Key points from article :
For decades, scientists have known that high LDL (“bad”) cholesterol drives heart disease, but a surprising genetic discovery transformed how doctors can lower that risk. In the late 1990s, French geneticist Catherine Boileau identified a mysterious mutation in families with extreme cholesterol levels. Around the same time, researchers including Helen Hobbs and Jonathan Cohen in the US found that people born with naturally “broken” versions of a little-known gene called PCSK9 had extraordinarily low LDL cholesterol—and were largely protected from heart attacks and strokes. These findings revealed PCSK9 as a powerful biological switch controlling cholesterol levels.
That insight sparked the development of PCSK9 inhibitor drugs, designed to block the protein and preserve LDL receptors in the liver. Amgen’s monoclonal antibody, evolocumab, produced dramatic LDL reductions—up to 80% when added to statins. The real test came in large clinical trials. In the FOURIER trial, led by Marc Sabatine and published in The New England Journal of Medicine, evolocumab reduced major cardiovascular events by about 15%, and heart attacks and strokes by around 20%, in patients with established heart disease.
More recently, the VESALIUS-CV trial, also published in The New England Journal of Medicine in 2025, showed that starting PCSK9 inhibition earlier can prevent first heart attacks and strokes. Among high-risk patients with no prior cardiovascular events, evolocumab cut major outcomes by 25%, with no increase in serious side effects. These results extend PCSK9 inhibitors from secondary prevention into the realm of primary prevention.
The final breakthrough may be convenience. A new oral PCSK9 inhibitor, enlicitide, achieved LDL reductions of roughly 55–60% in high-risk patients in a phase 3 trial, without safety concerns. If future studies confirm that pills can match injections in preventing heart attacks and strokes, PCSK9 inhibition could become one of the most powerful and accessible tools for reducing heart disease risk in a generation.
