Efficacy and Safety of the Pcsk9 Inhibitor Evolocumab in Patients With Mixed Hyperlipidemia

Abstract

Purpose Evolocumab significantly reduces low-density lipoprotein-cholesterol (LDL-C); we investigated its effects on LDL-C lowering in patients with mixed hyperlipidemia. Methods We compared the efficacy and safety of evolocumab in hypercholesterolemic patients selected from the phase 2 and 3 trials who had fasting triglyceride levels ≥1.7 mmol/L (150 mg/dL elevated triglycerides) and <1.7 mmol/L (without elevated triglycerides). Fasting triglyceride level ≥ 4.5 mmol/ L at screening was an exclusion criterion for these studies, but post-enrollment triglyceride levels may have exceeded 4.5 mmol/L (400 mg/dL). Efficacy was evaluated in four phase 3 randomized studies (n = 1148) and safety from the phase 2 and 3 studies (n = 2246) and their open-label extension studies (n = 1698). Efficacy analyses were based on 12-week studies, while safety analyses included data from all available studies. Treatment differences were calculated vs. placebo and ezetimibe after pooling dose frequencies. Results Mean treatment difference in percentage change from baseline in LDL-C for participants with elevated triglycerides and those without elevated triglycerides (mean of weeks 10 and 12) with evolocumab was approximately −67 % vs. placebo and −42 % vs. ezetimibe (all P < 0.001) compared to −6 % vs. placebo and −39 % vs. ezetimibe, respectively. Treatment differences for evolocumab vs. placebo and ezetimibe followed a similar pattern for non-high-density lipoprotein (HDL-C) and apolipoprotein B. Evolocumab was well tolerated, with balanced rates of adverse events leading to discontinuation of evolocumab vs. comparator (placebo and/or ezetimibe). Conclusion The significant reductions of atherogenic lipids including LDL-C, non-HDL-C, and apolipoprotein B seen with evolocumab are similar in patients with and without mixed hyperlipidemia.

Quantifying Atherogenic Lipoproteins: Current and Future Challenges in the Era of Personalized Medicine and Very Low Concentrations of LDL Cholesterol. A Consensus Statement from EAS and EFLM

“…The reductions of LDLC, non-HDLC, and apoB obtained with anti-PCSK9 therapy are similar in patients with and without mixed hyperlipidemia, reflecting higher circulating concentrations of TG and remnant-like lipoproteins. Efficacy analysis of 3146 participants in 4 studies of evolocumab showed that the mean percentage change from baseline for patients with or without increased fasting TG Ͼ150 mg/dL (1.7 mmol/L) followed a similar pattern for LDLC (Ϫ67% and Ϫ65% vs placebo), non-HDLC (Ϫ53% and Ϫ54%), and apoB (Ϫ49% and Ϫ50%) (133 ). A similarly high proportion of evolocumab-treated NCEP III high-risk patients with and without increased TG achieved the LDLC target of Ͻ70 mg/dL (1.8 mmol/L) (82% vs 81%, respectively) and Ͻ100 mg/dL (2.6 mmol/L) (92% vs 92%, respectively).…”

Effects of PCSK9 Inhibitors on Other than Low-Density Lipoprotein Cholesterol Lipid Variables

“…The reduction of PCSK9 with the PCSK9 inhibitors is associated with mild/moderate reductions of TRG levels (Table 1). 26 –31 For example, in the recently published FOURIER trial, evolocumab significantly reduced serum TRG levels compared with placebo (−16.7% vs −0.7%, P < .001). 3 Several mechanisms affecting both secretion and catabolism of TRG-rich lipoproteins can explain the PCSK9 inhibitors-mediated reduction of TRGs.…”

Quantifying atherogenic lipoproteins for lipid-lowering strategies: consensus-based recommendations from EAS and EFLM

“…This is consistent with the notion that risk of ASCVD is more directly related to the number of apoB-containing particles (reflected by apoB measurement) than to the cholesterol content of lipoproteins [10]. The implication of discordant LDLC vs. apoB (one normal, the other high) is most evident in patients with predominant small, cholesterol-depleted LDL particles who present with "optimal" concentrations of TC and LDLC -a profile that is especially prevalent among individuals with the metabolic syndrome or diabetes and in those taking medications, such as statins and anti-PCSK9, that reduce LDLC to a greater extent than apoB [87][88][89]. This necessarily results in on-treatment LDL and VLDL particle numbers that are higher than would be anticipated from the concurrent LDLC follow-up measurement and may explain part of residual risk among statin-treated patients [62,90].…”