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:
Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin
Abstract 1:
OBJECTIVE To investigate the associations of metformin , serum vitamin B12 , calcium supplements , and cognitive impairment in patients with diabetes . RESEARCH DESIGN AND METHODS Participants were recruited from the Primary Research in Memory ( PRIME ) clinics study , the Australian Imaging , Biomarkers and Lifestyle ( AIBL ) study of aging , and the Barwon region of southeastern Australia . Patients with Alzheimer disease ( AD ) ( n = 480 ) or mild cognitive impairment ( n = 187 ) and those who were cognitively intact ( n = 687 ) were included ; patients with stroke or with neurodegenerative diseases other than AD were excluded . Subgroup analyses were performed for participants who had either type 2 diabetes ( n = 104 ) or impaired glucose tolerance ( n = 22 ) . RESULTS Participants with diabetes ( n = 126 ) had worse cognitive performance than participants who did not have diabetes ( n = 1,228 ; adjusted odds ratio 1.51 [ 95 % CI 1.03–2.21 ] ) . Among participants with diabetes , worse cognitive performance was associated with metformin use ( 2.23 [ 1.05–4.75 ] ) . After adjusting for age , sex , level of education , history of depression , serum vitamin B12 , and metformin  use , participants with diabetes who were taking calcium supplements had better cognitive performance ( 0.41 [ 0.19–0.92 ] ) . CONCLUSIONS Metformin use was associated with impaired cognitive performance . Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes . Prospect i ve trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin


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:
Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer´s disease - protocol for a controlled, randomized double-blinded trial.
Abstract 3:
INTRODUCTION Type 2 diabetes ( DM-2 ) increases the risk of developing Alzheimer´s disease ( AD ) , and patients with AD are more likely to develop DM-2 . DM-2 and AD share some pathophysiological features . In AD , amyloid-β ( Aβ ) is accumulated as extracellular plaques in the gray matter of the brain , while in DM-2 islet amyloid polypeptide ( IAPP ) is accumulated in the pancreas . Premature cellular degeneration is seen in both diseases . Glucagon-like peptide-1 ( GLP-1 ) reduces the amount of Aβ and improves cognition in animal studies . The present study tests the hypothesis that treatment with the long-acting GLP-1 receptor agonist liraglutide affects the accumulation of Aβ in patients with AD . MATERIAL AND METHODS This is a r and omized , controlled , double-blinded intervention study with AD patients treated for six months with liraglutide ( n = 20 ) or placebo ( n = 20 ) . The primary outcome is change in deposition of Aβ in the central nervous system ( CNS ) by Pittsburgh compound B positron emission tomography ( PET )  . The secondary outcome is evaluation of cognition using a neuro-psychological test battery , and examination of changes in glucose uptake in the CNS by 18F-fluoro-deoxy-glucose PET  . Finally , a perfusion-weighted magnetic resonance imaging with contrast will be performed to evaluate blood flow . CONCLUSION No registered drug affects the deposition of Aβ in the brain of AD patients . Our goal is to find a new therapeutic agent that alters the pathophysiology in AD patients by decreasing the formation of Aβ plaques and thereby presumably improves the cognitive function . FUNDING The trial is investigator-initiated and investigator-driven and is supported by Novo Nordisk Sc and inavia . TRIAL REGISTRATION Clinical Trials.gov : NCT01469351


Title 4:
Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial.
Abstract 4:
OBJECTIVE To examine the effects of intranasal insulin administration on cognition , function , cerebral glucose metabolism , and cerebrospinal fluid biomarkers in adults with amnestic mild cognitive impairment or Alzheimer disease ( AD ) . DESIGN R and omized , double-blind , placebo-controlled trial . SETTING Clinical research unit of a Veterans Affairs medical center . PARTICIPANTS The intent-to-treat sample consisted of 104 adults with amnestic mild cognitive impairment ( n = 64 ) or mild to moderate AD ( n = 40 ) . Intervention Participants received placebo ( n = 30 ) , 20 IU of insulin ( n = 36 ) , or 40 IU of insulin ( n = 38 ) for 4 months , administered with a nasal drug delivery device ( Kurve Technology , Bothell , Washington ) . MAIN OUTCOME MEASURES Primary measures consisted of delayed story recall score and the Dementia Severity Rating Scale score , and secondary measures included the Alzheimer Disease 's Assessment Scale-cognitive subscale ( ADAS-cog ) score and the Alzheimer 's Disease Cooperative Study -activities of daily living ( ADCS-ADL ) scale . A subset of participants underwent lumbar puncture ( n = 23 ) and positron emission tomography with fludeoxyglucose F 18 ( n = 40 ) before and after treatment . RESULTS Outcome measures were analyzed using repeated- measures analysis of covariance . Treatment with 20 IU of insulin  improved delayed memory ( P < .05 ) , and both doses of insulin ( 20 and 40 IU ) preserved caregiver-rated functional ability ( P < .01 ) . Both insulin doses also preserved general cognition as assessed by the ADAS-cog score for younger participants and functional abilities as assessed by the ADCS-ADL scale for adults with AD ( P < .05 ) . Cerebrospinal fluid biomarkers did not change for insulin-treated participants as a group , but , in exploratory analyses , changes in memory and function were associated with changes in the Aβ42 level and in the tau protein-to-Aβ42 ratio in cerebrospinal fluid . Placebo-assigned participants showed decreased fludeoxyglucose F 18 uptake in the parietotemporal , frontal , precuneus , and cuneus regions and insulin-minimized progression . No treatment-related severe adverse events occurred . CONCLUSIONS These results support longer trials of intranasal insulin therapy for patients with amnestic mild cognitive impairment and patients with AD . Trial Registration clinical trials.gov Identifier : NCT00438568
The results of 29 pairwise comparisons indicated that cognition was significantly improved in subjects treated with antidiabetic agents compared with placebo .
Pioglitazone 15 to 30 mg demonstrated the greatest efficacy compared to placebo in network meta- analysis .
No significant differences in acceptability were identified when comparing agents with each other and with placebo .
The current findings indicate a pro-cognitive class effect of antidiabetic agents in AD/MCI .