COVID-19: Diabetics who took SGLT-2 inhibitor drugs reduced adverse outcomes


A new study by researchers from Fujian Medical University -China, Fujian Provincial Hospital-China and Fujian Academy of Medical Sciences-China has found that diabetics taking SGLT-2i drugs like canagliflozin, dapagliflozin, and empagliflozin prior to contracting COVID-19 have reduced adverse outcomes.

The study findings were published in the peer reviewed journal: JAMA Network Open.

This network meta-analysis was based on 31 studies that involved 3 689 010 individuals and compared the association between the risk of COVID-19–related adverse outcomes and 8 glucose-lowering therapies in patients with diabetes before diagnosis of COVID-19.

The principal findings of our study were that, compared with insulin, DPP-4is, secretagogues, glucosidase inhibitors, thiazolidinediones, and SGLT-2is were associated with lower COVID-19–related adverse outcomes in patients with diabetes and that, in addition to SGLT-2is, GLP-1RAs and metformin were also associated with relatively low risk of adverse outcomes.

It is unclear whether SGLT-2is should be used as glucose-lowering therapy during the COVID-19 pandemic because of the risk of dehydration and euglycemic diabetic ketoacidosis.56 Based on the updated evidence, however, Khunti et al57 and Koufakis et al58 proposed to reexamine the widespread policy of stopping use of SGLT-2is during acute illness.

Thus, accumulating evidence suggests that the benefits of SGLT-2is go beyond the improvement of glycemic control and have potential cardiovascular and kidney advantages.59-61

For instance, EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) showed that empagliflozin markedly reduced the end points of cardiovascular death and heart failure and was associated with lower serious kidney outcomes.62 In addition to increasing fatty acid oxidation, SGLT-2is can improve mitochondrial function and insulin sensitivity, enhance the organ’s ability to resist physiologic stress, and have potential therapeutic activities on hypertension and obesity.63

In addition, SGLT-2is reduced mortality in experimental pulmonary hypertension, in part because of the observed reduced pulmonary remodeling.64 We know that cardiometabolic comorbidities and their underlying obesity and insulin resistance may increase further impairment of oxidative stress, inflammation, and metabolic disorders in patients with COVID-19.65 Dapagliflozin can reduce the risk of cardiovascular events.66

Thus, SGLT-2is may be related to ameliorating COVID-19 risk factors in this context. Our results suggest that compared with other diabetes drugs, the use of SGLT-2is before COVID-19 infection in patients with diabetes was associated with a lower incidence of adverse outcomes after infection, which may be associated with improving blood glucose level, blood pressure, body weight, and lipid metabolism. However, the number of participants using SGLT-2is in our study was relatively small, so more participants and RCTs are needed to further verify this view.

Our study also found that GLP-1RAs and metformin were associated with a relatively low risk of adverse outcomes. Some researchers have speculated that GLP-1RAs were a candidate for treatment of patients with or without diabetes with COVID-19 owing to their multiple beneficial effects on excessive inflammation-induced acute lung injury.67

Excessive inflammatory responses, such as cytokine storms and disseminated thromboembolic events, are considered fatal complications of COVID-19 infection.68 In addition to the expected improvement in blood glucose control or obesity, metformin has also been shown to have antifibrinolytic activities and inhibit inflammatory cytokines.69,70 Therefore, some researchers speculated that metformin might play a role in the immune response to COVID-19, which might improve the prognosis.71

The result that needs further evaluation is that insulin was associated with a higher risk of adverse outcomes. This finding may be explained because insulin use may reflect more severe diabetes or longer diabetes duration, and these patients are at higher risk for adverse outcomes in the setting of COVID-19 infection.

In our study, because only observational studies were available and some baseline indicators were lacking, partial selection bias could not be ruled out. Patients with severe COVID-19 infection, especially those with respiratory distress, need insulin therapy.1 Insulin should always be the preferred medication in any emergency situation and can be used at any stage of COVID-19.6

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents acting on the SGLT-2 proteins expressed in the renal proximal convoluted tubules. It exerts its effect by preventing the reabsorption of filtered glucose from the tubular lumen.

To date, there are four SGLT-2 inhibitors: canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin that are approved by Food Drug Administration (FDA) for their use in adults. The indications for use vary per agent, but all four agents are approved for use in adults with type 2 diabetes mellitus (DM) to improve blood sugar control adjunct to diet and exercise.[1]

Canagliflozin was the first SGLT-2 inhibitor to receive approval on March 29, 2013. It is indicated in adult patients with type 2 DM to improve the control of blood glucose in addition to diet and exercise. It is also indicated to decrease the risk of cardiovascular (CV) adverse events in type 2 DM subjects with underlying CV illness and minimize the risk of end-stage renal disease (ESRD), CV mortality, hospitalization for heart failure, and increases in serum creatinine in type 2 DM patients with diabetic nephropathy and albuminuria.[1]

Dapagliflozin received FDA approval in January 2014. It is indicated in adult patients with type 2 DM to improve the control of blood glucose in addition to diet and exercise. Other indications include minimizing the hospitalization attributed to heart failure in type 2 DM patients with underlying CV illness or several CV risk factors, decreasing the risk of CV mortality and hospitalization in adult subjects with underlying heart failure, and decreased ejection fraction (EF) with New York Heart Association (NYHA) classification II-IV.[2] It is also indicated to minimize the risk of the continued decline of estimated glomerular filtration rate (eGFR), ESRD, CV mortality, and hospitalization for heart failure in chronic kidney disease (CKD) patients at risk of progressive disease.[1][3]

Soon after the approval of dapagliflozin, empagliflozin was the third SGLT inhibitor to receive approval by the FDA in August 2014.[4] It is indicated in adult patients with type 2 DM to improve the control of blood glucose in addition to diet and exercise, decrease the risk of CV adverse events in type 2 DM subjects with underlying CV illness, and minimize the risk of CV mortality and heart failure hospitalization in adult subjects with underlying heart failure and decreased EF. The latest SGLT inhibitor to receive approval by the FDA was ertugliflozin in 2017 and is indicated for adult subjects with type 2 DM to improve the control of blood glucose in addition to diet and exercise.

Mechanism of Action
SGLT-2 are proteins expressed in the proximal convoluted tubules of the kidneys that exert their physiologic function by reabsorbing filtered glucose from the tubular lumen. All four SGLT-2 inhibitors reduce the reabsorption of filtered glucose, decrease the renal threshold for glucose (RTG), and promote urinary glucose excretion.[5]

By inhibiting the SGLT-2-dependent glucose and sodium reabsorption, there is an increase in distal tubular sodium load. Not only does this inhibit the renin-angiotensin-aldosterone system, but it is also considered to regulate specific physiological functions, which include decreasing renal intraglomerular pressure, promoting tubuloglomerular feedback downregulating sympathetic activity, and reducing the heart’s preload and afterload.[6]

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