Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure

November 16, 2020
DOI: 10.1056/NEJMoa2030183

 

Abstract

BACKGROUND

Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure or death from cardiovascular causes among patients with stable heart failure.

However, the safety and efficacy of SGLT2 inhibitors when initiated soon after an episode of decompensated heart failure are unknown.

METHODS

We performed a multicenter, double-blind trial in which patients with type 2 diabetes mellitus who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin or placebo.

The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). The trial ended early because of loss of funding from the sponsor.

RESULTS

A total of 1222 patients underwent randomization (608 to the sotagliflozin group and 614 to the placebo group) and were followed for a median of 9.0 months; the first dose of sotagliflozin or placebo was administered before discharge in 48.8% and a median of 2 days after discharge in 51.2%. Among these patients, 600 primary end-point events occurred (245 in the sotagliflozin group and 355 in the placebo group).

The rate (the number of events per 100 patient-years) of primary end-point events was lower in the sotagliflozin group than in the placebo group (51.0 vs. 76.3; hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.85; P<0.001).

The rate of death from cardiovascular causes was 10.6 in the sotagliflozin group and 12.5 in the placebo group (hazard ratio, 0.84; 95% CI, 0.58 to 1.22);

the rate of death from any cause was 13.5 in the sotagliflozin group and 16.3 in the placebo group (hazard ratio, 0.82; 95% CI, 0.59 to 1.14).

Diarrhea was more common with sotagliflozin than with placebo (6.1% vs. 3.4%), as was severe hypoglycemia (1.5% vs. 0.3%). The percentage of patients with hypotension was similar in the sotagliflozin group and the placebo group (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively).

The benefits of sotagliflozin were consistent in the prespecified subgroups of patients stratified according to the timing of the first dose.

CONCLUSIONS

In patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure than placebo.

Funded by Sanofi and Lexicon Pharmaceuticals; SOLOIST-WHF ClinicalTrials.gov number, NCT03521934. opens in new tab.

Läs abstract och artikel med free access

https://www.nejm.org/doi/10.1056/NEJMoa2030183

 

From the article

Discussion

 The SOLOIST-WHF trial showed that among

patients with diabetes who had worsening heart

failure, the primary end point of the total number

of cardiovascular deaths and hospitalizations

and urgent visits for heart failure was significantly

lower with the SGLT2 and SGLT1 inhibitor

sotagliflozin than with placebo. This finding was

consistent across multiple prespecified subgroups,

including those stratified according to the timing

of the first dose of sotagliflozin or placebo

(before or after discharge) and left ventricular

ejection fraction (reduced or mid-range [<50%]

or preserved [≥50%]).

 

Accumulating evidence from randomized

clinical trials supports the use of SGLT2 inhibitors

in patients who have stable heart failure

(with or without diabetes) and a reduced ejection

fraction.4-22,35  The current trial showed that initiation

of SGLT2 inhibition before or shortly after

discharge in patients who were hospitalized

for worsening heart failure was also beneficial.

 

Despite the low estimated GFR (median, 49.7 ml

per minute per 1.73 m2 ) and the recent hospitalization

for worsening heart failure in this popu-

 lation, the percentage of patients who had hypotension

was similar in the sotagliflozin group and

the placebo group, although severe hypoglycemia

was more common in the sotagliflozin group.

 

Early initiation of therapy represents an important

opportunity to improve outcomes, as indicated

by the high rate of primary end-point events at

90 days after randomization among the patients

receiving placebo.

 

The SOLOIST-WHF trial had also intended to

evaluate whether the benefits of SGLT2 inhibition

extend to patients with heart failure with

preserved ejection fraction. However, although

such patients were enrolled in the trial and there

was no evidence of heterogeneity of treatment

effect according to ejection fraction, early termination

of the trial and the small sample size of

this subgroup made it difficult to draw any firm

conclusion in this regard. Two additional trials,

 

Dapagliflozin Evaluation to Improve the Lives of

Patients with Preserved Ejection Fraction Heart

Failure (DELIVER; ClinicalTrials.gov number,

NCT03619213) and Empagliflozin Outcome Trial

in Patients with Chronic Heart Failure with Preserved

Ejection Fraction (EMPEROR-Preserved;

NCT03057951), are examining SGLT2 inhibitors

in patients with heart failure with preserved ejection

fraction, with or without diabetes mellitus.

 

 The mechanisms of the benefit of SGLT2

inhibition are still being elucidated. Enhanced

renal glucose excretion is a well-established mechanism

of action, leading to a natriuretic and diuretic

effect. Weight loss, improved myocardial

energetics, decreases in uric acid level, adaptive

cellular reprogramming, and salutary effects on

endothelial progenitor cells have been described.

36-41  Reductions in blood pressure and in

left ventricular hypertrophy have also been reported.

42-44 

 

It is not clear, however, in the current

trial what, if any, clinical benefits were derived

through the inhibition of SGLT1 with sotagliflozin

therapy, and further direct comparative trials with

a selective SGLT2 inhibitor are needed to evaluate

whether there is any incremental value of

SGLT1 blockade beyond SGLT2 inhibition.

 

Limitations of this trial included loss of funding

from the sponsor that led to the trial being

stopped before enrollment of the initial planned

sample size. Although the trial suggested

that there was a beneficial effect with respect to

the original primary end point of the first occurrence

of either death from cardiovascular causes

or hospitalization for heart failure, the earlier than-

planned closure of the trial limited the statistical

power to assess the secondary end points,

such as death from cardiovascular causes.

 

The initial trial design had called for the adjudication

of events, but because of the loss of funding,

this was not completed, and while the investigators

remained unaware of the trial outcomes,

the primary end point was changed to be based

on investigator-defined events.5

 

 In this trial involving patients with diabetes

and a recent episode of acute decompensated

heart failure, sotagliflozin therapy — whether

initiated before or shortly after hospital discharge

— resulted in a lower total number of

deaths from cardiovascular causes and hospitalizations

and urgent visits for heart failure than

placebo.

 

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