Dapagliflozin in HFrEF Patients Treated With Mineralocorticoid Receptor Antagonists

Abstract

BACKGROUND MRAs and sodium glucose co-transporter 2 inhibitors each have diuretic activity, lower blood pressure, and reduce glomerular filtration rate (GFR). Therefore, it is important to investigate the safety, as well as efficacy, of their combination.METHODS A total of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) were randomized to placebo or dapagliflozin 10 mg daily. The efficacy of dapagliflozin on the primary composite outcome (cardiovascular death or episode of worsening heart failure) and its components was examined according to MRA use, as were predefined safety outcomes. RESULTS A total of 3,370 patients (71%) were treated with an MRA and they were younger (65 vs. 69 years of age), less often from North America (9% vs. 26%), had worse New York Heart Association functional class (35% vs. 25% in class III/ IV), lower left ventricular ejection fraction (30.7% vs. 31.9%) and systolic blood pressure (120.3 vs. 125.5 mm Hg), but higher estimated GFR (67.1 vs. 62.6 ml/min/1.73 m 2 ), than patients not taking an MRA. The benefit of dapagliflozin compared with placebo was similar in patients taking or not taking an MRA: hazard ratio: 0.74 (95% confidence interval [CI]: 0.63 to 0.87) versus 0.74 (95% CI: 0.57 to 0.95), respectively, for the primary endpoint (p value for interaction ¼ 0.97); similar findings were observed for secondary endpoints. In both MRA subgroups, safety outcomes were similar in patients randomized to dapagliflozin or placebo. CONCLUSIONS Dapagliflozin was similarly efficacious and safe in patients with HFrEF taking or not taking an MRA, supporting the use of both drugs together. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124)

Finerenone in Predominantly Advanced CKD and Type 2 Diabetes With or Without Sodium-Glucose Cotransporter-2 Inhibitor Therapy

“…Nevertheless, the benefits of SGLT-2is in patients with heart failure and reduced ejection fraction in the DAPA-HF study and the EMPEROR-Reduced trial were observed on top of concomitant treatment with a steroidal MR antagonist without any attenuation of response. 17,18 In FIDELIO-DKD, patients with a clinical diagnosis of chronic heart failure with reduced ejection fraction and persistent symptoms at the run-in visit were excluded from the trial, which limits the ability to compare these results with findings from DAPA-HF and EMPEROR-Reduced. 12 In the FIDELIO-DKD primary analysis, finerenone significantly reduced the primary composite kidney outcome and the key secondary cardiovascular composite outcome compared with placebo in patients with CKD and T2D receiving optimized RAS inhibitor therapy.…”

Cardiac, renal, and metabolic effects of sodium–glucose co‐transporter 2 inhibitors: a position paper from the European Society of Cardiology ad‐hoc task force on sodium–glucose co‐transporter 2 inhibitors

“…Data from HFrEF populations are similarly reassuring, with no effect of SGLT2 inhibitors on laboratory measurements of potassium or clinical events of hyperkalaemia overall, or among those co‐prescribed MRA 37,74 . DAPA‐HF sub‐analyses generated a hypothesis that SGLT2 inhibition may even reduce risk of severe hyperkalaemia among MRA users 37 . This hypothesis was not confirmed in EMPEROR‐Reduced, but intriguingly allocation to empagliflozin led to fewer discontinuations of MRA, and actually, also to fewer initiations of MRAs 74 …”

“…In particular, there was direct evidence of benefit in individuals with and without type 2 DM, among those with ischaemic and non‐ischaemic heart failure aetiologies, and among those with an ejection fraction above or below the recruited population median 16 . Concomitant therapy, including angiotensin receptor–neprilysin inhibitor and MRA use, also did not modify these benefits when assessed in a series of post‐hoc subgroup analyses 35–37 . Dapagliflozin is now approved for the treatment of symptomatic chronic HFrEF 38…”

“…Similarly in the CKD trials, CREDENCE and DAPA‐CKD reported no significant difference in adverse events for hyperkalaemia [CREDENCE: canagliflozin 29.7 vs. placebo 36.9 events per 1000 patient‐years 15 ; and DAPA‐CKD: 6 (0.3%) events of serious hyperkalaemia among those allocated dapagliflozin vs. 12 (0.6%) among those allocated placebo] 21 . Data from HFrEF populations are similarly reassuring, with no effect of SGLT2 inhibitors on laboratory measurements of potassium or clinical events of hyperkalaemia overall, or among those co‐prescribed MRA 37,74 . DAPA‐HF sub‐analyses generated a hypothesis that SGLT2 inhibition may even reduce risk of severe hyperkalaemia among MRA users 37 .…”

The Role of Dapagliflozin in the Management of Heart Failure: An Update on the Emerging Evidence

“… 20 71% of patients in the enrolled population in the DAPA-HF trial were taking MRA and an exploratory analysis of the trial data revealed similar results in the population with MRA compared with the population without MRA (HR 0.74; 95% CI 0.63–0.87 versus HR 0.74; 95% CI 0.57–0.95, respectively, for the primary combined endpoint of HF exacerbation or CV death). 21 10.7% of patients in the DAPA-HF cohort were on the sacubitril/valsartan combination, and were found to have similar outcomes in terms of primary endpoints of efficacy and safety with add-on of dapagliflozin, when compared with the remaining population that did not receive the sacubitril/valsartan combination, supporting the safe use of the drug in addition to GDMT. 22 The absolute risk reduction of the primary endpoint was also seen to be greatest in the subgroup that had a history of recent hospitalization (defined as within 12 months of randomization) from HF worsening (ARR 9.9%, 95% CI 3.3–16.5% compared with groups with hospitalization prior to the 12 month period of before randomization).…”