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Sex differences of lipoprotein(a) levels and associated risk of morbidity and mortality by age: The Copenhagen General Population Study

  • Sofie Bay Simony
    Affiliations
    The Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark

    The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark

    Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
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  • Martin Bødtker Mortensen
    Affiliations
    The Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark

    The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark

    Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark

    Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200 Aarhus N, Aarhus, Denmark
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  • Anne Langsted
    Affiliations
    The Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark

    The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark

    Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
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  • Shoaib Afzal
    Affiliations
    The Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark

    The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark

    Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
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  • Pia Rørbæk Kamstrup
    Affiliations
    The Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark

    The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark
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  • Børge Grønne Nordestgaard
    Correspondence
    Corresponding author. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, Entrance 7, 4th floor, N5, DK-2730, Herlev, Denmark.
    Affiliations
    The Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark

    The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Borgmester Ib Juuls Vej 73, opgang 7, 2730, Herlev, Denmark

    Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen N, Denmark
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Open AccessPublished:June 27, 2022DOI:https://doi.org/10.1016/j.atherosclerosis.2022.06.1023

      Highlights

      • Lipoprotein(a) levels increase with increasing age in women and men.
      • Lipoprotein(a) levels increase around age 50 selectively in women.
      • Risk of morbidity and mortality for high lipoprotein(a) levels was similar in women and men above age 50.
      • These results imply that elevated lipoprotein(a) above age 50 is a relatively more common cardiovascular risk factor in women than men.

      Abstract

      Background and aims

      Lipoprotein(a) is a well-known causal risk factor for cardiovascular morbidity and mortality. Little is known about the effect of age and sex on lipoprotein(a) levels, and it is largely unknown if the same elevation in lipoprotein(a) confers the same increase in risk in women and men. We investigated whether lipoprotein(a) levels and lipoprotein(a) associated risks of morbidity and mortality by age are similar in women and men.

      Methods

      We included 37,545 women and 32,497 men from the Copenhagen General Population Study.

      Results

      Plasma lipoprotein(a) increased with age, and in women we found an additional increase around age 50 (age by sex interaction p = 8∙10−7). In women, levels were 27% higher after menopause (p = 4∙10−61) and 12% lower during hormone replacement therapy (p = 2∙10−19). Adjustment for estimated Glomerular Filtration Rate in both sexes and plasma estradiol in women resulted in attenuated sex differences in lipoprotein(a) levels. In sex and age stratified multivariable adjusted models, lipoprotein(a) >40 mg/dL(83 nmol/L) versus <10 mg/dL(18 nmol/L) was associated with increased risk of myocardial infarction, ischemic heart disease, aortic valve stenosis, and heart failure (men only), but not statistically significant with risk of ischemic stroke, cardiovascular mortality, or all-cause mortality.

      Conclusions

      Lipoprotein(a) levels increased modestly around age 50 selectively in women; however, risk of morbidity and mortality for high lipoprotein(a) was similar in women and men above age 50. This implies that elevated lipoprotein(a) above age 50 is a relatively more common cardiovascular risk factor in women, pointing toward repeat measurements in women above age 50.

      Graphical abstract

      Keywords

      1. Introduction

      Lipoprotein(a) is a well-known causal risk factor for myocardial infarction, aortic valve stenosis, atherosclerotic disease, cardiovascular mortality, and all-cause mortality [
      • Kamstrup P.R.
      • Tybjaerg-Hansen A.
      • Steffensen R.
      • Nordestgaard B.G.
      Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.
      ,
      • Langsted A.
      • Kamstrup P.R.
      • Nordestgaard B.G.
      High lipoprotein(a) and high risk of mortality.
      ,
      • Kamstrup P.R.
      Lipoprotein(a) and cardiovascular disease.
      ,
      • Clarke R.
      • et al.
      Genetic variants associated with Lp(a) lipoprotein level and coronary disease.
      ]. It is currently recommended by the European Society of Cardiology, jointly with the European Atherosclerosis Society and the Canadian Cardiovascular Society, to screen all women and men for high levels of lipoprotein(a) once in a lifetime [
      • Mach F.
      • et al.
      2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
      ,
      • Pearson G.J.
      • et al.
      2021 Canadian cardiovascular society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults.
      ]. More than 90% of the variance in lipoprotein(a) levels is explained by genetics [
      • Kronenberg F.
      • Utermann G.
      Lipoprotein(a): resurrected by genetics.
      ] and the distribution varies with different ethnicities [
      • Nordestgaard B.G.
      • et al.
      Lipoprotein(a) as a cardiovascular risk factor: current status.
      ,
      • Pare G.
      • et al.
      Lipoprotein(a) levels and the risk of myocardial infarction among 7 ethnic groups.
      ].
      Little is known about the effect of age and sex on lipoprotein(a) levels. Despite the strong genetic contribution to lipoprotein(a) levels, some studies have found an increase in lipoprotein(a) levels with increasing age [
      • Jenner J.L.
      • et al.
      Effects of age, sex, and menopausal status on plasma lipoprotein(a) levels. The Framingham Offspring Study.
      ,
      • Akita H.
      • Matsubara M.
      • Shibuya H.
      • Fuda H.
      • Chiba H.
      Effect of ageing on plasma lipoprotein(a) levels.
      ,
      • Erhart G.
      • et al.
      Genetic factors explain a major fraction of the 50% lower lipoprotein(a) concentrations in Finns.
      ], while others have suggested that levels of lipoprotein(a) increase due to menopause in women [
      • Kim C.J.
      • Kim T.H.
      • Ryu W.S.
      • Ryoo U.H.
      Influence of menopause on high density lipoprotein-cholesterol and lipids.
      ,
      • Slunga L.
      • Asplund K.
      • Johnson O.
      • Dahlen G.H.
      Lipoprotein (a) in a randomly selected 25-64 year old population: the Northern Sweden Monica Study.
      ,
      • Ushioda M.
      • Makita K.
      • Takamatsu K.
      • Horiguchi F.
      • Aoki D.
      Serum lipoprotein(a) dynamics before/after menopause and long-term effects of hormone replacement therapy on lipoprotein(a) levels in middle-aged and older Japanese women.
      ]. Whether such menopause associated increase in lipoprotein(a) is caused by ageing per se or by hormonal changes is not fully understood, but women on hormone replacement therapy (HRT) have lower lipoprotein(a) levels than women not on HRT [
      • Suk Danik J.
      • Rifai N.
      • Buring J.E.
      • Ridker P.M.
      Lipoprotein(a), hormone replacement therapy, and risk of future cardiovascular events.
      ,
      • Shlipak M.G.
      • et al.
      Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause.
      ]. With high lipoprotein(a) levels risk of cardiovascular disease is increased in both women and men [
      • Nordestgaard B.G.
      • Langsted A.
      Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology.
      ,
      • Cook N.R.
      • Mora S.
      • Ridker P.M.
      Lipoprotein(a) and cardiovascular risk prediction among women.
      ,
      • Suk Danik J.
      • Rifai N.
      • Buring J.E.
      • Ridker P.M.
      Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women.
      ]. That said, it is largely unknown if the same elevation in lipoprotein(a) confers the same increase in risk of morbidity and mortality in women and men.
      We tested the hypothesis that lipoprotein(a) levels and lipoprotein(a) associated risks of morbidity and mortality by age are similar in women and men. To do so we used data from 70,042 individuals aged 20–89 years in the contemporary Copenhagen General Population Study (CGPS). Our main endpoint was myocardial infarction as this hard endpoint is registered above 99% correct in the Danish health registries [
      • Kamstrup P.R.
      • Tybjaerg-Hansen A.
      • Steffensen R.
      • Nordestgaard B.G.
      Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.
      ]; however, we conducted similar analyses for ischemic heart disease, ischemic stroke, aortic valve stenosis, heart failure, cardiovascular mortality, and all-cause mortality.

      2. Patients and methods

      Full Methods section in Supplementary Methods. Methods in brief below.

      2.1 Study population

      We examined white individuals of Danish descent from the CGPS. The study was approved by a Danish ethics committee and by the Herlev and Gentofte Hospital. We included 37,545 women and 32,497 men aged 20–89 years with information on plasma lipoprotein(a) levels.

      2.2 Endpoints

      Every individual living in Denmark is assigned a unique Civil Person Registration number at birth or immigration. This allows complete follow-up in Danish health registries for cardiovascular morbidity and mortality. All participants in CGPS were followed until studied endpoint, death, emigration (N = 242), or December 2018, whichever came first.

      2.3 Laboratory analyses

      All blood samples were drawn in the nonfasting state and analyzed using standard hospital assays. Lipoprotein(a) was analyzed with different assays over time due to differing availability, but all were calibrated corresponding to values using the Denka assay on fresh samples. The majority of all lipoprotein(a) measurements were performed on fresh samples using this assay. Samples stored prior to measurements were kept at −80° Celsius before measurement.

      2.4 Statistical analysis

      Stata statistical software version 15.1 was used. Covariates were complete for >99% of observations. In case of missing data, data were imputed, except for estradiol (N = 9,949) and testosterone (N = 9,909), in which we did analyses on a subgroup.
      Smooth polynomial functions were used to evaluate mean levels of lipoprotein(a) by increasing age, multivariable adjusted Cox regression restricted cubic splines were used to evaluate the relationship between lipoprotein(a) levels on continuous scales and risk of myocardial infarction, and multivariable adjusted Cox proportional hazards regressions were used to estimate hazard ratios for risk of cardiovascular morbidity and mortality with lipoprotein(a) levels divided into three groups on the basis of percentiles (1st-50th, 51st-80th, and 81st-100th percentile), to focus on normal, medium, and high levels of lipoprotein(a).

      3. Results

      The present study included 70,042 individuals aged 20–89 years with a median age of 60 years (interquartile range: 50–69 years). Baseline characteristics are shown in Table 1 stratified in 37,545 women and 32,497 men. The number of postmenopausal women increased markedly from below to above age 50 years. The distribution of lipoprotein(a) in the study population in women and men and in the age groups 60–69 years and 80–89 years are shown in Supplementary Figs. 1 and 2.
      Table 1Baseline characteristics of individuals in the Copenhagen General Population Study by sex and age group.
      Women (N = 37,545)Age, years
      20–4950–5960–6970–7980–89
      Number10,2289,2449,9186,1162,039
      Age, years45 (42–47)55 (52–57)65 (63–67)74 (72–77)83 (82–86)
      Plasma C-reactive protein, mg/L1.1 (0.6–2.0)1.2 (0.7–2.1)1.4 (0.8–2.5)1.6 (1.0–3.1)1.8 (1.2–3.2)
      eGFR, mL/min/1.73m291 (81–101)80 (72–89)73 (66–82)66 (58–75)57 (49–67)
      Plasma estradiol, nmol/La0.23 (0.09–0.45)0.04 (0.00–0.11)0.02 (0.00–0.06)0.00 (0.00–0.05)0.00 (0.00–0.04)
      Plasma testosterone, nmol/Lb0.9 (0.6–1.3)0.9 (0.6–1.3)0.9 (0.6–1.3)1.0 (0.6–1.3)0.8 (0.5–1.4)
      non-HDL cholesterol, mmol/Lc3.2 (2.6–3.8)3.7 (3.1–4.5)3.8 (3.2–4.6)3.7 (3.0–4.5)3.7 (3.0–4.5)
      non-HDL cholesterol, mg/dLc124 (100–147)143 (120–174)147 (124–178)143 (116–174)143 (116–174)
      HDL cholesterol, mmol/L1.7 (1.4–2.0)1.8 (1.4–2.1)1.8 (1.5–2.2)1.8 (1.5–2.2)1.8 (1.5–2.2)
      HDL cholesterol, mg/dL66 (54–77)70 (54–81)70 (58–85)70 (58–85)70 (58–85)
      Smoking, %1820151310
      Hypertension, %3658768591
      Statins, %17172320
      Body mass index, kg/m224 (22–27)25 (22–28)25 (23–29)26 (23–29)25 (23–28)
      Diabetes mellitus, %13576
      Postmenopausal, %1181100100100
      Postmenopausal with HRT, %2116161615
      Men (N = 32,497)Age, years
      20–4950–5960–6970–7980–89
      Number7,8067,7748,8266,0312,060
      Age, years45 (42–47)55 (53–58)65 (63–67)74 (72–77)83 (81–85)
      Plasma C-reactive protein, mg/L1.0 (0.6–1.7)1.2 (0.7–2.1)1.4 (0.9–2.5)1.6 (1.0–3.0)1.7 (1.1–3.2)
      eGFR, mL/min/1.73m297 (88–105)90 (81–97)84 (75–91)75 (65–84)66 (56–76)
      Plasma estradiol, nmol/La0.1 (0.0–1.1)0.1 (0.0–0.1)0.1 (0.0–0.1)0.1 (0.0–0.1)0.1 (0.0–0.1)
      Plasma testosterone, nmol/Lb11.0 (8.6–14.3)10.9 (8.5–14.3)11.0 (8.6–14.3)10.8 (8.0–14.4)10.7 (8.2–14.0)
      non-HDL cholesterol, mmol/Lc3.9 (3.2–4.7)4.0 (3.3–4.8)3.8 (3.1–4.6)3.5 (2.8–4.3)3.3 (2.6–4.1)
      non-HDL cholesterol, mg/dLc151 (123–181)154 (127–185)146 (120–178)135 (108–166)127 (100–158)
      HDL cholesterol, mmol/L1.3 (1.0–1.6)1.3 (1.1–1.7)1.4 (1.1–1.7)1.4 (1.2–1.8)1.5 (1.2–1.8)
      HDL cholesterol, mg/dL50 (39–62)50 (43–66)54 (43–66)54 (46–70)58 (46–70)
      Smoking, %1822201513
      Hypertension, %5772838889
      Statins, %311223027
      Body mass index, kg/m226 (24–28)26 (24–29)27 (25–29)27 (25–29)26 (24–28)
      Diabetes mellitus, %1491111
      Continuous variables are shown as median values (interquartile range). aMeasured in 5,387 women and 4,562 men. bMeasured in 5,365 women and 4,544 men. cCorrected for lipoprotein(a) cholesterol. eGFR: estimated glomerular filtration rate. HDL: High-density lipoprotein. HRT: hormone replacement therapy.

      3.1 Lipoprotein(a) levels across sex and age

      Lipoprotein(a) increased with age in both women and men (Fig. 1). While lipoprotein(a) increased steadily across the age span in men, there was an additional increase in lipoprotein(a) around age 50 in women. Lipoprotein(a) levels were similar in women and men aged 20–49 years, but at age 50–89 women had higher mean levels of lipoprotein(a) than men (27 mg/dL (55 nmol/L) versus 23 mg/dL (46 nmol/L); p for age by sex interaction = 8∙10−7), corresponding to 17% higher mean lipoprotein(a) levels.
      Fig. 1
      Fig. 1Mean plasma lipoprotein(a) levels for women and men with increasing age.
      Red line indicate levels for women and shaded pink area is 95% confidence interval. Blue line indicate levels for men and shaded blue area is 95% confidence interval. p for age by sex interaction on plasma lipoprotein(a) was calculated with linear regression. Based on 70,042 individuals aged 20–89 from the Copenhagen General Population Study; however, only values for individuals aged 40–80 are shown due to wide confidence intervals for those at lower or higher ages. Lp(a): Lipoprotein(a). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
      Compared to women aged <50 years, women aged 50–59 years had 18% higher lipoprotein(a) levels while the corresponding value in men was 6% (Fig. 2, upper panel). Similar sex differences, with highest lipoprotein(a) levels in women, were observed at age 60–89. The percent of women and men with lipoprotein(a) levels ≥30 mg/dL (62 nmol/L), ≥50 mg/dL (105 nmol/L), and ≥70 mg/dL (149 nmol/L) are shown in Supplementary Fig. 3.
      Fig. 2
      Fig. 2Mean plasma lipoprotein(a) levels for women and men in age categories.
      Red bars indicate women, blue bars indicate men. Black lines indicate upper 95% confidence interval. p values are calculated with two sample t-test with age as categorical variable. Based on 70,042 individuals from the Copenhagen General Population Study. eGFR: estimated glomerular filtration rate. Lp(a): Lipoprotein(a). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
      We further performed analyses adjusting lipoprotein(a) levels for estimated glomerular filtration rate (eGFR), C-reactive protein (CRP), estradiol, and testosterone levels. Adjustment for eGFR in both sexes and plasma estradiol in women resulted in attenuated lipoprotein(a) increases with age (Fig. 2, Supplementary Figs. 4 and 5) (p for age by eGFR interaction 2∙10−8 in women and 0.05 in men; p for age by estradiol interaction 0.03 in women and 0.17 in men); adjustment for plasma CRP and testosterone did not attenuate the age associated increase in lipoprotein(a) levels. When adjusting for both eGFR and estradiol, the increase in lipoprotein(a) around age 50 for women attenuated (Fig. 2 lower panel and Supplementary Fig. 6). When adjusting for plasma creatinine, results were similar to eGFR adjustment (Supplementary Fig. 7). When we excluded individuals with eGFR <60 mL/min/1.73 m2 it yielded similar results as Fig. 2 middle panel (results not shown). Intercorrelation between lipoprotein(a) and covariates used for adjustment are shown unadjusted in Supplementary Table 1 and age adjusted in Supplementary Table 2.
      Lipoprotein(a) levels increased with age irrespectively of whether women were on HRT or not (Supplementary Figs. 8 and 9). Lipoprotein(a) levels were 23 mg/dL (95% confidence interval (CI: 22–23 mg/dL)) (46 nmol/L(44–46 nmol/L)) for women on HRT and 26 mg/dL (26-26 mg/dL) (53 nmol/L(53-53 nmol/L)) for women without HRT (12% lower; t-test: p = 2∙10−19). After adjustment for age and eGFR, the corresponding values were 23 mg/dL (95% CI: 22–24 mg/dL) (46 nmol/L(44–48 nmol/L)) and 26 mg/dL (25–26 mg/dL) (53 nmol/L (51–53 nmol/L)) (12% lower; p = 2∙10−9); women on HRT constitute 17% of all women.
      In a subset of 1,473 women with lipoprotein(a) measurements both before and after menopause, the mean lipoprotein(a) levels were 22 mg/dL (95% CI: 21–24 mg/dL) (44 nmol/L(42–48 nmol/L)) premenopausal and 28 mg/dL (26–30 mg/dL) (57 nmol/L (53–62 nmol/L)) postmenopausal (27% higher; paired t-test: p = 4∙10−61) (waterfall plot in Supplementary Fig. 10).

      3.2 Lipoprotein(a) and morbidity and mortality across sex and age

      We included 904 and 1,513 first-time myocardial infarction events in women and men, and similarly 2,095 and 2,868 ischemic heart disease events, 1,161 and 1,365 ischemic stroke events, 500 and 715 aortic valve stenosis events, 1,242 and 2,072 heart failure events, 727 and 1,190 cardiovascular disease deaths, and 4,571 and 5,830 any cause deaths.
      Higher lipoprotein(a) levels were associated with increased risk of myocardial infarction in both women and men (Fig. 3). In multivariable adjusted models, lipoprotein(a) >40 mg/dL (83 nmol/L) versus <10 mg/dL (18 nmol/L) conferred hazard ratios for myocardial infarction of 1.44 (95% CI: 1.23–1.69) in women and 1.56 (1.38–1.77) in men (p for lipoprotein(a) by sex interaction 0.60) (Fig. 4 and Supplementary Fig. 11). At age <50 the corresponding hazard ratios were 1.78 (1.06–2.98) and 1.80 (1.26–2.58) (p for interaction 0.46). Finally, for women and men aged ≥50 the corresponding hazard ratios were 1.41(1.19–1.66) and 1.53(1.34–1.74) (p for interaction 0.81). These results were similar with and without adjustment for eGFR (Supplementary Fig. 11, right panel).
      Fig. 3
      Fig. 3Multivariable adjusted hazard ratios for myocardial infarction according to lipoprotein(a) levels.
      Solid lines are multivariable adjusted hazard ratios (women red line, men blue line), and dashed lines indicate 95% confidence intervals derived from restricted cubic spline regressions with four knots. The hazard ratio of no association of 1.0 is shown as solid black line. Cox regressions were adjusted for age, smoking status, hypertension, body mass index, statin use, diabetes mellitus, C-reactive protein, and non-HDL cholesterol corrected for lipoprotein(a) cholesterol content. p for lipoprotein(a) by sex interaction on risk of myocardial infarction was 0.60. Based on 68,229 individuals aged 20–89 from the Copenhagen General Population Study; those with myocardial infarction before baseline were excluded. The reference value with hazard ratio of 1.0 was 2.9 mg/dL (2.5 nmol/L). Graphs were truncated at lipoprotein(a) of 250 mg/dL (541 nmol/L) due to very wide confidence intervals above this value. CI: Confidence interval. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
      Fig. 4
      Fig. 4Multivariable adjusted hazard ratios for morbidity and mortality by high versus low lipoprotein(a) levels overall and stratified above and below age 50 in women and men.
      Multivariable adjustment was for age, smoking status, hypertension, body mass index, statin use, diabetes mellitus, C-reactive protein, and non-HDL cholesterol corrected for lipoprotein(a) cholesterol content. Based on 65,202–70,042 individuals from the Copenhagen General Population Study; those with the relevant endpoint before baseline were excluded in the specific analysis. For endpoints with events <10, hazard ratios are not shown due to unstable risk estimates. CI: Confidence interval, eGFR: estimated glomerular filtration rate, HR: Hazard ratio, Lp(a): Lipoprotein(a).
      As for risk of myocardial infarction, there was no convincing evidence for lipoprotein(a) by sex interaction on risk of ischemic heart disease, ischemic stroke, aortic valve stenosis, heart failure, cardiovascular mortality, or all-cause mortality, overall or in those aged <50 or ≥50 (p for interaction: 0.01 to 0.81; required p-value after Bonferroni correction for 21 parallel tests 0.05/21 = 0.0024) (Fig. 4). When examining lipoprotein(a) >40 mg/dL (83 nmol/L) versus <10 mg/dL (18 nmol/L) in these sex and age stratified analyses, the association of high versus low lipoprotein(a) reached statistical significance for increased risk of myocardial infarction, ischemic heart disease, aortic valve stenosis, and heart failure (men only), but not for ischemic stroke, cardiovascular mortality, or all-cause mortality. However, when using the same study population, we previously showed that extremely high lipoprotein(a) levels (>93 mg/dL (199 nmol/L)) were associated with increased risk of ischemic stroke, cardiovascular mortality, and all-cause mortality [
      • Langsted A.
      • Kamstrup P.R.
      • Nordestgaard B.G.
      High lipoprotein(a) and high risk of mortality.
      ,
      • Langsted A.
      • Nordestgaard B.G.
      • Kamstrup P.R.
      Elevated lipoprotein(a) and risk of ischemic stroke.
      ]. In sensitivity analyses, we excluded individuals with eGFR <60 mL/min/1.73 m2 and results were similar for all outcomes (data not shown). Further, we adjusted for non-high density lipoprotein (non-HDL) cholesterol instead of non-HDL cholesterol corrected for lipoprotein(a) cholesterol yielding similar results (data not shown).

      4. Discussion

      Based on a contemporary general population cohort including 70,042 individuals aged 20–89 years, we found that lipoprotein(a) levels increased with increasing age in both women and men; however, while the increase by age was steady in men, there was an additional modest increase around age 50 in women. Also, the association between high lipoprotein(a) levels and increased risk of morbidity and mortality was similar in women and men above age 50. Taken together, these two observations imply that elevated lipoprotein(a) above age 50 is a relatively more common cardiovascular risk factor in women than in men (due to higher levels but similar risk for the same levels), pointing toward repeat lipoprotein(a) measurement in women above age 50. Our sex and age stratified results on plasma levels and associated risk of morbidity and mortality are novel, including that lower kidney function with age explains a large part of the lipoprotein(a) increase with age in both women and men while plasma estradiol in women also contributes to the explanation.
      The mechanism behind the selective increase in lipoprotein(a) levels around age 50 in women was previously unclear. To explore the sex difference in increasing plasma lipoprotein(a) with age, we adjusted lipoprotein(a) levels for several variables that have been hypothesized to impact levels: somewhat surprisingly, mainly adjustment for kidney function using eGFR or plasma creatinine seemed to largely attenuate the age-related increase in lipoprotein(a) levels in both sexes, including attenuation of the selective increase in lipoprotein(a) levels around age 50 in women. It is also somewhat surprising that eGFR does not seem to ‘impact’ lipoprotein(a) in men as much as in women. In support of these findings, kidney function is inversely correlated to lipoprotein(a) levels [
      • Kronenberg F.
      Causes and consequences of lipoprotein(a) abnormalities in kidney disease.
      ,
      • Hopewell J.C.
      • Haynes R.
      • Baigent C.
      The role of lipoprotein (a) in chronic kidney disease.
      ,
      • Kronenberg F.
      • et al.
      Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure.
      ], an observation that together with our results indicate that declining kidney function with age contribute to the age-associated increase in lipoprotein(a) levels in both women and men. Excluding individuals with eGFR <60 mL/min/1.73 m2 did not change our results markedly, implying that individuals with very low kidney function are not the only individuals at high risk from high lipoprotein(a). On the contrary, these results indicate that at the population level, and beyond individuals with chronic kidney disease, kidney function is indeed a predictor of lipoprotein(a) levels. Although additional adjustment for plasma estradiol further attenuated the age-related increase in women, some residual unexplained increase in lipoprotein(a) levels by age remained in women, unlike in men. Adjustment for CRP did not change the lipoprotein(a) levels. This illustrates that a potential small increase in CRP due to minor inflammation has no influence on lipoprotein(a). However, it is well known that lipoprotein(a) increases as an acute phase reactant after myocardial infarction [
      • Maeda S.
      • Abe A.
      • Seishima M.
      • Makino K.
      • Noma A.
      • Kawade M.
      Transient changes of serum lipoprotein(a) as an acute phase protein.
      ].
      It has been shown that women taking HRT have lower levels of lipoprotein(a) than women not taking HRT [
      • Ushioda M.
      • Makita K.
      • Takamatsu K.
      • Horiguchi F.
      • Aoki D.
      Serum lipoprotein(a) dynamics before/after menopause and long-term effects of hormone replacement therapy on lipoprotein(a) levels in middle-aged and older Japanese women.
      ,
      • Suk Danik J.
      • Rifai N.
      • Buring J.E.
      • Ridker P.M.
      Lipoprotein(a), hormone replacement therapy, and risk of future cardiovascular events.
      ,
      • Shlipak M.G.
      • et al.
      Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause.
      ]. Further, a study has shown that women who underwent hysterectomy with bilateral oophorectomy had increased lipoprotein(a) levels after surgery, but in women who underwent hysterectomy with unilateral oophorectomy the lipoprotein(a) levels did not change after surgery (N = 44) [
      • Kim C.J.
      • Ryu W.S.
      • Kwak J.W.
      • Park C.T.
      • Ryoo U.H.
      Changes in Lp(a) lipoprotein and lipid levels after cessation of female sex hormone production and estrogen replacement therapy.
      ]. Accordingly, the loss of ovarian sex hormone production is associated with increased lipoprotein(a), but surgical cessation of menstrual bleeding with preservation of ovarian sex hormone production does not appear to be associated with changes in lipoprotein(a). Supporting the hypothesis that lower plasma estradiol explains part of the higher plasma lipoprotein(a) in women after age 50 and after menopause, we observed i) attenuation of the increase by age of plasma lipoprotein(a) in women after adjustment for plasma estradiol, unlike in men, ii) higher levels of lipoprotein(a) in women off versus on HRT, and iii) selective additional increase of lipoprotein(a) levels after menopause, where plasma estradiol is well known to decrease substantially in women.
      Four previous studies including 526–12,284 participants support some of our findings related to influence of age, eGFR, menopausal status, and HRT on lipoprotein(a) levels [
      • Jenner J.L.
      • et al.
      Effects of age, sex, and menopausal status on plasma lipoprotein(a) levels. The Framingham Offspring Study.
      ,
      • Erhart G.
      • et al.
      Genetic factors explain a major fraction of the 50% lower lipoprotein(a) concentrations in Finns.
      ,
      • Slunga L.
      • Asplund K.
      • Johnson O.
      • Dahlen G.H.
      Lipoprotein (a) in a randomly selected 25-64 year old population: the Northern Sweden Monica Study.
      ,
      • Ushioda M.
      • Makita K.
      • Takamatsu K.
      • Horiguchi F.
      • Aoki D.
      Serum lipoprotein(a) dynamics before/after menopause and long-term effects of hormone replacement therapy on lipoprotein(a) levels in middle-aged and older Japanese women.
      ]. First, Slunga et al. observed increasing plasma lipoprotein(a) with increasing age in both women (p <0.01) and men (p <0.01), with menopause as the strongest predictor for lipoprotein(a) levels in women [
      • Slunga L.
      • Asplund K.
      • Johnson O.
      • Dahlen G.H.
      Lipoprotein (a) in a randomly selected 25-64 year old population: the Northern Sweden Monica Study.
      ]. Second, Erhart et al. found age and eGFR to be the second and third largest contributors to reduced lipoprotein(a) levels with 26.4% and 10.4% respectively, with isoforms as the largest contributor (27.3%) [
      • Erhart G.
      • et al.
      Genetic factors explain a major fraction of the 50% lower lipoprotein(a) concentrations in Finns.
      ]. Third, Ushioda et al. found higher lipoprotein(a) levels in postmenopausal (26 ± 16 mg/dL) than in pre- and perimenopausal women (21 ± 11 mg/dL and 20 ± 19 mg/dL) (p <0.05), and that mean lipoprotein(a) levels after 6 months of HRT decreased by 20% [
      • Ushioda M.
      • Makita K.
      • Takamatsu K.
      • Horiguchi F.
      • Aoki D.
      Serum lipoprotein(a) dynamics before/after menopause and long-term effects of hormone replacement therapy on lipoprotein(a) levels in middle-aged and older Japanese women.
      ]. Finally, Jenner et al. observed association between age and lipoprotein(a) levels in women only (p = 0.04), and 19% higher lipoprotein(a) levels in postmenopausal versus premenopausal women (p <0.004); however, adjusting for age the latter difference disappeared [
      • Jenner J.L.
      • et al.
      Effects of age, sex, and menopausal status on plasma lipoprotein(a) levels. The Framingham Offspring Study.
      ]. Our analyses including 37,545 women and 32,497 men clearly show that plasma lipoprotein(a) levels increase by age in both women and men with an additional modest increase around age 50 in women, typically coinciding with menopause, and that levels were 12% lower in women on versus without HRT. Our observed minor “decrease” in lipoprotein(a) from age 70 to 80 in women could be related to survival bias. However, comparing the distribution of lipoprotein(a) levels in the age groups 60–69 years and 80–89 years showed very similar distributions.
      We could not document that plasma lipoprotein(a) >40 mg/dL (83 nmol/L) versus <10 mg/dL (18 nmol/L) was associated with increased risk of ischemic stroke. However, when using the same study population, we previously found that extremely high lipoprotein(a) levels (>93 mg/dL (199 nmol/L)) were associated with increased risk of ischemic stroke [
      • Langsted A.
      • Nordestgaard B.G.
      • Kamstrup P.R.
      Elevated lipoprotein(a) and risk of ischemic stroke.
      ]. These previous results are in line with a new study by Arnold et al. [
      • Arnold M.
      • et al.
      Lipoprotein(a) is associated with large artery atherosclerosis stroke aetiology and stroke recurrence among patients below the age of 60 years: results from the BIOSIGNAL study.
      ]. They found increased risk of recurrent cerebrovascular events in patients aged <60 years with lipoprotein(a) levels ≥100 nmol/L versus below 100 nmol/L (p = 0.03). This could imply that lipoprotein(a) is a less important risk factor for stroke except for patients with extreme high lipoprotein(a) levels.
      Elevated lipoprotein(a) is a causal risk factor for myocardial infarction, ischemic heart disease, ischemic stroke, aortic valve stenosis, heart failure, cardiovascular mortality, and all-cause mortality [
      • Kamstrup P.R.
      • Tybjaerg-Hansen A.
      • Steffensen R.
      • Nordestgaard B.G.
      Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.
      ,
      • Langsted A.
      • Kamstrup P.R.
      • Nordestgaard B.G.
      High lipoprotein(a) and high risk of mortality.
      ,
      • Kamstrup P.R.
      Lipoprotein(a) and cardiovascular disease.
      ,
      • Clarke R.
      • et al.
      Genetic variants associated with Lp(a) lipoprotein level and coronary disease.
      ,
      • Nordestgaard B.G.
      • Langsted A.
      Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology.
      ]. Based on such strong evidence, European and Canadian guidelines now recommend to measure plasma lipoprotein(a) once in a lifetime in all individuals [
      • Mach F.
      • et al.
      2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
      ,
      • Pearson G.J.
      • et al.
      2021 Canadian cardiovascular society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults.
      ]. However, hitherto very little was known about sex and age differences in the association between lipoprotein(a) and risk of morbidity and mortality. Despite higher lipoprotein(a) levels in women versus men with increasing age, we found similar risk for myocardial infarction, ischemic heart disease, ischemic stroke, aortic valve stenosis, heart failure, cardiovascular mortality, and all-cause mortality in women and men with lipoprotein(a) levels >40 mg/dL(83 nmol/L), overall and stratified for above and below age 50. This indicates that elevated lipoprotein(a) is a relatively more common cardiovascular risk factor in women than in men above age 50. It also suggests that it is reasonable to measure lipoprotein(a) both at younger and older ages, particularly in women.
      An interesting finding was the lack of any attenuation of lipoprotein(a) levels when adjusting for CRP given that existing data suggests an impact of inflammation on lipoprotein(a) levels as well as an increase in inflammatory parameters with age [
      • Langsted A.
      • Varbo A.
      • Kamstrup P.R.
      • Nordestgaard B.G.
      Elevated lipoprotein(a) does not cause low-grade inflammation despite causal association with aortic valve stenosis and myocardial infarction: a study of 100,578 individuals from the general population.
      ]. This raises the issue to what extent the subjects included were burdened with some element of chronic disease or whether they represented a “more healthy” population segment.
      An important strength of this study is the cohort. We studied 37,545 women and 32,497 men from a contemporary cohort of the general population with no one lost to follow-up, and due to the Danish registries we were able to capture every event of myocardial infarction, ischemic heart disease, ischemic stroke, aortic valve stenosis, heart failure, cardiovascular mortality, and all-cause mortality [
      • Langsted A.
      • Kamstrup P.R.
      • Nordestgaard B.G.
      High lipoprotein(a) and high risk of mortality.
      ,
      • Kamstrup P.R.
      Lipoprotein(a) and cardiovascular disease.
      ,
      • Clarke R.
      • et al.
      Genetic variants associated with Lp(a) lipoprotein level and coronary disease.
      ,
      • Nordestgaard B.G.
      • Langsted A.
      Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology.
      ] either leading to hospital contact or registered on the death certificate. A limitation of our study is that we only included data on white individuals, which therefore may not necessarily apply to all ethnicities. Also, plasma estradiol and testosterone measurements were only available in a subgroup and additional hormone measurements related to menopause including follicle stimulating hormone and progesterone were not available. Finally, it is a limitation that we in our sex and age stratified analyses could not document that plasma lipoprotein(a) >40 mg/dL(83 nmol/L) versus <10 mg/dL(18 nmol/L) is associated with increased risk of ischemic stroke, cardiovascular mortality, or all-cause mortality. However, when using the same study population, we previously found that extremely high lipoprotein(a) levels (>93 mg/dL(199 nmol/L)) were associated with increased risk of ischemic stroke, cardiovascular mortality, and all-cause mortality [
      • Langsted A.
      • Kamstrup P.R.
      • Nordestgaard B.G.
      High lipoprotein(a) and high risk of mortality.
      ,
      • Langsted A.
      • Nordestgaard B.G.
      • Kamstrup P.R.
      Elevated lipoprotein(a) and risk of ischemic stroke.
      ]. Future studies are needed to analyze the interactions of increased lipoprotein(a), increased LDL cholesterol, decreased estradiol, and changes in body fat, and their relative contribution to cardiovascular risk in postmenopausal women.
      Our results have important clinical implications. The modest increase in lipoprotein(a) levels selectively in women around age 50 seen in the present study challenge the current belief that only one lipoprotein(a) measurement in women and men is adequate to capture the life-time concentration of lipoprotein(a). This is particularly important in women with a lipoprotein(a) measurement before age 50, where additional lipoprotein(a) measurements should be considered at a later stage. Second, as elevated lipoprotein(a) increases the risk for morbidity and mortality equally in both sexes above and below age 50, the totality of data in the present study suggest that elevated lipoprotein(a) is a relatively more common risk factor in women compared with men above age 50.
      In conclusion, we found that lipoprotein(a) levels increased with age. While the increase in men was steady across the age span, an additional modest increase was seen in women around age 50 resulting in higher lipoprotein(a) levels in women than in men. Importantly, high lipoprotein(a) levels were associated equally with increased risk of morbidity and mortality in both women and men above age 50. Taken together, this implies that elevated lipoprotein(a) above age 50 is a relatively more common risk factor in women than in men. Further, although lipoprotein(a) is largely determined by genetics, lipoprotein(a) measurement may be repeated at a later age in women who have had lipoprotein(a) measurements before age 50.

      Financial support

      This work was supported by The Danish Heart Foundation [ 19-R134-A9219 ], Copenhagen, Denmark, Beckett Foundation [ 19-2-4567 ], Copenhagen, Denmark, Direktør Jacob Madsens og Hustru Olga Madsens fond, Copenhagen, Denmark , and Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark . Neither had any influence on the research conducted.

      CRediT authorship contribution statement

      Sofie Bay Simony: Conceptualization, Data curation, Funding acquisition, Writing – original draft. Martin Bødtker Mortensen: Conceptualization, Data curation, Supervision, Writing – review & editing. Anne Langsted: Conceptualization, Data curation, Funding acquisition, Methodology, Supervision, Writing – review & editing. Shoaib Afzal: Conceptualization, Data curation, Methodology, Supervision, Writing – review & editing. Pia Rørbæk Kamstrup: Conceptualization, Data curation, Methodology, Supervision, Writing – review & editing. Børge Grønne Nordestgaard: Conceptualization, Methodology, Supervision, Writing – review & editing.

      Declaration of competing interest

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests.
      Pia Rørbæk Kamstrup reports talks or consultancies sponsored by Physicians Academy for Cardiovascular Education, Novartis and Silence Therapeutics.
      Børge Nordestgaard reports consultancies or talks sponsored by AstraZeneca, Sanofi, Regeneron, Akcea, Amgen, Kowa, Amarin, Novartis, Novo Nordisk, Esperion, and Silence Therapeutics.
      Sofie Bay Simony, Martin Bødtker Mortensen, Anne Langsted, and Shoaib Afzal declare no competing interests.

      Acknowledgements

      We would like to thank participants and staff at the Copenhagen General Population Study for their valuable contribution.

      Appendix A. Supplementary data

      The following is the supplementary data to this article:

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