Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy

Abstract

IMPORTANCEThe PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Patients with metabolic syndrome (MetS) are at increased cardiovascular risk.OBJECTIVE To investigate outcomes with evolocumab in patients with and without MetS. DESIGN, SETTING, AND PARTICIPANTS The FOURIER trial randomized patients worldwide with stable atherosclerotic cardiovascular disease receiving statin to evolocumab vs placebo with follow-up for a median of 2.2 years. Data were collected February 2013 to November 2016. For this prespecified analysis, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria; in secondary analyses, patients were further substratified by diabetes at baseline. Analysis was intention to treat. Analysis began March 2018 and ended April 2020. INTERVENTIONS Patients were randomized to evolocumab or placebo. MAIN OUTCOMES AND MEASURES The primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was cardiovascular death, myocardial infarction, or stroke. RESULTS Of 27 342 patients (mean [SD] age, 63 [9] years; 20 623 men [75.4%]) included in this analysis, 16 361 (59.8%) with baseline MetS were, when compared with patients without MetS, at higher risk of cardiovascular events (adjusted hazard ratio [95% CI], 1.31 [1.18-1.46]; P < .001 for the primary and 1.38 [1.20-1.57]; P < .001 for the key secondary end point). Evolocumab reduced low-density lipoprotein cholesterol similarly in patients with MetS (median [interquartile range], 92 [79-109] mg/dL vs 30 [19-48] mg/dL; P < .001) and without MetS (median [interquartile range], 92 [81-108] mg/dL vs 29 mg/dl; P < .001). For the primary end point, the hazard ratios (95% CI) with evolocumab vs placebo were 0.83 (0.76-0.91) and 0.89 (0.79-1.01) in patients with and without MetS (P for interaction = .39). For the key secondary end point, the corresponding hazard ratios (95% CIs) were 0.76 (0.68-0.86) and 0.86 (0.74-1.01) (P for interaction = .23), respectively. Evolocumab did not increase the risk of new-onset diabetes or other major safety outcomes including worsening glycemic control, compared with placebo in patients with MetS.CONCLUSIONS AND RELEVANCE Patients with atherosclerotic cardiovascular disease and MetS have substantial residual risk of cardiovascular events despite statin therapy. Evolocumab significantly reduced low-density lipoprotein cholesterol and cardiovascular risk in patients with MetS without increasing new-onset diabetes, worsening glycemic control, or other major safety events. These data suggest the addition of evolocumab to statin therapy in patients with atherosclerotic cardiovascular disease and MetS is safe and efficacious to reduce residual cardiovascular risk.

2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults

“…This includes patients with recent ACS and those ASCVD and additional CV risk enhancers including diabetes mellitus, metabolic syndrome, polyvascular disease (vascular disease in ≥2 arterial beds), symptomatic peripheral artery disease (PAD), history of MI, MI in the past 2 years, previous coronary artery bypass graft (CABG) surgery, LDL ≥2.6 mmol/L, heterozygous FH and Lp (a) ≥60 mg/dl. 92,[107][108][109][110][111][112][113][114][115] Intensification of lipid-lowering therapy with PCSK9 inhibitors is especially recommended in these subsets of very high risk patients (see Table 3), with or without the addition of ezetimibe, which was used in only a minority of patients in these trials. Use of PCSK9 inhibitor therapy in these subsets of patients was shown to result in rapid and large reductions in LDL-C and in significant CVD event reduction.…”

Impact of cholesterol-pathways on breast cancer development, a metabolic landscape

“…For instance, in cohort studies, under hormonal treatment or chemotherapy, patients who presented an overexpression of LDL-R showed a reduced recurrence-free survival [48]. In this case, a novel possibility is the design of strategies that could modulate the expression of LDL-R on tumoral tissues, it is recommendable taking into account the know-how of the novel treatments directed to PCSK-9, based on monoclonal antibodies [57] and RNAi [58] used in cardiovascular-risk patients.…”

PCSK9 Biology and Its Role in Atherothrombosis

“…The median duration of follow-up was 26 months and the study showed that the percentage reduction in LDL-C levels with evolocumab (either 140 mg every 2 weeks or 420 mg every month) was 60%, from a median baseline value of 92 mg/dL to 30 mg/dL [ 155 ]. In addition, evolocumab treatment significantly reduced by 15% the risk of the primary end point (major cardiovascular events, MACE) [ 155 ], with benefits also in patients with diabetes [ 157 ], metabolic syndrome [ 158 ] or prior ischemic stroke [ 159 ]. Moreover, from the whole treated group, 0.3% of patients exhibited the production of binding antibodies against evolocumab, but not neutralizing.…”