Dataset Information

No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies.

ABSTRACT:

Aims

Statins have modest adverse effects on glycaemic control. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers low-density lipoprotein cholesterol. This study assessed the effects of alirocumab on new-onset diabetes and pre-diabetes incidence in individuals without diabetes at baseline.

Methods and results

Pooled analysis of 10 ODYSSEY Phase 3 trials (n = 4974) of 24-104 weeks duration. Six trials (n = 4211) were ?52 weeks in length. Most patients received background maximally tolerated statin. Alirocumab effect on the rate of diabetes-related treatment-emergent adverse events (TEAEs), and/or fasting plasma glucose (FPG) and glycated haemoglobin A_1C (HbA_1C) was measured at baseline and every 12-24 weeks. Transition to diabetes analysis combined TEAE and FPG/HbA_1C laboratory data. At baseline, 30.7% of individuals had diabetes and were excluded from the current analysis. The remaining 3448 individuals without diabetes had pre-diabetes (39.6%) or were normoglycaemic (29.7%). The hazard ratio (HR; 95% confidence interval) for diabetes-related TEAEs in alirocumab was 0.64 (0.36-1.14) vs. placebo and 0.55 (0.22-1.41) vs. ezetimibe. The HR associated for transition from pre-diabetes to new-onset diabetes for alirocumab was 0.90 (0.63-1.29) vs. placebo and 1.10 (0.57-2.12) vs. ezetimibe. Mean change in FPG/HbA_1C over time showed no difference between treatment groups in patients without diabetes.

Conclusions

There was no evidence of an effect of alirocumab on transition to new-onset diabetes in 3448 individuals without diabetes at baseline with a follow-up period of 6-18 months, compared to either placebo or ezetimibe. Longer follow-up with larger number of individuals is needed to conclusively rule out an effect.

SUBMITTER: Colhoun HM

PROVIDER: S-EPMC5081037 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies.

Colhoun Helen M HM Ginsberg Henry N HN Robinson Jennifer G JG Leiter Lawrence A LA Müller-Wieland Dirk D Henry Robert R RR Cariou Bertrand B Baccara-Dinet Marie T MT Pordy Robert R Merlet Laurence L Eckel Robert H RH

European heart journal 20160726 39

<h4>Aims</h4>Statins have modest adverse effects on glycaemic control. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers low-density lipoprotein cholesterol. This study assessed the effects of alirocumab on new-onset diabetes and pre-diabetes incidence in individuals without diabetes at baseline.<h4>Methods and results</h4>Pooled analysis of 10 ODYSSEY Phase 3 trials (n = 4974) of 24-104 weeks duration. Six trials (n = 4211) were ≥52 weeks in length. Most patients rec ...[more]

PMID: 27460890

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Project description:Background and objectivesAlirocumab is a cholesterol-lowering monoclonal antibody targeting proprotein convertase subtilisin kexin type 9 (PCSK9) indicated in the prevention of cardiovascular risk and exhibiting target-mediated drug disposition (TMDD). The aim of this work was to develop an integrated pharmacokinetic-pharmacodynamic model to describe the interaction of alirocumab with PCSK9 and its impact on the evolution of low-density lipoprotein cholesterol (LDL-C) levels and explore labeling specification for subpopulations.MethodsUsing data collected from nine phase I/II/III clinical studies (n = 527, subcutaneous or intravenous administration), a TMDD model considering the quasi-steady-state approximation was developed to characterize the interaction dynamics of alirocumab and PCSK9, combined with an indirect pharmacodynamic model describing the inhibition of LDL-C by PCSK9 in a one-step approach using nonlinear-mixed effects modeling. A "full fixed effects modeling" strategy was implemented to quantify parameter-covariate relationships.ResultsThe model captures the interaction between alirocumab and its target PCSK9 and how this mechanism drives LDL-C depletion, with an estimation of the associated between-subject variability of model parameters and the quantification of clinically relevant parameter-covariate relationships. Co-administration of statins was found to increase the central volume of distribution of alirocumab by 1.75-fold (5.6 L versus 3.2 L) and allow for a 14% greater maximum lipid-lowering effect (88% versus 74%), highlighting the synergy of action between anti-PCSK9 therapeutic antibodies and statins toward lowering LDL-C plasma levels. Baseline levels of PCSK9 were found to be related to the amplitude of LDL-C variations by increasing the concentration of free PCSK9 necessary to reach half its capacity of inhibition of LDL-C degradation.ConclusionThe maximum effect of alirocumab is achieved when free PCSK9 concentration is close to zero, as seen mostly after 150 mg every 2 weeks (Q2W) or 300 mg every 4 weeks (Q4W), indicating that there would be no additional clinical benefit of increasing the dose higher than these recommended dosing regimens.

Dataset Information

No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies.

Aims

Methods and results

Conclusions

Publications

No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies.

Similar Datasets

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