Should PCSK9 Inhibitors Be Added to Standard Practice?

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are human monoclonal antibodies that work by binding to PCSK9 and low-density lipoprotein receptors (LDLR) on hepatocyte surfaces. This mechanism of action promotes LDLR degradation within the liver and degrades circulating LDL throughout the body. These agents have been shown to significantly reduce LDL by 40% to 70% in both phase 2 and 3 trials as both monotherapy regimens and also as an addition to a statin.

The Competition

Statins are the most commonly prescribed treatment for lowering LDL cholesterol because they’ve demonstrated the greatest ability to do so while reducing the risk of cardiovascular disease (CVD). Recent additional studies have assessed the addition of ezetimibe to the statin treatment regimen, and results show a significant reduction in coronary heart disease events in high-risk patients. The guidelines typically recommend higher-intensity statins in high-risk patients who can tolerate them.

The Evidence

One study conducted from November 2012 to May 2014 included participants from 79 sites in 8 different countries. A total of 672 patients were screened; 367 were chosen based on inclusion criteria such as being 18 years or older, having LDL levels ≥100 mg/dL that weren’t adequately controlled on statin therapy, or having LDL levels ≥70 mg/dL that weren’t adequately controlled on a statin therapy. The study was a randomized, double-blind controlled trial of all subjects who had hypercholesterolemia at very-high or high CV risk and were receiving rosuvastatin 10 to 20 mg/day or another lipid-lowering therapy other than ezetimibe for at least 4 weeks prior to screening.¹

Patients were instructed to complete a 2- to 6-week screening at baseline, after which they were placed in a 240-week double-blind treatment group receiving either add-on therapy with subcutaneous alirocumab 75 mg every 2 weeks, add-on therapy with ezetimibe 10 mg per day, or a doubled dose of rosuvastatin. During this trial, patients also received subcutaneous or oral placebo as appropriate. If, at week 8, LDL levels were 70 mg/dL in patients with documented diabetes or CVD with target organ damage, or 100 mg/dL in all other patients, then the trial conductor was instructed to increase the alirocumab dose to 150 mg every 2 weeks at week 12 in a blinded manner.

The endpoint classification of the study was to assess overall safety and efficacy. As an intervention model, a parallel assignment was used. To eliminate bias, masking procedures were employed by blinding the subject, caregiver, investigator, and outcome assessor. The study concluded that adding alirocumab to rosuvastatin provided significant LDL lowering versus adding ezetimibe or doubling the rosuvastatin dose.¹

These findings can be implemented in practice when treating patients with hypercholesteremia. The PSCK9 inhibitors are still new on the market, and not a lot of data have been collected on these agents for them to be placed in guidelines, but results of studies such as these only help for further implementation of these drugs down the line. Ultimately, a PSK9 inhibitor should be added to the standard of practice in individuals who aren’t seeing LDL reductions with their established treatment.

Some argue that lowering LDL levels isn’t beneficial, especially for elderly patients. Another study basically ruled out the cholesterol hypothesis, saying that elderly patients with high LDL levels live just as long or longer than those with low levels. That review analyzed a total of 19 cohort studies and raised the issue of whether we even need to lower LDL levels in treatment.²

References

1. Farnier M, et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. Atherosclerosis. 2016;244:138-146.

2. Ravnskov U, et al. Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open. 2016;6:e010401.