Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease

Abstract

BACKGROUND Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approxi - mately 60%. Whether it prevents cardiovascular events is uncertain. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 pa - tients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for un - stable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confi - dence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for base - line LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (includ - ing new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with athero - sclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633.

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

“…Consistent with the overall patient populations mentioned above,63, 78 subanalyses by diabetes mellitus status demonstrated that overall alirocumab/evolocumab safety was comparable to that of control in those with and without diabetes mellitus 66, 67, 69, 71, 80. Overall safety was also comparable versus control between patients with diabetes mellitus and ASCVD,68 insulin‐treated patients with diabetes mellitus in the DM‐INSULIN study,75 patients with T2D and mixed dyslipidemia in the DM‐DYSLIPIDEMIA study,77 individuals with prediabetes and normoglycemia,72 and those with and without dysglycemia or metabolic syndrome 73.…”

“…The inclusion/exclusion criteria and other details of each phase 3 ODYSSEY and PROFICIO trial are shown in Table S2. LDL‐C reductions in the placebo‐controlled phase 3 trials were consistent with those found in the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) cardiovascular outcomes trial (Table), studying evolocumab versus placebo in 27 564 patients with clinically evident ASCVD and on a moderate‐to‐high‐intensity statin regimen over a median follow‐up duration of 2.2 years 63. The GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound) study (which included 968 statin‐treated patients with angiographic coronary disease to evaluate the effect of evolocumab versus placebo on the progression of coronary atherosclerosis) also showed comparable reductions in LDL‐C levels over 76 weeks of evolocumab treatment (from 93 mg/dL at baseline to 37 mg/dL at week 76) 64.…”

“…Overall safety was also comparable versus control between patients with diabetes mellitus and ASCVD,68 insulin‐treated patients with diabetes mellitus in the DM‐INSULIN study,75 patients with T2D and mixed dyslipidemia in the DM‐DYSLIPIDEMIA study,77 individuals with prediabetes and normoglycemia,72 and those with and without dysglycemia or metabolic syndrome 73. As shown in prior studies in the overall patient population,63, 78 higher rates of local injection‐site reactions (also generally mild) were typically seen with alirocumab/evolocumab compared with control for patients both with and without diabetes mellitus 69, 71, 80. However, in those with diabetes mellitus, several analyses showed lower rates of local injection‐site reactions with alirocumab/evolocumab versus control 66, 67, 75.…”

“…In the overall phase 3 patient populations, pooled safety analyses of 14 alirocumab ODYSSEY trials (including 5234 patients with 8–104 weeks’ treatment duration),78 12 evolocumab PROFICIO parent trials (including 6026 patients with 6–52 weeks’ treatment duration), and the first year of 2 open‐label extension trials (which included 4465 of the 6026 patients who were included in this analysis in the parent trials),79 and the FOURIER trial63 showed that the incidence of overall treatment‐emergent AEs, serious treatment‐emergent AEs, discontinuations because of treatment‐emergent AEs, and deaths was similar with the PCSK9 inhibitors versus controls. Among alirocumab‐ or evolocumab‐treated patients, nasopharyngitis, injection‐site reactions, and upper respiratory tract infections were the most commonly occurring AEs 78, 79.…”

“…Among alirocumab‐ or evolocumab‐treated patients, nasopharyngitis, injection‐site reactions, and upper respiratory tract infections were the most commonly occurring AEs 78, 79. Generally, a higher incidence of local injection‐site reactions (the majority of which were mild in nature) was seen with alirocumab/evolocumab versus controls 63, 78…”