Early prevention of diabetes microvascular complications in people with hyperglycaemia in Europe. ePREDICE randomized trial. Study protocol, recruitment and selected baseline data

Rafael Gabriel 1 2, Nisa Boukichou Abdelkader 3 4, Tania Acosta 3 5, Aleksandra Gilis-Januszewska 6, Ricardo Gómez-Huelgas 7, Konstantinos Makrilakis 8, Zdravko Kamenov 9, Bernhard Paulweber 10, Ilhan Satman 11, Predrag Djordjevic 12, Abdullah Alkandari 13, Asimina Mitrakou 14, Nebojsa Lalic 15, Stephen Colagiuri 16, Jaana Lindström 17, Jesús Egido 18, Andrea Natali 19, J Carlos Pastor 20, Yvonne Teuschl 21, Marcus Lind 22, Luis Silva 3, Ruy López-Ridaura 23, Jaakko Tuomilehto 1 2 17 24 25; e-PREDICE Consortium

Affiliations

13 April 2020

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doi: 10.1371/journal.pone.0231196

Abstract

Objectives: To assess the effects of early management of hyperglycaemia with antidiabetic drugs plus lifestyle intervention compared with lifestyle alone, on microvascular function in adults with pre-diabetes.

Methods: Trial design: International, multicenter, randomised, partially double-blind, placebo-controlled, clinical trial.

Participants: Males and females aged 45-74 years with IFG, IGT or IFG+IGT, recruited from primary care centres in Australia, Austria, Bulgaria, Greece, Kuwait, Poland, Serbia, Spain and Turkey.

Intervention: Participants were randomized to placebo; metformin 1.700 mg/day; linagliptin 5 mg/day or fixed-dose combination of linagliptin/metformin. All patients were enrolled in a lifestyle intervention program (diet and physical activity). Drug intervention will last 2 years. Primary Outcome: composite end-point of diabetic retinopathy estimated by the Early Treatment Diabetic Retinopathy Study Score, urinary albumin to creatinine ratio, and skin conductance in feet estimated by the sudomotor index. Secondary outcomes in a subsample include insulin sensitivity, beta-cell function, biomarkers of inflammation and fatty liver disease, quality of life, cognitive function, depressive symptoms and endothelial function.

Results: One thousand three hundred ninety one individuals with hyperglycaemia were assessed for eligibility, 424 excluded after screening, 967 allocated to placebo, metformin, linagliptin or to fixed-dose combination of metformin + linagliptin. A total of 809 people (91.1%) accepted and initiated the assigned treatment. Study sample after randomization was well balanced among the four groups. No statistical differences for the main risk factors analysed were observed between those accepting or rejecting treatment initiation. At baseline prevalence of diabetic retinopathy was 4.2%, severe neuropathy 5.3% and nephropathy 5.7%.

Conclusions: ePREDICE is the first -randomized clinical trial with the aim to assess effects of different interventions (lifestyle and pharmacological) on microvascular function in people with pre-diabetes. The trial will provide novel data on lifestyle modification combined with glucose lowering drugs for the prevention of early microvascular complications and diabetes.

Registration: - ClinicalTrials.Gov Identifier: NCT03222765 - EUDRACT Registry Number: 2013-000418-39.

Conflict of interest statement

the authors received funding from Merck Serono GmbH and Boehringer Ingelheim. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

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