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. 2018 Jan 15;18(1):7.
doi: 10.1186/s12883-018-1014-7.

Rationale and design of the CAROLINA® - cognition substudy: a randomised controlled trial on cognitive outcomes of linagliptin versus glimepiride in patients with type 2 diabetes mellitus

Geert Jan Biessels  1 , Jolien Janssen  2   3 , Esther van den Berg  2   4 , Bernard Zinman  5 , Mark A Espeland  6 , Michaela Mattheus  7 , Odd Erik Johansen  8 ; CAROLINA® investigators
Affiliations

Rationale and design of the CAROLINA® - cognition substudy: a randomised controlled trial on cognitive outcomes of linagliptin versus glimepiride in patients with type 2 diabetes mellitus

Geert Jan Biessels et al. BMC Neurol. .

Abstract

Background: Type 2 diabetes mellitus is associated with cognitive dysfunction and an increased risk of dementia. Linagliptin is a glucose-lowering agent of the dipeptidyl peptidase-IV (DPP-IV) inhibitor class that is of particular interest for the prevention of accelerated cognitive decline, because it may potentially benefit the brain through pleiotropic effects, beyond glucose lowering. This paper presents the design of a study that aims to establish if linagliptin is superior to the sulfonylurea glimepiride in the prevention of accelerated cognitive decline in patients with type 2 diabetes mellitus.

Methods: The cognition substudy is an integral part of the ongoing event-driven, randomised, double blind CARdiOvascular safety of LINAgliptin (CAROLINA®) trial, which evaluates the effect of treatment with linagliptin versus glimepiride on cardiovascular outcomes. CAROLINA® includes patients with type 2 diabetes mellitus with sub-optimal glycaemic control at elevated cardiovascular risk. The substudy will evaluate patients randomised and treated who have a baseline Mini Mental State Examination (MMSE) score ≥ 24, documented years of formal education with at least one valid cognitive assessment at baseline and during follow-up. The primary cognitive outcome is the occurrence of accelerated cognitive decline at the end of follow-up. The two treatment groups will be compared by using a logistic regression. Accelerated cognitive decline is defined as a rate of cognitive decline that falls at or below the 16th percentile of decline for the whole cohort on either the MMSE or a combined score of the trail making and verbal fluency test. Potential confounders are taken into account at an individual patient level, using a regression based index.

Discussion: Between December 2010 and December 2012, 6042 patients were randomised and treated with either linagliptin (5 mg) or glimepiride (1-4 mg) once daily in CAROLINA®. Cognitive tests were conducted in nearly 4500 participants at baseline and are scheduled for two subsequent assessments, after 160 weeks of follow-up and end of follow-up. This substudy of the ongoing CAROLINA® trial will establish if linagliptin is superior to glimepiride in the prevention of accelerated cognitive decline in patients with type 2 diabetes mellitus. Final results are expected in 2019.

Trial registration: ClinicalTrials.gov Identifier: NCT 01243424 .

Trial registration: ClinicalTrials.gov NCT01243424.

Keywords: Cognition; Dementia; Dipeptidyl peptidase-IV inhibitor; Oral glucose-lowering agent; Type 2 diabetes mellitus.

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Conflict of interest statement

Ethics approval and consent to participate

The trial will be carried out in compliance with the protocol, the principles laid down in the Declaration of Helsinki, version as of October 1996, in accordance with the ICH Harmonised Tripartite Guideline for Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures. The study protocol has been reviewed and approved by the respective Institutional Review Board / Independent Ethics Committee and competent authority according to national and international regulations.

Prior to patient participation in the trial, thorough study information is provided and written informed consent is obtained from each patient (or the patient’s legally accepted representative) according to ICH GCP and to the regulatory and legal requirements of the participating country. The study is registered with clinicaltrials.gov (registration number: NCT01243424).

Consent for publication

Not applicable.

Competing interests

We have read and understood BMC policy on declaration of interests and declare the following interests: Odd Erik Johansen is a clinical program leader employeed by Boehringer Ingelheim, Asker, Norway. Michaela Mattheus is the responsible trial statistician at Boehringer Ingelheim, Ingelheim, Germany. Prof Bernie Zinman, Toronto, Canada and Prof Mark Espeland, Winston-Salem, US, are members of the CAROLINA® executive steering committee and receive consultancy support from Boehringer Ingelheim. Prof. dr. GJ Biessels, neurologist at the University Medical Centre Utrecht receives research support from Boehringer Ingelheim.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
overview design CAROLINA®-cognition substudy. Abbreviations: FU: follow-up, A&E score: Attention and Executive functioning score, MMSE: Mini Mental State Examination, VFT: Verbal Fluency Test, TMT: Trail Making Test, CES-D: Centre for Epidemiologic Studies Depression Scale
See this image and copyright information in PMC

References

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