Mr. Steinbeck — a 65-year-old man — comes to your office to discuss his cholesterol level. He has stable coronary artery disease and is taking atorvastatin 80 mg daily. Despite good compliance, his low-density lipoprotein (LDL) cholesterol level is 120 mg/dL. Mr. Steinbeck wants to lower his cholesterol further to reduce his risk of a heart attack. He has heard about the new PCSK9 inhibitors, but is unsure whether he would be comfortable giving himself an injection every 2 to 4 weeks. Are any therapies currently under investigation that might give Mr. Steinbeck another option in the future?
The enzyme proprotein convertase subtilisin–kexin type 9 (PCSK9) promotes the degradation of the LDL receptor. Monoclonal antibodies to PCSK9 sequester PCSK9 in the extracellular space, prevent PCSK9 from degrading the LDL receptor, and lower LDL cholesterol and cardiovascular events in patients with atherosclerotic cardiovascular disease. However, targeting circulating PCSK9 with monoclonal antibodies is only one possible approach to reducing LDL levels. Recent studies have found that a small interfering RNA (siRNA) silences the translation of messenger RNA encoding PCSK9 and offers an alternative approach to lowering PCSK9 levels by blocking the synthesis of PCSK9 in the hepatocyte. In a phase 1 study, inclisiran, a PCSK9-specific siRNA modified to target hepatocytes, lowered PCSK9 and LDL for up to 6 months in healthy volunteers.
In this week’s issue of NEJM, investigators report findings from ORION-1, a phase 2 dose-finding study of the PCSK9 siRNA inclisiran. In this placebo-controlled randomized study, 501 patients with LDL levels >70mg/dL and atherosclerotic cardiovascular disease or LDL levels >100mg/dL and without atherosclerotic cardiovascular disease were randomized to one of eight study groups: a single dose of placebo or 200 mg, 300 mg, or 500 mg of inclisiran on day one, or two doses of placebo or 100 mg, 200 mg, or 300 mg of inclisiran on days 1 and 90. All patients were receiving a maximum statin dose for at least 30 days.
The primary efficacy endpoint was the percentage change from baseline in LDL cholesterol at day 180. Patients who received a single dose of inclisiran had reductions in LDL cholesterol ranging from 27.9% to 41.9%, compared with a 2.1% increase in LDL in the placebo group (P<0.001). Patients who received two doses of inclisiran had reductions in LDL ranging from 35.5% to 52.6%, compared with a 1.8% increase in LDL in placebo recipients (P<0.001). The group that received the highest dose of inclisiran (two doses of 300 mg) had the most marked reduction in LDL cholesterol levels (see figure). LDL reductions persisted up to day 240 (8 months). Eleven percent of patients who received inclisiran and 8% of patients who received placebo experienced serious adverse events, with higher rates of injection-site reactions in the treatment group.
Targeting PCSK9 could play an important role in reducing cardiovascular morbidity and mortality in the future. Use of siRNA appears to be an alternative way to effectively reduce LDL cholesterol. The major benefit of siRNA over monoclonal antibodies is the dosing strategy — currently approved monoclonal antibody PCSK9 inhibitors are dosed every 2 to 4 weeks, while inclisiran achieved LDL reduction at longer dosing intervals of at least 90 days. Further studies are needed to confirm that PCKS9 inhibition via siRNA is associated with a comparable reduction in cardiovascular events as the monoclonal antibodies. NEJM Deputy Editor John Jarcho comments, “The larger question is how we should be using PCSK9 inhibitors clinically.” Should these expensive medications be reserved for patients who are statin intolerant, at especially high risk of cardiovascular events, or unable to achieve target LDL levels with statins? The ORION study adds important new information about a novel mechanism to target the PCSK9 pathway, but its role in treating patients will remain unclear until more research is available. While these medications are still being studied, Mr. Steinbeck has time to consider whether he will want to try lowering his LDL with PCSK9 siRNA.
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Rebecca is a 2016-2017 NEJM Editorial Fellow and a hospitalist at Massachusetts General Hospital. She graduated from Columbia University College of Physicians and Surgeons in 2013 and completed internal medicine residency at Massachusetts General Hospital in 2016. Her interests include medical education, quality improvement, patient safety, health care delivery innovation, and teaching value in health care.