Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice

Abstract

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 estimated glomerular filtration or ethnic group was by the The or or and in a eGFR, estimated glomerular filtration or ethnic group was by the The or or and the canagliflozin group, participants with an acute drop in eGFR were more to be had a of had a mass index, blood pressure, and and were more to use at were to have heart (Table 1). the placebo group, was blood pressure, eGFR, and ratio that an acute drop in To participants to a drop in eGFR >10% with canagliflozin than we performed a regression analysis to the of effects of canagliflozin placebo on acute eGFR decline in subgroups by baseline canagliflozin the of an acute eGFR drop >10% compared with placebo 95% P < 0.001) 1). across baseline participants with a of heart were to an eGFR decline >10% following canagliflozin initiation to placebo (P The of an acute drop in eGFR of >10% with canagliflozin compared with placebo was similar across subgroups by the eGFR category at 1). characteristics at baseline were with a of a drop in eGFR with canagliflozin compared with the of canagliflozin placebo on change in eGFR the 3 was across subgroups by characteristics at baseline 4289 treatment the 3 of the week 3, in the canagliflozin and in the placebo group treatment was no significant in of participants who across of an acute eGFR change in each treatment group (Table were similar the canagliflozin group of eGFR decline were according to an acute change in eGFR 3 in the canagliflozin and placebo group group eGFR drop modest eGFR drop eGFR increase eGFR drop modest eGFR drop eGFR increase eGFR drop modest eGFR drop eGFR increase or renal eGFR drop modest eGFR drop eGFR increase eGFR drop modest eGFR drop eGFR increase or eGFR drop modest eGFR drop eGFR increase included therapy, and eGFR drop modest eGFR drop eGFR increase estimated glomerular filtration are as of participants in each across was using included therapy, and in a eGFR, estimated glomerular filtration are as of participants in each across was using with the placebo group, the decline in eGFR in the canagliflozin group was in each category of an acute change in multivariable the change in eGFR from week to the available measurements among participants canagliflozin with an acute eGFR drop >10% was similar compared with those canagliflozin who experienced an acute modest drop between and 10% or increase in eGFR (P the participants with an acute drop in eGFR >30% after canagliflozin long-term eGFR was similar compared with the the placebo group, was no significant in an change in eGFR across of an acute change in eGFR (P adjustment for acute in eGFR a the long-term eGFR trajectories the canagliflozin group were similar compared with the analysis in each of eGFR at The only was the with eGFR between and ml/min per 1.73 this participants with a drop in eGFR had a rate of eGFR decline long-term compared with participants with an increase in eGFR the 3 the of participants an was similar between the canagliflozin and placebo groups, for were more in those who experienced an acute eGFR drop of >10% with canagliflozin than the chronic after week 3, the for each safety outcome were in the canagliflozin compared with placebo group of the acute change in eGFR category the canagliflozin and placebo groups the and multivariable adjusted for overall and overall and acute kidney and across of an acute change in eGFR of eGFR decline were results were with the that in the of participants with an acute drop of >30% using canagliflozin, the overall and were compared with participants with an acute increase in eGFR using canagliflozin were observed across eGFR subgroups an analysis using the of an acute eGFR drop the effects of canagliflozin to placebo on were of a of an eGFR drop >10% or the median (P for this post hoc analysis of the CREDENCE trial, we demonstrated that an initial drop in eGFR in to canagliflozin is a drop of 30% in eGFR was a rare We demonstrated that the long-term eGFR trajectories as well as overall and renal safety canagliflozin treatment were similar of the initial eGFR and were more that an acute in eGFR to 30% be after treatment initiation with which patients with diabetes and chronic kidney disease are more to an acute drop in eGFR on SGLT2 inhibitor initiation is to use of SGLT2 inhibitors in clinical practice. in those to canagliflozin blood pressure, eGFR, of heart failure, and use of treatment as predictors of an acute in drops in eGFR occurred in placebo group which is by the of eGFR and the of regression of the et of estimated and in J 2018; Full Text Full Text PDF PubMed Scopus Google Scholar The characteristics with an acute drop in eGFR in the placebo group were blood pressure, eGFR, and the between canagliflozin and was only a of heart that acute drop in eGFR, with those with a of heart to an acute eGFR drop of at 10%. 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PubMed Google et in the following treatment of chronic kidney disease, and J PubMed Scopus Google Scholar a >30% drop in eGFR with canagliflozin was with a risk of we the the or canagliflozin this the of the available to the 3 of the trial, were more among with an acute drop in a of which in eGFR and in The the of the trial may be a of to the acute drop in than as an in patients with with or diabetes and treated with angiotensin-converting enzyme inhibitors or angiotensin receptor demonstrated that an acute drop in eGFR is with long-term of kidney the that the acute decline in eGFR is of hemodynamic and a reduction in intraglomerular pressure that is with long-term kidney de Zeeuw D. de to treatment long-term decline in patients with renal Google Scholar, de Zeeuw D. et acute in estimated glomerular filtration rate treatment with a in long-term renal Full Text Full Text PDF PubMed Scopus Google Scholar, A. et in after angiotensin-converting enzyme and effects of its on clinical outcomes in type 2 diabetes 2019; PubMed Scopus Google Scholar, et of blood pressure and on progression of kidney results from the PubMed Scopus Google Scholar However, this be in with angiotensin-converting enzyme inhibitors or angiotensin receptor in A. et in after angiotensin-converting enzyme and effects of its on clinical outcomes in type 2 diabetes 2019; PubMed Scopus Google et progression of as measured by estimated glomerular filtration post hoc analysis of the Nephropathy PubMed Scopus Google Scholar, D. et estimated glomerular filtration rate decline and long-term renal function a post hoc analysis of the and PubMed Scopus Google Scholar, et change in glomerular filtration rate with inhibition of the renal and cardiovascular Full Text Full Text PDF PubMed Scopus Google Scholar The of participants with an acute drop in eGFR participants with a acute drop in eGFR as well as participants with kidney function in eGFR to decline the chronic of the trial, the and of the between an acute drop in eGFR and long-term kidney A better characterization of the eGFR decline initiation of SGLT2 treatment in to the acute hemodynamic drop in eGFR from kidney function The of the and groups of the measurements of eGFR the CREDENCE trial, and the to for risk However, as was from a clinical trial of patients with type 2 diabetes and the results may to the according to the acute change in eGFR were no we adjusted the for in characteristics across drop in eGFR be eGFR was measured after treatment We therefore the acute drop in eGFR is reversible after treatment However, in patients with type 2 diabetes with cardiovascular disease or cardiovascular risk been shown that eGFR is reversible after canagliflozin 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 was measured with the which is more to than the Clinical for the Evaluation and of Full Text Full Text PDF Scopus Google Scholar in eGFR is et of estimated and in J 2018; Full Text Full Text PDF PubMed Scopus Google Scholar may have to and may the of the 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 of the acute eGFR decline. outcomes were similar among subgroups of initial drop in the effects of canagliflozin on renal and cardiovascular outcomes in patients with type 2 diabetes and that an acute drop in eGFR of no more than 30% following canagliflozin initiation may be no for safety of kidney function We performed a post hoc analysis from the CREDENCE trial which was a trial the effects of canagliflozin on renal outcomes in with type 2 diabetes and The of the trial and outcomes have been 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 M.J. Mahaffey K.W. Neal B. et Canagliflozin and Renal in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) and baseline J PubMed Scopus Google Scholar a of 4401 at in between and were were and had type 2 diabetes, with a of to were required to have as eGFR of to ml/min per 1.73 and of to All the participants were to a of inhibitors for at were to canagliflozin, or placebo using with by eGFR and 60–<90 ml/min per 1.73 The use of for and of cardiovascular risk was in with The median was the trial in or which occurred by the trial at each All participants The trial was according to the in the of was measured in a by use of the with rate at week 3, week week and as 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 M.J. Mahaffey K.W. Neal B. et Canagliflozin and Renal in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) and baseline J PubMed Scopus Google Scholar eGFR was using the et to glomerular filtration Med. PubMed Scopus Google Scholar the we included all participants with eGFR measurements at baseline and week 3 The acute change in eGFR was as the change in eGFR at week The was was the at which eGFR measurements were and have shown that the acute effects of SGLT2 inhibitors on eGFR are after 2 to 3 C. B. D. et of dapagliflozin and in with and of dapagliflozin and on in patients with type 2 diabetes and chronic kidney disease a trial.Lancet Diabetes Endocrinol. 2019; 7: Scopus Google B. et and safety of canagliflozin in with type 2 diabetes and chronic kidney PubMed Scopus Google Scholar were categorized by decline in eGFR at week >10% decline as acute eGFR between and 10% decline modest eGFR and no decline eGFR were post with the of and for each an we of acute change in >30% to 30% >10% to to 10% or subgroups were by a (eGFR), subgroups for The outcome for this was the eGFR which was as the rate of change in eGFR on all eGFR measurements from week to the available safety outcomes included acute kidney and The of the of and according to the for of was for the acute baseline to week and for the chronic week 3 after the for the safety of the were followed from the of the acute the of the or the of The as all participants who at of was for analysis. 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