Abstract
Background and objective
Approximately 20% of the global population has a Lp(a) concentrations above 50 mg/dL (> 125nmol/L), yet many remain unaware of the associated cardiovascular risks. In Mexico, routine measurement of Lp(a) is uncommon. This study aimed to investigate the frequency of Lp(a) testing, and the clinical actions taken by physicians upon detecting elevated Lp(a) concentrations in patients at a tertiary medical institution.
Methods
Using an algorithm-based screening system, we reviewed the clinical and biochemical data of patients with Lp(a) measurements from 2019 to 2024. Data were retrieved from the laboratory information system and electronic health records. Complementary assessment data were obtained from the radiology and cardiology departments.
Results
Of the 150,083 individuals evaluated at the institution, only 830 (0.5%) underwent Lp(a) testing, with testing rates increasing from 0.037% in 2019 to 0.24% in 2023. Elevated Lp(a) concentrations (> 50 mg/dL) were found in 21% of patients, and 2.2% had concentrations > 180 mg/dL. Patients with elevated Lp(a) had significantly higher rates of atherosclerotic cardiovascular disease (ASCVD) (p < 0.001) and familial hypercholesterolemia (p < 0.004) than those with lower Lp(a) levels. Interestingly, diabetes prevalence was higher in those with Lp(a) < 4 mg/dL (51.5% vs. 33.4%, p < 0.001). Despite the cardiovascular risk, only 26% of patients with elevated Lp(a) levels received interventions to modify risk factors.
Conclusions
Lp(a) testing was infrequent in a tertiary medical setting. Clinical interventions to modify cardiovascular risk factors were insufficient among patients with elevated Lp(a). These findings highlight the need for greater awareness among healthcare providers and the development of comprehensive screening and management algorithms to mitigate Lp(a) -related cardiovascular risk.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12944-025-02610-w.
Keywords: Lp(a), Awareness, Mexican cohort, Clinical interventions
Introduction
Lipoprotein(a) (Lp(a)) is a unique lipoprotein particle that has gained significant attention in the realm of cardiovascular risk assessment and management [1]. Lp(a) consists of an LDL-like particle with an additional apolipoprotein(a) (apo(a)) molecule attached to apolipoprotein B-100 (apoB-100) via a disulfide bond. This distinctive structure sets Lp(a) apart from other lipoproteins and contributes to its atherogenic potential owing to its high phospholipid content [2]. The concentration of Lp(a) is 90% genetically determined and is strongly associated with coronary heart disease (CHD) [1].
Elevated Lp(a) concentrations are linked to an increased risk of atherosclerotic cardiovascular disease (ASCVD) making it a crucial factor in primary prevention settings [3]. Additionally, Lp(a) has been associated with other cardiovascular diseases (CVDs) such as aortic valve stenosis, heart failure, and peripheral atherosclerosis [4].
However, the precise reduction in Lp(a) concentrations necessary to achieve a clinically meaningful decrease in CVD risk remains a topic of ongoing research [5]. Current guidelines recommend measuring Lp(a) at least once in a lifetime to accurately assess cardiovascular risk [5–8]. Notably, Lp(a) levels may fluctuate over time. A study using the Nashville Biosciences database found that Lp(a) levels increased by more than 25% from baseline in more than 609 individuals, leading to the reclassification of up to 33% of patients initially in the “gray zone” into the high-risk category [9]. The OCEAN-dose trial also reported an intraindividual Lp(a) variability of approximately 10% in patients with cardiovascular events and an Lp(a) > 150 nmol/L [10].
In addition to lifestyle modifications and pharmacological interventions, such as intensive low-density lipoprotein cholesterol (LDL-C) reduction, an integrated approach that addresses all cardiovascular risk factors is essential [11, 12].
Several pharmacological interventions can modestly reduce Lp(a) concentrations; however, none of them specifically inhibits Lp (a) synthesis. Niacin and cholesteryl ester transfer protein (CETP) inhibitors have shown potential in reducing Lp(a) concentrations by approximately 20–30% [13, 14]. On the other hand, statin therapy has a minimal effect on Lp(a) concentrations [15]. Recent studies have demonstrated that monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9), can lower Lp(a) concentrations by 20–30% [16]. Additionally, PCSK9 inhibition has been shown to improve coronary endothelial function, independent of LDL-C, particularly in high-risk populations [17].
Emerging RNA-based therapies such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), offer promising avenues for lowering Lp(a) concentrations by 80–90% [18–20]. These novel approaches target specific mRNA sequences involved in Lp(a) synthesis, providing a more effective strategy for Lp(a) reduction and mitigating cardiovascular disease [21–27]. Ongoing phase 3 clinical trials, such as OCEAN-OUTCOMES (NCT05581303), HORIZON (NCT04023552), FRONTIERS-CAVS (NCT05646381) and ACCLAIM-lp(a) (NCT06292013), are expected to confirm these findings.
In both clinical and research settings, the limited use of Lp(a) testing is attributed primarily to low awareness among healthcare professionals, inadequate infrastructure, and a lack of available treatments [28, 29]. Additionally, research environments face further challenges, including limited funding and the need for standardized laboratory methods that are not dependent on Lp(a) isoforms, which hinders the broader implementation of Lp(a) testing [7].
The frequency of Lp(a) testing is poorly defined, and clinical management responses to finding an elevated Lp(a) concentrations have not been extensively studied in our country. The aim of this study was to determine the Lp(a) concentration in patients from a tertiary medical institution, assess the frequency of testing, identify high-risk individuals with Lp(a) > 50 mg/dL (> 125 nmol/L), and evaluate the actions taken by physicians in response to elevated values. As a secondary objective, we aimed to explore the comorbidities and nongenetic factors associated with Lp(a) concentration.
Materials and methods
Study participants and study design
A retrospective analysis was conducted at a tertiary medical institution in Mexico City, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), a hospital specializing in inpatient and outpatient care, which is a nationwide reference centre. Between 2019 and 2024, a total of 150,000 individuals were seen in the outpatient clinic. Among them, data from 830 individuals, aged 18 years or older with at least one Lp(a) measurement were analysed.
Afterwards, we divided the study population into two risk groups, according to the cutoff point recommended by the guidelines [6], > 50 mg/dL (> 125 nmol/L) and < 50 mg/dL (< 125 nmol/L). Second, we compared individuals with Lp(a) levels < 4 mg /dL (< 10 nmol/L) to those with Lp (a) > 4 mg/dL (> 10 nmol/L) [6, 48, 49]. Finally, we examined subjects in the “gray zone” 30–50 mg/dL (75–125 nmol/L) and individuals with extreme Lp(a) levels > 180 mg/dL (430 nmol/L).
Individuals whose Lp(a) measurements but no clinical data in their electronic health records (EHR) were available were excluded from the study. The Ethics Committee Review Board declared this study exempt, as it used EHR data collected. Therefore, informed consent was not needed.
Data collection
The INVESTIGA system, which was designed to keyword filter data across institutional electronic platforms was used. Only physicians with a signed letter of responsibility for reviewing EHR, including a confidentiality agreement, were authorized to review the EHRs. Keywords included cardiovascular risk factors associated with elevated Lp(a) (ICD-10:E.78.4 such as aortic stenosis (ICD10: I35.0), heart failure (ICD-10:I50.9), myocardial infarction (ICD10: I21.9), peripheral arterial disease (ICD-10:I73.9), and ischemic cerebrovascular disease (ICD-10: I67.82)), as well as other known risk factors like hypertension (ICD10: I10), diabetes (ICD-10:E11.7, E11.9), obesity (ICD-10:E66.0-9), smoking (ICD-10:Z72.0), metabolic syndrome (ICD10:E88.810), and non-alcoholic fatty liver disease (ICD-10:K76.0).
Familial Hypercholesterolemia (FH) (ICD-10: E.78.0) was diagnosed based on Dutch Lipid Clinic Network criteria (> 8 points). Familial Combined Hyperlipidaemia (FCHL) (ICD-10:E.78.4) was diagnosed using the following criteria: (1) Total cholesterol (TC) and/or triglycerides (TG) concentrations > 200 mg/dL (> 5.1 nmol/L) and > 150 mg/dL (1.7 nmol/L), respectively; (2) at least one first degree relative with hyperlipidaemia with a different lipid phenotype, and (3) a concentration of apolipoprotein B (apo B) above the 90th percentile for the Mexican population (> 108 mg/dL and > 99 mg/dL in men and women, respectively) [30].
Familial hypertriglyceridemia (FHTG) (ICD-10: E.78.1) was defined as TG levels ≥ 1000 mg/dL (≥ 11.3 mmol/l) on at least one occasion, with apo B levels < 90th population percentile for age and gender and a 5:1 TG/cholesterol ratio, after excluding other causes of hypertriglyceridemia. Additionally, all potential cases had to have at least one first-degree relative with the same lipid patterns [31].
The INVESTIGA system allowed the research team to assess which clinical actions were taken when high Lp(a) values were found using diagnosis or treatment keywords and without revealing the identity of the physician who authored them. All procedures complied with regulations governing patient and physician privacy and confidentiality. Additionally, an alert was set up within INVESTIGA to help identify patients who should be referred to Lipid Clinic. Radiological studies, echocardiogram, liver elastography, carotid doppler, coronary angiotomography with calcium score, lower limb tomography, cerebral angio magnetic resonance image, were retrieved with the support of the radiology department using the electronic radiology consultation system (Carestream system).
Biochemical measurements
All measurements were performed after a 12-h fast. Samples were taken by venous puncture and distributed into tubes BD vacutainer RS RSTT and were immediately centrifuged at 1500 rpm for 15 min and processed. Glucose, TC and high-density lipoprotein cholesterol (HDL-C) measurements were measured using Synchron CX Delta (Beckman Coulter) colorimetric enzymatic methods and apo B measurements were performed by nephelometry (Beckman Coulter). Lp(a) concentrations were determined using an isoform-independent immunoturbidimetric assay on an Abbott® Alinity C analyzer with the Lp(a) reagent kit (Ref. 01R1420). LDL-C was directly measured using the beta-quantification method. Remnant cholesterol (RC) was calculated as TC minus LDL-C minus HDL-C. Non-HDL-C was calculated as TC minus HDL-C.
Statistical analyses
The distribution of continuous variables was explored using the Kolmogorov-Smirnov test. Data are presented as median and interquartile range. Categorical variables are reported as frequencies and percentages. Continuous variables were compared among individuals with Lp(a) concentrations > 50 mg/dL (> 125nmol/L) and < 50 mg/dL (< 125nmol/L) using the Mann-Whitney test. The frequency distribution of the categorical variables was compared using the chi squared test. Bivariate logistic regression models were performed, adjusted for confounding variables. Defined covariates were age, sex, diabetes status, hypertension, smoking index, BMI, and standard lipid profile. Data were analysed using SPSS V 22, RStudio version 4.2.1 and GraphPad Prism 8.0.for the figures.
Results
Clinical and biochemical characteristics of the study cohort with Lp(a) measurements
Among the 830 individuals who had at least one measurement of Lp(a) at our institute, 64.7% were women. The median value was 14.7 mg/dL (6.0-40.8). The Lp(a) values were not normally distributed as shown in (Supplementary Fig. 1A) and (Supplementary Fig. 1B).
Elevated Lp(a) concentrations, defined as > 50 mg/dL (> 125 nmol/L), were observed in 21.6% of the population, while Lp(a) concentrations > 180 mg/dL (> 430 nmol/L) were found in 2.2% of the individuals. Nearly half (48%) of the individuals had primary dyslipidaemia and 74.9% of the individuals were receiving lipid-lowering therapy (LLT). The clinical characteristics of the study population are summarized in (Table 1).
Table 1.
Clinical characteristics of the study population
| Variable | n = 830 |
|---|---|
| Sex, Women, (n, %) | 537 (64.7) |
| Age, (years) | 58 (45–66) |
| Lp(a), (mg/dL) | 14.7 (6-40.8) |
| Lp(a) > 50 mg/dL (> 125nmol/L), (n, %) | 179 (21.6) |
| Lp(a) > 180 mg/dL (> 430 nmol/L), (n, %) | 18 (2.2) |
| BMI, (kg/m2) | 26.4 (23.8–29.8) |
| Current smokers, (n, %) | 136 (16.4) |
| Hypertension, (n, %) | 300 (36.2) |
| Poor hypertension control, (n, %) | 126 (42) |
| Prediabetes, (n, %) | 169 (20.4) |
| Type 2 diabetes, (n, %) | 302 (36.6) |
| Poor glycaemic control, (n, %) | 103 (34) |
| Type 1 diabetes, (n, %) | 31 (3.7) |
| Overweight, (n, %) | 327 (39.4) |
| Obesity, (n, %) | 200 (24.1) |
| FH*, (n, %) | 135 (16.3) |
| FCHL, (n, %) | 222 (26.7) |
| FHTG, (n, %) | 43 (5.2) |
| On lipid-lowering therapy, (n, %) | 622 (74.9) |
| Liver fibrosis **, (n, %) | 57 (7) |
BMI: body mass index; FCHL: Familial Combined Hyperlipidaemia; FH: Familial Hypercholesterolemia; FHTG: Familial Hypertriglyceridemia; Lp: lipoprotein. * Diagnosis by Dutch Lipid Clinic Network (DLCN) criteria. ** Evaluated by NAFLD score in 816 individuals. The values of the dimensional variables are reported as medians and interquartile ranges (25–75)
According to cardiovascular risk categories defined by European guidelines [37] we observed an elevated Lp(a) > 50 mg/dL (> 125nmol/L) in 35.4% of individuals with high cardiovascular risk, 23% of those at moderate risk and 17% of those at low risk.
Notably, among individuals who achieved the LDL-C target, according to their initial cardiovascular risk category, Lp(a) still emerged as the principal determinant of ASCVD in our cohort, with an OR of 1.23 (95% CI: 1.04 to 1.48, p = 0.012). In contrast, non-HDL-C was not significantly associated (OR: 0.99, 95% CI: 0.99 to 1.00, p = 0.491), while HDL-C showed a protective association (OR: 0.75, 95% CI: 0.58 to 0.96, p = 0.028) (Fig. 1).
Fig. 1.
Lp(a) is the main cardiovascular risk factor for ASCVD despite LDL-C on target. C: cholesterol; HDL: high-density lipoprotein; LDL: low-density lipoprotein; Lp: lipoprotein
Adjusting by age, sex, BMI, diabetes, hypertension and smoking index.
Non-genetic factors influencing Lp(a) concentrations in the study cohort
In the entire cohort, inflammatory diseases were present in 4.84% of individuals, and 0.8% had a history of liver transplantation. Chronic kidney disease was present in 0.7% of the patients. Hypothyroidism was observed in 32.8% of the total population, while hyperthyroidism was found in 0.7%. Among female participants, 46.4% were postmenopausal, with only 1.4% receiving hormone replacement therapy.
The prevalence of non-genetic factors in individuals with Lp(a) < 50 mg/dL (< 125 nmol/L) compared to those with L (a) > 50 mg/dL (> 125nmol/L) is presented in (Table 2). Hypothyroidism was more frequent in individuals with Lp(a) < 50 mg/dL (< 125nmol/L) (p < 0.005). However, no significant difference was observed in the prevalence of uncontrolled hypothyroidism between the groups.
Table 2.
Non-genetic factors according to risk Lp(a) concentration
| Variable | Lp(a) > 50 mg/dL (> 125nmol/L) n = 179 |
Lp(a) < 50 mg/dL (< 125 nmol/L) n = 651 |
p |
|---|---|---|---|
| Hypothyroidism*, (n, %) | 43 (24) | 229 (35.2) | 0.005 |
|
Uncontrolled hypothyroidism, (n, %) |
12 (27) | 70 (30.6) | 0.857 |
| Hyperthyroidism, (n, %) | 1 (0.6) | 5 (0.8) | - |
| Menopause, (n, %) | 86 (48) | 299 (45.9) | 0.672 |
| Inflammatory diseases, (n, %) | 13 (7.3) | 27(4.1) | 0.112 |
| Impaired renal function, (n, %) | 2 (1.1) | 4 (0.6) | 0.616 |
| Liver transplantation, (n, %) | 1 (0.6) | 6 (0.9) | - |
* Controlled and uncontrolled hypothyroidism
Clinical and biochemical characteristics of individuals with extremely high concentrations of Lp(a)
The clinical and biochemical characteristics of this group are described in (Table 3). The prevalence of ASCVD in individuals with Lp(a) concentrations > 180 mg/dL (> 430 nmol/L) was 23%. Heart failure was observed in 40% while aortic valve stenosis was present in 16.7% of the study cohort.
Table 3.
Characteristics of the individuals with Lp(a) concentration > 180 mg/dl (> 430 nmol/L)
| Variable | n = 18 |
|---|---|
| Age, (years) | 64 (60–68) |
| Sex, women, (n, %) | 13 (68) |
| ASCVD, (n, %) | 4 (22.8) |
| Aortic valve stenosis*, (n, %) | 2 (16.7) |
| Heart failure **, (n, %) | 4 (40) |
| Total cholesterol, (mg/dL) | 162 (140–216) |
| LDL-C, (mg/dL) | 99 (75–144) |
| HDL-C, (mg/dL) | 45 (39–54) |
| Non-HDL-C, (mg/dL) | 117 (96–169) |
| Triglycerides, (mg/dL) | 146 (125–162) |
| Remnant cholesterol, (mg/dL) | 19 (12–25) |
| Apolipoprotein B, (mg/dL) | 111 (88–131) |
| HbA1c, (%) | 5.8 (5.7–6.1) |
ASCVD: atherosclerotic cardiovascular disease; C: cholesterol; Hb: haemoglobin; HDL: high-density lipoprotein; LDL: low-density lipoprotein; Lp: lipoprotein. * n = 12; **n = 10. The values of the dimensional variables are reported as medians and interquartile ranges (25–75). To convert total cholesterol, HDL-C, LDL-C, remnant cholesterol from mg/dL to mmol/L divide by 38.8. To convert triglycerides mg/dL to mmol/L divide by 88.8
Clinical and biochemical characteristics of individuals with Lp(a) > 50 mg/dL (> 125nmol/L) compared to individuals with Lp(a) < 50 mg/dL (< 125nmol/L)
When we compared individuals with Lp(a) concentrations > 50 mg/dL (> 125nmol/L) to those with Lp(a) concentrations < 50 mg/dL (< 125 nmol/L), 60.9% were women, a higher proportion were older (p = 0.009) and had a higher prevalence of ASCVD (p < 0.001), predominantly coronary heart disease (Table 4). Furthermore, the prevalence of primary dyslipidaemias was higher in this group, with FCHL being the most common (30.7%), followed by FH (20.7%, p < 0.001) and FHTG (1.7%) (Table 4). There were no statistical differences between individuals with or without elevated Lp(a) in terms of the prevalence of hypertension, diabetes, prediabetes, obesity, overweight or the use of LLT. (Table 4).
Table 4.
Cardiovascular risk factors and atherosclerotic cardiovascular disease according to risk Lp(a) concentration
| Variable | Lp(a) > 50 mg/dL (> 125nmol/L) n = 179 |
Lp(a) < 50 mg/dL (< 125nmol/L) n = 651 |
p |
|---|---|---|---|
| Sex, Women, (n, %) | 109 (60.9) | 428 (65.7) | 0.251 |
| Age, (years) | 61 (48.5–68) | 57 (44–76) | 0.009 |
| ASCVD, (n, %) | 33 (18.4) | 63 (9.7) | < 0.001 |
| Stroke, (n, %) | 2 (1.1) | 7 (1.1) | - |
| PAD, (n, %) | 1 (0.6) | 8 (1.2) | - |
| MI, (n, %) | 30 (16.8) | 48 (7.4) | < 0.001 |
| Aortic Stenosis++, (n, %) | 6 (8.8) | NR | - |
| Heart failure++, (n, %) | 17 (25) | NR | - |
| Current smokers, (n, %) | 31(17.3) | 105 (16) | 0.732 |
| Hypertension, (n, %) | 65 (36.3) | 235 (36.1) | 1.00 |
| Prediabetes, (n, %) | 44 (24.6) | 125 (19.2) | 0.117 |
| Diabetes, (n, %) | 57 (31.8) | 245 (37.5) | 0.161 |
| Overweight, (n, %) | 69 (38.5) | 258 (39.65) | 0.565 |
| Obesity, (n, %) | 40 (22.3) | 160 (24.6) | 0.442 |
| FH*, (n, %) | 43 (24) | 92 (14.1) | 0.002 |
| FCHL, (n, %) | 53 (29.6) | 169 (26) | 0.187 |
| FHTG, (n, %) | 3 (1.7) | 40 (6.1) | 0.059 |
| On lipid lowering therapy, (n, %) | 145 (81) | 477 (73.3) | 0.160 |
| HIS, (n, %) | 49 (27.3) | 171 (26.3) | 0.632 |
| MIS, (n, %) | 29 (16.2) | 154 (23.7) | 0.033 |
| LIS, (n, %) | 5 (2.8) | 17 (2.5) | 0.789 |
| Dual therapy**, (n, %) | 45 (25.1) | 96 (14.7) | 0.002 |
| Triple therapy**, (n, %) | 1 (0.6) | 0 | - |
| PCSK9 inhibitor, (n, %) | 1 (0.6) | 0 | - |
| Fibrates, (n, %) | 15 (8.4) | 39 (6.1) | 0.308 |
| Without treatment, (n, %) | 34 (19) | 174 (26.7) | 0.041 |
ASCVD: atherosclerotic cardiovascular disease basal; FCHL: Familial Combined Hyperlipidemia; FH: Familial Hypercholesterolemia; FHTG: Familial Hypertriglyceridemia; HIS: high-intensity statins; LIS: low-intensity statins; MI: myocardial infarction; MIS: moderate-intensity statins; NR: not reported; PAD: peripheral arterial disease, PCSK9: proprotein convertase subtisilin kexin 9. * Diagnosis by Dutch Lipid Clinic Network (DLCN) criteria. ** Dual therapy: statins plus ezetimibe or statins plus PCSK9 inhibitor; Triple therapy: statins plus ezetimibe plus PCSK9 inhibitor. ++n = 68 individuals in the group of Lp(a) > 50 mg/dL (> 125nmol/L). The values of the dimensional variables are reported as medians and interquartile ranges (25–75)
Advanced fibrosis was detected in 2.3% of individuals with Lp (a) > 50 mg/dL (> 125 nmol/L) based on the FIB-4 score [32] and in 8.6% based on the NAFLD fibrosis score [33], with no statistically significant differences compared to individuals with Lp(a) < 50 mg/dL (< 125 nmol/L).
Factors associated with Lp(a) > 50 mg/dL (> 125 nmol/L) were shown in (Fig. 2). The correlations between Lp(a) and additional factors are shown in (Supplementary Fig. 2).
Fig. 2.
Factors associated with Lp(a) concentrations > 50 mg/dL (> 125nmol/L). ASCVD: atherosclerotic cardiovascular disease; BMI: body mass index; FH: Familial Hypercholesterolemia
The lipid profile of individuals with Lp (a) concentrations > 50 mg/dL (> 125 nmol/L) compared to those with Lp(a) < 50 mg/dL (< 125nmol/L) is described in (Table 5). Individuals with Lp(a) < 50 mg/dL (< 125 nmol/L) had higher levels of remnant cholesterol (RC) (p = 0.041) and triglycerides (p = 0.007), as well as lower levels of HDL-C (p = 0.009).
Table 5.
Lipid profile and HbA1c in individuals at the time of the Lp(a) measurement according to risk Lp(a) concentration
| Variable | Lp(a) > 50 mg/dL (> 125 nmol/L) n = 179 |
Lp(a) < 50 mg/dL (< 125 nmol/L) n = 651 |
p |
|---|---|---|---|
| Total cholesterol, (mg/dL) | 180 (144–216) | 170 (139–208) | 0.110 |
| LDL-C, (mg /dL) | 98 (72–137) | 94 (68–126) | 0.111 |
| HDL-C, (mg/dL) | 48 (40–55) | 45 (37–53) | 0.009 |
| Non-HDL-C, (mg/dL) | 121 (93–167) | 122 (95–160) | 0.467 |
| Triglycerides, (mg/dL) | 131 (91–175) | 142 (102–205) | 0.007 |
| Remnant cholesterol, (mg/dL) | 21 (14–29) | 23 (15–37) | 0.041 |
| Apolipoprotein B, (mg/dL) | 95 (77–126) | 96 (74–115) | 0.126 |
| HbA1c, (%) | 5.8 (5.5–6.3) | 5.8 (5.4–6.7) | 0.670 |
C: cholesterol; Hb: haemoglobin; HDL: high-density lipoprotein; LDL: low-density lipoprotein; Lp: lipoprotein. The values of the dimensional variables are reported as medians and interquartile ranges (25–75). To convert total cholesterol, HDL-C, LDL-C and remnant cholesterol from mg/dL to mmol/L, divide by 38.8. To convert triglycerides mg/dL to mmol/L, divide by 88.8
Clinical profile of individuals in the “gray zone” (Lp(a) 30–50 mg/dL)(75-125nmol/L)
Individuals in the “Gray zone” (Lp(a) concentrations in 30–50 mg /dL (75–125 nmol/L), had a high prevalence of comorbidities such as prediabetes, diabetes, obesity, hypertension, impaired renal function, smokers, and inflammatory diseases. In addition, 11.9% of individuals in this group had documented ASCVD. (Supplementary Table 1).
Association between low Lp(a) concentrations and type 2 diabetes (T2D)
When we compared individuals with low Lp(a) concentrations < 4 mg/dL (< 10 nmol/L) (n = 136) to those with Lp(a) > 4 mg/dL (> 10 nmol/L) (n = 694), the prevalence of diabetes was significantly higher in the former group (51.5% vs. 33.4%, p < 0.001) (Supplementary Fig. 3).
Factors associated with diabetes included Lp(a) < 4 mg/dL with odds ratio (OR) of 2.10 (95% confidence interval (CI): 1.44 to 3.08), p < 0.001 and remnant cholesterol (RC) with OR 1.30 (95% CI: 1.11 to 1.54), p < 0.001 (Fig. 3).
Fig. 3.
Lower concentrations of Lp(a) are associated to increased risk of diabetes. BMI: body mass index; RC: remnant cholesterol; Lp: lipoprotein. Lp(a) < 4 mg/dL(< 10 nmol/L)
Physician actions based on Lp(a) risk concentrations
Only 26% of the individuals with Lp(a) > 50 mg/dL (> 125 nmol/L) had intensified their treatment based on their comorbidities (Supplementary Fig. 4). Physicians referred only 34% of these patients for additional investigations to evaluate subclinical cardiovascular risk. Evidence of atherosclerotic involvement was found in 32.7% of the individuals without prior ASCVD and in the 73.9% of individuals with documented ASCVD. The most common condition observed was heart failure (16%), followed by carotid plaque detected through doppler ultrasound (12%), aortic valve stenosis detected by echocardiogram (8%) and coronary heart disease detected by both, echocardiogram and coronary angiotomography (6.7%) In addition, peripheral arterial disease was detected by lower limb angiotomography in 4% of cases.
The most frequently requested diagnosis methods included coronary angiotomography with calcium score (5%), echocardiogram (35.2%), and carotid doppler ultrasound (7.9%).
Despite 81% of them were receiving LLT, only 27.9% were on high-intensity statins (HIS), and just 25.1% were on dual therapy (statin + ezetimibe or statin + PCSK9 inhibitor); just 1 individual received triple therapy (statin + ezetimibe + PCSK9 inhibitor) (Table 4). Following Lp(a) measurement, there was a decrease in the proportion of individuals without treatment (14% vs. 9.5%, p < 0.001) and an increase in dual therapy use (from 25 to 31.8%, p < 0.001) (Supplementary Fig. 5).
Among individuals with Lp(a) levels > 50 mg/dL (> 125nmol/L), few reached their treatment lipid goals according to their specific cardiovascular risk category [35]. Only 26.7% reached LDL-C goals, 33% achieved non-HDL-C targets, 65% met TG goals < 150 mg/dL, and 30% reached apo B targets.
Finally, in the whole study cohort, only a small proportion of individuals across cardiovascular risk categories achieved appropriate lipid goals according to European [34] and Mexican guidelines [35, 36] (Supplementary Table 2). The residual cardiovascular risk attributable to each lipid parameter, stratified by cardiovascular risk [34], is summarized in (Table 6). And the prevalence of ASCVD was increased across the Lp(a) concentrations. (Supplementary Fig. 6)
Table 6.
Percentage of individuals in residual risk according to their cardiovascular risk and LDL-C targets in the study population
| Individuals at LDL-C treatment goal < 55 mg/dL (very high risk) n = 99 | |
| Direct measured LDL-C, (mg/dL) | 16.2% |
| Residual cardiovascular risk in individuals with LDL-C < 55 mg/dL (very high risk) | |
| Non-HDL-C > 85 (mg/dL) | 78.8% |
| Apolipoprotein B > 65 (mg/dL) | 84.7% |
| Triglycerides > 150 (mg/dL) | 41.4% |
| Triglycerides > 100 (mg/dL) | 75.8% |
| Lp(a) > 50 mg/dL | 31.3% |
| Lp(a) > 180 mg/dL | 4% |
| Individuals at LDL-C treatment goal < 70 mg/dL (high risk) n = 466 | |
| Direct measured LDL-C, (mg/dL) | 28.7% |
| Residual cardiovascular risk in individuals with LDL-C < 70 mg/dL (high risk) | |
| Non-HDL-C > 100 mg/dL | 67% |
| Apolipoprotein B > 80 mg/dL | 67.4% |
| Triglycerides > 150 mg/dL | 48.2% |
| Triglycerides > 100 mg/dL | 76.7% |
| Lp(a) > 50 mg/dL | 20.4% |
| Lp(a) > 180 mg/dL | 2.6% |
C: cholesterol, HDL: high-density lipoprotein, LDL: low-density lipoprotein, Lp: lipoprotein. Lipid goals are according to ESC 2019 [37] and Mexican guidelines [40, 41]. To convert total cholesterol, HDL-C, LDL-C and remnant cholesterol from mg/dL to mmol/L divide by 38.8. To convert triglycerides mg/dL to mmol/L, divide by 88.8
Discordant Lp(a) values
Among the 830 individuals, 116 (14%) had Lp(a) measured twice without a documented reason. The initial median Lp(a) concentration was [20 (8.5–45.9) mg/dL] and at a follow-up it was [17.8 (8.9–49.1) mg/dL], and delta values did not show statistical significance (p = 0.84) (Supplementary Table 3).
Among individuals with two measurements, 9.5% showed discordant results, with Lp(a) concentrations either increasing or decreasing. 2.6% of individuals moved to a higher cardiovascular risk category, while a decrease in risk category was observed in 8 individuals (6.9%). Despite these changes, physicians intensified the treatment of cardiovascular risk factors in only 1 of the 3 individuals whose risk category increased. Individuals who moved to a lower risk category remained without any changes in the management of their comorbidities.
Notably, none of the individuals with discordant Lp(a) values had an infectious process or acute illness at the time of the second measurement.
Discussion
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality in Mexico [37], underscoring the need to address all components of the lipid profile and establish more targeted strategies for cardiovascular risk management based on individual profiles.
Residual cardiovascular risk, which remains even after optimizing traditional lipid targets, is largely determined by other components such as RC secondary to diseases such as diabetes, obesity, insulin resistance, etc. highly prevalent in our population [38]. In addition, Lp(a) and inflammatory markers play a significant role in residual risk [39, 40], particularly in premature acute coronary syndromes (ACS) as demonstrated in the RELACS study [41] This highlights the importance of a multidisciplinary evaluation [42].
Despite the recommendations of universal testing for Lp(a) in adults at least once in their life, given by the European Atherosclerosis Society [35, 43], Canadian Cardiovascular Society [44], the European Society of Cardiology, the Scientific Statement by the National Lipid Association [45], and Mexican lipid guidelines [35, 36] - its implementation remains inadequate in our institution.
Although it is important to recognize that the number of tests per year has increased, this has been observed predominantly in physicians specializing in lipid and metabolic disorders. Expanding awareness among other specialties is essential to ensure that Lp(a) is recognized as an independent cardiovascular risk factor. Women were more likely to undergo Lp(a) testing, possibly due to more frequent screening for autoimmune diseases, which may lead to additional lipid evaluations, including Lp(a) measurement. However, further investigation is needed to confirm this hypothesis.
In our cohort, the prevalence of elevated Lp(a) > 50 mg/dL (> 125 nmol/L) was higher than in other Hispanic populations [46], which could be due to selection bias since our institution is a national referral centre and academic leader in metabolic disease.
In addition, categorizing individuals with Lp(a) concentrations in the “Gray zone” (30–50 mg/dL) remains a challenge. In our cohort, individuals who fell into this category presented with multiple comorbidities; therefore, they should be considered at high cardiovascular risk.
Despite the established association between elevated Lp(a) and ASCVD [46], clinical action was limited. Our findings suggest that Lp(a) is not yet fully integrated into routine cardiovascular risk assessment and screening for Lp(a) in first-degree relatives is not yet a common practice. Moreover, interventions to reduce all cardiovascular risk factors were implemented only in 26.1% of the patients at the time of their physician consultation despite recommendations from the HEART UK group [12].
This suggests a gap in clinical practice, where elevated Lp(a) is not consistently recognized or managed as an additional risk factor. Our data emphasizes the urgent need for enhanced screening and risk stratification.
Several non-genetic factors known to influence Lp(a) concentrations by 10–15% [47] were assessed in the study population. Consistent with previous research, we found that non-genetic factors did not significantly contribute to Lp(a) concentrations in our study population. Although hypothyroidism was more prevalent in the low-risk group, there was no statistically significant difference in uncontrolled hypothyroidism between the high- and low-risk groups based on their Lp(a) levels and menopause was the primary non-genetic factor associated with an increased risk of discordant Lp (a) levels in individuals with more than one measurement.
Consistent with the threshold published in LP(a) Consensus Statement [6, 48, 49], the prevalence of diabetes was higher in individuals with Lp(a) < 4 mg/dL, although the mechanisms underlying this association are not yet well understood.
Additionally, we observed that individuals with Lp(a) < 50 mg/dL (> 125nmol/L) had higher RC and TG levels and lower HDL-C. This may be explained by a greater prevalence of familial hypertriglyceridemia and metabolic syndrome in this group, while individuals with Lp(a) > 50 mg/dL (> 125nmol/L) were more likely to have familial hypercholesterolemia (FH), a pattern also reported by other authors [50].
We observed discordant Lp(a) values compared to baseline in 16% in subjects with two measurements. The absolute change observed (> 25%) was higher than what has been reported in the ESC consensus statement [6]. Within the discordant group, greater variability was observed in women than in men, like findings reported by other authors [9, 10]. Much more evidence is still needed to confirm that an additional Lp(a) measurement over time is necessary. However, based on the reports available so far and the findings of this study, we suggest considering an additional measurement in certain groups that could benefit, such as postmenopausal women. Future genetic studies in the Latin American population can provide insight into whether there are specific allelic variants in Amerindian ancestry or any associated with a specific trait [50], as well as those that may explain the variability of Lp(a).
One important area that warrants further investigation is the low rate of Lp(a) measurement, both at the national level and across Latin America. Barriers such as the high cost of the test. Several barriers contribute to this issue, including the high cost of testing. One of the main challenges is the lack of universal coverage or reimbursement for Lp(a) testing in public healthcare systems, which often results in out-of-pocket expenses for patients. This leads to disparities in access, particularly among populations with limited financial resources. Additionally, the availability of Lp(a) assays is restricted to specialized laboratories, mainly in tertiary or academic medical centres, making access difficult for patients treated in primary or secondary care settings. These limitations further hinder its widespread adoption. With the development of RNA-based therapies, including pelacarsen, olpasiran, lepodisiran, zerlasiran, muvaliplin, etc [21–27]. there is hope for more effective Lp(a) lowering strategies.
We proposed several strategies that should be implemented: (1) Enhancing physician education across all specialties to promote recognition of Lp(a) as an independent cardiovascular risk factor. (2) Implementing standardized Lp(a) diagnostic and treatment algorithms (Fig. 4) to guide clinical decision-making.3) Improving therapeutic adherence through combined or long-acting treatment options (over weekly, month, six months), which could facilitate patient compliance, long-term management of cardiovascular risk factors. 4) Expanding public health initiatives by engaging government, industry, and social communication services to launch campaigns on popular social media platforms, delivering clear messages to patients about the importance of Lp(a) as a risk factor. 5) Standardizing Lp(a) measurement across laboratories across laboratories with governmental oversight to ensure accuracy, reliability, and consistency nationwide.
Fig. 4.
Algorithm for Lp(a) measurement and management in clinical practice. ASCVD: atherosclerotic cardiovascular disease; CAC: coronary artery calcium; Lp: lipoprotein
Strengths and limitations
The main limitation of this study is that the data were derived from a single institution, which limits the generalizability of the findings to the Mexican population. We must acknowledge that there was a selection bias associated with the data obtained from the EHR, as it may be incomplete, not entirely accurate, and may not reflect the reality of the entire population. Larger, multicentre studies or evaluations using national registries are needed to validate these findings and improve their generalizability. Nonetheless, our results highlight the inadequate screening and control of cardiovascular risk factors including Lp(a) particularly among patients at high or very high risk who are not meeting lipid targets.
Conclusions
The frequency of Lp(a) testing in our institution remains low. Notably, the prevalence of Lp(a) concentrations > 50 mg/dL (22.6%) in our tertiary medical institution was comparable to global reports. Additionally, 2.2% of individuals had Lp(a) concentrations > 180 mg/dL, a level associated with a cardiovascular risk equivalent to that of individuals with Familial Hypercholesterolemia. The lack of awareness regarding this lipoprotein and its role in cardiovascular disease may contribute to inefficient risk management strategies, particularly for individuals with residual cardiovascular risk.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Acknowledgements
We thank the technical personnel at the Informatic Department for their logistic support with INVESTIGA system. We want to express our gratitude to the patients enrolled in this study.
Abbreviations
- ACS
Acute coronary syndrome
- ASCVD
Atherosclerotic cardiovascular disease
- CETP
Cholesteryl ester transfer protein
- EHR
Electronic health records
- HEART UK
Hyperlipidaemia Education and Atherosclerosis Research Trust UK
- Lp (a)
Lipoprotein(a)
- LLT
Lipid-lowering treatment
- NAFLD
Non-alcoholic fatty liver disease
- PCSK9
Proprotein convertase subtilisin/kexin type 9
- siRNAs
Small interfering RNAs
Author contributions
C.B.I. conceived the study, wrote and reviewed the final version of the paper. Y.F.J wrote and collected data through the INVESTIGA system. G.R.A. wrote, reviewed the final version of this paper and collected data through the INVESTIGA system. M.S.A., F.H.F., M.A.P. collected the data through the INVESTIGA system. D.E.L., L.M.H., R.M. performed the clinical descriptions. A.S.M., A.V.V. analyzed the data and reviewed the final version in proper English. C.A.A.S. reviewed the final document.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
The Ethics Committee Review Board declared this study exempt, as it used EHR data collected. Therefore, informed consent was not required.
Consent for publication
All authors provided their final consent for publication of the manuscript. No personal or identifiable information is included in this publication.
Disclosure
During the preparation of this work the author(s) used generative AI (Elsevier and Curie) in order to spell check, grammar corrections and proof-read. After using this tool/service, the author(s) reviewed and edited the content as needed and take(s) full responsibility for the content of the publication.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Supplementary Materials
Data Availability Statement
No datasets were generated or analysed during the current study.