The importance of managing ‘fat neutral’ shakes… No cardiovascular benefits?

[메디칼업저버 박선혜 기자] The position of triglyceride, which was addressed following LDL-cholesterol, as a major target for lipid management for the prevention of cardiovascular events is staggering.

As a result of the CLEAR study of pemafibrate, a fibrate-like drug, the triglyceride-enhancing effect of pemafibrate did not lead to a reduction in the risk of cardiovascular events.

The PROMINENT study was conducted in patients with type 2 diabetes with mild to moderate hypertriglyceridemia and low HDL cholesterol. Pemafibrate is a selective PPARα modulator that improves lipid levels, including triglycerides. In Japan, it is approved as a treatment for hypertriglyceridemia.

“This result raises the question of whether patients with mild to moderate hypertriglyceridemia taking high-intensity statins should receive additional triglyceride-targeting therapy,” said Dr. Aruna Das Pradhan of Brigham and Women’s Hospital, who led the study. “Treating triglycerides as a potential control strategy to reduce disease risk is controversial.”

The results of the PROMINENT study were published in the November issue of NEJM (N Engl J Med 2022; 387(21):1923-1934).

The PROMINENT study was a multinational, double-blind, randomized controlled trial conducted to determine whether pemafibrata could prevent cardiovascular events by lowering triglyceride levels.

10,497 patients with type 2 diabetes mellitus with triglyceride levels of 200 to 499 mg/dL, mild to moderate hypertriglyceridemia, and HDL-cholesterol less than 40 mg/dL or LDL-cholesterol less than 100 mg/dL were recruited for the study. Two of the three patients had a history of cardiovascular disease. The entire patient group was randomized to either the pemafibrate 0.2 mg twice-daily dose group (the pemafibrate group) or the placebo group.

Of the total patient population, 69% took high-intensity statins and more than 95% received statin therapy. At the time of enrollment, the fasting triglyceride (median) was 271 mg/dL, the HDL cholesterol was 33 mg/dL, and the LDL cholesterol was 78 mg/dL.

The primary efficacy endpoint was evaluated by the composite of nonfatal myocardial infarction, ischemic stroke, coronary artery revascularization, and cardiovascular death. The follow-up period (median) was 3.4 years.

After 4 months, lipid levels in the pemafibrate group decreased by 26.2% in triglycerides, 25.8% in very low density lipoprotein (VLDL) cholesterol, 25.6% in residual cholesterol, and 27.6% in apolipoprotein C-III compared to the placebo group. Apolipoprotein B increased by 4.8% in the pemafibrata group compared to the placebo group.

As a result, the primary target point was found in 572 people in the pemafibrate group and 560 people in the placebo group, and the incidence rates per 100 people were 3.60 and 3.51, respectively. The pemafibrate group improved significantly in triglyceride levels compared to the placebo group, but there was no difference in the risk of developing the primary endpoint between the two groups (HR 1.03; 95% CI 0.91 to 1.15).

The incidence of serious adverse reactions did not differ significantly by treatment. However, the incidence of renal events and venous thromboembolism was high in the pemafibrate group, and the incidence of non-alcoholic fatty liver disease was low. The all-cause mortality rate per 100 person-years was 2.44 in the pemafibrate group and 2.34 in the placebo group.

Consequently, type 2 diabetic patients with mild to moderate hypertriglyceridemia and low HDL- and LDL-cholesterols failed to prevent significant cardiovascular events even though pemafibrate could improve lipid levels.

Although the academic community has recently emphasized the importance of managing residual cholesterol, such as triglycerides, to prevent cardiovascular events, the PROMINENT study raises questions about this management strategy.

The academic community estimates that the effect of pemafibrate may have been masked by statins, given that most patients in this study were taking statins.

Particularly noteworthy is the result of the increase in LDL-cholesterol in the pemafibrate group. Because fibrates increase the conversion of triglyceride-rich lipoprotein remnants to LDL rather than their removal from the liver, patients treated with fibrates may have elevated LDL-cholesterol and apolipoprotein B levels.

“In this study, the LDL-cholesterol level of the pemafibrate group increased slightly,” said Professor Cho Sang-ho of Hallym University Sacred Heart Hospital (Department of Cardiovascular Medicine). it is assumed to have affected cardiovascular events by offsetting the good effects.”

In a commentary, Professor Salim S. Virani from Baylor Medical School in the United States said, “For triglyceride-lowering drugs to be effective, there must be a mechanism that increases the clearance of triglyceride-rich lipoprotein cholesterol particles rather than converting residual lipoprotein. into LDL.” revealed

However, academia explains that neutral fat management cannot be neglected with this study alone.

Professor Cho said, “Currently, clinical studies of drugs that target APOC3 and ANGPTL3 that lower triglycerides are underway. Depending on these results, the effect of triglyceride control on cardiovascular events will become evident.” Triglyceride control is difficult to give up as a third A class study found that cardiovascular benefits can be obtained by controlling residual cholesterol. However, with this study, the guideline recommended grade for fibrin-based drugs for triglyceride control is higher than omega-3. It is likely to decrease,” he said.

Meanwhile, in the American Diabetes Association’s diabetes management guidelines published in June, which reflect the fact that the development of pemafibrata has ended, in the subsection relating to statin treatment, ‘statin combination therapy and fibrate’, ‘a proposed study of a new fibrate is in progress’. The content has been deleted.