Metformin Associated With Higher Incidence Of Acidosis, But Not Mortality In COVID-19 Infected Individuals With Pre-Existing Type 2 Diabetes

COVID-19 And Metformin: A new study comprising researchers from China, America and UK have shown that metformin as a diabetic drug for COVID-19 patients with type 2 diabetes was associated with higher incidence of acidosis which could lead to kidney complications but it was not associated with higher mortality rates.


 
The study findings were published in the journal: Cell Metabolism https://www.cell.com/action/showPdf?pii=S1550-4131%2820%2930426-5 or https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30426-5
 
The drug safety and efficacy of anti-diabetic medications are critical for maximizing the beneficial impacts of well-controlled blood glucose on the prognosis of individuals with COVID-19 and pre-existing type 2 diabetes (T2D).
 
To date, metformin is the most commonly prescribed first-line medication for T2D, but its impact on the outcomes of individuals with COVID-19 and T2D remains to be clarified.
 
This retrospective study in a cohort of 1,213 hospitalized individuals with COVID-19 and pre-existing T2D indicated that metformin use was significantly associated with a higher incidence of acidosis, particularly in cases with severe COVID19, but not with 28-day COVID-19-related mortality.
 
However interestingly, metformin use was significantly associated with reduced heart failure and inflammation.
 
The study findings provide clinical evidence in support of continuing metformin treatment in individuals with COVID-19 and pre-existing T2D, but acidosis and kidney function should be carefully monitored in individuals with severe COVID-19.
 
Studies have demonstrated that diabetes mellitus particularly type 2 diabetes (T2D), is a major comorbidity that significantly increases the risk of death and adverse complications in individuals with COVID-19. https://jamanetwork.com/journals/jama/fullarticle/2765184 and https://www.sciencedirect.com/science/article/pii/S1550413120302382
 
 
One of the largest retrospective cohort studies of in-hospital individuals have shown that well-controlled blood glucose is associated with a remarkable reduction of death and adverse complications in individuals with COVID-19 and pre-existing T2D, indicating the importance and likely the necessity of intensive blood glucose management in these individuals. https://www.sciencedirect.com/science/article/pii/S1550413120302382
 
The drug metformin is a leading first-line anti-diabetic medication (American Diabetes Association, 2019). It is the most commonly prescribed drug for the treatment of T2D (used by 30%–88% of individuals with T2D), owing to its low cost, good safety profile, and a broad spectrum of clinical benefits. https://pubmed.ncbi.nlm.nih.gov/28342563/
 
For individuals with COVID19 and pre-existing T2D, the established beneficial effects of metformin on blood glucose management, cardiac protection, and immune modulation may result in a more beneficial outcome of the viral disease than if metformin use is withheld. https://www.sciencedirect.com/science/article/pii/S1550413114004410 https://www.frontiersin.org/articles/10.3389/fimmu.2018.01236/full
 
But concerns have been raised regarding the potential side effects of metformin use as it can promote lactic acidosis in individuals with COVID-19 and pre-existing T2D, particularly for individuals with severe symptoms of COVID-19. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(20)30152-2/fulltext
 
The study team retrospectively enrolled 15,451 confirmed COVID-19 cases that were admitted among 16 hospitals from Hubei Province, China, among which 2,563 individuals had pre-existing T2D, to investigate the relationship between in-hospital use of metformin and the clinical outcomes in those individuals with COVID-19 and pre-existing T2D. The findings indicate that metformin use is associated with increased incidence of acidosis, but not 28-day all-cause mortality, in individuals with COVID-19 and pre-existing T2D.
 
Significantly, metformin use was significantly associated with reduced heart failure as well as an inflammatory response. These findings offer important information to assist clinicians in the decision to use metformin to manage diabetes in individuals with COVID-19.
 
The final cohort had 1,213 individuals with T2D, including 678 subjects (male, 53.8%) treated with metformin or metformin plus other anti-diabetic drugs (referred to as the metformin group) and 535 individuals (male, 49.9%) treated with anti-diabetic drugs other than metformin (referred to as the non-metformin group). The median ages were 62 (IQR, 55–68) and 64 (IQR, 58–70) years in the metformin and the non-metformin groups, respectively. The median body mass index (BMI) was 24.3 (IQR, 22.0–25.9) versus 24.5 (IQR, 22.6–26.2) kg/m2 in the metformin versus the non-metformin groups, respectively. While individuals in both groups exhibited similar levels of elevated systolic blood pressure (SBP), the metformin group had lower incidences of pre-existing coronary heart disease (12.4% versus 17.9%) and cerebrovascular disease (2.5% versus 5.2%) than the non-metformin group.
 
The proportion of individuals with increased C-reactive protein (CRP) levels in the metformin group was lower than that in the non-metformin group (46.9% versus 55.7%). The median fasting glucose level was higher in the metformin group (9.0, IQR, 6.7–13.1 mmol/L) compared to that in the non-metformin group (8.3, IQR, 6.4– 11.8 mmol/L). Meanwhile, the percentage of HbA1c in the metformin group (8.1, IQR, 7.0%–9.9%) was also higher than that in the non-metformin group (7.6, IQR, 6.7%–8.9%). Chest computed tomography (CT) scan and major lab examinations results were similar or marginally different between the two groups. There were similar numbers of cases with severe COVID-19 in the metformin group versus the non-metformin group (32.60% versus 33.83%, p = 0.695) on admission.
 
Metformin Use Is Associated with Lactic Acidosis and Acidosis in Individuals with COVID-19 and T2D. Metformin lowers glucose levels mainly by reducing hepatic glucose production through inhibiting the mitochondrial respiratory chain, preventing intestinal glucose absorption, and enhancing glucose uptake and utilization by peripheral tissues. The blockage of oxidative phosphorylation also promotes anaerobic metabolism, which increases the risk of accumulation of the by-product lactate.
 
Metformin-induced lactic acidosis was first reported when 66 individuals treated with metformin developed lactic acidosis within 1 year after metformin was introduced in the United States. https://pubmed.ncbi.nlm.nih.gov/9441244/
 
The actual incidence of lactic acidosis is approximately 1 in 23,000 to 30,000 persons per year among metformin users. However, in the setting of infection and sepsis, hyperlactatemia can be dramatically induced mainly due to inadequate oxygen delivery, leading to tissue hypoxia and enhanced anaerobic glycolysis. https://pubmed.ncbi.nlm.nih.gov/26378980/     
 
Elevated serum lactate is associated with increased mortality, independent of organ failure and shock https://pubmed.ncbi.nlm.nih.gov/19325467/.
 
The researchers in this study  first investigated the well-known lactic acidosis promoting effect of metformin. In the metformin group, 20 individuals (2.95%) developed acidosis and 12 individuals (1.77%) developed lactic acidosis, percentages that are higher compared to those of the non-metformin group (1.5% acidosis and 0.75% lactic acidosis, respectively). As metformin use could be dynamically determined by the medication status during hospitalization, the Cox regression model with time-varying exposure was applied to the entire cohort to analyze the association between metformin use and the incidence of acidosis, in which daily use of metformin was considered a covariable. Here, the adjusted variables for comparison between the metformin and the non-metformin groups included age, gender, comorbidities (cerebrovascular disease and coronary heart disease), blood glucose, CRP elevation, eGFR, alanine aminotransferase (ALT) elevation, and creatinine elevation. In this model, the risks for both lactic acidosis (adjusted HR, 4.66; 95% CI, 1.45–14.99; p = 0.010) and acidosis (adjusted HR, 2.45; 95% CI, 1.08–5.54; p = 0.032) were significantly higher in the metformin group than that in the non-metformin group.
 
Lactic Acidosis and Acidosis in the Metformin Group Were Associated with Higher Doses, Worse Kidney Function, and Severity of COVID-19.
 
The study team further analyzed the factors associated with the development of lactic acidosis and acidosis in individuals with COVID19 and pre-existing T2D by using binary logistic regression model analysis. The candidate factors included age, sex, the dosage of metformin, eGFR, comorbidities on admission, and baseline characteristics.
 
The study results indicated that metformin use at 2 % dose < 3 g/day was significantly associated with an increased incidence of developing lactic acidosis (OR, 22.57; 95% CI, 1.99–256.71; p = 0.012) and acidosis (OR, 12.79; 95% CI, 1.24–132.14; p = 0.032), while neither low-dose (<1 g/day) nor moderate-dose (1 % dose >< 2 g/day) metformin use was significantly associated with the acidosis and lactic acidosis.
Furthermore, insufficient kidney function, particularly eGRF < 60mL/min/1.73 m2 , was also associated with a higher risk of developing lactic acidosis (OR, 3.94; 95% CI, 1.05– 14.76; p = 0.042) and acidosis (OR, 5.21; 95% CI, 1.83–14.81; p = 0.002).
 
However fFurther subgroup analysis in individuals with an eGFR > 60 mL/min/1.73 m2 indicated that the incidences of acidosis were similar between the metformin and the non-metformin groups (Table S5). These results indicated that metformin use was not associated with acidosis in individuals with better renal function.
 
The team also noticed that the percentage of individuals with impaired renal function in the metformin group was significantly lower than that in the non-metformin group (7.82% versus 11.78%, p = 0.026). The indicators for the severity of COVID-19, including SpO2 < 93% (National Health Commission of China 2020; World Health Organization, 2020; Zhang et al., 2020) and neutrophil-to-lymphocyte ratio (NLR) > 3.13 (Liu et al., 2020), were also found to be associated with the onset of lactic acidosis and acidosis in individuals with COVID-19 and pre-existing T2D.
 
Significantly investigation indicated that no acidosis associated with metformin use was found in individuals with mild COVID-19.
 
Taken together, these findings suggest that using metformin in individuals with severe COVID-19 should be accompanied by carefully monitoring acidosis and kidney function. The 28-Day All-Cause Mortality Rate Is Similar between the Metformin and the Non-metformin Groups
 
The team also further investigated whether higher incidences of developing lactic acidosis and acidosis in the metformin group would translate into worse adverse outcomes in individuals with COVID-19 and pre-existing T2D.
 
The team first noticed that there was no difference between the durations of hospitalization in the metformin and the non-metformin users (21 days versus 21 days, p = 0.687), although individuals with acidosis did have non-significantly longer hospitalization than those without acidosis (26 days versus 21 days, p = 0.213). In the Cox regression model with time-varying exposure, there was no significant difference in the mortalities of individuals between the metformin and the non-metformin groups (adjusted HR, 0.87; 95% CI, 0.36–2.12; p = 0.757). Notably, comorbidities as well as other potential covariables, including blood glucose, at hospital admission were adjusted in the analysis. Meanwhile, secondary endpoints, including acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), heart failure, acute kidney injury, and acute.
 
In conclusion, the study team found metformin use is associated with increased incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing T2D. The association between metformin use and acidosis is significantly correlated with the high dose of metformin, lower kidney function, and severity of COVID-19. The study  findings provide clinical evidence in support of continuing metformin use in individuals with COVID-19 and pre-existing T2D, but such patients with severe COVID-19 should be monitored closely for the development of lactic acidosis, acidosis, and decreased kidney function.
 
The study findings also suggest that the dose of metformin administration might be critical to avoid the development of acidosis, while metformin use in individuals with impaired kidney function should be careful considered in the setting of COVID-19
 
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