International Consensus of Continuous Glucose Monitor Use in Pharmacological Clinical Trials in Diabetes

The clinical use of continuous glucose monitors (CGMs) has significantly increased in the past 10 years. More than 8 million (at the time of this writing) people with diabetes are using CGMs for their day-to-day diabetes management. In part, this is due to multiple changes in CGM technology that includes accuracy, standalone, nonadjunctive, and ease of use systems. ^{1 –5} Many randomized and real-life studies have convincingly shown improvements in acute (severe hypoglycemia and diabetic ketoacidosis) and possibly long-term health outcomes (micro- and macrovascular) related to diabetes. ⁶

Despite all these advances, their use in clinical trials on pharmacological agents (related to diabetes) has been limited. Part of the hesitancy of using CGMs in clinical trials was that regulators (Food and Drug Administration [FDA] and European Medicines Agency [EMA]) were not accepting the CGM data for clinical trials. The regulators insisted on self-monitoring of blood glucose and HbA1c values as the trial end points. The recent publication of an international consensus statement on CGM usage for clinical trials was a welcome step forward. ⁷

The international consensus statement includes 23 recommendations that emerged from an expert consensus meeting in Barcelona ahead of the annual Advanced Technologies and Treatment for Diabetes (ATTD) 2022 conference. The purpose of these recommendations was to create a standard approach to CGM data collection, analysis, and reporting in clinical trials, and, in doing so, to encourage the use of these metrics to establish a baseline for regulatory consideration and approval of newer medical therapies. The consensus statement brings guidelines, clarity, and coherence to a process that for too long had been left to guesswork for researchers, clinicians, and regulators.

Beyond the content of the specific recommendations, the consensus statement validates the role of CGM in diabetes care and concurrently supports time in range (TIR) as an accepted and validated enhancement to HbA1c results. The HbA1c, which estimates average blood sugar for the past 3 months, has been used for people with diabetes since the 1970s, ⁸ and HbA1c results have been the gold standard to assess diabetes care and glucose control. It is true that HbA1c is a good metric for population health for people with diabetes and correlates well with long-term diabetes complications. This metric is so deeply embedded in our culture that “A1c” is now used in many marketing campaigns for glucose-lowering diabetes drugs and devices.

But HbA1c itself, as a surrogate marker for mean glucose, is not as revealing or as helpful as TIR, which provides more actionable information on a daily basis. This information can easily help in therapeutic decisions, particularly in severe hypoglycemia, postprandial hyperglycemia, and glucose variability. Increased use of TIR in day-to-day clinical practice has been shown to minimize glycemic excursions and increase quality of life for people with diabetes. ⁹

Collecting CGM data prospectively, especially as it relates to TIR in randomized clinical trials involving pharmacological agents for diabetes, will, in turn, help determine the next steps in data collection and generation of medicines, devices, and therapies. That is why standardizing CGM use in trials is so important.

We hope that the international consensus statement will embed CGM more deeply into our diabetes care and regulatory culture. Regulatory agencies, for example, may include CGM metrics, including TIR and glycemic variability, in drug labeling, which may in turn improve diabetes outcomes.

The international consensus included many experts from around the globe and endorsed by leading U.S. (American Association of Clinical Endocrinologists [AACE], American Diabetes Association [ADA], Association of Diabetes Care and Education Specialists [ADCES], Juvenile Diabetes Research Foundation [JDRF]) and international diabetes organizations (DiabetesIndia, the European Association for the Study of Diabetes [EASD], the International Society for Pediatric and Adolescent Diabetes [ISPAD], and Japan Diabetes Society [JDS]). ⁷

We thank the experts from the FDA and EMA who offered their opinions, which were critical to the process, as we cannot advance new therapies to individuals unless we meet regulatory guidelines. The consensus meeting was coordinated by the diaTribe Foundation, ATTD, and the TIR coalition, and the statement was published in Lancet Diabetes and Endocrinology online on December 6, 2022. ⁷

The recommendations themselves spanned five expert panels that included CGM device selection in clinical trials, TIR reporting and other glycemic metrics, the application of CGM sensors in clinical trials, the interpretation of clinically meaningful differences in TIR in these trials, and CGM data inclusion in the clinical trials from the final data sets.

We hope you find this brief editorial useful for incorporating CGM metrics in future clinical trials for diabetes pharmacological agents. This will allow us to uniformly collect and analyze the CGM data from different clinical trials and help us improve the design for incorporating other CGM metrics in future clinical trials.