The Efficacy of Baricitinib Plus Remdesivir Compared to Dexamethasone Plus Remdesivir in Hospitalised COVID-19 Patients With Diabetes Mellitus

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first identified during an outbreak of a respiratory illness in Wuhan City of Hubei Province, China, in December 2019. On March 11, WHO declared COVID-19 a global pandemic. COVID-19 situation is sprouting rapidly with increasing case counts and deaths. So far (June 29, 2021), 182.2 million cases have been detected, with 3.95 million deaths worldwide. . High infection and case fatality rates warrant ongoing research to find safe and effective treatment protocols for hospitalized patients. To date, some of the most promising drugs used in treating COVID pneumonia are systemic corticosteroids, remdesivir and baricitinib. The first randomized clinical trial of remdesivir did not show an absolute decrease in mortality. Subsequently, the ATCC-1 trial conclusively demonstrated a benefit. A third open-label trial involvingCOVID-19 with moderate severity had a low overall mortality (<2%) and did not provide further insight. Finally, data from the SOLIDARITY trial, the largest remdesivir trial to date with 5451 patients (WHO Solidarity Trial Consortium, 2021), did not show a significant decrease in mortality for remdesivir alone (rate ratio 0.95, 95% CI 0.81-1.11) or their embedded meta-analysis of all available trials (rate ratio 0.91, 95% CI 0.79-1.05).Though remdesivir showed promising clinical benefit, the high mortality in the ATCC-1 trial underscored using an immunomodulator combined with remdesivir to achieve the desired outcome . There was a trend towards reduced mortality in patients who received remdesivir and dexamethasone combination. This observation supports the hypothesis that the combination of antiviral and anti-inflammatory agents could improve the outcomes of COVID-19.

Baricitinib is an inhibitor of Janus kinase (JAKs) 1 and 3, with partial selectivity to JAK 2. Baricitinib suppresses pro-inflammatory signals that may be pathogenetically important in the progression to more severe lung disease and ARDS in patients with COVID-19. So far, dexamethasone and baricitinib are the only two anti-inflammatory treatment options; those have been shown to be effective in large randomized clinical trials in treating adults with COVID-19 in hospitals. However, differences in study populations, mortality rates, and endpoint data collected in the ACTT-2 and RECOVERY studies make it difficult to draw firm conclusions about the value of interventions in different patient populations. A comparison between baricitinib and dexamethasone for treating patients with COVID-19 pneumonia who require supplemental oxygen is now a fascinating topic for clinical research, mentioned in an editorial in the New England Journal of Medicine.

ACTT-2showed that baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with COVID-19, notably among those receiving high-flow oxygen or non-invasive ventilation. The combination was associated with fewer serious adverse events like serious infections.Baricitinib was most effective in patients with an ordinal scale of 5 and 6, allowing expansion of therapeutic armament against COVID-19 pneumonia, mainly in patients receiving oxygen support without invasive mechanical ventilation.Evidence in favour of baricitinib is emerging; a recent meta-analysis and systematic review of five studies with a total of 1190 patients showed that the use of JAK inhibitors was significantly associated with a reduced risk of mortality (OR=0.51; 95% CI, 0.28 to 0.93; P = 0.02; I2: 7.8%, P = 0.354) and clinical improvement (OR=1.76; 95% CI, 1.05 to 2.95; P = 0.032; I2: 26.4%, P = 0.253) . Another systematic review of 6 cohort studies and 5 clinical trials involving 2367 subjects treated with ruxolitinib (N = 3) or baricitinib (N = 8) found a potential role for JAK-inhibitors in reducing the risk of death in persons with COVID-19. Use of JAK-inhibitors decreased use of invasive mechanical ventilation (RR = 0.63; 95% CI, 0.47 to 0.84; P = 0.002) and had borderline impact on rates of ICU admission (RR = 0.24; 95% CI, 0.06 to 0.02; P = 0.05) and ARDS (RR = 0.50; 95% CI, 0.19 to1.33; P = 0.16). Relative risks of death for both drugs were 0.42; 95% CI, 0.30 to 0.59; P < 0.001, for ruxolitinib, RR = 0.33; 95% CI, 0.13 to 0.88; P = 0.03) and for baricitinib RR = 0.44; 95% CI, 0.31 to 0.63; P < 0.001). A recent Brazilian study found that tofacitinib resulted in a lower risk of death or respiratory failure than placebo in patients hospitalized with Covid-19 pneumonia.

Dexamethasone has been established as life-saving by reducing mortality in patients needing supplemental oxygen and mechanical ventilation . Dexamethasone was evaluated at the University of Oxford-sponsored Global Study on the Randomised Evaluation of COVID-19 Therapy (RECOVERY). The study results showed that patients receiving dexamethasone had a lower death rate than patients receiving usual treatment. However, in this study, no ordinal stratification was used. The mortality benefit of dexamethasone was greater in patients receiving invasive mechanical ventilation. (assumed ordinal scale of 7). Nevertheless, no indication of the level of oxygen support was given; therefore, it is unknown whether dexamethasone was effective in patients who received low flow oxygen (ordinal scale 5) or in patients who received high flow oxygen (ordinal scale 6).

To date, ACTT-4 is the only head to head study comparing these two drugs in a similar population. The preliminary report of this study is equivocal. No differences in efficacy or adverse reactions were found between the two groups; no drugs were found to be superior or inferior to one another.