Positive collateral effect for metformin on diabetics with COVID-19?

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For about a year now, the current global COVID-19 situation has been the focus of political, economic and medical attention. The virus can be fatal - in particular connection with type 2 diabetics, who also belong to the risk group according to the Robert Koch Institute. Current studies show a possible connection between the drug metformin and the mortality rate of diabetics.

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Metformin in diabetics:

Metformin is an active ingredient that is approved for oral use in type 2 diabetics as soon as their own glucose level (i.e. blood sugar level) cannot be lowered sufficiently through physical activity or dietary changes. In the case of gestational diabetes and so-called prediabetes, i.e. a preliminary stage of diabetes, it can also be used off-label (i.e. outside the approved areas of application). The drug is often taken over a longer period of time so that the patient's own metabolism can be positively influenced.

The effect of metformin involves inhibiting the production of glucose by the liver. This can bypass the typically high fasting blood glucose levels (i.e. measured after a period of time without food intake). The drug can also delay the absorption of glucose in the intestines, keeping blood glucose levels low after meals. In addition, it also increases insulin sensitivity, which is the sensitivity of the corresponding cells in the body to insulin (i.e., this improves sugar utilization).

Study during the pandemic:

A retrospective study recently examined the association between metformin in COVID-19 patients with type 2 diabetes and their mortality rates. The study, published in January 2021 in the journal Frontiers in Endocrinology, explored survival using 25,326 patients who tested positive for SARS-CoV-2 between Feb. 25, 2020, and June 22, 2020. Of 604 patients treated in the southeastern part of America at the University of Alabama Hospital clinic during the first wave, 39.6% (239 patients) had diabetes. 67 patients did not survive the disease - 45 of whom were diabetic (67.2%). Those who had diabetes mellitus showed a more than threefold higher risk of dying from SARS-CoV-2 than people without diabetes. The group of type 2 diabetics, who had been treated with metformin before, is the most controversial. Here, 8 deaths were recorded. The study calculated an odds ratio of 0.38, which meant that mortality was two-thirds lower (i.e., measure from statistics that tells the strength of a relationship between two characteristics. Less than 1 means that the odds of the first comparative group are smaller).

Note: These studies do not prove that treatment with the drug is responsible for a more favourable chance of survival, as it is possible to attribute this to other characteristics.

Protective effect?

If the diabetes is in an advanced stage, patients are treated more often with insulin. The analysis also showed a slightly reduced risk of death with insulin treatment. The CORONADO study, publishedin the scientific journal Diabetologia in 2020, showed similar results in relation to metformin, as the risk of death in diabetics fell by 41% if they had been treated with the drug before the disease.

The American Society of Tropical Medicine and Hygiene also examined the mortality rate of diabetic patients with COVID-19 in connection with metformin treatment. While mortality in this group was 2.9% (3 of 104), the "non-metformin" group showed a mortality rate of 12.3% (22 of 179).

A final study from the U.S. published in 2021 in the journal Lancet Healthy Longevity presented research results suggesting that women with diabetes recorded a significantly reduced risk of death if treated with metformin.

Uncertain results?

However, such retrospective evaluations can quickly be flawed, as the remaining risk factors can also provide significant magnitudes to the results. Note that the patients who had not received metformin were older, at least in the last study, more often had elevated blood pressure, were more often diagnosed with coronary artery disease/heart failure, and noted more chronic kidney disease.

This imbalance was avoided by comparing only patients with similar characteristics. As a result, there was no advantage for metform input in terms of mortality rate - except in females. In female patients, metformin use was associated with an approximately 20% lower mortality rate. Previous studies have also been able to show that the drug was more efficient in women.

Further studies needed:

Randomized clinical trials are certainly needed to test the drug with more precise parameters. Just such trials are already being planned at the Minnesota School of Medicine with about 70 patients to be able to investigate a significant benefit of metformin in this context.

Active ingredients:

Source Notes:

Crouse AB, Grimes T, Li P, Might M, Ovalle F and Shalev A (2021) Metformin Use Is Associated With Reduced Mortality in a Diverse Population With COVID-19 and Diabetes. Front. Endocrinol. (2021)

Cariou, B., Hadjadj, S., Wargny, M. et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia 63, 1500-1515 (2020). https://doi.org/10.1007/s00125-020-05180-x

Luo P, Qiu L, Liu Y, Liu XL, Zheng JL, Xue HY, Liu WH, Liu D, Li J. Metformin Treatment Was Associated with Decreased Mortality in COVID-19 Patients with Diabetes in a Retrospective Analysis. Am J Trop Med Hyg. (2020)

Carolyn T Bramante, MD, Nicholas E Ingraham, MD, Thomas A Murray, PhD, Schelomo Marmor, PhD, Shane Hovertsen, PhD, Jessica Gronski, PhD, et al. Metformin and risk of mortality in patients hospitalised with COVID-19: a retrospective cohort analysis. Lancet Healthy Longevity. (2020) https://doi.org/10.1016/S2666-7568(20)30033-7






Danilo Glisic

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