A randomized controlled trial on the efficacy, safety, and pharmacokinetics of metformin in severe traumatic brain injury

• Published in: Journal of neurology Vol. 266; no. 8; pp. 1988 - 1997
• Main Authors: Taheri, Ali, Emami, Mahdi, Asadipour, Erfan, Kasirzadeh, Sara, Rouini, Mohammad-Reza, Najafi, Atabak, Heshmat, Ramin, Abdollahi, Mohammad, Mojtahedzadeh, Mojtaba
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-08-2019; Springer Nature B.V
• Subjects: Acidosis; Adult; Antidiabetics; Biomarkers - blood; Brain Injuries, Traumatic - blood; Brain Injuries, Traumatic - diagnosis; Brain Injuries, Traumatic - drug therapy; Clinical trials; Demography; Female; Follow-Up Studies; Glial fibrillary acidic protein; Hemodynamics; Humans; Hypoglycemia; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - blood; Hypoglycemic Agents - therapeutic use; Inflammation; Ischemia; Lactic acidosis; Longitudinal Studies; Male; Medicine; Medicine & Public Health; Metformin; Metformin - adverse effects; Metformin - blood; Metformin - therapeutic use; Middle Aged; Morbidity; Neurology; Neuroprotection; Neuroradiology; Neurosciences; Original Communication; Pharmacokinetics; S100 Calcium Binding Protein beta Subunit - blood; S100b protein; Serum levels; Severity of Illness Index; Single-Blind Method; Statistical analysis; Traumatic brain injury; Treatment Outcome; Young Adult; Biomarker; Traumatic brain injury; Metformin; Head trauma; S100b; Pharmacokinetics
• ISSN: 0340-5354; 1432-1459
• DOI: 10.1007/s00415-019-09366-1

Objective
Traumatic brain injury (TBI) is a leading cause of morbidity and mortality worldwide. Metformin is reported to have pleiotropic neuroprotective effects through anti-inflammatory, antioxidative, and anti-ischemic activity, and improvements in vascular hemodynamics and endothelial function. The aim of this study is to examine the efficacy and safety of metformin therapy in severe TBI patients.
Methods
This single-blind, parallel-group, randomized controlled trial enrolled adult TBI patients. Of 158 trauma patients assessed, 30 met the eligibility criteria and were randomly allocated in a one-to-one ratio to receive 1 g metformin every 12 h for five consecutive days (intervention group) or to usual management only (control group). For efficacy analysis, temporal profiles of serum levels of S100b, neutrophil to lymphocyte ratio (NLR), and glial fibrillary acidic protein (GFAP) were assessed. For pharmacokinetic analysis, serum concentrations of metformin were evaluated in the intervention group.
Results
The two study groups were similar in terms of demographics, baseline clinical characteristics, and on-admission biomarkers’ serum levels. Longitudinal analysis of S100b and NLR levels showed statistically significant declines in values toward normal levels in the intervention group (
p
values of < 0.001 and 0.030, respectively), different from the profiles of the control group (
p
values of 0.074 and 0.645, respectively). Pharmacokinetic analysis demonstrated that metformin absorption is delayed in TBI patients. No events of hypoglycemia and lactic acidosis occurred.
Conclusions
Metformin could potentially be an effective and safe therapeutic intervention in patients with severe TBI. Large-scale, multicentre studies are needed to confirm our encouraging results.