Objective To test the hypothesis that absolute mass changes in remnant cholesterol, LDL-C, and
apoB explain the results of the PROMINENT (Pemafibrate to Reduce Cardiovascular
OutcoMes by Reducing Triglycerides IN patiENts With diabeTes) trial, using the
Copenhagen General Population Study to mimic the study population of the PROMINENT
trial.

Study design

The Copenhagen General Population Study (CGPS) is a prospective cohort study (recruiting
during 2003–2015) in adults aged ≥20 years randomly selected from the Danish Civil
Registration System.

Study population

The analysis cohort was selected from 108,431 eligible individuals with full baseline
information on all lipid traits using key inclusion criteria in the PROMINENT trial.

Main study variables

Primary: Primary composite of the PROMINENT trial, i.e. cardiovascular death, myocardial
infarction, ischaemic stroke, and coronary revascularization.
Key secondary: Absolute and percent changes in lipid traits including total cholesterol,
LDL-C, apoB, triglycerides (TG), and remnant cholesterol (calculated as total cholesterol
minus LDL-C minus high-density lipoprotein cholesterol [HDL-C]). When TG were <354
mg/dL (<4.0 mmol/L), LDL-C was calculated using the Friedewald equation.

Methods Individuals in the CGPS with diabetes who were on statin therapy at inclusion, and who
were i) ≥18 years old with established atherosclerotic cardiovascular disease (ASCVD), ii)
≥50 years old for men without prior ASCVD, or iii) ≥55 years old for women without prior
ASCVD were selected for the analysis. Individuals with plasma TG <200 mg/dL (<2.26
mmol/L) or >499 mg/dL (>5.63 mmol/L) were not excluded as the analysis required
individuals with both high and low TG (or remnant cholesterol) to mimic trial designs for
untreated and treated patients, respectively. In sensitivity analysis, only individuals in the
entire CGPS with plasma TG 200–499 mg/dL (2.26–5.63 mmol/L) were included. Within
this CGPS mimicking cohort, the ASCVD risk that could be explained by study-specific
observed absolute mass changes in remnant cholesterol, LDL-C, and apoB was evaluated.
These estimated changes in ASCVD risk were compared with corresponding observed
changes in the PROMINENT trial.

Results

Overall, 2487 subjects in the CGPS fulfilled the key inclusion criteria for the PROMINENT
trial (the CGPS mimicking PROMINENT). Baseline characteristics of the PROMINENT trial
and CGPS mimicking PROMINENT are summarized in Table 1.
Table 1. Baseline characteristics, PROMINENT vs. CGPS mimicking PROMINENT

Abbreviations: apo apolipoprotein; ASCVD atherosclerotic cardiovascular disease; HDL-C high-density
lipoprotein cholesterol; LDL-C low-density lipoprotein cholesterol; TG triglycerides
In the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (− 0.18 mmol/L;
-18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) in LDL-C, and +5
mg/dL (+0.05 g/L; +5 %) in apoB. ASCVD risk by lipid changes in the CGPS mimicking
PROMINENT cohort, individually and combined, are summarized in Table 2. When
combining remnant cholesterol, LDL-C, and apoB absolute mass changes, the estimated
hazard ratio for ASCVD was 1.05 (0.96–1.14) in the CGPS mimicking PROMINENT, versus
1.03 (0.91–1.15) in PROMINENT.
Table 2. Lipid changes in PROMINENT and corresponding ASCVD risk in CGPS mimicking

Author conclusions

Absolute mass changes in remnant cholesterol, LDL-C, and apoB can explain the results of
the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol
together with 5 mg/dL (0.05 g/L) higher apoB seem to explain the trend toward more
ASCVD in the pemafibrate arm. These results therefore imply that to reduce ASCVD, TG-

and remnant cholesterol-lowering agents need to reduce total atherogenic cholesterol
(LDL-C and remnant cholesterol) as well as the total number of atherogenic lipoprotein
particles indicated by apo B.

Comment
Despite a well presented rationale (1), the PROMINENT trial returned a neutral result, with no effect
on the primary outcome, a 4-point major cardiovascular adverse event (MACE) outcome, with
pemafibrate (2). The reasons for this have been the subject of much debate. This latest report
suggests that absolute mass changes in remnant cholesterol, LDL-C, and apoB can explain these
findings, with the 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL
(0.05 g/L) higher apoB explaining the trend toward more MACE in the pemafibrate group. The
researchers propose that the mass cholesterol content may be more relevant (rather than percent
or absolute changes in lipids) as the total mass of cholesterol deposited in the arterial intima is the
main driver of atherosclerotic plaque size. The study findings are strengthened by the large number
of individuals in the CGPS fulfilling the key inclusion criteria of the PROMINENT trial, accounting of
well-known potential confounding factors between lipid levels and ASCVD, and lack of loss to follow-
up of individuals. Moreover, the CGPS includes individuals from a general population setting,
independent of any other clinical trials, minimizing selection bias.
The analysis is clinically relevant, in addressing the question which is more relevant for lowering
residual cardiovascular risk in patients with hypertriglyceridaemia: LDL or remnant cholesterol? The
results imply that cholesterol lowering agents should aim to reduce both, as well as total number of
atherogenic lipoprotein particles containing apoB.
References
1. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce
Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study.
Am Heart J 2018;206:80-93.
2. Das Pradhan A, Glynn RJ, Fruchart JC, et al. Triglyceride lowering with pemafibrate to reduce
cardiovascular risk. N Engl J Med 2022;387:1923-34.
Key words: PROMINENT; pemafibrate; Copenhagen General Population Study; total atherogenic
cholesterol; total atherogenic lipoprotein particles