Sotagliflozin, the cardiovascular and renal benefits: Chapter 2

Part 2: Cardiovascular and renal benefits in detail

with Deepak Bhatt MD, MPH, Julie B. Lewis MD, Massimo Volpe MD, Piero Baglioni MD, Lucien Marchand MD

Red padlock with engraved hearts locked onto a bridge

Two recent clinical studies, SCORE and SOLOIST-WHF, explored the renal and cardiovascular benefit of sotagliflozin in participants with type 2 diabetes. Sotagliflozin is a dual SGLT2/1 inhibitor with a 20-fold greater affinity for SGLT2 than SGLT1.

Pooling the data

Pooled data provides more power to see trends that support population-based conclusions. These trends were presented by the session chair, Deepak Bhatt MD, MPH (Brigham and Women’s Hospital, Boston, MA) and Julie B. Lewis MD (Division of Nephrology and Hypertension, Vanderbilt University Medical Center). The pooled data contained 11,784 participants overall and 4,500 patients with a history of heart failure (HF).  

Separating pooled data into intent-to-treat (all randomized subjects included) and on-treatment (only randomized subjects that adhered to treatment protocol) found significant trends on the effects on sotagliflozin and the risk of cardiovascular (CV) death. In those study participants who met the criteria for on-treatment, the risk of CV death was significantly reduced (hazard ratio (HR): 0.77 (0.60-0.98 95%CI)). The risk dropped further for those with a history of HF and who met on-treatment standards, HR: 0.73 (0.55-0.98 95%CI), supporting the notion that medications should be taken as instructed.

Cardiovascular benefits in patients with worsening heart failure

Ejection Fractions (EF)

Pooled data grouped by EF levels: reduced (<40% LVEF), mid-range (40-50%), and preserved EF (>=50%), revealed that all EF levels had a significant risk reduction in total HF events, ranging from 22% in reduced rates, 39% in mid-range, and 30% in preserved EF levels.  

This reduction was only slightly better when only those with a history of HF were included, with a reduction of 22% in the reduced rates, 43% in the mid-range, and 33% in the preserved. It is interesting to note that those with at least some reduction in EF had the greatest benefit.

Sex differences

One of the benefits of pooled data is the ability to evaluate differences between subpopulations, such as sex. With the larger sample size, participants were divided by sex and EF levels. Overall, each EF level had a reduced risk of total HF events, however this overall benefit appeared to be carried by the male participants. The trend indicated that those men with a mid-range EF had the greatest benefit regardless of their history of HF (HR: 0.59 (0.40-0.87 95% CI).

In women with a reduced or mid-range EF (<50%), the reported HR values were below 1 (HR: 0.94 and 0.64 respectively), but the 95% confidence intervals (CI) straddled the critical 1.0 ratio suggesting a high level of variability in these groups of women. Only in women with a preserved EF was there a reliable reduced total HF event risk (HR: 0.71 (0.54-0.92 95%CI). Presenting author Dr. Bhatt noted that women with heart failure and preserved EF who were treated with sotagliflozin had an even greater reduced risk of total HF events (HR:0.67 (0.51-0.89 95% CI).

Benefits in patients with diabetes and chronic kidney disease

For the SCORED study, Dr. Lewis presented the ad-hoc analyses of sotagliflozin as a function of estimated glomerular filtration rate (eGFR) levels. Initially, participants were grouped based on eGFR levels: 3a, 3b, and 4. With decreasing GFR levels, the reduced risk of total HF events increases; HR for level 3a was 0.76 (0.58-0.99 95% CI) and for level 3b, 0.74 (0.60-0.93 95% CI). In those with severe chronic kidney disease (CKD) (level 4), the HR was the lowest— 0.68, but there was an increased degree of uncertainty with a 95% CI range of 0.42 to 1.11. 

Renal effects of sotagliflozin emerged within 4 weeks. The mean change in eGFR in participants receiving sotagliflozin was nearly zero, indicating a preservation of renal function. The placebo treated group had a mean decrease of up to 1.5 mL/min/1.73m2. As a whole, the CKD group treated with sotagliflozin experienced a significant 0.5 percentage point decrease in HbA1C levels. 

The COVID pandemic takes an unlikely victim?

Firstly, these studies suggest that sotagliflozin is beneficial in people with type 2 diabetes who have renal or cardiovascular comorbidities at reducing their risk of a heart failure event. Significant cardiovascular benefit appeared early in both groups— by day 28 in the HF patients (SOLOIST) and by day 95 in CKD patients (SCORED). Effects of sotagliflozin appear to decrease emergence of HF events requiring hospitalization or emergency treatment in both groups. The risk of HF death was lower but failed to reach a significant level.

The broad range of sample populations— people with type 2 diabetes, worsening heart failure and varying levels of EF as well as those with CKD and different levels of eGFR— on which sotagliflozin had an effect— speaks highly of its prospects. However, comments from other researchers independent of the SCORED and SOLOIST studies suggest caution. The changes forced on the SOLOIST and SCORED research teams because of the COVID pandemic’s effect on their funding reduced the original power of the study. 

Comments published in the European Heart Journal by Massimo Volpe MD et al. suggest that they would be hesitant to draw firm conclusions due to the early termination of both studies. This foreshortening of the studies resulted in smaller-than-needed sample sizes for a robust study. As an example, Volpe et al. point to the small sample of HF patients with left ventricular ejection fractions (LVEF) < 50%. However, the commenters indicate that the SCORED and SOLOIST studies do give evidence that supports the early use of sotagliflozin in patients with type 2 diabetes, especially in those with a high cardiovascular risk.  

Comments by Piero Baglioni MD (Prince Charles Hospital, Merthyr Tydfil, UK) in the New England Journal of Medicine, also suggest caution. Dr. Baglioni questions the clinical benefit for people with diabetes when there is no clear risk reduction for death but certainly an additional monetary and time burden of adding yet another treatment. 

However, in the same commentary, Lucien Marchand MD (Centre Hospitalier Saint Joseph Saint Luc Lyon, France) and colleagues approach the use of sotagliflozin with more optimism. They anticipate that this dual SGLT2 inhibitor will be adopted for use by nephrologists and cardiologists, especially when working collaboratively with diabetologists. They see sotagliflozin almost like a bridge to enhance patient care through teamwork. 

Conclusion

The take-home message about sotagliflozin may not have been the one the medical community was hoping for, but it is still a good message. SOLOIST and SCORED research teams adapted to changing conditions and used the available data to draw broad-based conclusions about the efficacy of sotagliflozin in people with type 2 diabetes and coexisting renal and cardiovascular disease.   

 

Disclosures

SCORED and SOLOIST-WHF trial investigators were supported initially by Sanofi and shortly by Lexicon Pharmaceuticals.

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