Abstract
Aims/hypothesisType 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.MethodsThe 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 HbA1c 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.ResultsOf 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, HbA1c 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/interpretationIn 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.FundingThis study was sponsored by Boehringer Ingelheim.Trial registrationClinicalTrials.gov NCT01243424.Graphical abstract
Highlights
Type 2 diabetes is associated with increased risk for cognitive impairment, both mild cognitive impairment (MCI) and dementia [1], in particular in those patients with coexisting CVD [2]
There were very few hospitalisations due to hypoglycaemic events. In this comparative cognitive interventional trial of 3163 individuals with relatively early type 2 diabetes without impaired cognition at baseline, and elevated cardiovascular risk, the effects of linagliptin 5 mg or glimepiride 1–4 mg did not differ for the risk of accelerated cognitive decline (ACD) when assessed using three different instruments over a median follow-up of 6.12 years
This result was observed in the setting of glycaemic equipoise between treatment groups, but with differing effects on hypoglycaemia and weight
Summary
Type 2 diabetes is associated with increased risk for cognitive impairment, both mild cognitive impairment (MCI) and dementia [1], in particular in those patients with coexisting CVD [2]. Accelerated cognitive decline (ACD), which may evolve to MCI or dementia, predominantly occurs in higher numbers in the older age groups [1, 3,4,5]. Given the association between type 2 diabetes and MCI and dementia, it is of interest to assess whether the non-glycaemic effects of specific glucose-lowering medications affect cognitive function. This is of particular relevance in light of some conflicting results on cognitive functioning reported with the use of metformin [5, 14, 15] and insulin [16, 17]
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