Redefining Hypoglycemia in Clinical Trials: Validation of Definitions Recently Adopted by the American Diabetes Association/European Association for the Study of Diabetes.

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.