The glucose-lowering drug metformin has shown promise in non-diabetic conditions for improving endothelial dysfunction, but the literature of metformin’s effect on endothelial dysfunction and the biomarkers used to measure endothelial dysfunction have not yet been synthesised.

We aimed to map the extent and nature of the existing research related to metformin for endothelial dysfunction in non-diabetic non-communicable diseases (NCDs). This scoping review was conducted following the methodological framework by Arksey and O’Malley and the recommendations from the Joanna Briggs Institute, and was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews.

We considered any peer-reviewed studies in adult humans on the use of metformin for endothelial dysfunction in non-diabetic NCDs. Narrative reviews, expert opinion, preclinical studies and qualitative studies were excluded.

An unrestricted search was conducted on four electronic databases and three registries from inception to October 2024.

Data charting was performed using predetermined data extraction headings. We used a systematic charting method and narrative synthesis to organise, synthesise and report the data.

We identified 56 studies comprising 4620 participants (71.7% female). Polycystic ovarian syndrome was the most investigated NCD (57.1% of studies). 19 distinct biomarkers of endothelial dysfunction were identified, with flow-mediated dilation being the most frequently assessed (18 studies, 745 participants). Metformin showed a trend towards improvement for 7/19 (36.8%) biomarkers. Male participants were underrepresented in the literature and only five studies (9%) were conducted in the global south, potentially limiting the generalisability of repurposed metformin in diverse populations or settings. Studies with an active comparator reported a significant difference between the metformin and comparator groups in 20% (4/20), in contrast to studies without an active comparator (placebo or pre–post studies) reporting significant results favouring metformin in 83.3% (30/36). A knowledge gap also exists for metformin use in people with HIV, given that they are known to develop cardiovascular NCDs at a twofold higher rate than their HIV-negative counterparts.

While there is a growing evidence base supporting metformin as treatment for endothelial dysfunction in non-diabetic NCDs, our scoping review highlighted knowledge gaps in optimal biomarker selection and dosing strategies, and applications in a broader range of NCDs, including in people with HIV. More primary and secondary research using robust methodologies and study designs is needed to determine the quantitative effect of metformin on endothelial dysfunction.