P1226Very low achieved low-density lipoprotein cholesterol level with alirocumab treatment after acute coronary syndrome: ODYSSEY OUTCOMES
Authors: Schwartz G , Szarek M , Li Q H , Chiang C E , Diaz R , Hagstrom E , Huo Y , Jukema J W , Lecorps G , Moryusef A , Pordy R , White H D , Yusoff K , Zeiher A M , Steg P G 
Published: October 2019

Background

Recent guidelines for cholesterol management recognize uncertainty regarding long-term efficacy and safety of prolonged very low levels of LDL-C on treatment with a PCSK9 inhibitor, including risk of new-onset diabetes. ODYSSEY OUTCOMES used a treat-to-target approach to demonstrate reduction of coronary heart disease death, non-fatal myocardial infarction, ischaemic stroke, or unstable angina (MACE) with the PCSK9 inhibitor alirocumab (ALI) vs placebo (PBO) in 18,924 patients with recent acute coronary syndrome and elevated LDL-C despite intensive statin therapy. ALI was blindly adjusted (75 or 150 mg dose) to target LDL-C 0.6–1.3 mmol/L (25–50 mg/dL). To avoid sustained very low LDL-C, blind substitution of PBO for ALI was intended if 2 consecutive LDL-C levels were <0.39 mmol/L (15 mg/dL). Patients were followed for median of 2.8 years (maximum of 5 years).

Purpose

We report the efficacy and safety of ALI in patients who reached very low LDL-C (consecutively <0.39 mmol/L), compared with matched patients from the PBO group.

Methods

Of 9462 patients randomized to receive ALI, 730 (7.7%) reached very low LDL-C and had substitution of PBO a median 8.3 months after randomization. Using propensity score matching, they were compared (3:1) with 2152 patients initially assigned to PBO. Propensity score matching was also used to compare the incidence of new-onset diabetes in 525 patients without diabetes at baseline who had very low LDL-C levels on ALI with 1675 matched patients in the PBO group. Neurocognitive events and haemorrhagic stroke were also evaluated in relation to very low LDL-C.

Results

Overall, ALI reduced the incidence of MACE (9.5% vs 11.1%; HR 0.85, 95% CI 0.78–0.93; P<0.001). Characteristics used in propensity score matching (and associated with very low LDL-C on ALI) included sex (male), diabetes (present), baseline LDL-C and lipoprotein(a) (lower), region (Asia), statin treatment, smoking, hypertension, and body mass index. Despite being switched to PBO, patients with very low LDL-C on ALI had fewer MACE than matched patients from the PBO group (6.4% vs 8.5%; HR 0.71, 95% CI 0.52–0.98; P=0.039; Figure). Very low LDL-C on ALI was not associated with risk of new-onset diabetes, compared with matched patients from the PBO group (15.1% vs 13.0%; HR 1.10, 95% CI 0.85–1.43; P=0.46). There was no association of very low LDL-C on ALI with neurocognitive events or haemorrhagic stroke.

Conclusions

The overall efficacy of ALI on cardiovascular outcomes was not diminished by the patients who had blinded substitution of PBO for sustained very low LDL-C. Despite a short duration of active treatment, these patients had fewer MACE than matched controls from the PBO group. No adverse consequence of very low LDL-C was identified. However, because patients with sustained very low LDL-C were switched to PBO, the long-term safety of more prolonged very low LDL-C, including risk of new-onset diabetes, deserves further study.

Acknowledgement/Funding

Funded by Sanofi and Regeneron Pharmaceuticals