Management of Severe and Moderate Hypercholesterolemia in Young Women and Men

Cardiovascular guidelines advise statin therapy for adults aged 20 to 75 years with low-density lipoprotein cholesterol (LDL-C) levels of 190 mg/dL or greater, with a goal of lowering LDL-C by at least 50%.¹ Early-life accumulation of cholesterol exposure increases future cardiovascular risk independent of midlife² and total cumulative cholesterol exposure,^3,4 highlighting the importance of LDL-C management in young adults. However, contemporary real-world management of hypercholesterolemia in young adults is not well described.

Using clinical registry data from 7 Mass General Brigham hospitals and affiliated practices, we isolated 2 cohorts of patients with cholesterol testing on 2 or more occasions who were 20 to 39 years old at the time of a qualifying LDL-C value between 2005 and 2018: cohort 1 included individuals with an LDL-C value of 190 mg/dL or greater, and cohort 2 included those with an LDL-C value between 160 and less than 190 mg/dL. All follow-up LDL-C values were extracted through December 31, 2019. Prescriptions for lipid-lowering therapy (LLT), including statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors, were additionally extracted. Primary end points were a 50% reduction in LDL-C for cohort 1 and a 30% reduction in cohort 2. The Massachusetts General Hospital institutional review board approved these analyses as non–human subjects research with waived informed consent.

Among 17 591 individuals meeting inclusion criteria, 5438 (30.9%) had severe hypercholesterolemia (cohort 1; 37.9% female; mean age, 32.6 [SD, 5.1] years at qualifying LDL-C measurement), and 12 513 (71.1%) had moderate hypercholesterolemia (cohort 2; 39.8% female; mean age, 32.7 [SD, 5.1] years). In cohort 1, over a median follow-up of 7.8 (IQR, 4.5-11.4) years, 1638 individuals (30.1%) achieved at least a 50% LDL-C reduction (27.2% of women vs 31.9% of men; P < .001) (Figure). Younger individuals were less likely to achieve a 50% LDL-C reduction (eg, age 20-24 years, 24.9%; age 35-39 years, 33.0%; P < .001 for trend) (Table). Mean LDL-C at last follow-up was 152.9 (SD, 51.2) mg/dL, and 1271 patients (23.4%) had a last LDL-C value of 190 mg/dL or greater. Overall, LLT was prescribed for 48.5% of individuals, including 77.5% who achieved at least 50% LDL-C reduction vs 36.0% who did not (P < .001); LLT was less frequently prescribed for women vs men (43.7% vs 51.5%; P < .001).

In cohort 2, over a median 7.7 (IQR, 4.3-11.1) years of follow-up, 4515 individuals (36.1%) achieved at least a 30% LDL-C reduction, and 3800 (30.4%) had a last LDL-C value of 160 mg/dL or greater. Only 20.0% received LLT (14.9% of women vs 23.4% of men; P < .001).

In a large health care system composed of multiple academic and community-based practice sites, fewer than 1 in 3 young adults with severe hypercholesterolemia achieved guideline-directed LDL-C reduction (≥50%), and nearly 1 in 4 had an LDL-C level persistently 190 mg/dL or greater, over 8 years of follow-up. Fewer than half of patients with an LDL-C level of 190 mg/dL or greater were prescribed LLT. Furthermore, we observed lower likelihood of prescription for LLT and achievement of LDL-C reduction among women and younger patients. These data build on previous findings that only 45% of adults younger than 40 years with LDL-C levels of 190 mg/dL or greater were prescribed a statin⁵ and, using quantitative, longitudinal LDL-C data, demonstrate that treatment gaps persist over time. Lower rates of LLT prescription and LDL-C reduction in women may imply wariness of prescribing LLT in reproductive-aged women due to concerns about teratogenicity or underestimation of long-term cardiovascular risk in this population.

As expected, young adults with moderate hypercholesterolemia achieved even less LDL-C lowering. Current guidelines endorse aggressive lifestyle modification and consideration of statin therapy in adults aged 20 to 39 years with LDL-C levels of 160 to less than 190 mg/dL plus other high-risk features, eg, family history.¹ Our findings suggest significant underrecognition of the risks associated with persistent moderate hypercholesterolemia in young adulthood.^2,3,6

This study has limitations. Although findings are broadly consistent with prior national data,⁵ findings from a New England–based health care system may not generalize to nationwide practice patterns.

This study’s findings highlight the need for strategies to promote guideline-recommended cholesterol management in young adults.

Corresponding Author: Michael C. Honigberg, MD, MPP, Massachusetts General Hospital, 185 Cambridge St, CPZN 3.187, Boston, MA 02114 (mhonigberg@mgh.harvard.edu).

Accepted for Publication: October 12, 2021.

Published Online: November 15, 2021. doi:10.1001/jamacardio.2021.4983

Author Contributions: Drs Newton and Honigberg had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Newton, Natarajan, Honigberg.

Acquisition, analysis, or interpretation of data: Newton, Hoffmann, Yu, Haidermota, Honigberg.

Drafting of the manuscript: Newton, Hoffmann, Haidermota.

Critical revision of the manuscript for important intellectual content: Yu, Natarajan, Honigberg.

Statistical analysis: Newton, Hoffmann, Yu, Honigberg.

Obtained funding: Natarajan.

Administrative, technical, or material support: Haidermota, Natarajan.

Supervision: Natarajan, Honigberg.

Conflict of Interest Disclosures: Dr Natarajan reported receiving grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; is a scientific advisor to Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech, and Novartis; and reported spousal employment at Vertex, all unrelated to the present work. No other disclosures were reported.

Funding/Support: Dr Natarajan is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148050, R01HL151283, R01HL148565, and R01HL135242) and Foundation Leducq (TNE-18CVD04) and is the Paul and Phyllis Fireman Endowed Chair in Vascular Medicine, Massachusetts General Hospital.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Meeting Presentation: This article was presented at the American Heart Association Scientific Sessions 2021; November 15, 2021; Boston, Massachusetts.