Evolocumab Tied to 20% Lower Risk of Myocardial Infarction vs Ezetimibe in Real-World Study

Evolocumab (Repatha; Amgen) was associated with a 20% lower rate of fatal or nonfatal myocardial infarction (MI) compared with ezetimibe among adults with atherosclerotic cardiovascular disease (ASCVD) and prior statin use, according to a large real-world comparative effectiveness study published in the American Journal of Preventive Cardiology.¹

In the retrospective analysis of 544 103 US adults followed for up to 4 years, patients initiating evolocumab had a significantly lower rate of fatal or nonfatal MI than those initiating ezetimibe (hazard ratio [HR], 0.80; 95% CI, 0.70-0.91). Among patients with an available baseline low-density lipoprotein cholesterol (LDL-C) measurement, the estimated 4-year cumulative risk of MI was 5.88% with evolocumab versus 7.76% with ezetimibe.¹

The findings provide new head-to-head real-world cardiovascular outcomes evidence comparing 2 guideline-recommended nonstatin lipid-lowering therapies, potentially informing treatment selection for patients with ASCVD who do not achieve LDL-C goals with statins alone.

"While the recent ACC/AHA Multisociety Guideline update recognizes both ezetimibe and PCSK9 inhibitors like evolocumab as non-statin options for patients with ASCVD, clinicians have lacked direct cardiovascular outcomes evidence to help inform treatment choices for their patients that may allow them to fully achieve the recommended LDL-C goals of <70 mg/dL and <55 mg/dL," corresponding author Nihar Desai, MD, MPH, associate professor of medicine and vice chief of the Section of Cardiovascular Medicine at Yale University School of Medicine, said in a press release.² "These findings provide important comparative data that can help clinicians distinguish between these treatment options and make more informed choices to reduce their patients' cardiovascular risk.

Desai and colleagues conducted an active-comparator, new-user cohort study using deidentified data from the Komodo Health Healthcare Map database. The analysis included 64 421 patients who initiated evolocumab and 479 682 who initiated ezetimibe between January 2017 and December 2024, with follow-up continuing through June 2026. Eligible participants were aged 18 years or older, had documented ASCVD, and had previously received statin therapy.¹

The primary outcome was the first fatal or nonfatal MI during up to 48 months of follow-up.¹

To address potential differences between treatment groups, investigators used a target trial emulation framework with inverse probability weighting to balance measured baseline characteristics and account for treatment changes during follow-up. A calibrated statistical approach was also used to address incomplete baseline LDL-C data.¹

Evolocumab Associated With Lower MI Risk Across Analyses¹

Before adjustment, patients initiating evolocumab were younger than those receiving ezetimibe (median age, 65 vs 67 years) and were less likely to be receiving statins at treatment initiation (55% vs 76%). Median baseline LDL-C was also higher in the evolocumab group (114 vs 99 mg/dL) among participants with available measurements.

After weighting, measured baseline characteristics were balanced between treatment groups. During follow-up, investigators identified 1129 fatal or nonfatal MI events among evolocumab initiators and 10 306 among ezetimibe initiators.

Among 225 048 participants with available baseline LDL-C measurements, the estimated cumulative risk of fatal or nonfatal MI at 4 years was 5.88% (95% CI, 4.77%-7.00%) with evolocumab compared to 7.76% (95% CI, 7.31%-8.20%) with ezetimibe.

Among 319 055 participants without available baseline LDL-C measurements, corresponding estimated risks were 5.65% (95% CI, 4.83%-6.47%) and 7.06% (95% CI, 6.70%-7.42%), respectively.

When investigators combined estimates from both groups using a calibrated approach to account for missing LDL-C data, evolocumab initiation was associated with a 20% lower rate of fatal or nonfatal MI compared with ezetimibe (HR, 0.80; 95% CI, 0.70-0.91).

The results were consistent in a prespecified sensitivity analysis that continued follow-up regardless of changes in background statin therapy (HR, 0.79; 95% CI, 0.72-0.87).

Notably, among patients receiving statins at the time of nonstatin treatment initiation, evolocumab was associated with a 37% lower rate of fatal or nonfatal MI compared with ezetimibe (HR, 0.63; 95% CI, 0.54-0.75). This subgroup included 35 688 evolocumab initiators and 365 630 ezetimibe initiators.

The investigators noted that this subgroup more closely reflected the clinical setting in which a nonstatin medication is added to existing statin therapy.

Implications for LDL-C Management in Primary Care

The findings may be particularly relevant for primary care physicians managing patients with established ASCVD whose LDL-C remains above recommended treatment goals despite statin therapy.

Evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, lowers LDL-C by increasing the availability of hepatic LDL receptors, while ezetimibe reduces intestinal cholesterol absorption. Both are established nonstatin treatment options for patients requiring additional LDL-C lowering.

Although previous randomized trials demonstrated cardiovascular benefits for each medication compared with placebo or background therapy, large randomized trials directly comparing evolocumab and ezetimibe on cardiovascular outcomes have not been conducted.

"We have known for decades that lowering LDL cholesterol reduces cardiovascular risk, yet many patients with ASCVD cannot reach recommended levels with statins alone," Paul Burton, MD, PhD, chief medical officer at Amgen, said in the press release.² "For physicians deciding what treatment to add next, whether that's prescribing patients Repatha or ezetimibe, this large real-world study provides clear evidence to help inform that choice."

"While the recent ACC/AHA Multisociety Guideline update recognizes both ezetimibe and PCSK9 inhibitors like evolocumab as non-statin options for patients with ASCVD, clinicians have lacked direct cardiovascular outcomes evidence to help inform treatment choices for their patients that may allow them to fully achieve the recommended LDL-C goals of <70 mg/dL and <55 mg/dL," Desai said in the press release.²

"These findings provide important comparative data that can help clinicians distinguish between these treatment options and make more informed choices to reduce their patients' cardiovascular risk," he continued.

For primary care physicians, the results reinforce the importance of reassessing LDL-C after statin initiation or intensification and considering additional lipid-lowering therapy when treatment goals are not achieved.

However, the findings do not establish that all patients with ASCVD should receive evolocumab instead of ezetimibe. Treatment selection should continue to account for the magnitude of additional LDL-C lowering needed, baseline cardiovascular risk, medication cost and access, route of administration, and patient preferences.

Study Limitations and Clinical Considerations

Despite the large sample size and target trial emulation design, the investigators emphasized that the study was observational and could not eliminate residual confounding.

In particular, administrative claims data did not fully capture statin intolerance, payer denials, prior failure to achieve LDL-C targets, patient preferences, or other factors that may have influenced treatment selection and cardiovascular outcomes.

Baseline LDL-C measurements were available for only 41.4% of participants, requiring statistical calibration to account for missing data. Additionally, pharmacy claims documented medication dispensing but could not confirm whether patients took the medications as prescribed.

Although outcomes were estimated over a maximum follow-up of 4 years, actual median follow-up was substantially shorter: 4.3 months among evolocumab initiators and 5.8 months among ezetimibe initiators. The 4-year cumulative risk estimates therefore relied on the statistical methods used to account for censoring and treatment changes.

The study was funded by Amgen, whose employees participated in study design, data analysis, interpretation, and manuscript review.¹

The researchers concluded that initiating evolocumab was associated with a significantly lower rate of fatal or nonfatal MI compared with ezetimibe among patients with ASCVD and prior statin use, providing additional real-world evidence to inform nonstatin treatment decisions.

However, randomized head-to-head cardiovascular outcomes data would be needed to establish whether evolocumab provides superior clinical protection compared with ezetimibe.

References

1. Desai N, Jin R, Hurwitz K, et al. Real-world comparative effectiveness of evolocumab versus ezetimibe in adults with atherosclerotic cardiovascular disease: an active-comparator new-user study. Am J Prev Cardiol. Published online 2026. doi:10.1016/j.ajpc.2026.102577
2. Amgen. Repatha lowers risk of heart attacks by 20% compared with ezetimibe in a large real-world study. News release. November 5, 2026. Accessed November 5, 2026. https://investors.amgen.com/news-releases/news-release-details/repathar-lowers-risk-heart-attacks-20-compared-ezetimibe-large