PCSK9 Drug Improves Heart Outcomes
In the mid-2000s, researchers discovered that variability in the activity of the proprotein convertase subtilisin/kexin type 9 (PCSK9) enzyme produced wide-ranging effects on cholesterol levels in humans. Two monoclonal antibodies that inhibit PCSK9 were developed and were found to markedly reduce low-density lipoprotein (LDL) cholesterol. Evolocumab (Repatha) and alirocumab (Praluent) were approved in 2014 and 2015, respectively, to great anticipation. Although both drugs lowered LDL better than statins, evidence of cardiovascular benefit had been lacking — until now. The FOURIER trial was a randomized, double-blind, placebo-controlled trial comprised of 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of ≥ 70 mg per deciliter (1.8 mmol per liter) who already were taking a statin. Patients received evolocumab (either 140 mg every two weeks or 420 mg monthly) or matching placebo by subcutaneous injection. The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), stroke, unstable angina, or coronary revascularization. The secondary outcome was the composite of cardiovascular death, MI, or stroke. After 48 weeks, evolocumab lowered LDL 59% from baseline compared to placebo. Both the primary and secondary outcomes were reduced significantly relative to placebo (primary outcome 9.8% vs. 11.3%; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.79-0.92; P < 0.001; secondary outcome 5.9% vs. 7.4%; HR, 0.80; 95% CI, 0.73-0.88; P < 0.001). Overall mortality was not different between the two groups. Evolocumab was well-tolerated except for injection site reactions. The authors concluded that patients with atherosclerotic cardiovascular disease benefit from lowering LDL below current targets (N Engl J Med 2017;376:1713-1722).
A new PCSK9 inhibitor, bococizumab, also showed benefit in reducing major cardiovascular events in high-risk patients, although the study ended early because of a high level of anti-drug antibodies (N Engl J Med 2017;376:1527-1539). Researchers halted further development of bococizumab in November 2016. Several other PCSK9 drugs are in development, including inclisiran, which is administered once every three months.
Although evolocumab and alirocumab lowered low-density lipoprotein better than statins, evidence of cardiovascular benefit had been lacking — until now.
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