Risks of Incident Cardiovascular Disease Associated With Concomitant Elevations in Lipoprotein(a) and Low‐Density Lipoprotein Cholesterol—The Framingham Heart Study

BACKGROUND: Elevated lipoprotein(a) is a well‐established risk factor for atherosclerotic vascular disease but is not measured in routine clinical care. Screening of high lipoprotein(a) in individuals with moderate elevations of low‐density lipoprotein cholesterol (LDL‐C) may identify individuals at high risk of cardiovascular disease. METHODS AND RESULTS: We examined 2606 Framingham Offspring participants (median age, 54 years; 45% men) prospectively with a median follow‐up of 15 years (n=392 incident cardiovascular events). Individuals with higher (≥100 nmol/L) versus lower lipoprotein(a) were divided into groups based on LDL‐C <135 mg/dL versus ≥135 mg/dL. In Cox models, after adjustment for known risk factors, high lipoprotein(a) (≥100 nmol/L) and LDL‐C ≥135 mg/dL were each significant predictors of cardiovascular disease (LDL‐C ≥135 mg/dL: hazard ratio [HR], 1.34; 95% CI, 1.09–1.64; P=0.006; high lipoprotein (a): HR, 1.31; 95% CI, 1.03–1.66; P=0.026). Across the groups of high/low lipoprotein (a) and LDL‐C ≥135 mg/dL or <135 mg/dL, the absolute cardiovascular disease risks at 15 years were 22.6% (high lipoprotein(a)/LDL‐C ≥135 mg/dL, n=248), 17.3% (low lipoprotein(a)/LDL‐C ≥135 mg/dL, n=758), 12.7% (high lipoprotein(a)/LDL‐C <135 mg/dL, n=275) and 11.5% (low lipoprotein(a)/LDL‐C <135 mg/dL, n=1328, reference group). Among individuals with LDL‐C ≥135 mg/dL, those with high lipoprotein(a) had a 43% higher risk (HR, 1.43; 95% CI, 1.05–1.97; P=0.02). Presence of high lipoprotein(a) with moderate LDL‐C levels (135–159 mg/dL) yielded absolute risks equivalent to those with LDL‐C ≥160 mg/dL (23.5%, 95% CI, 17.4%–31.3%; and 20.7%, 95% CI, 16.8%–25.3%, respectively). CONCLUSIONS: Concomitant elevation of LDL‐C ≥135 mg/dL and lipoprotein(a) ≥100 nmol/L is associated with a high absolute risk of incident cardiovascular disease. lipoprotein(a) measurement in individuals with moderate elevations in LDL‐C, who do not otherwise meet criteria for statins, may identify individuals at high cardiovascular risk.