Impact of Statin or Fibrate Therapy on Homocysteine Concentrations: A Systematic Review and Meta-analysis

Introduction: Statins and fibrates are two lipid-lowering drugs used in patients with dyslipidemia. This systematic review and meta-analysis were conducted to determine the magnitude of the effect of statin and fibrate therapy on serum homocysteine levels. Methods: A search was undertaken of the PubMed, Scopus, Web of Science, Embase, and Google Scholar electronic databases up to 15 July 2022. Primary endpoints focused on plasma homocysteine levels. Data were quantitatively analyzed using fixed or random- effect models, as appropriate. Subgroup analyses were conducted based on the drugs and hydrophilic-lipophilic balance of statins. Results: After screening 1134 papers, 52 studies with a total of 20651 participants were included in the meta-analysis. The analysis showed a significant decrease in plasma homocysteine levels after statin therapy (WMD: -1.388 μmol/L, 95% CI: [-2.184, -0.592], p = 0.001; I2 = 95%). However, fibrate therapy significantly increased plasma homocysteine levels (WMD: 3.459 μmol/L, 95% CI: [2.849, 4.069], p < 0.001; I2 = 98%). The effect of atorvastatin and simvastatin depended on the dose and duration of treatment (atorvastatin [coefficient: 0.075 [0.0132, 0.137]; p = 0.017, coefficient: 0.103 [0.004, 0.202]; p = 0.040, respectively] and simvastatin [coefficient: -0.047 [-0.063, -0.031]; p < 0.001, coefficient: 0.046 [0.016, 0.078]; p = 0.004]), whereas the effect of fenofibrate persisted over time (coefficient: 0.007 [-0.011, 0.026]; p = 0.442) and was not altered by a change in dosage (coefficient: -0.004 [-0.031, 0.024]; p = 0.798). In addition, the greater homocysteine- lowering effect of statins was associated with higher baseline plasma homocysteine concentrations (coefficient: -0.224 [-0.340, -0.109]; p < 0.001). Conclusion: Fibrates significantly increased homocysteine levels, whereas statins significantly decreased them.