Effect of lipid-lowering treatment on lipid and glycemic profile of patients with elevated lipoprotein(a) levels

J Atherosclerosis Prev Treat. 2023 Sep-Dec;14(3):103-113| doi:10.53590/japt.02.1051

RESEARCH ARTICLE

Amalia Despoina Koutsogianni1, Fotios Barkas1,2, Constantinos Tellis3, Alexandros Tselepis3,4, George Liamis1, Evangelos Liberopoulos5

1Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
2Department of Hygiene and Epidemiology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
3Department of Chemistry, Division of Organic Chemistry and Biochemistry, School of Natural Sciences, University of Ioannina, Ioannina, Greece
4Atherothrombosis Research Center, Laboratory of Biochemistry, Department of Chemistry, School of Natural Sciences, University of Ioannina, Ioannina, Greece
51st Propaideutic Department of Medicine, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece

 

Abstract

Aim: The evaluation of the effect of lipid-lowering treatment in patients with elevated levels of lipoprotein(a) [Lp(a)].

Material and methods: A prospective study including 70 patients with dyslipidemia and elevated Lp(a) levels (>30 mg/dL) attending a Lipid Clinic in Greece. Subjects were allocated to the following therapies according to the national guidelines for cholesterol management: high-intensity statin monotherapy (S; n=28), ezetimibe added to high-intensity statin (SE; n=31), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor added to high-intensity statin plus ezetimibe (SEP; n=11). Follow-up duration was 3 months. We investigated the effect of these lipid-lowering interventions on participants’ lipidemic and glycemic profile. Comparisons between groups were adjusted for the baseline levels of the studied parameters.

Results: Mean age was 51 ± 15 years, 40% were male, 39% were diagnosed with familial hypercholesterolaemia (FH), 16% with atherosclerotic cardiovascular disease (ASCVD), while 36%, 33% and 15% were at very high, high, and moderate cardiovascular risk, respectively. All interventions significantly reduced apolipoprotein B (apoB), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), but only PCSK9 inhibitors significantly reduced Lp(a) levels (SEP: -28% vs SE: +11% vs S: +17%, p<0.05). Patients in the SE group achieved the highest rates of LDL-C target attainment (SEP: 36.4% vs SE: 12.9% vs S: 3.6% for LDL-C <55 mg/dL; SEP: 36.4% vs SE: 16.1% vs S: 7.1% for LDL-C <70 mg/dL, p<0.05 for the comparison among groups). No significant effect on glycemic profile across treatment groups was noted.

Conclusions: Add-on PCSK9 inhibitors were associated with the highest rates of LDL-C target achievement compared with high-intensity statin ± ezetimibe in high-risk patients with elevated Lp(a) and were the only class to significantly lower Lp(a) levels.

Key words: Lipoprotein(a), apolipoprotein B, total cholesterol, low-density lipoprotein cholesterol, glucose, statins, ezetimibe, PCSK9 inhibitors

Corresponding author: Prof Evangelos Liberopoulos, MD, PhD, 1st Propaideutic Department of Medicine, School of Medicine, National and Kapodistrian University of Athens, Laiko General Hospital, 115 27 Athens, Greece, Tel.: +30 213 2061061, +30 6972022747, E-mail: elibero@med.uoa.gr

Submission: 29.08.2023, Acceptance: 27.12.2023

INTRODUCTION

Over the past few years several studies have focused on lipoprotein(a) [Lp(a)], a lipid molecule with atherogenic, thrombogenic and inflammatory properties.1 Elevated Lp(a), mostly genetically determined by the LPA gene locus, has been identified as an important cardiovascular risk factor as well as a risk factor for calcific aortic valve stenosis (CAVS), with a prevalence rate of ~20% in the general population.2 Currently, there are no medications specifically approved for Lp(a) lowering.3–5 In this context, current guidelines recommend optimal control of other cardiovascular risk factors.6 In terms of cholesterol management, statins remain the cornerstone of lipid-lowering management, but they slightly increase Lp(a) levels.7–10 Although most lipid modifying agents do not significantly alter Lp(a) concentration,3–5 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce Lp(a) levels.11–13 On the other hand, type 2 diabetes (T2D) is a well-established adverse effect of statin therapy, mostly in those with predisposing factors, such as prediabetes, obesity, and increased triglycerides, albeit not superseding its cardiovascular benefit.14,15 Ezetimibe and PCSK9 inhibitors seem to have a neutral effect on glycemic profile.16–20

In this context, we aimed to evaluate the effect of hypolipidaemic therapies on the lipidemic and glycemic profile of patients with elevated levels of Lp(a) in the setting of a lipid clinic.

MATERIALS AND METHODS

This was a prospective study including 70 consecutive adult patients with elevated Lp(a) levels (>30 mg/dL) and dyslipidemia attending the Outpatient Lipid Clinic of the University Hospital of Ioannina. The study protocol was approved by the Local Institutional Ethics Committee and informed consent was obtained from each patient. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the University General Hospital of Ioannina, Greece (896/21-12-2020).

Patients were allocated to 3 treatment groups according to the national guidelines for the management of dyslipidemias.21 The 10-year total cardiovascular risk was estimated with the Systematic Coronary Risk Evaluation (SCORE) 2 model in apparently healthy subjects aged 40-69 years and with the SCORE 2 old persons (OP) model in those aged ≥70 years.22 These models are recommended for the implementation of primary prevention strategies in apparently healthy individuals.22 They have been integrated into the 2021 ESC prevention guidelines and are now available to low, moderate, high, and very high risk regions in Europe.22 According to these guidelines, 28 naïve patients received high-intensity statin monotherapy (S), 31 patients on stable high-intensity statin treatment received ezetimibe (SE) and 11 patients on stable high-intensity statin treatment plus ezetimibe received a PCSK9 inhibitor (evolocumab or alirocumab) (SEP) (Figure 1).

Figure 1. Study design and allocation groups.

High-intensity statins were considered those expected to result in low-density lipoprotein cholesterol (LDL-C) reduction >50%, namely rosuvastatin 20 – 40 mg and atorvastatin 40 – 80 mg.23 Follow-up duration was 3 months.

All study participants were of Caucasian origin. A complete assessment of clinical and laboratory profile was performed at baseline visit and 3 months after the initiation or modification of lipid-lowering treatment. Demographic and clinical characteristics included: i) sex, ii) age, iii) smoking history, iv) concomitant diseases with a particular emphasis on atherosclerotic cardiovascular disease (ASCVD), which included coronary artery disease, stroke, peripheral artery disease and carotid stenosis ≥50%, CAVS, and cardiometabolic risk factors, v) body mass index (BMI) and vi) blood pressure (BP). Office BP measurements were based on ESC/ESH guidelines and performed with a validated upper-arm cuff BP measurement device and an appropriate cuff size.24 The corresponding instruments measuring subjects’ height and weight were validated and calibrated, whereas BMI was calculated as: (weight, kg) / (height, m).2 Heterozygous Familial Hypercholesterolaemia (HeFH) was defined according to the Dutch Lipid Clinic Network (DLCN) criteria.25

Laboratory data included: i) fasting plasma glucose (FPG), ii) insulin (INS), iii) Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index (FPG, mg/dL x INS, mU/L /405), iv) uric acid (UA), v) a complete lipid profile, including total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), LDL-C, Lp(a) and apolipoprotein B (apoB) and vi) creatinine. Blood samples were collected in the morning into sterile Vacutainer-SST II advance tubes (Becton-Dickinson, Plymouth, UK) after overnight fasting for at least 8-12 h. Tubes were refrigerated immediately after collection, were centrifuged at 4oC within 40 min of blood sampling, and then were analyzed within 2 h. Serum concentrations of TC were determined enzymatically on an Olympus AU600 Clinical Chemistry Analyzer (Olympus Diagnostica, Hamburg, Germany). HDL-C was determined by a direct assay (Olympus Diagnostica, Hamburg, Germany). LDL-C was calculated using the Friedewald formula, provided that TG levels were <400 mg/dL (4.5 mmol/L). Serum apoB and Lp(a) levels were measured with a Behring Nephelometer BN100 and with reagents from Dade Behring GmbH analyzer (Liederbach, Germany). Renal function was estimated by eGFR with CKD-EPI (CKD Epidemiology Collaboration) formula using creatinine results from a method that had calibration traceable to isotope dilution mass spectrometry.26 The HOMA-IR has been used widely as an indirect method for quantifying insulin resistance and pancreatic β-cell function.27 Common reference levels for HOMA-IR range from 0.7-2.27 Lp(a) cholesterol content was estimated as 30% of Lp(a) mass and subtracted from LDL‐C to obtain LDL-CLp(a)corr [LDL-CLp(a)corr = LDL-C – 0,3 x Lp(a)].28 Concomitant therapy was additionally recorded.

Statistical analysis

Continuous variables were tested for normality by the Kolmogorov-Smirnov test. Data are presented as mean ± standard deviation (SD) and median [interquartile range (IQR)] for parametric and non-parametric data, respectively. For categorical values, frequency counts and percentages were applied. Chi-square (χ2) test was performed for interactions between categorical values. The independent sample t-test (parametric and non-parametric) was used for the comparison of continuous numeric values between 2 groups. One-way analysis of variance (one-way ANOVA) was performed to assess the difference of the variables of interest between ≥2 groups. Multivariate analysis of covariance (MANCOVA) was used for the comparison of continuous numeric values between ≥2 groups after adjusting for the baseline values of the investigated variable of interest. Two-tailed significance was defined as p<0.05. Analyses were performed with the SPSS v21.0 software (SPSS Statistics for Windows, Version 28.0. Armonk, New York, NY, USA: IBM Corp).

RESULTS

In total, 70 subjects were included in the present study. Subjects’ baseline characteristics are presented in Table 1. Briefly, mean age was 51 ± 15 years, 40% were male, 39% were diagnosed with HeFH, 16% with ASCVD, while 36%, 33% and 15% were at very high, high, and moderate cardiovascular risk, respectively. Among patients’ baseline characteristics, it is worth noting that among 3 groups, patients who received additionally ezetimibe ± PCSK9 inhibitors had an increased prevalence of arterial hypertension and T2D compared to naïve patients, while patients who finally received PCSK9 inhibitors also had an increased prevalence of cardiovascular and chronic kidney disease, compared to the patients of the other 2 groups.

All interventions significantly reduced apoB, TC and LDL-C, but only PCSK9 inhibitors reduced significantly Lp(a) (Table 2). Specifically, PCSK9 inhibitors achieved the highest reduction in LDL-C (SEP: -56% vs SE: -43% vs S: -22%, p<0.05) and Lp(a) levels (SEP: -28% vs SE: +11% vs S: +17%, p<0.05). The same was noted for the change in LDL-CLp(a)corr across 3 groups (Table 2). Patients in the SEP group achieved the highest rates of LDL-C target attainment (Table 3).

Among the study participants without diabetes (n=60), high-intensity statin treatment and the addition of ezetimibe to high-intensity statin had no significant effect on glycemic profile across treatment groups (Table 4). Similar results were noted for PCSK9 inhibitors, although it is worth mentioning the non-significant trend towards a decrease in HOMA-IR index by 19% (Table 4).

All therapeutic interventions were well tolerated, and no adverse events were mentioned during study.

DISCUSSION

The present study shows that add-on PCSK9 inhibitors achieved the highest rates of LDL-C target attainment compared with high-intensity statin monotherapy ± ezetimibe in patients with Lp(a) levels ≥30 mg/dL. Moreover, PCSK9 inhibitors were the only class to significantly lower Lp(a). Interestingly, no differences were noted regarding the effect of these lipid-lowering interventions on the participants’ glycemic profile.

Elevated Lp(a) is the most common inherited lipid disorder associated with ASCVD.29 About 90% of the Lp(a) levels is autosomal dominantly inherited and strongly determined by a single gene, the LPA gene.3 By the age of 2 the LPA gene is fully expressed.30 Afterwards, Lp(a) levels are stable over time and seem not to be affected by diet, physical activity, or other environmental factors.6 Evidence from experimental, observational, and genetic studies has demonstrated that increased Lp(a) is associated with increased risk for coronary heart disease (CHD), ischemic stroke, PAD, heart failure, CAVS, mitral valve stenosis and possibly retinopathy in diabetic patients.31–37 Although Lp(a) thresholds (>30 mg/dL or >50 mg/dL; >75nmol/L or >125 nmol/L, respectively) were initially proposed, there is a linear relationship between Lp(a) levels and ASCVD.6 There are no medications specifically approved for Lp(a) lowering yet.3–5 Specifically, novel therapies targeting apo(a), such as antisense oligonucleotides or silent RNAs, are effective in lowering Lp(a) by >90%, but their cardiovascular benefit is yet to be determined.3,38,39 However, a few available therapeutic agents have a modest effect on Lp(a).3–5 Although the effect of statin treatment on Lp(a) levels remains an area of controversy, it seems that statins slightly increase Lp(a) levels.7–10 Most other lipid modifying agents, including ezetimibe do not significantly alter Lp(a) concentration,3–5 except for PCSK9 inhibitors, which have been shown to reduce Lp(a) levels, by ~ 20-30%.11–13

Our results concerning the effect of high intensity statins, ezetimibe and PCSK9 inhibitors on patients with elevated Lp(a) levels agree with past evidence derived from the general population. Similar to our study, statins reduce LDL-C by 30-63%,40 TGs by 14-33%,41 and increase HDL-C up to 10%42 in patients with hypercholesterolemia, with atorvastatin 40-80 mg and rosuvastatin 20-40 mg being the most potent ones. Nevertheless, the effect of statin treatment on Lp(a) levels remains an area of controversy. Statin trials have shown mixed results regarding their impact on Lp(a) levels. A large meta-analysis of 6 trials including 5256 patients randomized to various statins or placebo indicated that most statins increase Lp(a) by 8-24%, although a significant heterogeneity in the response of Lp(a) levels to statin administration, as well as between different statins was reported.43 On the other hand, another meta-analysis of 39 trials including 24,448 patients randomized to receive various statins or placebo indicated a non-significant trend towards an increase in Lp(a) by 0.1% in statin groups (vs placebo), with no significant differences among statins or different intensities of statins.44 Similarly, our study indicated a non-significant increase in Lp(a) levels in the group of patients who received a high intensity statin by 11%. Ezetimibe, a cholesterol absorption inhibitor, has a modest LDL-C lowering efficacy; 17% when used alone45 and 14-25% when used in combination with statins.46 Its effect on Lp(a) remains also controversial.47 In a meta-analysis of 7 randomized controlled trials with ezetimibe monotherapy in 2237 patients with primary hypercholesterolemia, ezetimibe significantly reduced Lp(a) levels by 7.1%, whereas another meta-analysis including 11 double-blind randomized controlled trials with 1926 hypercholesterolemic adults, showed that ezetimibe, either as monotherapy vs placebo or in combination with statin vs statin monotherapy, did not significantly alter Lp(a) concentration.47 In contrast to this evidence, our study showed that the addition of ezetimibe on high-intensity statin treatment significantly increased Lp(a) levels by 10%. This could be attributed at least in part to the small sample size of the study or to the different design of our study including only patients with elevated Lp(a) levels. On the other hand, our results are in agreement with past evidence derived from FOURIER and the ODYSSEY OUTCOMES trials48–55 showing that PCSK9 inhibitors are highly effective in lowering LDL-C levels by ~60% in patients on statin therapy, as well as Lp(a) levels by 20-30%.11,12,56 Of interest, the cardiovascular efficacy of these drugs have been shown superior in individuals with elevated Lp(a).57 According to a post hoc analysis of the ODYSSEY OUTCOMES trial referring to statin-treated patients with LDL-C ~70 mg/dL, alirocumab was associated with a higher reduction in risk for major adverse cardiovascular events (MACE) in patients with mildly elevated Lp(a) levels (≥13.7 mg/dL) (adjusted treatment HR: 0.68, 95% confidence interval: 0.52-0.90) in comparison with those having lower Lp(a) levels (adjusted treatment HR: 1.11, 95% confidence interval: 0.83-1.49).57 Similarly, according to a post hoc analysis of the FOURIER trial, patients with higher baseline Lp(a) levels (>37 nmol/L) experienced greater absolute reductions in Lp(a) with evolocumab and tended to derive greater coronary benefit (HR: 0.77, 95% confidence interval: 0.67-0.88) in comparison with those having lower baseline Lp(a) levels (HR: 0.93, 95% confidence interval: 0.80-1.08).58

T2D development is the caveat of statin therapy, mainly concerning high-intensity statins. A meta-analysis of clinical trials (13 randomized controlled endpoint trials of statins with 91140 participants) showed that statins were associated with an increased risk of newly developed diabetes, with the absolute risk increase by statins being 0.4%.14,15,59 It is worth noting, however, that the increase in T2D development risk mainly concerns patients with predisposing factors, such as prediabetes and obesity and definitely this risk does not supersede the cardiovascular benefit of statins.14,15,59 In our study high-intensity statin treatment had no significant effect on the participants’ glycemic profile, but its small size and short follow-up, along with the lack of data on glycosylated hemoglobin test (HbA1C) levels consist major limitations. Our results showing a neutral effect of the addition of ezetimibe on the glycemic profile of patients with elevated Lp(a) levels are similar to past evidence in the general population. In the IMPOVE-IT Trial the addition of ezetimibe to simvastatin vs simvastatin alone did not increase the risk of new-onset diabetes (ΗR: 1.04, 95% confidence interval: 0.94-1.15).20 Furthermore, the results for PCSK9 inhibitors are also in agreement with the data from clinical trials so far. Published clinical studies to date have not demonstrated any correlation between PCSK9 inhibition, insulin resistance, plasma glucose levels, pancreas insufficiency, or increased rates of T2M.16–19

It is worth noting that this is the first study concerning exclusively patients with elevated Lp(a) levels, especially considering the association between very low Lp(a) levels and incident T2D, an association derived from large prospective epidemiological cohorts with robust durations of follow-up.60 T2D prevalence in our study (15%) was similar to that of a previous retrospective study (11%) conducted in our clinic and including 1241 patients with dyslipidemia.61 In addition, a non-significant trend towards a reduction in HOMA index was noted with PCSK9 inhibitors which lowered modestly Lp(a) in our study. Therefore, more evidence is needed to investigate the causality between Lp(a) and T2D and whether Lp(a) reduction by treatment modalities can lead to incident T2D.60

The major limitations of this study were its small sample size and follow-up, along with the lack of data on dietary habits and physical activity of the patients. Another limitation is the lack of Lp(a) values before any therapeutic intervention in patients receiving ezetimibe or PCSK9 inhibitors. On the other hand, this study is a real-world study conducted in an outpatient lipid clinic, investigating the effect of the available lipid-lowering therapies in dyslipidemic patients with elevated Lp(a) levels.

CONCLUSIONS

Add-on PCSK9 inhibitors were associated with the highest rates of LDL-C target attainment compared with high-intensity statin treatment ± ezetimibe, and the only class to significantly lower Lp(a) in patients with elevated Lp(a) levels. Although these interventions did not affect participants’ glycemic profile, longer follow up is needed.

Funding

The present study was supported with a research grant by Hellenic Atherosclerosis Society which was received by Koutsogianni Amalia Despoina.

Conflict of Interest

ADK has received personal fees from Novartis, outside the submitted work. FB has received honoraria and personal fees from Amgen, Novartis, Novo Nordisk and Viatris, outside the submitted work. GL has received honoraria, grants and non-financial support from Angelini, Bayer, Menarini, and Sanofi, outside the submitted work. EL reports personal fees and non-financial support from Amgen, personal fees from Servier, personal fees from Boehringer-Ingelheim, personal fees and non-financial support from AstraZeneca, personal fees from MSD, personal fees from Lilly, personal fees and non-financial support from Bayer, personal fees from Novartis, personal fees from Chiesi, outside the submitted work. CT and AT report no conflicts of interest associated with the present work.

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