Alirocumab safety in people with and without diabetes mellitus: pooled data from 14 ODYSSEY trials

Abstract

Aim: To evaluate the safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab according to diabetes mellitus status.

Methods: Safety data from 14 trials (8-104-week durations) were analysed by treatment (alirocumab or placebo/ezetimibe control) and diabetes status (yes/no, defined by medical history). Adverse event data were assessed using descriptive statistics and Cox models.

Results: Of the 5234 trial participants, 1554 (29.7%) had diabetes. Overall, treatment-emergent adverse events were similar in the alirocumab and control groups, except for more frequent local injection site reactions with alirocumab. Fewer people with diabetes experienced local injection site reactions [alirocumab, 3.5%, control, 2.9%; hazard ratio 1.24 (95% CI 0.68-2.25)] than those without diabetes [alirocumab, 7.5%; control, 4.9%; hazard ratio 1.51 (95% CI 1.13-2.01)]. Those with diabetes reported a greater number of serious adverse events (alirocumab, 19.4%; control, 19.7%) than those without diabetes (alirocumab, 14.5%; control, 13.5%). In people with diabetes, major adverse cardiac events occurred in 2.7% of alirocumab-treated people [control, 3.3%; hazard ratio 0.74 (95% CI 0.41-1.35)]; in those without diabetes, 1.8% of alirocumab-treated people had major adverse cardiac events [control, 1.7%; hazard ratio 0.95 (95% CI 0.56-1.62)]. Overall, no increase in HbA_1c or fasting plasma glucose vs control treatment groups was observed, regardless of diabetes status.

Conclusion: This pooled analysis across 14 trials demonstrated similar safety for alirocumab vs control treatment, irrespective of diabetes status, except for more frequent local injection site reactions with alirocumab. People with diabetes reported fewer local injection site reactions than those without diabetes.

Trial registration: ClinicalTrials.gov NCT01288443 NCT01288469 NCT01266876 NCT01812707 NCT01507831 NCT01617655 NCT01644175 NCT01623115 NCT01709500 NCT01644188 NCT01730040 NCT01730053 NCT01644474 NCT01709513.

Figure 1

Treatment‐emergent adverse events (TEAEs) in ≥5% of people with and without diabetes in the pool of 14 phase 2/3 trials (safety population). n/N = number of study participants with at least one event. ^†Number of people with an event per person‐year, calculated as number of people with an event divided by total person‐years. For people with an event, number of person‐years is calculated up to the date of the first event; for those without an event, it corresponds to the length of the TEAE period. DM, diabetes mellitus.

Figure 2

Adverse events of special interest according to diabetes status at baseline in the pool of 14 phase 2/3 trials (safety population). ^†Calculated as number of people with an event divided by total person‐years. For people with an event, the number of person‐years is calculated up to the date of the first event; for those without an event, it corresponds to the length of the treatment‐emergent adverse event (TEAE) period. ^‡Calculated using a Cox model stratified on the study. ^§Major adverse cardiac events (MACE) were defined as coronary heart disease death, non‐fatal myocardial infarction, ischaemic stroke or unstable angina requiring hospitalization, and were adjudicated by a central Clinical Events Committee only in phase 3 trials. Local injection site reactions (LISRs) were selected using an electronic case report form‐specific tick box on the adverse event page in phase 3 studies and phase 2 study DFI12361, selected using Medical Dictionary of Regulatory Activities (MedDRA) high‐level term ‘injection site reaction’ in the other phase 2 studies. Neurocognitive disorder: events selected using a custom MedDRA query, based on the five following high‐level group terms: deliria (including confusion); cognitive and attention disorders and disturbances; dementia and amnestic conditions; disturbances in thinking and perception; and mental impairment disorders. Neurological events: standardized MedDRA queries ‘demyelination’ (broad and narrow), ‘peripheral neuropathy’ (broad and narrow), and ‘Guillain–Barre syndrome’ (broad and narrow), excluding the following preferred terms: ‘acute respiratory distress syndrome’, ‘asthenia’, ‘respiratory arrest’ and ‘respiratory failure’. Hepatic disorder: standardized MedDRA query ‘hepatic disorder’. General allergic events: selected using a custom MedDRA query with standardized MedDRA query ‘hypersensitivity’ (broad and narrow), excluding the following preferred terms linked to LISRs: (‘infusion site dermatitis’, ‘infusion site hypersensitivity’, ‘infusion site rash’, ‘infusion site urticaria,’ ‘injection site dermatitis’, ‘injection site hypersensitivity’, ‘injection site rash’, ‘injection site urticaria’ and ‘vasculitis’. Ophthalmologic events: standardized MedDRA queries ‘optic nerve disorders’ (broad and narrow), ‘retinal disorders’ (narrow) and ‘corneal disorders’ (narrow). Diabetes or diabetic complications: high‐level group term ‘diabetes complications’, high‐level term ‘diabetes mellitus’ and high‐level term ‘carbohydrate tolerance analyses (including diabetes)’, excluding preferred term ‘blood glucose decreased’. In study participants with diabetes at baseline, terms such as ‘diabetes mellitus’ indicate a worsening of the condition or loss of glycaemic control. DM, diabetes mellitus; HR, hazard ratio; TEAE, treatment‐emergent adverse event.

Figure 3

Comparison of local injection site reactions (LISRs) according to diabetes status at baseline in the pool of 14 phase 2/3 trials (safety population). The category of LISRs included those judged to be related to the injection of study treatment by the investigator and not attributable to another injectable agent. If the investigator or study participant recognized any LISRs and/or signs of local intolerability at the injection site, this was to be treated and followed up as per the investigator's medical judgement, and recorded on a special case report form. Local injection site reactions were graded by severity and characterized by related signs and symptoms such as (but not limited to) redness and pain. Drug reactions and/or LISRs considered to be allergic (or that had an allergic component) were reported under the category of general allergic events. Adverse events with cutaneous involvement and with obvious allergic origin or LISRs that expanded/worsened were to be evaluated by a dermatologist as soon as possible 18. ALI, alirocumab; CTL, control; DM, diabetes mellitus.

Figure 4

Median (a) fasting plasma glucose (FPG) and (b) HbA_1c over time in people with and without diabetes in the pool of 14 phase 2/3 trials (safety population). Error bars indicate 95% CI values. Approximate values of FPG in mmol/l and HbA_1c in mmol/mol are shown on the left‐hand y‐axis in panels (a) and (b), respectively. For HbA_1c, the following formula was used to convert % to mmol/mol units: HbA_1c in mmol/mol = 10.93*(HbA_1c in %) – 23.5. DM, diabetes mellitus.