Continuous glucose monitoring and metrics for clinical trials: an international consensus statement.

Randomised controlled trials and other prospective clinical studies for novel medical interventions in people with diabetes have traditionally reported HbA _1c as the measure of average blood glucose levels for the 3 months preceding the HbA _1c test date. The use of this measure highlights the long-established correlation between HbA _1c and relative risk of diabetes complications; the change in the measure, before and after the therapeutic intervention, is used by regulators for the approval of medications for diabetes. However, with the increasing use of continuous glucose monitoring (CGM) in clinical practice, prospective clinical studies are also increasingly using CGM devices to collect data and evaluate glucose profiles among study participants, complementing HbA _1c findings, and further assess the effects of therapeutic interventions on HbA _1c . Data is collected by CGM devices at 1-5 min intervals, which obtains data on glycaemic excursions and periods of asymptomatic hypoglycaemia or hyperglycaemia (ie, details of glycaemic control that are not provided by HbA _1c concentrations alone that are measured continuously and can be analysed in daily, weekly, or monthly timeframes). These CGM-derived metrics are the subject of standardised, internationally agreed reporting formats and should, therefore, be considered for use in all clinical studies in diabetes. The purpose of this consensus statement is to recommend the ways CGM data might be used in prospective clinical studies, either as a specified study endpoint or as supportive complementary glucose metrics, to provide clinical information that can be considered by investigators, regulators, companies, clinicians, and individuals with diabetes who are stakeholders in trial outcomes. In this consensus statement, we provide recommendations on how to optimise CGM-derived glucose data collection in clinical studies, including the specific glucose metrics and specific glucose metrics that should be evaluated. These recommendations have been endorsed by the American Association of Clinical Endocrinologists, the American Diabetes Association, the Association of Diabetes Care and Education Specialists, DiabetesIndia, the European Association for the Study of Diabetes, the International Society for Pediatric and Adolescent Diabetes, the Japanese Diabetes Society, and the Juvenile Diabetes Research Foundation. A standardised approach to CGM data collection and reporting in clinical trials will encourage the use of these metrics and enhance the interpretability of CGM data, which could provide useful information other than HbA _1c for informing therapeutic and treatment decisions, particularly related to hypoglycaemia, postprandial hyperglycaemia, and glucose variability.
Competing Interests: Declaration of interests TB has received honoraria for participation on advisory boards for Novo Nordisk, Sanofi, Eli Lilly, Boehringer-Ingelheim, Medtronic, and Indigo Diabetes, and as a speaker for AstraZeneca, Eli Lilly, Novo Nordisk, Medtronic, Sanofi, and Roche. TB owns stocks of DreaMed Diabetes and his institution (University Medical Centre Ljubljana, University Children's Hospital) has received research grant support and travel expenses from Abbott Diabetes Care, Medtronic, Novo Nordisk, Sanofi, Sandoz, Novartis. SAA has served on advisory boards for Novo Nordisk and Medtronic and has spoken at educational events sponsored by Novo Nordisk and Sanofi in the last 12 months. She is a co-investigator on the EU IMI Hypoglycaemia Redefining Solutions for Better Lives programme, which has the industry partners Abbott Diabetes Care, Eli Lilly, Medtronic, Novo Nordisk, and Sanofi-Aventis. RWB reports that his institution (Jaeb Center for Health Research) has received funding on his behalf as follows: grant funding and study supplies from Tandem Diabetes Care, Beta Bionics, and Dexcom; study supplies from Medtronic, Ascencia, and Roche; consulting fees and study supplies from Eli Lilly and Novo Nordisk; and consulting fees from Insulet, Bigfoot Biomedical, vTv Therapeutics, and Diasome. RMB has received research support from Abbott Diabetes Care, Ascensia, Bigfoot Biomedical, CeQur, Dexcom, Eli Lilly, Hygieia, Insulet, and Medtronic. RMB has received consulting fees from Abbott Diabetes Care, Ascensia, Bigfoot Biomedical, CeQur, Dexcom, Eli Lilly, Hygieia, Insulet, Medtronic, Novo Nordisk, Onduo, Roche Diabetes Care, Sanofi, United Healthcare, Vertex Pharmaceuticals, and Zealand Pharma. RMB has participated on advisory boards for Abbott Diabetes Care, Ascensia, Bigfoot Biomedical, CeQur, Dexcom, Eli Lilly, Hygieia, Insulet, Medtronic, Novo Nordisk, Onduo, Roche Diabetes Care, Sanofi, United Healthcare, Vertex Pharmaceuticals, and Zealand Pharma. BAB has received honoraria for participating in advisory boards for Novo Nordisk, Lilly, and Arecor. TD has received honoraria from Abbott, AstraZeneca, Boehringer, Dexcom, Lilly, Medtronic, Novo Nordisk, Roche, Sanofi, and Ypsomed. TD has received research support from Abbott, AstraZeneca, Boehringer, Dexcom, Lilly, Medtronic, Novo Nordisk, Roche, Sanofi, and Ypsomed. TD has received consulting fees from Abbott, AstraZeneca, Boehringer, Dexcom, Lilly, Medtronic, Novo Nordisk, Roche, Sanofi, and Ypsomed. TD is a shareholder of DreaMed Diabetes. RG has received honoraria as an advisor to Lark, Sweetch, and Vida. AC has received honoraria from AstraZeneca, Berlin Chemie, Merck, Novo Nordisk, and Roche Diagnostics. AC has received consulting fees from AstraZeneca, Bayer, Elsevier, Roche Diagnostics, Sevier, and Theras. AC has participated on advisory boards for Eli Lilly and Roche Diagnostics. EC has received speaker fees from Sanofi and Novartis, and institutional research support from Medtronic, Sanofi, and Powder Pharmaceuticals. PC has received honoraria for speaking from Medtronic, Dexcom, Abbott, Glooko, DreaMed, Novo Nordisk, Lilly, and Sanofi, and has received research support from Medtronic, Dexcom, Abbott, and Novo Nordisk. KLC receives subscription revenue for the web blog Close Concerns from Abbott, Biolinq, Dexcom, GlySens, Medtronic, Percusense, and Senseonics. SG has received advisory board honoraria and consulting fees from Bayer, Eli Lilly, Lifescan, Medtronic, Novo Nordisk, and Zealand. He has received research grants from Dario, Dexcom, Eli Lilly, JDFR, Lexicon, Medtronic, Merck, Novo Nordisk, Sanofi, and T1D Exchange. JC, JH, and JK are employees of the diaTribe Foundation, which receives funding support from continuous glucose monitor manufacturers Abbott Diabetes Care, Dexcom, and Medtronic. IBH receives consulting fees from Abbott Diabetes Care, Roche, Lifescan, and GWave, and receives research support from Insulet and Dexcom. LL has received consulting fees from Janssen, Insulet, Boehringer Ingelheim, Medtronic, Dompe, Provention, Eli Lilly, Roche, and Dexcom. LL has participated on advisory boards for Janssen, Insulet, Boehringer Ingelheim, Medtronic, Dompe, Provention, Eli Lilly, Roche, and Dexcom. BK has received honoraria as a speaker from Dexcom and Tandem and reports research support, managed by the University of Virginia, from Dexcom, Novo Nordisk, and Tandem Diabetes Care. BK receives patent royalties, managed by the University of Virginia, for US Patent numbers; #7,815,569 B2, #8,135,548 B2, #8,718,958 B2, #9,882,660 B2, #10,194,850, and #11,289,201. TK has received honoraria from Medtronic, Abbott, Insulet, DexCom, Tandem, Sanofi, Eli Lilly, Novo Nordisk, Merck and Janssen. TK has participated in advisory boards for Medtronic, Abbott, Insulet, Dexcom, Tandem, Sanofi, Eli Lilly, Novo Nordisk, Merck, and Janssen. She has received research support from Abbott and Sanofi. DMaa has consulted for Abbott, Aditxt, Biospex, Dompe, Eli Lilly, the Helmsley Charitable Trust, Insulet, Lifescan, Mannkind, Medtronic, Novo Nordisk, and Sanofi. He has received research support from the Helmsley Charitable Trust, the Juvenile Diabetes Research Foundation, the National Institutes of Health, the National Science Foundation, and his institution (Stanford Diabetes Research Center) has had research support from Dexcom, Insulet, Medtronic, and Tandem. CM has received honoraria from Novo Nordisk, Sanofi, Merck Sharp and Dohme, Eli Lilly, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Imcyse, Insulet, Zealand Pharma, Avotres, Mannkind, Sandoz, and Vertex. CM has participated on advisory boards for Novo Nordisk, Sanofi, Merck Sharp and Dohme, Eli Lilly, Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Medtronic, ActoBio Therapeutics, Pfizer, Imcyse, Insulet, Zealand Pharma, Avotres, Mannkind, Sandoz, and Vertex. Financial compensation for these activities has been received by KU Leuven. CM has received research support through KU Leuven from Medtronic, Imcyse, Novo Nordisk, Sanofi, and ActoBio Therapeutics. DMau has received honoraria as a speaker and advisory board member for Almirall, Esteve, Ferrer, Janssen, Lilly, Menarini, Merck Sharp and Dohme, Novo Nordisk, and Sanofi. ER serves on advisory boards for Abbott, Air Liquide South Africa, Dexcom, Insulet, Sanofi, Roche Diabetes Care, Novo Nordisk, and Eli Lilly, and has received research support from Dexcom and Tandem. RNim has received speaking and consulting fees from Novo Nordisk, Eli Lilly, and DreaMed Diabetes. He has received research grants from the Helmsley Charitable Trust, Dexcom, Medtronic, Abbott Diabetes Care, and Insulet. RNim owns stock in DreaMed Diabetes. RNis has received honoraria as a speaker for Abbott, Astellas Pharma, Boehringer-Ingelheim, Eli Lilly, Kissei Pharmaceutical, Merck Sharp and Dohme, Medtronic, Novartis, Novo Nordisk, Sanofi, and Takeda. He has received both research fees and research expenses from Abbott, Boehringer-Ingelheim, Ono Pharmaceuticals, Taisho Pharmaceuticals, and Takeda. MS has received honoraria as a speaker and advisory board member from Pfizer, Medtronic, Abbott, Novo Nordisk, Merck, and Sanofi. He has received research grants from Novo Nordisk and is consultant doctor to Biomm and Cristalia. SDP declares grants from AstraZeneca and Boehringer Ingelheim; consulting fees from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hengrui Pharmaceutical, Merck Sharpe and Dohme, Novartis Pharmaceuticals, Novo Nordisk, and Sanofi; honoraria as a speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharpe and Dohme, Novartis Pharmaceuticals, Novo Nordisk, and Sanofi. JR has received consulting fees from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi, and fees for speaking for Eli Lilly, Novo Nordisk, and Sanofi. JR has served on advisory panels for Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Intarcia, Novo Nordisk, Oramed, Hanmi, Sanofi, and Zealand and has received research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Genentech, Hanmi, Novartis, Intarcia, Merck, Novo Nordisk, Oramed, Pfizer, and Sanofi. KU declares honoraria from Takeda, Novo Nordisk, Nippon, Boehringer Ingelheim, Mitsubishi Tanabe Pharma, AstraZeneca, MSD, Ono, Sumitomo Pharma, Sanofi, Astellas. KU has received grant support from Takeda, Novo Nordisk, Eli Lilly, Nippon, Boehringer Ingelheim, Abbott Japan, Mitsubishi Tanabe Pharma, Merck Sharp and Dohme, Ono, Sumitomo Pharma, Sanofi, Kyowa Kirin, and Daiichi-Sankyo. GEU has received research support, managed by Emory University, from AstraZeneca, Bayer, and Dexcom. SAW has received honoraria from Abbott and Dexcom, has received consulting fees from Zealand, and has received research support for his institution (Sackler Faculty of Medicine, Tel Aviv University) from Abbott and Medtronic. MP has received honoraria for participation on advisory boards from AstraZeneca, Eli Lilly, Insulet, Mannkind, Medtronic Diabetes, Pfizer, Sanofi, and Dompé. MP has received consulting fees from Eli Lilly, Medtronic Diabetes, Novo Nordisk, Pfizer, Sanofi, and Qulab Medical. MP has received research grants from Dexcom, Eli Lilly, Insulet, Medtronic Diabetes, Novo Nordisk, Pfizer, Roche Diagnostics, Sanofi, DreaMed Diabetes, NG Solutions, Dompe, Lumos, GWAVE, and OPKO. MP owns stocks in DreaMed-Diabetes and NG Solutions. All other authors declare no competing interests. Support for the CGMs in Clinical Trials consensus meeting and development was provided by the Time in Range Coalition, Abbott Diabetes Care, Novo Nordisk, Dexcom, Eli Lilly, Apple Pickers Foundation, Diasome, Insulet Corporation, Lifescan, Medtronic, Sanofi, Vertex, Zealand Pharma, and Zucara. C-DISC, Embecta, and Novartis also provided funding to support the consensus meeting. The contents of this consensus statement represent the authors' views and do not constitute an official position of the National Institutes of Health or the United States Government.
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