En ny studie publicerades igår i New England Journal Medicine. Det är en randomiserad klinisk prövning som visar att sotagliflozin, Zybquista®, ett läkemedel av typen SGLT2-hämmare,
• minskar sjuklighet och dödlighet hos patienter med typ 2-diabetes och nyligen förvärrad hjärtsvikt.
• det unika med studien är att behandlingen inleds redan på sjukhus
• att den är effektiv för patienter med hjärtsvikt med både sänkt och bevarad pumpförmåga.
Båda dessa grupper: patienter på sjukhus och patienter med bevarad pumpförmåga är grupper där det tidigare inte fanns någon bevisat effektiv behandling.
Läkemedelsbehandlingen resulterade i signifikant lägre antal dödsfall på grund av hjärt-kärlhändelser samt färre sjukhusinläggningar och brådskande sjukhusbesök för hjärtsvikt jämfört med placebo.
Lars Lund, professor, överläkare, Institutionen för medicin, Solna, Karolinska Institutet, Stockholm är en av medförfattarrna till studien.
Ett observandum, som anges i artikeln, är "severe hypoglycemia was more common in the sotagliflozin group."
Publikation: “Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure” N Engl J Med
Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure
- Deepak L. Bhatt, M.D., M.P.H.,
- Michael Szarek, Ph.D.,
- P. Gabriel Steg, M.D.,
- Christopher P. Cannon, M.D.,
- Lawrence A. Leiter, M.D.,
- Darren K. McGuire, M.D., M.H.Sc.,
- Julia B. Lewis, M.D.,
- Matthew C. Riddle, M.D.,
- Adriaan A. Voors, M.D., Ph.D.,
- Marco Metra, M.D.,
- Lars H. Lund, M.D., Ph.D., prof Karolinska, Instit för medicin,
- Michel Komajda, M.D.,
- et al
- for the SOLOIST-WHF Trial Investigators*
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.
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.
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.
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
From the article
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
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.
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
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