2. How low can you go?

If very low LDL-C levels are beneficial, then there is a need to reach these values in the majority of patients we treat. This argument has been answered by the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) [5] and the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER) [6] trials.

IMPROVE-IT [5] compared simvastatin (40 mg/day) + ezetimibe (10 mg/day) with simvastatin (40 mg/day) + placebo. The mean LDL-C level reached in the combination therapy group was 53.7 mg/dL (1.4 mmol/L) compared with 69.5 mg/dL (1.8 mmol/L) in the monotherapy group (p < 0.001). There was a significantly greater reduction (HR 0.936, 95% CI 0.89–0.99; p = 0.016) in the first vascular event in the combination therapy group. Moreover, this difference was even greater in an analysis of all events (total events, driven by reductions in myocardial infraction and stroke; RR 0.91, 95% CI 0.85–0.97; p = 0.007) [7] and when the patients who underwent coronary artery bypass graft (CABG, a higher risk group; HR 1.45, 95% CI 1.33–1.58 vs. without prior CABG) [8] were considered. In the more recent FOURIER trial [6], patients (n = 27,564) with cardiovascular disease and baseline LDL-C ≥ 70 mg/dL (1.8 mmol/L) already on a statin (± ezetimibe) were randomly assigned to subcutaneous evolocumab (a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor) or subcutaneous placebo injections. Evolocumab significantly reduced baseline LDL-C levels from 92 mg/dL (2.4 mmol/L) to 30 mg/dL (0.78 mmol/L); this was associated with a significant decrease in vascular events (HR 0.85, 95% CI 0.79–0.92; p < 0.001). The results were consistent even in the subgroup of patients in the lowest quartile for baseline LDL-C, and there was no significant difference in adverse events between the two trial arms. The secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke and was also significantly reduced (HR, 0.80; 95% CI, 0.73–0.88; p < 0.001).

IMPROVE-IT [5] and FOURIER [6] show that using ezetimibe or evolocumab on top of a statin can lead to very low LDL-C levels of 53.7 mg/dL (1.4 mmol/L) and 30 mg/dL (0.78 mmol/L), respectively. In the FOURIER trial [6], we should consider that 30.4% of the patients were on moderate-intensity statins and only 5.2% were on ezetimibe. Therefore, there may be some potential for achieving even lower LDL-C levels.

These results raise several points of interest. One, is what benefit, in terms of vascular event reduction, would be seen if reaching LDL-C levels of 53.7 mg/dL (1.4 mmol/L) and 30 mg/dL (0.78 mmol/L) were compared (i.e. levels reached in IMPROVE-IT [5] and FOURIER [6], respectively). Beyond that it remains to be investigated whether there is a differential class effect for the same LDL-C level reduction. There would also be a need to consider the massive cost difference between ezetimibe and evolocumab (will vary from country to country and may be influenced by ezetimibe becoming generic). Another key point is that two effective evidence-based drugs (ezetimibe and evolocumab) are now available for use on top of a statin.

3. Are the very low LDL-C levels achieved in IMPROVE-IT and FOURIER safe?

As mentioned above, based on the present evidence both ezetimibe and evolocumab safely reduced LDL-C levels. However, we need to consider that median follow-up was 6 years and 2.2 years for IMPROVE-IT [5] and FOURIER [6], respectively. The clinical experience of using ezetimibe involves a greater number of patients for a longer period of time. An extension of the FOURIER trial will follow, although this will have some design limitations (ClinicalTrials.gov Identifier: NCT03080935).

An interesting point is the possibility that very low LDL-C levels are associated with an increased risk of hemorrhagic stroke. However, there was no significant increase in hemorrhagic stroke in either IMPROVE-IT [5] or FOURIER [6]. In fact, overall stroke risk was significantly reduced in both trials.

4. The future

Based on the evidence described above, it is reasonable to expect changes in new guidelines regarding LDL-C target levels. In fact, some guidelines [9–12] already recommend LDL-C goals of 50–55 mg/dL (1.3–1.4 mmol/L) for very high risk patients.

Apart from even lower is even better for LDL-C, there is evidence that even sooner is even better. Exposure to lower LDL-C beginning early in life (related to genetic polymorphisms; e.g. PSCK9 or Niemann-Pick C1-Like 1 intestinal transporter) is associated with a 3-fold greater reduction in CHD risk per unit of lower LDL-C than statin treatment initiated later in life [13,14].

We await the endpoint-based results with alirocumab, another PCSK9 inhibitor. Further in the future, it may be possible to substantially decrease LDL-C levels by administering two injections per year of Inclisiran, which interferes with PCSK9 messenger RNA [15]. Key issues with such a new treatment option (i.e. Inclisiran) will be endpoint-based evidence, and the cost relative to the currently available PSCK9 inhibitors that are administered every 2 weeks or on a monthly basis.

Currently, the key lipid target mentioned in guidelines is the LDL-C level. However, other options beyond targeting LDL-C may become relevant in the future. For example, raising high-density lipoprotein cholesterol levels using a cholesteryl ester transfer protein inhibitor (anacetrapib) [16], improving high-density lipoprotein function [17] or lowering lipoprotein(a) levels using antisense technology [18], may further decrease vascular risk. If these trials are favorable, there will be a need to pursue lipid targets other than just LDL-C levels. This may result in a decrease in residual risk and provide more options for patients who cannot tolerate statins or reach LDL-C treatment goals [19,20].

5. Conclusions

1. Low levels of LDL-C (30–54 mg/dL; 0.8–1.4 mmol/L) can now be reached.

2. For vascular event reduction, the evidence supports that for LDL-C levels even lower is even better.

3. Two lipid lowering agents, ezetimibe and evolocumab, are now evidence-based for use together with a statin.

4. It is probably safe to assume that using ezetimibe and/or evolocumab in patients who cannot tolerate a statin might be a realistic option; however, this needs to be confirmed by outcome trials.

5. Guideline LDL-C target levels are likely to fall.

6. We may eventually simplify treatment with PCSK9 inhibitors by providing two injections per year.

7. The future may bring into play additional lipid targets, such as high-density lipoprotein cholesterol and lipoprotein(a).