VESALIUS-CV Secondary Analysis: Lower LDL-C Benefits Extend Into High-Risk Primary Prevention Without Atherosclerosis

The VESALIUS-CV trial primary prevention analysis was a prespecified evaluation of use of evolocumab in 3,655 trial participants who had elevated LDL cholesterol (LDL-C) values but no evidence of significant atherosclerotic cardiovascular disease (ASCVD), defined as no prior revascularization, no arterial stenosis ≥50%, and no coronary artery calcium (CAC) score ≥100. Yet nearly all were characterized by high-risk diabetes (≥10-year duration, on insulin, or with evidence of microalbuminuria).¹

All participants were taking maximally tolerated oral lipid-lowering therapy, and, like the overall VESALIUS-CV cohort, were randomized to evolocumab or placebo in addition to their lipid-lowering therapies. Statins were used in slightly <85% of patients, ezetimibe in 14%, and a small percentage were treated with statins plus ezetimibe. Overall, nearly two-thirds were taking high-intensity statins.

The baseline LDL-C pre-randomization measured 132 mg/dL in both groups, suggesting a significant cohort with difficult to manage dyslipidemia. Despite the absence of established ASCVD, intensification of lipid-lowering therapy with evolocumab yielded substantial and clinically meaningful benefits including:

• A 51% reduction in LDL-C by 48 weeks, with a median achieved LDL-C of 52 mg/dL in those taking evolocumab vs. 111 mg/dL in the placebo group.
• A 31% relative risk reduction in 3-point major adverse cardiovascular events (MACE) and a similar reduction in the expanded 4-point MACE including ischemia-driven revascularization from 10.5% to 7.6% in those taking evolocumab.
• A 24% reduction in all-cause mortality.
• In a landmark analysis, the effect of evolocumab was more apparent after the first year of treatment, with 41% (hazard ratio [HR], 0.59 [95% CI, 0.43-0.81]) and 39% (HR, 0.61 [95% CI, 0.48-0.79]) reductions in the risk of 3- and 4-point MACE, respectively, in the years that followed.

The findings demonstrate that lower, more aggressive lowering of LDL-C with use of evolocumab improves outcomes in a high-risk primary prevention population and likely endorses early clinical adoption of lower LDL-C thresholds in patients like those in the VESALIUS-CV cohort.

Current guidelines acknowledge diabetes as a risk-enhancing condition,^2,3 but often rely on surrogates such as CAC scoring to refine intensity. This analysis suggests that in high-risk diabetic populations, absence of detectable atherosclerosis should not preclude intensified LDL-C lowering. The data support:

• De-emphasizing presence of atherosclerosis as a factor to implement intensive lipid-lowering strategies in patients with high-risk diabetes.
• Broadening eligibility for combination and advanced lipid-lowering therapies in primary prevention.
• Reinforcing numeric LDL-C targets rather than stepwise treatment escalation alone.

Ez-PAVE: Pragmatic Validation of LDL-C Targets in Secondary Prevention

Whereas the VESALIUS-CV trial pushes boundaries in primary prevention, the Ez-PAVE trial solidifies LDL-C goal-based strategies in established ASCVD. Unlike purely explanatory trials, Ez-PAVE was pragmatic, testing real-world implementation of intensive LDL-C targeting (<55 mg/dL) versus conventional goals (<70 mg/dL).⁴

Patients with ASCVD, defined as the previous occurrence or presence of at least one of the following: previous acute coronary syndrome (myocardial infarction or unstable angina), stable angina with imaging or functional studies, coronary revascularization or other arterial revascularization, stroke or transient ischemic attack, or peripheral artery disease, and who had LDL-C values >70 mg/dL were included for randomization. Patients were randomly assigned in a 1:1 ratio to a target LDL-C level of <55 mg/dL (intensive-targeting group) or <70 mg/dL.

High-intensity statins, ezetimibe, or PCSK9 monoclonal antibodies were allowed in either arm but were used more frequently in the intensive targeted group. PCSK9 therapy was used in <3% of patients overall, as statin and ezetimibe therapy were predominantly used. High-intensity statins were used in approximately 50% of the patients.

After three years of follow-up, a primary endpoint occurred in 6.6% of patients randomized to the lower LDL-C threshold arm and in 9.7% of patients in the higher LDL-C threshold arm, despite a relatively modest median LDL-C difference between arms (median of 52 vs. 66 mg/dL). The magnitude of risk reduction observed with relatively modest differences of LDL-C thresholds achieved (52 vs. 66 mg/dL) is provocative but clearly demonstrated, and the data are compelling for consideration of adoption for lower LDL-C thresholds.

Ez-PAVE offers what guideline committees often lack: outcomes-based validation of LDL-C targets in a pragmatic setting. Its contributions include:

• Reinforcing <55 mg/dL LDL-C goals in secondary prevention as both achievable and beneficial.
• Demonstrating that combination therapy (statin plus ezetimibe, with selective PCSK9 inhibitor use) can be implemented effectively.
• Supporting a return to explicit LDL-C targets, rather than abandoning them in favor of intensity-based statin therapy alone.

Although the trial was limited to an Asian population and had a shorter follow-up, its findings align with global evidence and strengthen the argument for target-driven lipid management embedded directly into guidelines.

Perspective

ACC.26 will be remembered as a landmark meeting for broadening our understanding of primary and secondary prevention because the new guideline and data from these two studies reinforce several themes and form a coherent narrative:

• VESALIUS-CV extends "lower is better" into high-risk primary prevention – even without imaging-proven atherosclerosis.
• Ez-PAVE confirms that stricter LDL-C targets translate into superior outcomes when applied pragmatically in secondary prevention.

This convergence supports future guideline language that:

• Emphasizes earlier initiation, longer duration, and lower achieved LDL-C.
• Encourages broader prescribing authority for advanced lipid therapies.
• Reintegrates numeric LDL-C goals as a central organizing principle of lipid management.

GoFreshRx: Translating Lifestyle Therapy Into Guideline-Ready Evidence For Hypertension

The GoFreshRx trial addresses a long-standing gap in hypertension guidelines: the lack of scalable, outcomes-oriented evidence for structured dietary interventions in real-world, high-risk populations. This randomized trial compared a home-delivered DASH-pattern diet to a stipend-based self-directed approach among predominantly Black participants (81% women).⁵

The intervention achieved:

• Significant reductions in systolic and diastolic blood pressure (BP).
• Partial durability of BP benefit after intervention discontinuation.
• No significant changes in BMI or glycemic control, highlighting BP-specific efficacy.

Importantly, the trial demonstrates that removing structural barriers to healthy eating – not merely providing education – can produce guideline-relevant BP reductions. Although generalizability remains a limitation, upcoming expansions such as the GoFresh SouthEast research program promise to broaden applicability and inform more inclusive hypertension recommendations.

GoFreshRx strengthens the evidence base for:

• Elevating food-as-medicine interventions from adjunctive to core components of hypertension management.
• Explicitly addressing social and economic barriers within guideline frameworks.

Conclusion

VESALIUS-CV, Ez-PAVE, and GoFreshRx trials collectively signal a maturation of cardiovascular prevention guidelines. Lipid management is moving decisively toward earlier, lower, and goal-oriented therapy, whereas hypertension care increasingly recognizes the necessity of structural lifestyle interventions.

Together, these trials argue that optimal cardiovascular prevention requires not only controlling biomarkers – but also rethinking who qualifies for intensive therapy and how care is delivered in the real world addressing goal numbers but also social determinants of health.

References

1. Marston NA, Bohula EA, Bhatia AK, et al. Evolocumab to reduce first major cardiovascular events in patients without known significant atherosclerosis and with diabetes: results from the VESALIUS-CV trial. JAMA. Published online March 28, 2026. doi:10.1001/jama.2026.3277
2. Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of dyslipidemia: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol. Published online March 13, 2026. doi:10.1016/j.jacc.2025.11.016
3. Blumenthal RS, Morris PB; 2026 ACC/AHA Guideline on the Management of Dyslipidemia Writing Committee. Clinical guidelines as a continuous work in progress: moving at the speed of science. J Am Coll Cardiol. Published online March 13, 2026. doi:10.1016/j.jacc.2026.02.4869
4. Lee YJ, Lee SJ, Kim JW, et al. Intensive LDL cholesterol targeting in atherosclerotic cardiovascular disease. N Engl J Med. 2026;394(14):1365-1375. doi:10.1056/NEJMoa2600283
5. Juraschek SP, Col H, Ferro K, et al. DASH-patterned groceries and effects on blood pressure in adults treated for hypertension: the GoFreshRx randomized trial. Nat Med. Published online March 28, 2026. doi:10.1038/s41591-026-04319-4