CV and renal benefits of dapagliflozin extend to patients with established heart failure in DAPA-HF
Dapagliflozin is a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2) that inhibits renal glucose reabsorption and promotes glucosuria, thereby leading to reductions in plasma glucose concentrations. [Am Coll Cardiol 2018;72:1845-1855]
In CV outcome trials, SGLT2 inhibitors have been shown to prevent the development of HF and to delay the progression of chronic kidney disease (CKD) in patients with T2DM. [Lancet 2019;393:31-39]
“The extent to which SGLT2 inhibitors can be used to treat patients with established HF and patients without T2DM was previously unknown, as was the effect of SGLT2 inhibitors on renal function in patients with established HF,” said Solomon.
Dapagliflozin benefits HF patients with or without T2DM
The global phase III DAPA-HF trial prospectively evaluated the efficacy and safety of dapagliflozin in patients with HFrEF, regardless of the presence or absence of T2DM. Patients (n=4,744) were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy, and were followed up for a median of 18.2 months. [N Engl J Med 2019;381:1995-2008]
Key inclusion criteria included symptomatic HF, left ventricular ejection fraction (LVEF) ≤40 percent and elevated natriuretic peptides. Patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, symptomatic hypotension or systolic blood pressure <95 mm Hg, or type 1 diabetes mellitus were excluded.
At baseline, 45 percent of patients had a history of T2DM or were newly diagnosed with T2DM, and 68 percent had New York Heart Association class II HF; mean LVEF was 31 percent. [Eur J Heart Fail 2019;21:1402-1411]
“Dapagliflozin reduced the risk of the primary composite outcome of worsening HF [hospitalization or an urgent visit resulting in intravenous (IV) therapy for heart failure] or CV death by 26 percent,” noted Solomon. “Importantly, this benefit was observed in patients with or without T2DM at baseline.” (Figure 1) [N Engl J Med 2019;381:1995-2008]
In addition, dapagliflozin reduced the risk of CV death by 18 percent (hazard ratio [HR], 0.82; 95 percent confidence interval [CI], 0.69 to 0.98) and all-cause mortality by 17 percent (HR, 0.83; 95 percent CI, 0.71 to 0.97).
“We also explored the effect of dapagliflozin on the trial outcomes in patients with or without CKD [eGFR <60 mL/min/1.73 m2 and eGFR ≥60 mL/min/1.73 m2, respectively] and on the eGFR trajectory post-randomization,” noted Solomon.
Patients in the lower eGFR group (vs the higher eGFR group) at baseline were older (70.9 years vs 63.2 years of age), had higher levels of natriuretic peptides (1823.8 pg/mL vs 1261.1 pg/mL), and were more likely to have T2DM (51 percent vs 41 percent). [Solomon SD, et al, ASN 2019, abstract FR-OR133]
“Overall, patients in the study were well-treated with HF medications in accordance with guideline recommendations,” remarked Solomon.
Dapagliflozin was effective in reducing the composite outcome of worsening HF and CV death in patients with or without CKD. (Figure 2) [N Engl J Med 2019;381:1995-2008]
“There was no evidence of heterogeneity in the primary composite outcome between the two groups [pinteraction=0.64],” pointed out Solomon. “This treatment benefit also appeared consistent throughout the full spectrum of eGFR when assessed as a continuous variable [pinteraction=0.77].” [N Engl J Med 2019;381:1995-2008; Solomon SD, et al, ASN 2019, abstract FR-OR133]
Dapagliflozin was well tolerated in the study. Irrespective of CKD status, there were no differences in adverse events (AEs), including volume depletion, renal AEs and major hypoglycaemia, between dapagliflozin and placebo. Additionally, in the eGFR <60 mL/min/1.73 m2 group, significantly fewer patients on dapagliflozin experienced a serious AE, including death (p=0.03). [Solomon SD, et al, ASN 2019, abstract FR-OR133]
Favourable renal outcomes with dapagliflozin
A prespecified secondary objective of DAPA-HF was to determine whether dapagliflozin would delay the progression of worsening renal function, defined as time to renal death, reaching end-stage renal disease, or a ≥50 percent sustained decline in eGFR.
“Only 28 patients in the dapagliflozin group and 39 patients in the placebo group reached this renal composite outcome. This translated to a HR of 0.71 [95 percent CI, 0.44 to 1.16; pinteraction=0.17], which did not reach statistical significance. While the curves started to separate relatively early at 12 months and continued to separate, we didn’t have a lot of events here,” explained Solomon. [N Engl J Med 2019;381:1995-2008; Solomon SD, et al, ASN 2019, abstract FR-OR133]
“Furthermore, patients with diabetes were more likely to achieve the renal composite outcome than those without diabetes, but again, we saw no interaction. Patients with or without diabetes appeared to obtain the same amount of benefit from dapagliflozin,” he added.
“When we looked at the adjudicated acute kidney injury [AKI] endpoint, defined as doubling of serum creatinine since the last core lab measurement, we saw more events. There was a 64 percent overall reduction in AKI in patients treated with dapagliflozin vs placebo,” said Solomon. (Figure 3) [Solomon SD, et al, ASN 2019, abstract FR-OR133]
The change in eGFR trajectory over the course of the trial was similar to what has been observed in other SGLT2 trials, pointed out Solomon. “There was an initial rapid decline in eGFR in patients treated with dapagliflozin, followed by a flattening out of the eGFR slope. These slopes, when compared either from baseline or after 14 days, were significantly different in favour of dapagliflozin,” he clarified. “In longer-term trials of SGLT2 inhibitors, we have seen those two slopes eventually cross, and we expect that attenuation of decline will ultimately lead to better renal function.” [Mosenzon O, et al, ASN 2019, abstract TH-PO1205; Clin J Am Soc Nephrol 2017;12:700-710]
The DAPA-HF trial has demonstrated that dapagliflozin, when added to guideline-directed medical therapy, effectively reduces worsening HF events and CV death in patients with HFrEF, irrespective of the presence or absence of CKD or T2DM. Dapagliflozin was well tolerated in patients with or without CKD, and episodes of AKI (doubling of serum creatinine) were significantly reduced in patients receiving dapagliflozin vs placebo.
“These data suggest that after an initial small decline in eGFR common to SGLT2 inhibitors, dapagliflozin appears to attenuate long-term renal decline in patients with HF,” concluded Solomon.