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Empagliflozin add-on therapy to closed-loop insulin delivery in type 1 diabetes: a 2 × 2 factorial randomized crossover trial

Nature Medicine volume 28, pages 1269–1276 (2022)Cite this article

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Abstract

There is a need to optimize closed-loop automated insulin delivery in type 1 diabetes. We assessed the glycemic efficacy and safety of empagliflozin 25 mg d−1 as add-on therapy to insulin delivery with a closed-loop system. We performed a 2 × 2 factorial randomized, placebo-controlled, crossover two-center trial in adults, assessing 4 weeks of closed-loop delivery versus sensor-augmented pump (SAP) therapy and empagliflozin versus placebo. The primary outcome was time spent in the glucose target range (3.9–10.0 mmol l−1). Primary comparisons were empagliflozin versus placebo in each of closed-loop or SAP therapy; the remaining comparisons were conditional on its significance. Twenty-four of 27 randomized participants were included in the final analysis. Compared to placebo, empagliflozin improved time in target range with closed-loop therapy by 7.2% and in SAP therapy by 11.4%. Closed-loop therapy plus empagliflozin improved time in target range compared to SAP therapy plus empagliflozin by 6.1% but by 17.5% for the combination of closed-loop therapy and empagliflozin compared to SAP therapy plus placebo. While no diabetic ketoacidosis or severe hypoglycemia occurred during any intervention, uncomplicated ketosis events were more common on empagliflozin. Empagliflozin 25 mg d−1 added to automated insulin delivery improves glycemic control but increases ketone concentration and ketosis compared to placebo.

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Fig. 1
Fig. 2: The median (IQR) profiles of glucose levels during the interventions from midnight to midnight.

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Code availability

The code used for analysis is available from the corresponding author. The predictive control algorithm cannot be made publicly available because it is proprietary intellectual property. The control algorithm cannot be used in routine practice in the outpatient setting because regulatory approval has not yet been granted.

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Acknowledgements

This research was supported by the Juvenile Diabetes Research Foundation and by Diabetes Action Canada, a Canadian Institutes for Health Research (CIHR) Strategy for Patient-Oriented Research Network in Chronic Disease (grant no. 4-PAR-2017-327-A-N to A.H. and B.A.P.). B.A.P. holds the Sam and Judy Pencer Family Chair in Diabetes Clinical Research, University of Toronto and acknowledges research program support from the Menkes Fund and the David Wright Fund. A.H. holds the Canada Research Chair in Artificial Pancreas Systems (950-231305). We thank P. Jacob for providing the iPancreas research platform. No funder had any role in study design, data collection or interpretation, or writing of the manuscript. The study investigators had final responsibility for the decision to submit for publication.

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Authors and Affiliations

  1. Department of Biomedical Engineering, McGill University, Montreal, Quebec, Canada

    Ahmad Haidar, Adnan Jafar, Milad Ghanbari & Joanna Rutkowski

  2. The Research Institute of McGill University Health Centre, Montreal, Quebec, Canada

    Ahmad Haidar, Nikita Gouchie-Provencher, Michael A. Tsoukas & Jean-François Yale

  3. Division of Endocrinology, Department of Medicine, McGill University, Montreal, Quebec, Canada

    Ahmad Haidar, Michael A. Tsoukas & Jean-François Yale

  4. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

    Leif Erik Lovblom, Nancy Cardinez, Andrej Orszag, C. Marcelo Falappa, Devrim Eldelekli & Bruce A. Perkins

  5. Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    Bruce A. Perkins

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Contributions

A.H., N.C., A.O., L.E.L., J.R., J.-F.Y. and B.A.P. designed the study. A.H., N.C., N.G.-P., A.O., M.A.T., C.M.F., J.-F.Y. and B.A.P. conducted the study. A.H., L.E.L., A.J., M.G. and D.E. carried out the data and statistical analyses. A.H. and B.A.P. are the guarantors of this work and, as such, had full access to the data and take responsibility for the integrity of the data analysis. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Bruce A. Perkins.

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Competing interests

A.H. received research support/consulting fees from Eli Lilly, Medtronic, AgaMatrix, Tandem, Adocia and Dexcom, and has pending patents in the artificial pancreas area. M.A.T. received research support from AgaMatrix, consulting fees from Sanofi and speaker honoraria from Eli Lilly, Novo Nordisk, Boehringer Ingelheim, Janssen and AstraZeneca. J.-F.Y. received research support from Sanofi, Bayer and Novo Nordisk, and consulting fees and speaker honoraria from Sanofi, Eli Lilly, Novo Nordisk, Boehringer Ingelheim, Janssen, Takeda, Abbott, Merck and AstraZeneca. B.A.P. received speaker honoraria from Abbott, Medtronic, Insulet and Novo Nordisk, research support to his research institute from Boehringer Ingelheim and the Bank of Montreal, and has served as a consultant to Boehringer Ingelheim, Abbott and Novo Nordisk. N.C. has received speaker honoraria from AstraZeneca and consultation fees from Novo Nordisk and Antibody Research Corporation. L.E.L. received support from a CIHR Canada Graduate Scholarship Doctoral Award. The other authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks Tadej Battelino, Victor Volovici and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Riikka Jokinen and Jennifer Sargent were the primary editors on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1

The proportion of participants achieving glycemic targets in each arm. n = 24 independent participants in each of the four settings.

Extended Data Fig. 2

The median (IQR) profiles of basal insulin delivery during the interventions. n = 24 independent participants in each of the four settings.

Extended Data Fig. 3

The relationship between individual mean fasting ketone level and BMI in each intervention arm.

Extended Data Fig. 4

Brochure provided to participants for the management of ketone levels while on empagliflozin, page 1 of 2.

Extended Data Fig. 5

Brochure provided to participants for the management of ketone levels while on empagliflozin, page 2 of 2.

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Haidar, A., Lovblom, L.E., Cardinez, N. et al. Empagliflozin add-on therapy to closed-loop insulin delivery in type 1 diabetes: a 2 × 2 factorial randomized crossover trial. Nat Med 28, 1269–1276 (2022). https://doi.org/10.1038/s41591-022-01805-3

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