Cholesterol-lowering drugs known as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may not be well-known, but when added to statin therapy they provide powerful protection for individuals at high risk of heart attack and stroke.
“Research has found that PCSK9 inhibitors can decrease LDL cholesterol (LDL-C) by up to 70% and cut the risk of a heart attack by almost one-third,” says Cleveland Clinic preventive cardiologist Ashish Sarraju, MD.
Going Low with LDL Cholesterol
The optimal LDL-C goal depends on an individual’s risk of major cardiovascular events, which generally include heart attack, stroke, revascularization (i.e., reopening blocked coronary arteries with angioplasty and stenting or coronary artery bypass surgery) and cardiovascular death. Many individuals are able to achieve or surpass their LDL goal with a statin medication—examples include atorvastatin (Lipitor) and rosuvastatin (Crestor)—and ezetimibe (Zetia). Intensive statin therapy has been shown to lower LDL from 100 milligrams per deciliter (mg/dL) to 70 mg/dL. Adding Zetia can lower it further, to 54 mg/dL.
But that may not be low enough to protect certain individuals. Clinical trials have shown that high-risk patients continue to benefit from LDL as low as 20 mg/dL to 25 mg/dL—levels that simply cannot be attained with statins plus ezetimibe. They need the extra boost that PCSK9 inhibitors provide.
“Because LDL should be lower longer for high-risk patients, we tend to give them evolocumab (Repatha) or alirocumab (Praluent). We consider the two PCSK9 inhibitors comparable,” says Dr. Sarraju.
PCSK9 Inhibitors: Avoiding a First Event
The value of adding a PCSK9 inhibitor to conventional lipid-lowering therapy was validated by the Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke (VESALIUS-CV) study, which was presented at the American Heart Association Annual Scientific Sessions in November 2025.
In this phase 3 study, 12,000 participants with an LDL cholesterol level of 120 mg/dL were randomized to receive subcutaneous (under the skin) injections of evolocumab or a placebo for a median of 4½ years. All participants were considered at high risk for a cardiovascular event due to extensive atherosclerosis or type 2 diabetes, but had not yet suffered a heart attack or stroke.
At the end of the study, LDL-C levels in participants taking evolocumab had dropped from a median of 115 mg/dL to 45 mg/dL, and they had suffered 25% fewer cardiac deaths, ischemic strokes or revascularizations than the placebo recipients, whose LDL remained at 115 mg/dL.
“These are patients we would see in clinic,” says Dr. Sarraju. “The outcome is encouraging and validates our decision to use PCSK9 inhibitors in high-risk patients.”
Evolocumab Protects Those at High Risk
The results of VESALIUS reflect those of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial, reported in 2017. FOURIER randomized 27,564 patients with a history of heart attack, stroke, or symptomatic peripheral arterial disease to evolocumab or placebo. All had LDL cholesterol levels of 70 mg/dL or higher despite moderate- to high-intensity statin therapy.
At 48 months, individuals on the PCSK9 inhibitor had LDL cholesterol levels of 30 mg/dL. Their cardiovascular risk fell 16% during the first year and 25% during the second year of taking the drug, showing that risk reduction with lipid-lowering therapy improves over time.
Lifesaving PCSK9 Inhibitors
Dr. Sarraju likes the fact that PCSK9 inhibitors lower cardiovascular risk, regardless of whether an individual has already suffered a cardiovascular disease event or is at high risk of having one.
“Risk is a continuous spectrum ranging from mildly elevated with no heart attack yet to very high in someone who has suffered multiple prior events,” he says. A potent lipid-lowering medication that can prevent a first event or another event will save lives.”
