The Expanding Clinical Benefits Linked With Metformin Use: New Study Provides More Data Suggesting Metformin is Associated With Reduced COVID-19 Mortality Rates

By Yvette C. Terrie, BS Pharm, RPh, Consultant Pharmacist

Metformin is one of the most extensively prescribed drugs used to treat T2DM and is also recommended by the American Diabetes Association (ADA) as the preferred initial pharmacological agent for the treatment of T2DM either alone or in combination with other agents.¹ Additionally metformin is often prescribed off label as treatment for prediabetes, gestational diabetes and to treat women with polycystic ovarian syndrome.²  According to a recent publication in April 2020 issue of Frontiers in Endocrinology, since its approval, various uses of metformin have been discovered and the clinical benefits associated with its use in numerous diseases and even in aging were explored in clinical studies. ^3-12 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.^3-12 Research indicates that metformin may exert the various clinical effects via different signaling pathways; however, the precise mechanisms have not yet been determined and research is ongoing. ³

Examples of studies exploring other benefits associated with metformin include the following:

• A study published in 2019 in Current Rheumatology Reviews observed that metformin may protect bones, especially during the early stages of rheumatoid arthritis, and decrease inflammation, risk of CVD and cancer in RA patients.¹³
• A meta-analysis published in 2018 indicated that metformin may be effective in decreasing body weight in obese patients.¹⁴
• A study published in 2019 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.¹⁵

Highlights From Recently Published Study Exploring Effects of Metformin in Patients With COVID-19

According to results from a recent study, the use of metformin before a diagnosis of COVID-19 is also correlated with a threefold decrease in mortality in T2DM patients with COVID-19.¹⁶ 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. ¹⁶ Researchers, Crouse et al conducted a retrospective electronic health record data analysis of 25,326 subjects tested for COVID-19 between 2/25/20 and 6/22/20 at the University of Alabama at Birmingham Hospital. The primary outcome was mortality in COVID-19-positive subjects and the correlation with subject characteristics and comorbidities was evaluated utilizing simple and multiple linear logistic regression. They noted that overall, 2.4 % 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 Black/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 only representing 26% of the population in Alabama, the number of African-Americans who tested positive for COVID-19 was disproportionally elevated as African-Americans represented 52% of those who tested positive while accounting for only 30% 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).¹⁶ The overall mortality rate in COVID-19-positive patients was 11% and having diabetes was correlated with a markedly expanded risk of death (OR, 3.62; P < .0001), and persisted as an independent risk factor even after adjusting for age, race, gender, obesity, and hypertension. They also stated that particularly, the decrease in mortality among those with diabetes taking metformin prior to COVID-19 diagnosis was considerable: 11% of those patients died, compared with 23% of those with diabetes not taking metformin. They concluded that their findings imply that while diabetes is an independent risk factor for COVID-19-related mortality, this risk is noticeably decreased in subjects taking metformin prior to diagnosis of COVID-19, suggesting the possibility that metformin may provide a protective approach in this high-risk population and that further studies are warranted to explore the protective effects associated with the use of metformin.¹⁶  

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.” 

According to 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. More information can be found on the UAB News website.

While the FDA has only approved metformin to treat T2DM, there is growing evidence that its usage is associated with several other clinical benefits, however more research is warranted. It is important that pharmacists are familiar with these studies, so that they are prepared to answer patient questions or able to direct prescribers to the proper clinical sources regarding this topic. A list of studies titled, Metformin: Beyond Diabetes highlights various publications exploring the clinical benefits of metformin and can be reviewed.

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.

Yvette C. Terrie, Consultant Pharmacist, Medical Writer and creator of A Pharmacist’s Perspective (https://apharmacistsperspective.blogspot.com/).

References

1. American Diabetes Association. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021 Jan;44(Suppl 1):S111-S124. doi: 10.2337/dc21-S009. PMID: 33298420.
2. Beyond diabetes, metformin may prove to be a ‘wonder drug’. Healio website. Published February 17, 2017. Accessed January 26, 2021. https://www.healio.com/news/endocrinology/20170207/beyond-diabetes-metformin-may-prove-to-be-a-wonder-drug
3. Lv Z, Guo Y. Metformin and Its Benefits for Various Diseases. Front Endocrinol (Lausanne). 2020;11:191. Published 2020 Apr 16. doi:10.3389/fendo.2020.00191.
4. Papanagnou P, Stivarou T, Tsironi M. Unexploited antineo plastic effects of commercially available anti-diabetic drugs. Pharmaceuticals. (2016) 9:24 10.3390/ph9020024.
5. Blonde L, Dipp S, Cadena D. Combination glucose-lowering therapy plans in T2DM: case-based considerations. Adv Ther. (2018) 35:939–65. 10.1007/s12325-018-0694-0.
6. Gandini S, Puntoni M, Heckman-Stoddard BM, Dunn BK, Ford L, Decensi A, et al.  Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders. Cancer Prev Res. (2014) 7:867–85. 10.1158/1940-6207.CAPR-13-0424.
7. Morales DR, Morris AD. Metformin in cancer treatment and prevention. Annu Rev Med. (2015) 66:17–29. 10.1146/annurev-med-062613-093128.
8. 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) 13:221–8. 10.1111/j.1463-1326.2010.01349.x.
9. Bhat A, Sebastiani G, Bhat M. Systematic review: preventive and therapeutic applications of metformin in liver disease. World J Hepatol. (2015) 7:1652–9. 10.4254/wjh.v7.i12.1652.
10. Breining P, Jensen JB, Sundelin EI, Gormsen LC, Jakobsen S, Busk M, et al. . Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro. Diabetes Obes Metab. (2018) 20:2264–73. 10.1111/dom.13362.
11. Patrone C, Eriksson O, Lindholm D. Diabetes drugs and neurological disorders: new views and therapeutic possibilities. Lancet Diabetes Endocrinol. (2014) 2:256–62. 10.1016/S2213-8587(13)70125-6.
12. Neven E, Vervaet B, Brand K, Gottwald-Hostalek U, Opdebeeck B, De Mare A, et al. . Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder. Kidney Int. (2018) 94:102–13. 10.1016/j.kint.2018.01.027.
13. 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. doi: 10.2174/1573397114666180717145745. PMID: 30019648.
14. Ning HH, Le J, Wang Q, Young CA, Deng B, Gao PX, Zhang HQ, Qin SL. The effects of metformin on simple obesity: a meta-analysis. Endocrine. 2018 Dec;62(3):528-534. doi: 10.1007/s12020-018-1717-y. Epub 2018 Aug 27. PMID: 30151735.
15. Wang Y, Hussain SM, Wluka AE, Lim YZ, Abram F, Pelletier JP, Martel-Pelletier J, Cicuttini FM. 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 May 24;21(1):127. doi: 10.1186/s13075-019-1915-x. PMID: 31126352; PMCID: PMC6534888.
16. Andrew B. Crouse, Tiffany Grimes, Peng Li, Matthew Might, Fernando Ovalle, Anath Shalev. 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.