Abstract Body (Do not enter title and authors here): Background: Patients with acute coronary syndrome (ACS) and elevated LDL-C levels despite statin therapy may have genetic dyslipidemias, such as heterozygous familial hypercholesterolemia (HeFH) or type III hyperlipoproteinemia (T3HLP), which convey heightened cardiovascular (CV) risk due to lifelong exposure. In this post hoc analysis of the ODYSSEY OUTCOMES trial, we identified patients likely affected by HeFH or T3HLP and evaluated the lipid-lowering and CV efficacy of alirocumab.

Methods: Clinical HeFH was based upon ACS at age <55 (males) or <60 (females) with back-calculated untreated LDL-C ≥250 mg/dL, or ACS at any age with back-calculated LDL-C ≥330 mg/dL. T3HLP was based upon non-HDL-C:apolipoprotein (apo)B ratio >2.6, which was validated using the UK Biobank database. Additionally, a pharmacogenomics (PGx) subgroup (n=11,880) was studied for variants in genes causing HeFH and for apoE genotypes (T3HLP).

Results: Clinical HeFH was identified in 6.7% of the full trial cohort and 5.9% of the PGx subgroup. In the PGx subgroup, 295 patients (2.5%) had genetically confirmed HeFH, 45.8% of whom also qualified as clinical HeFH. Baseline LDL-C was higher in patients with vs without clinical or genetic HeFH (Table). Percent LDL-C-lowering was lower but absolute LDL-C lowering and hazard ratio for major adverse CV events (MACE) with alirocumab were similar in patients with versus without clinical or genetic HeFH. Only 0.09% of subjects in the UK Biobank carried the T3HLP biomarker ratio, with 89% of these carrying the apoE2/2 homozygote genotype. Only 30 of 18,924 patients (0.16%) in the trial were classified as T3HLP. Of these, 13 were in the PGx subgroup of whom 7 (53.8%) were apoE2/2 homozygotes. Lipid responses to alirocumab in patients with T3HLP were comparable with those in the overall population (>50% LDL-C lowering and numerically lower MACE rate).

Conclusions: In this post hoc analysis of ODYSSEY OUTCOMES, individuals with HeFH were common and those with T3HLP were rare. Carriers of either genetic condition benefited from alirocumab in terms of lipid response and clinical outcomes.