Financial Support: By Dexcom.
Disclosures: Dr. Beck reports grants from Dexcom during the conduct of the study and other support from Dexcom and Abbott Diabetes Care outside the submitted work. Ms. Ruedy reports grants from Dexcom during the conduct of the study and other fees from Dexcom and Abbott Diabetes Care outside the submitted work. Dr. Ahmann reports grants and personal fees from Dexcom during the conduct of the study; grants from Novo Nordisk, Sanofi, Lexicon, and Medtronic outside the submitted work; and personal fees from Novo Nordisk, Sanofi, Eli Lilly, and Janssen outside the submitted work. Ms. Kruger reports grants from Henry Ford Health System during the conduct of the study; grants from Novo Nordisk, Eli Lilly, Dexcom, and Abbott Diabetes Care outside the submitted work; personal fees from Novo Nordisk, Janssen, Eli Lilly, Boehringer Ingelheim, Sanofi, Dexcom, Abbott Diabetes Care, Intarsia, and AstraZeneca outside the submitted work; and holding Dexcom stock. Dr. McGill reports personal fees from Boehringer Ingelheim, Dexcom, Dynavax, Janssen, Intarcia, Merck, Novo Nordisk, and Valeritas and grants from Dexcom, AstraZeneca/Bristol-Myers Squibb, Novartis, and Lexicon outside the submitted work. Dr. Polonsky reports personal fees from Dexcom during the conduct of the study and from Dexcom and Abbott Diabetes Care outside the submitted work. Dr. Price reports being a Dexcom employee and a shareholder of Dexcom stock. Dr. Aronson reports research support from Merck, Boehringer Ingelheim, Regeneron, Abbott Diabetes Care, Quintiles, ICON, GlaxoSmithKline, Medpace, Novo Nordisk, Janssen, Sanofi, Bristol-Myers Squibb, AstraZeneca, Becton Dickinson, Eli Lilly, Amgen, and Takeda and personal fees from Novo Nordisk, Janssen, Sanofi, AstraZeneca, Becton Dickinson, Eli Lilly, and Amgen outside the submitted work. Dr. Kollman reports grants from Dexcom during the conduct of the study. Dr. Bergenstal reports grants and other fees from Abbott Diabetes Care, Becton Dickinson, Boehringer Ingelheim, Bristol-Myers Squibb/AstraZeneca, Calibra Medical, Eli Lilly, Hygieia, Johnson & Johnson, Medtronic, Novo Nordisk, Roche, Sanofi, Takeda, and Dexcom during the conduct of the study. Dr. Bergenstal is employed by HealthPartners Institute/Park Nicollet Health Services and has contracts with the listed companies for his services as a research investigator or consultant; no personal income from any of these services goes to Dr. Bergenstal. Dr. Bergenstal also reports holding stock in Merck. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-2855.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement: Study protocol and statistical code: See the
Supplement.
Data set: Not available.
Corresponding Author: Roy W. Beck, MD, PhD, Jaeb Center for Health Research, 15310 Amberly Drive, #350, Tampa, FL 33647; e-mail,
[email protected].
Current Author Addresses: Drs. Beck, Riddlesworth, and Kollman and Ms. Ruedy: Jaeb Center for Health Research, 15310 Amberly Drive, #350, Tampa, FL 33647.
Dr. Ahmann: Harold Schnitzer Diabetes Health Center, Oregon Health & Science University, 3147 SW Sam Jackson Park Road, Portland, OR 97239.
Ms. Haller: Diabetes & Glandular Disease Clinic, 5107 Medical Drive, San Antonio, TX 78229.
Ms. Kruger: Henry Ford Medical Center Division of Endocrinology, 3031 West Grand Boulevard, Suite 800, Detroit, MI 48202.
Dr. McGill: Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8127, St. Louis, MO 63110.
Dr. Polonsky: Behavioral Diabetes Institute, 5405 Oberlin Drive, Suite 100, San Diego, CA 92121.
Dr. Price: Dexcom, Inc., 6340 Sequence Drive, San Diego, CA 92121.
Dr. Aronoff: Research Institute of Dallas, 10260 North Central Expressway, Suite 100N, Dallas, TX 75231.
Dr. Aronson: LMC Diabetes & Endocrinology, 1929 Bayview Avenue #106, Toronto, Ontario M4G 3E8, Canada.
Dr. Toschi: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215.
Dr. Bergenstal: Park Nicollet Institute, International Diabetes Center, 3800 Park Nicollet Boulevard, St. Louis Park, MN 55416.
Author Contributions: Conception and design: R.W. Beck, K. Ruedy, A. Ahmann, W. Polonsky, D. Price, E. Toschi, C. Kollman, R. Bergenstal.
Analysis and interpretation of the data: R.W. Beck, T.D. Riddlesworth, J.B. McGill, W. Polonsky, D. Price, R. Aronson, E. Toschi, C. Kollman, R. Bergenstal.
Drafting of the article: R.W. Beck, T.D. Riddlesworth, A. Ahmann, S. Haller, D. Price, R. Bergenstal.
Critical revision of the article for important intellectual content: T.D. Riddlesworth, K. Ruedy, S. Haller, D. Kruger, J.B. McGill, W. Polonsky, D. Price, R. Aronson, E. Toschi, C. Kollman, R. Bergenstal.
Final approval of the article: R.W. Beck, T.D. Riddlesworth, K. Ruedy, A. Ahmann, S. Haller, D. Kruger, J.B. McGill, W. Polonsky, D. Price, S. Aronoff, R. Aronson, E. Toschi, C. Kollman, R. Bergenstal.
Provision of study materials or patients: K. Ruedy, A. Ahmann, J.B. McGill, S. Aronoff, R. Aronson, E. Toschi, R. Bergenstal.
Statistical expertise: R.W. Beck, T.D. Riddlesworth, C. Kollman.
Obtaining of funding: D. Price.
Administrative, technical, or logistic support: R.W. Beck, K. Ruedy.
Collection and assembly of data: T.D. Riddlesworth, K. Ruedy, D. Kruger, J.B. McGill, S. Aronoff, R. Aronson, E. Toschi, R. Bergenstal.
This article was published at
Annals.org on 22 August 2017.
* For members of the DIAMOND (Multiple Daily Injections and Continuous Glucose Monitoring in Diabetes) Study Group, see the Appendix.
Comment
The authors compared the results of their study with a recent study from our research group using a factory-calibrated CGM device (FreeStyle LibreTM) that showed no significant overall reduction in HbA1c but a significant improvement in time in hypoglycemia and certain QoL measures3. Beck and colleagues suggest that the different outcomes in terms of HbA1c between the two studies could be attributed to alarms with the device used in their study. While they provide no rationale for this hypothesis, we recommend considering the observed HbA1c result in REPLACE in the context of overall outcomes, especially hypoglycemia.
There is clear evidence in REPLACE that the participants significantly reduced hypoglycemia at all thresholds and time intervals analyzed, as this was likely a priority for the study clinicians given the immediate consequences of hypoglycemia versus HbA1c. Beck and colleagues did not report similar decreases in CGM-measured hypoglycemia. Unfortunately, their results are reported in median and interquartile range instead of the more commonly used format of mean and standard deviation, which precludes any conclusions on this outcome.
However, they did observe a slight increase in total daily dose of insulin and body weight of the intervention subjects compared with controls. In REPLACE, there was no statistical difference in total daily dose of insulin for the intervention participants compared with controls and no change in body weight was observed for either group. These findings may be the likely reason for the observed differences in HbA1c between DIAMOND and REPLACE. In our view, it is therefore inappropriate to conclude that the presence of alarms is the basis for the different HbA1c outcomes in the two studies.
It is also noteworthy that independent research has reported an association of real world use of FreeStyle Libre with HbA1c decrease among a population including predominantly insulin-using individuals with type 2 diabetes4.
References:
1. Beck RW, Riddlesworth TD, Ruedy K, Ahmann A, Haller S, Kruger D, McGill JB, Polonsky W, Price D, Aronoff S, Aronson R, Toschi E, Kollman C, Bergenstal R; DIAMOND Study Group. Continuous Glucose Monitoring Versus Usual Care in Patients With Type 2 Diabetes Receiving Multiple Daily Insulin Injections: A Randomized Trial. Ann Intern Med. 2017 Aug 22. doi: 10.7326/M16-2855. [Epub ahead of print]
2. Beck RW, Riddlesworth T, Ruedy K, Ahmann A, Bergenstal R, Haller S, Kollman C, Kruger D, McGill JB, Polonsky W, Toschi E, Wolpert H, Price D; DIAMOND Study Group. Effect of Continuous Glucose Monitoring on Glycemic Control in Adults With Type 1 Diabetes Using Insulin Injections: The DIAMOND Randomized Clinical Trial. JAMA. 2017 Jan 24;317(4):371-378. doi: 10.1001/jama.2016.19975. Supplement 1. http://jamanetwork.com/journals/jama/fullarticle/2598770 [assessed September 21st, 2017]
3. Haak T, Hanaire H, Ajjan R, Hermanns N, Riveline JP, Rayman G. Flash glucose-sensing technology as a replacement for blood glucose monitoring for the management of insulin-treated type 2 diabetes: a multicenter, open-label randomized controlled trial. Diabetes Ther. 2017;8:55-73. [PMID: 28000140] doi:10.1007/s13300-016-0223-6
4. Ish-Shalom, M., Wainstein, J., Raz, I., & Mosenzon, O. (2016). Improvement in glucose control in difficult- to-control patients with diabetes using a novel Flash Glucose Monitoring device. Journal of Diabetes Science and Technology, 5:1572-1583.
Author's Response
The treatment group difference used for a sample size calculation is the postulated estimate of the true population value and is not intended to indicate what would be considered clinically significant, a common misconception. The end of the 95% confidence interval on the observed treatment group difference was 0.6%, extending beyond the projected true population value of 0.4%. We believe that a treatment group difference of 0.3% represents a meaningful shift in the HbA1c distributions as evidenced by our finding of 73% of participants achieving a >0.5% reduction in HbA1c at 24 weeks in the CGM group compared with only 49% in the control group.1
Our conjecture that the presence of alerts with the Dexcom system but not the FreeStyle Libre may be an important factor in achieving lower HbA1c levels seems reasonable in the absence of an alternative explanation. Dr. Haak postulated that slight increases in insulin dose (0.1 units/kg/day and in weight (1.3 kg) in our CGM group were a possible explanation for our finding of a significant effect on HbA1c and the REPLACE study2 finding no effect. However, the small insulin increase in our study, even if meaningful, would still be a consequence of CGM use, and it is hard to understand how weight gain would produce a reduction in HbA1c. The central question is not why our study showed a reduction in HbA1c, since CGM has been consistently shown to reduce HbA1c in other populations, but why REPLACE did not.
For hypoglycemia metrics, we believe that median and interquartile range generally are more appropriate than mean and standard deviation due to the fact that the data are almost always skewed, as was the case in both our study and in REPLACE. For comparison purposes between studies, in our study, mean (SD) time <70 mg/dL in the CGM group was 30 (50) minutes/day at baseline and 16 (31) minutes/day at 24 weeks compared with 31 (43) and 27 (40), respectively in the control group. The participants in REPLACE had substantially more baseline hypoglycemia (~74 minutes/day) than the participants in our study (~30 minutes/day), possibly attributable to the low bias of the FreeStyle Libre in hypoglycemia.3 The limited amount of baseline hypoglycemia diminished our ability to statistically demonstrate a hypoglycemia reduction. However, the relative reduction in hypoglycemia in our study was of similar magnitude to that found in REPLACE.
Roy W. Beck, MD, PhD
Tonya Riddlesworth, PhD
References
1. Beck RW, Riddlesworth TD, Ruedy K, Ahmann A, Haller S, Kruger D, McGill JB, Polonsky W, Price D, Aronoff S, Aronson R, Toschi E, Kollman C, Bergenstal R, DIAMOND Study Group. Continuous Glucose Monitoring Versus Usual Care in Patients With Type 2 Diabetes Receiving Multiple Daily Insulin Injections: A Randomized Trial. Ann Intern Med. 2017 Aug 22. doi: 10.7326/M16-2855. [Epub ahead of print]
2. Haak T, Hanaire H, Ajjan R, Hermanns N, Riveline JP, Rayman G. Flash glucose-sensing technology as a replacement for blood glucose monitoring for the management of insulin-treated type 2 diabetes: a multicenter, open-label randomized controlled trial. Diabetes Ther. 2017;8:55-73. [PMID: 28000140] doi:10.1007/s13300-016-0223-6
3. https://www.accessdata.fda.gov/cdrh_docs/pdf15/p150021b.pdf (accessed October 28, 2017)