Results from PROMINENT are in

6 December 2022
In PROMINENT (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabetes) lowering triglyceride levels by 26% with pemafibrate on top of intense statin therapy did not significantly reduce cardiovascular events in patients with type 2 diabetes and hypertriglyceridemia. However, exploratory data suggest this treatment may have potential in non-alcoholic fatty liver disease (NAFLD).
Pradhan AD, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce cardiovascular risk. New Engl J Med 2022; DOI: 10.1056/NEJMoa2210645

 

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:
• the original primary end point (see above)
• a composite of MI, ischemic stroke, or death from cardiovascular causes
• a composite of the primary end point or hospitalization for heart failure
• a composite of the primary end point or death from any cause
• individual components of the primary end point
• new or worsening peripheral artery disease.
Other prespecified endpoints included lipid biomarkers, and protocol-defined retinopathy and nephropathy.
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.
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

Parameter

Pemafibrate

(N=5240)

Placebo

(N=5257)

Mean treatment effect. (95% CI)

TG

 

 

 

 Absolute change (mg/dL)

 % change

-84

 

-31.1%

-15

 

-6.9%

 

 

−26.2 (−28.4 to −24.10)

VLDL-C*

 

 

 

 Absolute change (mg/dL)

 % change

-18

 

-35.0%

-6

 

-10.5%

 

 

−25.8 (−27.8 to −23.9)

Remnant-C**

 

 

 

 Absolute change (mg/dL)

 % change

-26

 

−43.6%

-12

 

−20.2%

 

 

−25.6 (−27.3 to −24.0)

Apolipoprotein CIII

 

 

 

 Absolute change (mg/dL)

 % change

-4

 

−27.8%

0

 

 

−27.6 (−29.1 to −26.1)

* 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.

Parameter

Incidence rate per 100 person-years

 

Pemafibrate

(N=5240)

Placebo

(N=5257)

p-value

Any renal adverse event

10.67

9.55

0.004

 Chronic kidney disease

1.11

0.71

<0.001

 Acute kidney injury

0.97

0.64

0.001

 Diabetic nephropathy*

5.73

5.16

0.04

 

 

 

 

Any hepatic adverse event

1.35

1.64

0.04

 NAFLD

0.95

1.22

0.02

 

 

 

 

Other protocol-defined events of clinical interest*

 

 

 

 Venous thromboembolism

0.43

0.21

<0.001

 Pulmonary embolism

0.24

0.11

0.008

 Deep-vein thrombosis

0.27

0.11

0.001

* Predefined and queried at each visit
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
  1. Nicholls SJ, Lincoff AM, Garcia M, et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial. JAMA 2020;324:2268-80.
  2. The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
  3. The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
  4. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
  5. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.
  6. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies — a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021;42:4791-806.
  7. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.
  8. Fruchart J-C. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia. Cardiovasc Diabetol 2017;16:124.
Key words PROMINENT; pemafibrate; residual cardiovascular risk; triglycerides; remnant cholesterol