NLA 2026: Evolocumab Cuts Cardiovascular Events in High-Risk Patients Before First MI or Stroke

At the 2026 National Lipid Association (NLA) Scientific Sessions in Chicago, Illinois, a session titled "Rewriting the Rules for Primary Prevention: New Outcomes From Intensive LDL-C Reduction in High-Risk Patients" brought together 3 investigators from the TIMI Study Group at Brigham and Women's Hospital to discuss new findings from the VESALIUS-CV trial (NCT03872401) and what they mean for the future of cardiovascular risk reduction.¹

The session was moderated by Kevin Maki, PhD, CLS, MNLA, and featured presentations from Robert Giugliano, MD, SM, professor of medicine at Harvard Medical School and cardiovascular physician at Brigham and Women’s Hospital; Nicholas Marston, MD, MPH, assistant professor of medicine at Harvard Medical School and cardiologist at Brigham and Women’s Hospital; and Erin Bohula, MD, DPhil, assistant professor at Harvard Medical School and associate physician at Brigham and Women’s Hospital.¹

Giugliano opened with a history of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor development, tracing the field from the 2003 discovery of PCSK9 gain-of-function mutations causing familial hypercholesterolemia to the identification, just 3 years later, of loss-of-function variants associated with modestly lower low-density lipoprotein cholesterol (LDL-C) but an over 80% reduction in cardiovascular events.^1-3

"The field moved extremely rapidly," Giugliano said, recalling some of the earliest preclinical data on what would become evolocumab (Repatha; Amgen). "It was clear as day. If you could do this and give this safely to humans, we'd have a very potent, long-acting therapy that should reduce cardiovascular events."¹

That promise led to FOURIER (NCT01764633) and ODYSSEY Outcomes (NCT01663402), 2 phase 3 trials that each reduced major adverse cardiovascular events (MACE) by 15% in patients with established atherosclerotic cardiovascular disease (ASCVD). But Giugliano noted both trials had a key limitation. It had median follow-ups of just 2.2 and 2.8 years, respectively, "about half the duration of a typical traditional statin trial."^1,4,5

FOURIER-OLE: "Cumulative LDL Toxicity" and the Case for Starting Early

The FOURIER Open-Label Extension (FOURIER-OLE) addressed that gap. Over 5 additional years of open-label evolocumab, patients who were originally randomly assigned to evolocumab—who therefore had a head start on LDL-C lowering—showed an approximate 15% reduction in the primary cardiovascular composite, a 20% reduction in cardiovascular death, myocardial infraction (MI), or stroke, and, for the first time with this drug class, a significant reduction in cardiovascular death.⁶

Giugliano offered an analogy to explain why the mortality benefit took years to emerge. "If you think of, say, pack years of smoking history, and patients accrue that over years, and the risk of lung cancer increases over time...if you think of LDL as a toxin in the blood—almost a carcinogen—it makes sense that the earlier you started, the more aggressively you treat, the better the outcomes are going to be." He added that when the main FOURIER trial is stitched together with the open-label extension, "…there was nothing for the first 2 to 2.5 to 3 years, but then the curves diverge."¹

Long-term safety data from FOURIER-OLE were also reassuring. Giugliano noted that some patients maintained LDL-C below 20 mg/dL for over 8 years with no signal of increased adverse events across multiple safety categories.^1,6

How Low Is Too Low? Evidence Behind the Push Toward Sub-40 Targets

Marston picked up where Giugliano left off, reviewing 3 decades of progressively lower LDL-C treatment goals, from 130 mg/dL in 1993 to under 55 mg/dL for very-high-risk patients with ASCVD in the 2026 American Heart Association/American College of Cardiology dyslipidemia guideline, with European guidelines introducing an "extreme risk" category targeting under 40 mg/dL.¹

"At each of these levels we kind of doubted that going lower would be helpful, but we were proven wrong at every point," Marston said.^1,7,8

To test whether benefit plateaus below 40 mg/dL, Marston's team analyzed FOURIER patients whose LDL-C lowering occurred substantially below that threshold, in some cases up to 38% of their total reduction. "We actually saw no attenuation of the benefit, even when more than a third of the LDL lowering was occurring below 40 mg/dL," Marston said, noting the same pattern held in achieved-LDL analyses down to single digits, and that it mirrored plaque regression data from the GLAGOV trial (NCT01813422), where "we see no plateau, we see a continued gradient pushing all the way down to 20 mg/dL."^1,9,10

He also highlighted a FOURIER-OLE analysis in which roughly a quarter of patients achieved LDL-C below 20 mg/dL for as long as 7 to 8 years with no excess in neurocognitive events, muscle-related events, or new-onset diabetes. "We hear this a lot from physicians and from patients that say, 'Oh, the LDL is in the teens, I'm going to stop one of their lipid-lowering therapies,'" Marston said. "No, no, don't do that. We don’t need to do that."¹

From Reactive to Proactive: The Rationale for VESALIUS-CV

Marston framed the current treatment paradigm as reactive. "We wait until patients have an event before we get serious about their LDL lowering," he said, adding that FOURIER and ODYSSEY Outcomes were both conducted exclusively in secondary prevention populations, leaving open the question of whether benefit extends to patients who haven't yet had a first MI or stroke, what the speakers described as the "pre-event population.”¹

VESALIUS-CV was designed to answer that question, and Marston noted that 3 additional trials (VICTORION-1 PREVENT [NCT05739383], AZURE-Outcomes [NCT07000357], and CORALreef Outcomes [NCT06008756]) are testing other PCSK9-targeting therapies in similar populations, though results aren't expected until around 2029.¹

VESALIUS-CV Results: Reductions in MACE Across a Broad Pre-Event Population

Bohula presented the primary results of VESALIUS-CV, which enrolled 12,257 patients across more than 700 sites in 33 countries who were stable, at high cardiovascular risk, but had no prior MI or stroke. Patients qualified based on coronary artery disease without MI, cerebrovascular disease without stroke, peripheral artery disease, or high-risk diabetes (duration of at least 10 years, insulin use, or microvascular disease), plus elevated LDL-C, non-high-density lipoprotein cholesterol (non–HDL-C), or apolipoprotein B on optimized statin therapy. Median follow-up was 4.6 years, designed deliberately to mirror the longer duration of classic statin trials.¹¹

Evolocumab reduced median LDL-C to approximately 45 mg/dL, a 55% reduction, along with a 44% reduction in apolipoprotein B and a 27% reduction in lipoprotein(a). The trial met both dual primary endpoints: a 25% relative risk reduction in 3-point MACE (cardiovascular death, MI, or ischemic stroke) and a 19% relative risk reduction in 4-point MACE (adding ischemia-driven revascularization), translating to numbers needed to treat over 5 years in the 30s to 50s. Key secondary end points included a 36% reduction in MI and a 21% reduction in ischemia-driven revascularization, with nominal reductions in cardiovascular death (hazard ratio [HR], 0.79) and all-cause death (HR, 0.80; nominal P = .0005).¹¹

Echoing the FOURIER-OLE lesson, Bohula noted that mortality curves in VESALIUS-CV "are only diverging after about a year and a half," underscoring that benefit accrues over time. She also pointed out that VESALIUS-CV's results fell directly on the established Cholesterol Treatment Trialists' meta-regression line linking absolute LDL-C reduction to cardiovascular protection, "in terms of the importance of the lag of benefit."^1,11

What This Means for Pharmacists

The discussion repeatedly returned to practical implications for counseling patients, an area where pharmacists play a central role.

When asked how to communicate "lower is better" targets in everyday practice, Marston said imaging data resonates with patients, "I think that GLAGOV curve that we showed, where the lower you get your LDL...patients really like the idea that the plaque could kind of decrease, you could regress some of your plaque."¹

Giugliano described color-coding the same curve for patients in his office, a red zone for LDL-C above 70 mg/dL, yellow for 55 to 70, and green below 55, since "that's where you got [a] 95% probability" of plaque regression rather than progression. "I [ask], 'What LDL do you want?' We know you already have had atherosclerosis...and unless they're completely psychotic, they pick the green zone."¹

For pharmacists fielding patient concerns about very low LDL-C values, including questions about cataract risk raised from product labeling for alirocumab (Praluent; Regeneron, Sanofi), Marston pointed to the long-term FOURIER-OLE safety data as the most reassuring evidence base, particularly for evolocumab. Giugliano also addressed the common worry over extremely low or even "negative" calculated LDL-C values, noting that standard equations like Friedewald become inaccurate at very low levels and that single-digit LDL-C has not been associated with excess adverse events. For patients bothered by pill burden, he said deescalating adjunct therapies like ezetimibe (Zetia; Merck & Co) may be reasonable, but the PCSK9 inhibitor itself should generally be continued: "I think the lowest is best."^1,6

Pharmacists should also be aware of where this evidence does not yet extend. Audience members raised questions about generalizability to South Asian and Filipino patients, given that VESALIUS-CV was approximately 93% White, and about younger patients with type 2 diabetes and elevated Lp(a), for whom Marston and Giugliano agreed that earlier intervention is conceptually important even though dedicated trial data in younger populations does not yet exist.¹

As 3 additional outcomes trials testing PCSK9-pathway therapies in pre-event populations move toward 2029 completion, VESALIUS-CV will remain the primary evidence base for intensive, earlier LDL-C lowering in patients with high-risk diabetes, subclinical atherosclerosis, prior percutaneous coronary intervention without MI, or elevated Lp(a), populations pharmacists encounter regularly and can help identify for more aggressive lipid management.¹

REFERENCES

1. Maki K, Giugliano R, Marston N, Bohula E. “Session VI | Rewriting the rules for primary prevention: New outcomes from intensive LDL-C reduction in high-risk patients.” Presented: National Lipid Association 2026 Scientific Sessions; June 11–14, 2026; Chicago, Illinois. Accessed Via Online Virtual Platform on June 15, 2026.

2. Abifadel M, Varret M, Rabès JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34(2):154-156. doi:10.1038/ng1161

3. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272. doi:10.1056/NEJMoa054013.

4. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664

5. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097-2107. doi:10.1056/NEJMoa1801174

6. O'Donoghue ML, Giugliano RP, Wiviott SD, et al. Long-term evolocumab in patients with established atherosclerotic cardiovascular disease. Circulation. 2022;146(15):1109-1119. doi:10.1161/CIRCULATIONAHA.122.061620

7. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AHA/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625

8. Mach F, Koskinas KC, Roeters van Lennep JE, et al. 2025 focused update of the 2019 ESC/EAS guidelines for the management of dyslipidaemia. Eur Heart J. 2025;46(42):4359-4378. doi:10.1093/eurheartj/ehaf190

9. Marston NA, Giugliano RP, Park JG, et al. Cardiovascular benefit of lowering low-density lipoprotein cholesterol below 40 mg/dL. Circulation. 2021;144(20):1732-1734. doi:10.1161/CIRCULATIONAHA.121.056536

10. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316(22):2373-2384. doi:10.1001/jama.2016.16951

11. Bohula EA, Marston NA, Bhatia A, et al. Evolocumab in patients without a previous myocardial infarction or stroke. N Engl J Med. 2026;394(2):117-127. doi:10.1056/NEJMoa2514428