The Use of Metformin Beyond Type 2 Diabetes

Written By Jessica Cerka

Metformin is widely known as a first-line treatment for type 2 diabetes due to its efficacy in controlling blood glucose levels. However, recent research has revealed a multitude of potential benefits of metformin that extend beyond its traditional use. These emerging applications have prompted interest in metformin as a therapeutic option for a variety of health conditions. This article explores how metformin has shown to improve a number of common conditions with supporting scientific evidence in non diabetic and diabetic patients.

1. Polycystic Ovary Syndrome (PCOS)

Polycystic Ovary Syndrome (PCOS) is a common endocrine disorder in women of reproductive age, characterized by insulin resistance, hyperandrogenism, and ovulatory dysfunction. Metformin has been shown to improve insulin sensitivity, regulate menstrual cycles, and reduce androgen levels in women with PCOS.

  • The study by Moghetti et al. (2000) in The Journal of Clinical Endocrinology & Metabolism demonstrated that metformin treatment improved insulin sensitivity and reduced androgen levels in women with PCOS.

  • Lord et al. (2003) conducted a systematic review and meta-analysis published in BMJ, concluding that metformin is effective in improving clinical and biochemical features of PCOS.

2. Weight Management and Obesity

Metformin’s ability to improve insulin sensitivity and influence metabolic pathways makes it a valuable tool for weight management, especially in individuals with insulin resistance or metabolic syndrome.

  • The Diabetes Prevention Program (DPP) study, as reported in The New England Journal of Medicine (2002), found that metformin resulted in modest weight loss and a significant reduction in the incidence of type 2 diabetes in high-risk individuals.

  • A review by Seifarth et al. (2013) in Experimental and Clinical Endocrinology & Diabetes highlighted metformin’s role in weight loss and improvement in metabolic health in non-diabetic individuals with obesity.

3. Cardiovascular Protection

Metformin has shown potential in reducing cardiovascular risk factors, independent of its glucose-lowering effects. This includes benefits on lipid profiles, blood pressure, and endothelial function.

  • The UK Prospective Diabetes Study (UKPDS) Group (1998) in The Lancet reported that metformin significantly reduced the risk of cardiovascular events in overweight patients with type 2 diabetes.

  • Griffin et al. (2017) conducted a meta-analysis in Diabetic Medicine, concluding that metformin reduces cardiovascular disease risk in people with and without diabetes.

  • Cameron et al. (2016) in Circulation Research conducted a randomized controlled trial involving 173 non-diabetic patients with coronary artery disease and found that metformin significantly improved endothelial function and reduced carotid intima-media thickness (CIMT), a marker of atherosclerosis.

4. Cancer Prevention and Treatment

Metformin’s anti-cancer properties have been a subject of interest, given its ability to inhibit cell proliferation, reduce insulin and IGF-1 levels, and activate AMPK pathways, which play a role in cancer cell metabolism.

  • He et al. (2017) in Journal of Hepatology conducted a study involving 389 non-diabetic patients with cirrhosis and found that metformin use was associated with a reduced risk of hepatocellular carcinoma development.

  • Higurashi et al. (2016) in Lancet Oncology conducted a randomized controlled trial involving 151 non-diabetic patients with a history of colorectal adenomas and found that metformin significantly reduced the recurrence of adenomas.

  • Goodwin et al. (2011) in Journal of Clinical Oncology found that metformin use was associated with improved survival in diabetic patients with breast cancer.

  • Niraula et al. (2012) in Journal of Clinical Oncology conducted a neoadjuvant trial involving 200 non-diabetic breast cancer patients and found that metformin use was associated with a significant increase in pathologic complete response rates compared to the control group.

  • A meta-analysis by Noto et al. (2012) in Diabetologia showed that metformin use is linked to a lower risk of cancer incidence and mortality.

  • Reni et al. (2016) in The Lancet Oncology conducted a phase II clinical trial involving 60 patients with advanced pancreatic cancer, finding that metformin combined with chemotherapy improved overall survival compared to chemotherapy alone.

  • Margel et al. (2013) published in Diabetes Care analyzed data from 4,891 breast cancer patients and found that metformin use was linked to a reduced risk of cancer recurrence and mortality.

  • Zhang et al. (2013) published in Hepatology conducted a cohort study involving 504,409 diabetic patients and found that metformin use was associated with a significantly lower risk of hepatocellular carcinoma compared to non-users.

5. Neuroprotection and Cognitive Health

Research suggests that metformin may have neuroprotective effects, potentially reducing the risk of neurodegenerative diseases such as Alzheimer’s.

  • Freeman et al. (2014) in The Journal of Clinical Investigation explored the effects of metformin on insulin signaling in the brain and found that it improved cognitive function and reduced markers of insulin resistance in a mouse model of Alzheimer's disease.

  • Labuzek et al. (2010) in Pharmacological Reports showed that metformin has significant anti-inflammatory effects, reducing levels of pro-inflammatory cytokines that are implicated in neurodegeneration.

  • Li et al. (2012) in Pharmacology Biochemistry and Behavior demonstrated that metformin improved cognitive function and reduced Alzheimer’s disease-like neuropathology in animal models.

  • Wang et al. (2017) published in Cell Reports found that metformin activated AMPK and reduced inflammation, improving cognitive function in a mouse model of Alzheimer’s disease.

6. Anti-Aging and Longevity

Metformin’s role in promoting healthy aging and longevity is an area of active research. It is believed to influence aging-related pathways through its effects on AMPK activation and mTOR inhibition.

  • Martin-Montalvo et al. (2013) in Nature Communications found that metformin extended lifespan and improved healthspan in mice.

  • Bannister et al. (2014) published in Diabetes, Obesity and Metabolism analyzed data from the UK Clinical Practice Research Datalink, finding that diabetic patients on metformin had a survival advantage compared to non-diabetic controls.

7. Inflammatory and Autoimmune Conditions

Metformin’s anti-inflammatory properties make it a candidate for treating various inflammatory and autoimmune diseases, such as rheumatoid arthritis, lupus, multiple sclerosis (MS), inflammatory bowel disease (IBD) and psoriasis.

  • Cameron et al. (2016) in Circulation Research reported that metformin has anti-inflammatory effects irrespective of diabetes status.

Rheumatoid Arthritis (RA)

Rheumatoid arthritis is a chronic autoimmune disorder characterized by inflammation and joint damage. Metformin has shown potential in reducing disease activity and improving outcomes in RA patients.

  • Yin et al. (2015) published in Annals of the Rheumatic Diseases demonstrated that metformin reduced disease severity in a mouse model of RA by inhibiting the mTOR pathway and reducing pro-inflammatory cytokines.

Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus is a systemic autoimmune disease affecting multiple organs. Metformin has been studied for its immunomodulatory effects in SLE.

  • Koga et al. (2014) in Arthritis Research & Therapy found that metformin ameliorated disease activity in a lupus-prone mouse model by activating AMPK and reducing inflammatory cytokine production.

Multiple Sclerosis (MS)

Multiple sclerosis is a chronic inflammatory disease of the central nervous system. Metformin has shown neuroprotective and anti-inflammatory effects in MS models.

  • Nath et al. (2009) in Brain showed that metformin reduced demyelination and inflammation in a mouse model of MS by modulating AMPK and mTOR pathways.

Inflammatory Bowel Disease (IBD)

Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, involves chronic inflammation of the gastrointestinal tract. Metformin has been explored for its potential benefits in IBD.

  • Zhuang et al. (2019) published in Journal of Cellular Physiology found that metformin reduced colonic inflammation and improved gut barrier function in a mouse model of colitis by activating AMPK.

Psoriasis

Psoriasis is a chronic autoimmune skin disease characterized by hyperproliferation of keratinocytes and inflammation. Metformin’s anti-inflammatory properties have shown promise in managing psoriasis.

  • Singh et al. (2019) in Journal of the American Academy of Dermatology conducted a clinical trial showing that metformin significantly reduced psoriasis severity and inflammatory markers in patients.

  • Mahrouf-Yorgov et al. (2017) in Journal of Investigative Dermatology demonstrated that metformin reduced psoriasis-like inflammation in a mouse model by inhibiting mTOR signaling.

Conclusion

Metformin’s versatility as a therapeutic agent extends far beyond its traditional role in managing type 2 diabetes. Its potential benefits in treating and preventing a wide range of conditions, including PCOS, obesity, cardiovascular diseases, cancer, neurodegenerative diseases, and inflammatory disorders are supported by a growing body of scientific evidence in both diabetic and non diabetic patients. As research continues to uncover the full spectrum of metformin’s effects, it may become an integral part of strategies aimed at improving overall health, preventing disease and enhancing longevity. However, it is crucial to consult healthcare professionals before using metformin for off-label purposes.

References

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  28. Zhuang, Y., Moya, R., Conde, E., Hernández, J. S., & Costamagna, E. (2019). Metformin promotes microbiota-dependent reduction of colonic inflammation in a mouse model of colitis. Journal of Cellular Physiology, 234(7), 10592-10604.

  29. Reference: Singh, S., Young, P., Armstrong, A. W. (2019). An update on psoriasis and metabolic syndrome: The impact of metformin therapy. Journal of the American Academy of Dermatology, 80(2), 422-424.

  30. Reference: Mahrouf-Yorgov, M., Auge, N., Lajoie-Mazenc, I., Haddad, M., Nguyen, C., & Benoist, H. (2017). Activation of the AMP-activated protein kinase ameliorates psoriasis. Journal of Investigative Dermatology, 137(8), 1755-1764.

Jessica Cerka
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