Metformin (Glucophage) Lowers Risk Of Disease Severity And Fatal Outcomes In Diabetic Patients Infected With COVID-19

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Spanish researchers and physicians have in a new study found that the diabetic drug Metformin (Glucophage) lowers the risk of disease severity and fatal outcomes in diabetic patients infected with the SARS-CoV-2 coronavirus.

The study findings were published in the peer reviewed journal: Primary Care Diabetes.
https://www.primary-care-diabetes.com/article/S1751-9918(22)00167-X/fulltext

We analysed the outcomes of COVID-19 infection in 31,006 diabetic patients, comparing those chronically treated with metformin with those treated with other antidiabetic drugs. In our population, patients receiving only insulin, insulin combined with metformin or iDPP4 in monotherapy had a higher risk of experiencing hospitalization or death in comparison with people treated with metformin in monotherapy.

A recent study published in Spain analysed the sociodemographic, clinical and analytical variables associated with the need for hospital admission due to COVID-19 complications in a PHC cohort and specifically assessed whether diabetes entailed higher risk, finding that it did not increased risk of hospitalization in this population (OR 1.18, 95% CI 0.80–1.72) [[30]].

Different antidiabetic drugs have been studied for their anti-inflammatory properties and other effects which could help improving COVID-19 complications in diabetic patients from different settings. Yang W. et al. conducted a meta-analysis of 17 studies including 20,719 COVID-19 diabetic patients and found that metformin could benefit mortality and severity (OR 0.64, 95% CI 0.51–0.79; and OR 0.81, 95% CI 0.66–0.99, respectively) [[31]].

In our study, we found lower risk of severe outcomes for patients receiving metformin in monotherapy when compared to other antidiabetic treatments, as insulin alone or associated to metformin, or iDPP4, but not comparing with other treatments.

Chen Y et al. performed a meta-analysis of 35 studies and found that metformin, iDPP4, iSGLT2 and GLP1 (OR 0.74, 0.88, 0.82 and 0.91, respectively) were highly possible to reduce mortality risk and insulin might be related to increased mortality risk (OR 1.8) [[32]]. We also found a higher mortality risk with insulin.

In another review of 61 studies analysing pre-admission medication, the authors found protective effect against COVID-related death with metformin, GLP1, and iSGLT2 (OR 0.54, 0.50 and 0.60, respectively); and users of iDPP4 and insulin (OR 1.23 and 1.70) were more likely to die during hospitalization [[33]].

Metformin and sulfonylureas were studied in another meta-analysis including 18 studies with 17,338 patients, which found that both drugs were associated with lower mortality risk in COVID-19 diabetic patients (OR 0.69, 95% CI 0.55–0.86 for metformin and 0.80, 95% CI 0.66–0.96 for sulfonylureas) [[34]].

With regards to iDPP4, this meta-analysis also found that mortality was not different between users and non-users (OR 0.72, 0.51–1.01) [[34]]. Yang Y. et al. pooled the results of four articles to investigate if iDPP4 had a protective effect on the progression of COVID-19, and they found an improvement in the mortality risk in iDPP4 users (OR 0.58, 95% CI 0.34–0.99) [[35]].

Patoulias et al. found that these drugs administered during hospital admission decreased the risk for COVID-19-related death by 50% [[36]]. We found divergent results for this pharmacological group, with a higher risk of hospital admission or death in comparison with metformin users.

Regarding the insulins, the meta-analysis of Kan et al. mentioned above found that patients treated with insulin exhibited greater mortality (OR 2.20, 1.34–3.60) [[34]]. Other studies found negative outcomes associated with insulin, as Chen et al. with an OR= 3.58, 95% CI 1.37–9.35 for poor prognosis, [[37]] or Yu et al. with a significant increase in mortality (27.2% vs 3.5%, HR 5.38, 2.75–10.54) when they compared insulin users with non-users [[38]].

These results were similar to ours, as we also found a higher risk of severe outcomes for insulin in monotherapy or associated with metformin respect metformin alone. The fact that insulin is the hypoglycaemic agent of choice for managing critically ill patients or that it is a third-line therapy for diabetic patients could have influenced these outcomes, as all of them might have worst prognosis [18, 39].

We found a high percentage of diabetic patients not receiving treatment (31.8%) in our population and we do not know if the results would have been different analysing only antidiabetic users or only adherent patients. We are not able to rule out that the results obtained can be more associated with the level of metabolic control than to the chronic antidiabetic therapy. We have adjusted by years of evolution of the diabetes and by the metabolic control as per HbA1c.

Among other limitations of our study there is the reliability of the COVID-19 diagnoses; we included patients without a confirmed result as during the first wave of the pandemic in our setting PCR test were not always performed. This limitation has been described in other research as during the beginning of the pandemic diagnosis test for COVID-19 were not widely available, and clinical algorithms have been used to assess COVID-19 diagnosis [[40]].

Another limitation is that our database is a PHC database and it only records the dates of admission and diagnoses and cause of discharge, so it is necessary to consider the lack of hospital information; for instance, we cannot capture ICU admission, ventilation or treatments and interventions administered during the admission, which clearly have influence in the prognosis and outcomes of COVID-19.
Some strengths of our study include the large number of patients included, representativeness for general population, and complete socio-demographic data. We must highlight that our cohort are PHC patients, so we have estimated the risk of death and hospitalization for a different population from the only hospitalized ones that are usually studied.

Conclusions
We described hospital admission and mortality rates in a large cohort of diabetic patients infected with SARS-CoV-2.
Patients treated with metformin in monotherapy had lower risk of hospitalization and death in comparison to other frequent antidiabetic treatments in our setting.

With the data available, we cannot distinguish if better outcomes are related with the antidiabetic therapy or with other factors, such as metabolic control or interventions applied during the hospital admission.

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