Unlocking new potential: the evolving landscape of metformin repurposing trials

To the Editor,

Metformin, a classic treatment for type 2 diabetes, is widely used globally due to its exceptional glucose-lowering effects and safety profile. In recent years, research has revealed that metformin’s benefits extend beyond glycemic control. It exhibits potential therapeutic effects through multiple mechanisms, including anti-tumor, anti-inflammatory, and cardiovascular protective properties [1]. As a result, metformin repurposing has emerged as a research hotspot. This study systematically analyzes data from the ClinicalTrials.gov database to provide a comprehensive overview of the current landscape and trends in metformin repurposing trials, offering insights for future research directions.

We searched the ClinicalTrials.gov (https://clinicaltrials.gov) database using the keyword "Metformin" with a time frame from December 1, 2014, to December 1, 2024. Only interventional trials were included, while studies focused on conventional indications, such as diabetes and polycystic ovary syndrome, were excluded. After manual screening, 368 eligible trials were included in the analysis.

To systematically assess the distribution of these trials, we developed six visualizations: (1) Fig. 1A shows the temporal distribution of trials; (2) Fig. 1B presents trial statuses by phase; (3) Fig. 1C summarizes the major disease systems targeted in metformin repurposing trials; (4) Fig. 1D breaks down cancer-specific trials; (5) Fig. 1E highlights the geographic distribution of trials; and (6) Fig. 1F summarizes the core pharmacological mechanisms of metformin repurposing.

Fig. 1

The Clinical Trial Landscape of Metformin Repurposing. A shows the temporal distribution of trials from 2014 to 2024. B Presents the distribution of trials by phase. C Highlights the primary disease systems targeted by metformin repurposing. D Provides a detailed breakdown of cancer-related trials. E depicts the geographic distribution of trials. F Summarizes the core pharmacological mechanisms of metformin, including AMPK activation, mTOR/MAPK pathway inhibition, anti-inflammatory effects, and regulation of glucose metabolism

The number of metformin repurposing trials has shown an overall upward trend since 2014, peaking in 2019. However, there was a decline in 2020, likely due to disruptions caused by the COVID-19 pandemic, including challenges in patient recruitment and trial site restrictions. Trial numbers rebounded in 2021, reaching another peak in 2022, reflecting sustained interest in metformin’s potential across multiple fields (Fig. 1A).

Phase 2 trials accounted for the largest proportion (146 trials), with 67 still ongoing, indicating that metformin repurposing research primarily focuses on efficacy validation and dose optimization. Phase 1 and Early Phase 1 trials were relatively few, reflecting the exploratory stage of new indications, while Phase 3 and Phase 4 trials remain limited, highlighting the need for larger-scale validation studies. The high proportion of “Open” trials suggests that this field is still actively progressing, paving the way for accumulating more high-quality evidence.

As shown in Fig. 1C, cancer dominates metformin repurposing research, accounting for 34% of all trials. Cardiovascular diseases (10%), gynecological conditions (7%), and other areas such as orthopedics and ophthalmology also demonstrated notable interest. While studies on neurological and metabolic diseases are relatively fewer, metformin’s neuroprotective potential (e.g., for Alzheimer’s disease) is gaining attention [2].

Among cancer studies (Fig. 1D), breast cancer (17%), prostate cancer (11%), lung cancer (8%), and colorectal cancer (8%) are the most commonly investigated. This distribution highlights the potential of metformin in addressing common malignancies and its possible role in combination therapies. Current research emphasizes exploring metformin’s synergistic effects with existing chemotherapy or targeted therapies, particularly in improving treatment tolerance, reducing side effects, and delaying tumor progression [3]. However, despite promising evidence from preclinical studies and animal models, its efficacy in cancer treatment has yet to be validated by large-scale randomized controlled trials.

Metformin exerts its effects through several core mechanisms (Fig. 1F). First, it inhibits mitochondrial complex I and activates AMPK, thereby suppressing the mTOR/MAPK signaling pathway and regulating cellular metabolism (e.g., reducing gluconeogenesis and promoting fatty acid oxidation) [4]. Second, metformin reduces insulin and IGF-1 levels, mitigating growth-promoting signals to tumor cells and other tissues. Additionally, it has significant anti-inflammatory and antioxidant effects, reducing pro-inflammatory cytokines (e.g., IL-6, TNF-α) and reactive oxygen species (ROS), alleviating chronic inflammation, and improving the microenvironment in diseases such as cancer, cardiovascular conditions, and retinal diseases [5].

Globally, metformin repurposing trials are predominantly conducted in the United States (over 120 trials) (Fig. 1E), followed by China, Canada, and Europe. This uneven distribution likely reflects disparities in research resources, disease burdens, and funding allocation across regions. Notably, Egypt stands out in Africa, demonstrating increasing participation in drug repurposing research. However, South America, Central Asia, and most African countries show significantly fewer trials, indicating a need for greater involvement in these regions.

This study systematically analyzed 368 clinical trials on metformin repurposing, revealing a focus on cancer, cardiovascular diseases, and metabolic disorders, with most trials in Phase 2, reflecting ongoing efficacy validation. However, the lack of high-quality randomized controlled trials and late-phase studies limits broader clinical translation. As a safe and affordable multi-target drug, metformin shows great promise in cancer therapy and combination treatments. With the advancement of precision medicine and global collaborations, metformin may pave the way for innovative therapeutic strategies and serve as a model for fully exploiting the potential of existing drugs.