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Value of Measuring Lp(a) During Cascade Testing for FH
Study Questions:
Is lipoprotein (a) [Lp(a)] effective in detecting and risk stratifying individuals participating in a familial hypercholesterolemia (FH) cascade screening program?
Methods:
Background: Lp(a) is an atherogenic and prothrombotic small low-density lipoprotein (LDL)-like particle formed directly in the liver, with >70% of the level genetically determined and not affected by diet or statins. A level >30 mg/dl, the 75th percentile, is associated with a curvilinear increase in cardiovascular (CV) event rate and enhances the risk higher in persons with FH. Levels are reduced by about 25% with PCSK9 antibodies.
Methods: Family members (N = 2,927) from 755 index cases enrolled in the SAFEHEART (Spanish Familial Hypercholesterolemia Cohort Study) trial were tested for genetic FH and elevated Lp(a) via an established screening program. Elevated Lp(a) was defined as ≥50 mg/dl. The authors compared the prevalence and yield of new cases of high Lp(a) in relatives of FH probands both with and without high Lp(a), and prospectively investigated the association between elevated Lp(a) and atherosclerotic cardiovascular disease (ASCVD) events among family members.
Results:
Compared to the probands, the relatives had significantly lower mean LDL cholesterol (175 mg/dl vs. 166 mg/dl), lower Lp(a) (22.3 mg/dl vs. 18.8 mg/dl), less use of statins/ezetimibe (94% vs. 59%), and less ASCVD at baseline (18% vs. 9%). Systematic screening from index cases with both FH and Lp(a) ≥50 mg/dl identified one new case of elevated Lp(a) for every 2.4 screened, and in those <50 mg/dl, 1 in 5.8 screened. The frequency of FH in the relatives was 33% and elevated Lp(a) in 12.5%, FH and elevated Lp(a) in 30%, and neither in 25%. Similar proportions were found in an Australian lipid clinic. Over 5 years of follow-up, FH (hazard ratio [HR], 2.47; p = 0.036) and elevated Lp(a) (HR, 3.17; p = 0.024) alone were associated with a significantly increased risk of experiencing an ASCVD event or death compared with individuals with neither disorder; the greatest risk was observed in relatives with both FH and elevated Lp(a). Absolute incident 5-year mortality was about 9% vs. <2% for neither (HR, 4.40; p < 0.001) independent of conventional risk factors.
Conclusions:
Testing for elevated Lp(a) during cascade screening for FH is effective in identifying relatives with high Lp(a) and heightened risk of ASCVD, particularly when the proband has both FH and elevated Lp(a).
Perspective:
The absolute and relative risk of events in the FH cohort was lower than expected, likely due to early statin use in the longitudinal cohort study. Evidence suggests Lp(a) should be considered in premature ASCVD and cascade screening in those families, and those with recurrent events despite statin therapy. Statin guidelines include it as a risk enhancer in persons with a 5-19% 10-year risk of ASCVD events. Statins would be indicated when levels are ≥50 mg/dl even in those with relatively low risk, and high-intensity statins considered with very high values of Lp(a).
Keywords: Atherosclerosis, Cholesterol, LDL, Diet, Dyslipidemias, Genetic Testing, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipoproteinemia Type II, Lipoproteins, Primary Prevention, Risk Factors
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