How does information from the FOURIER study stack up against preventive lifestyle interventions?
What the FOURIER mortality reanalysis teaches us about cardiovascular prevention—and why lifestyle still carries the “biggest levers”
Cardiovascular disease (CVD) prevention is often framed as a debate: medications vs. lifestyle. In real clinical practice, the best outcomes sometimes come from both—with the right tool matched to the right patient.
A useful case study is the FOURIER cardiovascular outcomes trial of evolocumab (a PCSK9 inhibitor) in people with established atherosclerotic cardiovascular disease, on background statin therapy. The primary FOURIER publication reported significant LDL-lowering and fewer composite cardiovascular events (driven largely by non-fatal outcomes), without a clear reduction in all-cause mortality during the trial’s follow-up.
The BMJ Open reanalysis: “restoring” mortality data from regulatory records
A BMJ Open paper by Erviti and colleagues reanalyzed FOURIER mortality data using death narratives from the Clinical Study Report (CSR)—the detailed regulatory document set. The authors reported inconsistencies between the CSR narratives and the mortality information presented in the primary publication, and they attempted to “restore” cause-of-death classification using those narratives.
Importantly, the FOURIER investigators and TIMI group published a formal response disagreeing with aspects of the reanalysis, emphasizing that trial interpretation can be contested—especially when methods for adjudicating cause of death differ.
Why patients (and clinicians) should care
This is not simply an academic dispute. It’s a reminder to ask higher-quality questions when evaluating any therapy:
Does it reduce hard outcomes such as myocardial infarction, stroke, hospitalization, mortality, not only a biomarker?
What exactly drove the endpoint?
How complete and transparent are the underlying data?
What is the absolute risk reduction?
This is also where lifestyle matters: it often improves multiple upstream drivers of CVD risk simultaneously. Conditions such as insulin resistance, blood pressure, visceral adiposity, inflammation, cardiorespiratory fitness, sleep can all be drivers of disease.
A prevention framework that stacks benefits: 5 levers that meaningfully shift risk
Below are evidence-informed, practical strategies we use at Katallage Wellness Center—especially for patients with metabolic syndrome, insulin resistance, elevated triglycerides (above 80), low HDL, hypertension, or persistent inflammation.
1) Calorie restriction (moderate, sustainable)
In CALERIE, two years of moderate calorie restriction in healthy adults significantly improved multiple cardiometabolic risk factors—supporting the idea that even modest, consistent energy deficit can improve cardiovascular risk physiology.
Practical approach
Start with a modest target (often ~10% reduction from baseline intake).
Prioritize protein adequacy and resistance training to protect lean mass.
Use objective markers (waist circumference, BP, fasting insulin, triglycerides) to guide adjustment.
2) Ketogenic metabolic therapy (KMT) / lower-carbohydrate nutrition
For many patients—particularly those with insulin resistance—lower-carbohydrate patterns can improve triglycerides, HDL, glycemic control, and weight, which are major contributors to CVD risk. Meta-analytic data show beneficial effects on several cardiovascular risk factors, though responses vary and long-term outcomes depend on dietary composition and adherence.
Clinical nuance (important): Some individuals experience LDL-C/ApoB increases on very low-carb diets. That doesn’t mean KMT is “bad”—it means it must be monitored and individualized with the right lipid markers (ApoB, non-HDL-C, LDL-P, sdLDL when available) and dietary fat quality.
Practical approach
Emphasize fat quality (more unsaturated fats; minimize refined oils; keep saturated fat individualized- no “dirty keto”).
Measure response: triglycerides, HDL, ApoB/non-HDL-C, sdLDL, blood pressure, hs-CRP, and glycemic markers.
Pair nutrition with exercise (see below) to enhance metabolic flexibility.
3) Meal timing aligned with the circadian clock
Our metabolism is not the same at 9 AM as it is at 9 PM. Early time-restricted eating (eTRF) has been shown to improve insulin sensitivity, blood pressure, and oxidative stress markers—even without weight loss in a controlled trial. Broader time-restricted eating trials also report metabolic benefits, though results vary by study design and population.
Practical approach
Keep a consistent overnight fasting window (often 12–14 hours for many adults, individualized).
Aim to finish dinner earlier rather than “saving” calories for late night.
If adopting time-restricted eating, many do well with a front-loaded eating window (earlier in the day) rather than late-day restriction.
4) Exercise as a primary prevention “medication”
Physical activity has robust dose–response associations with lower risk of all-cause mortality and CVD outcomes across large prospective datasets.
Practical approach (simple weekly template)
Zone 2 aerobic: 150–300 minutes/week (or build toward it)
Resistance training: 2–3 sessions/week
Daily movement: step goals individualized
A quick note about Zone 2 training - Zone 2 training is steady, aerobic exercise performed at an intensity that is challenging but sustainable for an extended period. Physiologically, it sits below the lactate threshold and is fueled primarily by aerobic metabolism, which supports mitochondrial function and metabolic efficiency. Practically, it’s the pace where you can carry on a conversation in full sentences but would not want to sing, typically held for 30–60 minutes as a foundational endurance and cardiometabolic conditioning tool.
If you’re using KMT, exercise can be a powerful partner—helping reduce insulin resistance and improving mitochondrial efficiency.
5) Meditation / stress regulation as an adjunct (not a replacement)
The American Heart Association has noted that meditation may be a reasonable adjunct for cardiovascular risk reduction (e.g., blood pressure, stress-related behaviors.
Practical approach
Start small: 5–10 minutes/day of breath-based practice or guided meditation.
Pair with sleep consistency and morning light exposure every day, even from the kitchen window.
Track a measurable outcome (BP, resting HR, sleep quality, cravings, alcohol intake).
How we integrate this in our clinic
When we build a prevention plan, we aim to answer:
What is your dominant driver of risk? (High TG's, ApoB burden, insulin resistance, hypertension, inflammation, smoking, sleep apnea, etc.)
Which levers create the biggest absolute risk reduction for you?
What can you sustain for 12 months—not just 12 days?
The FOURIER reanalysis conversation is a timely reminder: we should always pair pharmacology with foundational physiology—because lifestyle interventions often improve multiple risk pathways at once.