Figure 1
Study selection flow diagram
Table 1
Characteristics of the studies included in the meta-analysis
| Author | Year [ref] | Country | Study design | Patients, n† | Type of statin (mg/dL) | Follow-up time (year) | Statin duration (year) | Study quality§ | |
|---|---|---|---|---|---|---|---|---|---|
| Nelson et al | 2009 [18] | USA | RCT | 10‡ | Simvastatin (40) | 1 | 1 | Low|| | |
| Ekstedt et al | 2007 [13] | Sweden | Retrospective | 17 | NA | 10.3–16.3 | 1–15.9 | Ser¶ | |
| cohort | |||||||||
| Hyogo et al | 2011 [14] | Japan | Prospective | 13 | Pitavastatin (2) | 1 | 1 | Mod¶ | |
| cohort | |||||||||
| Nakahara et al | 2012 [15] | Japan | Prospective | 9 | Rosuvastatin (2.5) | 2 | 2 | Mod¶ | |
| cohort | |||||||||
| Hyogo et al | 2012 [16] | Japan | Prospective | 42 | Atorvastatin (10) | 1 | 1 | Mod¶ | |
| cohort | |||||||||
| Kargiotis et al | 2015 [17] | Greece | Prospective | 20 | Rosuvastatin (10) | 1 | 1 | Mod¶ | |
| cohort |
Mod, moderate; NA, not available; RCT, randomized controlled trial; Ser, serious.
§ Quality assessment using Cochrane Collaboration’s tool for assessing risk of bias for RCT and Cochrane assessment of bias for non-randomized studies tool (ROBINS-I).
|| Risk of bias legend for RCT illustrated in Table 4
¶ Risk of bias legend for nonrandomized studies illustrated in Table 5.
¶ Risk of bias legend for nonrandomized studies illustrated in Table 5.
¶ Risk of bias legend for nonrandomized studies illustrated in Table 5.
¶ Risk of bias legend for nonrandomized studies illustrated in Table 5.
¶ Risk of bias legend for nonrandomized studies illustrated in Table 5.
Table 2
Summary effects of statins on liver steatosis and fibrosis parameters
| Outcomes | Studies, n | Patients, n | Standardized mean change† | P | Assessment of heterogeneityI2 index, %‡ Q-test, P‡ | |
|---|---|---|---|---|---|---|
| % of steatosis | 2 | 27 | –0.580 (–1.599, 0.439) | 0.265 | 93 | <0.001 |
| Steatosis grading | 3 | 42 | –2.580 (–4.623, –0.536) | 0.013 | 98 | <0.001 |
| NAFLD activity score | 4 | 84 | –1.488 (–2.506, –0.471) | 0.004 | 96 | <0.001 |
| Necroinflammatory activity grade | 2 | 23 | –0.112 (–0.372, 0.148) | 0.398 | 0 | 0.454 |
| Fibrosis stage | 4 | 49 | 0.156 (–0.553, 0.865) | 0.667 | 92 | <0.001 |
| Total cholesterol | 6 | 111 | –1.540 (–2.221, –0.859) | <0.001 | 93 | <0.001 |
| Triglyceride | 6 | 111 | –0.764 (–1.334, –0.195) | 0.009 | 94 | <0.001 |
| High-density lipoprotein | 4 | 84 | 0.423 (–0.070, 0.917) | 0.093 | 89 | <0.001 |
| Low-density lipoprotein | 5 | 94 | –1.865 (–2.416, –1.313) | <0.001 | 83 | <0.001 |
| Alanine transaminase | 5 | 91 | –0.511 (–0.650, –0.373) | <0.001 | 0 | 0.680 |
| Aspartate aminotransferase | 5 | 91 | –0.462 (–0.599, –0.325) | <0.001 | 0 | 0.594 |
[i] Data in parentheses denote 95% confidence limits. †By random-effects model meta-analysis. ‡A measure of statistical heterogeneity across study results; either I2 > 50% or χ2 test P < 0.1 indicates substantial heterogeneity [11].
[ii] NAFLD, non-alcoholic fatty liver disease.
Table 3
Outcomes and main findings of the studies included in the meta-analysis
| Author (year) | Outcomes | Main findings | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| % of steatosis | Steatosis grading | NAS | Necroinflammatory activity grade | Fibrosis stage | Total cholesterol | Triglyceride | HDL | LDL | ALT | AST | |||
| Nelson et al. (2009) [18] | Yes | No | No | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes | - 26% reduction in LDL between simvastatin vs placebo | |
| - No statistically significant improvement in ALT, AST, hepatic steatosis, necroinflammatory activity, or stage of fibrosis within or between groups | |||||||||||||
| Ekstedt et al. (2007) [13] | Yes | No | No | No | Yes | Yes | Yes | No | No | Yes | Yes | - Significant reduction in quantitative steatosis in the statin cohort between baseline and follow-up | |
| - AST/ALT did not differ significantly between the two cohorts | |||||||||||||
| Hyogo et al. (2011) [14] | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | - Significant decrease in ALT and lipid profiles | |
| - NAS tended to be decreased but statistical significance was not shown | |||||||||||||
| - Fibrosis stage did not change significantly | |||||||||||||
| Nakahara et al. (2012) [15] | No | Yes | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | - Mean AST/ALT did not significantly change during the treatment | |
| - NAS and fibrotic stage tended to decrease after the treatment but statistical significance was not shown | |||||||||||||
| Hyogo et al. (2012) [16] | No | No | Yes | No | No | Yes | Yes | Yes | Yes | Yes | Yes | - Significant decrease in AST and ALT | |
| - Significant improvement in NAS | |||||||||||||
| Kargiotis et al. (2015) [17] | No | Yes | Yes | No | No | Yes | Yes | Yes | Yes | No | No | - Complete resolution of NASH in 19 of 20 patients | |
| - AST, ALT, and lipid profiles were normalized by the 3rd month of treatment | |||||||||||||
[i] ALT, alanine transaminase; AST aspartate aminotransferase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NAS, non-alcoholic fatty liver disease activity score; NASH, non-alcoholic steatohepatitis.
Table 4
Risk of bias for the randomized controlled trial by Nelson et al. [18]
| Grade | Bias |
|---|---|
| • | Random sequence generation (selection bias) |
| • | Allocation concealment (selection bias) |
| ○ | Blinding of participants and personnel (performance bias) |
| ○ | Blinding of outcome assessment (detection bias) |
| ○ | Incomplete outcome data (attrition bias) |
| • | Selective reporting (reporting bias) |
[i] Black, high grade; gray, moderate grade; white, low grade.
Table 5
Risk of bias assessment for nonrandomized studies
| Domain | Ekstedt et al. [13] | Hyogo et al. [14] | Nakahara et al. [15] | Hyogo et al. [16] | Kargiotis et al. [17] |
|---|---|---|---|---|---|
| Confounding | Moderate | Moderate | Moderate | Moderate | Moderate |
| Selection | Serious | Low | Low | Low | Low |
| Measurement of interventions | Serious | Low | Low | Low | Low |
| Performance | Low | Low | Low | Low | Low |
| Missing data | Low | Low | Low | Low | Low |
| Measurement of outcomes | Low | Low | Low | Low | Low |
| Reporting | Low | Low | Low | Low | Low |
| Overall | Serious | Moderate | Moderate | Moderate | Moderate |
Figure 2
Forest plot displaying the effect of statin on Std diff of steatosis grading. CI, confidence interval; Std diff, standardized mean difference
Figure 3
Forest plot displaying the effect of statin on Std diff of NAFLD activity score (NAS). CI, confidence interval; NAFLD, non-alcoholic fatty liver disease; NAS, non-alcoholic fatty liver disease activity score; Std diff, standardized mean difference
Figure 4
Forest plot displaying the effect of statin on Std diff of fibrosis stage. CI, confidence interval; Std diff, standardized mean difference