Choline fenofibrate–statin combo a feasible triglyceride-lowering strategy in Asians

In Korean patients with well-controlled low-density lipoprotein (LDL) levels but elevated triglyceride (TG) levels, combination therapy with choline fenofibrate and statin helps reduce serum TG levels without increasing the number of adverse events compared with statin monotherapy, as shown in the results of a phase IV study.

Eight weeks of combination therapy led to a 45.57-percent drop in TG levels, with more than half of the patients treated (65.57 percent) achieving the target TG level of 150 mg/dL, according to a team of investigators based in South Korea. [Clin Ther 2021;doi:10.1016/j.clinthera.2021.08.005]

Furthermore, the patients on combination therapy group showed more favourable changes in mean serum high-density lipoprotein cholesterol (HDL-C) levels, which increased from 45.0 to 50.4 mg/dL (p=0.0004). There was barely any change observed in those on statin monotherapy (from 44.3 to 44.7 mg/dL).

“The test drug was a combined form of choline salt and fenofibric acid. On ingestion, the choline salt dissociates because of the pH conditions in the gastrointestinal tract and gets converted to the active form, fenofibric acid. Therefore, choline fenofibrate can be taken regardless of food, whereas traditional fenofibrate needs to be taken immediately after meals,” they pointed out. [Int J Pharm 2015;490:273-280; Arch Pharm Res 2016;39:531-538]

In the current study, 127 patients (mean age 58.7 years, 63.9 percent male) already on statin monotherapy (atorvastatin 10 or 20 mg or rosuvastatin 10 mg) for at least 4 weeks were randomized to receive either choline fenofibrate in addition to their current statin regimen (combination n=64; mean baseline TG 269.8 mg/dL) or continue taking statin (control n=63; mean baseline TG 271.1 mg/dL).

Mean serum TG levels significantly decreased from 269.8 to 145.5 mg/dL (p<0.0001) in the combination therapy group, whereas there was a slight increase noted in the control group (from 271.1 to 280.5 mg/dL).

Safety concerns

In terms of safety, none of the patients in the combination group developed serious adverse events. Meanwhile, serum creatinine levels increased by approximately 0.14 mg/dL in the combination group but remained unchanged in the control group. This increase, however, did not cause any clinical problems or symptoms. Changes in liver enzymes and total bilirubin levels did not markedly differ between the two treatment groups.

“Similar to what was seen in this study, most other clinical trials using fenofibrate have also found a slight elevation in serum creatinine levels within weeks of starting therapy. This elevation in serum creatinine level could be more severe in those with chronic kidney disease (CKD), those taking high doses of fenofibrate, those taking other medications that affect renal function (eg, angiotensin receptor blockers), and in elderly populations,” the investigators explained, adding that the elevation could be reversed by terminating fenofibrate therapy or, in some cases, without having to discontinue medication. [Eur J Clin Invest 2013;43:522-531; J Clin Lipidol 2012;6:19-26]

“Another concern in the administration of fenofibrate-statin combination therapy is the risk of rhabdomyolysis, which is slightly more common than that with statin monotherapy. The actual risk, however, is very low,” they said. “[So]fenofibrate-statin combination therapy should be used with caution in patients with CKD.” [Expert Opin Drug Saf 2015;14:1481-1493]

TG-lowering in Asians

With regard to the question of whether TG-lowering might be beneficial to Asians, the investigators cited several studies that suggested elevated TG levels as an independent predictor of cardiovascular disease in the Asian population. [Diabetes Metab Res Rev 2005;21:183-188; Atherosclerosis 2010;209:290-294]

“Among studies subsequently conducted in the Asian population, the Effectiveness of Fenofibrate Therapy in Residual Cardiovascular Risk Reduction in the Real World Setting (ECLIPSE-REAL) study published in 2019 is noteworthy… The most significant limitation of [it] was that it was not a double-blind, randomized study. However, the study included only Asian patients,” they noted. [BMJ 2019;366:l5125]

Asians, according to the investigators, are metabolically more susceptible to hypertriglyceridemia than people of other ethnicities, and this discrepancy may be genetic. This is the same reason that hypertriglyceridemia is an independent risk factor of cardiovascular disease in the Asian population. [Am J Clin Nutr 2004;80:832-840; Cardiology 2015;131:228-235]

“Therefore, management of lipid levels, including TG, is particularly important in those of Asian ethnicity, and fenofibrate-statin combination therapy could be an effective strategy to achieve this treatment goal,” they said. [Korean Circ J 2020;50:940-948]