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05-18-2022 | Empagliflozin | News

Pros and cons with empagliflozin addition to closed-loop insulin

Author: Eleanor McDermid


medwireNews: Adding daily empagliflozin to closed-loop insulin delivery improves time in range (TIR) but also increases ketone levels in people with type 1 diabetes, shows a randomized trial.

The study participants were assigned to take either empagliflozin 25 mg/day or placebo, and at the same time to undertake 4 weeks of closed-loop insulin delivery and 4 weeks of sensor-augmented pump (SAP) delivery in a randomly assigned order.

Among the 24 people who completed the study, the highest average TIR, of 75.5%, occurred during the closed-loop period in those taking empagliflozin. This was a significant 7.2 percentage point increase on the 68.2% achieved during the closed-loop phase by people taking placebo, and amounted to an additional 1.7 hours/day within the target range (3.9–10 mmol/L, 70–180 mg/dL).

“As per international consensus guidelines, an increase of more than 5% is considered clinically meaningful,” write Bruce Perkins (Mount Sinai Hospital, Toronto, Ontario, Canada) and study co-authors in Nature Medicine.

People taking empagliflozin also had significantly higher TIR than those taking placebo during SAP use, at 69.3% versus 57.9%. This 11.4 percentage point difference equated to an additional 2.7 hours/day within the target range.

Noting the greater TIR benefit of empagliflozin when paired with SAP rather than closed-loop delivery, the researchers observe that “both empagliflozin and closed-loop therapy work in a continuous glucose-responsive manner that might have led to a partial overlap in their action.”

They stress that the combination of empagliflozin and closed-loop insulin resulted in a 17.5% average increase in TIR (4.2 hours/day) when compared with placebo and SAP.

Ketone levels were significantly higher in people taking empagliflozin than those taking placebo, regardless of the means of insulin delivery, but the highest levels, averaging 0.27 mmol/L, occurred with the combination of empagliflozin plus closed-loop delivery. Twenty percent of participants experienced ketosis (>1.5 mmol/L) with this combination, compared with 5% for the other three combinations.

Two people withdrew because of symptomatic ketosis, both during closed-loop delivery; one was taking empagliflozin and the other placebo, and their ketone levels were 3.7 and 1.8 mmol/L, respectively.

No participant experienced ketoacidosis, which the researchers attribute to “daily ketone monitoring, the mitigation and education strategies put into place in the trial, the relatively small sample size and the short duration of the interventions.”

Nevertheless, they stress that the increased ketone levels observed with empagliflozin plus closed-loop therapy underline the need for preventive efforts, “including enhanced patient education, minimization of insulin reductions, clinical follow-up and ketone monitoring.”

Perkins and team say that future improvements in closed-loop systems may mean that adding a sodium-glucose cotransporter 2 inhibitor no longer gives added glycemic benefits, but note that it could remain worthwhile in some people for the medication class’s positive effects on cardiovascular and renal risk.

The study participants were aged between 19 and 66 years (average 38 years), 56% were women, and their average glycated hemoglobin level was 7.7% (61 mmol/mol), with a range of 6.0–9.4% (42–79 mmol/mol). During the SAP period participants used a Dexcom G5 or G6 with their own insulin pump and during the closed-loop period they used the iPancreas system, based on the McGill dosing algorithm.

However, the researchers believe their findings “likely generalize to other available and commercialized closed-loop systems.”

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group

Nat Med 2022; doi:10.1038/s41591-022-01805-3


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