FDA Expands Evolocumab Label for Adults With Increased MACE Risk From Uncontrolled LDL-C

The FDA has broadened the indication for evolocumab (Repatha; Amgen) to include adults at increased risk of major adverse cardiovascular events (MACE) due to uncontrolled low-density lipoprotein cholesterol (LDL-C), even in the absence of a formal cardiovascular disease diagnosis.¹

Previously, patients needed a documented history of cardiovascular disease to be eligible for the therapy. With this expanded label, evolocumab may now be prescribed to adults with persistently high LDL-C who remain at risk despite lifestyle interventions and statin therapy, or who are unable to tolerate statins, according to an Amgen news release.

"Far too many adults at risk of cardiovascular disease are not achieving their LDL-C goals, despite it being one of the most modifiable risk factors for a heart attack or stroke," Murdo Gordon, executive vice president of global commercial operations at Amgen, said in the news release. "This label update highlights the real-world need for additional treatment options for at-risk patients. Repatha is an effective therapy for reducing LDL-C, particularly in patients whose disease remains uncontrolled with statins or who cannot tolerate them."

Alongside the broadened cardiovascular risk indication, the FDA updated evolocumab’s label to expand its use as monotherapy for patients with homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder that leads to dangerously high cholesterol levels. In both expanded indications, the therapy must be used as an adjunct to diet and exercise.

The most common adverse events were diabetes, nasopharyngitis, and upper respiratory tract infection. | Image Credit: Pawel - stock.adobe.com

First approved in 2015, evolocumab has been used by more than 5 million individuals across the world. As an adjunct therapy, it is indicated for reducing LDL-C in adults with hypercholesterolemia, and adults and children aged 10 and older with either HoFH or heterozygous familial hypercholesterolemia (HeFH). Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). By blocking PCSK9, the therapy increases the number of LDL receptors available to clear LDL-C from the bloodstream, lowering cholesterol levels.

Evidence and Safety Profile

Since its initial FDA approval, evolocumab has been studied in more than 50 clinical trials involving more than 57,000 patients worldwide, according to the release. Clinical trials and postmarket data have consistently demonstrated reductions in LDL-C and associated cardiovascular risk, with a safety profile that remains comparable with placebo in most categories.

In outcomes studies, the most common adverse events in adults taking evolocumab vs placebo included diabetes (8.8% vs 8.2%), nasopharyngitis (7.8% vs 7.4%), and upper respiratory tract infection (5.1% vs 4.8%). Injection site reactions were reported in 3.2% of treated patients vs 3% with placebo, and hypersensitivity reactions—primarily rash—occurred in about 5.1% vs 4.7% of patients.

Managed Care Implications

Historically, PCSK9 inhibitors have faced access barriers due to cost, prior authorization, and step-therapy protocols. One study published in Circulation: Cardiovascular Quality and Outcomes, an American Heart Association journal, found a much higher proportion of rejected prescriptions with PCSK9 inhibitors (30.95%) compared with branded cardiometabolic therapies (3.53%-14.61%) between 2015 and 2021.² Specific barriers like prior authorization requirements (97% vs 44%) and provider intervention (100% vs 50-54%) were much higher for PCSK9 inhibitors than guideline-indicated cardiometabolic drugs.

Broader labeling may encourage earlier consideration of evolocumab in high-risk adults without documented cardiovascular disease, particularly for those who cannot meet LDL-C targets on standard therapy.¹

With cardiovascular disease remaining a leading cause of death in the US, the FDA’s decision underscores a shift toward earlier intervention in lipid management to prevent adverse outcomes.

References

1. Repatha now indicated for adults at increased risk for major adverse cardiovascular events due to uncontrolled LDL-C. News release. Amgen. August 25, 2025. Accessed August 25, 2025. https://www.amgen.com/newsroom/press-releases/2025/08/repatha-now-indicated-for-adults-at-increased-risk-for-major-adverse-cardiovascular-events-due-to-uncontrolled-ldl-c
2. MacDougall DE, Baum SJ, Ahmed CD, McGowan MP, Wilemon KA. Trends in patient access to and utilization of prescribed PCSK9 inhibitors in a large US claims database from 2015 to 2021. Circ Cardiovasc Qual Outcomes. 2024;17(2):e009988. doi:10.1161/CIRCOUTCOMES.123.009988