Practical Pearls: Should Lipid Recommendations for Children be Gender Specific?

It is well known that women are not protected from cardiovascular events but experience event rates at older ages equivalent to men after a 10-year lag time. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study showed similar findings regarding atherosclerosis, with 25- to 34-year-old women having much less atherosclerosis than similarly aged men and only slightly more atherosclerosis than 15- to 24-year-old adolescents/men.¹ This naturally raises the question: Should girls start statins at an older age than boys given equivalent risk?

To answer this question, one must consider two issues: Are there risk scenarios that obliterate the gender protection for women and does the need to interrupt medication during pregnancy and lactation influence treatment decisions — that is, could the “legacy effect” of more intensive treatment regimens in clinical trials be reasonable to apply in this setting?

There are, in fact, three scenarios in which risk overwhelms gender protection. The most important of these is childhood-onset diabetes mellitus, with which men and women experience cardiovascular events at similar rates.² In PDAY, atherosclerosis related to dysglycemia also is gender independent and more severe at young ages.¹ Smoking is the second great leveler of gender-specific risk. A female smoker has the same risk as a male non-smoker when other risk factors are equivalent.³ Height of low-density lipoprotein (LDL) cholesterol level is the third. Again based on PDAY estimates, an elevation of LDL cholesterol of about 60 mg/dl will undo gender protection; thus, girls with familial hypercholesterolemia (FH) and severe elevations of LDL cholesterol should be treated at a young age.

A further consideration with regard to FH will be the need to interrupt treatment during pregnancy. Thus, for several prolonged periods, women may be exposed not only to the impact of interrupted treatment but to physiologic increases in lipid levels during pregnancy and lactation. Legacy effects observed in large clinical trials show a sustained benefit from receiving more intense statin therapy for the duration of the trial.^4,5 This observation suggests that statin therapy at any point in life when risk is present is likely beneficial.

Which girls might get statin treatment in childhood or adolescence?⁶ There essentially are two groups: those with FH and those with elevated LDL cholesterol in combination with another major risk factor. For FH, the discussion above suggests that the “legacy effect” provides a rationale for treating boys and girls without a gender preference, despite known differences in the onset of cardiovascular disease in men and women with this disorder. Earlier initiation of treatment compensates for the need to interrupt treatment later in life, thus providing better treatment of atherosclerosis across the lifespan. Similarly, in the setting of diabetes, the absence of a gender gap in outcomes mandates against gender bias in lipid treatment recommendations.

For those with other risk factors (principally hypertension, tobacco use, and obesity) and LDL cholesterol that is elevated (above 130 mg/dl) but below 190 mg/dl, the PDAY study again provides some guidance. All the risk factors contribute to early atherosclerosis development independent of LDL cholesterol.¹ Thus, in a hypertensive girl or smoker with an LDL cholesterol above 160 mg/dl, initiating a statin is reasonable. Between 130 mg/dl and 160 mg/dl, patient discussion should be undertaken. Since the impact on atherosclerosis when a patient has obesity without other risk is much greater in boys than in girls in PDAY, I tend to be conservative in starting obese girls on statins.

To summarize, as a general rule, I tend to start statins at the same age and for the same indications in boys and girls. This is because either overall risk is sufficiently high that medication is warranted or the need to interrupt treatment later in life balances gender protection for atherosclerosis development. However, in the setting of multiple risk factors and borderline indications, there is no substitute for patient discussion, behavioral risk modification, and careful follow-up before initiating treatment.

Disclosure statement: Dr. Gidding has no disclosures to report.

References are listed on page 40 of the PDF.