No change in small low-density lipoprotein cholesterol levels with pemafibrate might explain the negative results of the PROMINENT trial

To the Editor

The Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial was recently published in the New England of Journal of Medicine,¹ and failed to show a preventive effect of pemafibrate on atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes and dyslipidemia. This study was designed to determine whether pemafibrate, a triglyceride (TG)-lowering drug, can reduce the incidence of ASCVD in hypertriglyceridemic and low high-density lipoprotein cholesterol patients, whose low-density lipoprotein cholesterol (LDL-C) is controlled <70 mg/dL with statins. As TG-rich lipoproteins (TRLs), especially its remnants, are considered to be atherogenic, like LDL, it was of interest to see if selective suppression of TRLs with pemafibrate would reduce CV events. The results showed that lowering TRL with pemafibrate did not lead to a reduction in CV events, suggesting that TRL does not play an important role in the development of atherosclerosis when LDL-C is tightly controlled. The results of this study will further solidify LDL's status as an unrivaled atherogenic lipoprotein.

LDL includes both large buoyant LDL and small density (sd) LDL particles, the latter of which are more atherogenic than the former. Recent large cohort studies showed that sdLDL-C is a powerful biomarker for ASCVD beyond LDL-C. It is well documented that sdLDL-C levels are substantially elevated in hypertriglyceridemic diabetes. As sdLDL-C is positively correlated with TG, pemafibrate treatment should reduce sdLDL-C by its TG-lowering effect. If so, why did the favorable change in LDL composition not lead to a reduction in CV events? Sampson et al.² proposed a formula for calculating sdLDL-C using LDL-C and TG as variables, based on our established direct sdLDL-C measurement.³ They also showed that calculated sdLDL-C is a strong predictor of ASCVD.³ As the PROMINENT study showed actual values of TG, total-C and high-density lipoprotein cholesterol at baseline, and 4 and 12 months,¹ sdLDL-C can be calculated. Table 1 shows calculated sdLDL-C in the PROMINENT study. Surprisingly, sdLDL-C levels were almost identical in the pemafibrate and placebo groups. This is supported by the fact that levels of non-high-density lipoprotein cholesterol and apolipoprotein B, known as surrogate markers for sdLDL-C, were not reduced by pemafibrate.¹ In the phase III study, pemafibrate alone or in combination with pemafibrate and a statin reduced the sdLDL fraction, but in the PROMINENT study, pemafibrate did not reduce the calculated value of sdLDL-C. A possible reason for this is that most participants in the phase III study had higher baseline LDL-C concentrations than in the PROMINENT trial, in which most participants received intensive statins, and lower LDL-C concentrations are presumed to attenuate the involvement of TG in sdLDL generation. Furthermore, pemafibrate activates hepatic TG lipase⁴ and promotes sdLDL generation, which might counteract the decrease in sdLDL-C due to lower TG. The favorable effect of pemafibrate on ASCVD might be limited only to hypertriglyceridemic patients whose LDL-C is not tightly controlled.

Tsutomu Hirano receives advisor fees from Denka Co., and lecture frees from Kowa Co.

Approval of the research protocol: N/A.

Informed Consent: N/A.

Approval date of Registry and the Registration: N/A.

Animal Studies: N/A.