Effects of evolocumab therapy and low LDL-C levels on vitamin E and steroid hormones in Chinese and global patients with type 2 diabetes

Abstract

Aims: We assessed the change from baseline in vitamin E, steroid hormones, adrenocorticotropic hormone (ACTH), and gonadotropins, overall and by lowest achieved low-density lipoprotein-cholesterol (LDL-C) level, in patients with type 2 diabetes and dyslipidaemia after 12 weeks of treatment with evolocumab.

Materials and methods: This was a prespecified analysis of vitamin E, cortisol, ACTH, gonadal hormones and gonadotropins in the 12-week, placebo-controlled BERSON trial of evolocumab in patients with type 2 diabetes and dyslipidaemia. In BERSON, 981 (451 in China) patients on daily atorvastatin 20 mg were randomized to placebo or one of two doses of evolocumab. We measured analyte levels at baseline and week 12 (vitamin E in all patients; steroid/gonadal hormones only in Chinese patients).

Results: In both the global and Chinese populations, absolute vitamin E levels decreased from baseline to week 12 by approximately 6 μmol/L (P < .0001) among evolocumab-treated patients; however, when normalized for LDL-C, apoB or non-HDL-C, we observed no decrease in vitamin E levels. In Chinese patients, levels of cortisol and ACTH as well as the cortisol:ACTH ratio did not change significantly from baseline to week 12. No patient had a cortisol:ACTH ratio <3.0 (nmol/pmol), suggestive of adrenocortical deficiency. We did not observe clinically relevant changes for gonadal hormones and gonadotropins (oestradiol and testosterone in female and male patients, respectively, luteinizing and follicle-stimulating hormones for both).

Conclusions: In the BERSON study, evolocumab did not adversely affect vitamin E, steroid hormone or gonadotropin levels in the Chinese or global type 2 diabetic populations.ClinicalTrials.gov NCT02662569.

Keywords: PCSK9 inhibitor; diabetes; dyslipidaemia; hypercholesterolaemia.

Conflict of interest statement

DJB reports personal fees from Amgen South Africa, during the conduct of the study; personal fees from Sanofi‐Aventis, outside the submitted work. JC, ZY, JLB and JG report no potential conflicts of interest. AWH and MLM are employees of and stockholders in Amgen Inc NW was an employee of Amgen when the work was conducted.

© 2020 The Authors. Endocrinology, Diabetes & Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1

Mean (SD) Vitamin E Levels in the Global Population at Baseline and Week 12 and by Minimum Postbaseline LDL‐C. A, Absolute vitamin E levels; B, absolute vitamin E levels in the evolocumab group; C, vitamin E levels normalized for LDL‐C; D, vitamin E levels in the evolocumab group normalized for LDL‐C; E, vitamin E levels normalized for apoB; F, vitamin E levels in the evolocumab group normalized for apoB; G, vitamin E levels normalized for non–HDL‐C; H, vitamin E levels in the evolocumab group normalized for non–HDL‐C. ApoB, apolipoprotein B; LDL‐C, low‐density lipoprotein‐cholesterol; non–HDL‐C, non–high‐density lipoprotein‐cholesterol; SD, standard deviation. Patients with vitamin E supplementation at baseline were excluded (3 in the placebo group, 1 in the evolocumab group). *P < .0001; P‐values (paired t test) are nonsignificant unless given above the comparison

Figure 2

Mean (SD) Vitamin E Levels in the Chinese Population at Baseline and Week 12 and by Minimum Postbaseline LDL‐C. A, Absolute vitamin E levels; B, absolute vitamin E levels in the evolocumab group; C, vitamin E levels normalized for LDL‐C; D, vitamin E levels in the evolocumab group normalized for LDL‐C; E, vitamin E levels normalized for apoB; F, vitamin E levels in the evolocumab group normalized for apoB; G, vitamin E levels normalized for non–HDL‐C; H, vitamin E levels in the evolocumab group normalized for non–HDL‐C. ApoB, apolipoprotein B; LDL‐C, low‐density lipoprotein‐cholesterol; non–HDL‐C, non–high‐density lipoprotein‐cholesterol; SD, standard deviation. Patients with vitamin E supplementation at baseline were excluded (3 in the placebo group, 1 in the evolocumab group). *P < .0001; **P < .0005; ***P = .0007. P‐values (paired t test) are nonsignificant unless given above the comparison

Figure 3

Mean (SD) Cortisol Levels, ACTH Levels and Cortisol:ACTH Ratio in the Chinese Population at Baseline and Week 12 and by Minimum Postbaseline LDL‐C. A, Cortisol levels; B, cortisol levels in the evolocumab group. C, ACTH levels; D, ACTH levels in the evolocumab group; E, cortisol:ACTH ratio; F, cortisol:ACTH ratio in the evolocumab group. ACTH, adrenocorticotropic hormone; LDL‐C, low‐density lipoprotein‐cholesterol; SD, standard deviation. *P = .02; P‐values (paired t test) are nonsignificant unless given above the comparison. aDue to abnormal distribution of the data in this group, the Wilcoxon signed‐rank test was also used in addition to the paired t test. The result (P = .06) confirmed the lack of a statistically significant difference

Figure 4

Mean (SD)Testosterone, FSH and LH Levels among Male Patients With Exclusion for Possibly Confounding Baseline Factors in the Chinese Population at Baseline and Week 12 and by Minimum Postbaseline LDL‐C. A, Testosterone; B, testosterone in the evolocumab group; C, FSH; D, FSH in the evolocumab group; E, LH; F, LH in the evolocumab group. Possibly confounding factors included the use of testosterone supplementation or LH levels ≥15 IU/L at baseline. Abbreviations: FSH, follicle‐stimulating hormone; LDL‐C, low‐density lipoprotein‐cholesterol; LH, luteinizing hormone; SD, standard deviation. Patients with testosterone supplementation or LH ≥15 IU/L at baseline were excluded (two in the placebo group, 10 in the evolocumab group). *P < .0001; **P = .0003;***P = .0032; ****P = .047; P‐values (paired t test) are nonsignificant unless given above the comparison