Pemafibrate for hypertriglyceridemia: a meta-analysis of randomized controlled trials evaluating efficacy and safety outcomes

Clinical trials have demonstrated significant triglyceride-lowering effects of pemafibrate across different dosing regimens.

“Clinical trials have evaluated pemafibrate in diverse patient populations with dyslipidemia, demonstrating significant TG-lowering effects across different dosing regimens [5–7].”

• cites [5] Khan MS, Ghumman GM, Baqi A, Shah J, Aziz M, Mir T, et al. Efficacy of pemafibrate versus fenofibrate administration on serum lipid levels in patients with dyslipidemia: network meta-analysis and systematic review. Am J Cardiovasc Drugs. 2023;23:547–58. https://doi.org/10.1007/S40256-023-00593-6 sourceNot checked — no full text of the source
• cites [6] Wang H, Li H, Zhou Y, Liu J, Wang F, Zhao Q. Pemafibrate tends to have better efficacy in treating dyslipidemia than fenofibrate. Curr Pharm Des. 2019;25:4725–34. https://doi.org/10.2174/1381612825666191126102943. sourceNot checked — no full text of the source
• cites [7] Ida S, Kaneko R, Murata K. Efficacy and safety of pemafibrate administration in patients with dyslipidemia: a systematic review and meta-analysis. Cardiovasc Diabetol. 2019. https://doi.org/10.1186/s12933-019-0845-x. sourceSupported

Evidence comparing 0.2 mg versus 0.4 mg pemafibrate dosing has produced conflicting results.

“Furthermore, evidence comparing 0.2 mg versus 0.4 mg dosing has produced conflicting results, leaving clinicians uncertain about optimal dose selection.”

• cites [7] Ida S, Kaneko R, Murata K. Efficacy and safety of pemafibrate administration in patients with dyslipidemia: a systematic review and meta-analysis. Cardiovasc Diabetol. 2019. https://doi.org/10.1186/s12933-019-0845-x. sourceCould not verify

  The Discussion mentions 0.2 and 0.4 mg/day as the highest doses and suggests a dose-dependent ALT effect. The Results compare pemafibrate with placebo or fenofibrate, but the passages found do not report conflicting results from a comparison of 0.2 mg versus 0.4 mg or uncertainty about which dose to select (searched: dose comparison and dose-dependent effects). (LLM, conf=0.73)

  Experimental — accuracy not yet measured

Previous meta-analyses reported high heterogeneity (I2 = 86%) when assessing the 0.2 mg dose.

“Previous meta-analyses reported high heterogeneity (I2 = 86%) when assessing the 0.2 mg dose, raising uncertainty about the consistency of its efficacy.”

• cites [7] Ida S, Kaneko R, Murata K. Efficacy and safety of pemafibrate administration in patients with dyslipidemia: a systematic review and meta-analysis. Cardiovasc Diabetol. 2019. https://doi.org/10.1186/s12933-019-0845-x. sourcePartly supported

  The Results > Efficacy section reports high heterogeneity (I² = 78%) for the pooled triglyceride analysis across pemafibrate doses. Our copy does not report I² = 86% for the 0.2 mg dose, so the dose-specific figure is unsupported. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Data from Arai 2017, Araki 2018, Araki 2019, Dai 2025, Das 2022, Ginsberg 2022, and Matsuba 2018 showed no significant difference in total adverse events between pemafibrate and placebo, with a risk ratio of 1.02 (95% CI: 0.98, 1.07, p = 0.30) and I2 = 0%.

“Data from Arai 2017, Araki 2018, Araki 2019, Dai 2025, Das 2022, Ginsberg 2022, and Matsuba 2018 showed an RR of 1.02 (95% CI: 0.98, 1.07, p = 0.30), suggesting no significant difference in total adverse events between pemafibrate and placebo (I2 = 0%) (high certainty).”

• Also stated in: § Adverse events compared with placebo · hedged

  “Data from Arai 2017, Araki 2018, Araki 2019, Dai 2025, Das 2022, Ginsberg 2022, and Matsuba 2018 showed an RR of 1.02 (95% CI: 0.98, 1.07, p = 0.30), suggesting no significant difference in total adverse events between pemafibrate and placebo (I2 = 0%) (high certainty).”

• cites Arai 2017 sourceSupported
• cites Araki 2018Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Araki 2019Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• AssumptionRests on an assumption: Adverse event definitions and reporting are consistent across the included trials.

In head-to-head clinical trials, pemafibrate showed similar or slightly greater reductions in triglyceride levels compared to fenofibrate in some comparisons.

“and showed similar or slightly greater reductions in some comparisons”

• cites [23] Ishibashi S, Arai H, Yokote K, Araki E, Suganami H, Yamashita S, K-877 Study Group. Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia: results from a 24-week, randomized, double blind, active-controlled, phase 3 trial. J Clin Lipidol. 2018;12(1):173–84. sourceSupported
• cites [24] Arai H, Yamashita S, Yokote K, Araki E, Suganami H, Ishibashi S, K-877 Study Group. Efficacy and safety of pemafibrate versus fenofibrate in patients with high triglyceride and low HDL cholesterol levels: a multicenter, placebo-controlled, double-blind, randomized trial. J Atheroscler Thromb. 2018;25(6):521–38. sourceSupported

Meta-analytic evidence suggests that pemafibrate's lipid-modifying effects, including reductions in triglycerides and modest improvements in HDL-C, are broadly comparable to those seen with conventional fibrates.

“Meta-analytic evidence also suggests that pemafibrate’s lipid-modifying effects, including reductions in triglycerides and modest improvements in HDL-C, are broadly comparable to those seen with conventional fibrates, although the certainty of evidence varies and long-term clinical implications remain uncertain [25, 26].”

• cites [25] Olmastroni E, Galimberti F, Xie S, Casula M, Catapano AL. Effects of fibrates on lipid profile: a meta-analysis of randomized controlled trials: effects of fibrates on lipid profile. European Atherosclerosis Journal. 2025;4(1):6–16. sourcePartly supported

  The Abstract (page unavailable) reports that all fibrates, including pemafibrate, significantly reduced triglycerides compared with placebo. It does not report HDL-C effects or establish that pemafibrate is broadly comparable to conventional fibrates; instead, it says fibrates differ substantially in their lipid effects. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [26] Ida S, Kaneko R, Murata K. Efficacy and safety of pemafibrate administration in patients with dyslipidemia: a systematic review and meta-analysis. Cardiovasc Diabetol. 2019;18(1):38. https://doi.org/10.1186/s12933-019-0845-x. sourceSupported

Available cardiovascular outcome trials, including PROMINENT, have not demonstrated a reduction in cardiovascular events corresponding to pemafibrate's triglyceride-lowering effect.

“While pemafibrate consistently reduces triglyceride levels, it is important to note that available cardiovascular outcome trials, including PROMINENT [16], have not demonstrated a corresponding reduction in cardiovascular events.”

• cites [16] Das Pradhan A, Glynn RJ, Fruchart JC, MacFadyen JG, Zaharris ES, Everett BM, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. N Engl J Med. 2022;24(21):1923–34. https://doi.org/10.1056/NEJMoa2210645. sourceSupported

In head-to-head clinical trials, pemafibrate reduced triglyceride levels relative to fenofibrate.

“In head-to-head clinical trials, pemafibrate was observed to reduce triglyceride levels relative to fenofibrate”

• cites [23] Ishibashi S, Arai H, Yokote K, Araki E, Suganami H, Yamashita S, K-877 Study Group. Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia: results from a 24-week, randomized, double blind, active-controlled, phase 3 trial. J Clin Lipidol. 2018;12(1):173–84. sourceSupported
• cites [24] Arai H, Yamashita S, Yokote K, Araki E, Suganami H, Ishibashi S, K-877 Study Group. Efficacy and safety of pemafibrate versus fenofibrate in patients with high triglyceride and low HDL cholesterol levels: a multicenter, placebo-controlled, double-blind, randomized trial. J Atheroscler Thromb. 2018;25(6):521–38. sourcePartly supported

  The Results > Efficacy passage reports that all tested pemafibrate doses reduced triglycerides more than fenofibrate 100 mg/day. It found pemafibrate 0.2 and 0.4 mg/day non-inferior, but not superior, to fenofibrate 200 mg/day, so the unqualified comparison overstates the result. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

In head-to-head clinical trials, pemafibrate had a generally lower incidence of hepatic and renal adverse events compared to fenofibrate.

“with a generally lower incidence of hepatic and renal adverse events reported in these studies [23, 24]”

• cites [23] Ishibashi S, Arai H, Yokote K, Araki E, Suganami H, Yamashita S, K-877 Study Group. Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia: results from a 24-week, randomized, double blind, active-controlled, phase 3 trial. J Clin Lipidol. 2018;12(1):173–84. sourceSupported
• cites [24] Arai H, Yamashita S, Yokote K, Araki E, Suganami H, Ishibashi S, K-877 Study Group. Efficacy and safety of pemafibrate versus fenofibrate in patients with high triglyceride and low HDL cholesterol levels: a multicenter, placebo-controlled, double-blind, randomized trial. J Atheroscler Thromb. 2018;25(6):521–38. sourceSupported

In patients not receiving statins, pemafibrate reduces triglyceride levels compared with placebo (SMD −1.31; 95% CI −1.62 to −1.00).

“In patients not receiving statins, pemafibrate significantly reduced TG levels compared to placebo, with a standardized mean difference of −1.31 (95% CI: −1.62, −1.00, p = 0.00001), corresponding to a mean difference of approximately −130.1 mg/dL (95% CI: −160.8, −99.3).”

There is no clinically meaningful difference between 0.2 mg and 0.4 mg pemafibrate doses.

“No clinically meaningful difference was observed between 0.2 and 0.4 mg doses (high-certainty evidence).”

In patients receiving statins, the heterogeneity for the TG effect of pemafibrate versus placebo was low (I2 = 0%).

“The heterogeneity was low (I2 = 0%) (High certainty).”

Pemafibrate 0.2 mg produces a statistically significant greater reduction in triglyceride levels than 0.4 mg (mean difference −8.43 mg/dL; 95% CI −14.40 to −2.45; p = 0.006).

“A comparison between pemafibrate 0.2 mg and 0.4 mg showed a statistically significant reduction in TG levels with the lower dose. The mean difference was −8.43 mg/dL (95% CI: −14.40, −2.45, p = 0.006), indicating a greater reduction in TG levels at the lower dose (high certainty).”

In the combined statin and non-statin analysis, heterogeneity for the TG effect was moderate (I2 = 65%).

“Moderate heterogeneity was observed (I2 = 65%) (Moderate certainty).”

Results for patients not receiving statins were consistent across studies, with minimal heterogeneity (I2 = 0%).

“Results were consistent across studies, with minimal heterogeneity (I2 = 0%) (high certainty).”

No significant publication bias was detected in the included randomized controlled trials.

“No significant publication bias was detected in the included RCTs.”

Pemafibrate reduces triglyceride levels compared with placebo (overall pooled SMD −0.87; 95% CI −1.07 to −0.67).

“Pemafibrate was associated with reductions in triglyceride (TG) levels compared with placebo (SMD −0.87; 95% CI −1.07 to −0.67; p = 0.00001), supported by moderate-certainty evidence.”

Pemafibrate did not significantly increase musculoskeletal adverse events compared to placebo, with a risk ratio of 0.95 (95% CI: 0.90, 1.01, p = 0.09).

“Pemafibrate did not significantly increase musculoskeletal adverse events, with an RR of 0.95 (95% CI: 0.90, 1.01, p = 0.09) (moderate certainty).”

Renal adverse events reported in included studies were generally not detailed as to whether they were laboratory changes, transient abnormalities, or clinically significant kidney injury.

“For renal outcomes, the included studies generally reported “renal adverse events,” but the specific nature of these events—whether laboratory changes, transient abnormalities, or clinically significant kidney injury—was often not detailed.”

In patients receiving statins, pemafibrate reduces triglyceride levels compared with placebo (SMD −0.70; 95% CI −0.74 to −0.66).

“those receiving statins (SMD −0.70; 95% CI −0.74 to −0.66), both high-certainty evidence.”

Pemafibrate was associated with a slight but significant increase in renal adverse events compared to placebo, with a risk ratio of 1.09 (95% CI: 1.02, 1.16, p = 0.008).

“Pemafibrate was associated with a slight but significant increase in renal adverse events, with a risk ratio (RR) of 1.09 (95% CI: 1.02, 1.16, p = 0.008) (moderate certainty).”

Dose-response relationships were inconsistent.

“Dose–response relationships were inconsistent and based on a few trials, and should be viewed as exploratory rather than definitive.”

The direction of effect was generally consistent across studies.

“While the direction of effect was generally consistent”

A test for subgroup differences showed moderate heterogeneity (I2 = 71.1%, p = 0.06).

“A test for subgroup differences showed moderate heterogeneity (I2 = 71.1%, p = 0.06), suggesting some variation between dose-dependent adverse effects and those observed in placebo-controlled studies.”

Most included studies reported renal and hepatic adverse events as cumulative incidences rather than time-to-event outcomes.

“Most included studies reported renal and hepatic adverse events as cumulative incidences rather than time-to-event outcomes”

Most included studies were conducted in Japanese populations.

“Most included studies were conducted in Japanese populations, which may limit generalizability to other ethnic groups.”

Musculoskeletal and hepatic adverse events did not appear to differ from placebo (moderate-certainty evidence).

“musculoskeletal and hepatic adverse events did not appear to differ from placebo (moderate-certainty evidence)”

• Also stated in: § Discussions · hedged

  “musculoskeletal and hepatic adverse events did not appear to differ meaningfully from placebo”

The overall pooled effect showed moderate heterogeneity.

“which showed moderate heterogeneity”

• Also stated in: § Discussions · plain

  “moderate heterogeneity was observed for some outcomes”

Pemafibrate may modestly reduce triglyceride levels.

“Evidence from our meta-analysis suggests that pemafibrate may modestly reduce triglyceride levels, with high-certainty evidence in some subgroups and moderate-certainty evidence overall, though moderate heterogeneity exists.”

Hepatic safety outcomes were reported in a limited number of studies.

“Hepatic safety outcomes were reported in a limited number of studies and showed moderate heterogeneity, reducing certainty.”

Dose-response relationships were based on a few trials.

“Dose–response relationships were inconsistent and based on a few trials, and should be viewed as exploratory rather than definitive.”

In the hepatic adverse events analysis, heterogeneity was high (I2 = 65%).

“However, heterogeneity was high (I2 = 65%) (moderate certainty: based on two RCTs).”

Hepatic safety outcomes showed moderate heterogeneity.

“Hepatic safety outcomes were reported in a limited number of studies and showed moderate heterogeneity, reducing certainty.”

Pooled analyses showed that pemafibrate reduces triglyceride levels (overall SMD -0.87, 95% CI -1.07 to -0.67).

“Pooled analyses suggest consistent evidence that pemafibrate may reduce triglyceride levels (overall SMD –0.87, 95% CI –1.07 to –0.67), although the certainty of evidence differs across outcomes.”

Evidence for pemafibrate's triglyceride reduction is high-certainty in some subgroups.

“Evidence from our meta-analysis suggests that pemafibrate may modestly reduce triglyceride levels, with high-certainty evidence in some subgroups and moderate-certainty evidence overall, though moderate heterogeneity exists.”

Hepatic outcomes showed moderate heterogeneity (I2 = 65%).

“hepatic outcomes showed moderate heterogeneity (I2 = 65%)”

Evidence for pemafibrate's triglyceride reduction is moderate-certainty overall.

“Evidence from our meta-analysis suggests that pemafibrate may modestly reduce triglyceride levels, with high-certainty evidence in some subgroups and moderate-certainty evidence overall, though moderate heterogeneity exists.”

Pemafibrate was associated with a small increase in renal adverse events (absolute risk increase 2.1%; NNH 48; moderate-certainty evidence).

“A small increase in renal adverse events was observed (moderate-certainty evidence)”

• Also stated in: § Discussions · plain

  “Pemafibrate was associated with a small increase in renal adverse events (absolute risk increase 2.1%; NNH 48)”

Pemafibrate was generally associated with reductions in triglyceride levels both with and without statin therapy.

“Pemafibrate was generally associated with reductions in triglyceride levels both with and without statin therapy”

• Also stated in: § Discussions · hedged

  “The results of this meta-analysis indicate that pemafibrate may reduce triglyceride (TG) levels in both statin-treated and non-statin-treated patients.”

• Also stated in: § Discussions · hedged

  “Standardized mean differences suggest reductions in TG levels across studies”

No consistent early or late occurrence of renal or hepatic adverse events was evident.

“No consistent early or late occurrence was evident”

Overall adverse event rates were generally similar between pemafibrate and placebo groups.

“overall adverse event rates were generally similar between groups”

Most subgroup analyses demonstrated low statistical heterogeneity.

“While most subgroup analyses demonstrated low statistical heterogeneity, moderate heterogeneity (I2 = 65%) was observed when statin-treated and non-statin-treated populations were pooled.”

Moderate heterogeneity exists in the evidence for pemafibrate's triglyceride reduction.

“Evidence from our meta-analysis suggests that pemafibrate may modestly reduce triglyceride levels, with high-certainty evidence in some subgroups and moderate-certainty evidence overall, though moderate heterogeneity exists.”

The findings did not demonstrate a significant difference in triglyceride reduction between 0.2 mg and 0.4 mg pemafibrate.

“our findings did not demonstrate a significant difference in triglyceride reduction between the two dosing regimens.”

Pemafibrate is associated with a slight but significant increase in renal adverse events (RR 1.09).

“The small (RR 1.09) renal safety issue”

• Also stated in: § Conclusions · plain

  “there is a slight but significant increase in renal adverse events”

Pemafibrate consistently reduces triglycerides regardless of diabetes status.

“In these studies, pemafibrate consistently reduced triglycerides, regardless of diabetes status.”

The short-term effects of pemafibrate on triglyceride reduction were consistent.

“While the short-term effects on triglyceride reduction were consistent”

Current data are sparse for patients with severe hypertriglyceridemia, chronic kidney disease, or hepatic impairment.

“These observations suggest that while pemafibrate is broadly effective, future trials should investigate its effects in patients with severe hypertriglyceridemia, chronic kidney disease, or hepatic impairment, where current data are sparse.”

Moderate heterogeneity (I2 = 65%) was observed when statin-treated and non-statin-treated populations were pooled.

“While most subgroup analyses demonstrated low statistical heterogeneity, moderate heterogeneity (I2 = 65%) was observed when statin-treated and non-statin-treated populations were pooled.”

Pemafibrate consistently reduced triglyceride levels across all included studies.

“Importantly, this variability did not affect the direction of the treatment effect, as pemafibrate consistently reduced triglyceride levels across all included studies.”

In statin-treated patients, TG reduction had an SMD of −0.70 with I2 = 0%.

“Multiple studies with low heterogeneity (e.g., TG reduction with statin-treated patients: SMD −0.70, I2 = 0%) were available, which results in strong and consistent evidence.”

Several of the included studies were industry-sponsored.

“Several of the included studies were industry-sponsored, which may introduce the possibility of selective reporting or influence by the sponsor, particularly in the reporting of safety outcomes.”

Pemafibrate significantly reduces triglyceride levels.

“Pemafibrate brings about a significant triglyceride reduction”

The dose-response pattern for pemafibrate is unexpected.

“The unexpected dose–response pattern”

Observations regarding patients with very high triglyceride levels are based on limited data.

“Observations regarding patients with very high triglyceride levels or the comparison between 0.2 and 0.4 mg doses are based on limited data and should be interpreted as hypothesis-generating rather than definitive.”

The included studies in this meta-analysis were predominantly conducted in Japanese populations.

“An important limitation of this meta-analysis is the predominance of studies conducted in Japanese populations, which may limit the external validity and global generalizability of the findings.”

Pemafibrate effectively lowers TG levels in patients with and without statin therapy.

“Pemafibrate effectively lowers TG levels in patients with and without statin therapy”

The hepatic adverse event analysis had high heterogeneity (I2 = 65%).

“high heterogeneity (I2 = 65%)”

The observed heterogeneity did not affect the direction of the treatment effect.

“Importantly, this variability did not affect the direction of the treatment effect, as pemafibrate consistently reduced triglyceride levels across all included studies.”

Pemafibrate appears to have a favourable safety profile.

“While the drug appears to have a favourable safety profile”

TG reduction is greater among non-statin users (SMD −1.31) than statin users (SMD −0.70).

“TG reduction appeared greater among non-statin users (SMD −1.31) than statin users (SMD −0.70).”

The certainty of evidence for the overall TG effect was moderate.

“Moderate heterogeneity was observed (I2 = 65%) (Moderate certainty).”

Further exploration through subgroup analyses was not feasible due to limitations in the available data.

“Although statistical heterogeneity was assessed in our meta-analysis, further exploration through subgroup analyses was not feasible due to limitations in the available data.”

The absence of sufficient studies restricted the application of formal statistical tests for publication bias.

“While this method provides an initial impression, the absence of sufficient studies in some comparisons restricted the application of formal statistical tests, such as Egger’s or Begg’s tests.”

The certainty of evidence for musculoskeletal adverse events was moderate.

“Pemafibrate did not significantly increase musculoskeletal adverse events, with an RR of 0.95 (95% CI: 0.90, 1.01, p = 0.09) (moderate certainty).”

The study provides updated and high-certainty evidence to inform clinical decision-making and future guideline development in hypertriglyceridemia management.

“By addressing prior heterogeneity and incorporating a larger pool of randomized controlled trials (RCTs), our study provides updated and high-certainty evidence to inform clinical decision-making and future guideline development in HTG management.”

The certainty of evidence for renal adverse events was moderate.

“Pemafibrate was associated with a slight but significant increase in renal adverse events, with a risk ratio (RR) of 1.09 (95% CI: 1.02, 1.16, p = 0.008) (moderate certainty).”

The certainty of evidence for the TG effect of pemafibrate versus placebo in patients receiving statins was high.

“The heterogeneity was low (I2 = 0%) (High certainty).”

The triglyceride-lowering effect of pemafibrate is not a validated surrogate for atherosclerotic cardiovascular disease risk reduction.

“Therefore, the triglyceride-lowering effect should be interpreted as a lipid-modifying outcome rather than a validated surrogate for atherosclerotic cardiovascular disease risk reduction.”

The evidence for the overall pooled effect was of moderate certainty.

“moderate-certainty evidence for the overall pooled effect”

The observed differences between 0.2 and 0.4 mg doses are based on limited data.

“The observed differences between 0.2 and 0.4 mg doses are based on limited data”

• Also stated in: § Discussions · hedged

  “Observations that the lower dose of pemafibrate (0.2 mg) appeared slightly more effective than the higher dose (0.4 mg) are based on a few trials and a limited participants”

The sensitivity checks support the reliability of the results across the evaluated outcomes.

“These checks support the reliability of the results across the evaluated outcomes.”

The evidence for the subgroup analyses was of high certainty.

“with high-certainty evidence for the subgroup analyses”

Pemafibrate may have a potential role in lowering triglyceride levels as adjunctive therapy for hypertriglyceridemia.

“Overall, pemafibrate may have a potential role in lowering TG levels as adjunctive therapy for hypertriglyceridemia.”

There is some variation between dose-dependent adverse effects and those observed in placebo-controlled studies.

“suggesting some variation between dose-dependent adverse effects and those observed in placebo-controlled studies.”

Reporting renal and hepatic adverse events as cumulative incidences rather than time-to-event outcomes limits the ability to assess temporal patterns.

“limiting the ability to assess temporal patterns”

Pemafibrate may have a potential role in managing hypertriglyceridemia.

“Overall, these findings suggest that pemafibrate may have a potential role in managing hypertriglyceridemia”

The certainty of evidence for adverse events between different pemafibrate doses was moderate.

“Data from Arai 2024 and Yamashita 2025 comparing different doses of pemafibrate showed an RR of 0.67 (95% CI: 0.43, 1.05, p = 0.08), indicating no statistically significant difference in adverse events between doses (I2 = 0%) (Moderate certainty).”

The certainty of the pooled evidence ranges from moderate to high depending on the subgroup.

“the certainty of the pooled evidence ranges from moderate to high depending on the subgroup”

The certainty of evidence for hepatic adverse events was moderate, based on two RCTs.

“However, heterogeneity was high (I2 = 65%) (moderate certainty: based on two RCTs).”

The certainty of evidence for total adverse events was high.

“Data from Arai 2017, Araki 2018, Araki 2019, Dai 2025, Das 2022, Ginsberg 2022, and Matsuba 2018 showed an RR of 1.02 (95% CI: 0.98, 1.07, p = 0.30), suggesting no significant difference in total adverse events between pemafibrate and placebo (I2 = 0%) (high certainty).”

Firm conclusions about temporal patterns of renal or hepatic adverse events cannot be drawn.

“but firm conclusions cannot be drawn”

The limited reporting and moderate heterogeneity of hepatic safety outcomes reduce certainty in those outcomes.

“Hepatic safety outcomes were reported in a limited number of studies and showed moderate heterogeneity, reducing certainty.”

The predominance of Japanese populations in included studies may limit generalizability to other ethnic groups.

“Most included studies were conducted in Japanese populations, which may limit generalizability to other ethnic groups.”

Most trials were assessed as having low risk of bias using the Cochrane RoB 2 tool.

“Although most trials were assessed as having low risk of bias using the Cochrane RoB 2 tool, the potential for sponsorship-related bias cannot be completely excluded.”

Individual patient-level data were unavailable.

“As individual patient-level data were unavailable, it was not possible to control for these unmeasured confounders, which may have influenced both the magnitude and variability of TG reduction.”

There is a lack of long-term cardiovascular outcome data.

“Currently, there is a lack of long-term cardiovascular outcome data”

The heterogeneity is likely attributable to variations in baseline triglyceride levels, patient metabolic profiles, concomitant therapies, and study design characteristics.

“Rather, the heterogeneity appears to reflect differences in magnitude of effect, likely attributable to variations in baseline triglyceride levels, patient metabolic profiles, concomitant therapies, and study design characteristics.”

The heterogeneity appears to reflect differences in magnitude of effect.

“Rather, the heterogeneity appears to reflect differences in magnitude of effect, likely attributable to variations in baseline triglyceride levels, patient metabolic profiles, concomitant therapies, and study design characteristics.”

There is moderate certainty for hepatic adverse events.

“moderate certainty for hepatic adverse events”

Other concomitant therapies, particularly glucose-lowering medications commonly used in diabetic populations, were inconsistently reported across included studies.

“other concomitant therapies—particularly glucose-lowering medications commonly used in diabetic populations—were inconsistently reported across included studies.”

The potential for sponsorship-related bias cannot be completely excluded.

“Although most trials were assessed as having low risk of bias using the Cochrane RoB 2 tool, the potential for sponsorship-related bias cannot be completely excluded.”

• AssumptionRests on an assumption: Industry sponsorship may introduce selective reporting or sponsor influence, particularly in the reporting of safety outcomes.

It was not possible to formally evaluate whether renal or hepatic adverse events occurred early or late during treatment.

“precluding formal evaluation of whether renal or hepatic adverse events occurred early or late during treatment.”

Several potential confounders that may influence triglyceride outcomes could not be fully accounted for in this meta-analysis.

“Several potential confounders that may influence triglyceride (TG) outcomes could not be fully accounted for in this meta-analysis.”

• Also stated in: § Heterogeneity and publication bias · plain

  “it was not possible to control for these unmeasured confounders”

Most included trials reported adverse events as overall frequencies without detailed temporal information.

“Most included trials reported adverse events as overall frequencies without detailed temporal information, precluding formal evaluation of whether renal or hepatic adverse events occurred early or late during treatment.”

The magnitude of triglyceride reduction and safety profile observed in predominantly Japanese cohorts may not be fully representative of other populations with different genetic backgrounds, dietary habits, and cardiometabolic risk profiles.

“Consequently, the magnitude of triglyceride reduction and safety profile observed in predominantly Japanese cohorts may not be fully representative of other populations with different genetic backgrounds, dietary habits, and cardiometabolic risk profiles.”

• AssumptionRests on an assumption: Regional differences in dietary patterns (e.g., higher fish and omega-3 consumption) and population-specific genetic factors affecting lipid metabolism and PPAR-α signaling may influence baseline triglyceride levels and response to pemafibrate therapy.

The predominance of Japanese populations in the included studies may limit the external validity and global generalizability of the findings.

“An important limitation of this meta-analysis is the predominance of studies conducted in Japanese populations, which may limit the external validity and global generalizability of the findings.”

• AssumptionRests on an assumption: Regional differences in dietary patterns (e.g., higher fish and omega-3 consumption) and population-specific genetic factors affecting lipid metabolism and PPAR-α signaling may influence baseline triglyceride levels and response to pemafibrate therapy.

The non-significant heterogeneity despite the subgroup analysis suggests population- or trial-design heterogeneity.

“The non-significant heterogeneity despite the subgroup analysis has been continuous, suggesting population- or trial-design heterogeneity, although further trials specifically designed to answer the question in heterogeneous clinical settings are needed to validate such effects.”

All outcomes included in this meta-analysis do not have the same evidentiary strength.

“All outcomes included in this meta-analysis do not have the same evidentiary strength.”

The short follow-up restricts the ability to draw firm conclusions about the long-term safety and efficacy of pemafibrate.

“which restricts the ability to draw firm conclusions about the long-term safety and efficacy of pemafibrate.”

Definitive conclusions regarding the optimal dosing strategy cannot yet be drawn due to restricted availability of dose-ranging trials.

“However, due to the restricted availability of dose-ranging trials, definitive conclusions regarding the optimal dosing strategy cannot yet be drawn.”

Evidence regarding sustained lipid control, cardiovascular outcomes, and long-term safety profiles of pemafibrate remains insufficient.

“evidence regarding sustained lipid control, cardiovascular outcomes, and long-term safety profiles remains insufficient.”

The hepatic adverse event analysis was based on only two randomized controlled trials.

“it was based on only two RCTs”

The number of studies directly comparing different doses of pemafibrate was limited.

“the number of studies directly comparing different doses was limited.”

These unmeasured confounders may have influenced both the magnitude and variability of triglyceride reduction.

“which may have influenced both the magnitude and variability of TG reduction.”

• AssumptionRests on an assumption: Glucose-lowering medications such as insulin, metformin, sodium–glucose cotransporter-2 inhibitors, and glucagon-like peptide-1 receptor agonists have independent effects on lipid metabolism.

The limited number of included studies precluded meta-regression or extensive subgroup analyses.

“In addition, the limited number of included studies precluded meta-regression or extensive subgroup analyses, restricting further exploration of sources of heterogeneity.”

There is high-certainty evidence supporting pemafibrate's efficacy.

“with high-certainty evidence supporting its efficacy”

Multiple studies with low heterogeneity for TG reduction with statin-treated patients provide strong and consistent evidence.

“Multiple studies with low heterogeneity (e.g., TG reduction with statin-treated patients: SMD −0.70, I2 = 0%) were available, which results in strong and consistent evidence.”

It is uncertain whether the observed triglyceride reductions will translate into clinically meaningful benefits.

“making it uncertain whether the observed TG reductions will translate into clinically meaningful benefits.”

Publication bias cannot be fully excluded.

“Publication bias cannot be fully excluded, as assessment relied on visual inspection of funnel plots without formal statistical testing.”

Pemafibrate is broadly effective.

“These observations suggest that while pemafibrate is broadly effective”

Heterogeneity should be interpreted as reflecting clinical diversity rather than inconsistency of treatment benefit.

“Accordingly, heterogeneity should be interpreted as reflecting clinical diversity rather than inconsistency of treatment benefit.”

Variations in dietary counseling, lifestyle modification, baseline glycemic control, and underlying metabolic status were not uniformly described across included studies.

“In addition, variations in dietary counseling, lifestyle modification, baseline glycemic control, and underlying metabolic status were not uniformly described, limiting adjustment for these factors.”

Pemafibrate may serve as a promising therapeutic option for patients with hypertriglyceridemia, particularly in those with residual cardiovascular risk despite statin therapy.

“The findings of this meta-analysis suggest that pemafibrate may serve as a promising therapeutic option for patients with hypertriglyceridemia, particularly in those with residual cardiovascular risk despite statin therapy.”

Robust data on long-term cardiovascular outcomes for pemafibrate are still lacking.

“Clinicians should interpret these results as preliminary evidence supporting its triglyceride-lowering efficacy, while recognizing that robust data on long-term cardiovascular outcomes are still lacking.”

The included studies had a relatively short duration of follow-up.

“A key limitation of the included studies is the relatively short duration of follow-up”

Inconsistent subgroup reporting prevented quantitative pooling by diabetes or baseline TG levels.

“However, inconsistent subgroup reporting prevented quantitative pooling by diabetes or baseline TG levels.”

Adjustment for dietary counseling, lifestyle modification, baseline glycemic control, and underlying metabolic status was limited because these factors were not uniformly described.

“In addition, variations in dietary counseling, lifestyle modification, baseline glycemic control, and underlying metabolic status were not uniformly described, limiting adjustment for these factors.”

The limited number of included studies restricted further exploration of sources of heterogeneity.

“In addition, the limited number of included studies precluded meta-regression or extensive subgroup analyses, restricting further exploration of sources of heterogeneity.”

The small sample size for hepatic adverse events (only two trials) limits the generalizability of this outcome.

“In addition, the small sample size for hepatic adverse events (only two trials) limits the generalizability of this outcome.”

The long-term impact of pemafibrate on cardiovascular outcomes remains unclear.

“the long-term impact of pemafibrate on cardiovascular outcomes remains unclear.”

The hepatic adverse event analysis had moderate certainty.

“The hepatic adverse event analysis had moderate certainty, as it was based on only two RCTs with high heterogeneity (I2 = 65%).”