Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice
Authors: Megumi Oshima, Meg J. Jardine, Rajiv Agarwal, George Bakris, Christopher P. Cannon, David M. Charytan, Dick de Zeeuw, Robert Edwards, Tom Greene, Adeera Levin, Soo Kun Lim, Kenneth W. Mahaffey, Bruce Neal, Carol Pollock, Norman Rosenthal, David C. Wheeler, Hong Zhang, Bernard Zinman, Vlado Perkovic, Hiddo J.L. Heerspink
Journal: Kidney International (2020)

Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop. Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop. Sodium glucose cotransporter 2 (SGLT2) inhibitors have been shown to reduce the risk of kidney and cardiovascular outcomes in people with type 2 diabetes. SGLT2 inhibitors increase distal tubular sodium and chloride delivery to the macula densa, which augments tubuloglomerular feedback, causing reversal of afferent arteriolar vasodilatation. As a result, SGLT2 inhibitors cause an acute reduction in intraglomerular pressure and glomerular filtration rate.1Heerspink H.J. Perkins B.A. Fitchett D.H. et al.Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications.Circulation. 2016; 134: 752-772Crossref PubMed Scopus (558) Google Scholar Large cardiovascular outcome trials have demonstrated that the initial drop in estimated glomerular filtration rate (eGFR) following initiation of SGLT2 inhibition is followed by a stabilization of long-term kidney function decline.2Perkovic V. de Zeeuw D. Mahaffey K.W. et al.Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials.Lancet Diabetes Endocrinol. 2018; 6: 691-704Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar, 3Perkovic V. Jardine M.J. Neal B. et al.Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med. 2019; 380: 2295-2306Crossref PubMed Scopus (1553) Google Scholar, 4Wanner C. Inzucchi S.E. Lachin J.M. et al.Empagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334Crossref PubMed Scopus (1591) Google Scholar, 5Mosenzon O. Wiviott S.D. Cahn A. et al.Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial.Lancet Diabetes Endocrinol. 2019; 7: 606-617Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar However, in clinical practice, an acute drop in eGFR may raise safety concerns that prevent clinicians from continuing SGLT2 inhibitors. A better characterization of the acute drop in eGFR and its association with long-term eGFR trajectories and safety outcomes is required to support appropriate use of SGLT2 inhibitors in clinical practice. We therefore performed a post hoc analysis of the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial to determine the predictors of an acute eGFR decline following initiation of the SGLT2 inhibitor canagliflozin and its associations with long-term eGFR trajectories and safety outcomes. Of the 4401 participants in the CREDENCE trial, 4289 (97.5%; 2144 in the canagliflozin group and 2145 in the placebo group) had eGFR measurements available at baseline and week 3 and were included in this analysis. All participants were using an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, as required by the protocol. At week 3, the mean acute change in eGFR was –7.0% (SE, 0.4%) and 0.3% (SE, 0.4%) in the canagliflozin and placebo groups, respectively (mean difference, –7.3%; 95% confidence interval [CI], –8.5% to –6.1%; P < 0.001). More participants in the canagliflozin (956 [45%]) than in the placebo (450 [21%]) group experienced an acute eGFR drop of >10% (P < 0.001) (Table 1). An acute drop in eGFR of >30% was rare and occurred in only 89 (4.2%) and 39 (1.8%) participants in the canagliflozin and placebo groups, respectively (P < 0.001).Table 1Baseline characteristics by treatment, according to an acute change in eGFR per 3 weeksCharacteristicCanagliflozinPlaceboAcute eGFR drop (>10%)Acute modest eGFR drop (>0%–10%)Acute eGFR increase (≥0%)P for trendAcute eGFR drop (>10%)Acute modest eGFR drop (>0%–10%)Acute eGFR increase (≥0%)P for trendNo. (%)956 (45)600 (28)588 (27)450 (21)646 (30)1049 (49)Age, mean (SD), yr63.3 (9.3)62.7 (8.9)62.1 (9.1)0.0162.7 (9.3)63.6 (9.1)62.9 (9.3)0.90Men, no. (%)635 (66)398 (66)375 (64)0.32288 (64)445 (69)699 (67)0.52Race or ethnic group, no. (%) White630 (66)423 (71)406 (69)298 (66)426 (66)685 (65) Black or African American51 (5)28 (5)28 (5)21 (5)32 (5)54 (5) Asian187 (20)108 (18)112 (19)82 (18)132 (20)224 (21) Other88 (9)41 (7)42 (7)49 (11)56 (9)86 (8)Current smoker, no. (%)153 (16)98 (16)82 (14)0.3250 (11)87 (13)155 (15)0.06History of hypertension, no. (%)926 (97)578 (96)572 (97)0.73432 (96)631 (98)1012 (96)0.93History of heart failure, no. (%)127 (13)86 (14)107 (18)0.0173 (16)94 (15)147 (14)0.29Duration of diabetes, mean (SD), yr16.0 (8.9)15.4 (8.5)15.0 (8.4)0.0316.2 (8.5)16.1 (8.7)15.8 (8.5)0.37History of cardiovascular disease, no. (%)477 (50)304 (51)303 (52)0.53220 (49)312 (48)548 (52)0.15History of amputation, no. (%)48 (5)34 (6)31 (6)0.6827 (6)32 (5)53 (5)0.52Body mass index, mean (SD), kg/m232 (6)31 (6)31 (6)0.0332 (6)31 (6)31 (6)0.30Systolic blood pressure, mean (SD), mmHg141 (16)140 (15)138 (15)0.001142 (17)141 (15)139 (15)<0.001Diastolic blood pressure, mean (SD), mmHg78 (9)79 (10)78 (9)0.9378 (9)79 (9)78 (10)0.21HbA1c, mean (SD), %8.2 (1.3)8.2 (1.3)8.4 (1.4)0.118.3 (1.3)8.3 (1.3)8.3 (1.4)0.97eGFR, mean (SD), ml/min per 1.73 m257.9 (18.1)56.9 (18.2)53.6 (18.1)<0.00158.1 (19.0)58.9 (18.5)53.3 (17.6)<0.001Screening eGFR, no. (%) 30–<45 ml/min per 1.73 m2301 (31)169 (28)164 (28)153 (34)173 (27)313 (30) 45–<60 ml/min per 1.73 m2290 (30)176 (29)157 (27)123 (27)199 (31)306 (29) 60–<90 ml/min per 1.73 m2365 (38)255 (43)267 (45)174 (39)274 (42)430 (41)UACR, median (IQR), mg/g923 (472–1794)956 (468–1943)878 (423–1728)0.071079 (526–2170)971 (496–1831)834 (438–1784)<0.001Total cholesterol, mean (SD), mmol/L4.6 (1.3)4.6 (1.3)4.8 (1.4)0.064.7 (1.2)4.7 (1.2)4.7 (1.3)0.99HDL cholesterol, mean (SD), mmol/L1.1 (0.3)1.2 (0.4)1.2 (0.4)0.151.2 (0.3)1.1 (0.3)1.1 (0.3)0.66LDL cholesterol, mean (SD), mmol/L2.5 (1.1)2.5 (1.1)2.6 (1.1)0.302.5 (1.0)2.5 (1.0)2.5 (1.1)0.55Triglycerides, median (IQR), mmol/L1.9 (1.3–2.7)1.8 (1.3–2.7)1.8 (1.4–2.6)0.671.7 (1.3–2.6)1.8 (1.3–2.8)1.8 (1.3–2.6)0.49Drug therapy, no. (%) Insulin637 (67)403 (67)376 (64)0.33310 (69)419 (65)671 (64)0.09 RAAS inhibitor956 (100)599 (100)588 (100)0.84449 (100)644 (100)1047 (100)0.82 Diuretic479 (50)271 (45)254 (43)0.01233 (52)284 (44)494 (47)0.24eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein; RAAS, renin-angiotensin-aldosterone system; UACR, urine albumin-to-creatinine ratio.Race or ethnic group was reported by the participants. The designation "other" includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple, other, unknown, and not reported. Open table in a new tab eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; IQR, interquartile range; LDL, low-density lipoprotein; RAAS, renin-angiotensin-aldosterone system; UACR, urine albumin-to-creatinine ratio. Race or ethnic group was reported by the participants. The designation "other" includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple, other, unknown, and not reported. In the canagliflozin group, participants with an acute drop in eGFR were more likely to be older; had a longer duration of diabetes; had a higher body mass index, systolic blood pressure, and eGFR; and were more likely to use diuretics at baseline, whereas they were less likely to have heart failure (Table 1). In the placebo group, it was higher systolic blood pressure, eGFR, and urine albumin-to-creatinine ratio (UACR) that predicted an acute drop in eGFR. To identify participants particularly prone to experience a drop in eGFR >10% with canagliflozin rather than placebo, we performed a logistic regression analysis to examine the consistency of effects of canagliflozin versus placebo on acute eGFR decline in subgroups defined by baseline characteristics. Overall, canagliflozin increased the likelihood of an acute eGFR drop >10% compared with placebo (odds ratio, 3.03; 95% CI, 2.65–3.47; P < 0.001) (Figure 1). In subgroup analyses across various baseline participant characteristics, participants with a history of heart failure were less likely to experience an eGFR decline >10% following canagliflozin initiation relative to placebo (P interaction = 0.04). The likelihood of an acute drop in eGFR of >10% with canagliflozin compared with placebo was similar across other subgroups defined by the eGFR category at screening (Figure 1). Other participant characteristics at baseline were also not associated with a higher likelihood of a drop in eGFR with canagliflozin compared with placebo. Finally, the effect of canagliflozin versus placebo on percentage change in eGFR during the first 3 weeks was also consistent across various subgroups defined by participant characteristics at baseline (Supplementary Table S1). Among these 4289 participants, none discontinued their assigned treatment during the first 3 weeks of the trial. After week 3, 519 (24.2%) in the canagliflozin and 629 (29.3%) in the placebo group discontinued their assigned treatment during follow-up. There was no statistically significant difference in number of participants who discontinued therapy across categories of an acute eGFR change in each treatment group (Table 2). Discontinuation rates were also similar within the canagliflozin group when finer categories of eGFR decline thresholds were used (Supplementary Table S2).Table 2Discontinuation reasons, according to an acute change in eGFR (per 3 weeks) in the canagliflozin and placebo groupsDiscontinuation reasonsCanagliflozin group (n = 2144)P valuePlacebo group (n = 2145)P valueTotal reasons All519/2144 (24.2)629/2145 (29.3) Acute eGFR drop (>10%)247/956 (25.8)0.13144/450 (32.0)0.25 Acute modest eGFR drop (>0%–10%)128/600 (21.3)193/646 (29.9) Acute eGFR increase (≥0%)144/588 (24.5)292/1049 (27.8)Adverse events All254/2144 (11.9)273/2145 (12.7) Acute eGFR drop (>10%)117/956 (12.2)0.1762/450 (13.8)0.53 Acute modest eGFR drop (>0%–<10%)59/600 (9.8)86/646 (13.3) Acute eGFR increase (≥0%)78/588 (13.3)125/1049 (11.9)Personal reasons All153/2144 (7.1)188/2145 (8.8) Acute eGFR drop (>10%)83/956 (8.7)0.0443/450 (9.6)0.31 Acute modest eGFR drop (>0%–<10%)33/600 (5.5)63/646 (9.8) Acute eGFR increase (≥0%)37/588 (6.3)82/1049 (7.8)Dialysis or renal transplant All18/2144 (0.8)28/2145 (1.3) Acute eGFR drop (>10%)7/956 (0.7)0.749/450 (2.0)0.34 Acute modest eGFR drop (>0%–<10%)6/600 (1.0)7/646 (1.1) Acute eGFR increase (≥0%)5/588 (0.9)12/1049 (1.1)Poor compliance All14/2144 (0.7)17/2145 (0.8) Acute eGFR drop (>10%)6/956 (0.6)0.754/450 (0.9)0.22 Acute modest eGFR drop (>0%–<10%)3/600 (0.5)8/646 (1.2) Acute eGFR increase (≥0%)5/588 (0.9)5/1049 (0.5)Safety or tolerability All13/2144 (0.6)19/2145 (0.9) Acute eGFR drop (>10%)4/956 (0.4)0.332/450 (0.4)0.39 Acute modest eGFR drop (>0%–<10%)6/600 (1.0)5/646 (0.8) Acute eGFR increase (≥0%)3/588 (0.5)12/1049 (1.1)OtheraOther included disallowed therapy, protocol violation, site closure, and other reasons. All67/2144 (3.1)104/2145 (4.9) Acute eGFR drop (>10%)30/956 (3.1)0.7424/450 (5.3)0.28 Acute modest eGFR drop (>0%–<10%)21/600 (3.5)24/646 (3.7) Acute eGFR increase (≥0%)16/588 (2.7)56/1049 (5.3)eGFR, estimated glomerular filtration rate.Data are given as number/total (percentage) of participants in each group. Difference across categories was tested using χ2 test.a Other included disallowed therapy, protocol violation, site closure, and other reasons. Open table in a new tab eGFR, estimated glomerular filtration rate. Data are given as number/total (percentage) of participants in each group. Difference across categories was tested using χ2 test. Compared with the placebo group, the annual decline in eGFR in the canagliflozin group was smaller in each category of an acute change in eGFR. After multivariable adjustment, the annual change in eGFR from week 13 to the last available measurements among participants receiving canagliflozin with an acute eGFR drop >10% was similar compared with those receiving canagliflozin who experienced an acute modest drop between 0% and 10% or increase in eGFR (P = 0.11; Figure 2a). In the few participants with an acute drop in eGFR >30% after canagliflozin initiation, long-term eGFR trajectory was similar compared with the main analyses (Supplementary Figure S1). Within the placebo group, there was no statistically significant difference in an annual change in eGFR across categories of an acute change in eGFR (P = 0.09; Figure 2b). Further adjustment for acute changes in eGFR did not alter these findings. In a subgroup analysis, the long-term eGFR trajectories within the canagliflozin group were similar compared with the main analysis in each subgroup of eGFR at screening (Supplementary Table S3). The only exception was the subgroup with eGFR between 30 and 45 ml/min per 1.73 m2. In this subgroup, participants with a drop in eGFR had a significantly slower rate of eGFR decline during long-term follow-up compared with participants with an increase in eGFR (Supplementary Table S3). During the first 3 weeks, the percentage of participants experiencing an adverse event was similar between the canagliflozin and placebo groups, except for renal-related adverse events (Supplementary Table S4). Renal-related adverse events were more frequently reported in those who experienced an acute eGFR drop of >10% with canagliflozin than placebo. During the chronic phase after week 3, the event rates for each safety outcome were lower in the canagliflozin compared with placebo group regardless of the acute change in eGFR category (Figure 3). Within the canagliflozin and placebo groups separately, the event rates and multivariable adjusted hazard ratios for overall and serious adverse events, overall and serious renal-related adverse events, acute kidney injury, and hyperkalemia did not differ across categories of an acute change in eGFR (Figure 3). When finer categories of eGFR decline thresholds were used, results were generally similar, with the exception that in the subgroup of participants with an acute drop of >30% using canagliflozin, the overall adverse event (multivariable-adjusted hazard ratio, 1.34 [95% CI, 1.05–1.72]) and renal-related adverse event rates (multivariable-adjusted hazard ratio, 2.15 [95% CI, 1.28–3.60]) were higher compared with participants with an acute increase in eGFR using canagliflozin (Supplementary Figure S2). Similar findings were observed across screening eGFR subgroups (Supplementary Table S5). In an additional analysis using the predicted likelihood of an acute eGFR drop >10%, the effects of canagliflozin relative to placebo on adverse events were consistent regardless of a likelihood of an eGFR drop >10% above or below the median (P for interaction >0.51; Supplementary Table S6). In this post hoc analysis of the CREDENCE trial, we demonstrated that an initial drop in eGFR in response to canagliflozin is common, but a larger drop of 30% in eGFR was a rare event. We also demonstrated that the long-term eGFR trajectories as well as overall and renal safety profiles during canagliflozin treatment were similar regardless of the initial eGFR drop, except when it unusually exceeded 30%, when adverse events and renal-related adverse events were reported more frequently. These data suggest that an acute decrease in eGFR up to 30% can be tolerated after treatment initiation with canagliflozin. Understanding which patients with diabetes and chronic kidney disease (CKD) are more likely to experience an acute drop in eGFR on SGLT2 inhibitor initiation is important to guide best use of SGLT2 inhibitors in clinical practice. Observational analyses done in just those assigned to canagliflozin identified older age, higher systolic blood pressure, higher eGFR, absence of heart failure, and use of diuretic treatment as predictors of an acute fall in eGFR. Acute drops in eGFR also occurred in some placebo group participants, which is likely explained by the large biological variability of eGFR and the phenomenon of regression of the mean.6Waikar S.S. Rebholz C.M. Zheng Z. et al.Biological variability of estimated GFR and albuminuria in CKD.Am J Kidney Dis. 2018; 72: 538-546Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar The participant characteristics associated with an acute drop in eGFR in the placebo group were higher systolic blood pressure, eGFR, and UACR. In the randomized comparison between canagliflozin and placebo, it was only a history of heart failure that predicted acute drop in eGFR, with those with a history of heart failure less likely to experience an acute eGFR drop of at least 10%. The interaction P value for this comparison was of borderline statistical significance and not adjusted for multiple testing; thus, the results should be cautiously interpreted, but it is possible that improvements in cardiac output following SGLT2 inhibition increase glomerular filtration and decrease the likelihood of a drop in glomerular filtration rate. The likelihood of experiencing a >10% decline in eGFR following canagliflozin was consistent regardless of the starting eGFR level. In the current analyses, the initial decline in eGFR was expressed as percentage decline and the absolute acute eGFR decline was smaller at lower compared with higher eGFR, as previously reported.7Jardine M.J. Zhou Z. Mahaffey K.W. et al.Renal, cardiovascular, and safety outcomes of canagliflozin by baseline kidney function: a secondary analysis of the CREDENCE randomized trial.J Am Soc Nephrol. 2020; 31: 1128-1139Crossref PubMed Scopus (28) Google Scholar In addition, among participants in the lowest eGFR category at screening, the long-term rate of eGFR decline was also less in participants with an acute eGFR decline compared with those with an increase. Taken together, we believe that practitioners may be reassured by these data that, in conjunction with the renal and cardiac benefits seen across the eGFR spectrum of 30 to 90 ml/min per 1.73 m2, support initiation of canagliflozin in patients with eGFR between 30 and 45 ml/min per 1.73 m2. The results of our study demonstrate that acute declines in eGFR up to 30% after initiation of canagliflozin treatment would not be a reason to discontinue treatment; eGFR trajectories during chronic treatment with canagliflozin were consistent within the canagliflozin group and significantly better than placebo regardless of the initial eGFR change. Moreover, safety outcomes within canagliflozin-treated subjects were consistent regardless of the initial eGFR change. Acute drops in eGFR of >30% were rare but were associated with a higher likelihood of adverse events during prolonged treatment, which should prompt careful monitoring. This 30% eGFR threshold is close to the 30% serum creatinine increase, equivalent to a 27% eGFR decline, deemed tolerable on initiation of renin-angiotensin-aldosterone system inhibition in light of the long-term kidney protective effects of these agents.8Bakris G.L. Weir M.R. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern?.Arch Intern Med. 2000; 160: 685-693Crossref PubMed Google Scholar,9Hirsch S. Hirsch J. Bhatt U. et al.Tolerating increases in the serum creatinine following aggressive treatment of chronic kidney disease, hypertension and proteinuria: pre-renal success.Am J Nephrol. 2012; 36: 430-437Crossref PubMed Scopus (26) Google Scholar Although a >30% drop in eGFR with canagliflozin was associated with a higher risk of adverse events, we cannot answer the question whether reducing the dose or discontinuing canagliflozin would attenuate this increased risk, given the nature of the data available to us. During the first 3 weeks of the trial, renal-related adverse events were more frequently reported among individuals with an acute drop in eGFR. Renal-related adverse events comprise a range of different investigator-reported events, which include decreases in eGFR and increases in serum creatinine. The higher frequency during the early stage of the trial may be a reflection of investigator response to the acute drop in eGFR. Rather than being interpreted as an adverse event, prior studies in patients with CKD with or without diabetes and treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers demonstrated that an acute drop in eGFR is associated with long-term preservation of kidney function, supporting the concept that the acute decline in eGFR is of hemodynamic origin and reflects a reduction in intraglomerular pressure that is associated with long-term kidney preservation.10Apperloo A.J. de Zeeuw D. de Jong P.E. Short-term antiproteinuric response to antihypertensive treatment predicts long-term GFR decline in patients with non-diabetic renal disease.Kidney Int Suppl. 1994; 45: S174-S178PubMed Google Scholar, 11Holtkamp F.A. de Zeeuw D. Thomas M.C. et al.An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function.Kidney Int. 2011; 80: 282-287Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 12Ohkuma T. Jun M. Rodgers A. et al.Acute increases in serum creatinine after starting angiotensin-converting enzyme inhibitor-based therapy and effects of its continuation on major clinical outcomes in type 2 diabetes mellitus.Hypertension. 2019; 73: 84-91Crossref PubMed Scopus (22) Google Scholar, 13Wright Jr., J.T. Bakris G. Greene T. et al.Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.JAMA. 2002; 288: 2421-2431Crossref PubMed Scopus (1526) Google Scholar However, this pattern could not be replicated in other studies with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers nor in our trial.12Ohkuma T. Jun M. Rodgers A. et al.Acute increases in serum creatinine after starting angiotensin-converting enzyme inhibitor-based therapy and effects of its continuation on major clinical outcomes in type 2 diabetes mellitus.Hypertension. 2019; 73: 84-91Crossref PubMed Scopus (22) Google Scholar,14Evans M. Bain S.C. Hogan S. et al.Irbesartan delays progression of nephropathy as measured by estimated glomerular filtration rate: post hoc analysis of the Irbesartan Diabetic Nephropathy Trial.Nephrol Dial Transplant. 2012; 27: 2255-2263Crossref PubMed Scopus (33) Google Scholar, 15Collard D. Brouwer T.F. Olde Engberink R.H.G. et al.Initial estimated glomerular filtration rate decline and long-term renal function during intensive antihypertensive therapy: a post hoc analysis of the SPRINT and ACCORD-BP randomized controlled trials.Hypertension. 2020; 75: 1205-1212Crossref PubMed Scopus (10) Google Scholar, 16Clase C.M. Barzilay J. Gao P. et al.Acute change in glomerular filtration rate with inhibition of the renin-angiotensin system does not predict subsequent renal and cardiovascular outcomes.Kidney Int. 2017; 91: 683-690Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar The subgroup of participants with an acute drop in eGFR comprised participants with a canagliflozin-induced acute (reversible) drop in eGFR as well as participants with preexisting progressive kidney function loss in whom eGFR will likely continue to decline during the chronic phase of the trial, thereby diluting the association. This complicates assessment and interpretation of the relationship between an acute drop in eGFR and long-term kidney function. A better characterization of the eGFR decline before initiation of SGLT2 treatment would help in future studies to distinguish the acute hemodynamic drop in eGFR from progressive kidney function loss. The strengths of our study include the large number and diverse groups of participants, the sequential measurements of eGFR during the CREDENCE trial, and the ability to adjust for multiple important risk factors. However, our study has several limitations. First, as our study cohort was derived from a clinical trial of patients with type 2 diabetes and CKD, the results may limit generalizability to broader populations. Second, the analyses according to the acute change in eGFR were no longer randomized. Although we adjusted the analyses for differences in participant characteristics across drop in eGFR categories, residual confounding cannot be excluded. In addition, eGFR was not measured after treatment discontinuation. We therefore could not establish whether the acute drop in eGFR is reversible after treatment discontinuation. However, in patients with type 2 diabetes with established cardiovascular disease or cardiovascular risk factors, it has been shown that eGFR is completely reversible 30 days after canagliflozin discontinuation.2Perkovic V. de Zeeuw D. Mahaffey K.W. et al.Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials.Lancet Diabetes Endocrinol. 2018; 6: 691-704Abstract Full Text Full Text PDF PubMed Scopus (249) Google Scholar Finally, serum creatinine was measured with the Jaffe method, which is more susceptible to interferences than the enzymatic methods.17Kidney Disease: Improving Global Outcomes (KDIGO) Work GroupKDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1095) Google Scholar In addition, within-individual variability in eGFR is high.6Waikar S.S. Rebholz C.M. Zheng Z. et al.Biological variability of estimated GFR and albuminuria in CKD.Am J Kidney Dis. 2018; 72: 538-546Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Both factors may have led to misclassifications and may limit the precision of the results. In conclusion, although acute drops in eGFR >10% occurred in nearly half of all participants following initiation of canagliflozin, the benefit of canagliflozin compared with placebo was observed regardless of the acute eGFR decline. Safety outcomes were also similar among subgroups of initial drop in eGFR. Considering the beneficial effects of canagliflozin on renal and cardiovascular outcomes in patients w