Effects of Pemafibrate on Cardio-Ankle Vascular Index (CAVI) in Patients with Type 2 Diabetes or Ischemic Heart Disease: A 24-Week Observational Study

doi:10.21203/rs.3.rs-5268285/v1

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Effects of Pemafibrate on Cardio-Ankle Vascular Index (CAVI) in Patients with Type 2 Diabetes or Ischemic Heart Disease: A 24-Week Observational Study

https://doi.org/10.21203/rs.3.rs-5268285/v1

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Background: Pemafibrate is a novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) that improves lipid profile, but its effects on cardiovascular events remain unproven. This study examined changes in the cardio-ankle vascular index (CAVI), a marker of arterial stiffness, in high-risk patients with type 2 diabetes mellitus (T2DM) or ischemic heart disease (IHD) treated with pemafibrate.

Methods: In this single-center, prospective, observational study, 95 patients with T2DM and/or IHD, who had hypertriglyceridemia (≥150 mg/dL) and started pemafibrate (0.2 mg/day) were analyzed. The primary outcome was change in CAVI after 24 weeks. Secondary outcomes included changes in lipid profile, apolipoproteins, and liver enzymes.

Results: No significant change in CAVI was observed after 24 weeks of treatment (median [interquartile range (IQR)]; baseline vs 24 weeks: CAVI 9.4 [8.8-10.6] vs. 9.6 [8.9-10.8], p=0.715). However, pemafibrate significantly reduced triglycerides (233 mg/dL [171-329] to 143 mg/dL [111-187], p<0.001), apolipoprotein C-II (8.1 mg/dL [6.1-10.2] to 6.3 mg/dL [5.3-8.3], p<0.001), apolipoprotein C-III (15.3 mg/dL [12.2-18.3] to 11.6 mg/dL [9.3-14.2], p<0.001) and liver enzymes; and increased high-density lipoprotein cholesterol (45 mg/dL [39-52] to 50 mg/dL [40-60], p<0.001), apolipoprotein A-I and apolipoprotein A-II (both p<0.05). Calculated small dense low-density lipoprotein cholesterol also decreased significantly (40 mg/dL [31-49] to 36 mg/dL [28-45], p=0.002).

Conclusion: Although pemafibrate improves lipid profile and liver enzymes, its direct impact on vascular stiffness, as measured by CAVI, may be limited in short-term treatment. Further studies with extended follow-up are necessary to clarify its potential cardiovascular benefits, particularly in high-risk patients with T2DM and/or IHD.

pemafibrate

cardio-ankle vascular index

type 2 diabetes mellitus

ischemic heart disease

small dense low-density lipoprotein cholesterol

Atherosclerosis significantly contributes to the development of cardiovascular diseases, necessitating strict lipid-lowering therapies to mitigate associated risks. The cardio-ankle vascular index (CAVI) is a non-invasive measure of arterial stiffness, and its predictive value for cardiovascular events has been well established [1–4]. Additionally, hypertriglyceridemia has been linked to both cardiovascular diseases and increased CAVI [5, 6], highlighting the importance of triglyceride (TG) management in reducing arterial stiffness and cardiovascular risk.

Bezafibrate, a traditional fibrate, has been shown to improve CAVI by reducing TG, remnant-like particle cholesterol (RLP-C), glycated hemoglobin (HbA1c), and derivatives of reactive oxygen metabolites (d-ROMs), while increasing high-density lipoprotein cholesterol (HDL-C) level [7]. The primary mechanism by which fibrates exert TG-lowering effects involves the activation of lipoprotein lipase (LPL) [8]. LPL is an endothelial enzyme responsible for the hydrolysis of TG in lipoproteins, and its activity is influenced by insulin. Hence LPL activity reflects insulin sensitivity and endothelial function [9]. Fibrates typically enhance LPL activity, leading to reduced TG levels. However, comprehensive outcome studies for fibrates are limited, and the direct impact on cardiovascular events is still under investigation.

Pemafibrate is a novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) that significantly reduces TG, non-HDL cholesterol, and apolipoprotein C-III levels, while increasing HDL-C level [10]. Recent studies have also highlighted the importance of small dense low-density lipoprotein cholesterol (sdLDL-C) in the development of atherosclerosis, due to its high atherogenic potential [11].

Despite the favorable effects of pemafibrate on lipid profile, its ability to reduce cardiovascular events remains unproven. For example, the PROMINENT trial reported no significant reduction in cardiovascular events among type 2 diabetes mellitus (T2DM) patients with hypertriglyceridemia, despite reductions in TG, very low-density lipoprotein (VLDL) cholesterol, remnant cholesterol, and apolipoprotein C-III levels [12].

The primary aim of this study was to evaluate the effect of pemafibrate on CAVI, a key marker of arterial stiffness and a predictor of cardiovascular events, in high-risk patients with T2DM and/or ischemic heart disease (IHD). We hypothesized that pemafibrate may improve CAVI through its lipid-lowering effects, particularly by reducing TG and sdLDL-C levels that are known contributors to arterial stiffness.

Study Design

This clinical research was a single-center, prospective, observational study conducted at Toho University Sakura Medical Center.

Study Patients

This study enrolled patients with T2DM and/or a history of IHD, who had hypertriglyceridemia (TG ≥ 150 mg/dL) and started pemafibrate (0.2 mg/day) treatment between December 2021 and December 2022 and had undergone CAVI measurement within one month before or at the initiation of treatment. Exclusion criteria were an ankle-brachial index (ABI) below 0.9, severe liver or kidney dysfunction. A total of 102 patients were included.

Data Collection

Before treatment was started, data were collected on patient demographics, medical history, current medications, lifestyle factors, and baseline measurements. At baseline and after 24 weeks of pemafibrate treatment, the following were measured: CAVI, body weight, BMI, blood pressure, fasting blood glucose, HbA1c, total cholesterol (TC), TG, HDL-C, low-density lipoprotein cholesterol (LDL-C), uric acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), blood urea nitrogen, creatinine, estimated glomerular filtration rate (eGFR), lipoprotein fractions, LPL, urine albumin, high-sensitive C-reactive protein (CRP), and d-ROMs.

Measurement of Lipid Concentrations

Plasma levels of TC, TG, HDL-C and LDL-C (except for the LDL-C level used for calculating sdLDL-C) were measured by a colorimetric method using an automatic analyzer BioMajesty JCA-BM6070 from JEOL Ltd. (Tokyo, Japan) with an enzymatic kit from Sekisui Medical Co., Ltd. (Tokyo, Japan). Apolipoprotein (Apo) (A-I, A-II, B, C-II, C-III, E) concentrations were determined by a turbidimetric immunoassay using an automatic analyzer BioMajesty JCA-BM8060 from JEOL Ltd. with a kit from Nittobo Medical Co., Ltd. (Tokyo, Japan).

Calculation of SdLDL-C

LDL-C in this study was measured using a direct method as described above, but the LDL-C level used in computing sdLDL-C was calculated using TC, TG and HDL-C, as described below. The equations reported by Sampson et al. [13, 14] were used for calculating LDL-C and sdLDL-C, which are calculated based only on the standard lipid test panel values as follows:

1. First, LDL-C is calculated using the formula:

LDL-C = TC/0.948 - HDL-C/0.971 - [TG/8.56 + (TG × Non-HDL-C)/2140 - TG²/16100] − 9.44

2. Large buoyant LDL-C (lbLDL-C) is then calculated using the formula:

lbLDL-C = 1.43 × LDL-C – [0.14 × (ln (TG) × LDL-C)] − 8.99,

where ln (TG) is the natural logarithm of TG

3. Finally, sdLDL-C is calculated by subtracting lbLDL-C from LDL-C:

sdLDL-C = LDL-C - lbLDL-C

Preheparin LPL Mass Assay

Preheparin serum LPL mass was measured by a sandwich enzyme-linked immunosorbent assay (ELISA) utilizing a specific monoclonal antibody against bovine milk LPL, following the methods described by Kobayashi et al. [15]. A commercial kit from Sekisui Medical Co., Ltd. and a VERSAmax microplate reader (Molecular Devices Co., Ltd.) were used. The measurement range was 4-500 ng/mL, with a coefficient of variation less than 10% and measurement accuracy of 85–115% of the nominal value.

Measurement of CAVI

CAVI was determined using a VaSera CAVI instrument (Fukuda Denshi Co., Ltd, Tokyo). The procedure has been detailed in prior report [16]. Cuffs were placed on both upper arms and ankles of a subject positioned supine with the head in a midline position. Measurements were taken after the subject had rested for 10 minutes. Brachial and ankle pulse waves were detected using low cuff pressures (30 to 50 mmHg) to minimize the impact of cuff pressure on hemodynamics. CAVI was calculated using the formula:

CAVI = a{(2ρ/ΔP)×Ln(Ps/Pd) PWV²} + b, where Ps is systolic blood pressure, Pd is diastolic blood pressure, PWV is pulse wave velocity, ΔP is Ps - Pd, ρ is blood density, and a and b are constants.

Fibrosis-4 (FIB-4) Index and Nonalcoholic Fatty Liver Disease (NAFLD) Fibrosis Score

As markers of liver fibrosis, FIB-4 index and NAFLD fibrosis score (NFS) were evaluated in the patient cohort. These items were calculated using established formulas [17, 18], and their correlation with CAVI was analyzed to assess the potential association between liver fibrosis and arterial stiffness.

Statistical Analysis

Primary outcome was the change in CAVI from baseline to after 24 weeks of treatment. Secondary outcomes included changes in biochemical parameters and stratified analyses based on patient background factors. Comparisons of baseline data and changes in clinical parameters between the group with increase in CAVI (ΔCAVI ≥ 0) and the group without (ΔCAVI < 0) were performed using Wilcoxon signed-rank test or Mann-Whitney U test. Correlation between changes in TG level and other clinical parameters was analyzed using Spearman's rank correlation coefficient. A two-tailed p-value < 0.05 was considered statistically significant.

Patient Characteristics

This study included 102 patients, 95 of whom were analyzed after excluding three patients with an ABI below 0.9 and four patients with missing data. No patients discontinued medication due to adverse effects or serious adverse reactions. Patient background characteristics are summarized in Table 1. The 95 subjects analyzed had a median age of 70 years [interquartile range (IQR): 61–75], with a male to female ratio of 69.5–30.5%. The prevalence of hypertension and diabetes was 63.2% and 78.9%, respectively, while 41.1% had a history of ischemic heart disease (IHD). In addition, 65.3% of the patients were current or former smokers. Among the subjects, 47.4% were on ACE inhibitors or ARBs, 61.1% were on statins, 16.8% were taking ezetimibe, 38.9% were on metformin, 40.0% were using sodium–glucose co-transporter 2 (SGLT2) inhibitors, and 7.4% were on glucagon-like peptide-1 analogues.

Table 1

Patient background characteristics
Characteristic	Median (IQR) or %
Median age (IQR) (yr)	70	(	61	-	75	)
Female (%)	30.5
Hypertension (%)	63.2
Diabetes (%)	78.9
Ischemic heart disease (%)	41.1
Current or past smoking history (%)	65.3
ACE inhibitor or ARB (%)	47.4
Statin (%)	61.1
Ezetimibe (%)	16.8
Metformin (%)	38.9
SGLT2 inhibitor (%)	40.0
GLP-1 analogue (%)	7.4
This table provides an overview of the baseline characteristics of the study population. Median age, sex distribution, and prevalence of common comorbidities are listed, along with the percentage of patients using various medications at the start of the study. Data are presented as median (IQR) or percentage.
IQR, interquartile range; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; SGLT2, sodium-glucose cotransporter 2; GLP-1, glucagon-like peptide-1.

Primary Endpoint (Change in CAVI after 24 weeks of pemafibrate treatment)

There was no significant change in CAVI after 24 weeks of pemafibrate treatment (median 9.4 [IQR 8.8–10.6] at baseline vs. 9.6 [IQR 8.9–10.8] at 24 weeks, p = 0.715) (Fig. 1). Subgroup analyses of patients with diabetes and those with IHD also showed no significant CAVI changes in both subgroups (p = 0.447 and p = 0.136, respectively) (data not shown).

Secondary Endpoints: Changes in Lipid Parameters and Liver Enzymes over 24 weeks

Figure 2 shows the changes in various lipid parameters and Fig. 3 shows the changes in liver enzymes from baseline to after 24 weeks of pemafibrate treatment. TG decreased significantly from 233 mg/dL (171–329) to 143 mg/dL (111–187) (p < 0.001) and non-HDL-C decreased from 137 mg/dL (112–164) to 131 mg/dL (106–153) (p = 0.005). HDL-C increased significantly from 45 mg/dL (39–52) to 50 mg/dL (40–60) (p < 0.001) and LDL-C increased significantly from 92 mg/dL (70–111) to 103 mg/dL (79–128) (p < 0.001). There was no significant change in total cholesterol (p = 0.307).

Apolipoprotein C-II and C-III decreased significantly [ApoC-II: 8.1 mg/dL (6.1–10.2) to 6.3 mg/dL (5.3–8.3), p < 0.001; ApoC-III: 15.3 mg/dL (12.2–18.3) to 11.6 mg/dL (9.3–14.2), p < 0.001]. There were no significant changes in LPL and apolipoprotein B (ApoB) (p = 0.990 and p = 0.956 respectively). The calculated sdLDL-C value decreased significantly from 40 mg/dL (31–49) to 36 mg/dL (28–45) (p = 0.002).

Among liver enzymes, significant reductions in ALT and γ-GTP [ALT: 25 U/L (18–35) to 18 U/L (13–26), p < 0.001; γ-GTP: 34 U/L (21–64) to 21 U/L (14–43), p < 0.001] were observed. AST levels did not show a significant change (p = 0.373).

Changes in Clinical Parameters According to CAVI Change

The changes in clinical parameters from baseline to 24 weeks were compared between two groups divided by CAVI status: a group with no change or increase in CAVI (ΔCAVI ≥ 0) and a group with decrease in CAVI (ΔCAVI < 0). The results are shown in Table 2. The group with decrease in CAVI showed a significant reduction in LDL-C compared to the group with increase in CAVI (p = 0.044). Additionally, Apo B level decreased significantly in the group with decrease in CAVI compared to that with increase in CAVI (p = 0.001).

Table 2

Changes in clinical parameters according to the status of change in CAVI
	ΔCAVI ≥ 0						ΔCAVI < 0						p-value*
ΔTotal cholesterol (mg/dL)	5	(	-7	-	21	)	-8	(	-35	-	9	)	0.268
ΔTriglyceride (mg/dL)	-57	(	-122	-	-37	)	-86	(	-126	-	-35	)	0.849
ΔHDL-C (mg/dL)	5	(	1	-	13	)	2	(	-1	-	8	)	0.133
ΔLDL-C (mg/dL)	15	(	2	-	29	)	-2	(	-13	-	14	)	0.044
Δnon-HDL-C (mg/dL)	-2	(	-9	-	12	)	-14	(	-28	-	10	)	0.471
ΔSdLDL-C (mg/dL) (calculated)	0	(	-5	-	3	)	-6	(	-11	-	2	)	0.608
ΔLPL (ng/mL)	1	(	-7	-	12	)	-3	(	-9	-	8	)	0.285
ΔApolipoprotein A-I level, measured (mg/dL)	8	(	-2	-	15	)	1	(	-4	-	7	)	0.051
ΔApolipoprotein A-II level, measured (mg/dL)	8.9	(	5.7	-	13.5	)	6.9	(	3.1	-	12.9	)	0.067
ΔApolipoprotein B level, measured (mg/dL)	3	(	-4	-	12	)	-7	(	-14	-	3	)	0.001
ΔApolipoprotein C-II level, measured (mg/dL)	-1.1	(	-2.6	-	-0.2	)	-0.9	(	-2.6	-	0.4	)	0.579
ΔApolipoprotein C-III level, measured (mg/dL)	-3.0	(	-5.0	-	-1.8	)	-3.7	(	-6.3	-	-1.2	)	0.863
ΔApolipoprotein E level, measured (mg/dL)	0.1	(	-0.4	-	0.5	)	-0.6	(	-1.2	-	0.5	)	0.117
ΔFIB-4 index	0.0	(	-0.1	-	0.3	)	0.0	(	-0.1	-	0.2	)	0.652
ΔNAFLD fibrosis score (NFS)	-0.201	(	-0.557	-	0.295	)	0.017	(	-0.542	-	0.217	)	0.730
This table presents the changes in clinical parameters from baseline to 24 weeks between a group with increase in CAVI (ΔCAVI ≥ 0) and a group with decrease in CAVI (ΔCAVI < 0) during this period. Data are expressed as median (interquartile range). *p values were obtained by Mann-Whitney U test, ΔCAVI ≥ 0 vs ΔCAVI < 0.
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; non-HDL-C, non-high-density lipoprotein cholesterol; sdLDL-C, small dense low-density lipoprotein cholesterol; LPL, lipoprotein lipase; FIB-4, Fibrosis-4; NAFLD, Nonalcoholic Fatty Liver Disease.

Correlation Between Change in TG Levels and Change in LPL or Apolipoprotein C-III

The correlation between the change in TG level and change in LPL or ApoC-III from baseline to 24 weeks was analyzed. The results are shown in Fig. 3. There was no significant correlation between the changes in TG and LPL (Rs = -0.106, p = 0.394), while a significant positive correlation between the changes in TG and ApoC-III was observed (Rs = 0.541, p < 0.001).

Other Clinical Parameters

No significant changes in body weight, BMI, systolic blood pressure, diastolic blood pressure, HbA1c, urinary albumin, hs-CRP, FIB-4 index, NFS, and d-ROM levels were observed (Table 3). Estimated GFR decreased significantly from 66 mL/min/1.73m² (51–77) to 61 mL/min/1.73m² (50–75) (p < 0.001). ApoA-I and ApoA-II levels increased significantly [ApoA-I: 137 mg/dL (118–153) to 140 mg/dL (127–158), p = 0.020; ApoA-II: 29.7 mg/dL (26.9–33.3) to 38.1 mg/dL (32.7–43.7), p < 0.001]. ApoE showed an apparent decrease but did not reach a significant difference (p = 0.069). A positive correlation was found between CAVI and both the FIB-4 index and NAFLD fibrosis score (Supplementary Figure S1).

Table 3

Clinical data before and after pemafibrate administration
	0W						24W						p-value*
Body Wight (kg)	68.0	(	60.0	-	76.1	)	69.2	(	60.0	-	76.0	)	0.943
BMI (kg/m2)	25.8	(	22.8	-	28.5	)	25.6	(	22.5	-	27.5	)	0.891
SBP (mmHg)	133	(	122	-	145	)	135	(	125	-	152	)	0.110
DBP (mmHg)	81	(	71	-	90	)	81	(	72	-	88	)	0.895
eGFR (mL/min/1.73m2)	66	(	51	-	77	)	61	(	50	-	75	)	< 0.001
Uric acid (mg/dL)	5.5	(	4.8	-	6.3	)	5.6	(	4.7	-	6.5	)	0.405
HbA1c (%)	6.9	(	6.2	-	7.8	)	6.9	(	6.1	-	7.8	)	0.433
Urinary albumin (mg/gCr)	14.8	(	6.6	-	70.6	)	20.2	(	9.7	-	75.0	)	0.248
hs-CRP (mg/dL)	0.081	(	0.037	-	0.194	)	0.081	(	0.028	-	0.165	)	0.474
d-ROM (U.CARR)	313	(	276	-	356	)	304	(	267	-	357	)	0.494
Apolipoprotein A-I level, measured (mg/dL)	137	(	118	-	153	)	140	(	127	-	158	)	0.020
Apolipoprotein A-II level, measured (mg/dL)	29.7	(	26.9	-	33.3	)	38.1	(	32.7	-	43.7	)	< 0.001
Apolipoprotein E level, measured (mg/dL)	3.4	(	2.3	-	4.7	)	2.9	(	2.2	-	3.7	)	0.069
FIB-4 index	1.6	(	1.1	-	2.2	)	1.6	(	1.1	-	2.3	)	0.588
NAFLD Fibrosis Score (NFS)	-0.233	(	-1.127	-	0.466	)	-0.422	(	-1.311	-	0.631	)	0.116
This table presents a comparison of clinical parameters before and after 24 weeks of pemafibrate treatment. Data are presented as median (interquartile range). *p values were obtained by Wilcoxon signed-rank test, 0W vs 24W.
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1; hs-CRP, high-sensitivity C-reactive protein; d-ROM, derivatives of reactive oxygen metabolites; FIB-4, Fibrosis-4; NAFLD, Nonalcoholic Fatty Liver Disease; W, week.

This observational study demonstrated that 24-week treatment with pemafibrate in patients with T2DM and/or a history of IHD significantly improved lipid profile, including reduction in TG. However, no significant change was observed in CAVI, suggesting that the effect of pemafibrate on arterial stiffness may be limited in short-term treatment. CAVI is a well established marker for arterial stiffness and a predictor of cardiovascular events. In a previous study, bezafibrate treatment reduced CAVI, indicating improvement in arterial stiffness [7]. However, pemafibrate did not show similar result in the present study.

The lack of significant change in CAVI despite improvements in lipid profile may be attributed to several factors. One possible explanation for this discrepancy is the study duration. While a period of 24 weeks is sufficient to observe changes in lipid profile, it may not be long enough to detect changes in vascular structure and function, and observation of a longer treatment period may be needed. Additionally, due to the advanced age (median 70 years) and high prevalence of comorbidities, our study population may have had more established arterial changes that were less responsive to short-term interventions. Another consideration is that, although there was a significant reduction in TG levels, it may not have been enough to influence arterial stiffness as measured by CAVI. Study has demonstrated that TG levels ≥ 93 mg/dL contribute to high CAVI (≥ 90th percentile) [5]. In our study, despite significant reduction in TG from baseline, the levels may not have decreased sufficiently to impact arterial stiffness as measured by CAVI. This suggests that achieving more substantial reduction in TG level may be necessary to observe significant improvement in arterial stiffness.

Another important factor to consider is that lipid-lowering agents that do not increase LPL level may not be as effective in reducing CAVI than those that elevate LPL. High serum LPL may contribute to improve arterial stiffness [9]. Among statins, pitavastatin has been reported to increase LPL and decrease CAVI [19, 20]. Among fibrate drugs, bezafibrate has also been reported to elevate LPL and reduce CAVI [7, 8], suggesting that LPL may play a role in the reduction of CAVI by bezafibrate. In our study, although pemafibrate significantly reduced TG and ApoC-III, it did not significantly alter LPL levels. The lack of increase in LPL may explain why a reduction in CAVI was not observed, despite favorable changes in the lipid profile.

Previous research has established a correlation between sdLDL-C and carotid artery intima-media thickness (IMT) [21–24], as well as between IMT and CAVI [25, 26]. Furthermore, sdLDL-C has been linked to cardiovascular events [27–32], suggesting that reducing sdLDL-C could potentially lower CAVI. Although sdLDL-C was not directly measured in the present study, new equations for calculation of LDL-C and sdLDL-C have recently been devised by Sampson et al [13, 14]. The clinical usefulness of the sdLDL-C levels calculated by these equations has been reported [33, 34]. Our study observed a reduction in calculated sdLDL-C level, but this did not translate to a change in CAVI. This finding could suggest that progressed arterial stiffening caused by long-term lipid exposure and cumulative atherosclerotic burden may not be improved readily by short-term changes in lipid profile.

Komiya et al. reported that pemafibrate decreased the LDL-migration index, a marker of small, dense LDL, particularly in patients with higher baseline triglycerides and lower baseline LDL-C [35]. This is consistent with our findings of a significant reduction in calculated sdLDL-C, suggesting that pemafibrate improves LDL composition even when total LDL-C increases. This reduction in sdLDL-C, despite an increase in total LDL-C, is particularly important because sdLDL-C has been linked to increased cardiovascular risk. The ability of pemafibrate to improve LDL composition by reducing the more atherogenic sdLDL-C fraction may contribute to its potential cardiovascular benefits, even in the absence of a reduction in total LDL-C or immediate improvement in arterial stiffness as measured by CAVI.

The 24-week study period may have been insufficient to capture the full impact of sdLDL-C reduction on vascular remodeling, particularly in patients with advanced diabetes or established cardiovascular disease. In Japan, sdLDL-C levels are classified as follows: less than 25 mg/dL, normal; 25-34.9 mg/dL, mildly abnormal; 35-44.9 mg/dL. re-examination and lifestyle modification required; and 45 mg/dL or higher, close monitoring and treatment required. In our study, calculated sdLDL-C level decreased significantly from 40 mg/dL (IQR 31–49) before pemafibrate treatment to 36 mg/dL (IQR 28–45) after 24 weeks of treatment. However, this change was within the range that requires re-examination and lifestyle modification, and it was not a dramatic reduction. The mild decrease in sdLDL-C may be one factor associated with the lack of CAVI response.

On the other hand, a study suggests that an increase in serum LPL mass level may be associated with a decrease in sdLDL-C [36]. The conflicting result in the present study–serum LPL mass did not increase despite decreased sdLDL-C– may be attributed to the same reason mentioned above. Hirano et al. [37] also suggested that no difference in sdLDL-C reduction between the pemafibrate and placebo groups may contribute to the lack of reduction in cardiovascular events in the PROMINENT trial. Furthermore, the relationship between sdLDL-C and vascular function may be modulated by other factors such as inflammation, oxidative stress, and endothelial dysfunction [38–40]. These pathophysiological processes are known to be dysregulated in diabetes and cardiovascular disease and may not be fully resolved by lipid-lowering therapies alone. This highlights the importance of comprehensive management of all risk factors and the potential need for combination therapies targeting multiple pathways.

Although CAVI did not change, pemafibrate showed significant efficacy in improving several lipid parameters including TG, HDL-C, and non-HDL-C. The significant reduction in ApoC-III supports the mechanism of action of pemafibrate in lowering TG levels through modulation of LPL [41]. In our study, LPL protein level did not change after pemafibrate treatment, but ApoC-III level was reduced, suggesting that LPL activity was sufficiently increased. The reductions in TG and non-HDL-C potentially reduce cardiovascular risk, even though this may not be reflected as decrease in CAVI. Hypertriglyceridemia has also been shown to contribute to the high prevalence of high sdLDL-C in patients with T2DM [42].

Contrary to the PROMINENT trial that showed no significant reduction in ApoB [12], our study found a significant decrease in ApoB in the group with reduced CAVI. This suggests that improvement in arterial stiffness is associated with reduction in ApoB. Thus, pemafibrate not only improves lipid profile but may also contribute to cardiovascular risk reduction in a subgroup of patients with decreased ApoB.

Another important aspect of this study is the significant reduction in liver enzyme levels, including ALT and γ-GTP, indicating a hepatoprotective effect of pemafibrate. This is particularly beneficial, since hepatic adverse effects are often associated with other lipid-lowering therapies. Although pemafibrate is not considered to affect eGFR [43], eGFR decreased after pemafibrate treatment in the present study. In the PROMINENT trial, decrease in eGFR was observed in the pemafibrate group compared with placebo, and the decrease in eGFR was reversible. The exact mechanism for the decrease in eGFR is not fully understood, but reduction in eGFR appears to be a known reversible effect of fibrates [44, 45]. A phase 3 trial in Japan comparing pemafibrate with fenofibrate also found similar effects on renal function, suggesting that this may be a class effect of fibrates rather than an effect specific to pemafibrate [46]. Another reason for the decrease in eGFR is that patients with high CAVI are susceptible to rapid eGFR decline [47], which may mask the vascular improvement effect of pemafibrate. Our study participants were older individuals with significantly high baseline CAVI, indicating that they were at an advanced stage of atherosclerosis. The observed renal function decline was likely a consequence of progression of atherosclerosis, rather than an adverse effect of pemafibrate treatment.

In this study, a significant correlation was observed between CAVI and both the FIB-4 index and NAFLD fibrosis score, suggesting a close relationship between arterial stiffness and liver fibrosis. Previous studies have also shown that liver stiffness measured by elastography is associated with CAVI [48], further strengthening the connection between liver fibrosis and vascular stiffness. These findings imply that underlying inflammation and oxidative stress, which are common in patients with dyslipidemia, diabetes, and cardiovascular diseases, may contribute to both liver dysfunction and arterial stiffness.

This study has several limitations. First, the sample size was relatively small and the observational study design limits the ability to establish causality. In addition, the study was conducted at a single center, and the results may not be generalizable to other populations. Finally, the 24-week study period may have been too short to observe significant changes in vascular stiffness, and longer observation is needed to evaluate the long-term effects of pemafibrate.

In patients with high TG and either T2DM and/or IHD, treatment with pemafibrate for 24 weeks significantly improved plasma lipid profile and liver enzyme levels but did not significantly alter CAVI. These findings suggest that while pemafibrate is effective in improving dyslipidemia, its impact on vascular function may be limited in short-term treatment. The lack of improvement in CAVI despite favorable lipid profile changes highlights the complex nature of vascular health in high-risk populations. Further research with longer follow-up and larger sample size is necessary to fully elucidate the potential cardiovascular benefits of pemafibrate.

CAVI Cardio-Ankle Vascular Index

TG Triglyceride

RLP-C Remnant-like particle cholesterol

HbA1c Glycated hemoglobin

d-ROMs Derivatives of reactive oxygen metabolites

HDL-C High-density lipoprotein cholesterol

LPL Lipoprotein lipase

SPPARMα Selective peroxisome proliferator-activated receptor alpha modulator

sdLDL-C Small dense low-density lipoprotein cholesterol

T2DM Type 2 diabetes mellitus

VLDL Very low-density lipoprotein

IHD Ischemic heart disease

ABI Ankle-brachial index

BMI Body mass index

TC Total cholesterol

LDL-C Low-density lipoprotein cholesterol

AST Aspartate aminotransferase

ALT Alanine aminotransferase

γ-GTP Gamma-glutamyl transpeptidase

eGFR Estimated glomerular filtration rate

Apo Apolipoprotein

ELISA Enzyme-linked immunosorbent assay

FIB-4 Fibrosis-4

NAFLD Nonalcoholic fatty liver disease

NFS NAFLD fibrosis score

ACE Angiotensin-converting enzyme

ARB Angiotensin receptor blocker

SGLT2 Sodium-glucose co-transporter 2

CRP C-reactive protein

IMT Intima-media thickness

Acknowledgements

We thank the patients who participated in the study and Takayuki Kawai, Masumi Kurihara, Yukie Takahira and Aki Shimada for assistance in data collection.

Author contributions

A.S. and K.S. designed the study. Y.W., S.N., S.Y., S.N., O.H., T.Y., S.S., S.T., Y.S., T.I., H.M., M.T., K.S., and A.S. performed data collection. Y.W. and D.N. performed statistical analyses. Y.W. and S.N. wrote the paper. All authors approved the final version of the manuscript.

Funding

This study was supported by a research grant from Kowa Company., Ltd. (Tokyo, Japan).

Data availability

The datasets generated and analyzed during the current study are not publicly available due to the sensitive nature of the patients' personal information and the ethical restrictions imposed by the Ethics Committee of Toho University Sakura Medical Center. However, de-identified data may be available from the corresponding author on reasonable request and with permission from the Ethics Committee of Toho University Sakura Medical Center. Any data sharing will be subject to ethical approval and will be in accordance with the guidelines of the institution.

Ethics approval and consent to participate

This study was performed in compliance with the principles of the Declaration of Helsinki, and written informed consent was obtained from all participants. The study protocol was reviewed and approved by the Ethics Committee of Toho University Sakura Medical Center (approval number: S21038).

Consent for publication

Not applicable.

Competing interests

AS has received grant support from Kowa Company., Ltd. (Tokyo, Japan). The other authors declare that they have no competing interests.

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Competing interest reported. AS has received grant support from Kowa Company., Ltd. (Tokyo, Japan). The other authors declare that they have no competing interests.

SupplementaryFigure1trimming.pdf
Supplementary Figure S1. Correlation between CAVI and liver fibrosis markers: FIB-4 Index (A) and NAFLD fibrosis score (B). Significant correlation is observed between CAVI and FIB-4 index, and between CAVI and NAFLD fibrosis score. FIB-4, Fibrosis-4; NAFLD, Nonalcoholic Fatty Liver Disease.

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Effects of Pemafibrate on Cardio-Ankle Vascular Index (CAVI) in Patients with Type 2 Diabetes or Ischemic Heart Disease: A 24-Week Observational Study

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Abstract

Figures

Introduction

Materials and methods

Study Design

Study Patients

Data Collection

Measurement of Lipid Concentrations

Calculation of SdLDL-C

Preheparin LPL Mass Assay

Measurement of CAVI

Fibrosis-4 (FIB-4) Index and Nonalcoholic Fatty Liver Disease (NAFLD) Fibrosis Score

Statistical Analysis

Results

Patient Characteristics

Primary Endpoint (Change in CAVI after 24 weeks of pemafibrate treatment)

Secondary Endpoints: Changes in Lipid Parameters and Liver Enzymes over 24 weeks

Changes in Clinical Parameters According to CAVI Change

Correlation Between Change in TG Levels and Change in LPL or Apolipoprotein C-III

Other Clinical Parameters

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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