What is the role of dapagliflozin for treatment of heart failure?

Background

Dapagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that has historically been used as an anti-diabetic agent in adults with type 2 diabetes mellitus (T2DM) to improve glycemic control.1,2 After expedited drug review via fast track and priority review designations, the Food and Drug Administration (FDA) approved dapagliflozin on May 5, 2020 to reduce the risk of cardiovascular (CV) death and hospitalization due to heart failure (HF) in adults with New York Heart Association (NYHA) class II, III, or IV symptoms and HF with reduced ejection fraction (HFrEF).3 This FDA approval makes dapagliflozin the first SGLT2 inhibitor to be approved for this indication or for use in patients without T2DM.4

Prior data with dapagliflozin in patients with HF

There have been multiple studies demonstrating a reduction in HF deaths and hospitalizations in patients with T2DM using SGLT2 inhibitors.5-7 The Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial investigated safety and efficacy outcomes in more than 17,000 patients with T2DM who were at risk or had preexisting atherosclerotic CV disease.5 In this randomized, blinded, placebo-controlled trial, dapagliflozin did not significantly impact major adverse CV events (MACE) compared to placebo. However, dapagliflozin did demonstrate a lower rate of hospitalization for HF or CV death compared to placebo (4.9% vs 5.8%; hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.73 to 0.95; p=0.005) that was consistent across multiple subgroups. This outcome was largely driven by a lower rate of hospitalization for HF in the dapagliflozin group. Since most patients did not have underlying HF upon entry into the study, dapagliflozin seemed to protect against developing HF, which raised the question of its efficacy as a treatment for HF.

The mechanism for how SGLT2 inhibitors may lead to favorable CV outcomes is still under investigation. Dapagliflozin blocks glucose and sodium reabsorption in the proximal renal tubules.8-12 Consequently, glucose and sodium are excreted in the urine, plasma volume decreases following sodium excretion, and glomerular pressure is reduced. These diuretic and natriuretic effects may help explain the cardiac and renal hemodynamic benefits of SGLT2 inhibitors. Improved metabolic control may also have indirect CV benefits since underlying T2DM is a risk factor for developing HF.13

The DAPA-HF trial

The multicenter, randomized, placebo-controlled trial that garnered priority review of dapagliflozin for use in HF was the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial. Patients with HFrEF, ejection fraction (EF) ≤ 40%, and NYHA class II, III, or IV, received either dapagliflozin 10 mg once daily or placebo for a median of 18 months in addition to guideline-directed HF therapy.14 Patients were excluded if they had an estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2. Most patients (67%) had moderate HF (NYHA class II) at baseline and 42% had T2DM. Standard HF device therapy was required for inclusion in the study, such as an implantable cardioverter-defibrillator, cardiac resynchronization therapy, or both. Standard drug therapy included either an angiotensin-converting enzyme inhibitor (ACEi, 56%), an angiotensin-receptor blocker (ARB) (27%), or sacubitril-valsartan (10%) plus a beta-blocker (96%). While not required for inclusion, 71% of patients at baseline were also taking a mineralocorticoid receptor antagonist. Additionally, 18% of patients were taking digoxin at baseline for HF. For symptom management, 93% were taking loop diuretics at baseline. Table 1 highlights the relevant efficacy results from the study.

Table 1. DAPA-HF trial: CV efficacy outcomes from baseline to 8 months. 14

Outcome

Dapagliflozin (N=2373)

n (%)		Placebo (N=2371)

n (%)

Hazard, rate ratio, or difference (95% CI)

P-value

Worsening HF or death from CV causes (primary composite outcome) 

386 (16.3)

502 (21.2)

0.74 (0.65 to 0.85)

<0.001

Worsening HF (hospitalization or an urgent visit for HF)

237 (10.0)

326 (13.7)

0.70 (0.59 to 0.83)

NAa

Hospitalization for HF

231 (9.7)

318 (13.4)

0.70 (0.59 to 0.83)

NAa

Urgent HF visit

10 (0.4)

23 (1.0)

0.43 (0.20 to 0.90)

NAa

CV death

227 (9.6)

273 (11.5)

0.82 (0.69 to 0.98)

NAa

Secondary outcomes

Change in KCCQ total symptom scoreb

6.1 + 18.6

3.3 + 19.2

1.18 (1.11 to 1.26)

<0.001

aP-values were only reported for efficacy outcomes that were included in the hierarchical testing strategy.
bSymptom scores on the KCCQ range from 0 to 100 – fewer symptoms and physical limitations associated with HF are indicated by higher scores. The treatment effect for change in KCCQ score is expressed as a ratio in the table, with values > 1 indicating superiority.
Abbreviations: CI=confidence interval; CV=cardiovascular; HF=heart failure; KCCQ=Kansas City Cardiomyopathy Questionnaire; NA=not applicable.

The primary composite outcome of worsening HF or death from CV causes occurred significantly less in the dapagliflozin group compared to the placebo group.14 A subgroup analysis of patients with T2DM (HR, 0.75; 95% CI, 0.63 to 0.90) and without T2DM (HR, 0.73; 95% CI, 0.60 to 0.88) showed similar results for the primary outcome. Laboratory values and other surrogate markers at 8 months were significantly reduced in the dapagliflozin group compared to the placebo group, including hemoglobin A1C (-0.24%; 95% CI, -0.34 to -0.13; p<0.001), N-terminal pro-B type natriuretic peptide (-303 pg/mL; 95% CI, -457 to -150; p<0.001), weight (-0.87 kg; 95% CI, -1.11 to -0.62; p<0.001), and systolic blood pressure (-1.27 mm Hg; 95% CI, -2.09 to -0.45; p=0.002).  Renal outcome results are summarized in Table 2. Dapagliflozin did not worsen renal function compared to placebo. The placebo group had significantly more acute kidney injuries and adverse events due to renal impairment compared to the dapagliflozin group.

Table 2. DAPA-HF trial: Secondary and safety renal outcomes.14

Outcome

Dapagliflozin (N=2373)


n (%)

Placebo (N=2371)


n (%)

Hazard or rate ratio, or difference (95% CI)

P-value

Secondary outcomes

Worsening renal functionb

28 (1.2)

39 (1.6)

0.71 (0.44 to 1.16)

NAa

Safety outcomes

Acute kidney injuriesc

23 (1.0)

46 (1.9)

⁻⁻

0.007

Adverse events due to renal impairmentd

38 (1.6)

65 (2.7)

⁻⁻

0.009

aP-values were only reported for efficacy outcomes that were included in the hierarchical testing strategy.
bWorsening renal function refers to the composite outcome of ESRD (defined as eGFR < 15 mL/min/1.73 m2 sustained over 28 days, long-term dialysis requirements, or need for kidney transplantation), reduction of ≥50% in eGFR sustained for 28 days, or death from renal causes.
cAcute kidney injury was defined as doubling of serum creatinine from baseline.
dAdverse events due to renal impairment included renal failure, renal impairment, chronic kidney disease, ureterolithiasis, ESRD, haematuria, hydronephrosis, anuria, cystitis noninfective, nephrolithiasis, postrenal failure, prerenal failure, renal artery stenosis, renal colic, renal cyst, renal injury, and urethral stenosis.
Abbreviations: CI=confidence interval; eGFR=estimated glomerular filtration rate; ESRD=end stage renal disease.

Adverse event frequencies did not significantly differ between treatment groups and dapagliflozin was generally well tolerated.14 Volume depletion adverse events occurred in 29 patients (1.2%) in the dapagliflozin group compared to 40 patients (1.7%) in the placebo group (p=0.23), although what was considered a volume depletion adverse event was not defined. Major hypoglycemic events were noted in 4 patients (0.2%) in each treatment group. Rates of genitourinary infections were not reported in this study.

Limitations of the DAPA-HF study included lack of a diverse patient population, with most patients being middle-aged white males, few patients with more severe HF (NYHA class III or IV), and few patients on sacubitril-valsartan (which is endorsed over ACEi or ARB therapy in current guidelines).14-16 Since doses of all HF agents were not reported, it is unknown whether guideline-directed therapies were optimized prior to enrollment or during the trial. Overall, the DAPA-HF trial demonstrated a benefit in symptom scores and decreased risk of death from CV events and worsening HF in patients with HFrEF with dapagliflozin compared to placebo, regardless of T2DM diagnosis.

Other SGLT2 inhibitor trials examining HF outcomes

A clinical trial with empagliflozin in patients with HFrEF (EF≤40%), and NYHA class II, III, or IV (EMPORER-Reduced) reported a significant reduction compared to placebo in a composite outcome of cardiovascular death and hospitalization for heart failure (HR, 0.75, 95% CI, 0.65 to 0.86; p<0.001).17 The primary outcome results were consistent in patients with and without diabetes. Multiple ongoing clinical trials with SGLT2 inhibitors are investigating HF outcomes (Table 3).

Table 3. Ongoing SGLT2 inhibitor trials examining HF outcomes.18-26

Intervention or treatment

Population of interest

HF outcomes of interest

Dapagliflozin 10 mg once daily vs only protocolized diuretic therapya,18

Patients with T2DM hospitalized with hypervolemic acute decompensated HF

Cumulative change in weight, incidence of worsening HF during hospitalization, and hospital readmission within 30 days of discharge

Dapagliflozin 10 mg once daily vs placebo19

Patients with chronic HFpEF (EF > 40%) and NYHA class II to IV

Change in exercise capacity and patient-reported symptoms in patients with HFpEF based on KCCQ symptom scores and 6MWD

Dapagliflozin 10 mg once daily vs placebo20

Patients with chronic HFrEF (EF≤  40%) and NYHA class II to IV

Change in exercise capacity and patient-reported symptoms in patients with HFrEF based on KCCQ symptom scores and 6MWD

Dapagliflozin 10 mg once daily vs placebo21

Patients with HFrEF (EF≤ 40%) and NYHA class II to IV discharged after hospital admission with acute decompensated HF

Composite number of hospital admissions, ED visits, urgent clinic visits for HF and death after admission with acute decompensated HF

Dapagliflozin 10 mg once daily vs placebo22

Patients with HFpEF (EF >40%) and NYHA class II to IV

Time to first occurrence of either CV death, hospitalization for HF, or urgent HF

Dapagliflozin 10 mg once daily vs placebo23

Patients with HFrEF (EF≤40%) stabilized during hospitalization for acute HF

CV death or worsening HF

Canagliflozin vs alternative anti-hyperglycemic agentsb,24

Patients with T2DM and established CV disease

Number of hospitalizations for HF

Canagliflozin 100 mg once daily vs placebo25

Clinically stable symptomatic HF (HFrEF and HFpEF)

Changes in KCCQ symptom score in patients with HF

Empagliflozin 10 mg once daily vs placebo26

Patients with chronic HFpEF (EF> 40%) and NYHA class II to IV

Time to first event of CV death or hospitalization for HF

aBoth groups will receive protocolized loop diuretic therapy.
bAlternative anti-hyperglycemic agents include empagliflozin, dapagliflozin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 agonists, thiazolidinediones, sulfonylureas, and insulin.
Abbreviations: 6MWD=6-minute walk distance; CV=cardiovascular; ED=emergency department; EF=ejection fraction; HF=heart failure; HFpEF=heart failure with preserved ejection fraction; HFrEF=heart failure with reduced ejection fraction; KCCQ= Kansas City Cardiomyopathy Questionnaire; NYHA=New York Heart Association; SGLT2=sodium-glucose cotransporter 2; T2DM=type 2 diabetes mellitus.

Conclusion

As of September 2020, guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA) have not been updated to include recommendations on the use of dapagliflozin in patients with HF but without T2DM.15,16 With multiple ongoing clinical trials, ample efficacy and safety data will be available soon to determine a place in therapy for SLGT2 inhibitors in patients with HF.18-26 Dapagliflozin is contraindicated in patients with T2DM with an eGFR<30 mL/min/1.73 m2.1,2,12 It is reassuring that dapagliflozin did not worsen renal function in the DAPA-HF trial despite its diuretic effects, but more data are needed to determine safety in patients with HF and renal impairment.14 Prior studies have demonstrated that SGLT2 inhibitors, specifically dapagliflozin, have a beneficial effect on CV outcomes in patients with HFrEF. Based on the results from the DAPA-HF trial, dapagliflozin appeared to be beneficial compared to placebo and was associated with a reduction in HF events and CV deaths in patients with and without T2DM.14 The use of dapagliflozin in patients with HF could provide additional benefit to guideline-directed therapies, regardless of T2DM diagnosis.

References

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  24. A Study for Comparison of Canagliflozin Versus Alternative Antihyperglycemic Treatments on Risk of Heart Failure Hospitalization and Amputation for Participants With Type 2 Diabetes Mellitus and the Subpopulation With Established Cardiovascular Disease. Clinicaltrials.gov identifier: NCT03492580. Updated August 27, 2018. Accessed September 29, 2020. https://clinicaltrials.gov/ct2/show/NCT03492580?term=canagliflozin&cond=Heart+Failure&cntry=US&draw=2&rank=2
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  26. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved). Clinicaltrials.gov identifier: NCT03057951. Updated September 25, 2020. Accessed September 29, 2020. https://clinicaltrials.gov/ct2/show/NCT03057951?term=empagliflozin&cond=%22Heart+Failure%22&draw=2

 

Prepared by:
Rachel Brunner, PharmD
PGY2 Drug Information Resident
University of Illinois at Chicago College of Pharmacy

October 2020

The information presented is current as of September 28, 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.