Ertugliflozin, renoprotection and potential confounding by muscle wasting. Reply to Groothof D, Post A, Gans ROB et al [letter]

Cherney, David Z.I.; Charbonnel, B.; Cosentino, Francesco; Dagogo‐Jack, Samuel; McGuire, Darren K.; Pratley, Richard E.; Shih, Weichung J.; Frederich, Robert; Maldonado, Mario; Pong, Annpey; Cannon, Christopher P.

doi:10.1007/s00125-021-05623-z

Cited by 2 publications

(3 citation statements)

References 22 publications

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“…For example, post hoc analyses of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study (T2D and CKD) 17 and the EMPA-REG Outcome study (T2D and established cardiovascular disease) 16 reported similar rates of longer-term eGFR decline in patients assigned to active therapy with vs without an initial decline in eGFR, whereas a post hoc analysis of the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS CV; T2D and atherosclerotic cardiovascular disease) reported that patients in the largest (vs lowest) tertile of initial eGFR decline with ertugliflozin actually experienced the slowest rate of decline in longer-term eGFR slope. 18 Realworld observational data from the Veterans Affairs database is consistent with these findings. In adjusted analyses, SGLT2i use was associated with a lower risk of cardiovascular and kidney outcomes in those with a higher-than-average probability of eGFR dip greater than 10% or greater than30%.…”

Section: Discussionsupporting

confidence: 59%

“…A total of 1881 patients (32%) had a decline of greater than 10%, of which 1144 (61%) were assigned to dapagliflozin, and 737 (39%) were assigned to placebo. At baseline, those experiencing higher initial declines vs those experiencing an increase in eGFR were more likely to be older (mean [SD] age, 72 [9] years vs 71 [10] years), have higher systolic blood pressure (mean [SD], 129 [16] mm Hg vs 128 [15] mm Hg), BMI level (mean [SD], 30.2 [6.3] vs 29.6 [6.0]; calculated as weight in kilograms divided by height in meters squared), ejection fraction (mean [SD], 55% [9%] vs 54% [9%]), and eGFR level (mean [SD], 61 [18] vs 58 [19]). They were more likely to have a history of hypertension and diabetes, to be taking an ACEi or ARB, and to be assigned to dapagliflozin (Table 1).…”

Section: Patient Characteristicsmentioning

confidence: 99%

“…Although this has been shown to be reversible upon SGLT2i withdrawal in some studies, 13,14 concerns remain that such acute functional changes in eGFR may lead to inappropriate drug cessation, thus preventing patients from benefiting from long-term risk reduction. 15 Among those randomly assigned to SGLT2i treatment, post hoc analyses of patients with CKD have observed similar slowing of long-term kidney function decline in those with or without an initial eGFR decline, [16][17][18] and analyses from the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG Outcome) program reported that the risk reduction in cardiovascular outcomes with empagliflozin was not modified by the initial eGFR decline. 16 In the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial of patients with heart failure and reduced ejection fraction, the development of an eGFR decline greater than 10% was associated with a lower risk of cardiovascular outcomes among those assigned to dapagliflozin, compared with those with a similar decline assigned to placebo.…”

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confidence: 99%

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Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Mc Causland,

Claggett,

Vaduganathan

et al. 2024

JAMA Cardiol

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ImportanceAn initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure.ObjectiveTo examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial.Design, Setting, and ParticipantsThis was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were analyzed from February to October 2023.InterventionDapagliflozin, 10 mg per day, or placebo.Main Outcomes and MeasuresIn this prespecified analysis, the frequency of an initial eGFR decline (baseline to month 1) was compared between dapagliflozin and placebo. Cox models adjusted for baseline eGFR and established prognostic factors were fit to estimate the association of an initial eGFR decline with cardiovascular (cardiovascular death or heart failure event) and kidney (≥50% eGFR decline, eGFR&lt;15 or dialysis, death from kidney causes) outcomes, landmarked at month 1, stratified by diabetes.ResultsStudy data from 5788 participants (mean [SD] age, 72 [10] years; 3253 male [56%]) were analyzed. The median (IQR) change in eGFR level from baseline to month 1 was −1 (−6 to 5) with placebo and −4 (−9 to 1) with dapagliflozin (difference, −3; P &lt; .001). A higher proportion of patients assigned to dapagliflozin developed an initial eGFR decline greater than 10% vs placebo (1144 of 2892 [40%] vs 737 of 2896 [25%]; odds ratio, 1.9; 95% CI, 1.7-2.1; P difference &lt;.001). An initial eGFR decline of greater than 10% (vs ≤10%) was associated with a higher risk of the primary cardiovascular outcome among those randomized to placebo (adjusted hazard ratio [aHR], 1.33; 95% CI, 1.10-1.62) but not among those randomized to dapagliflozin (aHR, 0.90; 95% CI, 0.74-1.09; P for interaction = .01). Similar associations were observed when alternative thresholds of initial eGFR decline were considered and when analyzed as a continuous measure. An initial eGFR decline of greater than 10% was not associated with adverse subsequent kidney composite outcomes in dapagliflozin-treated patients (aHR, 0.94; 95% CI, 0.49-1.82).Conclusions and RelevanceAmong patients with HFmrEF or HFpEF treated with dapagliflozin, an initial eGFR decline was frequent but not associated with subsequent risk of cardiovascular or kidney events. These data reinforce clinical guidance that SGLT2is should not be interrupted or discontinued in response to an initial eGFR decline.Trial RegistrationClinicalTrials.gov Identifier: NCT03619213

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Section: Discussionsupporting

confidence: 59%

Section: Patient Characteristicsmentioning

confidence: 99%

mentioning

confidence: 99%

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Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Mc Causland,

Claggett,

Vaduganathan

et al. 2024

JAMA Cardiol

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Frailty, Multimorbidity, and Polypharmacy

Mayne,

Sardell,

Staplin

et al. 2024

CJASN

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Background: Sodium-glucose co-transporter-2 (SGLT2) inhibitors are recommended treatment for adults with chronic kidney disease (CKD), but uncertainty exists regarding their use in patients with frailty and/or multimorbidity, among whom polypharmacy is common. We derived a multivariable logistic regression model to predict hospitalization (reflecting frailty) and assessed empagliflozin’s risk-benefit profile in a post-hoc analysis of the double-blind, placebo-controlled EMPA-KIDNEY trial. Methods: The EMPA-KIDNEY trial randomized 6609 patients with CKD (estimated glomerular filtration rate [eGFR] ≥20<45 mL/min/1.73m2, or ≥45<90 mL/min/1.73m2 with urinary albumin-to-creatinine ratio ≥200 mg/g) to receive either empagliflozin 10 mg daily or matching placebo and followed for two years (median). Additional characteristics analysed in subgroups were multimorbidity, polypharmacy and health-related quality of life (HRQoL) at baseline. Cox regression analyses were performed with subgroups defined by approximate thirds of each variable. Results: The strongest predictors of hospitalization were N-terminal prohormone of brain natriuretic peptide, poor mobility and diabetes; then eGFR and other comorbidities. Empagliflozin was generally well-tolerated independent of predicted risk of hospitalization. In relative terms, allocation to empagliflozin reduced the risk of the primary outcome of kidney disease progression or cardiovascular death by 28% (hazard ratio [HR] 0.72, 95% confidence interval [CI] 0.64-0.82); and all-cause hospitalization by 14% (HR 0.86, 95% CI 0.78-0.95); with broadly consistent effects across subgroups of predicted risk of hospitalization, multimorbidity, polypharmacy or HRQoL. In absolute terms, the estimated benefits of empagliflozin were greater in those at highest predicted risk of hospitalization (reflecting frailty) and outweighed potential serious harms. Conclusions: These findings support the use of SGLT2 inhibitors in CKD, irrespective of frailty, multimorbidity or polypharmacy.

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Ertugliflozin, renoprotection and potential confounding by muscle wasting. Reply to Groothof D, Post A, Gans ROB et al [letter]

Cited by 2 publications

References 22 publications

Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction

Frailty, Multimorbidity, and Polypharmacy

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