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

Apr 02, 2022
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Presenter/Author:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Kim A. Eagle, MD, MACC
Trial Sponsor:
Sanofi, Lexicon Pharmaceuticals
Date Presented:
04/02/2022
Date Published:
08/23/2021
Date Updated:
04/02/2022
Original Posted Date:
11/16/2020
References

Contribution To Literature:

Highlighted text has been updated as of April 2, 2022.

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)

History of cardiovascular disease (CVD): Total CV death, nonfatal MI, nonfatal stroke for sotagliflozin vs. placebo: 13.4% vs. 15.8% (p = 0.02) for those with CVD; 6.7% vs. 7.6% (p = 0.046) for those without CVD (p for interaction = 0.76). Total MI: 5.4% vs. 6.3% (p = 0.023) for those with CVD; 2.5% vs. 3.0% (p = 0.088) for those without CVD (p for interaction = 0.87). Total stroke: 2.5% vs. 3.9% (p = 0.063) for those with CVD; 1.4% vs. 2.6% (p = 0.08) for those without CVD (p for interaction = 0.76).

Pooled SCORED and SOLOIST-WHF data (n = 11,784):

Total CV death, HF hospitalization, or urgent HF visit for sotagliflozin vs. placebo was 15.5 vs. 21.1/100 patient-years (p = 0.000002).

  • EF <40%: 47.8% vs. 60.4% (p = 0.02)
  • EF 40 to <50%: 45.2% vs. 71.3% (p = 0.02)
  • EF ≥50%: 37.5% vs. 59.0% (p = 0.009)
  • No history of HF, EF ≥50%: 5.2% vs. 6.2% (p = 0.04)

Total HF hospitalization and urgent HF visits were similarly reduced in each trial with sotagliflozin, and also in the pooled analysis. CV death was not reduced in the pooled intention-to-treat analysis, but a reduction was noted in the on-treatment analysis (HR 0.77, 95% CI 0.60-0.98). Benefits were also preserved for men and women. In various analyses accounting for adherence to the study drug and desired target dose, sotagliflozin consistently reduced the primary endpoint, HF hospitalization, myocardial infarction, stroke, kidney endpoints, cardiovascular death, and all-cause mortality. The reductions in HF endpoints with the target dose of sotagliflozin were particularly pronounced.

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, including both MI and stroke. This was noted among patients with and without prior CVD. A reduction in renal events was not observed, likely due to early cessation of the trial due to loss of funding. In the pooled analysis of SCORED and SOLOIST-WHF data, benefits were preserved irrespective of baseline EF (including among patients with HF with preserved EF [HFpEF]) and prior history of HF.

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. In the pooled analysis, a benefit was also noted among patients with T2DM and HFpEF. This is the first agent to show this benefit; trials with other agents such as EMPEROR-Preserved with empagliflozin are ongoing. 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:

Presented by Dr. Deepak L. Bhatt at the American College of Cardiology Annual Scientific Session (ACC 2022), Washington, DC, April 2, 2022.

Presented by Dr. Deepak L. Bhatt at the European Society of Cardiology Virtual Congress, August 23, 2021.

Presented by Dr. Deepak L. Bhatt at the American College of Cardiology Virtual Annual Scientific Session (ACC 2021), May 17, 2021.

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 2021;384:129-39.

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: ACC22, ACC Annual Scientific Session, AHA20, AHA Annual Scientific Sessions, ESC Congress, ESC21, Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Heart Failure, Kidney Diseases, Kidney Transplantation, Metabolic Syndrome, Myocardial Infarction, Renal Dialysis, Renal Insufficiency, Chronic, Risk Factors, Secondary Prevention, Sodium-Glucose Transporter 2, Stroke, Stroke Volume


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