An Overview of SGLT2 Inhibitors in Heart Failure With Preserved Ejection Fraction

Background

Heart failure with preserved ejection fraction (HFpEF), otherwise known as diastolic heart failure, is a complex clinical syndrome associated with major morbidity and mortality with limited availability of treatments. HFpEF is defined as a clinical diagnosis of heart failure (HF) with left ventricular ejection fraction (LVEF) >50%.¹

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Although the overall incidence of HF in the United States appears to be stable, the prevalence of HFpEF compared to heart failure with reserved ejection fraction (HFrEF) is increasing overtime.² In fact, HFpEF now encompasses more than 50% of all cases of HF, with more cases seen in women than men. HFpEF also often goes unrecognized, and treatment was previously limited to managing comorbidities, but with advancements in the understanding of pathophysiology of the disease, improved methods of diagnosis, and new therapeutic options, timely implementation of guideline-directed medical therapy is now possible which may improve outcomes.¹

The goals of HFpEF therapy are improving functional status, improving symptoms, and reducing risk of hospital admission. Current guidelines recommend treating HFpEF using a multidisciplinary approach including management of comorbidities (i.e. diabetes, obesity, atrial fibrillation, chronic kidney disease, etc.), lifestyle modifications (i.e., weight loss, exercise, etc.), and pharmacological management with loop diuretics, angiotensin receptor-neprilysin inhibitors, mineralocorticoid inhibitors, angiotensin receptor blockers, and sodium-glucose cotransporter-2 (SGLT2) inhibitors.¹

SGLT2 Inhibitors

Initially developed for the management of type 2 diabetes (T2D), SGLT2 inhibitors have recently shown significant cardiovascular (CV) benefit in patients with and without diabetes and should be considered the backbone of HFpEF treatment. SGLT2 inhibitors exert their action by blocking the SGLT2 protein which is responsible for the resorption of 90% of filtered glucose in the proximal convoluted tubule, resulting in the decrease of plasma glucose concentrations. SGLT2 inhibitors also inhibit sodium resorption to increase sodium in the distal tubules which may lower both preload and afterload and decrease intraglomerular pressure.^3-5 The newly approved sotagliflozin (Inpefa; Lexicon) exhibits dual inhibition of SGLT2 and SGLT1, with SGLT1 inhibition reducing the intestinal absorption of glucose and sodium.⁶

The exact mechanism of how SGLT2 inhibitors improve HF outcomes in not understood, but key theories include improved glycemic control, diuresis and subsequent control of blood pressure, weight loss, increase in hematocrit, and potential reversal of cardiac remodeling.⁷ Key clinical trials have shown that SGLT2 inhibitors have the potential to reduce risk of hospitalization and CV death across all ejection fraction (EF) groups.⁷

Empagliflozin

The EMPEROR-Preserved trial was the first phase 3 clinical trial to show the benefit of using an SGLT2 inhibitor, specifically empagliflozin (Jardiance; Boehringer Ingelheim, Lilly), in patients with HFpEF. Before this trial, the benefit of SGLT2 had only been proven in HFrEF. EMPEROR-Preserved was a multi-center, double-blind trial that enrolled 5988 patients with New York Heart Association (NYHA) functional class II-IV HF with LVEF >40%. The trial also required patients to have a N-terminal pro-B-type natriuretic peptide (NT-proBNP) of >300 pg/mL, or, for patients with atrial fibrillation at baseline, NT-proBNP >900 pg/mL.⁸

Patients were randomized in a 1:1 ratio to either receive empagliflozin 10 mg once daily or placebo in additional to usual therapy. The primary outcome was a composite of adjudicated CV death or hospitalization for HF. Of the 5988 patients enrolled, 2997 patients received empagliflozin and 2991 received placebo. Baseline characteristics were similar between the 2 treatment groups with half having eGFR <60 mL/min/1.73 m², half having diabetes mellitus, and a median age of 72. With a median follow-up of 26 months, the primary composite end point of death from CV causes or hospitalization for HF occurred in 13.8% of patients treated with empagliflozin compared with 17.1% of patients in the placebo group (6.9 vs. 8.7 events per 100 patient-years; HR, 0.79; 95% CI, 0.69 to 0.90; P<0.001). The benefit of empagliflozin was seen in patients with and without diabetes.⁸

Dapagliflozin

Similarly to the trial above, the DELIVER trial was designed assess another SGLT2 agent, dapagliflozin (Farxiga; AstraZeneca), in patients with mildly reserved or reduced ejection fraction. The DELIVER trial was a phase 3, international, multicenter, double-blind trial in patients with chronic HF. Patients were randomized to dapagliflozin 10 mg daily or placebo in addition to standard of care therapies. Patients could be enrolled if they had stabilized HF with or without diabetes, LVEF >40%, and an elevated natriuretic peptide. The primary end point was a composite of worsening HF which included unplanned hospitalization or urgent care visit for HF, or CV death. Secondary outcomes were total number of worsening HF events or CV death and improvement in quality of life. The median age of patients included in this study was 72.^9,10

With a median follow up of 2.3 years and 6263 patients enrolled, the primary outcomes occurred in 16.4% of patients receiving dapagliflozin compared with 19.5% patients receiving placebo (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). In addition, CV death and worsening HF were less likely in patients treated with dapagliflozin (rate ratio, 0.77; 95% CI, 0.67 to 0.89; P<0.001). Dapagliflozin also showed quality of life improvements in the Kansas City Cardiomyopathy Questionnaire from baseline to 8 months (win ratio, 1.11; 95% CI, 1.03 to 1.21; P=0.009). Adverse effects were comparable between dapagliflozin and placebo.5 In addition, dapagliflozin was also shown to increase symptoms, physical limitations, and exercise function in the PRESERVED-HF trial.¹⁰

Sotagliflozin

Sotagliflozin was recently approved based on the results of the SOLOIST-WHF trial. This multicenter, double-blind, placebo control trial evaluated patients who were recently hospitalized for worsening HF, received intravenous diuretic therapy, had T2D, and were clinically stable. Patients were randomized to receive sotagliflozin 200 mg daily (with dose increase to 400 mg based on adverse effects) or placebo to be started 1 to 3 days prior to discharge. The primary end point was first occurrence of CV-related death or hospitalization for HF. Secondary end points included total number of hospital or urgent care visits for HF, incidence of death from any CV cause, total number of CV deaths, hospitalizations for HF, nonfatal myocardial infarctions, nonfatal stores, and improvement in quality of life using Kansas City Cardiomyopathy Questionnaire–12. Of the 1222 patients enrolled, only 20.9% of patients had a LVEF >50%, and the median age of patients included was 70.⁶

The primary end point was seen at a rate of 51 per 100 patient-years in patients treated with sotagliflozin, compared with 76.3 per 100 patients years in patients treated with placebo (HR, 0.67; 95% CI, 0.52 to 0.85; P<0.001). This showed an absolute difference of 25.3 events per 100 patient-years (95% CI, 5.1 to 45.6). This benefit was also seen in patients with LVEF >50%. The incidence of CV death or death from any cause was similar between groups, and the difference in KCCQ-12 score was 4.1 points (95% CI, 1.3 to 7.0) in favor of the sotagliflozin group.⁶

Safety and Tolerability

SGLT2 inhibitors have demonstrated tolerable safety profiles, with the most common adverse effects being urinary tract infections, nasopharyngitis, yeast infections, increased urination, volume depletion, and hypoglycemia.^3-5 Patients treated with sotagliflozin are more likely to experience diarrhea due to the additional inhibition of SGLT1, which decreases intestinal absorption of glucose and sodium.⁶ These agents should not be considered in patients with ketoacidosis and volume status should assessed and corrected prior to initiation. Patients should be monitored as appropriate. Additional considerations are listed in Table 1.^1,3-5

Table 1.^1,3-5 SGLT2 Inhibitors' Safety and Tolerability

Summary

HFpEF is a complex clinical syndrome that poses challenges in diagnosis and treatment. New data have emerged supporting potential therapeutic agents that may improve morbidity and mortality for this growing patient population. The results of the EMPEROR-Preserved, DELIVER, and SOLOIST-WHF trials have shown benefits in preventing hospitalization for HF and CV death in patients with HFpEF when treated with empagliflozin, dapagliflozin, or sotagliflozin, respectively. Due to these results, current guidelines recommend a backbone of SLGT2 therapy in patients with HFpEF who have no contraindications.

A meta-analysis of the EMPEROR-Preserved and DELIVER trials that included 12,251 participants demonstrated that SGLT2 inhibitors reduced composite CV death or first hospitalization for HF (HR [95% CI 0.73-0.87]). In addition to these 2 trials, this metanalysis also explored the incorporation of patients in the SOLOIST-WHF trial and patients with reduced ejection fraction (DAPA-HF and EMPEROR-Reduced trials), which included 21,947 participants and demonstrated reduction in composite CV death or hospitalization for HF (HR 0.77 [0.72-0.82]) and all-cause mortality (HR 0.92 [0.86-0.99]), showing benefit of this drug class across all ejection fractions.11 Therefore, SGLT2 inhibitors may play a critical role in improving outcomes in patients with HF. Dosing considerations are included in Table 2^1,3-5 and Table 3^1,3-5 highlights drug interactions and clinical implications.

Table 2.^1,3-5 SGLT2 Dosing Considerations

Table 3.^1,3-5 Drug Interactions and Clinical considerations for SGLT2 Inhibitors

REFERENCES

1. Kittleson MM, Panjrath GS, Amancherla K, et al. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction: A Report on the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2023;81(18):1835-1878. doi:10.1016/j.jacc.2023.03.393

2. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics–2020 update: a report from the American Heart Association. Circ. 2020;141(9):e139-e596. doi:10.1161/CIR.000000000000757

3. Farxiga (dapagliflozin) [package insert]. AstraZeneca Pharmaceuticals LP; Wilmington, DE: 2023.

4. Jardiance (empagliflozin) [package insert]. Ingelheim Pharmaceuticals, Inc; Ridgefield, CT: 2023.

5. Inpefa (sotagliflozin) [package insert]. Lexicon Pharmaceuticals, Inc; The Woodlands, TX: 2023.

6. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384(2):117-128. doi:10.1056/NEJMoa2030183

7. Joshi SS, Singh T, Newby DE, Singh J. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart. 2021;107(13):1032-1038. doi:10.1136/heartjnl-2020-318060

8. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-1461. doi:10.1056/NEJMoa2107038

9. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387(12):1089-1098. doi:10.1056/NEJMoa2206286

10. Nassif ME, Windsor SL, Borlaug BA, et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med. 2-21;27(11):1954-1960. doi:10.1038/s41591-021-01536-x

11. Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomized controlled trials. Lancet. 2022;400(10354):757-767. doi:10.1016/S0140-6736(22):01429-5