The SCORED and SOLOIST-WHF trials of the dual sodium–glucose cotransporter 1/2 (SGLT1/2) inhibitor sotagliflozin were both presented at the virtual American Heart Association Scientific Sessions and published simultaneously in the New England Journal of Medicine in November 2020.
SCORED aimed to assess the efficacy and safety of sotagliflozin in preventing cardiovascular (CV) events in people living with type 2 diabetes and chronic kidney disease (CKD), with or without albuminuria, the latter of which has not been investigated previously. SOLOIST-WHF aimed to assess the safety and efficacy of sotagliflozin initiated soon after an episode of decompensated heart failure (HF) in people living with type 2 diabetes. The benefits, or indeed harms, of using SGLT2 inhibitors upstream for decompensated HF have yet to be elucidated and remain hotly debated.
Unfortunately, both studies were prematurely stopped after Sanofi withdrew funding during the ongoing COVID-19 pandemic. Notably, in March 2019 the US Food and Drug Administration ruled against approving sotagliflozin alongside insulin for the treatment of type 1 diabetes, whereas the drug has been licensed for use in this group in Europe for some time now, although it was never launched in the UK.
This early closure of the trial and the lower than planned number of events led to revised trial protocols and endpoints to compensate for the resultant reduction in power. In SCORED, the primary endpoint was originally a composite of major adverse cardiovascular events (MACE) and first occurrence of CV death or hospitalisation for heart failure. This was changed to the total number of deaths from CV causes, hospitalisations for HF and urgent visits for HF. In SOLOIST-WHF, the primary endpoint was changed from the first occurrence of either CV death or hospitalisation for HF to the total number of deaths from CV causes and hospitalisations and urgent visits for HF (first and subsequent). Notably, due to loss of funding, not all trial clinical events were adjudicated (i.e. independently and blindly reviewed), which does bring into question the reliability of the outcomes data and subsequent interpretation.
Changing protocols during a trial is not unusual; for example, DECLARE-TIMI 58 (the dapagliflozin CV outcomes trial) amended its protocol in response to the compelling results of EMPA-REG OUTCOME to include co-primary endpoints of MACE and CV death or hospitalisation for HF; however, in that trial all clinical events were independently adjudicated.
The SCORED trial demonstrated a lower risk of the composite primary endpoint with sotagliflozin compared to placebo. The relative risk reduction was 26%, but there was no significant difference in CV mortality. Notably, SCORED recruited individuals across the full range of albuminuria (approximately one third had an albumin:creatinine ratio [ACR] <30 mg/mmol, one third 30–300 mg/mmol and one third ≥300 mg/mmol) yet it still demonstrated benefits. However, the revised secondary renal-specific endpoint was not significantly reduced. In terms of harms, diarrhoea, mycotic genital infections (a nearly threefold increased risk), volume depletion and diabetic ketoacidosis (around double the risk) were all more common with sotagliflozin than with placebo. There was no imbalance in lower limb amputations observed. The fact that sotagliflozin is also an inhibitor of SGLT1 may account for the imbalance seen with diarrhoea adverse events, as the SGLT1 protein is found largely in the gut. The SOLOIST-WHF trial demonstrated that sotagliflozin initiated before or within 3 days of hospital discharge resulted in significantly lower numbers of deaths from CV causes and hospitalisations and urgent visits for HF in people living with type 2 diabetes and recent worsening HF. The relative risk reduction was 33% and driven by a reduction in hospitalisation and urgent visits for HF. Benefits were observed early, within 4 weeks of randomisation, which is consistent with other SGLT2 inhibitor HF studies such as DAPA-HF (albeit in stable HF). The results of the EMPULSE trial of empagliflozin should add to this evidence base on the use of SGLT2 inhibitors in acute HF. Notably, benefits were evident both in people with preserved ejection fraction and in those with reduced ejection fraction. This is the first observed benefit of SGLT2 inhibitors in people with type 2 diabetes and HF with preserved ejection fraction (HFpEF), although in view of the small number of participants with HFpEF recruited (n=127 with ejection fraction >50%), as well as the early termination of the trial, this result should be considered as hypothesis-generating only. We await the results of DELIVER (dapagliflozin) and EMPEROR-Preserved (empagliflozin) to assess the benefits of SGLT2 inhibitors in HFpEF more robustly.
SCORED and SOLOIST-WHF were clearly limited by their unexpected loss of funding but, nevertheless, both studies raise some very interesting questions about the benefits of SGLT2 inhibitors in people with type 2 diabetes and CKD without albuminuria and also in the context of decompensated HF.
Click here to read the SCORED analysis in full.
Click here to read the SOLOIST-WHF analysis in full.