Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk - SCORED

Contribution To Literature:

The SCORED trial showed that sotagliflozin has salutary effects on CV outcomes among patients with T2DM and CKD.

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 chronic kidney disease (CKD).

Study Design

Eligible patients were randomized in a 1:1 fashion to either sotagliflozin 400 mg daily (n = 5,292) or placebo (n = 5,292). Sotagliflozin was started at 200 mg daily and increased to target dose if there were no unacceptable side effects.

  • Total screened: 19,188
  • Total number of enrollees: 10,584
  • Duration of follow-up: 24 months
  • Mean patient age: 69 years
  • Percentage female: 45%

Inclusion criteria:

  • T2DM
  • Estimated glomerular filtration rate (eGFR) between 25-60 ml/min/1.73 m2
  • CV risk factors (at least 1 major if age >18 years, at least 2 minor if age ≥55 years)

Exclusion criteria:

  • Planned use of sodium-glucose cotransporter-2 (SGLT2) inhibitor

Other salient features:

  • Left ventricular ejection fraction (LVEF): 60%
  • History of heart failure (HF): 31%
  • Median eGFR: 44.4 ml/min/1.73 m2
  • Median glycated hemoglobin (HbA1c): 8.3%
  • Blood pressure: 139/78 mm Hg
  • Urinary albumin-to-creatinine ratio: 75 mg/g
  • Use of any renin-angiotensin-aldosterone system inhibitor: 88%
  • Metformin: 55%

Principal Findings:

The trial stopped early due to loss of funding due to COVID-19. The primary endpoint had to be changed to CV death, HF hospitalization, urgent visit for HF for sotagliflozin vs. placebo: 11.3% vs. 14.4% (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.63-0.88, p = 0.0004). This achieved significance by 95 days of follow-up.

The original coprimary endpoint of first occurrence of major adverse CV events (CV death, myocardial infarction [MI], stroke) for sotagliflozin vs. placebo was 8.4% vs. 8.9% (HR 0.84, 95% CI 0.72-0.99, p = 0.035).

  • First occurrence of CV death or HF hospitalization: 8.3% vs. 9.5% (HR 0.77, 95% CI 0.66-0.91, p = 0.001)

Secondary outcomes for sotagliflozin vs. placebo:

  • CV death: 2.2% vs. 2.4% (p = 0.35)
  • First sustained ≥50% decrease in eGFR, chronic dialysis, renal transplant, or sustained eGFR <15: 0.5% vs. 0.7% (p = 0.11)

Safety:

  • Diarrhea: 8.5% vs. 6.0% (p < 0.0001)
  • Volume depletion: 5.3% vs. 4.0% (p = 0.003)
  • Genital fungal infections: 2.4% vs. 0.9% (p < 0.0001)

Interpretation:

The results of this trial indicate that sotagliflozin has salutary effects on CV outcomes among patients with T2DM and CKD. The benefit was primarily in reduction of HF events, but there was also a reduction in CV death/MI/stroke, primarily due to reduction in MI and stroke. A reduction in renal events was not observed, likely due to early cessation of the trial due to loss of funding.

Sotagliflozin is an 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 canagliflozin in the CREDENCE trial and with empagliflozin in the EMPA-REG OUTCOME trial. In addition, in the DAPA-CKD trial, dapagliflozin reduced renal events even in the absence of T2DM. As a class, these agents will likely play a prominent role among patients with CKD and HF, and possibly even in the absence of T2DM.

References:

Bhatt DL, Szarek M, Pitt B, et al., on behalf of the SCORED Investigators. Sotagliflozin in Patients With Diabetes and Chronic Kidney Disease. 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: Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Lipid Metabolism, Acute Heart Failure

Keywords: AHA20, AHA Annual Scientific Sessions, Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Heart Failure, Kidney Diseases, Kidney Transplantation, Metabolic Syndrome X, Myocardial Infarction, Renal Dialysis, Renal Insufficiency, Chronic, Risk Factors, Secondary Prevention, Sodium-Glucose Transporter 2, Stroke Volume


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