ESSENTIAL: Ezetimibe plus statin reduces liver fat

Ezetimibe plus rosuvastatin reduces liver fat in people with nonalcoholic fatty liver disease (NAFLD) in the randomized, active-controlled ESSENTIAL trial.

There was a significant 5.9 percent reduction in liver fat following 24 weeks of treatment with ezetimibe + rosuvastatin compared with baseline magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) values, which was significant (18.2 percent vs 12.3 percent; p<0.001). [EASD 2022, abstract 118]

Rosuvastatin monotherapy also reduced liver fat from 15 percent at baseline to 12.4 percent after 24 weeks, a reduction that was also significant (p=0.003). This translated to an absolute mean difference of 3.2 percent (p=0.02) between the two arms.

“We used MRI-PDFF, which is a highly reliable method of assessing hepatic steatosis,” said study investigator Dr Youngjoon Kim from the Yonsei University College of Medicine, Severance Hospital in Seoul, Korea at EASD 2022. “It enables accurate, repeatable, and reproducible quantitative assessment of liver fat.”

Ezetimibe is commonly added to other regimens to help augment cholesterol lowering in the blood and treat other lipid abnormalities. Ezetimibe + rosuvastatin is widely used in clinical practice, and there had been suggestions that ezetimibe might have effects on liver fat.

“Although the effect of ezetimibe on hepatic steatosis is still controversial, it has been reported to reduce visceral fat and improve insulin resistance in several studies,” Kim said. [Eur J Clin Investig 2012;42:1287-94; [FEBS Lett 2007;581:5664–5670]

Recently, his group reported that the use of ezetimibe affects the autophagy of hepatocytes and NOD-like receptors containing pyrin domain 3 inflammasomes. “Ezetimibe improved nonalcoholic steatohepatitis in an animal model. However, the effects of ezetimibe have not been clearly elucidated in a human study,” he said.  

A previous randomized controlled trial of ezetimibe in 50 patients with NASH showed no benefit for the drug over a placebo in reducing liver fat. [Hepatology 2015;61:1239-1250]

A closer look at ESSENTIAL

ESSENTIAL investigated the effect of ezetimibe on hepatic steatosis in the setting of statin therapy in 70 patients with NAFLD enrolled into this single centre, phase IV trial. Patients were randomly assigned to receive either ezetimibe 10 mg plus rosuvastatin 5 mg daily or rosuvastatin 5 mg for up to 24 weeks.

Both treatments with ezetimibe + rosuvastatin and rosuvastatin monotherapy reduced BMI, waist circumference, triglycerides, and LDL-cholesterol, all of which are associated with a negative outcome in NAFLD. C-reactive protein levels in the blood and interleukin-18 are also reduced. There was no change in liver enzymes.

“These data suggest that ezetimibe + rosuvastatin is a safe and effective therapeutic option for patients with NAFLD and dyslipidaemia,” Kim said.