Dapagliflozin is missing in COVID-19 but intriguing sign of benefit


In hospitalized patients with COVID-19 infection, the sodium-glucose transporter 2 inhibitor dapagliflozin showed a trend toward placebo-related benefit in multiple outcomes, including the primary outcome of time to organ failure or death, according to the results of the DARE-19 randomized trial.

Due to the failure to achieve statistical significance, these results are not immediately relevant, but trends support the interest in further testing SGLT2 inhibitors in acute diseases that present a high risk of organ failure, according to Mikhail Kosiborod , MD.

In a trial that did not meet its main purpose, Kosiborod acknowledged that the positive interpretations are speculative, but believes there is an immediate message to take home.

“Our results do not support discontinuation of SGLT2 inhibitors in the context of COVID-19 as long as patients are monitored,” said Kosiborod, director of cardiometabolic research at the Heart Institute of South America. Saint Luke, Kansas City, Mo.

In many institutions, it has been common to discontinue SGLT2 inhibitors in patients admitted with COVID-19. One reason was the concern that drugs in this class could exacerbate organ damage, especially in the case of induced ketoacidosis. However, only 2 (0.003%) of 613 patients treated with dapagliflozin developed ketoacidosis and the overall, although not significant, organ protection signal was consistent.

“Numerically, fewer patients treated with dapagliflozin experienced organ failure and death, and this was consistent across all systems, including the kidney,” Kosiborod said when presenting the study at the annual scientific sessions of the American College of Cardiology. .

Overall, the study suggests that in the context of COVID-19, dapagliflozin showed no harm and could have a potential benefit, he added.

DARE-19 was conceived, designed, and implemented rapidly during the early stages of the COVID-19 pandemic. Based on previous evidence that SGLT2 inhibitors “favorably affect a number of pathophysiological pathways interrupted during acute disease” and that drugs of this class have provided organ protection in the context of heart attack, chronic kidney disease, and other cardiometabolic conditions, the study was designed to test the hypothesis that this mechanism could improve outcomes in hospitalized patients with COVID-19, Kosiborod said.

Entry criteria include confirmed or suspicious COVID-19 with a start of 4 days less and an additional risk factor, such as atherosclerotic cardiovascular disease, hypertension, o type 2 diabetes. Patients with significant renal impairment or a history of diabetic ketoacidosis they were excluded.

In addition to standard treatments for COVID-19, patients were randomized to 10 mg of dapagliflozin or placebo once daily. There were two main final criteria. Prevention was the time to meet the criteria for respiratory, cardiovascular or renal failure or death. The second primary outcome, for recovery, was a hierarchical compound for four final criteria: death, organ failure, state at 30 days if hospitalized, and time to discharge if it occurred prior to day 30.

Of the 1,250 patients randomized to 95 sites in seven countries, 617 in the dapagliflozin group and 620 in the placebo group completed the study. Baseline characteristics, which included a mean age of 62 years; types of comorbidities; and the types of treatments were similar.

Results for two main endpoints

The curves of the primary outcome of prevention had already separated on day 3 and continued to widen during the 30 days in which the results were compared. After 30 days, 11.2% of the dapagliflozin group and 13.8% of the placebo group had an event. By proportion of danger, dapagliflozin was related to 20% relative insignificant protection against events (hazard ratio, 0.80; 95% confidence interval, 0.58–1.10).

The trend (Pg = 0.168) for the main endpoint of prevention was reflected in the individual components. For placebo-related dapagliflozin, similar or greater reductions in new or worsening organ failure (HR, 0.80), cardiac decompensation (HR, 0.81), respiratory decompensation (HR, 0, 85) and renal decompensation (HR, 0.65). None were statistically significant, but confidence intervals were reduced, with the upper end never exceeding 1.20.

In addition, the reduction in the relative risk of all-cause mortality moved in the same direction (HR, 0.77; 95% CI, 0.52–1.16).

At the hierarchical composite endpoint of recovery, there were no significant differences in discharge time, but again many recovery metrics numerically favored dapagliflozin, with an overall difference producing a statistical trend (Pg = .14) similar to the events of organ failure and death.

In safety analyzes, dapagliflozin consistently outperformed placebo in a wide range of safety measures, including any serious adverse event (65% vs. 82%), any adverse event resulting in death (32% vs. 48%). , the suspension caused by an adverse event (44% vs. 55%), and acute kidney injury (21% vs. 34%).

The data could feed into related studies

According to Ana Barac, MD, PhD, director of the cardio-oncology program at the Medstar Heart and Vascular Institute, Washington, these data are “motivating.” Although it was a negative trial, he said it generates an “exciting hypothesis” about the potential of SGLT2 inhibitors to provide organ protection. He asked for studies to follow this path of research.

More immediately, Barac agreed that these data argue against the arrest of SGLT2 inhibitors in patients admitted to a hospital for COVID-19 infection.

“These data show that these drugs will not cause harm, but they could generate benefits,” he said.

For James Januzzi, MD, a cardiologist at Massachusetts General Hospital and a professor of medicine at Harvard Medical School, both in Boston, DARE-19 was perhaps most impressive for its rigorous design and execution in the midst of a pandemic. .

Over the past year, “medical literature has been inundated with poorly designed and poorly designed monocentric studies,” which have yielded results that are difficult to interpret, Januzzi said. Although this study did not confirm his hypothesis, he said the researchers deserve praise for the quality of the work.

Januzzi also believes the study is not free of clinically relevant results, particularly the fact that dapagliflozin was associated with a lower rate of adverse events than placebo. This, at a minimum, provides certainty about the safety of this drug in the context of COVID-19 infection.

Kosiborod reported financial relations with more than ten pharmaceutical companies, including AstraZeneca, which provided funding for DARE-19. Barac reported financial relations with Bristol-Myers Squibb and CTI BioPharma. Januzzi reported financial relationships with Boehringer Ingelheim, GE Healthcare, Johnson & Johnson, Merck, Novartis, Pfizer and Roche.

Scientific session of the American College of Cardiology (ACC) 2021: Session 411-16. Filed May 16, 2021.

This article originally appeared on MDEdge.com.

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