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higher levels of AGE receptors were noted in the 1,021 participants with dementia at the beginning of the study 295 Study 5 Study Design: Observational/Correlational Subjects: 764 adults Results: Skin AGE levels were correlated with poorer cognitive performance and the relationship was similar in those with and without diabetes 296 Confidence of Harmfulness: Low* Glutamate Description: An amino acid and excitatory neurotransmitter Potential Mechanism(s): Excitotoxicity triggering neuroinflammation, oxidative stress, protein aggregation, mitochondrial dysfunction, and nerve cell death 297,298 Scientific Evidence: Study 1 Study Design: Two placebo-controlled intervention trials Subjects: Veterans with Gulf War Illness Dose: A challenge dose of glutamate, in the form of monosodium glutamate (MSG), versus placebo after eating a low-glutamate diet for one month Results: Glutamate inconsistently caused return of symptoms, although symptoms, including cognitive impairment, were reduced after the low-glutamate diet 299,300 Study 2 Study Design: RCT Subjects: 159 dementia patients Dose: 900 mg glutamate in the form of MSG three times daily versus placebo Results: Dementia scores improved in those receiving glutamate 301 Study 3 Study Design: Two research reviews Results: No compelling evidence for glutamate sensitivity as a cause of cognitive or other symptoms in otherwise healthy individuals 302,303 Confidence of Harmfulness: Low* RCT = Randomized controlled trial *High = supportive evidence from multiple randomized controlled trials (RCTs) and observational studies

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Because the side effect profile of SGLT2is differs from that of GLP-1RAs, any additive negative interaction is not expected when these two classes of anti-diabetic medications are used in combination [11]