![]() The extent to which these side effects can be extrapolated to the adolescent population remains unclear. The use of drug-target Mendelian randomization studies has gained popularity in recent years, although only a few studies have been conducted to study the side effects of medications in European adult populations, such as anti-hypercholesteremia and antihypertensives. ![]() Real-world data, such as pharmaco-epidemiologic studies of medication side effects, are susceptible to confounding by indication or immortal time bias. As such, it would be of public health interest to evaluate any possible side effects of the use of these medications in the general adolescent population. ![]() Unfortunately, a recent review commented a lack of safety studies on these medications in adolescents. However, with increasing rates of obesity in the adolescent populations, in particular East Asians, prescriptions of lipid-modifying medications may have to be considered for non-FH adolescents who have elevated, uncontrolled lipid profiles to mitigate the subsequent risk of atherosclerotic cardiovascular disease. Three-hydroxy-3-methylglutaryl coenzyme A (HMGCR) reductase inhibitors, collectively referred to as statins, are the first-line pharmacologic treatments for children with familial hypercholesterolemia (FH), which demonstrated a reduction in cardiovascular risk in adulthood. This study serves as a proof of principle study to inform the medication safety among adolescents via genetics. Larger studies were warranted to verify these findings. Statins and PCSK9 inhibitors in East Asian adolescents appeared to be safe based on the outcomes concerned. Genetic inhibition of PCSK9 was not associated with the safety outcomes assessed. After correcting for multiple comparisons ( p-value < 0.006), genetic inhibition of HMGCR was associated with lower linoleic acid − 0.79. Genetic inhibition of HMGCR and PCSK9 were associated with reduction in cholesterol-related NMR metabolomics, e.g., apolipoprotein B (HMGCR: beta , − 1.06 PCSK9: − 0.93 ) and had the expected effect on the positive control outcomes. Positive control outcomes were cholesterol markers from the “Children of 1997” birth cohort and coronary artery disease from Biobank Japan. Safety outcomes ( n = 100) included anthropometric and hematological traits, renal, liver, lung function, and other nuclear magnetic resonance metabolomics. MethodsĪ drug-target Mendelian randomization study leveraging the Global Lipid Genetics Consortium (East Asian, n = 146,492) and individual-level data from Chinese participants in the Biobank clinical follow-up of Hong Kong’s “Children of 1997” birth cohort ( n = 3443, aged ~ 17.6 years). This study aims to investigate the longer-term safety of HMGCR inhibitors and PCSK9 inhibitors among East Asian adolescents using genetics. With increasing hypercholesterolemia prevalence in East Asian adolescents, pharmacologic interventions (e.g., HMGCR inhibitors (statins) and PCSK9 inhibitors) may have to be considered although their longer-term safety in the general adolescent population is unclear.
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