Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial

Abstract

Amgen.

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

“…Consistent with the overall patient populations mentioned above,63, 78 subanalyses by diabetes mellitus status demonstrated that overall alirocumab/evolocumab safety was comparable to that of control in those with and without diabetes mellitus 66, 67, 69, 71, 80. Overall safety was also comparable versus control between patients with diabetes mellitus and ASCVD,68 insulin‐treated patients with diabetes mellitus in the DM‐INSULIN study,75 patients with T2D and mixed dyslipidemia in the DM‐DYSLIPIDEMIA study,77 individuals with prediabetes and normoglycemia,72 and those with and without dysglycemia or metabolic syndrome 73.…”

“…Findings were consistent in the prespecified diabetes mellitus subanalysis of FOURIER, which analyzed 11 031 patients with diabetes mellitus versus 16 533 patients without diabetes mellitus; compared with placebo, median LDL‐C levels were reduced by 57% in those with diabetes mellitus and by 60% in those without diabetes mellitus 71. Other subanalyses of ODYSSEY and PROFICIO phase 3 trials showed that LDL‐C reductions were also similar in those with and without prediabetes,72 impaired fasting glucose, and metabolic syndrome (Table).…”

“…Overall safety was also comparable versus control between patients with diabetes mellitus and ASCVD,68 insulin‐treated patients with diabetes mellitus in the DM‐INSULIN study,75 patients with T2D and mixed dyslipidemia in the DM‐DYSLIPIDEMIA study,77 individuals with prediabetes and normoglycemia,72 and those with and without dysglycemia or metabolic syndrome 73. As shown in prior studies in the overall patient population,63, 78 higher rates of local injection‐site reactions (also generally mild) were typically seen with alirocumab/evolocumab compared with control for patients both with and without diabetes mellitus 69, 71, 80. However, in those with diabetes mellitus, several analyses showed lower rates of local injection‐site reactions with alirocumab/evolocumab versus control 66, 67, 75.…”

“…Analyses of ODYSSEY phase 3 trials with alirocumab with duration of 78 to 104 weeks of follow‐up showed no changes in fasting plasma glucose or hemoglobin A1c levels over time with alirocumab or control in patients with and without diabetes mellitus 67, 68, 75, 77, 80, 85 or in individuals with prediabetes or normoglycemia at baseline 72. Analyses of PROFICIO trials of 48 to 52 weeks of follow‐up and the diabetes mellitus subanalysis of the FOURIER trial of 168 weeks of follow‐up also did not show changes in fasting plasma glucose or hemoglobin A1c levels with evolocumab in patients with and without diabetes mellitus,71 high risk of diabetes mellitus,70 impaired fasting glucose, metabolic syndrome, or normoglycemia,73 although a small but statistically significant increase in fasting plasma glucose with evolocumab (but no change in hemoglobin A1c) at 78 weeks of treatment was found in the GLAGOV study 64. Furthermore, in contrast to the results seen in the statin and PCSK9 genetic variant studies mentioned above,4, 81, 82, 83, 84 no evidence of increased transition from normoglycemia to new‐onset diabetes mellitus following alirocumab or evolocumab treatment was found in pooled analyses 70, 73, 85.…”

“…However, in those with diabetes mellitus, several analyses showed lower rates of local injection‐site reactions with alirocumab/evolocumab versus control 66, 67, 75. Furthermore, alirocumab/evolocumab‐treated individuals with diabetes mellitus showed a lower incidence of local injection‐site reactions compared with alirocumab/evolocumab‐treated individuals without diabetes mellitus 66, 67, 69, 71, 80…”