PCSK9 inhibitors lower LDL cholesterol. The question that matters to patients is what that lowering accomplishes: fewer heart attacks, fewer strokes, longer life, or some combination of those outcomes.
At Toward Health, we had concerns about the early mortality data and questions about how deaths were classified. We have since reviewed the longer-term studies and newer trials. Our assessment has changed.
We now consider PCSK9 inhibitors such as evolocumab (Repatha) and alirocumab (Praluent) effective options for selected patients with coronary artery disease or other high-risk conditions. Here is how we got there.
The early evidence raised questions:
FOURIER, published in 2017, found that evolocumab reduced major cardiovascular events in patients with established cardiovascular disease. It did not demonstrate a reduction in all-cause mortality or cardiovascular mortality.
In fact, both were numerically higher in the evolocumab group:
- Deaths from any cause: 3.2% with evolocumab versus 3.1% with placebo.
- Cardiovascular deaths: 1.8% versus 1.7%.
Neither difference was statistically significant. These findings did not prove that evolocumab increased deaths, but they also did not demonstrate that it extended life during the trial.
ODYSSEY OUTCOMES and its 2019 mortality analysis require a distinction. All-cause deaths were lower with alirocumab, 3.5% versus 4.1%. That result was only nominally significant: the trial’s prespecified statistical testing sequence had already stopped at a nonsignificant outcome. Cardiovascular mortality was not significantly reduced.
The early trials therefore did not establish a consistent, definitive survival benefit across the class. A reduction in cardiovascular events still matters. It should be described accurately, alongside what the mortality results did and did not show.
Why the mortality reanalysis concerned us:
A BMJ Open reanalysis of FOURIER added to our concerns. The manuscript was submitted in 2021 and published in December 2022.
The investigators examined regulatory clinical-study reports and identified discrepancies in death classifications. Their readjudication found more cardiovascular deaths with evolocumab, with a relative risk of 1.20 and a 95% confidence interval of 0.95–1.51.
That was a concerning signal. The confidence interval included no difference, so it did not establish increased mortality. The investigators also could not re-evaluate nonfatal events using the available reports.
For us, the mortality findings and reporting discrepancies warranted caution. Those questions deserved attention even though the original trial had shown fewer cardiovascular events.
What changed our assessment:
We have now reviewed three important sets of longer-term and newer evidence.
FOURIER-OLE, 2022: The extension study followed 6,635 participants for a median of five additional years. Earlier evolocumab treatment was associated with fewer cardiovascular events and cardiovascular deaths than delayed initiation. These were exploratory comparisons: both groups received evolocumab during the extension, so this was not a continued randomized comparison against placebo.
Long-term ODYSSEY OUTCOMES analysis, 2023: Among 8,242 patients eligible for longer follow-up after a recent acute coronary syndrome, the analysis supported sustained cardiovascular benefit and reassuring safety over follow-up extending to five years. Overall adverse events were similar to placebo, apart from more injection-site reactions.
VESALIUS-CV, 2026, published online in 2025: This trial included 12,257 patients with atherosclerosis or high-risk diabetes who had not had a heart attack or stroke. Over a median follow-up of 4.6 years, the estimated five-year risk of coronary death, heart attack or ischemic stroke was 6.2% with evolocumab versus 8.0% with placebo. That is an absolute reduction of 1.8 percentage points, or approximately 56 people treated to prevent one such event over five years.
A subsequent prespecified mortality analysis from VESALIUS-CV, published in August 2026, added important context. Over a median follow-up of 4.6 years, deaths from any cause occurred in 434 patients receiving evolocumab and 539 receiving placebo. The estimated five-year risk of death was 7.9% versus 9.7%, corresponding to a hazard ratio of 0.80. Cardiovascular deaths were also lower, with a hazard ratio of 0.79. Because mortality was not reached within the trial’s protected hierarchical testing sequence, these findings are considered supportive rather than formally confirmatory. Even so, they provide randomized evidence that longer-term evolocumab treatment may reduce not only cardiovascular events, but also mortality in appropriately selected high-risk patients.
Together, these findings strengthened the case for treatment in appropriately selected patients. They also reinforced the need to distinguish fewer cardiovascular events from a claim that every patient will live longer.
What about coronary plaque:
Separate imaging trials, GLAGOV and PACMAN-AMI, found greater coronary plaque regression when a PCSK9 inhibitor was added to statin therapy.
That supports a potential role in treating coronary atherosclerosis. These studies measured plaque with specialized coronary imaging. They do not establish that a coronary artery calcium score will fall.
Our commitment to metabolic research:
At Toward Health, our clinic works at the forefront of metabolic clinical research, turning questions from patient care into published studies. Our team’s contributions include:
- Carbohydrate reintroduction and the lean mass hyper-responder phenomenon. Dr. Tro co-authored research examining this pattern of cholesterol elevation, including a five-patient case series in which moderate carbohydrate reintroduction reduced LDL cholesterol. Read our research summary and the original study.
- Ezetimibe for ketogenic diet-induced hypercholesterolemia. Our 2026 retrospective case series documented marked LDL reductions with ezetimibe in 14 selected patients. Read our ezetimibe research summary and the original study.
These studies examined cholesterol responses; long-term cardiovascular outcomes remain an open research question in this population. We remain committed to reviewing the evidence, pursuing research to answer unresolved questions and refining care as we learn more. Explore Toward Health’s published research.
Where we stand now:
Our current view reflects the full course of the evidence: early uncertainty about mortality, legitimate concerns about death classification, and subsequent data supporting cardiovascular benefit.
PCSK9 inhibitors can be useful for selected patients with coronary artery disease or other high-risk conditions. Decisions should account for existing disease, overall risk, other treatment, tolerability, cost and patient preferences.
Nutrition, physical activity, blood pressure, glucose control and smoking cessation remain part of that conversation. Medication decisions belong within a complete plan for the person in front of us.
As the evidence changes, our interpretation should change with it. Patients deserve to understand both the earlier concerns and the reasons for our reassessment.
