Reduced adrenal stress response in patients on PCSK9 inhibitor therapy
BACKGROUND: Treatment with proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i), in addition to statin therapy, reduces LDL-cholesterol (LDL-c) in some patients to extremely low levels (i.e.< 20mg/dl = 0.52 mmol/l). There is concern that at such low levels, the physiologic role of cholesterol may be impaired, e.g. the adrenal cortisol stress response might be compromised. We therefore evaluated the effect of PCSK9i therapy on the cortisol response to ACTH in patients with LDL-c down to extremely low levels. METHODS: Nineteen patients on PCSK9i therapy and 18 controls matched for age, gender and comorbidities were included. The cortisol response to adrenocorticotropic hormone (ACTH) was tested after application of 250 micrograms ACTH. RESULTS: LDL-c levels ranged from 0.42 - 3.32 mmol/l (mean 1.38 ± 0.84 mmol/l) in the PCSK9i group and 0.81- 4.82 mmol/l (mean 2.10 ± 0.97) in the controls. By ANCOVA, the PCSK9i group had significantly lower cortisol levels compared to the control group with a mean cortisol level difference of -97.26 nmol/l (95% CI -178.60 to -15.93, p=0.021) after 60 minutes. The LDL-c correlated negatively with cortisol levels with a decrease in cortisol of 6.1 nmol/l per 0.1 mmol/l of LDL-c (-61.59 nmol/l, 95% CI -105.02 to -18.14, per 1 mmol/l LDL-c after 60 minutes, p= 0.007). All tested patients achieved cortisol values > 500 nmol/l. CONCLUSION: Patients on PCSK9i therapy showed a statistically significantly lower cortisol response to ACTH. This suggests that the adrenal stress response in patients on PCSK9 inhibitor therapy is reduced. Lower LDL-c levels however were not associated with lower cortisol responses, which indicated an effect of the PCSK9i antibody therapy per se rather than a reduced cortisol response in extremely low LDL-c levels.