Evolocumab vs. Ezetimibe in Statin-Intolerant Hyperlipidemic Japanese Patients: Phase 3 GAUSS-4 Trial

Abstract

Aim: In patients with hyperlipidemia, intolerance to statins presents a challenge in reducing the risk of events associated with cardiovascular disease. This phase 3, randomized, double-blind trial in Japanese patients with statin intolerance aimed to evaluate the efficacy and safety of evolocumab vs. ezetimibe in lowering low-density lipoprotein-cholesterol (LDL-C).

Methods: This study was conducted in a 12-week, double-blind period followed by an open-label extension designed to characterize 1 year of evolocumab treatment. Statin intolerance was defined as failure of two or more statins due to myalgia, myositis, or rhabdomyolysis. Eligible patients were randomized at 2:2:1:1 into four groups: 420 mg evolocumab every 4 weeks (Q4W)＋oral placebo daily, 140 mg evolocumab every 2 weeks (Q2W)＋oral placebo daily, subcutaneous (SC) placebo Q4W＋10 mg ezetimibe daily, and SC placebo Q2W＋ 10 mg ezetimibe daily.

Results: Sixty-one patients were randomized to evolocumab (n=40) or ezetimibe (n=21). For the co-primary endpoints of percent change from the baseline in mean LDL-C to the mean of weeks 10 and 12 and to week 12, the evolocumab-ezetimibe treatment differences were -39.4% (95% CI, -47.2% to -31.5%) and -40.1% (95% CI, -48.7% to -31.6%), respectively (adjusted p＜0.0001). The most common adverse events were diarrhea (9.5%) and nasopharyngitis (12.5%) in the ezetimibe and evolocumab groups, respectively, during the double-blind period and nasopharyngitis (29%) during the open-label extension.

Conclusion: Evolocumab was superior to ezetimibe in reducing LDL-C during the 12-week double-blind period in this population of Japanese patients with statin intolerance, with efficacy and safety results maintained for 1 year.

Trial registration: ClinicalTrials.gov, NCT02634580.

Keywords: Cardiovascular disease; PCSK9 inhibitor; Statin intolerance.

Conflict of interest statement

Shinji Koba reports speaker's honoraria from MSD and Takeda.

Ikuo Inoue reports honoraria from Sanofi.

Kouji Kajinami reports unrestricted research grants (modest) from Daiichi-Sankyo, Takeda, Astellas, Dainippon-Sumitomo, Boehringer-Ingelheim, Bayer, Fujifilm, Central Medical, and St. Jude Medical; research grant (modest) from Bristol-Myers Squibb.

Marcoli Cyrille, Chen Lu, and Hyoe Inomata are employees of Amgen Inc. and hold Amgen Inc. stock.

Junichiro Shimauchi is an employee of Amgen Astellas Biopharma K.K.

Figures

Fig. 1.

Diagram of Patient Disposition Abbreviations: AE, adverse event; IP, investigational product; PBO, placebo; PO, peroral; Q2W, every 2 weeks; Q4W, every 4 weeks; QD, daily; SC, subcutaneous; SOC, standard of care.

Supplemental Fig. 1.

Forest Plot of Treatment Differences in Percent Change from the Baseline in LDL-C at the Mean of Weeks 10 and 12 and at Week 12—Subgroup Analyses When the calculated LDL-C was 400 mg/dL, calculated LDL-C was replaced with ultracentrifugation LDL-C from the same blood sample, if available. Least squares mean differences and 95% CI are from the repeated-measure model. No imputation is used for missing values. n1 = number of patients receiving evolocumab in the subgroup of interest with an observed value at the mean of weeks 10 and 12 or at week 12; n2 = number of patients receiving ezetimibe in the subgroup of interest with an observed value at the mean of weeks 10 and 12 or at week 12. Abbreviations: BMI, body mass index; LDL-C, low-density lipoprotein cholesterol; NCEP, National Cholesterol Education Program; PCSK9, proprotein convertase subtilisin/kexin type 9; QD, daily; SC, subcutaneous.

Fig. 2.

Plot of Mean Percent Change from the Baseline in LDL-C by Scheduled Visit and Treatment Group Abbreviation: LDL-C, low-density lipoprotein-cholesterol. When the calculated LDL-C was 400 mg/dL, calculated LDL-C was replaced with ultracentrifugation LDL-C from the same blood sample, if available. Vertical lines represent the standard error around the mean. Plot is based on observed data, and no imputation is used for missing values.

Supplemental Fig. 2-1.

Plot of Mean Percent Change from the Baseline by Scheduled Visit and Treatment Group. A, Total Cholesterol; B, Non-HDL-C; C, ApoB; D, HDL-C; E, Triglycerides; F, Lp(a) Vertical lines represent the standard error around the mean. Plot is based on observed data, and no imputation is used for missing values. Abbreviations: ApoB, apolipoprotein B; HDL-C, high-density lipoprotein-cholesterol; Lp(a), lipoprotein(a).

Supplemental Fig. 2-2.

Plot of Mean Percent Change from the Baseline by Scheduled Visit and Treatment Group. A, Total Cholesterol; B, Non-HDL-C; C, ApoB; D, HDL-C; E, Triglycerides; F, Lp(a) Vertical lines represent the standard error around the mean. Plot is based on observed data, and no imputation is used for missing values. Abbreviations: ApoB, apolipoprotein B; HDL-C, high-density lipoprotein-cholesterol; Lp(a), lipoprotein(a).