No need to stop SGLT2i therapy when early eGFR decrease occurs in HFrEF patients

Early changes in estimated glomerular filtration rate post-initiation of empagliflozin in EMPEROR-Reduced

Literature - Zannad F, Ferreira JP, Gregson J, et al. - Eur J Heart Fail. 2022 Jun 16 [Online ahead of print]. doi: 10.1002/ejhf.2578

Introduction and methods

Background

In patients with HFrEF, SGLT2i treatment slows the rate of eGFR decline compared with placebo, starting from week 4 after treatment initiation [1-4]. However, SGLT2is may induce an initial eGFR decrease, possibly due to acute intraglomerular pressure reduction [5-9]. This decrease may tempt clinicians to stop or withhold the therapy, but is that justified?

Aim of the study

The authors aimed to describe the occurrence, characteristics, determinants, and prognostic significance of early eGFR changes in HFrEF patients who had been treated with empagliflozin or placebo in the EMPEROR-Reduced (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction) trial.

Methods

The EMPEROR-Reduced trial was a multinational, randomized, double-blind, parallel-group, placebo-controlled, event-driven, phase 3 study in which 3730 patients with chronic HF (NYHA functional class II–IV) and LVEF ≤40% were randomized to empagliflozin 10 mg daily or placebo, in addition to their usual therapy (including HF treatment) [10,11]. In this secondary analysis, 3547 patients (95%) were included who had received at least one dose of the study drug and for whom eGFR measurements at randomization and week 4 were available. Median follow-up duration was 16 months.

The researchers categorized the percent (%) eGFR change in the early post-initiation period (from randomization to week 4) into tertiles in each treatment group separately and used landmark analyses (with landmark at week 4) to study the associations of % eGFR change with outcomes.

Outcomes

The primary endpoint was the composite of adjudicated CV death and HF hospitalization (analyzed as time to first event). In addition, CV death, all-cause mortality, and a composite renal outcome (i.e., need for chronic dialysis or renal transplant; sustained eGFR decrease ≥40%; or sustained eGFR <10–15 mL/min per 1.73 m2, depending on baseline eGFR) were analyzed.

The prespecified safety assessment focused on the occurrence of acute kidney injury or acute renal failure, until 7 days following discontinuation of the study medication.

Main results

eGFR change at week 4

Although eGFR changes occurred in both treatment groups from randomization to week 4, the overall mean difference was–2.5 mL/min per 1.73 m2 (95%CI: –3.1 to –1.9) for the empagliflozin group (n=1765) versus the placebo group (n=1782).
The tertiles of % eGFR change for the empagliflozin group were: tertile 1 (T1): ≤–11.4%; T2: –11.4% to –1.0%; and T3: ≥0.0%. The placebo group tertiles were: T1: ≤–6.5%; T2: –6.4% to +3.6%; and T3: ≥+3.6%.

Association of early eGFR change with outcomes

In the empagliflozin group, patients in the T1 and T3 groups had a similar risk of CV death or HF hospitalization (hazard ratio (HR): 0.86; 95%CI: 0.66–1.11), but the T2 group had a lower risk of this primary endpoint compared with the T3 group (HR: 0.72; 95%CI: 0.54–0.95). There were no differences between the T1 and T3 groups nor between the T2 and T3 groups with regard to risk of CV death, all-cause mortality, or the composite renal outcome.
In the placebo group, the T1 group had a higher risk of sustained worsening kidney function (HR: 2.38; 95%CI: 1.25–4.55) and all-cause mortality (HR: 1.37; 95%CI: 1.01–1.85) compared with the T3 group.

Safety

In the empagliflozin group, patients in the T1 and T3 groups had a similar risk of acute renal failure (HR: 1.46; 95%CI: 0.96–2.21) and acute kidney injury (HR: 1.01; 95%CI: 0.44–2.29).
In the placebo group, the T1 group had a higher risk of acute renal failure compared with the T3 group (HR: 1.58; 95%CI: 1.08–2.32), but there was no difference in the risk of acute kidney injury (HR: 1.63; 95%CI: 0.83–3.24).

Conclusion

HFrEF patients showed a mild eGFR decrease in the first 4 weeks after initiating empagliflozin treatment compared with placebo, but this was not associated with adverse CV or renal outcomes. The authors stress that clinicians should not be concerned about early eGFR changes following empagliflozin initiation. They do not recommend to routinely monitor eGFR in the first month and advise to leave this decision to the discretion of the treating physician.

References

Show references

1. Packer, M.; Anker, S. D.; Butler, J.; Filippatos, G.; Pocock, S. J.; Carson, P.; et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med 2020. DOI: 10.1056/NEJMoa2022190

2. Zannad, F.; Ferreira, J. P.; Pocock, S. J.; Zeller, C.; Anker, S. D.; Butler, J.; et al. Cardiac and Kidney Benefits of Empagliflozin in Heart Failure Across the Spectrum of Kidney Function: Insights from the EMPEROR-Reduced Trial. Circulation 2020. DOI: 10.1161/circulationaha.120.051685

3. McMurray, J. J. V.; Solomon, S. D.; Inzucchi, S. E.; Kober, L.; Kosiborod, M. N.; Martinez, F. A.; et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019. DOI: 10.1056/NEJMoa1911303

4. Jhund, P. S.; Solomon, S. D.; Docherty, K. F.; Heerspink, H. J. L.; Anand, I. S.; Böhm, M.; et al. Efficacy of Dapagliflozin on Renal Function and Outcomes in Patients with Heart Failure with Reduced Ejection Fraction: Results of DAPA-HF. Circulation 2020. DOI: 10.1161/circulationaha.120.050391

5. Vallon, V.; Thomson, S. C. The tubular hypothesis of nephron filtration and diabetic kidney disease. Nat Rev Nephrol 2020, 16 (6), 317-336. DOI: 10.1038/s41581-020-0256-y

6. Thomson, S. C.; Rieg, T.; Miracle, C.; Mansoury, H.; Whaley, J.; Vallon, V.; Singh, P. Acute and chronic effects of SGLT2 blockade on glomerular and tubular function in the early diabetic rat. Am J Physiol Regul Integr Comp Physiol 2012, 302 (1), R75-83. DOI: 10.1152/ajpregu.00357.2011

7. Kidokoro, K.; Cherney, D. Z. I.; Bozovic, A.; Nagasu, H.; Satoh, M.; Kanda, E.; et al. Evaluation of Glomerular Hemodynamic Function by Empagliflozin in Diabetic Mice Using In Vivo Imaging. Circulation 2019, 140 (4), 303-315. DOI: 10.1161/circulationaha.118.037418

8. Vallon, V.; Traynor, T.; Barajas, L.; Huang, Y. G.; Briggs, J. P.; Schnermann, J. Feedback control of glomerular vascular tone in neuronal nitric oxide synthase knockout mice. J Am Soc Nephrol 2001, 12 (8), 1599-1606.

9. Ziyadeh, F. N.; Hoffman, B. B.; Han, D. C.; Iglesias-De La Cruz, M. C.; Hong, S. W.; Isono, M.; et al. Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A 2000, 97 (14), 8015-8020. DOI:10.1073/pnas.120055097

10. Packer, M.; Anker, S. D.; Butler, J.; Filippatos, G. S.; Ferreira, J. P.; Pocock, S.; et al. Effect of Empagliflozin on the Clinical Stability of Patients with Heart Failure and a Reduced Ejection Fraction: The EMPEROR-Reduced Trial. Circulation 2020. DOI: 10.1161/circulationaha.120.051783

11. Packer, M.; Anker, S. D.; Butler, J.; Filippatos, G.; Ferreira, J. P.; Pocock, S. J.; et al. Empagliflozin in Patients With Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial. J Am Coll Cardiol 2021, 77 (11), 1381-1392. DOI: 10.1016/j.jacc.2021.01.033

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