Efficacy of enlicitide across ESC cardiovascular risk categories in two CORALreef phase 3 trials

Background/Introduction Enlicitide, an oral PCSK9 inhibitor, has demonstrated robust LDL-C lowering efficacy of ~60% in the phase 3 CORALreef Lipids and CORALreef HeFH trials. ESC Guidelines emphasize that lipid-lowering therapy should be guided by an individual’s estimated cardiovascular risk. Purpose To evaluate the efficacy of enlicitide versus placebo in a pooled analysis of CORALreef Lipids and HeFH across ESC cardiovascular risk categories. Methods Data from two randomized, double-blind, placebo-controlled phase 3 trials evaluating enlicitide 20 mg once daily were pooled. Baseline cardiovascular risk categories were assigned using ESC guideline criteria. Endpoints evaluated across baseline cardiovascular risk categories included placebo-corrected mean percent change in LDL-C from baseline at Week 24 and Week 52, placebo-corrected percent changes in non-HDL-C, ApoB, and Lp(a), LDL-C goal attainment (<55 mg/dL and ≥50% reduction for very-high-risk; <70 mg/dL and ≥50% reduction for high-risk; <100 mg/dL for moderate risk), and ApoB goal attainment (<65 mg/dL for very-high-risk; <80 mg/dL for high-risk) at Week 24. Results The pooled cohort comprised 3212 participants (enlicitide n=2142; placebo n=1070), with a mean age of 61.8 years, 40.4% women. The baseline ESC cardiovascular risk distribution was 61.5% very-high, 30.0% high, 6.9% moderate, and 1.5% unable to categorize. Baseline mean ± SD LDL-C levels were 92.6 ± 42.3, 108.8 ± 33.5, and 103.8 ± 28.6 mg/dL in the very-high, high, and moderate risk categories, respectively. The proportions receiving no statin therapy were 2.8%, 3.2%, and 4.9%, while high intensity statin use was 65.6%, 44.0%, and 39.0% across the same groups. Significant placebo-corrected reductions in LDL-C, non-HDL-C, ApoB, and Lp(a) at Week 24 were demonstrated across all ESC risk categories (nominal p<0.001) (Figure A). LDL-C lowering efficacy was sustained at Week 52 across all risk categories. At Week 24, LDL-C goal attainment was consistently higher with enlicitide versus placebo (Figure B). Concordantly, ApoB goals were achieved in 81% versus 16% of participants receiving enlicitide versus placebo in the very-high risk group (goal <65 mg/dL) and in 84% versus 22% in the high risk group (goal <80 mg/dL). Conclusions Across ESC cardiovascular risk strata, enlicitide achieved robust reductions in LDL-C, non-HDL-C, ApoB, and Lp(a), with profoundly higher LDL-C and ApoB goal attainment versus placebo. Amid the global cardiovascular disease epidemic, these findings highlight enlicitide’s potential to meaningfully reduce atherogenic lipids across a broad cardiovascular risk spectrum and help more patients achieve LDL-C and ApoB goals.