Cardiovascular risk assessment in the treatment of nonalcoholic steatohepatitis: a secondary analysis of the MOZART trial

Abstract

Background: Nonalcoholic steatohepatitis (NASH) is associated with increased cardiovascular risk and mortality. No US Food and Drug Administration (FDA) approved therapies for NASH are available; clinical trials to date have not yet systematically assessed for changes in cardiovascular risk. This study examines the prospective utility of cardiovascular risk assessments, the Framingham risk score (FRS) and coronary artery calcium (CAC) score, as endpoints in a NASH randomized clinical trial, and assesses whether histologic improvements lead to lower cardiovascular risk. Methods: Secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial (MOZART) in which 50 biopsy-proven NASH patients received oral ezetimibe 10 mg daily (n = 25) versus placebo (n = 25). Biochemical profiling, FRS, CAC scores, liver biopsies were obtained at baseline and endpoint. Results: Ezetimibe improved FRS whereas placebo did not (4.4 ± 6.2 to 2.9 ± 4.8, p = 0.038; 3.0 ± 4.4 to 2.9 ± 4.2, p = 0.794). CAC scores did not change with ezetimibe or placebo (180.4 ± 577.2 to 194.1 ± 623.9, p = 0.293; 151.4 ± 448.9 to 183.3 ± 555.7, p = 0.256). Ezetimibe improved FRS and CAC scores in more patients than placebo (48% versus 23%, p = 0.079, and 21% versus 0%, p = 0.090, respectively), though not significantly. No differences were noted in cardiovascular risk scores among histologic responders versus nonresponders. Conclusions: Ezetimibe improved FRS whereas placebo did not. FRS and CAC scores improved in a greater proportion of patients with ezetimibe; this trend did not reach significance. These findings indicate the utility and feasibility of monitoring cardiovascular risk in a NASH trial. The utility of CAC scores may be higher in trials of longer duration (⩾52 weeks) and with older patients (age ⩾45). ClinicalTrials.gov registration: NCT01766713.

Assessment of treatment response in non‐alcoholic steatohepatitis using advanced magnetic resonance imaging

“…Future studies should incorporate large number of patients and how these MRI measures change in relation to other biomarkers, and metabolic and cardiovascular endpoints . Furthermore, total liver fat index will require further validation, although the reference standard for this index is still unknown.…”

“…Future studies should incorporate large number of patients and how these MRI measures change in relation to other biomarkers, and metabolic and cardiovascular endpoints. 23,40,41 Furthermore, total liver fat index will require further validation, although the reference standard for this index is still unknown. Conceptually, this measure better reflects total liver fat burden as it accounts for fat fraction given a certain volume, the latter of which will vary depending on individual height and weight.…”

“…This is of significance as changes in liver volume may be an important marker of disease progression or regression, as they are associated with metabolic syndrome . Strong associations have also been found between liver enlargement and various cardiovascular risk factors . However, no studies to date have examined the cross‐sectional and longitudinal relationships of these advanced MRI‐derived measures vs. histological features.…”

“…20,21 Strong associations have also been found between liver enlargement and various cardiovascular risk factors. 22,23 However, no studies to date have examined the cross-sectional and longitudinal relationships of these advanced MRI-derived measures vs. histological features.…”

The therapeutic landscape of non‐alcoholic steatohepatitis

“…NAFLD has been significantly associated with an increased risk of fatal and non‐fatal cardiovascular events . An optimal treatment of NASH might reduce liver‐related complications and the risk of cardiovascular events …”