Redefining hypoglycemia in clinical trials: Validation of definitions recently adopted by the American Diabetes Association/European Association for the study of diabetes

Simon R. Heller, John B. Buse, Robert Ratner, Elizabeth Seaquist, Lars Bardtrum, Charlotte Thim Hansen, Deniz Tutkunkardas, Alan C. Moses

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

OBJECTIVE: To determine if the International Hypoglycaemia Study Group (IHSG) level 2 low glucose definition can identify clinically relevant hypoglycemia in clinical trials and offer value as an end point for future trials. RESEARCH DESIGN AND METHODS: A post hoc analysis was performed of the SWITCH (SWITCH 1: n = 501, type 1 diabetes; SWITCH 2: n = 721, type 2 diabetes) and DEVOTE (n = 7,637, type 2 diabetes) trials utilizing the IHSG low glucose definitions. Patients in all trials were randomized to either insulin degludec or insulin glargine 100 units/mL. In the main analysis, the following definitions were compared: 1) American Diabetes Association (ADA) 2005 (plasma glucose [PG] confirmed ≤3.9 mmol/L with symptoms); and 2) IHSG level 2 (PG confirmed <3.0 mmol/L, independent of symptoms). RESULTS: In SWITCH 2, the estimated rate ratios of hypoglycemic events indicated increasing differences between treatments with decreasing PG levels until 3.0 mmol/L, following which no additional treatment differences were observed. Similar results were observed for the SWITCH 1 trial. In SWITCH 2, the IHSG level 2 definition produced a rate ratio that was lower than the ADA 2005 definition. CONCLUSIONS: The IHSG level 2 definition was validated in a series of clinical trials, demonstrating its ability to discriminate between basal insulins. This definition is therefore recommended to be uniformly adopted by regulatory bodies and used in future clinical trials.

Original languageEnglish (US)
Pages (from-to)398-404
Number of pages7
JournalDiabetes care
Volume43
Issue number2
DOIs
StatePublished - Feb 1 2020

Bibliographical note

Funding Information:
Acknowledgments. Medical writing assistance and editorial/submission support were provided by Francesca Hemingway and Richard McDonald of Watermeadow Medical, an Ashfield company, part of UDG Healthcare plc (Dublin, Ireland), funded by Novo Nordisk A/S. Novo Nordisk was involved in the design of this secondary analysis, provided logistical support, and obtained the data, which were evaluated jointly by the authors and the sponsor. Funding. J.B.B. is supported by grants from the National Institutes of Health (UL1-TR-002489, U01-DK-098246, UC4-DK-108612, and U54-DK-118612), Patient-Centered Outcomes Research Institute, and ADA. Duality of Interest. These trials and this secondary analysis were funded by Novo Nordisk. S.R.H. has served on speaker panels for Eli Lilly and Company and Novo Nordisk, for which he has received remuneration, and has served on ad-visorypanelsor asa consultantforZeeland,UNEEG Medical, Boehringer Ingelheim, Novo Nordisk, Eli Lilly and Company, Sanofi Aventis, and Takeda Pharmaceutical Company, for which his institution has received remuneration. J.B.B. has received contracted consulting fees paid to the University of North Carolina by Adocia, Astra-Zeneca, Dance Biopharm Inc., Eli Lilly and Company, MannKind Corporation, NovaTarg Therapeutics, Novo Nordisk, Senseonics, vTv Therapeutics, and Zafgen and grant support from Novo Nordisk, Sanofi, and vTv Therapeutics; is a consultant to Cirius Therapeutics, CSL Behring, Neurimmune Holding AG, and Whole Biome; and holds stock options in Mellitus Health, PhaseBio Pharmaceuticals, Inc., Stability Health, and Whole Biome. R.R. has served as a consultant to Novo Nordisk, Merck, Dexcom, Intarcia Therapeutics, and Virta Health. E.S. has served as a consultant for Eli Lilly and Company, Zucara Therapeutics, Sanofi, MannKind Corporation, WebMD, and 360 Consulting and received grant funding from Eli Lilly and Company and Locemia Solutions that went to her institution. L.B., C.T.H., and D.T. are full-time employees of and hold stock in Novo Nordisk A/S. A.C.M. was a full-time employee of Novo Nordisk until 30 June 2018 and currently serves as an independent consultant and holds shares in Novo Nordisk A/S. Author Contributions. S.R.H., J.B.B., and A.C.M. conceived and designed the study, acquired, analyzed, and interpreted the data, and drafted and revised the manuscript. R.R., E.S., C.T.H., and D.T. analyzed and interpreted the data and drafted and revised the manuscript. L.B. conceived and designed the study, acquired, analyzed, and interpreted the data, performed statistical analyses, and drafted and revised the manuscript. S.R.H. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding Information:
J.B.B. is supported by grants from the National Institutes of Health (UL1-TR-002489, U01-DK-098246, UC4-DK-108612, and U54-DK-118612), Patient-Centered Outcomes Research Institute, and ADA.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Validation Study

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