In a prespecified analysis of the DELIVER trial, an initial eGFR decline >10% was more frequent in patients with HFmrEF or HFpEF treated with dapagliflozin versus placebo, but this was not associated with an increased risk of CV or renal events.

This summary is based on the publication of Mc Causland FR, et al. - JAMA Cardiol. 2023 Nov 12:e234664. doi: 10.1001/jamacardio.2023.4664

Introduction and methods

Background

Initiation of SGLT2 inhibitor therapy is often accompanied by an acute decrease in eGFR, but this decline has been shown to be reversible upon discontinuation of the drug [1,2]. In addition, despite the initial eGFR decline, SGLT2 inhibitors slow down the longer-term decline in kidney function compared with placebo [3,4]. Inappropriate drug cessation, however, may prevent patients from benefiting from long-term risk reduction [5].

Aim of the study

In a prespecified secondary analysis of the DELIVER trial, the authors evaluated the magnitude and frequency of an initial eGFR decline (from baseline to 1 month), its predictors, and its association with clinical outcomes among patients with HFmrEF or HFpEF.

Methods

The DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial was an international, multicenter, parallel-group, event-driven, double-blind, phase 3 RCT [6]. In this trial, patients aged ≥40 years with symptomatic HF (LVEF >40%), elevated NT-proBNP levels, structural heart disease, and eGFR ≥25 mL/min/1.73 m² (calculated using the CKD-EPI 2009 equation) were randomized to dapagliflozin 10 mg once daily or placebo. In the prespecified secondary analysis, 5788 patients with baseline and 1-month measurements of serum creatinine and eGFR levels were included.

Outcomes

The primary endpoint was a composite outcome of CV death or a worsening HF event (hospitalization or urgent visit). The post-hoc renal composite outcome consisted of the first occurrence of either (1) ≥50% eGFR decline relative to the 1-month value (initial eGFR decline was calculated from baseline to 1 month); (2) development of end-stage kidney disease (reported adverse event or eGFR decline to <15 mL/min/1.73 m²); or (3) death from renal causes. In addition, frequencies of serious adverse events, adverse events leading to study drug discontinuation, and select other adverse events (including kidney-related adverse events) were examined.

Main results

Initial eGFR decline

• The median change in eGFR level from baseline to 1 month was –4 mL/min/1.73 m² (IQR: –9 to 1) (equaling –6%; IQR: –16% to 3%) in patients treated with dapagliflozin and –1 mL/min/1.73 m² (IQR: –6 to 5) (equaling –1%; IQR: –10% to 8%) in those receiving placebo (placebo-corrected difference: –3 mL/min/1.73 m²; –5%; P<0.001).
• A higher proportion of dapagliflozin-treated patients versus placebo-treated patients showed an initial eGFR decline >10% (40% vs. 25%; OR: 1.9; 95%CI: 1.7–2.1; P<0.001).
• Analyses assessing an initial eGFR decline >25% or different thresholds for change in serum creatinine level from baseline to 1 month (≥0.3 or ≥0.5 mg/dL) showed similar patterns.

Risk of adverse CV and renal outcomes

• Landmark analyses (at-risk time beginning at 1 month) demonstrated that among patients assigned to placebo, the incidence rate of the primary CV endpoint was higher in those with an initial eGFR decline >10% compared with those with an eGFR decline ≤10% (22% vs. 17%; adjusted HR (aHR): 1.33; 95%CI: 1.10–1.62). On the other hand, the incidence rates were comparable among patients receiving dapagliflozin (15% vs. 16%; aHR: 0.90; 95%CI: 0.74–1.09; P for interaction=0.01).
• Similar patterns of association were found when an initial eGFR decline >25% or different increases in serum creatinine level were considered and when eGFR change was analyzed as a continuous variable.
• In the placebo group, the risk of the post-hoc renal composite outcome did not differ between patients experiencing an initial eGFR decline >10% and those with an eGFR decline ≤10% (2.3% vs. 1.8%; aHR: 1.62; 95%CI: 0.90–2.89). In the dapagliflozin group, similar risks were also observed (1.3% vs. 1.3%; aHR: 0.94; 95%CI: 0.49–1.82; P for interaction=0.35).

Adverse events

• The overall frequency of adverse events was higher in patients with an initial eGFR decline >10% compared with those with an eGFR decline ≤10%, in both early (≤1 month) and later (>1 month) periods.
• Most incidence rates were similar between the 2 treatment groups. However, in the placebo arm, the frequency of any serious adverse events from baseline to 1 month was higher in patients with an initial eGFR decline >10% compared with those with an eGFR decline ≤10%, as opposed to the dapagliflozin arm.

Conclusion

In this prespecified secondary analysis of the DELIVER trial, an initial eGFR decline >10% was more frequently observed in patients with HFmrEF or HFpEF treated with dapagliflozin versus placebo, but this was not associated with an increased risk of CV or renal events compared with an eGFR decline ≤10%. Among placebo-treated patients, an initial eGFR decline >10% was associated with a higher risk of the primary CV endpoint. The authors therefore believe an initial eGFR decline does not warrant SGLT2 inhibitor discontinuation in this patient population.  

References

1. Wanner C, Heerspink HJL, Zinman B, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and kidney function decline in patients with type 2 diabetes: a slope analysis from the EMPA-REG OUTCOME trial. J AmSoc Nephrol. 2018;29(11):2755-2769. doi:10.1681/ASN.2018010103
2. Cherney DZI, Ferrannini E, Umpierrez GE, et al. Efficacy and safety of sotagliflozin in patients with type 2 diabetes and severe renal impairment. Diabetes Obes Metab. 2021;23(12):2632-2642. doi:10.1111/dom.14513
3. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816
4. HerringtonWG, Staplin N,Wanner C, et al; The EMPA-KIDNEY Collaborative Group. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388(2):117-127.
5. Xie Y, Bowe B, Gibson AK, McGill JB, Maddukuri G, Al-Aly Z. Clinical implications of estimated glomerular filtration rate dip following sodium-glucose cotransporter-2 inhibitor initiation on cardiovascular and kidney outcomes. J Am Heart Assoc. 2021;10(11):e020237. doi:10.1161/JAHA.120.020237
6. Solomon SD, McMurray JJV, Claggett B, et al; DELIVER Trial Committees and Investigators. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387(12):1089-1098. doi:10.1056/NEJMoa2206286

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