Reviwer : Dr. Süleyman Çağan Efe

Name of the Study : Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk – SCORED

Published in Congress : ACC 2021

Link : https://www.nejm.org/doi/full/10.1056/NEJMoa2030186

Background :

It is known that SGLT2 inhibitors have positive contributions on cardiovascular events independent of diabetes mellitus in patients with heart failure . The effects of SGLT2 inhibitors on patients with chronic kidney disease have been shown in the previous DAPA-CKD study to reduce renal events even in the absence of T2DM.

Objective :

This study evaluated the safety and efficacy of sotagliflozin in reducing cardiovascular (CV) events in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD).

Method :

Patients with T2DM, estimated glomerular filtration rate (eGFR) between 25-60 ml/min/1.73 m2, and CV risk factors (at least 1 major if age >18, at least 2 minor if age ≥55) were included in the study. Patients were randomized 1:1 to receive sotagliflozin 400 mg daily (n = 5,292) or placebo (n = 5,292). Sotagliflozin was started at 200 mg daily and was increased to the target dose if there were no side effects. Total follow-up time was 24 months, mean patient age was 69 years, and the percentage of female patients was 45%. RAAS inhibitor usage rate of the patients was determined as 88% and metformin usage rate as 55%.

Results :

Although the study was terminated prematurely due to COVID-19 . The primary endpoint was CV death, heart failure hospitalization, and emergency heart failure hospital admission for sotagliflozin versus placebo: 11.3% vs 14.4% (hazard ratio [HR] 0.74, 95% [CI] 0.63-0.88, p = 0.0004)). These results reached significance at 95 days of follow-up. The original endpoint of first occurrence of major adverse CV events (CV death, myocardial infarction, stroke) for sotagliflozin versus placebo was 8.4% versus 8.9% (HR 0.84, 95% CI 0.72-0.99, p = 0.035). First CV death or hospitalization for heart failure was determined as 8.3% vs. 9.5% (HR 0.77, 95% CI 0.66-0.91, p = 0.001).
Looking at secondary outcomes for sotagliflozin versus placebo CV death was 2.2% vs 2.4% (p = 0.35) and 50% reduction in eGFR, chronic dialysis, kidney transplant, or sustained reduction in eGFR: <15 :  was 0.5% vs. 0.7% (p = 0.11), no difference was found between the two groups. Considering the side effects , diarrhea , volume depletion and genital infections were observed at a significantly higher rate in the sotagliflozin group .

Conclusion :

The SCORED study demonstrated that sotagliflozin has beneficial effects on CV outcomes in patients with T2DM and CKD. The benefit was primarily in the reduction of HF events, but there was also a reduction in CV death/MI/stroke mainly due to a reduction in MI and stroke.

Interpretations :

It is known that some of the studies conducted with CKD patients did not show  benefit in terms of cardiovascular outcomes. As a class, these agents will likely play an important role in patients with chronic kidney disease and heart failure, and possibly even in the absence of T2DM.

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

For sotagliflozin versus placebo, the total CV death, heart failure hospitalization, HF emergency visit was 15.5/100 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 heart failure hospitalizations and emergency HF visits were similarly reduced in subgroupings with sotagliflozin as well as in the pooled analysis. In the pooled data intention-to-treat analysis, CV death was not reduced, but in the in-treatment analysis a reduction was noted (HR 0.77, 95% CI 0.60-0.98).

Total hospitalizations: ≥1 hospitalizations for sotagliflozin versus placebo: 38.5% versus 41.4% (p = 0.3); >1 hospitalization was  16.3% vs. 22.1% (p = 0.009). Mean number of days lived and spent out of hospital was 280 vs 267 (odds ratio 1.03, 95% CI 1.00-1.06; p = 0.027).

Conclusion :

In the pooled analysis of SCORED and SOLOIST-WHF data, benefits were preserved regardless of baseline EF (including HF patients with preserved EF) and prior history of HF. A benefit was also noted in patients with T2DM and HFpEF in the combined analysis of SOLOIST and SCORED. It is the first agent in the HFpEF group to demonstrate this benefit.

Interpretations :

When the pooled data of the SCORED and SOLOIST-WHF studies are examined, it is important that the positive effects of the active ingredient sotagliflozin have been demonstrated, especially in the HFpEF patient group that does not have a clinically proven agent for treatment .