Dapagliflozin in patients with COVID-19: truth or dare
Authors: Xavier Rossello, Francisca Caimari
Journal: The Lancet Diabetes & Endocrinology (2021)

In 2019, the DAPA-HF trial showed a substantial clinical benefit of dapagliflozin among patients with heart failure and reduced ejection fraction, regardless of the presence or absence of diabetes.1McMurray JJV Solomon SD Inzucchi SE et al.Dapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381: 1995-2008Crossref PubMed Scopus (4074) Google Scholar For many people, this trial was a breaking point after years of speculation:2Rossello X Yellon DM A new era in the management of type 2 diabetes: is cardioprotection at long last a reality?.Int J Cardiol. 2017; 228: 198-200Summary Full Text Full Text PDF PubMed Scopus (9) Google Scholar SGLT2 inhibitors became not only a good medication for diabetes but also an excellent drug for cardiovascular disease. About half a year after the publication of the DAPA-HF, COVID-19 was characterised as a pandemic by WHO. Using the confluence of these two facts, Mikhail Kosiborod and colleagues3Kosiborod M Esterline R Furtado RHM et al.Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Diabetes Endocrinol. 2021; (published online July 21.)https://doi.org/10.1016/S2213-8587(21)00180-7Summary Full Text Full Text PDF PubMed Scopus (146) Google Scholar conducted, against the clock, a timely randomised, double blind, placebo-controlled trial assessing the efficacy of dapagliflozin in patients with cardiometabolic risk factors who were hospitalised with COVID-19 pneumonia, regardless of their diabetes status. In the DARE-19 trial, published in the Lancet Diabetes & Endocrinology, there was no difference between groups in terms of the primary endpoint of prevention and coprimary endpoint of recovery. Although the main hypothesis was based on mechanistic studies indicating that SGLT2 inhibitors have favourable effects on pathways that are dysregulated in the context of acute illness, showing efficacy in COVID-19 patients might have been seen unlikely. In addition to the underlying hypothesis, several methodological issues should be highlighted. The standard of care for patients with COVID-19 has been fluctuating in accordance with the changing situation generated by the pandemic. Even other acute conditions were described to have lower incidence of hospitalisations than in previous years,4Rodríguez-Leor O Cid-Álvarez B Pérez de Prado A et al.Impact of COVID-19 on ST-segment elevation myocardial infarction care. The Spanish experience.Rev Esp Cardiol. 2020; 73: 994-1002Crossref PubMed Scopus (104) Google Scholar reflecting the varying medical needs of the population, and the effect of COVID-19 on the quality of care provided by those hospitals more widely hit by the pandemic. Local standards of care for COVID-19 varied widely not only across countries but also within the same country over time. In DARE-19, the heterogeneity of the study population might have had an effect on the internal validity of the study. The problem is not whether patients who have been hospitalised are similar in terms of disease severity and management across countries and across waves of the pandemic within the same country, which is always assumed to vary to some degree, but how much they were different. As such, the population might have been too heterogenous (eg, different management or severity, because at the worst of each wave only people who were more ill were hospitalised) to explain the neutral findings of the study. Although a Cox regression model stratified by country was used to mitigate this issue,5Rossello X González-Del-Hoyo M Survival analyses in cardiovascular research, part I: the essentials.Rev Esp Cardiol (Engl Ed). 2021; (published online June 29.)https://doi.org/10.1016/j.rec.2021.06.003Google Scholar differences in the characteristics and management of the study population within the same country over time were not considered. In addition to the study population, the use of two coprimary efficacy outcomes also deserves further attention. Since the original protocol was designed, the unpredictable nature of the evolving global pandemic resulted in lower than expected event rates for the outcome of prevention. As a consequence, the outcome of recovery became as important as the outcome of prevention, prompting a protocol amendment to make both coprimary endpoints. The coprimary outcome of prevention was a composite of respiratory, cardiovascular, or kidney organ dysfunction during the index hospitalisation, or death within 30 days of enrolment. The other coprimary outcome of recovery was a hierarchical composite that ranked patients into categories by severity and timing of events experienced during the 30-day treatment period: death, organ dysfunction during the index hospitalisation, supplemental oxygen requirement for patients hospitalised at day 30 without organ dysfunction, and hospital discharge before day 30. This second outcome was elegantly evaluated using a win ratio approach, which facilitates the analysis of composite endpoints based on clinical priorities.6Pocock SJ Ariti CA Collier TJ Wang D The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities.Eur Heart J. 2012; 33: 176-182Crossref PubMed Scopus (369) Google Scholar In general, the conventional use of composite endpoints (without hierarchical assessment) has an inherent limitation by emphasising each patient's first event, which is often the outcome of lesser clinical importance. To overcome this problem, the win ratio method gives appropriate priority to the more clinically important events (eg, mortality). In the DARE-19 trial, the prevention outcome (70 [11·2%] of 625 patients in the dapagliflozin group vs 86 [13·8%] of 625 patients in the placebo group) was driven by the individual component of new or worsening organ dysfunction (64 [10·2%] of 625 patients vs 80 [12·8%] of 625), which must happen before the other individual component of death (41 [6·6%] of 625 patients vs 54 [8·6%] of 625 patients). For the other coprimary outcome (recovery), the win ratio approach might have worked well by ranking death and new or worsening organ dysfunction, but it might have not worked so well by adding very soft outcomes (eg, need for oxygen during hospitalisation) to the equation, and might have diluted any potential treatment effect. Regardless of the p value (p=0·14 for the hierarchical testing), we wonder whether it might be clinically relevant, in absolute terms, to observe a difference of 547 (87·5%) of 625 patients in the dapagliflozin group versus 532 (85·1%) of 625 patients in the placebo group for clinical improvement at day 30. Effectively, the win ratio approach added little statistical gain in this case. DARE-19 trial suggests some lessons. First, dapagliflozin can be safely used in patients with cardiometabolic risk factors who were hospitalised with COVID-19 pneumonia, regardless of their diabetes status. Second, although findings of dapagliflozin failed to show efficacy in the acute setting, SGLT2 inhibitors have a promising future not only in patients with diabetes but also in patients with chronic cardiovascular disease, chronic kidney disease, and perhaps even in asymptomatic people.1McMurray JJV Solomon SD Inzucchi SE et al.Dapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381: 1995-2008Crossref PubMed Scopus (4074) Google Scholar, 7Heerspink HJL Stefánsson B V Correa-Rotter R et al.Dapagliflozin in patients with chronic kidney disease.N Engl J Med. 2020; 383: 1436-1446Crossref PubMed Scopus (2445) Google Scholar, 8Rossello X Raposeiras-Roubin S Oliva B et al.Glycated hemoglobin and subclinical atherosclerosis in people without diabetes.J Am Coll Cardiol. 2021; 77: 2777-2791Crossref PubMed Scopus (47) Google Scholar Third, a trial done in the middle of a pandemic in such a short time is not an easy task and the authors should take credit for adding evidence when it was most needed. Regardless of the significance of the primary hypothesis, the authors adequately tested whether dapagliflozin was effective and safe in hospitalised patients with cardiometabolic risk factors and COVID-19. Finally, the win ratio is still a new method that needs to be optimised in future trials, especially when it comes to selecting its individual components. We declare no competing interests. Dapagliflozin in patients with cardiometabolic risk factors hospitalised with COVID-19 (DARE-19): a randomised, double-blind, placebo-controlled, phase 3 trialIn patients with cardiometabolic risk factors who were hospitalised with COVID-19, treatment with dapagliflozin did not result in a statistically significant risk reduction in organ dysfunction or death, or improvement in clinical recovery, but was well tolerated. Full-Text PDF