Commentary
Article
Cardioprotective antihyperglycemic agents are underutilized for inpatient care in heart failure patients. Lack of use can lead to preventable patient deaths and hospital readmissions.
Introduction
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are known to decrease the risk of heart failure (HF) and/or major cardiovascular (CV) events in patients with type 2 diabetes. Various placebo-controlled studies have evaluated the efficacy of these drugs in HF for patients with and without a diagnosis of diabetes.
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Currently, the FDA has approved the use of dapagliflozin (Farxiga; AstraZeneca), empagliflozin (Jardiance; Boehringer Ingelheim Pharmaceuticals), and sotagliflozin (Inpefa; Lexicon Pharmaceuticals) to reduce the risk of CV death and hospitalization in patients with confirmed HF or risk factors for CV disease. Despite the recommendation of SGLT2 inhibitors in guideline-directed medical therapy (GDMT) for the chronic management of HF, worldwide studies reveal that only a minority of patients with type 2 diabetes or HF are treated with these agents in the inpatient setting.
Heart Failure
HF is a clinical syndrome associated with signs and symptoms of cardiac structural or functional abnormalities that involve the impaired ability of the ventricle to fill or eject blood. Left ventricular ejection fraction (LVEF) is used to classify patients with HF. Patients with HF with preserved ejection fraction (HFpEF), defined as LVEF >50%, experience diastolic HF due to structural changes that prevent the left ventricle from filling with blood during relaxation. Patients with HR with reduced ejection fraction (HFrEF), or LVEF <40%, experience systolic failure in which enlarged ventricles fill with blood that cannot be ejected during contraction due to narrowing of necessary arteries or tissues.
The American College of Cardiology (ACC) stages HF based on the development and progression of disease.1 Therapeutic interventions aim to modify risk factors (stage A), treat risk and structural heart disease to prevent HF (stage B), and reduce symptoms, morbidity, and mortality (stages C and D).
Review of SGLT2 Inhibitors
SGLT2 inhibitors block glucose transport proteins that facilitate reabsorption of glucose in the proximal tubules of the kidney, thereby promoting glucose excretion. SGLT2 inhibitors also have a mild diuretic effect with decreased sodium reabsorption, leading to reduction in plasma volume and blood pressure. Additional CV benefits include improvement of arterial stiffness through smooth muscle relaxation, protection of cardiac myocytes, and promotion of ketone production, which can be used for energy generation. These agents also function as disease-modifying therapies for patients with chronic kidney disease.
Clinical Trials
Several trials have examined the efficacy of SGLT2 inhibitors on outcomes in patients with HF. The Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial studied the efficacy of dapagliflozin compared to placebo in patients with HFrEF.2 Results included worsening HF in 10% of the dapagliflozin group vs 13.7% of the placebo group. The risk of CV death was significantly lowered with dapagliflozin as was the risk of all-cause mortality. Results were similar in patients with and without type 2 diabetes. There was no notable excess of adverse events in the dapagliflozin group, which suggests the treatment is safe to administer in HFrEF.
The trial, however, did have some limitations. The majority of patients had moderate HF, defined as New York Heart Association class II, which exercises caution in generalizing findings to patients with more severe symptoms. Additionally, it was unclear if patients were on maximally tolerated doses of GDMT.
There was also a low baseline usage of angiotensin receptor/neprilysin inhibitors(ARNI). Use of an ARNI is more effective at reducing the incidence of hospitalization for HF and death from CV causes than renin-angiotensin system blockade alone. However, in a post-hoc subgroup analysis, the benefit of dapagliflozin was similar in patients treated with ARNI compared to those that were not.
Similar to the DAPA-HF trial, the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction (EMPEROR-Reduced) study evaluated the effects of empagliflozin in patients with HFrEF compared to placebo, irrespective of the presence of type 2 diabetes.3 Overall, there was a 25% reduction in the composite outcome of CV death and hospitalization for HF. In addition to the CV benefits, empagliflozin reduced the rate of decline in the estimated glomerular filtration rate (eGFR) and the risk of composite renal outcome was lower in the treatment arm compared to placebo. However, there was no significant decrease in all-cause mortality with empagliflozin.
Patients included in the EMPEROR-Reduced trial had more severe HF than patients in the DAPA-HF study, based on ejection fraction and baseline natriuretic peptides, limiting comparability between the 2 trials. Statistical analysis was not conducted for adverse events.
The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) trial showed a significant benefit with empagliflozin in patients with chronic symptomatic HFpEF.4 Treatment with empagliflozin was associated with a 21% lower risk of the primary composite outcome of HF hospitalization or CV death when compared to placebo. As with the EMPEROR-Reduced trial, this trial proved benefit in the reduction of HF hospitalization, but not mortality. The pooled analysis of EMPEROR-Reduced and EMPEROR-Preserved trials suggest renal benefit is shown primarily among patients with HFrEF and eGFR may not be predictive of renal outcomes for patients with HF.
The Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes and Worsening Heart Failure (SOLOIST-WHF) trial found that sotagliflozin reduced the combined endpoint of CV death, HF hospitalization, or urgent HF visits by 33%.5 At the time of the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure release, sotagliflozin was not approved by the FDA. However, in May 2023, based on the phase 3 results of the SCORED and SOLOIST-WHF trials, the first dual SGLT1 and SGLT2 inhibitor sotagliflozin was approved for the treatment of HF, including both HFpEF and HFrEF. Prior to SOLOIST-WHF, limited data were available on the initiation of SGLT2 inhibitors for inpatient prevention of HF hospitalization. In this trial, early initiation of sotagliflozin, prior to discharge, appeared to improve patient outcomes within 90 days. Limitations of this trial included earlier than planned closure of trial enrollment (due to loss of funding), which impacted the statistical power to assess secondary endpoints, such as death from CV causes.
Table 1. Summary of large-scale HF trials with sodium–glucose cotransporter 2 inhibitors, dapagliflozin and empagliflozin, and the dual SGLT1/2 inhibitor, sotagliflozin.
Current Recommendations and Guidelines
SGLT2 inhibitors were added to GDMT in the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. These agents carry a class 1 recommendation for reducing HF hospitalization and CV mortality in patients with symptomatic chronic HFrEF, regardless of the presence of type 2 diabetes. In patients with HFpEF or mildly reduced ejection fraction (HFmrEF), the guidelines provide a class 2a recommendation, noting the use of these agents can be beneficial in reducing HF hospitalizations and CV mortality.1
Are SGLT2 Inhibitors Underused in Inpatient Settings?
Physicians are hesitant with inpatient initiation of SGLT2 inhibitors due to limited data on in-hospital efficacy.6 However, there is a lack of evidence to suggest that deferring initiation of SGLT2 inhibitors to the outpatient setting provides benefits or improves medication tolerance.
The argument for increased risk of adverse effects or intolerance is based on minimal clinical evidence. Randomized trials have exhibited little to no effect with SGLT2 inhibitors on symptomatic hypotension. Although a small drop in eGFR may be expected, there were no trials that showed excess risks of acute kidney injury. In both DAPA-HF and EMPEROR-Reduced trials, the incidence of hypoglycemic and diabetic ketoacidosis events were rare. As previously mentioned, the SOLOIST-WHF trial supports the efficacy and safety of inpatient initiation of sotagliflozin. Failure to discharge eligible patients on GDMT significantly increases the chance of therapies being delayed or never started.
Another example of a trial that involves inpatient SGLT2 inhibitor initiation is the Empagliflozin in Patients Hospitalized with Acute Heart Failure who have been Stabilized (EMPULSE) trial.7 This double blind, randomized trial evaluated the effectiveness of the early initiation of empagliflozin and its clinical benefits among patients with acute HF 90 days post hospital admission. EMPULSE has proven to be distinct from previous trials because it involved patients early in the course of hospitalization, at a median of 3 days post admission for HF. EMPULSE also included patients without a previous history of HF who were naive to standard HF GDMT. The results of this trial found that adding empagliflozin to standard therapy was well tolerated and should be considered as an efficacious treatment in patients hospitalized for both de novo and decompensated acute HF. The results of EMPULSE complement those of EMPEROR-Reduced and EMPEROR-Preserved and add to the accumulating evidence on the benefits of SGLT2 inhibitors in HF.
The high cost of SGLT2 inhibitors also poses a potential barrier to initiation. To help overcome this barrier, several pharmaceutical companies supplying SGLT2 inhibitors have patient assistance programs in place to assist with alleviating copays. Clinicians who utilize these programs can ensure that patients are able to afford these medications and receive evidence-based care.
Conclusion
SGLT2 inhibitors are well suited for initiation during hospitalization, presenting numerous clinical benefits along with a strong safety and tolerability profile. Early initiation of SGLT2 inhibitors would provide a key opportunity to utilize GDMT, especially in patients naive to HF treatment. Currently, there are limited data directly comparing the benefits of early initiation to deferred, post-discharge therapy. However, failure to embrace routine in-hospital initiation of SGLT2 inhibitors would be a significant missed opportunity leading to preventable patient deaths and hospital readmissions.
Christine Philipose is a 2024 PharmD candidate in the College of Pharmacy and Health Sciences at St. John's University in Queens, New York.
Richa Tamakuwala, PharmD, BCPS, is a clinical pharmacist at Mount Sinai South Nassau in Oceanside, New York.
References
1. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18). doi:https://doi.org/10.1161/cir.0000000000001063
2. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. New England Journal of Medicine. 2019;381(21). doi:https://doi.org/10.1056/nejmoa1911303
3. Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. New England Journal of Medicine. 2020;383(15). doi:https://doi.org/10.1056/nejmoa2022190
4. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. New England Journal of Medicine. 2021;385(16). doi:https://doi.org/10.1056/nejmoa2107038
5. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. New England Journal of Medicine. 2020;384. doi:https://doi.org/10.1056/nejmoa2030183
6. Rao VN, Murray E, Butler J, et al. In-Hospital Initiation of Sodium-Glucose Cotransporter-2 Inhibitors for Heart Failure with Reduced Ejection Fraction. Journal of the American College of Cardiology. 2021;78(20):2004-2012. doi:https://doi.org/10.1016/j.jacc.2021.08.064
7. Kosiborod MN, Angermann CE, Collins SP, et al. Effects of empagliflozin on symptoms, physical limitations, and quality of life in patients hospitalized for acute heart failure: Results from the EMPULSE trial. Circulation. 2022;146(4):279-288. doi:10.1161/circulationaha.122.059725
