Are PCSK9 Inhibitors the New Statins?

Some cardiologists are going wild for new class of cholesterol medications.

At the American College of Cardiology's (ACC's) Annual Scientific Session hosted in littoral downtown San Diego in mid-March 2015, the air was heavy with talk of PCSK9 inhibitors. Specifically, many cardiologists in attendance were palpably bullish about results from year-long trials on Amgen's Repatha (evolocumab). In clinical trials, PCSK9 inhibitors like evolocumab and Regeneron/Sanofi's Praluent (alirocumab) have been shown to decrease LDL-C ("bad" cholesterol) at least as much as statins and maybe more. (Statins are drugs such as Zocor and Crestor.

Ultimately, simply lowering LDL cholesterol levels just to lower them may confer no real benefit without also lowering risk of future cardiovascular events like stroke and heart attack. And in order to figure out whether such long-term preventive benefit exists, we need long-term study ... years longer than the encouraging, yet, single-year results that we are currently witnessing.

What Are PCSK9 inhibitors?

Proprotein convertase subtilisin/Kexin type 9 or PCSK9 is a gene which plays a role in cholesterol and fatty acid metabolism. People with rare genetic variants of PCSK9 were observed as having levels of LDL-C ("bad" cholesterol) comparable to those on moderate-intensity statins. Furthermore, mutations in the gene have been linked to autosomal dominant familial hypercholesterolemia, a dangerous disease which causes very high levels of lipids or cholesterol and heart disease. 

In light of such observations, drug companies Amgen and Regeneron/Sanofi have created monoclonal antibodies that target the PCSK9 protein (coded for by the PCSK9 gene): Repatha and Praluent respectively. 

Results After One Year(ish) of Therapy With PCSK9 Inhibitors

On March 17, 2015, The New England Journal of Medicine published two papers detailing 52-week results from evolocumab's OSLER-1 and OSLER-2 trials and 78-week results from Regeneron/Sanofi's ODYSSEY clinical trials.

Some important results from the OSLER trials include the following:

  • Through 48 weeks of therapy, evolocumab sustained a reduction of LDL-C levels by 61 percent in participants with various levels of cardiovascular risk.
  • Through 52 weeks of therapy, the rate of cardiovascular events (heart attack, stroke, TIA and so forth) was 2.18 percent in those participants not taking evolocumab but on standard-of-care background therapy (taking statins) versus 0.95 percent for those taking evolocumab and on standard-of-care background therapy (taking statins).
  • Neurocognitive adverse events along with nonspecific adverse effects including arthralgia, headache, limb pain, and fatigue were reported more frequently in participants taking evolocumab.

Some important results from ODYSSEY trials include the following:

  • Through 78 weeks of therapy, alirocumab reduced LDL-C levels by about 60 percentage points in all participants including high-risk patients (those with familial hypercholesterolemia or multiple cardiovascular risk factors like smoking, diabetes and so forth).
  • Adverse effects attributable to treatment with alirocumab included injection-site reactions, myalgia, neurocognitive and ophthalmologic events.
  • All patients in this study were already on statins—either high-dose or at maximum tolerated dose. In patients receiving alirocumab, the rate of cardiovascular events was 1.7 percent versus 3.3 percent in those taking placebo.

Are PCSK9 Inhibitors the New Statins?

Cardiologists are now questioning cholesterol's status as an end-all-be-all biomarker. As we've learned from previous research, some drugs that only reduce LDL-C, increase HDL and so forth may confer no real-world benefit such as prevention of stroke or heart attack. The way that cholesterol and lipids interact in our body is more complex than we currently understand. By far, the best option that we have for treating heart disease are the statins, a unique drug class that prevents future cardiovascular events. These drugs probably work by not only lowering LDL levels but also by stabilizing plaques that clog up our arteries. 

In order for PCSK9 inhibitors to be considered as useful as the statins, we need several years of results, which is why Amgen is currently putting together the FOURIER study. The FOURIER study is going to be a five-year examination of the administration of evolocumab in those taking statins and at higher risk for cardiovascular events like stroke and heart attack. (If you're interested, AMGEN is currently soliciting participants for the study.)  With results from the FOURIER study, researchers hope to extend the decrease in adverse cardiovascular events observed during one year to several years.  Moreover, results from the study may help us better understand which patient populations best benefit from PCSK9 inhibitors. 

In a few years, if we see conferred long-term cardiovascular benefit, then we could be looking at a statin-like success for Amgen, evolocumab's maker. Such success is conditional because in addition to not knowing for sure which patient populations could best benefit from evolocumab, there is one quite worrisome thing about PCSK9 inhibitor:  Research suggests that in some people, evolocumab and alirocumab may mess with the central nervous system. More specifically, the ODYSSEY trial suggested that alirocumab may somehow impair memory, cause amnesia or cause confusion.

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Article Sources

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  • Article titled "Efficacy and Safety of Alirocumab in Reducing lipids and Cardiovascular Events" by JG Robinson and co-authors from NEJM 3/17/2015.  Accessed on 3/15/2015.
  • Article titled "Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events" by MS Sabatine and co-authors from NEJM 3/17/2015.  Accessed on 3/15/2015.
  • Article titled "Lowering LDL Cholesterol Is Good, but How and in Whom?" by NJ Stone and DML James from NEJM 3/17/2015.
  • Article titled "PCSK9 inhibition in patients with hypercholesterolemia" by NR Desai and MS Sabatine from Elsevier in 2015.  Accessed from Clinical Key on 3/15/2015.