Examining The Expanding Clinical Benefits Linked With Metformin Use
Metformin is one of the most extensively prescribed drugs used to treat type 2 diabetes. The American Diabetes Association (ADA) also recommends metformin as the preferred initial pharmacological agent for the treatment of type 2 diabetes either alone or in combination with other agents.1 Additionally, off-label prescription of metformin often occurs as treatment for prediabetes, gestational diabetes, and to treat patients with polycystic ovarian syndrome (PCOS).2
The mechanisms of action of metformin are complex and not fully understood; however, metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity via increasing peripheral glucose uptake and utilization.3 Metformin was the first insulin-sensitizing drug (ISD) used in PCOS to examine the role of insulin resistance in the pathogenesis of the syndrome. In an observational study, Velazquez and colleagues reported a significant improvement in menstrual regularity and reduction in circulating androgen levels, as well as a significant decrease in body weight, which confounded their findings.4 Clinical studies also reveal that with regard to patients with PCOS, insulin-sensitizing agents such as metformin work via diminishing circulating insulin levels.5 Moreover, research reports that several clinical effects may take place when using metformin for those with PCOS, including restoring ovulation, decreasing weight, reducing levels of circulating androgen levels, reducing risk of miscarriage and decreasing risk of gestational diabetes.5
According to the April 2020 issue of Frontiers in Endocrinology, since its approval, scientists continue to discover various uses of metformin and explore the clinical benefits associated with its use in numerous diseases, even in aging, in clinical studies.6-15 Examples of these diseases include cancers (e.g., breast cancer, endometrial cancer, bone cancer, colorectal cancer, and melanoma), obesity, hepatic diseases, neurodegenerative disease, cardiovascular disease, and renal diseases.6-15 Research indicates that metformin may exert the various clinical effects via different signaling pathways; however, ongoing research continues to investigate the precise mechanisms.6
Examples of studies exploring other benefits associated with metformin include:
• A 2019 study in Current Rheumatology Reviews which observed that metformin may protect bones, especially during the early stages of rheumatoid arthritis, and decrease inflammation, risk of cardiovascular disease and cancer in patients with rheumatoid arthritis;16
• A 2018 meta-analysis indicated that metformin may be effective in decreasing body weight in patients with obesity; 17 and
• A 2019 study indicated that the use of metformin may have a beneficial effect on long-term knee joint outcomes in those with knee osteoarthritis and obesity. Researchers noted that randomized controlled trials are necessary to validate these findings and ascertain whether metformin would be a potential therapy.18
What Impact Might Metformin Have For Patients With COVID-19?
According to results from a recent study, the use of metformin before a diagnosis of COVID-19 also correlated with a three-fold decrease in mortality in patients with type 2 diabetes and COVID-19.19 Results from the study published in the January 2021 issue of Frontiers of Endocrinology suggest that individuals who take metformin are at a lower risk of dying from COVID-19, and these findings add to data from previous research including an early report from Wuhan, China, findings from the French CORONADO study, and a US study connecting treatment with diminished mortality among women with COVID-19.19 Crouse and colleagues conducted a retrospective electronic health record data analysis of 25,326 subjects tested for COVID-19 between February 25, 2020 and June 22, 2020 at the University of Alabama at Birmingham Hospital. The primary outcome was mortality in COVID-19-positive subjects, and they evaluated the correlation with subject characteristics and comorbidities utilizing simple and multiple linear logistic regression. They noted that overall, 2.4 percent tested positive for COVID-19 (n = 604), which the authors indicated is probably a low figure because screening included asymptomatic hospital staff and patients having elective procedures.
Researchers revealed that African-American patients had a substantially greater risk of COVID-19 positivity, compared with Caucasian patients (odds ratio (OR), 2.6; P < .0001). The authors noted that despite representing 26 percent of the population in Alabama, there was a disproportionately elevated COVID-19 positivity rate among African-Americans, representing 52 percent of those who tested positive, while accounting for only 30 percent of those who tested negative.16 Additionally, positivity rates were also greater among those with hypertension (OR, 2.46), diabetes (OR, 2.11), and obesity (OR, 1.93), compared with those without each condition (all P < .0001).19 The overall mortality rate in COVID-19-positive patients in this study was 11 percent and having diabetes correlated with a markedly expanded risk of death (OR, 3.62; P < .0001). Diabetes persisted as an independent risk factor even after adjusting for age, race, gender, obesity, and hypertension. The authors also stated that particularly, the decrease in mortality among those with diabetes taking metformin prior to COVID-19 diagnosis was considerable: 11 percent of those patients died, compared with 23 percent of those with diabetes not taking metformin.19
They concluded that their findings imply that while diabetes is an independent risk factor for COVID-19-related mortality, this risk noticeably decreases in subjects taking metformin prior to diagnosis with COVID-19, suggesting the possibility that metformin may provide some protection in this high-risk population. The authors add that further studies are warranted to explore the protective effects associated with the use of metformin.19
In a press release, one of the researchers, Dr. Anath Shalev, stated, “How metformin improves prognosis in the context of COVID-19 is not known. The UAB findings suggest that the mechanisms may go beyond any expected improvement in glycemic control or obesity, since neither body mass index, blood glucose nor hemoglobin A1C were lower in the metformin users who survived as compared to those who died. The mechanisms may involve metformin’s previously described anti-inflammatory and anti-thrombotic effects.”20
According to University of Alabama at Birmingham (UAB) news website, this study is part of a new Precision Diabetes Program, a collaboration between the UAB Comprehensive Diabetes Center and the Hugh Kaul Precision Medicine Institute at UAB.20
In Conclusion
While currently there is only FDA-approval for metformin to treat type 2 diabetes, there is growing evidence that its usage has associations with several other clinical benefits, however more research is necessary. It is important that podiatrists become familiar with these studies, so they may properly answer patient questions and more fully understand the potential medical history and treatment plan for a patient that presents with metformin as part of a medication list. A list of studies titled, “Metformin: Beyond Diabetes” highlights various publications exploring the clinical benefits of metformin and is available for review.21
The key question for many health care professionals that remains is the following: “Is metformin a wonder or super drug?” Hopefully with the ongoing research efforts, researchers will be able to validate the answer soon. n
Ms. Terrie is a consultant pharmacist, medical writer, and creator of A Pharmacist’s Perspective (https://apharmacistsperspective.blogspot.com/).
Editor’s Note: A version of this piece originally appeared as a blog on the HMP Global Pharmacy Learning Network and is adapted with permission. To read the original blog, go to https://tinyurl.com/ptvwbheu .
M
etformin is one of the most extensively prescribed drugs used to treat type 2 diabetes. The American Diabetes Association (ADA) also recommends metformin as the preferred initial pharmacological agent for the treatment of type 2 diabetes either alone or in combination with other agents.1 Additionally, off-label prescription of metformin often occurs as treatment for prediabetes, gestational diabetes, and to treat patients with polycystic ovarian syndrome (PCOS).2
The mechanisms of action of metformin are complex and not fully understood; however, metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity via increasing peripheral glucose uptake and utilization.3 Metformin was the first insulin-sensitizing drug (ISD) used in PCOS to examine the role of insulin resistance in the pathogenesis of the syndrome. In an observational study, Velazquez and colleagues reported a significant improvement in menstrual regularity and reduction in circulating androgen levels, as well as a significant decrease in body weight, which confounded their findings.4 Clinical studies also reveal that with regard to patients with PCOS, insulin-sensitizing agents such as metformin work via diminishing circulating insulin levels.5 Moreover, research reports that several clinical effects may take place when using metformin for those with PCOS, including restoring ovulation, decreasing weight, reducing levels of circulating androgen levels, reducing risk of miscarriage and decreasing risk of gestational diabetes.5
According to the April 2020 issue of Frontiers in Endocrinology, since its approval, scientists continue to discover various uses of metformin and explore the clinical benefits associated with its use in numerous diseases, even in aging, in clinical studies.6-15 Examples of these diseases include cancers (e.g., breast cancer, endometrial cancer, bone cancer, colorectal cancer, and melanoma), obesity, hepatic diseases, neurodegenerative disease, cardiovascular disease, and renal diseases.6-15 Research indicates that metformin may exert the various clinical effects via different signaling pathways; however, ongoing research continues to investigate the precise mechanisms.6
Examples of studies exploring other benefits associated with metformin include:
• A 2019 study in Current Rheumatology Reviews which observed that metformin may protect bones, especially during the early stages of rheumatoid arthritis, and decrease inflammation, risk of cardiovascular disease and cancer in patients with rheumatoid arthritis;16
• A 2018 meta-analysis indicated that metformin may be effective in decreasing body weight in patients with obesity; 17 and
• A 2019 study indicated that the use of metformin may have a beneficial effect on long-term knee joint outcomes in those with knee osteoarthritis and obesity. Researchers noted that randomized controlled trials are necessary to validate these findings and ascertain whether metformin would be a potential therapy.18
What Impact Might Metformin Have For Patients With COVID-19?
According to results from a recent study, the use of metformin before a diagnosis of COVID-19 also correlated with a three-fold decrease in mortality in patients with type 2 diabetes and COVID-19.19 Results from the study published in the January 2021 issue of Frontiers of Endocrinology suggest that individuals who take metformin are at a lower risk of dying from COVID-19, and these findings add to data from previous research including an early report from Wuhan, China, findings from the French CORONADO study, and a US study connecting treatment with diminished mortality among women with COVID-19.19 Crouse and colleagues conducted a retrospective electronic health record data analysis of 25,326 subjects tested for COVID-19 between February 25, 2020 and June 22, 2020 at the University of Alabama at Birmingham Hospital. The primary outcome was mortality in COVID-19-positive subjects, and they evaluated the correlation with subject characteristics and comorbidities utilizing simple and multiple linear logistic regression. They noted that overall, 2.4 percent tested positive for COVID-19 (n = 604), which the authors indicated is probably a low figure because screening included asymptomatic hospital staff and patients having elective procedures.
Researchers revealed that African-American patients had a substantially greater risk of COVID-19 positivity, compared with Caucasian patients (odds ratio (OR), 2.6; P < .0001). The authors noted that despite representing 26 percent of the population in Alabama, there was a disproportionately elevated COVID-19 positivity rate among African-Americans, representing 52 percent of those who tested positive, while accounting for only 30 percent of those who tested negative.16 Additionally, positivity rates were also greater among those with hypertension (OR, 2.46), diabetes (OR, 2.11), and obesity (OR, 1.93), compared with those without each condition (all P < .0001).19 The overall mortality rate in COVID-19-positive patients in this study was 11 percent and having diabetes correlated with a markedly expanded risk of death (OR, 3.62; P < .0001). Diabetes persisted as an independent risk factor even after adjusting for age, race, gender, obesity, and hypertension. The authors also stated that particularly, the decrease in mortality among those with diabetes taking metformin prior to COVID-19 diagnosis was considerable: 11 percent of those patients died, compared with 23 percent of those with diabetes not taking metformin.19
They concluded that their findings imply that while diabetes is an independent risk factor for COVID-19-related mortality, this risk noticeably decreases in subjects taking metformin prior to diagnosis with COVID-19, suggesting the possibility that metformin may provide some protection in this high-risk population. The authors add that further studies are warranted to explore the protective effects associated with the use of metformin.19
In a press release, one of the researchers, Dr. Anath Shalev, stated, “How metformin improves prognosis in the context of COVID-19 is not known. The UAB findings suggest that the mechanisms may go beyond any expected improvement in glycemic control or obesity, since neither body mass index, blood glucose nor hemoglobin A1C were lower in the metformin users who survived as compared to those who died. The mechanisms may involve metformin’s previously described anti-inflammatory and anti-thrombotic effects.”20
According to University of Alabama at Birmingham (UAB) news website, this study is part of a new Precision Diabetes Program, a collaboration between the UAB Comprehensive Diabetes Center and the Hugh Kaul Precision Medicine Institute at UAB.20
In Conclusion
While currently there is only FDA-approval for metformin to treat type 2 diabetes, there is growing evidence that its usage has associations with several other clinical benefits, however more research is necessary. It is important that podiatrists become familiar with these studies, so they may properly answer patient questions and more fully understand the potential medical history and treatment plan for a patient that presents with metformin as part of a medication list. A list of studies titled, “Metformin: Beyond Diabetes” highlights various publications exploring the clinical benefits of metformin and is available for review.21
The key question for many health care professionals that remains is the following: “Is metformin a wonder or super drug?” Hopefully with the ongoing research efforts, researchers will be able to validate the answer soon. n
Ms. Terrie is a consultant pharmacist, medical writer, and creator of A Pharmacist’s Perspective (https://apharmacistsperspective.blogspot.com/).
Editor’s Note: A version of this piece originally appeared as a blog on the HMP Global Pharmacy Learning Network and is adapted with permission. To read the original blog, go to https://tinyurl.com/ptvwbheu .
References
1. American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S111-S124.
2. Beyond diabetes, metformin may prove to be a ‘wonder drug’. Healio website. Available at: https://www.healio.com/news/endocrinology/20170207/beyond-diabetes-metformin-may-prove-to-be-a-wonder-drug. Published February 17, 2017. Accessed October 8, 2021.
3. Metformin Prescribing Information. Food and Drug Administration website. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021748s002lbl.pdf . Accessed December 21, 2021.
4. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy. Metabolism. 1994;43:647–654.
5. Lashen H. Role of metformin in the management of polycystic ovary syndrome. Ther Adv Endocrinol Metab. 2010;1(3):117-128.
6. Lv Z, Guo Y. Metformin and Its Benefits for Various Diseases. Front Endocrinol (Lausanne). 2020;11:191.
7. Papanagnou P, Stivarou T, Tsironi M. Unexploited antineoplastic effects of commercially available anti-diabetic drugs. Pharmaceuticals. 2016;9:24.
8. Blonde L, Dipp S, Cadena D. Combination glucose-lowering therapy plans in T2DM: case-based considerations. Adv Ther. 2018;35:939–965.
9. Gandini S, Puntoni M, Heckman-Stoddard BM, et al. Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res. 2014;7:867–885.
10. Morales DR, Morris AD. Metformin in cancer treatment and prevention. Annu Rev Med. 2015;66:17–29.
11. Lamanna C, Monami M, Marchionni N, Mannucci E. Effect of metformin on cardiovascular events and mortality: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2011;13:221–228.
12. Bhat A, Sebastiani G, Bhat M. Systematic review: preventive and therapeutic applications of metformin in liver disease. World J Hepatol. 2015;7:1652–1659.
13. Breining P, Jensen JB, Sundelin EI, et al. Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro. Diabetes Obes Metab. 2018;20:2264–2273.
14. Patrone C, Eriksson O, Lindholm D. Diabetes drugs and neurological disorders: new views and therapeutic possibilities. Lancet Diabetes Endocrinol. 2014;2:256–262.
15. Neven E, Vervaet B, Brand K, et al. Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder. Kidney Int. 2018;94:102–113.
16. Rajaei E, Haybar H, Mowla K, Zayeri ZD. Metformin one in a Million Efficient Medicines for Rheumatoid Arthritis Complications: Inflammation, Osteoblastogenesis, Cardiovascular Disease, Malignancies. Curr Rheumatol Rev. 2019;15(2):116-122.
17. Ning HH, Le J, Wang Q, et al. The effects of metformin on simple obesity: a meta-analysis. Endocrine. 2018;62(3):528-534.
18. Wang Y, Hussain SM, Wluka AE, et al. Association between metformin use and disease progression in obese people with knee osteoarthritis: data from the Osteoarthritis Initiative-a prospective cohort study. Arthritis Res Ther. 2019;21(1):127.
19. Crouse AB, Grimes T, Li P, Might M, Ovalle F, Shalev A. Metformin Use Is Associated With Reduced Mortality in a Diverse Population With COVID-19 and Diabetes. Frontiers in Endocrinology, 2021; 11 DOI: 10.3389/fendo.2020.600439.
20. Use of metformin reduces risk of death for patients with COVID-19 and diabetes. UAB News. Available at: https://www.uab.edu/news/research/item/11795-metformin-use-reduces-risk-of-death-for-patients-with-covid-19-and-diabetes . Published January 14, 2021. Accessed October 7, 2021.
21. Bost F, Rena G, Viollet B (eds). Metformin: Beyond Diabetes. Frontiers in Endocrinology website. Available at: https://www.frontiersin.org/research-topics/7028/metformin-beyond-diabetes. Accessed October 8, 2021.
