The metformin in tuberous sclerosis (MiTS) study: A randomised double-blind placebo-controlled trial

Amin, Sam; Mallick, Andrew A; Edwards, Hannah B; Cortina‐Borja, Mario; Laugharne, Matthew; Likeman, Marcus; O'Callaghan, Finbar

doi:10.1016/j.eclinm.2020.100715

Cited by 19 publications

(10 citation statements)

References 40 publications

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“…One trial involved 12 patients with Lafora disease who were treated with metformin and were found to experience a slower progression of the disease [ 25 ]. The second trial was a multicentre, randomised, double-blind, placebo-controlled clinical trial of metformin in the treatment of tuberous sclerosis, which found that metformin reduced seizure frequency compared with the placebo [ 26 ]. From a clinical practice perspective, the present findings, together with previous randomised controlled trials, provide some support for the potential therapeutic role of metformin in patients with epilepsy.…”

Section: Discussionmentioning

confidence: 99%

Genetic prediction of antihyperglycemic drug targets and risk of epilepsy: a mendelian randomisation study

Zhou,

Yang,

Xie

et al. 2024

BMC Pharmacol Toxicol

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A connection between diabetes and an increased risk of epilepsy has been suggested by observational studies. Animal studies have also shown that antihyperglycemic drugs can improve seizures. However, it is unclear whether antihyperglycemic drugs have a causal role in epilepsy in humans. To investigate this potential causal relationship, a Mendelian randomisation study was conducted using International League Against Epilepsy data as the discovery set and FinnGen data as the replication set. It was discovered that three antidiabetic drug target genes, ETFDH, CYP21A2 and CYP2D6, were involved in the occurrence of epilepsy. In particular, ETFDH was identified as a target gene in both the discovery set (inverse variance weighting [IVW], odds ratio [OR] = 1.018, 95% confidence interval [CI], 1.004–1.033, p = 0.009) and replication set (IVW, OR = 1.074, 95% CI, 1.034–1.114, p = 0.00016), and CYP21A2 was identified in the discovery set (IVW, OR = 1.029, 95% CI, 1.005–1.053, p = 0.016) and replication set (IVW, OR = 1.057, 95% CI, 1.001–1.116, p = 0.045) as having a causal association with an increased risk of epilepsy. Conversely, the CYP2D6 gene was found to be a protective factor for epilepsy in both the discovery set (IVW, OR = 0.0984, 95% CI, 0.969–0.998, p = 0.025) and replication set (IVW, OR = 0.977, 95% CI, 0.955–1.000, p = 0.046). A search of DrugBank revealed that metformin, an anti-glucose drug, is an inhibitor of the ETFDH gene and may have a potential therapeutic effect on epilepsy.

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Section: Discussionmentioning

confidence: 99%

Genetic prediction of antihyperglycemic drug targets and risk of epilepsy: a mendelian randomisation study

Zhou,

Yang,

Xie

et al. 2024

BMC Pharmacol Toxicol

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“…Such an approach might even allow employing a less strict dietary protocol. Metformin may be a primary candidate for this, since it has recently demonstrated clinical activity in the model brain tumors driven by the metabolic master regulator mTOR in tuberous sclerosis patients [ 43 ]. Synergistic effects may also be expected by combination with inhibitors of glycolysis like WP1122 [ 44 ] or by blocking glutamine metabolism [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Short-term fasting in glioma patients: analysis of diet diaries and metabolic parameters of the ERGO2 trial

et al. 2021

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Purpose The prospective, randomized ERGO2 trial investigated the effect of calorie-restricted ketogenic diet and intermittent fasting (KD-IF) on re-irradiation for recurrent brain tumors. The study did not meet its primary endpoint of improved progression-free survival in comparison to standard diet (SD). We here report the results of the quality of life/neurocognition and a detailed analysis of the diet diaries. Methods 50 patients were randomized 1:1 to re-irradiation combined with either SD or KD-IF. The KD-IF schedule included 3 days of ketogenic diet (KD: 21–23 kcal/kg/d, carbohydrate intake limited to 50 g/d), followed by 3 days of fasting and again 3 days of KD. Follow-up included examination of cognition, quality of life and serum samples. Results The 20 patients who completed KD-IF met the prespecified goals for calorie and carbohydrate restriction. Substantial decreases in leptin and insulin and an increase in uric acid were observed. The SD group, of note, had a lower calorie intake than expected (21 kcal/kg/d instead of 30 kcal/kg/d). Neither quality of life nor cognition were affected by the diet. Low glucose emerged as a significant prognostic parameter in a best responder analysis. Conclusion The strict caloric goals of the ERGO2 trial were tolerated well by patients with recurrent brain cancer. The short diet schedule led to significant metabolic changes with low glucose emerging as a candidate marker of better prognosis. The unexpected lower calorie intake of the control group complicates the interpretation of the results. Clinicaltrials.gov number: NCT01754350; Registration: 21.12.2012.

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“…Furthermore, pretreatment with metformin reduced inflammatory cytokines and increased the neuroprotective progranulin and anti‐inflammatory cytokines in rats with experimental temporal lobe epilepsy 43 . A randomized clinical trial revealed that metformin reduced epileptic seizure frequency in children with tuberous sclerosis 44 . In addition, metformin is effective against Lafora disease which is a progressive form of myoclonic epilepsy due to a mutation in the EPM2A gene 45 .…”

Section: Metformin and Epilepsymentioning

confidence: 99%

“… 43 A randomized clinical trial revealed that metformin reduced epileptic seizure frequency in children with tuberous sclerosis. 44 In addition, metformin is effective against Lafora disease which is a progressive form of myoclonic epilepsy due to a mutation in the EPM2A gene. 45 A cohort study involved 18 patients with Lafora disease, 8 treated with metformin and 10 untreated showed that metformin was effective in reducing epileptic seizure severity and frequency.…”

Section: Metformin and Epilepsymentioning

confidence: 99%

New insights on the potential anti‐epileptic effect of metformin: Mechanistic pathway

Alnaaim,

Al‐kuraishy,

Al‐Gareeb

et al. 2023

J Cellular Molecular Medi

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Epilepsy is a chronic neurological disease characterized by recurrent seizures. Epilepsy is observed as a well‐controlled disease by anti‐epileptic agents (AEAs) in about 69%. However, 30%–40% of epileptic patients fail to respond to conventional AEAs leading to an increase in the risk of brain structural injury and mortality. Therefore, adding some FDA‐approved drugs that have an anti‐seizure activity to the anti‐epileptic regimen is logical. The anti‐diabetic agent metformin has anti‐seizure activity. Nevertheless, the underlying mechanism of the anti‐seizure activity of metformin was not entirely clarified. Henceforward, the objective of this review was to exemplify the mechanistic role of metformin in epilepsy. Metformin has anti‐seizure activity by triggering adenosine monophosphate‐activated protein kinase (AMPK) signalling and inhibiting the mechanistic target of rapamycin (mTOR) pathways which are dysregulated in epilepsy. In addition, metformin improves the expression of brain‐derived neurotrophic factor (BDNF) which has a neuroprotective effect. Hence, metformin via induction of BDNF can reduce seizure progression and severity. Consequently, increasing neuronal progranulin by metformin may explain the anti‐seizure mechanism of metformin. Also, metformin reduces α‐synuclein and increases protein phosphatase 2A (PPA2) with modulation of neuroinflammation. In conclusion, metformin might be an adjuvant with AEAs in the management of refractory epilepsy. Preclinical and clinical studies are warranted in this regard.

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The metformin in tuberous sclerosis (MiTS) study: A randomised double-blind placebo-controlled trial

Abstract: Please cite this article as: S. Amin et al., The metformin in tuberous sclerosis (MiTS) study: A randomised double-blind placebo-controlled trial,

Cited by 19 publications

References 40 publications

Genetic prediction of antihyperglycemic drug targets and risk of epilepsy: a mendelian randomisation study

Genetic prediction of antihyperglycemic drug targets and risk of epilepsy: a mendelian randomisation study

Short-term fasting in glioma patients: analysis of diet diaries and metabolic parameters of the ERGO2 trial

New insights on the potential anti‐epileptic effect of metformin: Mechanistic pathway

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