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      Effects of linagliptin vs glimepiride on cognitive performance in type 2 diabetes: results of the randomised double-blind, active-controlled CAROLINA-COGNITION study

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          Abstract

          Aims/hypothesis

          Type 2 diabetes, particularly with concomitant CVD, is associated with an increased risk of cognitive impairment. We assessed the effect on accelerated cognitive decline (ACD) of the DPP-4 inhibitor linagliptin vs the sulfonylurea glimepiride in individuals with type 2 diabetes.

          Methods

          The CAROLINA-COGNITION study was part of the randomised, double-blind, active-controlled CAROLINA trial that evaluated the cardiovascular safety of linagliptin vs glimepiride in individuals with age ≥40 and ≤85 years and HbA 1c 48–69 mmol/mol (6.5–8.5%) receiving standard care, excluding insulin therapy. Participants were randomised 1:1 using an interactive telephone- and web-based system and treatment assignment was determined by a computer-generated random sequence with stratification by center. The primary cognitive outcome was occurrence of ACD at end of follow-up, defined as a regression-based index score ≤16th percentile on either the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning, in participants with a baseline MMSE score ≥24. Prespecified additional analyses included effects on ACD at week 160, in subgroups (sex, age, race, ethnicity, depressive symptoms, cardiovascular risk, duration of type 2 diabetes, albuminuria), and absolute changes in cognitive performance. Participants, caregivers, and people involved in measurements, examinations or adjudication, were all masked to treatment assignment.

          Results

          Of 6033 participants recruited from hospital and primary care sites, 3163 (38.0% female, mean age/diabetes duration 64/7.6 years, MMSE score 28.5, HbA 1c 54 mmol/mol [7.1%]) represent the CAROLINA-COGNITION cohort. Over median 6.1 years, ACD occurred in 27.8% (449/1618, linagliptin) vs 27.6% (426/1545, glimepiride), OR 1.01 (95% CI 0.86, 1.18). Also, no differences in ACD were observed at week 160 (OR 1.07 [0.91, 1.25]), between treatments across subgroups, or for absolute cognitive changes.

          Conclusions/interpretation

          In a large, international outcome trial in people with relatively early type 2 diabetes at elevated cardiovascular risk, no difference in risk for ACD was observed between linagliptin and glimepiride over 6.1 years.

          Funding

          This study was sponsored by Boehringer Ingelheim.

          Trial registration

          ClinicalTrials.gov NCT01243424.

          Graphical abstract

          Supplementary Information

          The online version contains peer-reviewed but unedited supplementary material available at 10.1007/s00125-021-05393-8.

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          Most cited references30

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          The CES-D Scale: A Self-Report Depression Scale for Research in the General Population

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            The Mini-Mental State Examination: A Comprehensive Review

            The purpose of this paper is to provide a comprehensive review of information accumulated over the past 26 years regarding the psychometric properties and utility of the Mini-Mental State Examination (MMSE).
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              Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications

              Cognitive dysfunction is increasingly recognized as an important comorbidity of diabetes mellitus. Different stages of diabetes-associated cognitive dysfunction can be discerned, with different cognitive features, affected age groups, prognosis, and likely also different underlying mechanisms. Relatively subtle, slowly progressive cognitive decrements occur in all age groups. More severe stages, particularly mild cognitive impairment and dementia, with progressive deficits, occur primarily in older individuals. The latter are clearly most relevant for patient management and are the focus of this review. Evolving insights from studies on risk factors, brain imaging, and neuropathology provide important clues on mechanisms. In the majority of patients multiple etiologies likely determine the cognitive phenotype. Although both the risk of -clinically diagnosed- Alzheimer’s disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical Alzheimer’s pathologies is not. A major challenge is therefore to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond Alzheimer’s pathologies. Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists. Development of targeted treatment and preventive strategies depends on these translational efforts.
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                Author and article information

                Contributors
                G.J.Biessels@umcutrecht.nl
                odd_erikj@hotmail.com
                Journal
                Diabetologia
                Diabetologia
                Diabetologia
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0012-186X
                1432-0428
                9 February 2021
                9 February 2021
                2021
                : 64
                : 6
                : 1235-1245
                Affiliations
                [1 ]GRID grid.7692.a, ISNI 0000000090126352, Department of Neurology, UMC Utrecht Brain Center, , University Medical Center Utrecht, ; Utrecht, the Netherlands
                [2 ]GRID grid.5645.2, ISNI 000000040459992X, Department of Neurology, , Erasmus MC - University Medical Center, ; Rotterdam, the Netherlands
                [3 ]GRID grid.420061.1, ISNI 0000 0001 2171 7500, Biostatistics and Data Sciences, , Boehringer Ingelheim, ; Ingelheim, Germany
                [4 ]GRID grid.17063.33, ISNI 0000 0001 2157 2938, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, , University of Toronto, ; Toronto, Canada
                [5 ]GRID grid.241167.7, ISNI 0000 0001 2185 3318, Department of Biostatistics and Data Science, , Wake Forest School of Medicine, ; Winston-Salem, NC USA
                [6 ]GRID grid.497612.f, ISNI 0000 0004 0544 6765, Therapeutic Area Cardiometabolism, , Boehringer Ingelheim, ; Asker, Norway
                Author information
                http://orcid.org/0000-0003-2470-0530
                Article
                5393
                10.1007/s00125-021-05393-8
                8099814
                33559704
                b38bc3f4-ad06-4915-9d57-ccea1e12ca12
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 7 August 2020
                : 11 December 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100001003, Boehringer Ingelheim;
                Categories
                Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2021

                Endocrinology & Diabetes
                cardiovascular disease,cognitive decline,dpp-4 inhibitors,sulfonylureas,type 2 diabetes

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