US Public Health Gains from Improved Treatment of Hypercholesterolemia: A Simulation Study of NHANES Adults Treated to Guideline-Directed Therapy

G Caleb Alexander^{1

2

3}, Jill Curran^{4

5}, Alejandro Victores⁶, Hemalkumar B Mehta^{4

5}, Shanshan Lin⁷, Xuya Xiao^{4

5}, Erin D Michos^{5

8}, Jeromie Ballreich^{4

9}, Lori D Bash⁶, Jason Exter⁶, Kathryn Foti¹⁰, Seth S Martin^{5

8

11}

Affiliations

¹ Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. galexan9@jhmi.edu.
² Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. galexan9@jhmi.edu.
³ Division of General Internal Medicine, Johns Hopkins Medicine, Baltimore, MD, USA. galexan9@jhmi.edu.
⁴ Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁶ Merck & Co., Inc., Rahway, NJ, USA.
⁷ Division of General Internal Medicine, Johns Hopkins Medicine, Baltimore, MD, USA.
⁸ Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁹ Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁰ Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
¹¹ Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, MD, USA.

PMID: 40586962
DOI: 10.1007/s11606-025-09625-0

US Public Health Gains from Improved Treatment of Hypercholesterolemia: A Simulation Study of NHANES Adults Treated to Guideline-Directed Therapy

G Caleb Alexander et al. J Gen Intern Med. 2025.

. 2025 Jun 30.

doi: 10.1007/s11606-025-09625-0. Online ahead of print.

Authors

Affiliations

¹ Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. galexan9@jhmi.edu.
² Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. galexan9@jhmi.edu.
³ Division of General Internal Medicine, Johns Hopkins Medicine, Baltimore, MD, USA. galexan9@jhmi.edu.
⁴ Center for Drug Safety and Effectiveness, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁶ Merck & Co., Inc., Rahway, NJ, USA.
⁷ Division of General Internal Medicine, Johns Hopkins Medicine, Baltimore, MD, USA.
⁸ Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁹ Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁰ Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, AL, USA.
¹¹ Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, MD, USA.

PMID: 40586962
DOI: 10.1007/s11606-025-09625-0

Abstract

Importance: Hypercholesterolemia is widely undertreated.

Objective: To project anticipated improvements in treatment and outcomes under full implementation of US and European pharmacologic treatment recommendations.

Design, setting, and participants: The study sample included a total of 4980 adults aged 40-75 years from the 2013 through March 2020 US National Health and Nutrition Examination Survey (NHANES). We estimated the number of individuals eligible to receive versus currently receiving lipid lowering therapy (LLT) after applying: (1) the AHA/ACC guideline ("2018 US guideline"); (2) the ESC/EAS guideline ("2019 EU guideline"); and (3) the ACC expert decision pathway ("2022 US pathway").

Main outcomes and measures: (1) Number of individuals eligible for LLT; and (2) expected reduction in LDL-C and major cardiovascular events.

Results: The study sample represented 131 million US adults. A total of 23% of the NHANES primary prevention cohort was currently using LLT compared to the 2018 US guideline/2022 US pathway (47% eligible) and the 2019 EU guideline (87% eligible). LLT use was significantly lower than the proportion of eligible patients for all therapies, including statins (66% use vs. 100% eligibility), ezetimibe (4% vs. 31-74% eligibility under the various recommendations) and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) (0% vs. 11-53% eligibility). The additional overall median LDL-C reduction expected under fully guideline concordant care was 37.2 (IQR 6.7-57.6) mg/dL, 48.5 (IQR 33.0-69.9) mg/dL, and 46.8 (IQR 7.2-67.6) mg/dL based on the 2018 US guideline, 2019 EU guideline and the 2022 US pathway, respectively. These reductions in LDL-C could yield a 21-27% relative reduction in risk of major cardiovascular events.

Conclusions and relevance: Aligning treatment of hypercholesterolemia with US and European guidelines would generate major clinical and public health gains.

Keywords: Cardiovascular disease; Cholesterol; LDL-C; Treatment guidelines.

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Conflict of interest statement

Declarations:. Human Ethics and Consent to Participate:: The National Center for Health Statistics ethics review board approved the original survey protocols which were utilized to collect data for the NHANES tike periods included herein. Accordingly, informed consent was obtained from all NHANES participants. Conflict of Interest:: Dr. Alexander is past Chair of FDA’s Peripheral and Central Nervous System Advisory Committee and is a co-founding Principal and equity holder in Stage Analytics. Outside of this work, Dr. Martin has received personal consulting fees from Amgen, AstraZeneca, BMS, Kaneka, Merck, NewAmsterdam, Novartis, Novo Nordisk, Premier, Sanofi, and 89bio. Outside of this work, Dr. Michos has received personal consulting fees from Amgen, Arrowhead, AstraZeneca, Boehringer Ingelheim, Edwards Lifescience, Esperion, Ionis, Lilly, Medtronic, Merck, NewAmsterdam, Novartis, Novo Nordisk, and Pfizer. These arrangements have been reviewed and approved by Johns Hopkins University in accordance with its conflict of interest policies. Dr. Victores and Dr. Bash are, and Dr. Exter was employed by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Ms. Curran is now employed by Boehringer Ingelheim.

References

1. Heart Disease Facts. U.S. Centers for Disease Control and Prevention. Available at: https://www.cdc.gov/heartdisease/facts.htm . Accessed 4 April 2022.
1. American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2023 update: a report from the American Heart Association. Circulation. 2023;147:e93-e621.
1. Bradley CK, Wang TY, Li S, et al. Patient-reported reasons for declining or discontinuing statintherapy: insights from the PALM registry. J Am Heart Assoc. 2019;8:e011765 - DOI - PubMed - PMC
1. Dayoub EJ, Eberly LA, Nathan AS, Khatana SAM, Adusumalli S, Navar AM, Giri J, Groeneveld PW. Adoption of PCSK9 inhibitors among patients with atherosclerotic disease. J Am Heart Assoc. 2021;10(9):e019331. https://doi.org/10.1161/JAHA.120.019331 .
1. Cannon CP, Khan I, Klimchak AC, Reynolds MR, Sanchez RJ, Sasiela WJ. Simulation of lipid- lowering therapy intensification in a population with atherosclerotic cardiovascular disease. JAMA Cardiol. 2017;2:959–966. - DOI - PubMed - PMC

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US Public Health Gains from Improved Treatment of Hypercholesterolemia: A Simulation Study of NHANES Adults Treated to Guideline-Directed Therapy

Affiliations

US Public Health Gains from Improved Treatment of Hypercholesterolemia: A Simulation Study of NHANES Adults Treated to Guideline-Directed Therapy

Authors

Affiliations

Abstract

Conflict of interest statement

References

LinkOut - more resources

Full Text Sources