EXPLORE SOLOIST‑WHF

The first and largest HF outcomes study of patients initiating an SGLT inhibitor—demonstrated significant risk reduction in the primary composite endpoint of CV death, hospitalization for HF, and urgent HF visit in patients with worsening HF, regardless of EF1-7

SOLOIST‑WHF STUDY:

a multi-center, randomized, double‑blind, placebo‑controlled, Phase 3 study in patients with T2DM who had been admitted to the hospital, HF unit, infusion center, or emergency department for worsening HF (N=1,222), evaluating the HF outcomes and safety of INPEFA® (n=608) versus placebo (n=614) when added to standard of care.1

Patients enrolled in SOLOIST-WHF received the standard of care regimen, including GDMT. At baseline, patients received RAAS inhibitors (91%), beta-blockers (92%), loop diuretics (95%), and additional diuretics (10%).1

CV=cardiovascular; EF=ejection fraction; GDMT=guideline-directed medical therapy; HF=heart failure; RAAS=renin-angiotensin-aldosterone system; SGLT=sodium-glucose cotransporter; T2DM=type 2 diabetes mellitus; WHF=worsening heart failure.

Assigned treatment was initiated in the hospital or within 3 days following hospital discharge.1,4

33% risk reduction*

In the primary composite endpoint of CV death, hospitalization for HF, and urgent HF visit.1

HR=0.67 (95% CI: 0.53, 0.85), p=0.001

*Relative risk reduction.

SEE DETAILS

A low NNT of 48

Number Needed to Treat to prevent 1 primary composite event of CV death, hospitalization for HF, and urgent HF visit.8

Calculation: The rate of primary endpoint events was 51.3 events per 100 patient years in the INPEFA group and 76.4 events per 100 patient years in the placebo group. Absolute difference=76.4‑51.3=25.1, NNT=1/ARR=1/0.25=4 patient years.4

Post hoc analysis in patients initiated on INPEFA on or before discharge showed:

>50% risk reduction*

in readmission for HF‑related event or CV death at 30 days, with consistent efficacy extending over 90 days.9

30 days: HR=0.49 (95% CI: 0.27, 0.91)

90 days: HR=0.54 (95% CI: 0.35, 0.82)

*Relative risk reduction.

Limitations of analysis: This post hoc analysis occurred after the protocol-specified final analysis.9 No formal statistical testing was planned for this analysis; therefore, no conclusions can be drawn. These data are not in the USPI and results should be interpreted with caution.

SEE DETAILS

ARR=absolute risk reduction; CI=confidence interval; HR=hazard ratio; NNT=number needed to treat; USPI=United States Prescribing Information.

ARR=absolute risk reduction; CI=confidence interval; HR=hazard ratio; NNT=number needed to treat; USPI=United States Prescribing Information.

PRIMARY ENDPOINT1

INPEFA provided significant clinical benefits

for patients already on standard of care HF regimen.1

33% risk reduction* in the primary composite endpoint of CV death, hospitalization for HF, and urgent HF visit1

The early separation of curves shown in SOLOIST-WHF underscores rapid impact of INPEFA in adults with HF.1

Primary endpoint graph from the SOLOIST-WHF trial
Primary endpoint graph from the SOLOIST-WHF trial

Primary composite endpoint (total occurrence of CV death, hospitalization for HF, and urgent HF visit) was based on investigator-reported events in all randomized patients, analyzed according to the treatment group allocated by randomization.1

*Relative risk reduction.

†Post hoc analysis considered exploratory; therefore, no conclusions can be drawn.

POST HOC ANALYSIS9

>50% risk reduction* in readmission for HF‑related event or CV death at 30 days.9

Readmission for HF‑related event or CV death at 30 and 90 days from hospital discharge‡

Post hoc analysis graph from the SOLOIST-WHF trial
Post hoc analysis graph from the SOLOIST-WHF trial

Limitations of analysis: This post hoc analysis occurred after the protocol-specified final analysis.9 No formal statistical testing was planned for this analysis; therefore, no conclusions can be drawn. These data are not in the USPI and results should be interpreted with caution.

*Relative risk reduction.

‡Patients included in this analysis received INPEFA prior to discharge in either the hospital or urgent care setting.9

The INPEFA safety profile in the 30‑ and 90‑day post-randomization windows was generally consistent with that observed for the overall study duration.9

SOLOIST-WHF Study Adverse Events

Adverse reactions reported in ≥2% of patients treated with INPEFA and at greater frequency than placebo.1

SOLOIST‑WHF
(N=1,216)
Adverse ReactionINPEFA
(n=605)		Placebo
(n=611)
Urinary tract infection8.6%7.2%
Volume depletion9.3%8.8%
Diarrhea6.9%4.1%
Hypoglycemia4.3%2.8%
Dizziness2.6%2.5%
Discover scored

References:

1. INPEFA [prescribing information]. Lexicon Pharmaceuticals, Inc.; 2024. 2. Maddox, T, Januzzi, J, Allen, L. et al. 2024 ACC Expert consensus decision pathway for treatment of heart failure with reduced ejection fraction: a report of the American College of Cardiology solution set oversight committee. J Am Coll Cardiol. 2024;83(15):1444‑1488. doi.org/10.1016/j.jacc.2023.12.024 3. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American Colege of Cardiology/American Heart Association joint committee on clinical practice guidelines [published correction appears in Circulation. 2022 May 3;145(18):e1033]. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063 4. 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 5. 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 6. Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28(3):568‑574. doi:10.1038/s41591‑021‑01659‑1 7. FARXIGA (dapagliflozin) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2023. 8. Verma S, Anker SD, Butler J, Bhatt DL. Early initiation of SGLT2 inhibitors is important, irrespective of ejection fraction: SOLOIST-WHF in perspective. ESC Heart Fail. 2020;7(6):3261-3267. doi:10.1002/ehf2.13148 9. Pitt B, Bhatt DL, Szarek M, et al. Effect of sotagliflozin on early mortality and heart failure-related events: a post hoc analysis of SOLOIST-WHF [published correction appears in JACC Heart Fail. 2023 Sep;11(9):1288]. JACC Heart Fail. 2023;11(8 Pt 1):879-889. doi:10.1016/j.jchf.2023.05.026 10. Verma S, Bhatt DL, Dhingra NK, et al. Time to benefit with sotagliflozin in patients with worsening heart failure. J Am Coll Cardiol. 2023;81(15):1546-1549. doi:10.1016/j.jacc.2023.02.022

Important Safety Information

Dosing:

Assess renal function and volume status and, if necessary, correct volume depletion prior to initiation of INPEFA. INPEFA dosing for patients with decompensated heart failure may begin when patients are hemodynamically stable, including when hospitalized or immediately upon discharge.

Contraindications:

INPEFA is contraindicated in patients with hypersensitivity to any component.

Warnings and Precautions

  • Ketoacidosis:

    INPEFA increases the risk of ketoacidosis in patients with type 1 diabetes mellitus (T1DM). Type 2 diabetes mellitus (T2DM) and pancreatic disorders are also risk factors. The risk of ketoacidosis may be greater with higher doses. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes using sodium glucose transporter 2 (SGLT2) inhibitors. Before initiating INPEFA, assess risk factors for ketoacidosis. Consider ketone monitoring in patients with T1DM and consider ketone monitoring in others at risk for ketoacidosis, and educate patients on the signs/symptoms of ketoacidosis. Patients receiving INPEFA may require monitoring and temporary discontinuation of therapy in clinical situations known to predispose to ketoacidosis.

    Assess patients who present with signs and symptoms of metabolic acidosis or ketoacidosis, regardless of blood glucose level. If suspected, discontinue INPEFA, evaluate, and treat promptly. Monitor patients for resolution of ketoacidosis before restarting INPEFA.

  • Volume Depletion:

    INPEFA can cause intravascular volume depletion which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors. Patients with impaired renal function (eGFR < 60 mL/min/1.73 m2), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating INPEFA in patients with one or more of these characteristics, assess volume status and renal function, and monitor for signs and symptoms of hypotension during therapy.

  • Urosepsis and Pyelonephritis:

    Treatment with SGLT2 inhibitors, including INPEFA, increases the risk for urinary tract infections. Serious urinary tract infections including urosepsis and pyelonephritis requiring hospitalization have been reported. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly.

  • Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues:

    Insulin and insulin secretagogues are known to cause hypoglycemia. INPEFA may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used with INPEFA.

  • Necrotizing Fasciitis of the Perineum (Fournier's Gangrene):

    Reports of Fournier's Gangrene, a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in post-marketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors. Assess patients who present with pain, tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue INPEFA, closely monitor patient signs and symptoms, and provide appropriate alternative therapy for heart failure.

  • Genital Mycotic Infections:

    INPEFA increases the risk of genital mycotic infections. Monitor and treat as appropriate.

  • Urinary Glucose Test and 1,5‑anhydroglucitol (1,5‑AG) Assay:

    These are not reliable for patients taking SGLT2 inhibitors. Use alternative testing methods to monitor glucose levels.

Common Adverse Reactions:

The most commonly reported adverse reactions (incidence ≥ 5%) were urinary tract infection, volume depletion, diarrhea, and hypoglycemia.

Drug Interactions:

  • Digoxin:

    Monitor patients appropriately as there is an increase in the exposure of digoxin when coadministered with INPEFA 400 mg.

  • Uridine 5'‑diphospho‑glucuronosyltransferase (UGT) Inducer:

    The coadministration of rifampicin, an inducer of UGTs, with sotagliflozin resulted in a decrease in the exposure of sotagliflozin.

  • Lithium:

    Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Monitor serum lithium concentration more frequently during INPEFA initiation and with dosage changes.

Use in Specific Populations:

  • Pregnancy and Lactation:

    INPEFA is not recommended during the second and third trimesters of pregnancy, nor while breastfeeding.

  • Geriatric Use:

    No INPEFA dosage change is recommended based on age. No overall differences in efficacy were detected between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients may be at increased risk for volume depletion adverse reactions, including hypotension.

  • Renal Impairment:

    INPEFA was evaluated in patients with chronic kidney disease (eGFR 25 to 60 mL/min/1.73 m2) and in patients with heart failure with eGFR <60 mL/min/1.73 m2. The safety profile of INPEFA across eGFR subgroups in these studies was consistent with the known safety profile. There was an increase in volume-related adverse events (e.g., hypotension, dizziness) in patients with eGFR <30 mL/min/1.73 m2 relative to the overall safety population. Efficacy and safety studies with INPEFA did not enroll patients with an eGFR less than 25 mL/min/1.73 m2 or on dialysis. After starting therapy in the studies, patients were discontinued if eGFR fell below 15 mL/min/1.73 m2 or were initiated on chronic dialysis.

  • Hepatic Impairment:

    INPEFA is not recommended in patients with moderate or severe hepatic impairment.

Indication

INPEFA® is indicated to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visit in adults with:

  • heart failure or
  • type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors

Please see full Prescribing Information and Patient Medication Guide.