Glucose and antidiabetic therapy in temozolomide resistance in glioblastoma

Table 2 Summary of current limitations and directions for future research on metformin in glioblastoma

Limitation	Underlying issues	Proposed solutions /future directions
Heterogeneous trial designs	Inconsistent patient selection (MGMT status, IDH mutation)	Stratify future trials by molecular subtypes and metabolic profiles
Variable dosing and exposure	Metformin doses ranged from 1000 to 2250 mg/day; durations varied	Standardize dosing protocols; consider longer duration studies
Inadequate CNS penetration	Metformin is hydrophilic, and the blood-brain barrier limits delivery	Explore alternative delivery systems (nanoerythrosomes, liposomal carriers)[58,60]
Lack of metabolic data	Poor glycemic control and steroid use are often unreported	Integrate glycemic monitoring and steroid adjustment protocols in trial design
Biomarker absence	No validated predictors of response	Identify and validate predictive biomarkers (AMPK activity, gemistocyte index, insulin resistance)

MGMT: O6-methylguanine-DNA methyltransferase; CNS: Central nervous system; IDH: Isocitrate dehydrogenase.