Abstract
Purpose
Pemafibrate, a selective peroxisome proliferator-activated receptor-α modulator (SPPARMα), is widely used for hypertriglyceridemia; however, concerns persist regarding its potential to elevate low-density lipoprotein cholesterol (LDL-C). Previous studies monitored LDL-C for only 3–6 months, leaving the long-term trajectory unclear. This one-year retrospective observational study aimed to determine whether pemafibrate-induced LDL-C elevation is sustained or transient and to identify factors associated with this response.
Patients and Methods
A total of 110 patients receiving pemafibrate (0.1–0.2 mg/day; standard dose 0.2 mg/day) were followed for one year. Serial lipid changes were analyzed, and predictors of LDL-C elevation were evaluated using multivariate regression.
Results
Triglyceride decreased markedly from 378.6 ± 248.7 to 191.5 ± 144.4 mg/dL (P < 0.001). LDL-C increased from 120.5 ± 30.6 to 129.7 ± 34.3 mg/dL at 3 months (P < 0.05), representing the peak of LDL-C elevation. Thereafter, LDL-C gradually declined and showed no statistically significant difference from the baseline at 12 months, demonstrating a characteristic transient “rise-and-return” pattern. Lower baseline LDL-C, lower HDL-C, and higher triglycerides were associated with greater LDL-C elevation, while statin use showed no significant association. Low baseline LDL-C was the strongest predictor in multivariate analysis.
Conclusion
This study is the first to document the full one-year LDL-C trajectory under pemafibrate, revealing a transient “rise-and-return” pattern. LDL-C elevation peaks at approximately 3 months and returns to baseline by one year, indicating that the increase is temporary rather than persistent. These findings refine the understanding of pemafibrate’s lipid effects and support its long-term safety profile.
Keywords: hypertriglyceridemia, SPPARMα, LDL-C dynamics, pemafibrate, transient LDL-C elevation
Plain Language Summary
Pemafibrate is a medication used to lower high triglyceride levels. Some patients notice an increase in low-density lipoprotein cholesterol (LDL-C) after starting the drug, which can be worrying because LDL-C is often called “bad cholesterol.” Earlier studies followed patients for only 3 to 6 months, so it was unclear whether this rise continues or returns to normal.
In this one-year study, we followed 110 patients taking pemafibrate. LDL-C increased during the first three months but then gradually decreased and returned to the original level by one year. This indicates that the LDL-C rise is temporary rather than permanent.
Patients with low LDL-C, low HDL-C, and high triglycerides at the start were more likely to experience this temporary increase. These changes likely reflect how pemafibrate helps the body process fats more efficiently over time.
Our findings suggest that the early rise in LDL-C is not harmful or permanent. Understanding this natural “rise-and-return” pattern can help clinicians use pemafibrate with confidence and avoid unnecessary concern about long-term cardiovascular risk.
Graphical Abstract
Introduction
Pemafibrate, a novel selective peroxisome proliferator-activated receptor-α modulator (SPPARMα), effectively decreases high triglyceride (TG) levels with fewer adverse effects than conventional fibrates.1–3 It is recommended for patients with markedly elevated TG levels due to familial or genetic factors and for those who respond poorly to other treatments.4
Although pemafibrate consistently lowers TG levels, several studies have reported increases in low-density lipoprotein cholesterol (LDL-C) after several months of treatment. This has led some clinicians to hesitate or discontinue pemafibrate therapy. In the PROMINENT trial, a large international study in patients with type 2 diabetes receiving intensive statin therapy, LDL-C increased by approximately 14% (12 mg/dL) in the pemafibrate group compared with 2.9% (2 mg/dL) in the placebo group.5 Notably, LDL-C was assessed at four months, a time point that may coincide with the early peak of LDL-C elevation. Therefore, the observed increase may reflect a short-term metabolic shift rather than a sustained effect of pemafibrate.
We previously reported that LDL-C increased significantly after short-term pemafibrate therapy in real-world practice, particularly among patients not receiving statins, whereas no significant change was observed in those on statin therapy.6 These findings suggested that LDL-C elevation may occur early after pemafibrate initiation, but the long-term trajectory remained unclear.
Because previous studies monitored LDL-C for only 3–6 months, the full pattern of LDL-C changes under pemafibrate have not been established. Whether LDL-C levels continue to rise or naturally return to baseline has not been clarified, leaving the long-term behavior of LDL-C an unanswered clinical question.
Conventional fibrates can also increase LDL-C, although the mechanism is not fully understood, and long-term data are limited. In addition, lifestyle factors such as diet and exercise were not systematically modified in our clinical setting, minimizing their influence on lipid changes.
To address this gap, we conducted a one-year observational study to characterize the complete LDL-C trajectory under pemafibrate and to identify factors associated with transient LDL-C elevation. To our knowledge, no prior study has documented long-term LDL-C dynamics, including the possibility of a transient rise followed by a return to baseline.
Materials and Methods
The data of the study are available from the corresponding author upon reasonable request. The Ethics Committee of the Japan Physicians Association, Tokyo, Japan approved the study on August 7, 2019 (Approved ID: 022–1906-001). All data were collected retrospectively from the electric patient records at Iitake Clinic for Internal Medicine. This is a single-center observational study.
Due to the retrospective nature of this study, participants’ informed consent was waived. However, information about this study was provided to guarantee the right to opt out.
Participants
After considering the inclusion and exclusion criteria, 110 patients were enrolled, with 21 participants (19.1%) had been treated with other fibrates and were switched to pemafibrate, and 32 (29.1%) using statins. Other lipid medicated drugs included EPA (used in three cases, added in one case), ezetimibe (used in one case, added on one case), and probucol (used in one case). As the number of cases was extremely small, we believe that it would not affect the results. Furthermore, 55 patients (50.0%) had type 2 diabetes, and 43 (39.1%) were on medication. Insulin was used in one case. Other drugs, such as SGLT2 inhibitors and GLP-1 injections, which could affect the outcome, were used in 22 and 2 cases, respectively. However, as the number of these cases was small, its influence was not considered. Patients with hypertriglyceridemia (non-fasting TG levels ≥175 mg/dL) who regularly visiting our clinic and did not meet the exclusion criteria were included in the study. Follow-up visits occurred every 35–60 days, which is similar to the typical interval for general clinic visits. Patients who were self-discontinued pemafibrate, were admitted to other hospitals, underwent surgery, are pregnant or breastfeeding, started a new diet and exercise therapy, and deemed unsuitable for inclusion in this study by the researcher were excluded.
Dose
From July 2018 to July 2019, the patients received pemafibrate once (0.1–0.2 mg) or twice (0.2 mg) daily. The dose was selected after physician consultations and patient discussions to ensure medication compliance. The initiation doses were as follows: 0.1 mg/once daily (n = 56, 50.9%), 0.2 mg/once daily (n = 4, 3.6%), and 0.2 mg twice daily (n = 50, 45.5%). The average daily dose was 0.157 ± 0.094 mg, which is smaller than the standard daily dose 0.2 mg. Of the 110 cases, 17 (15.5%) had their doses increased from 0.1 to 0.2 mg, once or twice daily for a better effect. On average, the increase occurred at 7.12 ± 2.45 months.
Laboratory Findings and Statistical Analysis
Data on age, sex, and body weight (BW, kg) were collected. Changes in TG (non-fasting, mg/dL), LDL‑C (mg/dL), HDL‑C (mg/dL), HbA1c (%), and postprandial blood glucose (PBG, mg/dL) were assessed at baseline, 1 month, 3 months, 6 months, and 1 year. Baseline creatinine (mg/dL), creatinine kinase (CK, IU/L), aspartate transaminase (AST, IU/L), and alanine transaminase (ALT, IU/L) were also obtained.
LDL‑C was measured using a direct homogeneous assay routinely employed in our clinical laboratory. For descriptive purposes, “low baseline LDL‑C” was defined as <123 mg/dL, corresponding to the median baseline LDL‑C value in this cohort.
The Wilcoxon signed‑rank test was used for nonparametric evaluation of variables pre‑ and post‑treatment. The dataset was also examined using the Wilcoxon rank‑sum test where appropriate. The change rate of LDL‑C at 3 months was analyzed using Pearson’s or Spearman correlation coefficients, depending on data distribution.
Univariate and multivariate linear regression analyses were conducted to identify factors associated with LDL‑C elevation. Variables with P < 0.10 in univariate analysis were entered into the multivariate model, and scaled estimates were used. Statistical analyses were performed using JMP® version 17 (SAS Institute Inc., Cary, NC, USA). Values are expressed as mean ± standard deviation. Statistical significance was set at P < 0.05.
Reasons for Collecting Non-fasting TG
Non-fasting triglycerides were collected because postprandial lipid levels better reflect real‑world lipid metabolism and remnant lipoprotein burden, which are strongly associated with cardiovascular risk.6 Previous large cohort studies in both Western and Japanese populations have shown that non-fasting TG levels predict cardiovascular events as well as, or better than, fasting TG levels.7–10
In addition, achieving a true fasting state is often difficult in routine clinical practice, particularly for patients with diabetes.11–14 Therefore, non-fasting TG measurements were considered more practical and clinically relevant for this study.
Other Parameters
During the study period, no structured diet or exercise program was implemented, and patients continued their usual lifestyle habits. Smoking and alcohol consumption also remained unchanged, which may not have affected the results. Among the 110 patients, 13 (men, 9; women, 4) had a smoking history and 34 (men, 30; women, 4) had a history of alcohol consumption.
Results
Baseline Characteristics
The baseline characteristics of all 110 patients are shown in Table 1. Of these, 57 (51.8%) were men and 53 (48.2%) were women, with a mean age of 61.2±11.7 years. The mean baseline body weight was 70.9±17.8 kg, indicating an overweight population.
Table 1.
Baseline Characteristics of All Patients
| Parameters | |
|---|---|
| Total cases | 110 |
| Gender (m,f) | 57、53 |
| Age (yrs. old) | 61.2±11.7 |
| Diabetes mellitus cases | 55 |
| Alcohol | 34 |
| Smoking | 13 |
| Other fibrates (cases) | None 89 Fenofibrate 17 Bezafibrate 4 |
| Use of statins (cases) | None 78 Using statins 32 |
| LDL-C (mg/dL) | 120.5±30.6 |
| HDL-C (mg/dL) | 48.8±14.4 |
| TG (non-fasting, mg/dL) | 378.6±248.7 |
| AST (U/L) | 31.7±19.1 |
| ALT (U/L) | 38.0±32.7 |
| CK (U/L) | 141.4±122.2 |
| Creatinine (mg/dL) | 0.76±0.18 |
| Postprandial glucose (mg/dL) | 117.7±37.7 |
| HbA1c (%) | 6.2±0.9 |
| Body weight (kg) | 70.9±17.8 |
Note: Data are expressed as mean ± standard deviation (SD).
Abbreviations: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; AST, aspartate transaminase; ALT, alanine transaminase; CK, creatinine kinase; HbA1c, hemoglobin A1c (NGSP).
Baseline laboratory values were as follows: TG, 378.6 ± 248.7 mg/dL; LDL-C, 120.5 ± 30.6 mg/dL; HDL-C, 48.8 ± 14.4 mg/dL; HbA1c, 6.2% ± 0.9%; and postprandial blood glucose (PBG), 117.7 ± 37.7 mg/dL. Baseline creatinine was 0.76 ± 0.18 mg/dL; CK, 141.4 ± 122.2 IU/L; AST, 31.7 ± 19.1 IU/L; and ALT, 38.0 ± 32.7 IU/L.
Changes in Lipid Parameters Over One year
The changes in all parameters are summarized in Table 2.
Table 2.
Changes of Each Parameter from Baseline to 1 Year
| A. Changes in Lipid and Liver Function Parameters from Baseline to 1 Year | |||||
| Baseline | Month 1 | Month 3 | Month 6 | Month 12 | |
| LDL-C (mg/dL) | n=110 | n=39 | n=70 | n=102 | n=110 |
| mean±SD(p value) | 120.5±30.6 | 122.7±31.2 (p=0.8213) | 129.7±34.3 (p=0.0237) | 125.7±31.6 (p=0.1231) | 120.6±28.3 (p=0.6760) |
| change±SD | -3.1±41.5 | 9.6±33.6 | 4.8±34.3 | 0.1±32.0 | |
| HDL-C (mg/dL) | n=110 | n=39 | n=70 | n=103 | n=110 |
| mean±SD(p value) | 48.8±14.4 | 52.8±14.3 (p<0.0001) | 53.2±13.5 (p<0.0001) | 55.8±16.2 (p<0.0001) | 56.0±16.9 (p<0.0001) |
| change±SD | 4.0±5.3 | 6.2±9.1 | 7.4±9.0 | 7.2±11.1 | |
| TG(non-fasting,mg/dL) | n=110 | n=39 | n=73 | n=102 | n=110 |
| mean±SD(p value) | 378.6±248.7 | 242.4±160.3(p<0.0001) | 216.5±138.1 (p<0.0001) | 211.7±146.3(p<0.0001) | 191.5±144.4 (p<0.0001) |
| change±SD | -158.4±258.4 | -159.0±253.0 | -164.9±216.0 | -187.1±250.8 | |
| AST (U/L) | n=110 | n=27 | n=96 | n=105 | n=110 |
| mean±SD(p value) | 31.7±19.1 | 36.3±18.7 (p=0.5973) | 28.4±10.5 (p=0.1438) | 29.2±14.1 (p=0.3394) | 27.8±12.8(p=0.0603) |
| Change±SD | -1.8±15.2 | -3.5±15.0 | -2.5±17.4 | -4.0±17.0 | |
| ALT (U/L) | n=110 | n=27 | n=96 | n=105 | n=110 |
| mean±SD(p value) | 38.0±32.7 | 41.0±27.0 (p=0.2663) | 31.2±21.1 (p=0.0011) | 29.9±19.7 (p=0.008) | 28.6±20.1(p<0.0001) |
| Change±SD | -7.4±29.7 | -6.6±18.3 | -7.7±25.9 | -9.4±26.3 | |
| B. Changes in Renal Function, Glycemic Parameters, and Body Weight from Baseline to 1 Year | |||||
| Baseline | Month 1 | Month 3 | Month 6 | Month 12 | |
| CK (U/L) | n=57 | n=18 | n=43 | n=52 | n=55 |
| mean±SD(p value) | 141.4±122.2 | 125.0±83.5 (p=0.7483) | 117.8±77.3 (p=0.3911) | 123.0±77.1 (p=0.7047) | 117.8±67.6(p=0.3796) |
| Change±SD | -18.9±88.5 | -18.8±82.4 | -16.2±105.4 | -20.5±94.2 | |
| Creatinine (mg/dL) | n=107 | n=17 | n=91 | n=105 | n=110 |
| mean±SD(p value) | 0.76±0.18 | 0.82±0.18 (p=0.4913) | 0.75±0.18 (p=0.6258) | 0.72±0.18 (p=0.0181) | 0.74±0.20(p=0.2795) |
| Change±SD | -0.02±0.12 | -0.01±0.13 | -0.03±0.14 | -0.02±0.15 | |
| postprandial glucose(mg/dL) | n=99 | n=29 | n=79 | n=93 | n=97 |
| mean±SD(p value) | 117.7±37.7 | 136.1±50.0 (p=0.5903) | 121.2±37.4 (p=0.7020) | 119.2±40.2 (p=0.8757) | 122.5±40.4(p=0.2050) |
| Change±SD | 8.3±43.8 | 1.4±32.9 | 1.2±40.6 | 4.2±38.9 | |
| HbA1c (%) | n=108 | n=33 | n=63 | n=91 | n=108 |
| mean±SD(p value) | 6.2±0.9 | 6.6±0.7 (p=0.9853) | 6.5±0.8 (p=0.2164) | 6.3±0.8 (p=0.0167) | 6.2±0.7(p=0.0321) |
| Change±SD | 0.01±0.2 | 0.02±0.7 | 0.06±0.58 | 0.04±0.50 | |
| body weight (kg) | n=105 | n=27 | n=57 | n=78 | n=104 |
| mean±SD(p value) | 70.9±17.8 | 79.2±13.9 (p=0.4663) | 76.8±18.5 (p=0.3547) | 74.2±18.3 (p=0.1511) | 71.1±17.5(p=0.3994) |
| Change±SD | 0.03±1.0 | 0.14±1.9 | 0.22±1.9 | -0.27±2.5 | |
Notes: Data are expressed as the mean ± standard deviation (SD), and P-values were calculated using the paired t-test
Abbreviations: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride; AST, aspartate transaminase; ALT, alanine transaminase; CK, creatinine kinase; HbA1c, hemoglobin A1c (NGSP). P-values were calculated using Student’s t-test.
Triglycerides (TG)
TG levels decreased significantly and consistently throughout the study period:
1 month: 242.4 ± 160.3 mg/dL (P < 0.0001***)
3 months: 216.5 ± 138.1 mg/dL (P < 0.0001***)
6 months: 211.7 ± 146.3 mg/dL (P < 0.0001***)
1 year: 191.5 ± 144.4 mg/dL (P < 0.0001***)
HDL-C
HDL-C levels significantly increased from the baseline steadily:
1 month: 52.8 ± 14.3 mg/dL (P < 0.0001***)
3 months: 53.2 ± 13.5 mg/dL (P < 0.0001***)
6 months: 55.8 ± 16.2 mg/dL (P < 0.0001***)
1 year: 56.0 ± 16.9 mg/dL (P < 0.0001***)
LDL-C (Rise-and-Return Pattern)
LDL-C demonstrated a distinct transient elevation:
1 month: 122.7 ± 31.2 mg/dL
3 months(peak): 129.7 ± 34.3 mg/dL (P < 0.05*)
6 months: 125.7 ± 31.6 mg/dL
1 year: 120.6 ± 28.3 mg/dL (return to baseline)
Figure 1 illustrates this trajectory. LDL-C increased from month 1, peaked at 3 months, and then gradually declined to baseline by 1 year. The LDL-C change rate showed the same pattern, with a peak of 11.7% ± 31.6% at 3 months, confirming the transient nature of the elevation.
Figure 1.
(a) Mean LDL-C trajectory (b) Change rate of LDL-C (c) Mean TG changes (d) Mean HDL-C changes in 110 patients, observed for 12 months. P-values were calculated using the paired t-test. * p < 0.05, *** p < 0.001.
Identifying Contributors to LDL-C Elevation
We attempted to identify the most significant factors contributing to LDL-C elevations at 3 months. The LDL-C changes with different parameters are presented in Table 3. Statin use, which is the most likely contributing factor, was neither related nor statistically significant (P = 0.225). The prescribed pemafibrate dose (new or switched) was also not related. In addition, alcohol habits did not exhibit a significant correlation, but smoking habits did (P < 0.05*). Sex and diabetes complications were also not statistically significant. Regression analysis (Table 4) revealed six statistically significant factors associated with to LDL-C elevation.
Table 3.
LDL-C Changes at 3 Months with Different Backgrounds
| Backgrounds | LDL-C Change(mg/dL), (n, p value) |
LDL-C Change(mg/dL), (n, p value) |
P value (Between Groups) |
||
|---|---|---|---|---|---|
| Statins | With statin | 2.7 (23, p=0.6370) | Non-statin | 13.0 (47, p=0.0151) | 0.2251 |
| Dose of pemafibrate | 0.2 mg/day | –0.5 (26, p=0.9508) | 0.1 mg/day | 15.6 (44, p=0.0026) | 0.1154 |
| Prescription | First time | 10.0 (55, p=0.0592) | Switched | 8.4 (18, p=0.1722) | 0.8300 |
| Alcohol habits | Drinker | 20.0 (23, p=0.0074) | Non-drinker | 4.5 (47, p=0.3600) | 0.0950 |
| Smoking habits | Smoker | 34.4 (11, p=0.0098) | Non-smoker | 5.0 (59, p=0.2302) | 0.0158 |
| Gender | Male | 15.2 (41, p=0.0048) | Female | 1.8 (29, p=0.7438) | 0.1817 |
| Diabetes | Diabetic | 8.5 (36, p=0.3101) | Non-diabetic | 10.8 (34, p=0.0244) | 0.4843 |
Notes: The change rate at 3 months of each background is shown. P-values were calculated using Student’s t-test.
Table 4.
LDL-C Changes and Correlation with Baseline at 3 Months
| Factor | Baseline | Amount of Change | ||
|---|---|---|---|---|
| Correlation Coefficient (r) | P value | Correlation Coefficient (r) | P value | |
| TG | 0.4408 | 0.0001 | –0.3931 | 0.0008 |
| LDL-C | –0.4482 | <0.0001 | ― | |
| HDL-C | –0.4707 | <0.0001 | 0.2496 | 0.0450 |
| Cr | –0.0620 | 0.6152 | –0.0148 | 0.9030 |
| CK | –0.1100 | 0.4881 | –0.0503 | 0.7739 |
| AST | –0.0082 | 0.9460 | –0.0763 | 0.5300 |
| ALT | –0.0290 | 0.8118 | 0.0430 | 0.7239 |
| Body weight | 0.0904 | 0.4704 | 0.0263 | 0.8532 |
| Postprandial glucose | 0.2055 | 0.1090 | –0.1262 | 0.2978 |
| HbA1c | 0.2084 | 0.0881 | –0.0448 | 0.7271 |
| Age | –0.2708 | 0.0234 | ― | |
Note: Univariate regression was conducted.
Abbreviations: TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; Cr, creatinine; CK, creatinine kinase; AST, aspartate transaminase; ALT, alanine transaminase; HbA1c, hemoglobin A1c (NGSP).
1. The higher the baseline TG levels before administration, the higher the LDL-C levels afterward (correlation coefficient r = 0.4408, P= 0.0001***).
2. The lower the baseline LDL-C levels before administration, the higher the LDL-C levels afterward (correlation coefficient r = −0.4482, P<0.0001***).
3. The lower the baseline HDL-C levels before administration, the higher the LDL-C levels afterward (correlation coefficient r = −0.4707, P < 0.0001***).
4. The younger the age, the higher the LDL-C levels afterward (correlation coefficient r = −0.2708, P < 0.05*).
5. The larger the decrease in TG changes, the higher the LDL-C levels afterward (correlation coefficient r = −0.3931, P < 0.001***).
6. The larger the elevation in the HDL-C changes, the higher the LDL-C levels afterward (correlation coefficient r=0.2496, P < 0.05*).
We conducted a multivariate regression analysis (Table 5). The most significant factor associated with LDL-C elevation was a low baseline LDL-C level (standardized coefficient r = −0.2622, P < 0.05*). This was followed by a low baseline HDL-C level (standardized coefficient r = −0.3210, P < 0.01**) and high baseline TG level (standardized coefficient r=0.2262, P < 0.05*). Age and smoking habits did not exhibit statistically significant associations.
Table 5.
Key factors influencing 3-month LDL-C changes
| standardized coefficient | P value | |
|---|---|---|
| baseline LDL-C | -0.2622 | 0.0121 |
| baseline HDL-C | -0.3210 | 0.0019 |
| baseline TG | 0.2262 | 0.0426 |
| age | -0.1361 | 0.1668 |
| smoking habits | 0.0782 | 0.4639 |
Notes: Multivariate regression was conducted.
Abbreviations: LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglyceride.
Discussion
The LDL-C levels initially increased after pemafibrate treatment. In some cases, the serum LDL-C level increased to about 20 mg/dL, which requires further evaluation in future studies. However, the level was within the expected increase range because of the VLDL catabolic pathway. This attributed to the fact that the conversion of VLDL to VLDL remnants is enhanced by LPL activation, leading to increased transformation of VLDL remnants to LDL by hepatic lipase. In our study, the factors statistically significant for LDL-C elevation were high TG, low HDL-C, and low LDL-C levels at the baseline. Patients with lower baseline LDL‑C may have a higher proportion of small, TG‑rich LDL particles or relatively preserved LDL receptor activity. Pemafibrate enhances LPL‑mediated lipolysis and alters LDL particle composition, which can transiently increase the cholesterol content within LDL particles without increasing ApoB. This may explain why patients with low baseline LDL‑C exhibited a greater rise in LDL‑C at 3 months. When administering pemafibrate, which effectively stimulates LPL activity, the catabolic pathway is upregulated, resulting in increased accumulation of downstream LDL-C. This process is estimated to occur between 3 and 6 months, depending on the change rate of LDL-C, as shown in Figure 1. After the peak, the levels gradually reach equilibrium. The PROMINENT Study monitored LDL-C at 4 months to observe the best peak in LDL-C levels after pemafibrate administration. While pemafibrate may appear to worsen LDL-C levels, criticizing LDL-C elevation as a hasty conclusion is warranted.
The subsequent decline and normalization of LDL‑C by 12 months likely reflect improvements in hepatic metabolic function during long‑term pemafibrate therapy. Several mechanisms may explain why LDL-C levels subsequently declined and returned to baseline after the initial 3-month rise. First, pemafibrate has been shown to improve hepatic insulin sensitivity and glucose uptake, as demonstrated in an insulin-clamp study. Improved hepatic insulin action reduces VLDL overproduction and enhances lipid handling, which may gradually attenuate the transient LDL-C increase observed during the early phase of treatment.15 Second, pemafibrate has been reported to ameliorate hepatic inflammation and stiffness in patients with metabolic dysfunction-associated steatotic liver disease. Improvement in hepatic metabolic function and reduced inflammatory stress may enhance LDL receptor activity and remnant clearance, contributing to the normalization of LDL-C levels over time.16 Third, studies combining pemafibrate with dietary interventions have suggested potential improvements in hepatic steatosis and overall lipid metabolism. These hepatic benefits collectively support the interpretation that the LDL-C rise represents a temporary metabolic shift rather than a persistent adverse effect.17
Considering the aforementioned metabolic process, enhanced β-oxidation of fatty acids in the liver via PPARα activation causes downregulation of hepatic TG synthesis. Therefore, the synthesis and secretion of large VLDL particles are reduced, with consequent decreases in sdLDL particles and formation of cholesterol-rich large LDL. In turn, the enhanced hepatic clearance of chylomicron remnants by pemafibrate promotes hepatic influx of cholesterol, increasing the hepatic cholesterol content, which may lead to the downregulation of hepatic LDL receptors. Thus, the quality of the elevated LDL-C is expected to be fair. Many studies reported that pemafibrate may reduce sdLDL-C levels, improving the LDL-C quality. In their study of 98 patients of whom 34% were statins users, almost the same size and backgrounds as our study, Hida et al reported that the level of sdLDL-C significantly decreased from 111 to 104 mg/dL at three months18 but the LDL-C level did not increase Komiya et al reported similar findings to ours, demonstrating that pemafibrate decreased TGs and sdLDL but increased LDL-C levels depending on baseline TGs and LDL-C levels19 Their study focused on patients with type 2 diabetes who were likely to have low LPL activity. In their 24-weeks observational study, the LDL-C levels increased in 69% of the patients, with an average change rate was 5.3%. Based on the findings from these two studies, the timing and the peak of LDL-C elevation are estimated to occur between 3 and 6 months after administration. Our 1-year study further supports this explanation.
In a prospective randomized comparative study of the effect of adding pemafibrate or doubling statin dose to decrease sdLDL-C in patients with type 2 diabetes,20 Hirano et al reported that such an addition exerted superior effects The evaluation period of the study was 12 weeks, and LDL-C did not significantly increase (107 ± 21 to 108 ± 25 mg/dL). However, sdLDL decreased by about −32.8%, which was statistically significant (P < 0.01). The findings indicate that pemafibrate increases LDL-C after 3 to 6 months and simultaneously reduces sdLDL.
Previous studies reported that pemafibrate reduces sdLDL and TG, but the observation point is 3 or 6 months at the most. To the best of our knowledge, no other study has followed up their patients for 1 year like ours, and our study is the first to demonstrate long-term LDL-C changes.
Limitations
This study has several limitations. First, it was a single‑center observational study with a relatively small sample size, which may limit generalizability. Second, although we discussed potential mechanisms such as hepatic insulin sensitivity and LDL receptor activity, these pathways were not directly evaluated in this study and should be interpreted cautiously. Third, although no structured diet or exercise interventions were implemented during the study period, unmeasured lifestyle factors may still have influenced lipid parameters to some extent.
Conclusion
In this one‑year observational study, we demonstrated that pemafibrate induces a distinct and transient “rise and return” pattern in LDL‑C levels—an early increase peaking at approximately 3 months, followed by a spontaneous return to baseline by one year. Patients with low baseline LDL‑C were most susceptible to this temporary rise, yet the overall lipid profile improved through sustained reductions in triglycerides and increases in HDL‑C, supporting the metabolic rather than adverse nature of this phenomenon. To our knowledge, this is the first study to characterize the full one‑year LDL‑C trajectory under pemafibrate, providing clinically relevant insight into how LDL‑C should be interpreted during treatment.
This study was conducted in a real‑world single‑center setting and includes inherent limitations such as heterogeneous patient backgrounds, multiple comorbidities, and concomitant medications. Some laboratory parameters could not be collected due to the retrospective design and insurance constraints. Despite these limitations, our findings offer important guidance for clinicians: transient LDL‑C elevation should not be misinterpreted as a harmful effect, and careful evaluation of baseline lipid profiles may help anticipate this short‑term response. Future prospective studies with broader datasets are warranted to validate and expand upon these observations.
In addition to the transient rise and subsequent normalization of LDL‑C, triglycerides and HDL‑C showed sustained improvement throughout the 12‑month period, supporting the overall metabolic benefit of long‑term pemafibrate therapy.
Acknowledgments
The authors are grateful to the study participants, and also would like to thank Enago (www.enago.jp) for the manuscript review and editing support.
Funding Statement
This research received no external funding.
Data Sharing Statement
All datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.
Ethics Approval and Informed Consent
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Ethics Committee of the Japan Physicians Association, Tokyo, Japan approved the study on August 7, 2019 (Approved ID: 022-1906-001). Due to the retrospective nature of this study, participants’ informed consent was waived. However, information about this study was provided to guarantee the right to opt out.
Consent for Publication
All clinical data included in this study were anonymized and do not contain any information that could identify individual participants. Therefore, consent for publication was not required.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Disclosure
The authors report no conflicts of interest in this work.
References
- 1.Yamashita S, Masuda D, Matsuzawa Y. Pemafibrate, a new selective PPARα modulator: drug concept and its clinical applications for dyslipidemia and metabolic diseases. Curr Atheroscler Rep. 2020;22:5. doi: 10.1007/s11883-020-0823-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Yamashita S, Masuda D, Matsuzawa Y. Clinical applications of a novel selective PPARα modulator, pemafibrate, in dyslipidemia and metabolic diseases. J Atheroscler Thromb. 2019;26:389–11. doi: 10.5551/jat.48918 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Araki E, Yamashita S, Arai H, et al. Effects of pemafibrate, a novel selective PPARα modulator, on lipid and glucose metabolism in patients with type 2 diabetes and hypertriglyceridemia: a randomized, double-blind, placebo-controlled, Phase 3 trial. Diab Care. 2018;41:538–546. doi: 10.2337/dc17-1589 [DOI] [PubMed] [Google Scholar]
- 4.Iitake C, Masuda D, Koseki M, Yamashita S. Marked effects of novel selective peroxisome proliferator-activated receptor α modulator, pemafibrate in severe hypertriglyceridemia: preliminary report [preliminary report]. Cardiovasc Diabetol. 2020;19:201. doi: 10.1186/s12933-020-01172-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Das Pradhan A, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med. 2022;387:1923–1934. doi: 10.1056/NEJMoa2210645 [DOI] [PubMed] [Google Scholar]
- 6.Iitake C, Iitake K. Half dose once-daily pemafibrate effectively improved hypertriglyceridemia in real practice. Clin Med Res. 2019;11:690–695. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Tada H, Nohara A, Inazu A, Mabuchi H, Kawashiri MA. Remnant lipoproteins and atherosclerotic cardiovascular disease. Clin Chim Acta. 2019;490:1–5. doi: 10.1016/j.cca.2018.12.014 [DOI] [PubMed] [Google Scholar]
- 8.Aguib Y, Al Suwaidi JA. The Copenhagen city heart study (Østerbroundersøgelsen). Glob Cardiol Sci Pract. 2015;2015:33. doi: 10.5339/gcsp.2015.33 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Iso H, Imano H, Yamagishi K, et al. Fasting and non-fasting triglycerides and risk of ischemic cardiovascular disease in Japanese men and women: the circulatory risk in communities study (CIRCS). Atherosclerosis. 2014;237:361–368. doi: 10.1016/j.atherosclerosis.2014.08.028 [DOI] [PubMed] [Google Scholar]
- 10.Tada H, Nomura A, Yoshimura K, et al. Fasting and non-fasting triglycerides and risk of cardiovascular events in diabetic patients under statin therapy. Circ J. 2020;84:509–515. doi: 10.1253/circj.CJ-19-0981 [DOI] [PubMed] [Google Scholar]
- 11.Mora S, Chang CL, Moorthy MV, Sever PS. Association of nonfasting vs fasting lipid levels with risk of major coronary events in the Anglo-Scandinavian cardiac outcomes trial–lipid lowering arm. JAMA Intern Med. 2019;179:898–905. doi: 10.1001/jamainternmed.2019.0392 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Nakamura K, Miyoshi T, Yunoki K, Ito H. Postprandial hyperlipidemia as a potential residual risk factor. J Cardiol. 2016;67:335–339. doi: 10.1016/j.jjcc.2015.12.001 [DOI] [PubMed] [Google Scholar]
- 13.Tanaka A, Tomie N, Nakano T, et al. Measurement of postprandial remnant-like particles (RLPs) following a fat-loading test. Clin Chim Acta. 1998;275:43–52. doi: 10.1016/S0009-8981(98)00073-4 [DOI] [PubMed] [Google Scholar]
- 14.Ooi TC, Cousins M, Ooi DS, et al. Postprandial remnant-like lipoproteins in hypertriglyceridemia. J Clin Endocrinol Metab. 2001;86:3134–3142. doi: 10.1210/jcem.86.7.7627 [DOI] [PubMed] [Google Scholar]
- 15.Matsuba I, Saito Y, Yamashita S, et al. Effect of pemafibrate on hepatic insulin sensitivity and glucose uptake assessed by hyperinsulinemic–euglycemic clamp in patients with dyslipidemia. J Atheroscler Thromb. 2020;27:134–145. doi: 10.5551/jat.49767 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Shinozaki S, Tahara T, Kawashima H, et al. Pemafibrate improves hepatic inflammation and stiffness in patients with metabolic dysfunction-associated steatotic liver disease. Hepatol Res. 2023;53:123–132. [Google Scholar]
- 17.Yamamoto K, Fujii H, Yoneda M, et al. Combined effects of pemafibrate and dietary intervention on hepatic steatosis and lipid metabolism in patients with hypertriglyceridemia. Nutr Metab Cardiovasc Dis. 2022;32:987–995. [Google Scholar]
- 18.Hida Y, Imamura T, Kinugawa K. Impact of pemafibrate therapy on reducing small dense low-density-lipoprotein-cholesterol levels in patients with hypertriglyceridemia. J Clin Med. 2023;12:6915. doi: 10.3390/jcm12216915 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Komiya I, Yamamoto A, Sunakawa S, Wakugami T. Pemafibrate decreases triglycerides and small, dense LDL, but increases LDL-C depending on baseline triglycerides and LDL-C in type 2 diabetes patients with hypertriglyceridemia: an observational study. Lipids Health Dis. 2021;20:17. doi: 10.1186/s12944-021-01434-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Hirano T, Hayashi T, Sugita H, et al. Prospective randomized comparative study of the effect of pemafibrate add-on or double statin dose on small dense low-density lipoprotein-cholesterol in patients with type 2 diabetes and hypertriglyceridemia on statin therapy. J Diab Investig. 2023;14:1401–1411. doi: 10.1111/jdi.14076 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.