High Lipoprotein(a) Levels Predictive of Heart Disease in (Some) Older Women

A strong case is made for testing lipoprotein(a) levels at least once early in life to ascertain future risk of coronary artery disease.

with Samia Mora, MD, and Margo B. Minissian, PhD

Lipoprotein (a) has been deemed an independent risk factor in predicting the presence and severity of new-onset coronary disease (CAD) in post-menopausal women,1 according to a study published in the Journal of Women’s Health.

To date, Lp(a) has been confirmed as a strong genetic biomarker for atherosclerotic cardiovascular disease events and mortality with an elevated prevalence affecting an estimated 20% of the adult population.2

Time to incorporate lipoprotein(a) in cholesterol testing for heart disease risk.

Raising Attention to Sex-Specific Role of Lp(a) Levels 

This new study, ‘’with a smaller cohort, is confirming in women what has been demonstrated in general population studies,” said Samia Mora, MD, a cardiovascular medicine specialist at Brigham & Women’s Hospital and associate professor of medicine at Harvard Medical School in Boston, Massachusetts.  

While CAD is relatively rare in younger women, the prevalence of atherosclerotic heart disease in postmenopausal women rising precipitously, reaching a morbidity rate similar to that of men2 as well as a  higher mortality rates than did men.3

Evidence from previous studies indicate that the Lp(a) is useful to predict atherosclerotic cardiovascular diseases, the studies focusing on women have had mixed results, 4 as reported by the researchers from the Cardiovascular Institute of Jianghan University and other institutions in China.

Evaluating Relationship between CAD and Lp(a) Levels

The researchers evaluated 783 postmenopausal women who had their first angina-like chest pain prior to enrollment. Based on results of their coronary angiography, these women were classified into the CAD group (n=309) or the age-matched non-CAD group (n=309).1

Individuals with confirmed coronary artery disease were further divided into the three groups based on their Gensini score (GS), in which  zero reflected the absence of atherosclerotic disease.1 Then the researchers examined the relationship of the plasma Lp(a) levels to the presence and severity of CAD and the predictive value of Lp(a) levels for CAD.4

The investigators reported that the Lp(a) in the coronary artery disease group was significantly higher than of the women in the non-CAD group (P < 0.001). Based on multivariate logistic regression analysis, the researchers found that Lp(a) was an independent predictor of CAD (P < 0.001) with plasma levels of Lp(a) strongly associated with the Gensini score (GS) and independently association with a high GS (P < 0.001).1

Levels of 50 mg/dL of Lp(a) or higher put people at higher risk of CAD (50 mg/dL or 125 nmol/L or 500 mg/L). On average, study participants with CAD had an Lp(a) of 214.99 mg/dL (21.4 mg/L) in comparison to those who without a CAD diagnosis had Lp(a) levels that averaged 106.81 mg/dL.1

The researchers classified the three groups with CAD based on their GS level:

  • Group 1 (GS Low): Lp(a) averaging 17.5 mg/dL
  • Group 2 (GS Intermediate): Lp(a) averaging 25.7 mg/dL
  • Group 3 (GS High): Lp(a) averaging 27.5 mg/dL

From a multivariate analysis, the researchers found that Lp(a) remained a significant and independent predictor for the presence of CAD in post-menopausal women (OR =7.24, 95% CI: 4.49-11.70, P < 0.001). Those with an Lp(a) of more than 255.69 mg/L (25.5 mg/dL) had a higher prevalence of CAD.1

The average age across the three groups was comparable: 62.36 years, 62.44, 63.17 years respectively, as was body mass index which was 25.78 k/m2, 25.33 k/m2, and 25.82, respectively. Prevalence of diabetes was more common in the group with the highest Gensini score (group 3) with a rate of 40% versus 30% in group 2 and 21% in group 1.

The researchers postulted that since Lp(a) is found to be an independent risk for for both the presence and severity of new-onset CAD in postmenopausal women, it may be a lipid target for prevention and treatment in these patients.1

Adjusting Clinical Considerations in Assesing CVD Risk

These findings will no doubt produce an ongoing consideration for clinicians—When should a postmenopausal woman be screened for Lp(a)?

“This is a complex topic of discussion,” said Dr. Mora, who recently wrote an editorial on a study that evaluated the effect of alirocumab on Lp(a) and cardiovascular risk after acute coronary syndrome.5,6

“Guidelines do not give sex-specific recommendations," she said, thus, not offering adjustments for any differences that may arise in men and women. "The [upcoming] European guidelines take a stronger stand on measuring Lp(a) with some consensus-based recommendations for checking Lp(a) once in a lifetime (since levels are generally stable) using an isoform-insensitive assay."7,8

‘’The US [2019 AHA/ACC prevention] guidelines do not give specific advice on who should be tested (other than saying that a relative indication for testing in the presence of personal or family history of premature CVD), but do say that if Lp(a) is tested, then a level of more than 50 mg/dL (> 125 nmol/L) could be considered a risk enhancer and useful in the discussion to initiate a statin or other preventive therapies.”8,9

Important for clinicians to remember, Dr. Mora told EndocrineWeb, is that ‘’statins do not reduce Lp(a), working instead to reduce cardiovascular risk by 20-30%, and statins have been found to reduce CVD risk in patients with high Lp(a).”9 Other therapies, such as a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor reduces Lp(a) by about 20%, she said, "which appears to be contributing to the benefit in reducing CVD events."5,10

“Novel therapies that reduce Lp(a) substantially —by 80% or more—are being tested in clinical trials currently to determine if they will result in cardiovascular event reduction."

Dr. Mora suggests that every patient be tested once in a lifetime, especially those with the following risk factors:

  • Premature onset of CVD (ie, before 65 years for women; before 55 years for men)
  • Family history of premature CVD or High Lp(a)
  • Recurrent CVD despite statin treatment
  • Anyone with borderline cardiovascular risk

“Also, given the recent accumulated evidence, I would measure Lp(a) in patients with prior acute coronary syndrome after resolution of the initial period of inflammation associated with the heart attack,” she added.

Sinces Lp(a) levels reach stable levels around the second year of  life, ‘’if the aim is to identify genetic/inherited syndromes of high Lp(a), then earlier screening would be best such as after age 2 years, or at least by approximately 10 years when at-risk children often undergo their first blood cholesterol testing.”

“This [assessment approach] will become more relevant once we have more therapies that specifically target Lp(a),” she told EndocrineWeb.

Data Reflective of Effect in Chinese Women, Beyond that Uncertainty Prevails

"What I found most compelling is, the Lipoprotein(a) numbers were actually not very high compared to the national average," said Margo B. Minissian, PhD, ACNP, FNLA, FAHA, director of the postpartum heart health program and a clinical lipidologist at the Barbara Streisand Women's Heart Center at the Schmidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles, California, who reviewed and offered comment on the study at the behest of EndocrineWeb.

The levels did not have to be ''skyrocket high" to produce a viable associate. As such, Dr. Minissian speculated that because it appears this study population was mainly Chinese women, it begs the question of whether ethnic differences may mean some women with a normal or high normal level may still be at increased risk.

Her take-home message? "If you see a higher than normal lipoprotein(a) level in an Asian woman, you may want to be more aggressive with their treatment.” That sais, she added: "Lipoprotein(a) has been around forever but is only now being more appreciated for its predictive value."

Dr. Mora has received research support from Atherotech Diagnostics and has been a consultant for request Diagnostics and Pfizer. Dr. Minissian is a consultant for Amgen.

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