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. 2024 Jan 31;16(1):23.
doi: 10.1186/s13195-023-01355-x.

A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol

Mariagnese Barbera  1   2 , Jenni Lehtisalo  3   4 , Dinithi Perera  5   6 , Malin Aspö  7   8 , Mary Cross  9 , Celeste A De Jager Loots  5 , Emanuela Falaschetti  9 , Naomi Friel  5 , José A Luchsinger  10 , Hanna Malmberg Gavelin  11 , Markku Peltonen  4   6 , Geraint Price  5 , Anna Stigsdotter Neely  12   13 , Charlotta Thunborg  7   8 , Jaakko Tuomilehto  4   14   15 , Francesca Mangialasche  6   7   8 , Lefkos Middleton  5   16 , Tiia Ngandu  4   7 , Alina Solomon #  17   18   19 , Miia Kivipelto #  5   7   8   20 ; MET-FINGER study team
Collaborators, Affiliations

A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol

Mariagnese Barbera et al. Alzheimers Res Ther. .

Abstract

Background: Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer's Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60-79 years) at increased risk of dementia.

Methods: MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded.

Conclusion: MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field.

Trial registration: ClinicalTrials.gov (NCT05109169).

Keywords: APOE; Alzheimer’s; Cognitive impairment; Dementia prevention; Drug repurposing; Lifestyle intervention; Lifestyle-drug combination therapy; Metformin; World-Wide FINGERS.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Summary of the mechanisms linking type 2 diabetes (T2D) and its risk factors to dementia/AD and possible metformin targets (Modified from Yarchoan M and Arnold SE, Diabetes, 2014)
Fig. 2
Fig. 2
Diagram of the MET-FINGER trial. The main trial comparison is between the FINGER 2.0 Multimodal (combining a Structured Multimodal Lifestyle Intervention (SMLI) and metformin, where appropriate) vs the Self-Guided Multimodal intervention (SGMI). Metformin treatment is included in the FINGER 2.0 Multimodal Intervention through a trial-within-trial where participants who are eligible for metformin treatment will be randomly allocated to one of the three metformin/placebo treatments in addition to the SMLI. Ineligible participants for the metformin treatment will continue participation receiving the SMLI alone. The study, therefore, includes two screening and randomisation steps. The first screening step will assess eligibility for full study participation and eligible participants will be equally randomised to either the FINGER 2.0 or the SGMI. The second screening step will determine specific eligibility to the metformin treatment and eligible participants will be randomised as described above
See this image and copyright information in PMC

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