SOLOIST-WHF: Sotagliflozin in patients with diabetes and recent worsening heart failure

Among patients with type 2 diabetes who were within 3 days of discharge from an acute HF admission (any ejection fraction), sotagliflozin (combined SGLT1+SLGTI2 inhibitor) reduced the risk of a composite of CV death, HF hospitalization or urgent visit for HF requiring IV diuretics vs placebo (NNT 7) at 9 months.
These results are consistent with & extend those of the DAPA-HF and EMPEROR-Reduced trials in patients with HFrEF +/- diabetes, as well as CANVAS, DECLARE and EMPA-REG in patients with type 2 diabetes +/- HF.
Sotagliflozin increased the risk of diarrhea (by 3%) and severe hypoglycemia (by 1%), which may be unique to this agent due to its effect on SGLT1.

From June 2019-March 2020, 1549 screened -> 1222 randomized
Included
- Acute HF (before discharge or within 3 after discharge)
  - Hospitalization or urgent visit to emergency department, HF unit, or infusion center for worsening HF
  - Treated with IV loop diuretics during hospitalization/urgent visit
  - BNP 150+ pg/mL (450+ if AF) or NT-proBNP 600+ (1800+ if AF)
  - HF diagnosis for 3+ months
  - Prior chronic treatment with loop diuretic 30+ days
- Clinically stable (no need for supplemental O2, SBP 100+ mm Hg, no IV inotropes/vasodilators, transitioned from IV to PO diuretics)
- Type 2 diabetes (existing diagnosis prior to HF admission or lab diagnosis during admission)
- No ejection fraction restriction
Key exclusion criteria:
- Age <18 or >85
- Acute HF triggered by PE, CVA or MI, or not caused primarily by volume overload (e.g. infection, arrhythmia, severe anemia)
- Specific HF etiologies (HOCM, peripartium cardiomyopathy, uncorrected primary valvular disease, uncorrected thyroid disorder)
- eGFR <30
Baseline (average/proportions)
- 70 y/o, female 34%
- White 93%, Black 4%, Asian 1%
- North America ~7%
- HF characteristics
  - Median KCCQ-12 35/100
  - Median LVEF 35% (LVEF<50% in 79%)
  - Median NT-proBNP ~1800
- Clinical variables: SBP 122, eGFR 50, HbA1c 7.1%
- Therapies
  - ACEI 42%, ARB 40%, ARNI 15%
  - Beta-blocker 92%
  - MRA ~65%
  - Antihyperglycemics: Metformin 53%, sulfonylurea (19%,, DPP4i 16%, GLP1RA 3%, insulin 36%

Intervention: Sotagliflozin
- Starting dose: 200 mg once daily (median time from discharge to first dose: 2 days)
- Uptitrated to 400 mg once daily as tolerated after 2 weeks
Control: Matching placebo

CV outcomes @ median 9 months

Death from any cause: Sotagliflozin 13.5% vs placebo 16.3% (HR 0.82, 0.59-1.14)
Composite of time to first CV death or HF hospitalization:
- Sotagliflozin 33% vs placebo 48% (15% absolute reduction, number needed to treat [NNT]=7
- Hazard ratio (HR) 0.71 (95% confidence interval 0.56-0.89)
Primary outcome (total number of CV death, HF hospitalization, or urgent visit for HF resulting in IV therapy): 51.0 vs 76.3 /100 patient-years (difference 25.3 events/100 patient-years)
- Consistent across subgroups, including by LVEF (LVEF <50%: HR 0.72 [95% CI 0.56-0.94] & LVEF >=50%: HR 0.48 [95% CI 0.27-0.86]

Quality of life (QoL) @ month 4

Measured using short-form Kansas City Cardiomyopathy Questionnaire [KCCQ-12], range from 0 [worst] to 100 [best], Minimal clinically-important difference is a 5-point improvement/worsening)
Mean difference between groups: +4.1 points (/100) in favor of sotagliflozin

Safety @ median 18 months (none statistically significant vs placebo)

Significant increases in:
- Diarrhea: 6.1% vs 3.4%
- Severe hypoglycemia: 1.5% vs 0.3%
No significant differences in:
- Serious adverse events leading to study drug discontinuation: 3.0% vs 2.8%
- Discontinuation study drug: 13.0% vs 15.3%
- Hypotension: 6.0% vs 4.6%
- Acute kidney injury: 4.1% vs 4.4%
- UTI: 4.8% vs 5.1%
- Hyperkalemia: 4.3% vs 5.1%
- Diabetic ketoacidosis: 0.3% vs 0.7%