Poll Results: SGLT2 Inhibitors for Patients with Heart Failure with Reduced Ejection Fraction: Who Should Prescribe Them?
- Among patients with HFrEF, SGLT2 inhibitors reduce the composite of HF hospitalization and CV death, regardless of DM status, and 65% of poll respondents agree that cardiologists should take the lead prescribing SGLT2 inhibitors for eligible patients.
- Dapagliflozin (an SGLT2 inhibitor) has received FDA approval for patients with NYHA functional class II-IV HFrEF, regardless of DM status, based upon DAPA-HF results, and a similar FDA application is pending for empagliflozin based upon EMPEROR-Reduced.
- Poll respondents endorsed potential barriers to SGLT2 inhibitor initiation for treatment of HFrEF even for patients with T2DM, specifically including insurance approval, cost to patients, lack of prescriber experience with SGLT2 inhibitors and concern for hypoglycemia.
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have recently made a surprising transition from the realm of type 2 diabetes mellitus (T2DM) pharmacotherapy into a new role within heart failure with reduced ejection fraction (HFrEF) medical therapy. The EMPA-REG OUTCOME study was the first to identify a benefit of empagliflozin for reduction of hospitalizations for worsening heart failure (HF) among patients with T2DM at high risk of cardiovascular (CV) events.1 Similar reductions in HF hospitalizations were subsequently observed with canagliflozin and dapagliflozin,2,3 but importantly baseline HF prevalence was only 10-15% in these trials.
The 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) recruited adults with New York Heart Association (NYHA) II-IV HF symptoms, ejection fraction (EF) ≤40%, and elevated plasma N-terminal pro–B-type natriuretic peptide (NT-proBNP), with or without T2DM, who were already prescribed guideline-directed medical therapy (GDMT). The dapagliflozin group had a significantly lower rate of hospitalization for HF or CV death than placebo (hazard ratio 0.74, 95% confidence interval 0.65-0.85, p<0.001).4 This effect was consistent in the subgroup without baseline DM. Subsequently the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) strengthened the assertion that addition of an SGLT2 inhibitor to HFrEF GDMT can reduce the risk of HF hospitalization or CV death in patients with or without T2DM.5-7
Given this recent evolution of the SGLT2 inhibitor into a novel HFrEF therapy, this ACC.org poll is a welcomed and timely assessment of cardiology clinicians' interest and attitudes. There was a robust response to the two poll questions (390 and 369 votes, respectively) reflecting considerable enthusiasm for understanding safe and effective approaches towards prescribing this medication class.
Question 1 addresses the uncertainties regarding whom should act as primary prescribers of this drug class for eligible recipients. It is encouraging to see that two-thirds (65.38%) of participants were interested in taking ownership of SGLT2 inhibitor initiation to optimize the HFrEF medical regimen, regardless of T2DM status. This suggests that the majority of cardiology clinicians are poised to embrace the drug class within their HF clinical practice, which bodes well for patient access and outcomes. Dapagliflozin is already approved by the Food and Drug Administration (FDA) for treatment of NYHA class II-IV HFrEF with or without T2DM and similar approval is currently being sought for empagliflozin. Empagliflozin is currently FDA approved for patients with T2DM and CV disease to reduce CV death. Conversely, a third of respondents would prefer that another provider initiate SGLT2 inhibitors. This highlights the importance of clear communication within the medical team to ensure the drug class is considered when it could yield clinical benefits and be introduced in a safe fashion.
Question 2 explores perceived barriers to the initiation of SGLT2 inhibitors by cardiology clinicians for patients with both HFrEF and concomitant T2DM. A range of very valid financial, logistical, clinician knowledge and patient safety concerns were endorsed by poll respondents. SGLT2 inhibitor insurance authorization is currently highly variable, and even when approved the patient copay cost may unfortunately be prohibitive. It is anticipated that insurance coverage will expand as DAPA-HF and EMPEROR-Reduced results are widely disseminated and if future HF practice guidelines incorporate SGLT2 inhibition.
The following tips may be helpful when considering SGLT2 inhibitors for the treatment of HFrEF: a) the insurance approval process can be less onerous if there is an opportunity for collaboration with a clinical pharmacist or pharmacy technician familiar with the prior authorization process; b) SGLT2 inhibitors are available in combination tablets with metformin to minimize pill burden for patients with T2DM; c) pharmacists are valuable members of the cardiology care team and are trained to provide medication counseling sessions before pharmacotherapy initiation. They can closely monitor laboratory tests and side effects after initiation, as is already routine for HFrEF GDMT initiation, and are poised to collaborate with multi-specialty prescribers to adjust concurrent therapies as needed; d) even when a pharmacist is not available, cardiology clinicians are already experts at monitoring serum chemistries, blood pressure, and patient symptoms during GDMT titrations. Diuretic down-titration is usually advisable if the patient has significant hyperglycemia, due to the potential for an osmotic diuresis upon starting the SGLT2 inhibitor.
Cardiology clinicians' concerns for hypoglycemia and other potential noncardiac side-effects are certainly valid, but the HFrEF trials were reassuring in this regard: safety events including major hypoglycemia, acute kidney injury, urinary tract infections and ketoacidosis were rare (even amongst older subjects) and equivalent between randomization groups (Table 1).4,5,8 Further educational opportunities for cardiology clinicians to become familiar with SGLT2 inhibitor patient counselling and risk mitigation are clearly essential, and the American College of Cardiology plays a crucial role in providing such content across its online and scientific session platforms.
The poll did not address awareness of glomerular filtration rate (GFR) thresholds for SGLT2 inhibitor initiation and continuation. These thresholds may evolve given that EMPEROR-Reduced enrolled patients with eGFR as low as 20 mL/min/1.73m2, whereas the current package insert eGFR threshold is higher and recommends empagliflozin discontinuation if persistently below 45 mL/min/1.73m2. Both DAPA-HF and EMPEROR-Reduced showed less renal function decline over time for patients receiving the SGLT2 inhibitor.4,5 The poll also did not assess awareness of the SGLT1/2 inhibitor sotagliflozin, which was recently demonstrated to reduce recurrent HF hospitalization and CV death for patients with T2DM and recent hospitalization for HF (any EF).9 It is not yet known whether SGLT2 inhibitors will claim a role in the management of HF with preserved EF, where therapeutic options are currently limited, but this is under investigation in two clinical trials (EMPEROR-Preserved and DELIVER).
As we embark upon this journey towards a more medically and financially complex HFrEF medication regimen, the cardiology community will need to carefully define the optimal sequence for SGLT2 inhibitor initiation. Despite the residual unknowns, this ACC.org poll confirms vigorous cardiology clinician interest in optimizing patient outcomes by incorporating SGLT2 inhibitors into the contemporary arsenal of HFrEF therapies.
|Select adverse events of interest||Dapagliflozin in DAPA-HF
|Placebo in DAPA-HF (n=2368)||Empagliflozin in EMPEROR-Reduced (n=1863)||Placebo in EMPEROR-Reduced (n=1863)|
|Renal adverse events *||6.5%||7.2%||1.6%||3.1%|
|Hypoglycemic events **||0.2%||0.2%||1.4%||1.5%|
|Urinary tract infections||0.5%||0.7%||4.9%||4.5%|
|Lower limb amputation||0.5%||0.5%||0.7%||0.5%|
* Renal adverse events: defined in EMPEROR-reduced as chronic dialysis, renal transplantation, or a profound and sustained reduction in GFR
** Hypoglycemic events: defined in DAPA-HF as hypoglycemia requiring assistance of another person to take corrective action (all cases occurred in patients with baseline DM); defined in EMPEROR-Reduced as plasma glucose £70 mg/dL or requiring assistance
- Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
- Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.
- Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57.
- McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.
- Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-24.
- Anker SD, Butler J, Filippatos G, et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status - results from the EMPEROR-Reduced trial. Circulation 2020;Nov 11:[Epub ahed of print].
- Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020;396:819-29.
- Martinez FA, Serenelli M, Nicolau JC, et al. Efficacy and safety of dapagliflozin in heart failure with reduced ejection fraction according to age: insights from DAPA-HF. Circulation 2020;141:100-11.
- Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2020;Nov 16:[Epub ahead of print].
Keywords: Heart Failure, Sodium-Glucose Transporter 2, Pharmacists, Diabetes Mellitus, Type 2, Metformin, Incidence, Prevalence, Diuretics, ESC20, ESC Congress
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