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September 30, 2026Circulation Population Health and Outcomes

Multi-National Evaluation of Low-Density Lipoprotein Cholesterol Equations in Young Adulthood for Long-Term Risk of Atherosclerotic Cardiovascular Disease

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Key result

Martin-Hopkins-estimated elevated young-adult LDL-C is linked to ~69% higher incident ASCVD risk.

HR 1.69
95% CI 1.35-2.12
n=10,550

Why the study?

Accurate LDL-C assessment in young adulthood is critical for ASCVD prevention, yet the optimal LDL-C estimation equation remains uncertain.

Does LDL-C estimation using the Martin-Hopkins equation improve long-term ASCVD risk classification compared to Friedewald and Sampson equations in young adults?

Key Points

To compare the performance of the Friedewald, Martin-Hopkins, and Sampson LDL-C equations measured during young adulthood for predicting long-term incident atherosclerotic cardiovascular disease (ASCVD).
Analyzed 10,550 participants (56.8% female, mean baseline age 29.8 years) from 7 population-based cohorts in the International Childhood Cardiovascular Cohort Consortium followed for a mean of 22.7 years.
Calculated LDL-C using Friedewald, Martin-Hopkins, and Sampson equations, classifying levels as normal (<130 mg/dL) versus elevated (≥130 mg/dL) and grouping participants by pairwise concordance and discordance.
Evaluated incident adjudicated ASCVD events using Fine-Gray subdistribution hazard models.
Over follow-up, 376 incident ASCVD events occurred (3.6%); elevated LDL-C by each equation was linked to events, with the strongest association for Martin-Hopkins (sHR 1.69, 95% CI 1.35–2.12), followed by Sampson (sHR 1.52, 95% CI 1.22–1.90) and Friedewald (sHR 1.47, 95% CI 1.17–1.84).
Total discordance between equations ranged from 2.3% to 2.9%; individuals with normal Friedewald but elevated Martin-Hopkins LDL-C had higher ASCVD risk (sHR 3.32, 95% CI 1.94–5.66), whereas reverse discordance showed no excess risk (sHR 1.19, 95% CI 0.47–3.05).
Participants with normal Sampson but elevated Martin-Hopkins LDL-C demonstrated elevated ASCVD risk (sHR 3.94, 95% CI 1.80–8.64), while reverse discordance had no significant increase in risk (sHR 0.86, 95% CI 0.39–1.91).

Study Design

Type

Cohort (n=10,550)

Multicenter

Yes

Structured PICO

Does LDL-C estimation using the Martin-Hopkins equation improve long-term ASCVD risk classification compared to Friedewald and Sampson equations in young adults?

P

Population

10,550 young adults aged 20-39 years from multinational population-based cohorts were followed for a mean of 22.7 years to assess the association of various LDL-C estimation equations with incident atherosclerotic cardiovascular disease.

E

Exposure

LDL-C estimation and risk classification using the Martin-Hopkins equation

C

Comparator

LDL-C estimation and risk classification using the Friedewald and Sampson equations

O

Outcome

Composite of fatal and nonfatal incident ASCVD events (first occurrence of myocardial infarction, stroke, transient ischemic attack, ischemic heart failure, angina, peripheral artery disease, carotid intervention, abdominal aortic aneurysm, or coronary revascularization) over a mean 22.7 years follow-upcomposite

Main Result

Hazard Ratio: 1.69 (95% CI 1.35–2.12)

The Martin-Hopkins equation provides a more accurate assessment of long-term ASCVD risk in young adults compared to the Friedewald and Sampson equations, particularly in reclassifying high-risk individuals when estimation formulas are discordant.

Limitations

Low prevalence of severe hypertriglyceridemia limits evaluation of equation performance at higher TG levels.
May not fully represent all contemporary lipid disorders, such as familial combined hyperlipidemia.
Relatively low number of ASCVD events may reduce statistical power for certain comparisons.
Cohorts were predominantly White participants from developed countries, which may limit generalizability to other ethnicities or socioeconomic backgrounds.
Inconsistent HDL-C measurement methods across cohorts.
Low prevalence of severe hypertriglyceridemia, limiting evaluation at higher TG levels
May not fully represent all contemporary lipid disorders such as familial combined hyperlipidemia
Relatively low number of ASCVD events may reduce statistical power for certain comparisons
Predominantly White participants from developed countries, limiting generalizability to other ethnicities or socioeconomic backgrounds
Inconsistent HDL-C measurement methods across cohorts

Key expert perspectives

Captured external expert commentary on this paper, strongest first. Original sources are linked where available.

DADr. Allison W. Peng and Dr. Seth S. MartinCardiology

“The Martin-Hopkins equation identifies high-risk young adults missed by other equations and is the most reliable equation to guide evidence-based treatments that reduce ASCVD events and mortality. Especially in this era of earlier ASCVD prevention and lower LDL-C goals, choosing the right equation to estimate LDL-C matters now more than ever.”

Johns Hopkins Medicine

DADr. Allison W. Peng and Dr. Seth S. MartinCardiology

“These findings add to a growing body of evidence supporting the Martin-Hopkins equation for LDL-C estimation as the preferred equation. In prior studies, it has outperformed Friedewald and Sampson across a diverse range of lipid profiles.”

Johns Hopkins Medicine

Implication

Martin-Hopkins LDL-C estimation may better flag ASCVD risk in young adults missed by other equations; observational data leave adoption open pending trials.

Abstract

BACKGROUND: Accurate low-density lipoprotein cholesterol (LDL-C) assessment in young adulthood is critical for atherosclerotic cardiovascular disease (ASCVD) prevention, yet the optimal estimation equation remains uncertain. We compared the Friedewald, Martin-Hopkins, and Sampson equations for evaluating long-term ASCVD risks. METHODS: We included participants from 7 population-based cohorts within the International Childhood Cardiovascular Cohort Consortium who had LDL-C measurements in young adulthood (aged 20-39 years) and follow-up data for incident ASCVD. LDL-C levels were estimated using the Friedewald, Martin-Hopkins, and Sampson equations. For each pair of equations, participants were categorized into concordant (normal/normal, elevated/elevated) and discordant (normal/elevated, elevated/normal) groups based on LDL-C classifications (normal <130 mg/dL versus elevated ≥130 mg/dL). ASCVD events (myocardial infarction, stroke, transient ischemic attack, ischemic heart failure, angina, peripheral artery disease, carotid intervention, abdominal aortic aneurysm, coronary revascularization) were adjudicated from medical records. Associations between discordance and incident ASCVD were estimated using Fine-Gray regressions. RESULTS: Among 10 550 participants (56.8% females; mean baseline age [SD], 29.8 [4.3] years), 376 ASCVD events occurred over a mean follow-up of 22.7 years. Elevated LDL-C by all equations was associated with ASCVD events (subdistribution hazards ratio [95% CI]: Martin-Hopkins, 1.69 [1.35-2.12]; Sampson, 1.52 [1.22-1.90]; Friedewald, 1.47 [1.17-1.84]). Total discordance ranged from 2.3% to 2.9%. Compared with the concordant normal LDL-C group, normal LDL-C by Friedewald but elevated by Martin-Hopkins had higher ASCVD risks (3.32 [1.94-5.66]), with no excess risk in the reverse discordance (1.19 [0.47-3.05]). Normal Friedewald but elevated Sampson LDL-C had higher ASCVD risks (1.69 [0.93-3.05]); no participants had the reverse discordance. Normal Sampson LDL-C but elevated Martin-Hopkins LDL-C had higher ASCVD risks (3.94 [1.80-8.64]), whereas the reverse discordance showed no increased risk (0.86 [0.39-1.91]). CONCLUSIONS: The Martin-Hopkins equation provides more accurate LDL-C-based risk classification, identifying high-risk young adults missed by other equations and minimizing misclassification of those at normal risk.

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Cite This Study

Meng et al. (2026) conducted a cohort in Atherosclerotic cardiovascular disease (n=10,550). Elevated LDL-C (≥130 mg/dL) estimated by the Martin-Hopkins equation vs. Normal LDL-C (<130 mg/dL) estimated by the Martin-Hopkins equation was evaluated on Incident atherosclerotic cardiovascular disease events (HR 1.69, 95% CI 1.35-2.12). Elevated LDL-C in young adulthood estimated by the Martin-Hopkins equation was strongly associated with incident ASCVD events (HR 1.69) and accurately identified high-risk individuals missed by the Friedewald and Sampson equations.

synapsesocial.com/papers/6abf498f2e90968d19e1c64a https://doi.org/10.1161/circoutcomes.125.013678

Topics

Coronary artery disease

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