Certain glucose-lowering drugs may be better for COVID patients with diabetes

Finger-prick test for diabetes

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A meta-analysis of 31 studies by Chinese scientists concludes that glucose-lowering sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and metformin were tied to a lower risk of adverse COVID-19–related outcomes in hospitalized type 2 diabetes patients.

In the study, published yesterday in JAMA Network Open, researchers from Fujian Medical University evaluated 31 studies involving more than 3.6 million hospitalized type 2 diabetes patients receiving one of eight glucose-lowering drugs at least 14 days before COVID-19 diagnosis.

The studies, published up to Sep 5, 2022, included 148 active-treatment groups receiving insulin (26 groups), metformin (27), dipeptidyl peptidase-4 inhibitors (DPP-4is; 26), glucagon-like peptide-1 receptor agonists (GLP-1RAs; 15), secretagogues (22), sodium-glucose cotransporter-2 inhibitors (SGLT-2is; 14), thiazolidinediones (9), and alpha-glucosidase inhibitors (AGIs; 9). Five studieshad more than 7 treatment groups, while 18 studies had 4 to 6 groups, and 5 studies had 3.

Average participant age across studies was 55 to 85 years, diabetes duration in most studies was more than 10 years, and average baseline hemoglobin A1c levels were above normal, ranging from 7.1% to higher than 8.7%.

Most adverse events tied to metformin

A total of 22,006 adverse outcomes occurred, mostly in patients who took metformin before COVID-19 diagnosis (37.1%), while 19.5% each had used insulin or DPP-4is, followed by secretagogues (14.7%), GLP-1RAs (3.9%), SGLT-2is (3.3%), thiazolidinediones (1.5%), and AGIs (0.3%).

The team found that SGLT-2is were the most effective at lowering the risk of poor COVID-19 outcomes compared with insulin (log of odds ratio [logOR], 0.91), followed by GLP-1RAs (logOR, 0.44) and metformin (logOR, 0.71), compared with DPP-4is (logOR, 0.61), secretagogues (logOR, 0.37), and AGIs (logOR, 0.50).

"Based on the surface under the cumulative ranking curves value, SGLT-2is were associated with the lowest probability for adverse outcomes (6%), followed by glucagon-like peptide-1 receptor agonists (25%) and metformin (28%)," the researchers wrote.

The researchers also analyzed two randomized, controlled trials (RCTs). One multicenter RCT of the DPP-4i linagliptin versus standard treatment in 64 diabetes inpatients diagnosed as having COVID-19 in three Israeli hospitals found no difference in time to clinical improvement compared with standard care.

Based on the surface under the cumulative ranking curves value, SGLT-2is were associated with the lowest probability for adverse outcomes (6%), followed by glucagon-like peptide-1 receptor agonists (25%) and metformin (28%).

And a parallel, double-blind RCT that assessed treatment with linagliptin and insulin or insulin alone in 73 inpatients with COVID-19 and diabetes found that the combination of linagliptin and insulin reduced the relative risk of assisted mechanical ventilation by 74%, but there was no difference in risk of death by 30 days. The results of the two studies don't completely elucidate the effect of DPP-4is on adverse outcomes in patients hospitalized for diabetes and COVID-19, the authors of the current study said.

SGLT-2is have pros, cons

The authors noted that COVID-19 patients have a high rate of diabetes and that diabetes and poor blood-glucose control can lead to intensive care unit admission and death.

"The risk and severity of infection in patients with diabetes and COVID-19 are associated with increased angiotensin-converting enzyme 2 expression, increased furin levels, impaired T-cell function, and increased interleukin (IL)-6, which makes it possible for diabetes to promote COVID-19 infection because of increased viral entry into cells and impaired immune response," they wrote.

The research team said that, despite the findings and the knowledge that SGLT-2is also have potential cardiovascular and kidney advantages, it is still unclear whether they should be used to lower glucose levels during the COVID-19 pandemic because they can lead to dehydration and the life-threatening complication euglycemic diabetic ketoacidosis.

And further research, they said, is needed on insulin, which was linked to a higher risk of adverse COVID-19–related 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," they wrote.

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