Sotagliflozin, the cardiovascular and renal benefits

PART 1: The SOLOIST-WHF and SCORED Studies in a nutshell

with Deepak L. Bhatt MD, MPH

Red structural heart against the sky with a few cloudsImage by Jean-Louis Paulin

Two recent clinical studies, SCORE and SOLOIST-WHF, explored the renal and cardiovascular benefit of sotagliflozin in participants with type 2 diabetes. Both studies were co-authored by Deepak L. Bhatt MD, MPH (Brigham and Women’s Hospital, Boston, MA) and chair of the SOLOIST-WHF executive committee.

Sotagliflozin is a dual SGLT2/1 inhibitor with a 20-fold greater affinity for SGLT2 than SGLT1. By comparison, other SGLT inhibitors considered to be specific for type 2 transporters (SGLT2) have 250-fold (canagliflozin) and 2500-fold (empagliflozin) greater affinity for SGLT2. This low but significant attraction to SGLT1 by sotagliflozin could be the key behind much of the reported renal and cardiovascular benefits. The research was presented at the 81st Scientific Sessions of the American Diabetes Association.

Sodium Glucose Co-Transporters (SGLT)

SGLT2 transporters are dominant in the kidneys, where they reabsorb 90% of filtered sodium and glucose as the filtrate passes through the proximal convoluted tubules of the nephron. Inhibiting SGLT2 transport occurs independent of insulin but requires functioning kidneys.

SGLT1 transporters, on the other hand, can be found in the GI tract, heart and brain, with only a small presence in the proximal straight tubules of the nephrons, reabsorbing only a fraction (3-10%) of sodium and glucose. In the GI tract, it is the primary transporter for glucose and galactose absorption. Inhibition of SGLT1 action is independent of both insulin and kidney function.

SOLOIST-WHF

The SOLOIST research team sought to address the vulnerable period for worsening heart failure (WHF) surrounding the hospital discharge period in patients with type 2 diabetes.

Study design
Patients with acute decompensated heart failure (HF) were recruited either in-hospital or within 3 days post-discharge. They were randomized to either 200 mg sotagliflozin (n=588 completed) or placebo (n=591 completed). Baseline characteristics were similar between groups with approximately 33.8% females and an age range of 63-76. Most patients were recruited from Europe (~65%).

Inclusion criteria

  • Type 2 diabetes  
  • Hospital admission with signs and symptoms of heart failure
  • Treatment with intravenous diuretics but transitioning to oral
  • Stabilized, off oxygen  
  • BNP>=150 pg/mL or NT-pro-BNP >= 600 pg/mL  
  • in patients with atrial fibrillation, BNP >= 450 or NT-proBNP >= 1800

Exclusion criteria

  • End stage heart failure
  • Recent acute coronary syndrome (ACS), stroke, angioplasty with stent, or a coronary artery bypass graft (CABG)

Chart detailing baseline characteristics in the SOLOIST study

SCORED

Unique to the SCORED study, as compared to other SGLT2 studies investigating renal benefits, is that they recruited patients with a wider range of chronic kidney disease (CKD), they tended to be older, and women were well represented. Furthermore, study authors did not limit the sample by presence or absence of albuminuria.

Study Design
This was a randomized (1:1), double blind, placebo controlled clinical study. Participants (N=10,584) with level 3-4 CKD were given either 200mg sotagliflozin (n=5232 completed) or placebo (n=5210 completed). Baseline characteristics were similar between groups with approximately 45% females and an age range of 63-74. Most patients were recruited out of Europe and the Americas (~ 44% each).

Inclusion criteria

  • Type 2 diabetes with A1C >=7%
  • eGFR >=25 and <=60 mL/min/1.73m2 (no requirement for macro-/micro-albumineria)
  • cardiovascular risk factors

Exclusion criteria

  • Planned start of SGLT2 inhibitors

Chart detailing baseline characteristics in the SCORED study

 

Primary Endpoints: Total Heart Failure Events (SCORED-WHF and SOLOIST)

Primary endpoints in both studies were revised and foreshortened due to both the COVID-19 pandemic and a switch to alternative funding sources. The primary endpoints reported at the ADA2021 meeting for both studies were Total HF Events defined as the number of cardiovascular (CV) deaths, hospitalizations for HF, or urgent HF visits.

SOLOIST-WHF Study

After 18 months, patients on sotagliflozin were less likely to experience a HF event (urgent visit, hospitalization, or death) compared to those on placebo (hazard ratio (HR): 0.67 (0.52-0.85 95% CI). This effect on Total HF Events emerged early in the study, whereby day 28 the HR was 0.61 (p=0.035).

The effect of sotagliflozin on Total HF Events appears to be most significant when looking at non-fatal events, such as hospitalizations or urgent visits (HR: 0.64 (0.49-0.83 95% CI). The reductions in CV death (HR: 0.84 (0.58-1.22 95% CI) and all-cause death (HR: 0.82 (0.59-1.14 95% CI) were not significantly reduced (p= 0.36 and 0.23 respectively).

Sotagliflozin treatment appeared beneficial regardless of whether dosing occurred before or after discharge and showed benefit in patients with LVEF values both greater and less than 50%.  

SCORED Study

            Similarly, the SCORED study found a reduction in Total HF events in their sotagliflozin treated participants with CKD. At 24 months the HR for Total HF events was 0.74 (0.63-0.88 95%CI). The significant reduction emerged within 95 days of treatment (HR= 0.70, p=0.038). Again, the risk was reduced more in the emergence of non-fatal HF events (HR: 0.67 (0.55-0.82 95%CI)) than in cardiovascular death (HR: 0.90 (0.73-1.12 95%CI, p=0.35) or in all-cause death (HR: 0.99 (0.83-1.18 95%CI), p= 0.93)

            In subgroup analyses, sotagliflozin treatment benefited all participants regardless of eGFR rates, however there appeared to be a more consistent effect in those with more severe CKD (eGFR 30 to <45 mL/min/1.73m2) (HR: 0.74 (0.6-0.93 95%CI). Those with a urine ACR >=30 mg/g also experience greater risk reduction benefit from sotagliflozin (HR: 0.67 (0.55-0.80 95%CI).

Adverse Events

Among patients with type 2 diabetes hospitalized for heart failure (SOLOIST-WHF), adverse events were evenly distributed between sotagliflozin and placebo treated groups, with the exception of diarrhea and severe hypoglycemia which affected more sotagliflozin-treated patients. Seven patients in the placebo group experienced venous thrombotic events, while no one in the sotagliflozin treated group was affected.

            In patients with type 2 diabetes and CKD (SCORED), diarrhea and volume depletion were more frequent in the sotagliflozin treated groups (8.5% and 5.3% respectively) compared to placebo (6.0% and 4.0%).  There was also a slight increase in genital mycotic infections (2.4%) and diabetic ketoacidosis (0.6%) in those treated with the SGLT-2/1 inhibitor. Pancreatitis, severe hypoglycemia, and urinary tract infections were evenly distributed across both groups.

Conclusion

During the critical period surrounding discharge after an acute HF event in patients with type 2 diabetes, early treatment with sotagliflozin reduced the risk of total HF events by up to 33%. In people with type 2 diabetes and CKD, sotagliflozin significantly reduced the total HF events by 26%.

The reduced risk in both groups emerged within 1-3 months after treatment initiation. Sotagliflozin was generally well tolerated and determined to be safe for use in both groups.                 

 

Disclosures

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

Continue Reading:
Sotagliflozin, the cardiovascular and renal benefits: Chapter 2
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