Evidence and Gaps in Clinical Outcomes of L-Glutamine in Sickle Cell Disease: A Systematic Literature Review Highlighting Insights from Clinical Trials and Real-World Studies
Authors: Yassin Mohamed A 
Published: December 2024

Recent advances in pharmacotherapy have led to the development of novel disease-modifying therapies that target cellular adhesion, inflammation, oxidant injury, vascular tone, and haemoglobin polymerisation. In 2017, L-glutamine was approved by the US Food and Drug Administration (FDA) for oral administration in adults and paediatric patients aged above 5 years with SCD
The objective of the current review is to summarise the safety and efficacy outcomes of L-glutamine in SCD based on data from clinical trials and real-world settings and to identify any differences or gaps in clinical outcome data
Methods:
We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Evidence-Based Medicine (EBM) Reviews-Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase (2017-2024), and Ovid MEDLINE(R) ALL were the electronic databases searched for clinical trials, observational studies, case series, and case reports published in English. The key terms used in searches included: “sickle cell disease”, “sickle cell anaemia”, “L-glutamine”, “real-world studies”, “clinical trials”, and “HbSS”. The search included all articles published up to 31 May 2024. Studies on gene therapies and haematopoietic stem-cell transplantation were excluded.
Results:
In the 3 included clinical trials of L-glutamine, the mean number of pain crises was reported in the Niihara et al. study, a placebo-controlled, double-blind, phase 3 trial. The study reported a median of 3.0 pain crises related to SCD in the L-glutamine group (n=152) and a median of 4.0 (n=78) in the placebo group (p=0.005) at 48 weeks. The median time to the first pain crisis was 84 days in the L-glutamine group, as compared with 54 days in the placebo group, and the median time to the second pain crisis was 212 days in the L-glutamine group and 133 days in the placebo group..
Of the 5 real-world observational studies on L-glutamine, the Elenga et al. 2022 study (n=19) reported a median change in pain crisis from 3.0 (at baseline) to 0.0 (at 24, 48, and 72 weeks) (p&lt;0.00001) following L-glutamine therapy initiation. None of the real-world studies reported the median time to the first and The Niihara et al. study reported a median of 2 hospitalisations in the L-glutamine group compared with a median of 3 in the placebo group. The number of emergency department visits that did not result in hospitalisation did not differ significantly between the trial groups (p=0.09), with a median of 1 visit in each group.
The Elenga et al. (2022) real-world study reported a significant reduction in the rate of annual hospitalisations over 72 weeks from baseline (median change from 3.0 to 0.0; P &lt; 0.00001). Additionally, patients spent fewer days in hospital compared to baseline (median change from 15.0 to 0.0; In the Niihara et al. study, 13 patients (8.6%) experienced at least one episode of ACS in the L-glutamine group (n=152), as compared with 18 patients (23.1%) in the placebo group (n=78) during the study period . Real-world data from the Elenga et al. (2022) study reported only 2 ACS events after 48 weeks of L-glutamine treatment
In the real-world study by Elenga et al. (2023), marked improvements in renal parameters, including albumin creatinine ratio (ACR), albuminuria levels, serum creatinine, urea creatinine, and eGFR, were observed at 48 weeks following L-glutamine therapy, which remained sustained until 120 weeks compared with 11 ACS events at baseline P &lt; 0.00001) .
In a case series (n=4) from Wilson et al. (2019), each patient reported a reduction in acute and chronic SCD-related pain following initiation of L-glutamine therapy. Additionally, a reduction in opioid use at 4 months, ranging from 21% to 100%, was observed after initiation of L-glutamine therapy
change in haematological parameters, including change in Hb levels, reticulocyte count, and LDH levels from baseline, was not recorded in any clinical trials on L-glutamine. Findings from 2 observational studies showed an improvement in Hb levels and a reduction in haemolysis markers from baseline following treatment with L-glutamine
Conclusion:
The current review support the efficacy and safety of L-Gluatmine for patients with SCD confirming the findings from clinical trials and proposing further protentional benefits, however further studies are required to confirm these findings.