Influence of Metformin Therapy on Mortality in COVID-19

Metformin therapy & mortality: glucose-lowering medication can influence COVID-19 pathogenesis and could have implications for treating patients with diabetes and COVID-19.

Diabetes is an epidemic with many complications and presents a major global health threat. The International Diabetes Federation determined that 1 in 11 adults had diabetes. The presence of diabetes, different degrees of hyperglycemia, and the general complications of diabetes are associated with the severity and increased mortality in COVID-19. Hyperglycemia can modulate immune and inflammatory responses, thus predisposing patients to severe COVID -19 and possibly deadly outcomes. Glucose-lowering medication can influence COVID-19 pathogenesis and could have implications for treating patients with diabetes and COVID-19. Dipeptidyl-peptidase (DPP4) and the renin-angiotensin-aldosterone systems (RAAS) are genetically connected to the risk of SARS-CoV-2 infection. Glucagon-like peptide 1 (GLP1) analogs are not a good option for COVID-19 patients because they will need more time to become effective. Sodium-glucose cotransporter 2 (SGLT2) inhibitors might produce side effects such as osmotic diuresis and dehydration in patients with COVID-19, and therefore cannot be recommended.

Researchers intensely studied the relationship between metformin and COVID-19. However, knowledge in this field is rapidly developing, with many publications frequently emerging. The current study carried out a meta-analysis to detect the overall influence of metformin treatment on COVID-19 patients with diabetes. The odds ratio correlated to the 95% confidence interval determined the efficacy of metformin on COVID-19 patients with diabetes. The Q test and I2 Statistics evaluated the statistical heterogeneity between studies. In no apparent heterogeneity, the fixed-effects model (the Mantel-Haenszel method) approximated the summary odds ratio.  Otherwise, the random-effects models (the Dersimonian and Lair method) were utilized. Ultimately, the random effects models evaluated the overall odds ratio estimates and 95% confidence interval to determine the effect of metformin on mortality and severity in COVID-19 patients with diabetes. Logistic meta-regression analyses analyzed the origins of heterogeneity between studies. Funnel plot and Beggs rank association method determined publication bias. STATA 12.0 software performed statistical analyses.

Researchers gathered 17 studies that included 20,719 COVID-19 patients with diabetes. The results indicated that metformin was linked with a significantly lower mortality rate and severity in COVID-19 patients with diabetes. Omission of one study at a time-analyzed general meta-analysis; the deletion of any research created no significant difference, proving that the results were statistically reliable. COVID-19 spread widely with a substantial impact on most countries. Therapeutic methods in COVID-19 patients with diabetes are finite. Diabetes was linked with poor outcomes in COVID-19 patients. Prior meta-analysis showed that metformin therapy was correlated with decreased mortality in COVID-19 patients with diabetes.

Metformin can encourage lifespan and ease health through mitohormesis and lysosomal pathways to synchronize mTORC1 and AMPK. In addition, metformin reportedly contains anti-inflammation properties and lowers oxidative damage. Metformin’s ability to lower neutrophil count and reduce extracellular traps have also been suggested as potential mechanisms for its benefits in patients with diabetes and COVID-19.

Acute respiratory distress syndrome (ARDS) is one of the most familiar complications in patients with COVID-19. Preventing ARDS is essential to facilitate the outcome of patients. The influence of metformin on ARDS creates controversy. Metformin was significantly linked to reduced heart failure and inflammation. However, some research did not find reliable results of metformin use on the clinical severity of the disease. An additional study determined that an antidiabetic treatment with metformin was linked with a greater risk of disease progression in COVID-19 patients with diabetes during hospitalization. Results with accrued data showed that metformin was linked with significantly lowered severity in COVID-19 patients with diabetes.

The study presents a few limitations, such as heterogeneity between studies in general comparisons. Although the study found no likely factors that could potentially influence the original heterogeneity, the heterogeneity could affect the results. In conclusion, the meta-analysis showed that following metformin therapy in COVID-19 patients with diabetes might lower the mortality and severity. However, the use of metformin was significantly linked with a greater likelihood of acidosis, specifically in severe cases of COVID-19. Therefore, patients with severe COVID-19 should be observed closely for signs of developing lactic acidosis, acidosis, and lowered kidney function.

Practice Pearls:

• COVID-19 expanded worldwide, affected millions of people, and caused more than 3.7 million deaths globally.
• Metformin was linked with significantly lowered mortality in COVID-19 patients with diabetes.
• Individuals with severe COVID-19 should be observed closely for signs of lactic acidosis, acidosis, and lowered kidney function.

Yang, Wenxing et al. “The effect of metformin on mortality and severity in COVID-19 patients with diabetes mellitus.” Diabetes Research and Clinical Practice, vol. 178 108977. July 22. 2021.

Wang, Jingya et al. “Association of Metformin with Susceptibility to COVID-19 in People with Type 2 Diabetes.” The Journal of Clinical Endocrinology and Metabolism vol. 106,5 05. April. 2021.

Emmanuella Louissaint, PharmD candidate, LECOM College of Pharmacy