Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure - SOLOIST-WHF

Contribution To Literature:

The SOLOIST-WHF trial showed that sotagliflozin has salutary effects on CV outcomes among patients with T2DM and HF.

Description:

The goal of the trial was to assess the safety and efficacy of sotagliflozin in reducing cardiovascular (CV) events among patients with type 2 diabetes mellitus (T2DM) and recent heart failure (HF) admission.

Study Design

Eligible patients were randomized in a 1:1 fashion to either sotagliflozin 400 mg daily (n = 608) or placebo (n = 614). Sotagliflozin was started at 200 mg daily and increased to target dose if there were no unacceptable side effects. The drug was initiated either prior to or within 3 days of discharge.

  • Total screened: 1,549
  • Total number of enrollees: 1,222
  • Duration of follow-up: median 9 months
  • Mean patient age: 69 years
  • Percentage female: 34%

Inclusion criteria:

  • Admission with HF
  • Treatment with diuretics
  • Stabilized, off oxygen, transitioned to oral diuretics
  • B-type natriuretic peptide (BNP) ≥150 pg/ml (≥450 pg/ml if atrial fibrillation) or N-terminal pro–BNP ≥600 pg/ml (≥1800 pg/ml if atrial fibrillation)
  • T2DM

Exclusion criteria:

  • End-stage HF
  • Recent acute coronary syndrome, stroke, percutaneous coronary intervention, or coronary artery bypass grafting
  • Estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2

Other salient features:

  • Left ventricular ejection fraction (LVEF): 35%; <50%: 79%
  • Median eGFR: 50 ml/min/1.73 m2
  • Median glycated hemoglobin (HbA1c): 7.2%
  • Use of any renin-angiotensin-aldosterone system inhibitor: 92%
  • Metformin: 52%

Principal Findings:

The trial stopped early due to loss of funding due to COVID-19. The primary endpoint of total CV death, HF hospitalization, or urgent visit for HF for sotagliflozin vs. placebo, was 70 vs. 98 events/100 patient-years (hazard ratio 0.67, 95% confidence interval 0.52-0.85, p = 0.0009). This achieved significance by 28 days of follow-up.

Secondary outcomes for sotagliflozin vs. placebo:

  • Total CV death and hospitalization for HF (HHF): 60 vs. 86 events/100 patient-years (p = 0.003)
  • First CV death and HHF: 33% vs. 48% (p = 0.003)
  • CV death: 10.6 vs. 12.5 events/100 patient-years (p = 0.36)
  • Change in Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 score: 17.7 vs. 13.6 (p = 0.005)
  • Change in eGFR: -0.34 vs. -0.18 (p = 0.78)

Safety for sotagliflozin vs. placebo:

  • Diarrhea: 6.9% vs. 4.1% (p = 0.032)
  • Genital fungal infections: 0.8% vs. 0.2% (p = 0.12)
  • Severe hypoglycemia: 1.5% vs. 0.3% (p = 0.037)

Interpretation:

The results of this trial indicate that sotagliflozin has salutary effects on CV outcomes among patients with T2DM and HF. Earlier termination may have affected the ability to see reductions in individual components of the primary outcome.

Sotagliflozin is a sodium-glucose cotransporter-2 (SGLT2) inhibitor, but also inhibits SGLT1, which primarily exists in the gut and appears to delay glucose absorption. The results of this trial are similar to those noted with dapagliflozin in the DAPA-HF trial and with empagliflozin in the EMPEROR-Reduced trial, although these two trials included patients with HF with reduced EF, irrespective of T2DM status. As a class, these agents will likely play a prominent role among patients with chronic kidney disease and HF, and possibly even in the absence of T2DM.

SOLOIST-WHF is the first large randomized controlled trial to show that initiation of SGLT2 inhibition in acute HF in stabilized patients prior to discharge or shortly thereafter is safe and effective. The benefits were consistent in those with HF with reduced but also preserved EF.

References:

Bhatt DL, Szarek M, Steg PG, et al., on behalf of the SOLOIST-WHF Trial Investigators. Sotagliflozin in Patients With Diabetes and Recent Worsening Heart Failure. N Engl J Med 2020;Nov 16:[Epub ahead of print].

Presented by Dr. Deepak Bhatt at the American Heart Association Virtual Scientific Sessions, November 16, 2020.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Vascular Medicine

Keywords: AHA20, AHA Annual Scientific Sessions, Atrial Fibrillation, Diabetes Mellitus, Type 2, Diuretics, Heart Failure, Metabolic Syndrome X, Natriuretic Peptide, Brain, Patient Discharge, Secondary Prevention, Sodium-Glucose Transporter 2, Stroke Volume


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