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

Abstract

Objective: The purpose of this study was to determine if the International Hypoglycemia Study Group (IHSG) Level 2 low glucose definition can identify clinically relevant hypoglycemia in clinical trials and offer value as an endpoint for future trials. Research design and methods: A post hoc analysis of the SWITCH (SWITCH 1: n=501, type 1 diabetes; SWITCH 2: n=721, type 2 diabetes) and DEVOTE (n=7637, type 2 diabetes) trials utilizing the IHSG low glucose definitions. Patients in all trials were randomized to either insulin degludec (degludec) or insulin glargine 100 units/mL (glargine U100). In the main analysis, the following definitions were compared: 1) ADA 2005 (plasma glucose [PG] confirmed ≤3.9 mmol/L with symptoms); 2) IHSG Level 2 (glucose confirmed <3.0 mmol/L). 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. In SWITCH 2, the IHSG Level 2 definition produced a rate ratio that was lower than the ADA 2005 definition. Similar results were observed for the SWITCH 1 trial. 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.

The Need to Change Regulatory Evaluation of Hypoglycemia in Trials of Diabetes Treatments

“…The optimal definition of hypoglycemia for distinguishing outcomes between the two insulins was therefore concluded to be located at level 2 or less rate ratio. 8 Similar results were noted for DEVOTE data, even though the hypoglycemic endpoints in this trial were different from those of the SWITCH trial. 8 While the DCCT gold standard definition of SH was necessary in the era before glucose measurement technology was available, this should no longer be the sole definition of meaningful hypoglycemia events for regulatory purposes.…”

“…8 Similar results were noted for DEVOTE data, even though the hypoglycemic endpoints in this trial were different from those of the SWITCH trial. 8 While the DCCT gold standard definition of SH was necessary in the era before glucose measurement technology was available, this should no longer be the sole definition of meaningful hypoglycemia events for regulatory purposes. Continuous glucose monitoring (CGM) technology has matured to the point that it provides a reliable, meaningful, and more robust means of evaluating hypoglycemia risk than the DCCT definition of the 1990s.…”

“…The optimal definition of hypoglycemia for distinguishing outcomes between the two insulins was therefore concluded to be located at level 2 or less rate ratio. 8 Similar results were noted for DEVOTE data, even though the hypoglycemic endpoints in this trial were different from those of the SWITCH trial. 8…”

Comparison of Second-Generation Basal Insulin Analogs: A Review of the Evidence from Continuous Glucose Monitoring

“…Even with second-generation basal insulin analogs, clinically relevant hypoglycemia still occurs 3 ; it is therefore imperative that glycemic control is assessed in detail. How glucose data are used to compare basal insulin therapies is currently under scrutiny, 23 and CGM data will contribute further to such discussion. 8,24 CGM data offer the prospect of exploring the glycemic profile of basal insulin in more depth than HbA 1c data, including measures of glucose variability, glucose TIR, TBR, and TAR.…”

Standardized Hybrid Closed-Loop System Reporting

“…The primary goal of the currently available HCL systems is to minimize, or eliminate all levels of hypoglycemia. 80 We suggest including level 1 (CGM glucose <70 mg/dL) and level 2 hypoglycemia (CGM glucose <54 mg/dL) 81 in the AP Dashboard.…”