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STUDY SUMMARY | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Objective | To test whether lowering triglyceride (TG) levels with pemafibrate in type 2 diabetes mellitus (T2DM) patients with high TG and low high-density lipoprotein cholesterol (HDL C) and well controlled low-density lipoprotein cholesterol (LDL-C) levels reduces major adverse cardiovascular events (MACE). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Study design | PROMINENT was a double-blind, randomized, placebo-controlled trial. Patients initially entered a 21-day placebo run-in period, and those eligible with high adherence were then randomly allocated to treatment with pemafibrate (0.2-mg tablets twice daily) or matching placebo, stratified by sex, history of cardiovascular disease, and statin use. Patients attended for study visits at 2, 4, 6, 8, and 12 months and every 4 months thereafter. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Study population | Patients with T2DM and TG between 200 to 499 mg/dL (2.23-5.6 mmol/L), HDL-C ≤40 mg/dL (1.03 mmol/L). The study population included patients with atherosclerotic cardiovascular disease (ASCVD) aged ≥18 years and those without ASCVD aged ≥50 years (men) or ≥55 years (women). Patients were required to be on a stable dose (≥12 weeks) of moderate-intensity or high-intensity statin, were untreated or were receiving other lipid-lowering therapy with an LDL-C ≤70 mg/dL (1.8 mmol/L) in the previous 12 months. Those with statin intolerance were required to have an LDL-C ≤100 mg/dL (≤2.6 mmol/L) within the previous 12 months. Major exclusions were T1DM, uncontrolled diabetes, untreated or inadequately treated hypothyroidism or hyperthyroidism, severe heart failure, severe kidney disease, and clinically significant liver disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Main study variables |
The primary outcome was first MACE, defined as a composite of myocardial infarction (MI), ischemic stroke, hospitalization for unstable angina warranting unplanned coronary revascularization, or death from cardiovascular causes. On March 18, 2020, this was subsequently modified after blinded review to include any coronary revascularization. Prespecified secondary end points included: |
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Methods |
This was an event-driven trial designed to have 90% power to detect an 18% relative reduction in the risk of an original primary endpoint with pemafibrate versus placebo. Randomization aimed for inclusion of about 10,000 patients, with at least 300 enrolled in Japan, at least 20% women, and no more than one-third in the primary prevention cohort. With modification of the primary endpoint, the target number of events was increased from 1092 to 1304, allowing for a 90% power to detect a 16.6% relative difference in this primary endpoint with pemafibrate versus placebo. Data were reviewed by an independent data and safety monitoring board (DSMB) for safety throughout the trial, and for futility and efficacy at three prespecified interim time points. On March 18, 2022, on review of the interim data (after 75% of the target number of events had accrued), the DSMB unanimously recommended early termination of the trial as the prespecified futility boundaries had been crossed. In the analysis, patients were evaluated according to their randomized group irrespective of adherence. Analysis of the time to a primary end-point event was performed using a likelihood-ratio test based on a proportional-hazards model stratified according to sex, history of cardiovascular disease, and baseline statin use. |
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Results |
The study randomized 10,538 patients, of whom 10,497 (5240 allocated pemafibrate and 5257 allocated placebo) were included in the intention-to-treat (ITT) efficacy population. Overall, median age was 64 years, 27.5% of patients were women, 19.4% identified as Hispanic or Latin, 33.1% were primary prevention and almost all (95.7%) were receiving a statin. Baseline characteristics of the two groups were balanced. At baseline, median fasting TG was 271 mg/dL (3.1 mmol/L), median HDL‑C was 33 mg/dL (0.9 mmol/L), and median LDL-C was 78 mg/dL (2.0 mmol/L). Table 1. Change in key lipids at 4 months and treatment effect
* calculated, **measured, CI confidence interval The median percentage change in fasting TG from baseline to 4 months was −31.1% in the pemafibrate group and −6.9% in the placebo group (between-group difference of −26.2%). Similar effects were reported for very low-density lipoprotein cholesterol (VLDL-C), remnant cholesterol (remnant-C) and apolipoprotein (apo) CIII (Table 1). These treatment effects were durable over time. As LDL-C levels increased with pemafibrate (median increase of 14.0%) with no change in non-HDL-C or total cholesterol levels (mean treatment effect versus placebo -0.2% and 0.8%, respectively), there was a small increase in apoB (4.8% versus placebo). Over the median follow-up of 3.4 years (maximum 5.0 years), 572 patients in the pemafibrate group and 560 patients in the placebo group experienced a first MACE (hazard ratio, 1.03; 95% CI 0.91 to 1.15, p=0.67). Effects were neutral for all composite secondary cardiovascular endpoints and the individual components of these endpoints. With respect to safety, statistically significant differences were reported for renal adverse events, hepatic adverse events and thromboembolic events (Table 2). There were no differences between the two groups for serious adverse events, infections, musculoskeletal events or other adverse events. Table 2. Statistically significant differences in adverse events.
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Author conclusion | Among patients with T2DM, mild-to-moderate hypertriglyceridemia, and low HDL-C and LDL-C levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglycerides, VLDL-C, remnant cholesterol, and apo C-III levels. |
COMMENT
Despite significant and clinically meaningful reduction in non-LDL-lipoproteins, specifically TG, VLDL-C, remnant-C and apoCIII, pemafibrate treatment did not reduce MACE in T2DM patients (with and without ASCVD) with well-controlled LDL-C levels. These findings align with other trials investigating TG-lowering trials in patients with mild to moderate hypertriglyceridemia, with or without low HDL-C [i.e., STRENGTH with high-dose n−3 fatty acids (1), AIM-HIGH with niacin (2), and ACCORD Lipid with fenofibrate (3)], which also showed no significant clinical benefit despite lowering TG levels by 20-30%. Furthermore, while REDUCE-IT showed significant reduction in cardiovascular events with high-dose icosapent ethyl, the magnitude of clinical benefit did not correlate with the extent of TG reduction (18%) (4). Treatment with pemafibrate was also associated with increases in the numbers of patients with renal adverse events or thromboembolic events, similar to observations with fenofibrate (5). Significant reduction in hepatic adverse events merits investigation of pemafibrate in the setting of non-alcoholic fatty liver disease; an ongoing trial is testing this (NCT05327127).
What do the findings of PROMINENT mean for research into lipid-related residual cardiovascular risk? There is undoubtedly extensive evidence from observational, pre-clinical, and clinical studies supporting an association between TG, TG-rich lipoproteins (TRL), and TRL remnants and cardiovascular risk (6,7), which provides a basis for considering these lipoproteins as contributors to lipid-related residual cardiovascular risk. Establishing this in clinical trials, however, is complicated by the complexity of pathways involved in production, clearance and metabolic processing of TRL and their remnants (6). Pemafibrate lowers plasma TG levels by increasing the activity of lipoprotein lipase, the key regulator of TG metabolism, and reducing the number of large nascent TRL in the circulation (8). Indeed, increases in LDL-C and apoB observed in PROMINENT are consistent with increased efficacy of conversion of TRL remnants to LDLs rather than their removal by the liver or decreased production of VLDLs. Thus, a key inference from the neutral PROMINENT trial is that targeting VLDL production, remnant formation and TRL clearance pathways may be needed for clinically meaningful clinical benefit in patients with mixed dyslipidemia or mild to moderate hypertriglyceridemia.
References |
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Key words | PROMINENT; pemafibrate; residual cardiovascular risk; triglycerides; remnant cholesterol |