NEJM: Can diabetic patients lower blood lipids, can it reduce cardiovascular risk? The latest research says so

Previous STRENGTH trial results have shown no reduction in cardiovascular event rates despite a 20% reduction in triglyceride levels
.
Coincidentally, the FIELD trial yielded similar results
.
However, subgroup analysis of other studies suggests that patients with high triglyceride levels, low HDL cholesterol levels, and type 2 diabetes may benefit
from lowering triglyceride levels.

The answer doesn't seem certain
.

Recently, the New England Journal of Medicine (NEJM) published the results of the PROMINENT trial online, confirming that although the new drug Pemafibrate can reduce triglyceride levels in patients with type 2 diabetes, it does not reduce the risk of myocardial infarction, stroke or cardiovascular disease death
。 Lead author Dr Aruna Pradhan, from the Department of Cardiology at Brigham and Women's Hospital, said: "The results are puzzling, but at the same time have important clinical value"
.

Screenshot source: NEJM

The PROMINENT trial is an international, double-blind, randomized, controlled trial that finally included 10,497 patients
in 24 countries around the world during 2017~2022.
These patients had type 2 diabetes, mildly to moderately elevated triglycerides (200~499 mg/dl), low HDL cholesterol levels (≤40 mg/dl), and all received statin therapy
.
Patients were randomized to pesmafibrate (5240) and placebo (5257).

At 4 months of follow-up, it was found that compared with the placebo group, the pemafibrate group decreased triglyceride levels by 26.
2%, VLL cholesterol decreased by 25.
8%, residual cholesterol decreased by 25.
6%, apolipoprotein C-III.
decreased by 27.
6%, and apolipoprotein B increased by 4.
8
%.
The level of LDL cholesterol was elevated in the peimafibrate group, and there was no change in total cholesterol and non-HDL cholesterol levels
.

▲Figure 1: The effect of permafibrate on fasting blood lipid level at 4 months of follow-up (screenshot source: Reference [1])

The primary endpoint event occurred in 572 and 560 patients in the pemafibrate group and placebo, respectively (HR = 1.
03, 95% CI: 0.
91 to 1.
15, P = 0.
67, non-statistically significant).

There were 432 and 417 patients with key secondary endpoint events (myocardial infarction, ischaemic stroke, angina, and cardiovascular mortality), respectively (HR = 1.
04, 95% CI: 0.
91 to 1.
19).

▲Figure 2: Cumulative incidence of cardiovascular events in the two groups (screenshot source: Reference [1])

The risk ratio of death due to cardiovascular disease in the two groups was HR=1.
00, 95% CI: 0.
79-1.
28, and the risk ratio of death from any cause was HR=1.
04, 95% CI: 0.
91-1.
20
.
Pemafibrate did not reduce the risk of combined events of myocardial infarction, stroke, and cardiovascular death, and the results within the subgroup preset by the researchers were not significantly different
.

▲Figure 3: Efficacy endpoints of the two groups (screenshot source: Reference [1])

There was no significant difference in the incidence of serious adverse reactions, infection, and skeletal muscle complications between the two groups, but the number of patients with renal adverse events and venous embolism was higher in the pemafibrate group, while the number of patients with liver adverse events in the placebo group was more, and the incidence of nonalcoholic fatty liver disease was lower in the permafibrate group, which has potential therapeutic significance.

▲Figure 4: Comparison of the safety of the two groups of treatment (screenshot source: Reference [1])

THE PROMINENT TRIAL FAILED TO DEMONSTRATE THAT FIBRATES HELPED IMPROVE PATIENT OUTCOMES, AND TRIGLYCERIDE LEVELS WERE NOT EFFECTIVE TARGETS FOR DRUG INTERVENTION
.
The study authors suggest that this may be related to the properties of fibrates, which are PPARalpha agonists that reduce triglyceride levels
by increasing lipoprotein lipase activity.
Thus, after the use of pemafibrate it is manifested by a decrease in triglyceride-rich lipoprotein residues, accompanied by an increase in the levels of LDL cholesterol and apolipoprotein B, while there is no change
in the levels of non-HDL cholesterol and total cholesterol.

In addition, based on the results of the current study, the increase in LDL cholesterol and apolipoprotein B levels in patients in the pemafibrate group does not negate the possible benefits
of lowering triglycerides and residual cholesterol.
More research is needed on the relationship between high triglyceride levels, type 2 diabetes and cardiovascular disease
.