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Exploring the Potential Benefits of Metformin Beyond Diabetes
Metformin continues to be one of the most extensively prescribed drugs used to treat diabetes and is recommended by the American Diabetes Association Standards of Medical Care1 as the preferred initial pharmacological agent for the treatment of type 2 diabetes, either alone or in combination with other agents. Furthermore, metformin is often prescribed off label as treatment for prediabetes, gestational diabetes, and insulin resistance in women with polycystic ovarian syndrome.
Multiple studies and publications have explored the use of metformin in the treatment and prevention of other medical conditions.
Inflammatory Bowel Disease
Research has established that metformin has anti-inflammatory properties and effects on the gut microbiome.2 In a recent publication in the Journal of Gastroenterology, researchers investigated whether metformin protects against inflammatory bowel disease (IBD) onset in the older patient population. In this study, the average age at IBD diagnosis was 66 years.
The researchers discovered the use of metformin was not correlated with a diminished risk of IBD onset in older patients, in spite of its effects on inflammation and the gut microbiome.
Age-Related Macular Degeneration
In a presentation at the recent American Society of Retina Specialists Annual Meeting,3 researchers proposed patients taking metformin may be at lower risk for developing age-related macular degeneration (AMD), revealing a possible novel therapy strategy for preventing AMD.
Researchers conducted a case-control study using the IBM MarketScan Commercial and Medicare Supplemental Databases to investigate the impact of metformin use on AMD risk. The analysis included 312,404 patients with newly diagnosed AMD and a control group comprised of 312,376 individuals. Metformin use correlated with lower risk for developing AMD, with the lowest odds ratios associated with low to moderate doses. This effect was consistent among patients with diabetes, for whom metformin use appeared to diminish the risk for AMD in those without diabetic retinopathy but not with diabetic retinopathy.3
A similar association was also found for insulin and sulfonylureas. Study authors said more research is warranted, including more prospective clinical studies.
Colorectal Cancer
In another recent publication in Scientific Reports,4 researchers said, “Evidence from previous studies suggests a protective effect of metformin in patients with colorectal cancer.”
Investigators assessed correlations between metformin use and overall survival (OS) and disease-free survival (DFS) among patients with colorectal cancer and diabetes. The study included patients who were diagnosed with type 2 diabetes mellitus and underwent surgery for colorectal cancer between 2005 and 2019. Using electronic medical records, the researchers identified 290 patients eligible for the study, of whom a total of 144 (49.7%) patients were treated with metformin.
Compared to patients not treated with metformin, those who received metformin tended to be significantly younger, had higher body mass index, and experienced fewer diabetes-related complications. In addition, 2-year OS was considerably greater in metformin users compared to non-users (86.9 ± 2.9% vs 71.0 ± 4.0%, P = .001). Researchers also conducted a multivariate analysis that showed metformin use correlated with better OS (adjusted hazard ratios [aHR] = 0.45; 95% confidence interval [95% CI]: 0.21-0.96) and better DFS (aHR = 0.31, 95% CI: 0.18-0.54).
The researchers concluded the use of metformin may enhance OS and DFS in patients with colorectal cancer and comorbid type 2 diabetes mellitus. They also suggested more studies should be performed targeting cancer localization and colorectal cancer survival outcomes in patients taking metformin.
Total Knee Replacement
In another study published in Scientific Reports,5 researchers examined the correlation between regular metformin use with total knee replacement in patients with diabetes. In this retrospective study, investigators followed patients with diabetes for a 4-year period from 2011 to 2014. Patients were at least 45 years of age and visited a primary care clinic between 2007 and 2010.
There were 196,930 patients eligible for the study. Of these, “93,330 regular metformin users (defined as ≥4 prescriptions over the previous year) and non-users were matched.” Findings showed 184 total knee replacement surgeries were conducted among 46,665 regular users, which was 17.1% fewer than the total among non-users. Cox regression analysis indicated metformin users were at 19% lower risk of total knee replacement compared to non-users, with a dose-response relationship [hazard ratio (HR) = 0.81, 95% confidence interval: 0.67-0.98, P = .033].
Authors said their data implies a potential deceleration of knee osteoarthritis disease progression with regular use of metformin in patients with type 2 diabetes mellitus. Additionally, given metformin’s impact on inflammation and weight, metformin may be beneficial as a possible disease-modifying agent for patients with knee osteoarthritis; however, additional research is needed.
Conclusion
The clinical benefits of metformin in the treatment of diabetes have been well established. Moreover, metformin is generally well tolerated, associated with minimal adverse effects, and affordable. Research continues to explore an expanding number of the potential clinical benefits associated with the use of metformin beyond the treatment of diabetes. While there is accumulating evidence that metformin has other potential clinical benefits, more trials and data are needed.
The Clinical Trials.gov website lists over 425 clinical trials that are exploring or will investigate the potential use of metformin for a variety of medical conditions including osteosarcoma, endometrial carcinoma, metastatic prostate cancer, age-related macular degeneration, heart failure, coronary artery disease, cervical cancer, cystic fibrosis, breast cancer, amyotrophic lateral sclerosis, and more.
References:
- American Diabetes Association Professional Practice Committee. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care. 2022;45(Suppl 1):S125-S143. doi:10.2337/dc22-S009
- Allin KH, Jensen CB, Jacobsen RK, Jess T. Metformin use is not associated with reduced risk of older onset inflammatory bowel disease: a Danish nationwide population-based study. J Gastroenterol. Published online July 2, 2022. doi:10.1007/s00535-022-01896-2
- Skondra D, et al. Association of metformin and other antidiabetic medication use with risk of age-related macular degeneration. Presented at: American Society of Retina Specialists annual meeting; July 13-16, 2022; New York.
- Tarhini Z, Manceur K, Magne J, Mathonnet M, Jost J, Christou N. The effect of metformin on the survival of colorectal cancer patients with type 2 diabetes mellitus. Sci Rep. 2022;12(1):12374. doi:10.1038/s41598-022-16677-312
- Lai FTT, Yip BHK, Hunter DJ, et al. Metformin use and the risk of total knee replacement among diabetic patients: a propensity-score-matched retrospective cohort study. Sci Rep. 2022;12(1):11571. doi:10.1038/s41598-022-15871-7
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