Oral nonstatin medication significantly lowers cholesterol in high-risk patients

1. In this randomized controlled trial, once-daily oral enlicitide was associated with sustained reductions in low-density lipoprotein cholesterol levels compared to placebo among those at high risk of atherosclerotic cardiovascular disease.

2. Enlicitide also lowered non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) levels without notable safety differences between groups.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Cardiovascular disease remains the leading global cause of mortality, and lowering low-density lipoprotein (LDL) cholesterol is a cornerstone of prevention of atherosclerotic cardiovascular events. While guidelines now recommend aggressive LDL targets for high-risk individuals, many patients are unable to attain these levels even with statin and ezetimibe therapy. Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have shown potent LDL-lowering effects but may be underused due to a reliance on injections for administration. This large, multinational randomized controlled trial evaluated enlicitide, a novel oral PCSK9 inhibitor, in adults with established cardiovascular disease or elevated risk. Participants received either enlicitide or placebo for one year while on background lipid-lowering therapy. Enlicitide use was associated with robust reductions in LDL compared to placebo which persisted through the entire duration of the study. Non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) levels also declined substantially in the enlicitide group. Strengths of the study include its rigorous design, diverse international cohort, and high adherence. However, some limitations were the short duration relative to lifelong lipid management, imputation of some missing data, and use of a protocol that initially mishandled certain LDL measurements. Overall, these results suggest that oral PCKS9 inhibition may be useful in achieving lipid goals among patients at risk of cardiovascular disease.

Click to read the study in NEJM

Relevant Reading: Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol

In-Depth [randomized controlled trial]: This multinational, double-blind, randomized controlled trial evaluated the efficacy and safety of enlicitide, an oral PCSK9 inhibitor, in adults either with a history of atherosclerotic cardiovascular disease (ASCVD) or considered at intermediate-to-high risk. Participants were required to have elevated LDL cholesterol despite stable background lipid-lowering therapy, primarily statins. A total of 2912 individuals were stratified by renal function, baseline statin use, and region, and then randomized in a 2:1 ratio to receive once-daily oral enlicitide (20 mg) or placebo for 52 weeks. The primary endpoint was the percent change in LDL cholesterol at 24 weeks, with secondary endpoints including lipid changes at 52 weeks and specific effects on non-HDL cholesterol, apolipoprotein B, and lipoprotein(a). At week 24, enlicitide had reduced LDL cholesterol by 57.1% (95% CI, −61.8 to −52.5) as compared to a 3.0% increase with placebo, yielding an adjusted between-group difference of −55.8 percentage points (P<0.001). This reduction persisted through week 52. Enlicitide also significantly reduced non-HDL cholesterol (−53.4 percentage points), apolipoprotein B (−50.3 percentage points), and lipoprotein(a) levels (−28.2 percentage points) at 24 weeks compared to placebo (all P<0.001). The majority of enlicitide-treated participants reached LDL targets recommended by current guidelines (e.g., <55 mg/dL with ≥50% reduction from baseline). Safety outcomes were similar between groups, with no significant differences in serious adverse events, discontinuations, or deaths. New or worsening diabetes occurred at comparable rates (6.1% with enlicitide vs. 5.8% with placebo). Adherence exceeded 97%. Overall, enlicitide demonstrated potent and sustained LDL-lowering effects among previously treated patients with elevated cardiovascular risk.

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