You will be presented with a collection of medical randomized controlled trial (RCT) reports addressing a shared clinical question -- for instance, the efficacy of a medical intervention on a disease or condition. Given the titles and abstracts of these reports, your task is to generate the conclusion of the systematic review article synthesizing the key findings. Your conclusion should be a few sentences long. In your response, include only the conclusion and no other text. The RCT reports are below.



Title 1:
Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial.
Abstract 1:
BACKGROUND & AIMS Given the long term benefits observed with metformin use in diabetes patients , a role in modulating oxidative stress is imputable . Effects of metformin on markers of oxidative stress , antioxidant reserve , and HDL-c associated antioxidant enzymes were investigated . METHODS In a clinical trial setting ( Registered under Clinical Trials.gov Identifier no. NCT01521624 ) 99 medication-naïve , newly diagnosed type 2 diabetes patients were r and omly assigned to either metformin or lifestyle modification .  AOPP , AGE , FRAP , activities of LCAT , and PON were measured at baseline and after 12-weeks . RESULTS Baseline values of the oxidative stress markers did not differ significantly between the two groups . In cases , after three months treatment , there was a significant reduction in AOPP ( 137.52 ± 25.59 , 118.45 ± 38.42 , p < 0.001 ) , and AGE ( 69.28 ± 4.58 , 64.31 ± 8.64 , p = 0.002 ) . FRAP and PON increased significantly ( 1060.67 ± 226.69 , 1347.80 ± 251.40 , p < 0.001 and 29.85 ± 23.18 , 37.86 ± 27.60 , p = 0.012 respectively ) . LCAT levels remained unchanged ( 45.23 ± 4.95 , 46.15 ± 6.28 , p = 0.439 ) . Comparing the two groups in a final multivariate model , AOPP , FRAP , and AGE levels changed more significantly in metformin compared with lifestyle modification alone ( p = 0.007 , p < 0.001 and p < 0.001 respectively ) . Escalation in LCAT or PON activities did not differ between the two groups ( p = 0.199 and 0.843 respectively ) . CONCLUSIONS Use of metformin is more effective in reducing oxidative stress compared with lifestyle modification alone


Title 2:
Effects of the Insulin Sensitizer Metformin in Alzheimer Disease: Pilot Data From a Randomized Placebo-controlled Crossover Study
Abstract 2:
Epidemiological studies have identified a robust association between type II diabetes mellitus and Alzheimer disease ( AD ) , and neurobiological studies have suggested the presence of central nervous system insulin resistance in individuals with AD . Given this association , we hypothesized that the central nervous system – penetrant insulin-sensitizing medication metformin would be beneficial as a disease-modifying and /or symptomatic therapy for AD , and conducted a placebo-controlled crossover study of its effects on cerebrospinal fluid ( CSF ) , neuroimaging , and cognitive biomarkers . Twenty nondiabetic subjects with mild cognitive impairment or mild dementia due to AD were r and omized to receive metformin then placebo for 8 weeks each or vice versa . CSF and neuroimaging ( Arterial Spin Label MRI ) data were collected for biomarker analyses , and cognitive testing was performed . Metformin was found to be safe , well-tolerated , and measureable in CSF at an average steady-state concentration of 95.6 ng/mL. Metformin was associated with improved executive functioning , and trends suggested improvement in learning/memory and attention . No significant changes in cerebral blood flow were observed , though post hoc completer analyses suggested an increase in orbitofrontal cerebral blood flow with metformin exposure . Further study of these findings is warranted


Title 3:
Differential metformin dose-dependent effects on cognition in rats: role of Akt
Abstract 3:
RationalE pidemiological evidence suggests that individuals with diabetes mellitus are at greater risk of developing Alzheimer ’s disease , and controversy overwhelms the usefulness of the widely prescribed insulin-sensitizing drug , metformin , on cognition . Objectives Through the scopolamine-induced memory deficit model , we investigated metformin influence on cognitive dysfunction and explored underlying mechanisms . Methods Sixty adult male Wistar rats were r and omly assigned into 5 groups ( 12 rats each ) to receive either normal saline , scopolamine 1 mg/kg intraperitoneally once daily , scopolamine + oral metformin ( 100 mg/kg/day ) , scopolamine + oral metformin ( 300 mg/kg/day ) or scopolamine + oral rivastigmine ( 0.75 mg/kg/day ) for 14 days . Cognitive behaviours were tested using Morris water maze and passive avoidance tasks . Biochemically , brain oxidative ( malondialdehyde ) and inflammatory ( TNF-α ) markers , nitric oxide , Akt , phospho-Akt , phospho-tau and acetyl cholinesterase activity in hippocampal and cortical tissues were assessed . Results The lower dose of metformin ( 100 mg/kg ) ameliorated scopolamine-induced impaired performance in both Morris water maze and passive avoidance tasks , and was associated with significant reduction of inflammation and to a lesser extent oxidative stress versus rivastigmine . Given the role of total Akt in regulation of abnormal tau accumulation and degradation , our finding that metformin 100 decreased the elevated total Akt while increasing its phosphorylated form explains its beneficial modulatory effect on phosphorylated tau in both tissues , and could further clarify its protection against memory impairment . Conclusion Metformin , only in the average human antidiabetic dose , offers a protective effect against scopolamine-induced cognitive impairment , while no deleterious effect was observed with the higher dose , which may support a bonus effect of metformin in type 2 diabetic patients


Title 4:
Effect of metformin on oxidative stress, nitrosative stress and inflammatory biomarkers in type 2 diabetes patients.
Abstract 4:
AIM Advanced research has radically changed both diagnosis and treatment of diabetes during last three decades ; a number of classes of oral antidiabetic agents are currently available for better glycemic control . Present study aims to evaluate the effect of metformin on different stress and inflammatory parameters in diabetic subjects . METHODS 208 type 2 diabetes patients were r and omly assigned for metformin and placebo . RESULTS Reactive oxygen species generation , advanced oxidation protein products ( 179.65±13.6 , 120.65±10.5 μmol/l ) and pentosidine ( 107±10.4 , 78±7.6 pmol/ml ) were found to be reduced by metformin treatment compared to placebo . On the other h and metformin administration enhanced total thiol and nitric oxide level ( p<0.05 ) . But nutrient level ( Mg(+2 ) , Ca(+2 ) ) in plasma was not altered by the treatment . Significant restoration of C reactive protein ( p<0.05 ) was noticed after metformin therapy . Metformin administration also improved Na(+)K(+)ATPase activity ( 0.28±0.08 , 0.41±0.07 μmol Pi/mg/h ) in erythrocyte membrane . CONCLUSIONS This study explores that metformin treatment restores the antioxidant status , enzymatic activity and inflammatory parameters in type 2 diabetic patients . Metformin therapy improves the status of oxidative and nitrosative stress altered in type 2 diabetes . This study unfolds the cardio protective role of metformin as an oral hypoglycemic agent


Title 5:
Neuroprotective effects of metformin against Aβ-mediated inhibition of long-term potentiation in rats fed a high-fat diet
Abstract 5:
Metformin ( Met ) is used to treat neurodegenerative disorders such as Alzheimer 's disease ( AD ) . Conversely , high-fat diets ( HFD ) have been shown to increase AD risk . In this study , we investigated the neuroprotective effects of Met on β-amyloid (Aβ)-induced impairments in hippocampal synaptic plasticity in AD model rats that were fed a HFD . In this study , 32 adult male Wistar rats were r and omly assigned to four groups : group I ( control group , regular diet ) ; group II ( HFD+vehicle ) ; group III ( HFD+Aβ ) ; or group IV ( Met+HFD+Aβ ) . Rats fed a HFD were injected with Aβ to induce AD , allowed to recover , and treated with Met for 8 weeks . The rats were then anesthetized with intraperitoneal injections of urethane and placed in a stereotaxic apparatus for surgery , electrode implantation , and field potential recording . In vivo electrophysiological recordings were then performed to measure population spike ( PS ) amplitude and excitatory postsynaptic potential ( EPSP ) slope in the hippocampal dentate gyrus . Long-term potentiation ( LTP ) was induced by high-frequency stimulation of the perforant pathway . Blood sample s were then collected to measure plasma levels of triglycerides , low-density lipoproteins , very low-density lipoprotein , and cholesterol . After induction of LTP , PS amplitude and EPSP slope were significantly decreased in Aβ-injected rats fed a HFD compared to vehicle-injected animals or untreated animals that were fed a normal diet . Met treatment of Aβ-injected rats significantly attenuated these decreases , suggesting that Met decreased the effects of Aβ on LTP . These findings suggest that Met treatment is neuroprotective against the detrimental effects of Aβ and HFDs on hippocampal synaptic plasticity


Title 6:
Antioxidants as a Preventive Treatment for Epileptic Process: A Review of the Current Status
Abstract 6:
Epilepsy is known as one of the most frequent neurological diseases , characterized by an enduring predisposition to generate epileptic seizures . Oxidative stress is believed to directly participate in pathways leading to neurodegeneration , which serves as the most important propagating factor , leading to the epileptic condition and cognitive decline . Moreover , there is also a growing body of evidence showing the disturbance of antioxidant system balance and consequently increased production of reactive species in patients with epilepsy . A meta- analysis , conducted in the present review confirms an association between epilepsy and increased lipid peroxidation . Furthermore , it was also shown that some of the antiepileptic drugs could potentially be responsible for additionally increased lipid peroxidation . Therefore , it is reasonable to propose that during the epileptic process neuroprotective treatment with antioxidants could lead to less sever structural damages , reduced epileptogenesis and milder cognitive deterioration . To evaluate this hypothesis studies investigating the neuroprotective therapeutic potential of various antioxidants in cells , animal seizure models and patients with epilepsy have been review ed . Numerous beneficial effects of  antioxidants on oxidative stress markers and in some cases also neuroprotective effects were observed in animal seizure models . However , despite these encouraging results , till now only a few antioxidants have been further applied to patients with epilepsy as an add-on therapy . Based on the several positive findings in animal models , a strong need for more carefully planned , r and omized , double-blind , cross-over , placebo-controlled clinical trials for the evaluation of  antioxidants efficacy in patients with epilepsy is warranted


Title 7:
The Effect of Eighteen-Month Metformin Treatment in Obese Adolescents: Comparison of Results Obtained in Daily Practice with Results from a Clinical Trial
Abstract 7:
Background . In a recent r and omized controlled trial ( RCT ) in obese adolescents , 18 month-treatment with metformin versus placebo was reported to lead to stabilisation of the BMI . This study aim ed to compare the effect of metformin on BMI in obese adolescents in daily practice versus results obtained in an RCT . Methods . Obese adolescents treated off label with metformin in daily practice in an outpatient clinic with a follow-up of ≥18 months were identified . Anthropometric and biochemical data were collected at baseline and at 18 months . Patients treated with metformin for 18 months in an RCT were used for comparison . BMI was compared between the two groups . Results . Nineteen patients ( median age 14.3 ( interquartile range 11.7–15.7 ) years , BMI 31.3 ( 28.8–33.8 ) kg/m2 ) treated in daily practice were compared to 23 patients receiving metformin in the RCT ( age 13.6 ( 12.6–15.3 ) years , BMI 29.8 ( 28.1–34.5 ) kg/m2 ) . BMI change after 18 months was −0.36 ( −2.10–1.58 ) versus + 0.22 ( −2.87–1.27 ) kg/m2 for the two groups , respectively . In the multivariable model , BMI change was not statistically significantly different between the two groups ( p = 0.61 ) . Conclusion . Treatment with metformin in obese adolescents in daily practice result ed in a comparable change in BMI as observed in an RCT . This trial is registered with Clinical Trials.gov number : NCT01487993
In these studies , metformin showed to control seizure attacks by attenuating seizure generation , delaying the onset of epilepsy , reducing hippocampal neuronal loss , and averting cognitive impairments in both acute and chronic models of an epileptic seizure .
The possible mechanisms for its antiseizure or antiepileptic action might be due to activation of AMPK , antiapoptotic , antineuroinflammatory , and antioxidant properties , which possibly modify disease progression through affecting epileptogenesis .
Conclusion This review revealed the benefits of metformin in alleviating symptoms of epileptic seizure and modifying different cellular and molecular changes that affect the natural history of the disease in addition to its good safety profile