PCSK9 antibody does not increase HbA1c, fasting glucose or diabetes risk
Effect of the Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitor Evolocumab on Glycemia, Body Weight, and New-Onset Diabetes Mellitus
Although statin therapy is safe and effective lowering LDL-c and cardiovascular risk, it can lead to a modest increase in HbA1c levels and risk of developing diabetes [1,2]. Evolocumab, a PCSK9 antibody, leads to significant reductions of LDL-c and cardiovascular events, and first data showed that it has no notable effect on measures of glycemia and new-onset diabetes mellitus compared with placebo [3,4].
In this study, the effect of evolocumab on measures of glycemic control, weight or new-onset diabetes mellitus was evaluated for the duration of 1 year, in two open-label extension studies: OSLER-1 and OSLER-2 . In these studies, which included 4,802 participants from 13 parent trials, patients were randomized in a 2:1 ratio to evolocumab plus standard of care (SOC) or to SOC alone for the first year, regardless of treatment allocation in the parent trial. Evolocumab was administered at a dose of 420 mg once a month in OSLER-1 and, based on participant choice, at a dose of either 140 mg every 2 weeks or 420 mg once a month in OSLER-2. In OSLER-1, randomization was stratified by treatment arm in the parent study, while in OSLER 2 it was stratified by parent study and frequency of subcutaneous dosing.
- Evolocumab plus SOC lowered LDL-c by 50-60% over 48 weeks compared with SOC alone.
- Change in median HbA1c was identical over 48 weeks in both treatment arms, namely 0.1%.
- Change in median fasting plasma glucose was also very similar between treatment arms over 48 weeks in the analysis of all participants: both 0.06 mmol/L. Subgroup analyses for those with diabetes, without diabetes and at high risk of diabetes were consistent with this lack of effect.
- The mean weight change was 0.3 kg on evolocumab plus SOC compared with -0.1 kg on SOC alone.
- In those with diabetes, the mean weight change was -0.4 kg in participants with evolocumab plus SOC and -0.6 kg in participants receiving SOC alone.
- In participants without diabetes, the mean weight change was 0.4 kg in participants with evolocumab plus SOC and 0.0 kg in participants on SOC alone.
- In participants at high risk for diabetes, the mean change in weight was 0.1 kg in participants on evolocumab and 0.2 kg in participants on SOC alone.
- Of those without diabetes at parent-study baseline, the exposure-adjusted incidence of new-onset diabetes was 3.85 cases per 100 patient-years on evolocumab/evolocumab plus SOC treatment and 3.69 cases per 100 patient-years on control/SOC alone.
In two open-label extension studies, treatment with evolocumab plus SOC for the duration of 1 year did not increase HbA1c, fasting glucose or diabetes risk in comparison to SOC alone. Participants in the evolocumab plus SOC group had a slight increase in weight, which was mainly driven by participants without diabetes or with a low risk for diabetes.