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.

Keywords: Framingham risk; coronary artery calcium; fatty liver; hepatic steatosis; score.

Conflict of interest statement

Conflict of interest statement: The authors declare no conflicts of interest in preparing this article.

Figures

Figure 1.

Mean baseline coronary artery calcium (CAC) scores by age groups. At baseline, the mean CAC scores by age groups are as follows: 18–24, 0 (n = 4); 25–34, 0.3 (n = 3); 35–44, 0 (n = 9); 45–54, 9.2 (n = 12); 55–64, 213.1 (n = 9); ages ⩾65, 412.5(n = 8).

Figure 2.

Changes in mean Framingham risk score (FRS) and coronary artery calcium (CAC) scores between treatment arms. (a) Over 24 weeks of treatment for nonalcoholic steatohepatitis (NASH), ezetimibe (n = 23) improved mean FRS from 4.4 ± 6.2 to 2.9 ± 4.8, p = 0.0383, while no change was observed with placebo (n = 22, 3.0 ± 4.4 to 2.9 ± 4.2, p = 0.7944). The mean difference of FRS between the ezetimibe and placebo arms was −0.79 ± 2.6 (p = 0.0759). (b) In the ezetimibe arm (n = 14), mean CAC scores changed from 180.4 ± 577.2 to 194.1 ± 623.9, p = 0.2928. In the placebo arm (n = 16), mean CAC scores changed from 151.4 ± 448.9 to 183.3 ± 555.7, p = 0.2560. However, these changes were not statistically significant. The mean difference of CAC scores between the two treatment arms was 23.4 ± 84.2, p = 0.5507.

Figure 3.

Coronary artery calcium (CAC) imaging of a patient prior to and after 24-week treatment with ezetimibe. The green shaded areas denote the presence of coronary calcification in the left anterior descending (LAD) coronary artery before (a) and after (b) treatment with ezetimibe for 24 weeks. The green outline indicates the area drawn by the radiologist for the computer software to calculate the Agatston score for the LAD, which is added to the Agatston score of the other coronary arteries for a composite coronary artery calcium score. Note that the patient is slightly rotated during the second imaging session.

Figure 4.

Proportion of patients with corresponding changes in cardiovascular risk scores. Among 23 patients treated with ezetimibe, 11 (48%) had improved Framingham risk score (FRS), versus 5 of 22 patients (23%) in the placebo arm (chi-squared p value = 0.079). Coronary artery calcium (CAC) scores also improved in 3 of 14 patients (21%) in the ezetimibe arm, versus 0 of 16 (0%) in the placebo arm, though this was not a significant difference (Fisher’s p value = 0.090).