In the Journals

SAFEHEART: Lp(a) predicted CVD in patients with familial hypercholesterolemia

Lipoprotein(a) is an independent predictor of CVD in patients with heterozygous familial hypercholesterolemia, according to new findings from the SAFEHEART study.

In particular, CV risk appears highest in patients with Lp(a) >50 mg/dL who are carriers of a receptor-negative mutation in the LDLR gene, researchers reported.

The aim of the SAFEHEART study was to determine whether Lp(a) predicts CVD and the relationship with the type of LDLR gene mutation.

Rodrigo Alonso, MD, PhD, of IIS-Fundación Jiménez Díaz, Madrid, and colleagues enrolled 1,960 patients with a molecular diagnosis of heterozygous familial hypercholesterolemia (mean age, 44 years) and 957 relatives without familial hypercholesterolemia (mean age, 40 years) in the long-term, observational study. Mutations in the LDLR gene were classified as receptor-negative, receptor-defective or unknown.

Higher Lp(a) levels

Patients with familial hypercholesterolemia had higher levels of Lp(a), LDL and total cholesterol compared with their unaffected relatives (P<.001) and also had higher incidence of Lp(a) levels >50 mg/dL (P<.001).

Patients with both familial hypercholesterolemia and CVD had higher levels of Lp(a) compared with those with familial hypercholesterolemia who did not have CVD (43.3 mg/dL vs. 21.3 mg/dL; P<.001) and were more likely to have levels >50 mg/dL (46.2% vs. 26.9%; P<.0001). The same was not observed in relatives without familial hypercholesterolemia.

When the researchers compared the 500 patients with the five most common receptor-negative mutations with the 246 patients with the four most common receptor-defective mutations, the receptor-negative group had higher median Lp(a) concentrations compared with the receptor-defective group (26.8 mg/dL vs. 17.6 mg/dL; P<.0016).

In addition, CVD-free survival time was lower in patients who had receptor-negative mutations and Lp(a) >50 mg/dL compared with patients who had receptor-defective mutations. However, the researchers found no difference between patients with receptor-negative mutations and Lp(a) <50 mg/dL and those with receptor-defective mutations and Lp(a) >50 mg/dL.

Lp(a) was identified as an independent predictor of CVD in men with familial hypercholesterolemia (OR=1.007; 95% CI, 1.004-1.011) and in women with familial hypercholesterolemia and Lp(a) >50 mg/dL (OR=2.387; 95% CI, 1.46-3.9).

“The increased risk is independent of age, gender, smoking status, other lipoproteins and the type of mutation in the LDLR gene,” the researchers wrote. “Our results support the recent recommendations that Lp(a) levels should be measured in all [familial hypercholesterolemia] patients as a marker that might help identify high-risk individuals who could benefit from more aggressive lipid-lowering treatments.”

Role of LDL receptor mutations

In a related editorial, Raul D. Santos, MD, PhD, MSc, from the Lipid Clinic Heart Institute (InCor) University of Sao Paolo Medical School Hospital, Brazil, said the investigators conducted “a well-done proof-of-concept study” that “advances the knowledge in the field and adds important information of a possible interaction between more severe [LDL receptor] mutations [and] higher Lp(a) concentrations, with a greater CVD risk.

“It’s important to show that newer therapies that reduce Lp(a) in addition to LDL concentrations will prevent CVD,” Santos wrote.

For more information:

Alonso R. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.01.063.

Santos RD. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2013.12.049.

Disclosure: The researchers report no relevant financial disclosures. Santos reports receiving honoraria for consulting and speaking activities from Aegerion, Amgen, AstraZeneca, Biolab, Boehringer Ingelheim, Genzyme, Merck, Nestle, Novartis, Novo Nordisk, Pfizer and Regeneron.

Lipoprotein(a) is an independent predictor of CVD in patients with heterozygous familial hypercholesterolemia, according to new findings from the SAFEHEART study.

In particular, CV risk appears highest in patients with Lp(a) >50 mg/dL who are carriers of a receptor-negative mutation in the LDLR gene, researchers reported.

The aim of the SAFEHEART study was to determine whether Lp(a) predicts CVD and the relationship with the type of LDLR gene mutation.

Rodrigo Alonso, MD, PhD, of IIS-Fundación Jiménez Díaz, Madrid, and colleagues enrolled 1,960 patients with a molecular diagnosis of heterozygous familial hypercholesterolemia (mean age, 44 years) and 957 relatives without familial hypercholesterolemia (mean age, 40 years) in the long-term, observational study. Mutations in the LDLR gene were classified as receptor-negative, receptor-defective or unknown.

Higher Lp(a) levels

Patients with familial hypercholesterolemia had higher levels of Lp(a), LDL and total cholesterol compared with their unaffected relatives (P<.001) and also had higher incidence of Lp(a) levels >50 mg/dL (P<.001).

Patients with both familial hypercholesterolemia and CVD had higher levels of Lp(a) compared with those with familial hypercholesterolemia who did not have CVD (43.3 mg/dL vs. 21.3 mg/dL; P<.001) and were more likely to have levels >50 mg/dL (46.2% vs. 26.9%; P<.0001). The same was not observed in relatives without familial hypercholesterolemia.

When the researchers compared the 500 patients with the five most common receptor-negative mutations with the 246 patients with the four most common receptor-defective mutations, the receptor-negative group had higher median Lp(a) concentrations compared with the receptor-defective group (26.8 mg/dL vs. 17.6 mg/dL; P<.0016).

In addition, CVD-free survival time was lower in patients who had receptor-negative mutations and Lp(a) >50 mg/dL compared with patients who had receptor-defective mutations. However, the researchers found no difference between patients with receptor-negative mutations and Lp(a) <50 mg/dL and those with receptor-defective mutations and Lp(a) >50 mg/dL.

Lp(a) was identified as an independent predictor of CVD in men with familial hypercholesterolemia (OR=1.007; 95% CI, 1.004-1.011) and in women with familial hypercholesterolemia and Lp(a) >50 mg/dL (OR=2.387; 95% CI, 1.46-3.9).

“The increased risk is independent of age, gender, smoking status, other lipoproteins and the type of mutation in the LDLR gene,” the researchers wrote. “Our results support the recent recommendations that Lp(a) levels should be measured in all [familial hypercholesterolemia] patients as a marker that might help identify high-risk individuals who could benefit from more aggressive lipid-lowering treatments.”

Role of LDL receptor mutations

In a related editorial, Raul D. Santos, MD, PhD, MSc, from the Lipid Clinic Heart Institute (InCor) University of Sao Paolo Medical School Hospital, Brazil, said the investigators conducted “a well-done proof-of-concept study” that “advances the knowledge in the field and adds important information of a possible interaction between more severe [LDL receptor] mutations [and] higher Lp(a) concentrations, with a greater CVD risk.

“It’s important to show that newer therapies that reduce Lp(a) in addition to LDL concentrations will prevent CVD,” Santos wrote.

For more information:

Alonso R. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.01.063.

Santos RD. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2013.12.049.

Disclosure: The researchers report no relevant financial disclosures. Santos reports receiving honoraria for consulting and speaking activities from Aegerion, Amgen, AstraZeneca, Biolab, Boehringer Ingelheim, Genzyme, Merck, Nestle, Novartis, Novo Nordisk, Pfizer and Regeneron.