Editorial <\/p>\n\n\n\n
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have constituted a major advancement for the treatment of patients with chronic kidney disease and\/or heart failure, with sizeable benefits in reducing progression of kidney disease and in reducing rates of kidney failure and adverse cardiovascular events. As a result, their use is recommended by leading guideline groups in nephrology and cardiovascular medicine.1<\/a>,2<\/a><\/sup>\u00a0Secondary analyses of pivotal trials have suggested that SGLT2 inhibitors may also reduce the risk of acute kidney injury (AKI). In a recent meta-analysis of 10 randomized placebo-controlled clinical trials of canagliflozin, dapagliflozin, or empagliflozin, Neuen et al3<\/a><\/sup>\u00a0found that SGLT2 inhibitors reduced the risk of serious AKI: based on investigator-reported adverse events, AKI was reduced by 26% (95% CI, 18%-34%). Another meta-analysis including 3 additional trials (2 trials of sotagliflozin and 1 trial of ertugliflozin) showed an overall risk reduction of 20% (95% CI, 13%-26%).4<\/a><\/sup><\/p>\n\n\n\n In the current issue of JAMA,<\/em> Oosterom-Eijmael et al5<\/a><\/sup> report the results of their investigator-initiated randomized placebo-controlled clinical trial testing whether the perioperative use of the SGLT2 inhibitor dapagliflozin was effective as a preventive strategy to reduce AKI. Across 7 hospitals in the Netherlands, the investigators enrolled patients undergoing elective cardiac surgery who had not previously been treated with SGLT2 inhibitors. Patients were ineligible if they had type 1 diabetes, type 2 diabetes with a body mass index less than 25 using multiple daily doses of insulin, an estimated glomerular filtration rate less than 20 mL\/min\/1.73 m2<\/sup>, or a history of diabetic ketoacidosis. Enrolled participants were randomized to receive dapagliflozin 10 mg for 4 days, starting on the day prior to surgery, or a matching placebo. Participants and investigators were blinded to the randomized exposure. The primary outcome was AKI within 7 days from surgery. Acute kidney injury was defined using the full Kidney Disease: Improving Global Outcomes (KDIGO) definition, including criteria based on urine output as well as on serum creatinine concentrations.6<\/a><\/sup><\/a><\/p>\n\n\n\n Of 784 randomized participants, 6 ended up not undergoing surgery, all others completed follow-up. Median age was 68 years, 76% were male, 97% were White, 11% had type 2 diabetes, and 6% had heart failure. The majority of participants had normal or near-normal kidney function at enrollment: more than three-fourths of participants had an estimated glomerular filtration rate of 67 mL\/min\/1.73 m2<\/sup> or higher. Adherence with the intervention was excellent (87% and 88% in the dapagliflozin and placebo groups, respectively). The incidence of AKI was 28% in the dapagliflozin group and 52% in the placebo group, which translated into a relative risk reduction of 46% (95% CI, 35%-55%) and an absolute risk reduction of 24% (95% CI, 17%-31%). The majority of AKI cases were stage 1 (serum creatinine increase by \u226526.5 \u00b5mol\/L or 1.5\u2009\u00d7\u2009baseline, or urine output <0.5 mL\/kg\/h for 6-12 hours); 19 participants in the dapagliflozin group and 50 participants in the placebo group had stage 2 or 3 AKI. In secondary analyses separating the stages of AKI, dapagliflozin reduced stage 1 AKI (risk difference, \u201316% [95% CI, \u201322% to \u201310%]) and stage 2 AKI (risk difference, \u20138% [95% CI, \u201312% to \u20135%]) but not stage 3 AKI, for which only 4 outcomes were observed overall. The incidence of adverse events was balanced between the groups. Ketoacidosis was reported in 1 participant randomized to dapagliflozin (0.26%).<\/a><\/p>\n\n\n\n Whenever clinical trials of modest sample size demonstrate a relative treatment effect in excess of 40%, one should evaluate trial results with a healthy dose of skepticism; several aspects of this trial warrant comment. The incidence of AKI in the placebo group was higher than what has been reported in most cardiovascular clinical trials. However, this is likely attributable to the meticulous collection of urine output data. While the bulk of AKI events were KDIGO stage 1, and the majority of those were recorded based on the urine output criterion, there was a clinically meaningful and statistically significant difference in the incidence of more severe (KDIGO stage 2) AKI. Moreover, results were consistent across key patient subgroups.<\/a><\/p>\n\n\n\n The investigators provided evidence that the reduced incidence of AKI was not due to the short-term natriuretic effects of dapagliflozin. In a subset of 105 participants randomized at hospitals in Amsterdam, those randomized to receive dapagliflozin received numerically lower volumes of intravenous fluid and lower doses of norepinephrine, suggesting that the significantly higher urine output observed among participants randomized to dapagliflozin was neither forced nor inappropriate and more likely reflected improved kidney function. In a related pilot trial, the urinary biomarkers TIMP-2\u2009\u00d7\u2009IGFBP7 (tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7) and KIM-1 (kidney injury molecule 1) were significantly lower in patients treated with SGLT2 inhibitors on postoperative day 1 and numerically lower on postoperative day 2, also supporting a kidney protective effect.<\/a><\/p>\n\n\n\n The authors highlighted key limitations of the trial, including relative homogeneity of the study sample by race (97% White), and the exclusion of patients previously treated with SGLT2 inhibitors, those requiring urgent or emergent cardiac surgery, as well as those with diabetes who had normal or low body mass index and required multiple daily doses of insulin. Only 11% of participants in this trial had diabetes. The authors did not address the possibility that the observed treatment effect might have exceeded a lower, perhaps more biologically plausible, result. Nevertheless, given the magnitude of the observed benefit, the likelihood that the provision of an SGLT2 inhibitor in this setting provides no benefit or results in harm is extremely low.<\/a><\/p>\n\n\n\n The authors\u2019 conclusion that \u201cthese findings support prescribing dapagliflozin to prevent [AKI] during the 7-day postoperative period\u201d should probably be limited to the population of stable patients undergoing elective cardiac surgery until confirmatory studies in other populations are conducted. It is noteworthy (and ironic) that the American Diabetes Association,7<\/a><\/sup> the UK Centre for Perioperative Care,8<\/a><\/sup> several other professional organizations, and\u2014until recently\u2014the US Food and Drug Administration recommend withholding SGLT2 inhibitors for 3 days in advance of surgery to reduce the risk of euglycemic diabetic ketoacidosis. When balancing risks and benefits, the very low risk of euglycemic diabetic ketoacidosis does not appear to warrant withholding of a drug with the potential to significantly reduce the risk of postoperative AKI. Further studies of AKI prevention by SGLT2 inhibitors will likely require larger sample sizes, particularly in populations with lower event rates or if the true treatment effect falls short of the 46% observed here. Ideally, these trials should be powered not only for short-term AKI outcomes and those ascertained by measured urine output but also to determine effects on creatinine-based measures of AKI. Confirmatory trials should also aim to enroll a more diverse sample of patients than was possible in the racially uniform Dutch population. It will also be important to establish evidence on any longer-term benefits on kidney function, such as chronic kidney disease incidence and progression, from perioperative SGLT2 inhibitor treatment.<\/a><\/p>\n\n\n\n Hereon, investigators should aim to better understand the mechanism(s) by which SGLT2 inhibitors reduce the risk of AKI among patients undergoing elective cardiac surgery as well as those with type 2 diabetes, heart failure, and chronic kidney disease treated with SGLT2 inhibitors longer-term. Moreover, they should briskly and rigorously conduct randomized, placebo-controlled clinical trials of SGLT2 inhibitors in established AKI, aiming to arrest or attenuate its evolution and\/or hasten its recovery.<\/p>\n","protected":false},"excerpt":{"rendered":" Editorial Dapagliflozin to Reduce the Risk of Per […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[24,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/31470"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=31470"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/31470\/revisions"}],"predecessor-version":[{"id":31471,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/31470\/revisions\/31471"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=31470"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=31470"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=31470"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}