Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a new treatment paradigm for hypercholesterolemia. The normal function of PCSK9 is to bind to the low density cholesterol (LDL-C) receptor, and to promote its lysosomal destruction in the hepatocyte. Thus, inhibition of PCSK9 protects the LDL-C receptor from lysosomal destruction, resulting in increased recirculation of the LDL-C receptor to the hepatocyte cell surface, and as a consequence, increased hepatic uptake and lower circulating levels of LDL-C.

The PCSK9 inhibitor evolocumab has been approved in 2015 for the treatment of patients with homocygote familial hypercholesterolemia (FH), as well as for treatment of patients with heterocygote familial or non-familial hypercholesterolemia in which target LDL-C levels cannot be achieved by standard cholesterol-lowering therapy, or who are statin-intolerant. Evolocumab achieves a reduction in LDL-C regardless of background therapy in the order of 50-70% (including those on a statin). This therapy substantially increases the number of patients achieving lower LCL-C target levels. Recently, the results of a large prospective study (FOURIER) in 27.500 patients at high CV risk have been published. This study showed that evolocumab lowered LDL cholesterol in patients already on optimized lipid lowering therapy including a statin to a median of 30 mg per deciliter and substantially reduced CV events (hazard ratio 0.85, confidence interval 0.79 to 0.92; P<0.001). However, the mechanisms mediating the improvement of CV outcomes under therapy with evolocumab are unclear at present.

Intact function of the endothelium is a key component of vascular health. Conversely, impaired endothelial function has been linked with increased future CV event rates. Intact endothelium has many protective and anti-atherosclerotic effects on the vasculature. At least in part, these protective effects are due to endothelial release of nitric oxide (NO). A well-established and non-invasive method of assessing endothelial function in humans is by measurement of flow-mediated vasodilation (FMD). In addition, recent evidence suggests concurrent assessment of low flow-mediated vasoconstriction (L-FMC) improves characterization of underlying CV and coronary disease compared with each parameter alone. Further, endothelial function has been found to impact large artery function. Endothelial dysfunction leads to vasoconstriction, greater peripheral wave reflection and arterial stiffness, and as a consequence, augmentation of central (aortic) systolic blood pressure (BP). This is of prognostic relevance, since aortic stiffness (e.g. determined by pulse wave velocity [PWV]), central systolic BP (cSBP) and central BP augmentation have been identified as strong and independent predictors of CV events in several patient cohorts. Exciting technical developments of recent years have now made the ambulatory (24-h) measurement of arterial stiffness possible.

The investigator group has been amongst the first to show that statin treatment improves endothelial function in patients with elevated LDL-C, which at least in part serves to explain the beneficial effects of statins on CV outcomes. The investigator Group was also able to show that an improvement in endothelial function during statin therapy is linked with an improvement of pulse wave reflection. Rapid improvement of endothelial and large artery function is considered to be particularly important in patients at high CV risk, such as those that have suffered a recent CV event. The investigator Group hypothesize that the beneficial effects of evolocumab, such as recently demonstrated in the FOURIER trial, are linked to a rapid improvement of endothelial and large artery function, even in patients already on optimized lipid lowering therapy including a statin. Of note, improvement of basal NO activity in the renal circulation and NO-dependent vasodilation of the peripheral vasculature occurs already 3 days after initiating treatment of statins. In the current study we focus on FMD of the brachial artery as the primary objective parameter. This parameter, which is widely accepted as an integrated measure of vascular function, is partly dependent on endothelial NO production. These data would help to explain the results of IMPROVE-IT and FOURIER, and add to the evidence that it is lower cholesterol levels that matter most for CV outcomes.