Arginine therapy in sickle cell disease: A systematic review and meta-analysis of clinical outcomes.

2026-04
Clinical nutrition ESPEN 72
- Favour M L Foncha
- Joseph Y Bena Nnang
- Samuel G J Fodop
- Best C I Poudjoum
- Dimitri S Tcheuko
- Joel G K Mekontso

PubMed: 41534622
DOI: 10.1016/j.clnesp.2025.102898

Study Design

Type: Meta-Analysis
Sample size: n = 830
Population: patients with sickle cell disease experiencing vaso-occlusive crises
Methods: meta-analysis of RCTs comparing l-arginine with placebo or standard care; PubMed, Embase, and Cochrane databases searched; pooled estimates using random-effects models

Background & aims

Vaso-occlusive crises (VOCs) in sickle cell disease involve nitric oxide deficiency, creating a rationale for l-arginine. This meta-analysis evaluates its efficacy on clinical VOC outcomes including pain, opioid use, and hospitalization by synthesizing evidence from RCTS.

Methods

The PubMed, Embase, and Cochrane databases were searched for RCTs comparing l-arginine with placebo or standard care in SCD patients. Primary outcomes were pain scores, opioid consumption, time to crisis resolution, and length of hospital stay. Pooled estimates were calculated using random-effects models.

Results

Eight RCTs comprising 830 patients were included. Analysis revealed no statistically significant benefit of arginine on primary outcomes. The evidence, of low certainty, indicated no significant effect on pain scores (SMD -1.55, 95 % CI [-6.72, 3.62]) or opioid consumption (MD -0.78 mg/kg, 95 % CI [-2.80, 1.23]). Similarly, no significant differences were observed for time to crisis resolution (MD -12.64 h, 95 % CI [-25.82, 0.54]) or length of hospital stay (MD -24.83 h, 95 % CI [-71.18, 21.51]). A non-significant 23 % increase in hospital readmission risk was observed (RR 1.23, 95 % CI [0.92, 1.65]). Pharmacodynamic analysis confirmed increased plasma arginine levels but showed no significant change in the arginine-to-ornithine ratio.

Conclusion

In summary, this meta-analysis found that l-arginine showed no statistically significant benefit on any primary clinical outcome in patients with sickle cell disease experiencing VOC. This absence of proven efficacy, coupled with a potential safety signal regarding hospital readmissions, precludes its recommendation for routine clinical use. Consequently, these findings underscore the urgent need for a large, definitive RCT to determine the efficacy and safety of arginine therapy.

Research Insights

L-Arginine→Reduced Hospital Readmission Risk
A non-significant 23 % increase in hospital readmission risk was observed (RR 1.23, 95 % CI [0.92, 1.65])
Effect
Neutral
Effect size
Small
L-Arginine→Reduced Length of Hospital Stay
no significant differences were observed for ... length of hospital stay (MD -24.83 h, 95 % CI [-71.18, 21.51])
Effect
Neutral
Effect size
Small
L-Arginine→Reduced Opioid Consumption
no statistically significant benefit ... or opioid consumption (MD -0.78 mg/kg, 95 % CI [-2.80, 1.23])
Effect
Neutral
Effect size
Small
L-Arginine→Reduced Pain
no statistically significant benefit ... no significant effect on pain scores (SMD -1.55, 95 % CI [-6.72, 3.62])
Effect
Neutral
Effect size
Small
L-Arginine→Reduced Time to Crisis Resolution
no significant differences were observed for time to crisis resolution (MD -12.64 h, 95 % CI [-25.82, 0.54])
Effect
Neutral
Effect size
Small

Adverse Events Reported

L-Arginine→hospital readmission
A non-significant 23% increase in hospital readmission risk was observed (RR 1.23, 95% CI [0.92, 1.65]).
Finding
No significant difference
Severity
Serious adverse event
Magnitude
RR 1.23, 95% CI [0.92, 1.65]
Significant
No