What if we could spot early vascular risk—before plaque builds, before symptoms surface—and respond thoughtfully? That’s the value of combining tools like the ASCVD Risk Calculator and PREVENT model with personalized interpretation and a prevention-first mindset.
Let’s walk through how this can look in a real-world style scenario.
Patient Profile: The “Healthy” 40-Year-Old
Age: 40-year-old male
Lipids:
Total cholesterol: 218 mg/dL
LDL-C: 158 mg/dL
HDL-C: 52 mg/dL
Triglycerides: 141 mg/dL
VLDL: 28 mg/dL
TC/HDL ratio: 4.2
HbA1c: 5.2%
Triglyceride/HDL ratio: 2.7 (upper end of normal)
🔍 Calculated ASCVD Risk:
10-Year ASCVD Risk: 1.3%
“Optimal” 10-Year Risk: 0.6%
PREVENT Model Risk:
10-Year: 1.2%
30-Year: 6.8%
Optimal 30-Year: 1.0%
On paper, this is low short-term risk—but also the kind of moment where “primordial prevention” (acting before the first plaque forms) can have outsized long-term benefits.
Step 1: Use Risk Tools… but Look Past the Numbers
A 1.3% 10-year risk may seem reassuring, but it doesn’t capture the cumulative burden of cholesterol over decades.
Risk models like PREVENT help estimate lifetime risk, yet individual factors—family history, lipoprotein(a), insulin resistance, cardiorespiratory fitness—add nuance that algorithms can’t fully reflect.
Step 2: Think in Prevention Tiers
Primordial Prevention: Prevent atherosclerosis from ever forming
Primary Prevention: Manage risk before a first event
Secondary Prevention: Treat intensively after an event
This case sits squarely in the primordial-to-primary category, where early intervention is about protecting decades of vascular health.
Step 3: Individualize Targets
Research supports tailoring LDL-C goals to overall risk:
Moderate risk: <70 mg/dL
Added risk factors (family history, high Lp(a), insulin resistance): <55 mg/dL
Aggressive primordial approach: sometimes <40 mg/dL in research settings
Step 4: Lifestyle First, But Know the Ceiling
Typical LDL-C reductions from dietary changes:
From a baseline LDL-C of 158 mg/dL, dietary change alone might bring levels into the 120–130 mg/dL range—meaning additional options could be considered if further lowering is desired.
Step 5: Overview of Lipid-Lowering Approaches
Commonly used tools include:
Statins – ~30–50% LDL-C reduction
Ezetimibe – ~15–20%
Bempedoic acid – ~20%
PCSK9 inhibitors – ~60%
small interfering RNA (si-RNA) – ~50% (twice-yearly dosing; outcome data pending)
In clinical settings, combinations are often used when greater LDL-C reduction is desired. One widely used example is a statin plus ezetimibe, which can achieve substantial reductions with generally good tolerability. This is not a one-size-fits-all prescription—rather, an illustration of how medications may be combined in practice, depending on patient goals, preferences, and clinical factors.
Lp(a) – A Key Risk Modifier
Genetically determined; elevated levels are linked to higher cardiovascular risk
Lifestyle changes do not significantly lower it
When elevated, it may prompt aiming for lower LDL-C targets to offset added risk
Emerging Therapies for Lp(a)
Several promising therapies are in late-stage development, with results expected over the next few years:
Olpasiran (Amgen) – siRNA therapy, Phase 3 (NCT05581303)
SLN360 (Silence Therapeutics) – siRNA therapy, Phase 3 (NCT05755212)
Pelacarsen (Ionis/Novartis) – antisense oligonucleotide, Phase 3 (NCT04023552)
If cardiovascular (CV) outcomes are reduced (improved), these agents could change how we approach inherited Lp(a)-related risk.
How Lifestyle and Combination Therapy Can Shift the Numbers
Below is a purely illustrative example of how a 40-year-old male with the profile above might see lipid values and estimated cardiovascular risk change over time using two different strategies:
Scenario 1: Focused lifestyle changes (dietary fiber, reduced saturated fat, Mediterranean-style eating, regular exercise)
Scenario 2: Lifestyle plus a common two-drug combination (statin + ezetimibe)
*Changes are average ranges reported in large clinical trials; individual responses vary.
Estimated ASCVD and PREVENT Risk Shifts
Key takeaways from the model:
Even small LDL-C reductions shift lifetime risk more than 10-year risk.
Lifestyle changes alone can be meaningful, especially when started early.
Larger LDL-C reductions—when appropriate—can bring a more substantial drop in calculated long-term risk.
Numbers are only part of the picture; fitness, inflammation, and other metabolic markers matter too.
Final Thoughts
This is a classic case of low short-term but meaningful lifetime risk—where early, personalized strategies can keep arteries healthier for longer.
By combining numeric tools, clinical judgment, and a prevention mindset, the goal becomes not just lowering a lab value, but delaying or preventing the first plaque from forming.
That’s training for life.
References
Sabatine MS, et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017;376(18):1713–1722. https://doi.org/10.1056/NEJMoa1615664
Cholesterol Treatment Trialists’ Collaboration. The effects of lowering LDL cholesterol with statin therapy in people at low risk. Lancet. 2012;380(9841):581–590.
NCT05581303. A Study of Olpasiran in Participants With Atherosclerotic Cardiovascular Disease and Elevated Lipoprotein(a). ClinicalTrials.gov
NCT05755212. A Study of SLN360 in Adults With High Lipoprotein(a). ClinicalTrials.gov
NCT04023552. Lp(a) HORIZON: A Study of Pelacarsen (TQJ230) in Patients With Cardiovascular Disease and Elevated Lipoprotein(a). ClinicalTrials.gov
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Great post Jake. Would you be comfortable with the baseline mentioned in your example if the patient had a low lp(a) and a CAC of 0? I’ve always been in the lower is better for LDL camp, but in an otherwise healthy (primordial prevention) patient is it beneficial to strive for lower?