***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objectives Possible association between diabetes mellitus ( DM ) and Alzheimer ’s disease ( AD ) has been controversial . This study used a nationwide population -based data set to investigate the relationship between DM and subsequent AD incidence . Methods Data were collected from Taiwan ’s National Health Insurance Research Data base , which released a cohort data set of 1,000,000 r and omly sample d people and confirmed it to be representative of the Taiwanese population . We identified 71,433 patients newly diagnosed with diabetes ( age 58.74±14.02 years ) since January 1997 . Using propensity score , we matched them with 71,311 non-diabetic subjects by time of enrollment , age , gender , hypertension , hyperlipidemia , and previous stroke history . All the patients were followed up to December 31 , 2007 . The endpoint of the study was occurrence of AD . Results Over a maximum 11 years of follow-up , diabetic patients experienced a higher incidence of AD than non-diabetic subjects ( 0.48 % vs. 0.37 % , p<0.001 ) . After Cox proportional hazard regression model analysis , DM ( hazard ratio [ HR ] , 1.76 ; 95 % confidence interval [ CI ] , 1.50–2.07 , p<0.001 ) , age ( HR , 1.11 ; 95 % CI , 1.10–1.12 , p<0.001 ) , female gender ( HR , 1.24 ; 95 % CI , 1.06–1.46 , p = 0.008 ) , hypertension ( HR , 1.30 ; 95 % CI , 1.07–1.59 , p = 0.01 ) , previous stroke history ( HR , 1.79 ; 95 % CI , 1.28–2.50 , p<0.001 ) , and urbanization status ( metropolis , HR , 1.32 ; 95 % CI , 1.07–1.63 , p = 0.009 ) were independently associated with the increased risk of AD . Neither monotherapy nor combination therapy with oral antidiabetic medications were associated with the risk of AD after adjusting for underlying risk factors and the duration of DM since diagnosis . However , combination therapy with insulin was found to be associated with greater risk of AD ( HR , 2.17 ; 95 % CI , 1.04–4.52 , p = 0.039 ) . Conclusion Newly diagnosed DM was associated with increased risk of AD . Use of hypoglycemic agents did not ameliorate the risk 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 Background : Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer ’s disease dementia ( AD ) or amnestic mild cognitive impairment ( MCI ) . The investigation of longer-term administration is necessary to determine whether benefits persist , whether they are similar to benefits provided by regular insulin , and whether either form of insulin therapy affects AD biomarkers . Objective : The present study aim ed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition , daily functioning , and AD biomarkers for adults with MCI or AD . Methods : This r and omized , double-blind , placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD . Participants received placebo ( n = 12 ) , 40 IU of insulin detemir ( n = 12 ) , or 40 IU of regular insulin ( n = 12 ) daily for four months , administered with a nasal delivery device . A cognitive battery was administered at baseline and after two and four months of treatment . MRI was administered for all participants and lumbar puncture for a subset ( n = 20 ) at baseline and four months . The primary outcome was change from baseline to four months on a memory composite ( sum of Z scores for delayed list and story recall ) . Secondary outcomes included : global cognition ( Alzheimer ’s Disease Assessment Scale-Cognition ) , daily functioning ( Dementia Severity Rating Scale ) , MRI volume changes in AD-related regions of interest , and cerebrospinal fluid AD markers . Results : The regular insulin treated group had better memory after two and four months compared with placebo ( p < 0.03 ) . No significant effects were observed for the detemir-assigned group compared with the placebo group , or for daily functioning for either group . Regular insulin treatment was associated with preserved volume on MRI . Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio . Conclusion : Future research is warranted to examine the mechanistic basis of treatment differences , and to further assess the efficacy and safety of intranasal insulin Diabetes mellitus is a leading cause of death in the United States and is associated with microvascular and macrovascular complications . Approximately 29.1 million persons , or 9.3 % of the U.S. population , have type 2 diabetes ( 1 ) . In 2012 , the total direct and indirect costs associated with diabetes in the United States were $ 245 billion ( 1 ) . Markedly elevated glucose levels can result in subacute symptoms , such as polyuria , polydipsia , weight loss , and dehydration . Over time , the metabolic derangements associated with diabetes may lead to vision loss , painful neuropathy or sensory loss , foot ulcers , amputations , myocardial infa rct ions , strokes , and end-stage renal disease . Lowering blood glucose may decrease risk for complications , but lowering strategies come with harms , patient burden , and costs . Blood glucose can be measured in various ways , including the hemoglobin A1c ( HbA1c ; also called glycosylated or glycated hemoglobin ) level , which approximates average blood glucose control over about 3 months . As with all laboratory tests , HbA1c measurements are associated with variability ( 2 ) and can vary further with race and ethnicity ( 35 ) . Guidelines have historically recommended initiation or intensification of pharmacologic therapy to achieve specific HbA1c targets , depending on the population in question . The ideal target that optimally balances benefits and harms remains uncertain . Guidance Statement Focus and Target Population The purpose of this American College of Physicians ( ACP ) guidance statement is to critically review the available guidelines from various organizations and the evidence included therein to assist clinicians in making decisions about targets when using pharmacologic therapy in adults with type 2 diabetes . Recent data suggesting that newer agents reduce cardiovascular morbidity and mortality in high-risk patients with type 2 diabetes have prompted calls for a fundamental shift in diabetes management . Some anticipate that treatment decisions will eventually be based more on cardiovascular risk than achievement of specific HbA1c targets , analogous to recent changes in lipid management . However , for the foreseeable future , glycemic targets will continue to influence management decisions by front-line clinicians ( 6 ) . This statement focuses on the benefits and harms of targeting lower versus higher HbA1c levels and does not cover use of specific medications outside of their use to achieve HbA1c targets . The intended audience is all clinicians , and the target population is nonpregnant adults with type 2 diabetes . Methods The Clinical Guidelines Committee ( CGC ) of ACP develops guidance statements on topics where several conflicting guidelines are available . We provide clinicians with a rigorous review of the guidelines and the evidence they include . We then adopt the clinical recommendations if we agree with their evaluation of benefits and harms or adapt them if changes are needed based on our assessment of the recommendations and evidence . Data Sources and Guideline Selection We search ed the National Guideline Clearinghouse and the Guidelines International Network library ( May 2017 ) for guidelines on recommended HbA1c targets in the treatment of type 2 diabetes in nonpregnant outpatient adults . We included guidelines that were developed by national organizations , were published in English , and targeted the correct population . We review ed titles and abstract s and excluded guidelines that were modified or adapted from other organizations or addressed specific population s ( such as pregnant women or patients with kidney disease ) . Our search yielded guidelines from the National Institute for Health and Care Excellence ( NICE ) ( 7 ) and the Institute for Clinical Systems Improvement ( ICSI ) ( 8) . On the basis of the knowledge and expertise of ACP CGC members , we also selected the following 4 guidelines not identified in either data base at the time of the search but commonly used in clinical practice : the American Association of Clinical Endocrinologists and American College of Endocrinology ( AACE/ACE ) guideline ( 9 ) , the American Diabetes Association ( ADA ) guideline ( 10 ) , the Scottish Intercollegiate Guidelines Network ( SIGN ) guideline ( 11 ) , and the U.S. Department of Veterans Affairs and Department of Defense ( VA/DoD ) guideline ( 12 ) . Quality Assessment Six co authors independently review ed and assessed each guideline using the AGREE II ( Appraisal of Guidelines for Research and Evaluation II ) instrument ( 13 ) . This instrument asks 23 questions in the following 6 domains : scope and purpose , stakeholder involvement , rigor of development , clarity of presentation , applicability , and editorial independence . The authors scored each guideline independently , and the scores were compared ( Appendix Figure and Appendix Table 1 ) . Authors then provided a summary determination of whether they would recommend this guideline for use by recording yes , no , or yes with modifications . Appendix Figure . Mean AGREE II scores for items in each domain across the 6 review ers . Each question was rated on a Likert scale with a minimum of 1 point and a maximum of 7 points . The scores were averaged for each of the 6 review ers . Error bars represent calculated st and ard deviation . AACE/ACE = American Association of Clinical Endocrinologists and American College of Endocrinology ; ADA = American Diabetes Association ; AGREE II = Appraisal of Guidelines for Research and Evaluation II ; GDG = guideline development group ; ICSI = Institute for Clinical Systems Improvement ; NICE = National Institute for Health and Care Excellence ; SIGN = Scottish Intercollegiate Guidelines Network ; VA/DoD = U.S. Department of Veterans Affairs and Department of Defense . Appendix Table 1 . Scaled AGREE II Domain Scores for Each Guideline and Overall Assessment Peer Review The draft guidance statement was peer- review ed through Annals of Internal Medicine and was posted online for comments from ACP Regents and Governors , who represent ACP members at the regional level . The final guidance statement incorporated comments from peer review ers and ACP Regents and Governors . Public Panel Review The development of this guidance statement also included perspectives , values , and preferences of 2 CGC members who represent the public and a 7-member public panel . Summary of Evaluated Guidelines Using the AGREE II Instrument We review ed and rated 6 guidelines ( AACE/ACE [ 9 ] , ADA [ 10 ] , ICSI [ 8 ] , NICE [ 7 ] , SIGN [ 11 ] , and VA/DoD [ 12 ] ) , focusing solely on sections addressing HbA1c targets in patients with type 2 diabetes . Appendix Table 1 shows the detailed scaled domain scores and average quality ratings for each guideline , and the Appendix Figure shows average AGREE II scores for each item in each of the 6 domains . The fundamental difference between high- and low-scoring guidelines was methodology . The 2 lowest-scoring guidelines , AACE/ACE and ADA , scored lowest on stakeholder involvement , applicability , editorial independence , and scientific rigor . A systematic review is the backbone for any trustworthy guideline , but some guidelines might not be based on a systematic review or may not 
    Output:
    
Conclusions and limitations The association between treatment for diabetes and dementia is differential according to drug class , which is potentially mediated by hypoglycemic risk .