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Honigberg MC, Trinder M, Natarajan P. Lipoprotein(a), Menopausal Hormone Therapy, and Risk of Coronary Heart Disease in Postmenopausal Individuals. JAMA Cardiol. 2022;7(5):565–568. doi:10.1001/jamacardio.2022.0716
Lipoprotein(a) (Lp[a]) is associated with atherosclerotic cardiovascular disease (ASCVD) events with preclinical evidence suggestive of causality.1 Menopausal hormone therapy (HT) has been suggested to lower Lp(a) levels in women by 15% to 20%.2 However, HT also increases C-reactive protein and prothrombin levels, and systemic inflammation may be synergistic with Lp(a) for increased ASCVD risk.3 A previous study of approximately 28 000 women enrolled nearly 30 years ago suggested Lp(a)-associated ASCVD risk was lessened among women using HT.2 Using a large, contemporary cohort, we reexamined whether HT use modifies the association of Lp(a) with coronary heart disease (CHD).
The Mass General Brigham institutional review board approved these analyses. We included patients in the UK Biobank who were postmenopausal at enrollment from 2006 to 2010; had complete reproductive history and covariate data; lacked preexisting ASCVD, heart failure, aortic stenosis, or venous thromboembolism; and underwent phlebotomy with measurement of Lp(a) at enrollment. Ever use and current use of HT were ascertained from UK Biobank field IDs 2814 and 6153/3546, respectively. Incident CHD during follow-up was ascertained using qualifying International Classification of Diseases codes as used previously.1,4 Cox proportional hazards regression models tested the association of Lp(a) with CHD in the overall sample and stratified by current vs previous vs never use of HT, with adjustment for age, age squared, race, socioeconomic status, current/former tobacco use, type 2 diabetes, natural/surgical menopause at younger than 40 years, body mass index, and systolic blood pressure; aspirin, antihypertensive, and cholesterol-lowering medication use; total and high-density lipoprotein cholesterol; and C-reactive protein. We generated individual-level LPA genetic risk scores using 43 single-nucleotide variation significantly associated with Lp(a) in data sets external to the UK Biobank.1 In sensitivity analyses, we assessed (1) a subcohort propensity score–matched for use of HT (previous and never users each matched 3:1 to current HT users) using all covariates plus LPA genetic risk with the nearest-neighbor algorithm in ‘MatchIt’ (R 3.6.0) and (2) LPA genetic scores in lieu of measured Lp(a). Two-sided P values were statistically significant at .05.
Of 114 028 postmenopausal patients with measured Lp(a), 88 266 met inclusion criteria (mean age, 60.0 years). At enrollment, 4550 (5.2%) were using HT, and 34 396 (39.0%) reported previous HT use. The median Lp(a) was lower in HT users than nonusers, but the median LPA genetic score was higher in HT users (Table 1). After adjustment for age, cholesterol-lowering medication use, and LPA genetic risk, current HT users had lower Lp(a) than previous HT users by 7.5 nmol/L (95% CI, −8.5 to −6.4 nmol/L; P < .001) and never HT users by 7.9 nmol/L (95% CI, −8.9 to −6.8 nmol/L; P < .001).
Throughout a median (IQR) follow-up of 11.1 (10.4-11.7) years, 3537 incident CHD events occurred. Individuals in the highest vs lowest Lp(a) quartiles had the highest risk of CHD (adjusted hazard ratio, 1.15; 95% CI, 1.05-1.26; P = .003). Hazards associated with greater Lp(a) appeared larger in those who previously used HT (P for interaction = .046) and those currently taking HT (Pfor interaction = .04) vs those who never used HT (Table 2). Observations were consistent in the propensity-matched subcohort and when examining LPA genetic risk scores in lieu of measured Lp(a), albeit with no significant interactions.
In a primary prevention cohort of 90 000 postmenopausal patients in midlife, higher Lp(a) values were associated with increased risk of incident CHD. Consistent with prior observations,2 HT use was associated with modest Lp(a) reduction. However, we found no evidence of lower Lp(a)-associated risks in HT users vs nonusers, in contrast with prior work.2 Differences between study findings likely stem from stark differences in HT use patterns before and after publication of the Women’s Health Initiative and other randomized trials.5 HT is not recommended for the indication of ASCVD risk reduction, but current consensus holds that HT is reasonable for treatment of vasomotor symptoms in female individuals who are younger than 60 years, less than 10 years from menopause, and without high estimated ASCVD risk.6
This study has limitations. As the study population was more than 95% White, whether findings extend to individuals of other races and ethnicities requires further study. Overall, our findings suggest that Lp(a) levels remain prognostic in individuals taking menopausal HT. Clinicians should not be dissuaded from measuring Lp(a) in postmenopausal individuals if clinically indicated irrespective of HT use.
Accepted for Publication: March 11, 2022.
Published Online: April 4, 2022. doi:10.1001/jamacardio.2022.0716
Corresponding Author: Pradeep Natarajan, MD, MMSc, Massachusetts General Hospital, 185 Cambridge St, CPZN 3.184, Boston, MA 02114 (email@example.com).
Author Contributions: Drs Honigberg and Natarajan 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: Honigberg, Natarajan.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Honigberg, Natarajan.
Critical revision of the manuscript for important intellectual content: Trinder, Natarajan.
Statistical analysis: Honigberg, Trinder.
Obtained funding: Natarajan.
Administrative, technical, or material support: Trinder, Natarajan.
Conflict of Interest Disclosures: Dr Honigberg reports consulting income from CRISPR Therapeutics. Dr Natarajan reports grant support from Amgen, Apple, AstraZeneca, Boston Scientific, and Novartis; consulting income from Apple, AstraZeneca, Novartis, Genentech/Roche, Blackstone Life Sciences, Foresite Labs, and TenSixteen Bio; and is a scientific advisor board member and shareholder of TenSixteen Bio and geneXwell, all unrelated to this work. No other disclosures were reported.
Funding/Support: Dr Natarajan is supported by the National Heart Lung and Blood Institute (grants R01HL142711, R01HL127564, R01HL148050, R01HL151283, R01HL148565, R01HL135242, and R01HL151152), National Institute of Diabetes and Digestive and Kidney Diseases (grant R01DK125782), Fondation Leducq (grant TNE-18CVD04), and Massachusetts General Hospital (Paul and Phyllis Fireman Endowed Chair in Vascular Medicine).
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; and decision to submit the manuscript for publication.
Meeting Presentation: This paper was presented at ACC.22; April 4, 2022; Washington, DC.
Additional Information: This research was conducted under UK Biobank application 7089.