inhibitors cut hard, and they have all been antibodies given by injection, which limits who ends up taking one. Enlicitide is an oral version, and a phase 2 trial had already shown it lowers LDL. A phase 3 trial then randomized 2,909 adults at or after cardiovascular risk two to one against placebo for 52 weeks. How far does a tablet get you?
It got 55.8 below placebo. At week 24 the mean change in LDL cholesterol was -57.1 percent with enlicitide against plus 3.0 percent with placebo, an adjusted between-group difference of -55.8 percentage points. Baseline LDL averaged 96.1 milligrams per deciliter, the participants averaged 63 years old, and 39.3 percent were women. That is injection-scale lowering from a daily tablet.
PCSK9 inhibitors lower LDL cholesterol further than statins manage on their own, and until now every one of them has been an injected antibody. That route works clinically and narrows the population in practice, because an injection every few weeks is a larger ask than a tablet.
Enlicitide decanoate is an oral PCSK9 inhibitor, and a phase 2 trial had already shown it reduces LDL. What was missing was longer-term data in the people who would actually take it. This multinational, double-blind, randomized, trial enrolled two groups. One had already had a major atherosclerotic cardiovascular event, with LDL at or above 55 milligrams per deciliter. The other was at risk of a first event, with LDL at or above 70 milligrams per deciliter.
Participants were assigned two to one to enlicitide 20 milligrams daily or placebo for 52 weeks. Of 2,909 in the intention-to-treat population, 1,935 received the drug and 969 the placebo. Mean age was 63 years, 39.3 percent were women, and mean baseline LDL was 96.1 milligrams per deciliter.
At week 24 the mean percent change in LDL was -57.1 percent with enlicitide and plus 3.0 percent with placebo, an adjusted between-group difference of -55.8 percentage points. Read what that is and is not. It is a large, placebo-controlled reduction in a marker whose link to cardiovascular events is about as well established as such links get. It is still a marker, and this trial did not measure heart attacks, strokes or deaths.
wat. A daily tablet dropped LDL cholesterol by about 57 percent while placebo drifted slightly upward, over twenty-four weeks.
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Adherence is the weak point of lipid lowering, and an injectable adds a barrier that a tablet does not. A pill reaching the same depth of LDL reduction changes who can realistically be treated.
How do we know?
Navar and colleagues ran a multinational, double-blind, randomized, placebo-controlled trial, assigning 2,909 adults two to one to 20 milligrams of enlicitide daily or placebo for 52 weeks. LDL change at week 24 was the primary end point.
What is still unknown
The primary end point is a surrogate: LDL cholesterol, not heart attacks, strokes or deaths. Lowering LDL is strongly tied to lowering events, and this trial measured the marker rather than the outcome patients care about.
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