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Antidiabetic drugs may have a role in guarding organs affected by COVID-19, researchers say, with trials now underway to confirm it.

"Because it's a viral disease, we see a lot of emphasis on antiviral therapies. But it's also a systemic disease -- in fact a cardiometabolic disease," said Mikhail Kosiborod, MD, of Saint Luke's Mid America Heart Institute in Kansas City, Missouri, speaking at the virtual .

It's still unclear exactly why COVID-19 has been more severe and more often fatal in diabetes and other cardiometabolic diseases.

COVID-19 attacks the same systems damaged by metabolic syndrome and type 2 diabetes, "probably predisposing patients to developing more severe pathology during the infection," noted a .

It's not just diminished immune function from those chronic conditions, but also synergy in causing inflammation, endothelial dysfunction, and kidney injury, for example, wrote Janelle Ayres, PhD, of the Salk Institute for Biological Studies in La Jolla, California.

COVID's vascular complications that disproportionately affect cardiometabolic disease patients might be tackled with GLP-1 receptor agonist diabetes drugs, noted Mansoor Husain, MD, of Toronto General Hospital Research Institute. "They prevent vascular inflammation, they promote vasodilation, they prevent smooth muscle cell activation, and platelet aggregation," he noted at the Heart in Diabetes meeting.

The SEMPATICO trial, funded by the Canadian counterpart of the National Institutes of Health, will assess whether a low dose of the GLP-1 drug semaglutide (Ozempic) can reduce mortality or the need for cardiorespiratory support in a broad elevated risk population with COVID-19 (older, obese, hypertensive patients, with established cardiovascular disease, or an elevated troponin on presentation).

"There's some data in preclinical studies looking at models of sepsis to show that GLP-1 would be beneficial in this concept," Husain noted.

SGLT2 inhibitors also make sense mechanistically as they reverse a lot of the processes like SARS-CoV-2, Kosiborod noted -- for example, improving endothelial function, reducing inflammation and insulin levels, and inhibiting glycolysis.

"We already know that SGLT2's provide organ protection," he said, citing trials done in diabetes, heart failure, and chronic kidney disease.

And, contrary to popular opinion, the drugs do work fast enough to have an effect in acute viral illness, he said. Improvement in endothelial function can occur very quickly, he said. In the DAPA-HF trial, dapagliflozin (Farxiga) started to have an effect on cardiovascular death, heart failure hospitalization, and urgent heart failure visits within days, and that effect became significant vs placebo by day 28.

A literature review in Diabetologia had suggested that when diabetes patients get infected with the pandemic virus, " unless the illness is mild." The review cited risk of and dehydration as well as difficulties in maintaining the usual perineal hygiene. Some suggested the same thing for severe COVID-19, although acknowledging that such ketoacidosis is a .

GLP-1 receptor agonists also may have to be discontinued if there's dehydration risk, noted Zachary Bloomgarden, MD, of Icahn School of Medicine at Mount Sinai in New York City, speaking at the session.

However, there are no formal guidelines because there's no good data in COVID-19 to date, Kosiborod argued.

"If you look at the history of SGLT2 inhibitors, when they first came out in clinical use there were a lot of cautions," such as volume depletion in people with heart failure who may already be on diuretics, he said. "That's now been studied in clinical trials and, in fact, all of those patient groups -- those with heart failure, chronic kidney disease, older patients -- not only do they benefit from these agents, they actually have a greater absolute benefit than other groups."

He argued that the best way to determine whether SGLT2 inhibitors are a boon or liability in COVID-19 is with a rigorous randomized controlled trial.

And his group has just such a randomized trial underway, dubbed . It is randomizing about 1,000 hospitalized adults with COVID-19 to the SGLT2 inhibitor dapagliflozin (Farxiga) versus placebo with a primary outcome of all-cause mortality or new or worsened organ dysfunction (respiratory decompensation requiring initiation of mechanical ventilation, new or worsening heart failure, requirement for vasopressors or mechanical circulatory support, unstable cardiac arrhythmia, or initiation of dialysis).

The trial will include a diverse cardiometabolic disease population of patients with hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease stage 3 or 4. Notably, severe COVID-19, dialysis, type 1 diabetes, and prior diabetic ketoacidosis are all excluded from the trial. There's also close, daily monitoring of acid-base balance in the trial to reduce diabetic ketoacidosis risk, which is a key safety endpoint, Kosiborod noted.

An existing drug approved for other indications is appealing from the standpoint of immediate availability if proven effective and safe, Kosiborod told 乌鸦传媒.

Still, he argued that clinicians should follow the local standard of care until the data is in, rather than jumping ahead on clinical use. "As of right now, we have no data on the use of glucose-lowering drugs in the setting of acute COVID-19 hospitalization," he said.

"One of the things we will need to start thinking about is the interplay of mechanisms between antivirals, anti-inflammatory agents, and an agent for organ protection, like an SGLT2 inhibitor," because these could be complementary, he said. "COVID-19 is a complex disease. I don't think a single drug is going to be the answer to all of the issues. It's possible that the best treatment may be combination therapy."

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