A 2019 systematic review and meta-analysis assessed the effects of statins compared to placebo on the risk of developing hypertransaminasemia. A total of 73 randomized controlled trials (RCTs) were included, comprising 123,051 patients. Overall, there was a notable rise in hypertransaminasemia observed in individuals undergoing statin treatment when compared to those receiving placebo (odds ratio [OR] 1.45; 95% confidence interval [CI] 1.24 to 1.69; p<0.001; I2= 14%). Treatment with rosuvastatin and lovastatin was linked to a 35% and 53% increase in the odds of developing hypertransaminasemia, respectively. Conversely, pravastatin, simvastatin, and fluvastatin did not increase the odds of developing high transaminase levels compared to placebo. Among all statins, atorvastatin demonstrated the highest odds (OR 2.66; 95% CI 1.74 to 4.06; p<0.001; absolute effect of 10 more per 1,000 patients), followed by rosuvastatin (OR 1.35; 95% CI 1.06 to 1.70; p<0.01; absolute effect of 3 more per 1,000 patients), and lovastatin (OR 1.53; 95% CI 1.03 to 2.28; p<0.04; absolute effect of 3 more per 1,000 patients). High doses of atorvastatin resulted in an absolute increase of 48 events per 1,000 patients. While fluvastatin similarly raised the absolute risk of developing hypertransaminases, the odds ratio did not reach statistical significance, and the level of evidence certainty was low. [1]
The overall class analysis was stratified based on high-dose statins and standard doses of statins against placebo. High-dose statin treatment significantly increased the risk of hypertransaminasemia compared to placebo (OR 1.64; 95% CI 1.30 to 2.06; p<0.001). Notably, fluvastatin, pravastatin, and simvastatin did not exhibit a significant difference in odds compared to placebo. Elevated odds of hypertransaminasemia were observed with high doses of atorvastatin (78% increase), rosuvastatin (47% increase), and lovastatin (53% increase). The same analysis was performed with standard doses of statins, to which findings demonstrated no difference compared with placebo (OR 1.19; 95% CI 0.98 to 1.46; p= 0.08; I2= 0%). In trials with standard doses of lovastatin, pravastatin, and fluvastatin, hypertransaminasemia did not occur. Atorvastatin sensitivity analysis revealed an elevated risk of liver toxicity across all subgroups, with the highest rates observed in those with acute coronary syndrome (ACS) and acute cerebrovascular events. Atorvastatin sensitivity analysis showed no effects from diabetes, hypercholesterolemia, or renal failure. However, focusing solely on studies involving ACS or cerebrovascular events significantly increased the overall risk (OR 4.49; 95% CI 2.79 to 7.22; p<0.001; I2= 0%). It was suggested that various statin types and doses exhibit distinct potentials for increasing hypertransaminasemia incidence. High doses of atorvastatin, rosuvastatin, and lovastatin pose higher risks of liver function tests (LFT) abnormalities. [1]
A 2022 meta-analysis (N= 47 RCTs; 107,752 participants) explored the association of transaminase elevations with varying statin types and dosages. Participants with established atherosclerotic cardiovascular diseases (ASCVD) and statin treatments (either monotherapy or add-on) were followed for up to ~4 years. Studies with less than 4 weeks of intervention or less than 100 patients were excluded. Compared to non-statin treatments, statins were associated with an increased risk of transaminase elevations (OR 1.62; 95% CI 1.20 to 2.18). Of the statins, atorvastatin exhibited a higher risk of transaminase elevations versus non-statin control (OR 4.0; 95% CI 2.2 to 7.6), pravastatin (OR 3.49; 95% CI 1.77 to 6.92), and simvastatin (OR 2.77; 95% CI 1.31 to 5.09). When directly comparing treatments (N= 35 RCTs), simvastatin was associated with a lower risk of muscle problems versus atorvastatin (OR 0.70; 95% CI 0.55 to 0.90), whereas rosuvastatin was associated with a higher risk versus atorvastatin (OR 1.75; 95% CI 1.17 to 2.61). Based on surface under the cumulative ranking values, of the statins, pravastatin had the highest rank (i.e., a better outcome for the intervention) for transaminase elevations (76.3%), followed by simvastatin (62.0%), lovastatin (56.2%), rosuvastatin (43.0%), fluvastatin (37.2%), pitavastatin (22.8%), and atorvastatin (15.3%). Based on these analyses, the investigators advise avoiding atorvastatin use in the event of transaminase elevations, especially high-intensity doses, and that pravastatin may be preferable instead. [2]
A 2021 meta-analysis (N= 62 RCTs; 120,456 participants) evaluated the association between statins and adverse events in primary prevention of cardiovascular disease while exploring variations in these associations based on statin types and dosages. The analysis identified several adverse events associated with statin use, including increased risks of self-reported muscle symptoms, liver dysfunction, renal insufficiency, and eye conditions. The findings revealed that statin use was associated with an increased risk of liver dysfunction, characterized by elevated serum liver enzyme concentrations across all studies (N= 21 trials; OR 1.33; 95% CI 1.12 to 1.58). In the comparative analysis of different statin types atorvastatin (N= 17 studies; OR 1.41; 95% CI 1.08 to 1.85) and lovastatin (N= 5 trials; OR 1.81; 95% CI 1.23 to 2.66) were associated with increased risks of liver dysfunction. However, there were no statistically significant risks associated with other statins. Notably, a dose-response analysis revealed that atorvastatin exhibited a maximum effect, doubling the risk of liver dysfunction compared to non-statin controls (maximum OR 2.03; 95% credible interval 1.03 to 12.64). Conversely, the analysis did not find any significant dose-response relationships for the other statins concerning adverse effects. Based on these findings, it was concluded that statins showcased a small increased risk of liver dysfunction in patients without a history of cardiovascular disease. However, it is essential to note that many of the analyses lacked sufficient power to detect differences between groups, and some trials excluded vulnerable patients who may have been more likely to experience adverse events. Additionally, many of the included trials (27/62) had follow-up periods ≤ 6 months, potentially resulting in an underestimation of severe long-term complications such as significant liver injury. [3]
A 2017 review examined the hepatotoxicity associated with statins and other lipid-lowering drugs. Notably, the analysis on statins revealed distinct patterns in their association with hepatotoxicity. Categorization, based on case reports, places both simvastatin (68 cases) and atorvastatin (65 cases) within Category A (drugs with more than 50 well-documented cases of hepatotoxicity), showcasing instances of positive rechallenge and reported fatal liver injury. Fluvastatin (28 cases) also exhibited substantial hepatotoxicity and documented positive rechallenge; however, there was no incidence of fatal liver injuries within these reports. In contrast, rosuvastatin, lovastatin, and pravastatin, with 13, 12, and 11 reported cases, respectively, showed no associations with positive rechallenge or fatal liver injury based on available reports. Regarding the tolerance of other statins in patients with statin-induced liver injury, it was highlighted that data remains limited. One case report describes a patient recovering from fluvastatin-induced liver injury subsequently experiencing liver injury with atorvastatin. However, in a Swedish study, five cases switched to another statin post-recovery without subsequent liver injury during follow-up. Importantly, these statin transitions were successful without causing further liver-related issues. Overall, it is essential to interpret these findings with caution as they are based solely on reported cases and do not consider the varying prescription rates of each statin. [4]