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

Colhoun HM, Ginsberg HN, Robinson JG, et al.
Eur Heart J 2016; published online ahead of print

Background

Statin therapy increases the risk of DM in patients with one or more DM risk factors [1]. Therefore, the FDA implemented safety label changes stating increase in haemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) levels with statin use [2]. However, the exact mechanism of the statin-associated glycaemic effect is not understood, nor is it clear whether other lipid-lowering therapies have similar effects [3].

Alirocumab, a PCSK9 inhibitor, is approved for use in hypercholesterolemia patients who require additional LDL-c lowering beyond diet and maximally tolerated statin therapy, as well as in patients with clinical atherosclerotic CV disease [4].  

In this study, the effects of subcutaneous alirocumab (every 2 weeks 75/150 mg) on the development of new-onset DM and pre-diabetes was evaluated in individuals without DM at baseline (but with pre-diabetes or normoglycaemia), in a pooled analysis of 10 ODYSSEY Phase 3 randomized, double blind, controlled trials (n = 4974 patients) of 24–104 weeks duration, in which alirocumab was compared to either placebo or ezetimibe (number of patients 818 placebo vs 1620 alirocumab and 428 ezetimibe vs 582 alirocumab). Four sources of data were used: medical history data at baseline, treatment-emergent adverse events (TEAEs), HbA1c and FPG.

Main results

• Based on TEAE data alone, there was no increase in the incidence of DM in the alirocumab group: HR compared with the placebo group was 0.64; 95% CI: 0.36–1.14, HR compared with the ezetimibe group was 0.55; 95% CI: 0.22–1.41, HR compared with both groups was 0.62; 95% CI: 0.38–1.00.
• Mean HbA1c and FPG change from baseline between alirocumab and placebo groups showed no meaningful difference in individuals without DM at baseline: HbA1c was increased with 0.04% and 0.05% in the alirocumab group and placebo group respectively and FPG was decreased with 0.02 mmol/L in both groups.

• Based on TEAE data, HbA1c and FPG levels, 8.7% pre-diabetic patients at baseline transitioned to new-onset diabetes. The HRs for transitions associated with alirocumab was not significant in either the placebo group (HR: 0.90; 95% CI: 0.63–1.29) or the ezetimibe group (HR: 1.10; 95% CI: 0.57–2.12).  
• Among those with pre-diabetes at baseline, regression to normoglycaemia was common but there was no difference between alirocumab and control groups.
• Based on HbA1c and FPG levels, transition of normoglycaemia to pre-diabetes was similar across all treatment groups: HR alirocumab compared to placebo (1.20, 95% CI: 0.96-1.49) or ezetimibe (0.88, 95% CI: 0.59-1.32), not-significantly different.

Conclusion

A pooled analysis of 10 ODYSSEY Phase 3 trials showed that the PCSK9 inhibitor alirocumab had no effect on DM incidence during a follow-up of 6-18 months. The ongoing ODYSSEY OUTCOMES trial, including approximately 18 000 individuals with a longer (2–5 yrs) follow-up, will provide further data to establish whether alirocumab has any effect on glycaemic measures.

Find this article online at Eur Heart J

References

1. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010;375:735–742.
2. FDA. Important Safety Label Changes to Cholesterol Lowering Statin Drugs: FDA Drug Safety Communication. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm (21 June 2016).
3. Brault M, Ray J, Gomez YH, et al. Statin treatment and new-onset diabetes: a review of proposed mechanisms. Metabolism 2014;63:735–745.
4. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489–1499.