REPLACE-BG: A Randomized Trial Comparing Continuous Glucose Monitoring With and Without Routine Blood Glucose Monitoring in Adults With Well-Controlled Type 1 Diabetes

In the past decade, continuous glucose monitoring (CGM) has evolved as an essential part of diabetes management for many people with type 1 diabetes (T1D) (1–3). This technology offers advantages to traditional self-monitoring of blood glucose by providing real-time information on high- and low-glucose patterns, directions and rate of glucose changes, and hypo/hyperglycemia alerts. Several multicenter randomized controlled trials have demonstrated the benefits of CGM in reducing HbA_1c and hypoglycemia, particularly in adults with T1D (2,4–11).

Before December 2016, the CGM systems commercially available in the U.S. were approved by the U.S. Food and Drug Administration (FDA) for use only as adjunctive devices to information obtained from standard home blood glucose monitoring (BGM). Therefore, according to the labeling of these CGM systems, a BGM measurement was required to confirm the CGM sensor glucose concentration before making an insulin dosing decision. This regulatory decision presumably was made because the accuracy of the CGM systems was considered to be inadequate for dosing insulin without BGM confirmation. However, with each new generation of sensors, accuracy has improved (12–17), suggesting that CGM may now be sufficiently accurate to be safely implemented as a stand-alone tool for glucose monitoring and therapeutic decisions. In December 2016, the FDA expanded the indications for the Dexcom G5 sensor (Dexcom, San Diego, CA) to allow for replacement of fingerstick blood glucose testing for diabetes treatment decisions.

Even when the FDA labeling limited CGM use to an adjunct-only tool, many CGM users were making insulin dosing decisions by CGM alone. Among adult participants in the T1D Exchange Clinic registry, only 26% of 999 surveyed CGM users indicated that they always confirmed the CGM glucose concentration with a BGM measurement before administering an insulin bolus, and 41% indicated that they dosed insulin based on CGM alone more than one-half of the time (R.W.B., unpublished data). In another survey of 222 CGM users, 50% of respondents indicated that during the night, they would treat a CGM low-glucose alert without a confirmatory fingerstick glucose, and 34% would dose insulin for hyperglycemia without a confirmatory BGM measurement (18).

To date, no clinical trials have confirmed the safety and effectiveness of CGM used without BGM to make therapeutic decisions in people with T1D. We conducted a multicenter randomized noninferiority clinical trial to determine whether the routine use of CGM without BGM confirmation is as safe and effective as CGM used as an adjunct to BGM in adults with T1D.

The trial was conducted at 14 endocrinology practices in the U.S. of which 4 were community-based and 10 were academic centers. The protocol and Health Insurance Portability and Accountability Act–compliant informed consent forms were approved by institutional review boards. Written informed consent was obtained from each participant. The study is listed on ClinicalTrials.gov under identifier NCT02258373. An investigational device exemption was obtained from the FDA to conduct the trial. The full protocol is available at http://t1dexchange.org/pages/resources/clinic-network/studies and is summarized below.

Major eligibility criteria were age ≥18 years, T1D for ≥1 year being treated with an insulin pump for at least 3 months (and not currently using a low-glucose-suspend function), and point of care HbA_1c ≤9.0% (≤75 mmol/mol). Exclusion criteria included the occurrence of a severe hypoglycemic event resulting in seizure or loss of consciousness in the past 3 years or an event without seizure or loss of consciousness requiring the assistance of another individual in the past 12 months, significant hypoglycemia unawareness based on the Clarke Hypoglycemia Unawareness Survey (19), >10.0% of baseline CGM glucose concentrations <60 mg/dL, more than one episode of diabetic ketoacidosis (DKA) in the past year, history of seizures other than those due to hypoglycemia, current use of a threshold-suspend pump feature, myocardial infarction or stroke in the past 6 months, estimated glomerular filtration rate <30 mL/min/1.73 m², abnormal thyroid function, use of a systemic β-blocker, regular use of oral corticosteroids, initiation of a noninsulin drug for glucose control during the past 3 months, pregnancy, inpatient psychiatric treatment in the past 6 months, and presence of a contraindicated medical condition or medication, including ongoing use of acetaminophen. (Supplementary Table 1 provides a complete list of the inclusion and exclusion criteria.)

A run-in phase of 2–10 weeks preceded the 6-month randomized trial. After successful completion of the run-in phase and after verification of eligibility from data entered on the study website, each participant was randomly assigned from a computer-generated sequence to the CGM-only or CGM+BGM group in a 2:1 ratio on the basis of a permuted block design with stratification by clinical site. Both groups used a Dexcom G4 Platinum CGM System with an enhanced algorithm (Software 505) (referred to as the study CGM), which measures glucose concentrations from interstitial fluid in the range of 40–400 mg/dL every 5 min for up to 7 days. The study BGM was the CONTOUR NEXT (Ascensia Diabetes Care US, Parsippany, NJ). The Abbott Precision Xtra (Abbott Diabetes Care, Alameda, CA) was used to measure blood ketone levels (β-hydroxybutyrate).

Informed consent was signed by 295 individuals, 19 of whom did not pass the screening assessment. The run-in phase, which was initiated by 276 participants, lasted for 2–10 weeks, depending on whether the participant was a CGM user at the time of study entry. There were two parts of the run-in phase of which participants completed various portions, depending on whether they were using CGM at study entry: 1) Dexcom CGM system configured to record glucose concentrations not visible to the participant (referred to as a blinded CGM) for 14 days to collect baseline data and 2) standard CGM for 2–8 weeks for CGM training. In both phases, the participant’s willingness and ability to use the study CGM and BGM were assessed. Participants who used a Dexcom CGM for at least 21 of the 28 days before study enrollment skipped the blinded CGM phase and were required to have only 2 weeks of unblinded study CGM use. Participants who used a Medtronic CGM for at least 21 of the 28 days before enrollment skipped the blinded CGM phase and were required to have at least 4 weeks of unblinded study CGM use. All other participants completed the 14-day blinded phase and 8 weeks of unblinded CGM use. Successful completion of the blinded phase required study CGM wear on a minimum of 11 of 14 days and an average of three blood glucose measurements per day by the study BGM. Successful completion of the unblinded CGM phase required CGM use on ≥21 days during the past 28 days and an average of four or more BGM measurements on at least 90% of days; for participants whose run-in phase was shortened, the number of days of CGM use were reduced accordingly. Of 276 participants who entered the run-in phase, 50 did not enter the randomized trial for the following reasons: 24 did not meet the BGM criterion, 6 had >10% of CGM readings of <60 mg/dL, and 20 were withdrawn for a variety of other reasons (Supplementary Figs. 1 and 2).

After randomization, participants in both groups were instructed to calibrate the study CGM per Dexcom specifications and to use it daily. Both groups also were instructed to perform a BGM measurement when the fasting CGM glucose concentration was >300 mg/dL or when the CGM glucose concentration during the day was >300 mg/dL for 1 h. In both instances, if the BGM measurement confirmed that the glucose level was >300 mg/dL, the participant was instructed to perform a blood ketone measurement with the study ketone meter.

The CGM+BGM group was instructed to perform a BGM measurement with the study meter for CGM calibrations whenever an insulin bolus was administered, when treating or attempting to prevent hypoglycemia, and before going to bed. The CGM-only group was instructed to dose insulin and make management decisions on the basis of the CGM sensor glucose concentration, except in the following circumstances that required BGM testing: 1) for 12 h after insertion of a new sensor, 2) on a sick day (e.g., nausea, vomiting), 3) for 4 h after taking acetaminophen, 4) for symptoms suggestive of hypoglycemia but the CGM sensor glucose concentration was not hypoglycemic or dropping rapidly, 5) for 20 min after treating a low CGM sensor glucose concentration if the CGM sensor glucose level had not begun to rise, 6) before administering an insulin bolus when the CGM sensor glucose concentration was >250 mg/dL, and 7) for a fasting CGM glucose >300 mg/dL or CGM glucose concentration during the day >300 mg/dL for 1 h. If a CGM calibration measurement coincided with a meal, the participant was instructed to base the meal bolus on the CGM sensor value and then perform a BGM measurement to calibrate the CGM.

Follow-up visits for both groups occurred at 3, 6, 13, 19, and 26 weeks, with a ±1-week window. Data were uploaded from the study CGM and BGM devices and the participant’s personal insulin pump by using the Tidepool platform (http://tidepool.org). For insulin pumps that were unable to be uploaded to the Tidepool platform, the data were obtained by using Diasend (Chicago, IL) software. At each visit, compliance with CGM and BGM use was assessed, and additional training was given as needed. Glucose and pump data were reviewed to determine whether changes were indicated in diabetes management.

HbA_1c was measured at baseline, 13 weeks, and 26 weeks at the Northwest Lipid Research Laboratories, University of Washington, by using the Diabetes Control and Complications Trial standardized analyzer (Tosoh Bioscience, South San Francisco, CA). The following questionnaires were completed at baseline and 26 weeks: the Diabetes Technology Questionnaire, which consists of 30 questions about diabetes self-treatment practices and the impact of living with diabetes on the individual (20), and the Hypoglycemia Fear Survey, which consists of 23 questions about the effect of or worry about hypoglycemia on the individual with diabetes (21).

The primary outcome was CGM-measured time in the range of 70–180 mg/dL over the entire 26-week trial. To be included in the primary and secondary analyses of CGM metrics, the participant had to have at least 200 h of CGM data during the 26 weeks of the trial. Secondary outcomes included CGM measures of mean glucose, glycemic variability (coefficient of variation), hypoglycemia (time <70 mg/dL, 60 mg/dL, and 50 mg/dL; area above curve 70 mg/dL; and percentage of days with ≥20 consecutive min of glucose concentrations <60 mg/dL), hyperglycemia (time >180 mg/dL, 250 mg/dL, 300 mg/dL; area under the curve 180 mg/dL; and percentage of days with ≥20 consecutive min of glucose concentrations >300 mg/dL), change in HbA_1c, and proportion of participants with both no worsening of HbA_1c by >0.3% (3.3 mmol/mol) and no severe hypoglycemic event. Safety outcomes were severe hypoglycemia (defined as an event that required assistance from another person to administer carbohydrate, glucagon, or other resuscitative actions); DKA; hyperglycemia not meeting the definition of DKA for which emergency evaluation or treatment was obtained from a health care provider or blood ketone levels ≥0.6 or ≥1.0 mmol/L; and other occurrences meeting the regulatory definition of a serious adverse event.

Sample size was determined for a noninferiority limit of 7.5% for the difference between treatment groups in the time in the range of 70–180 mg/dL over the course of 26 weeks. For 90% power, a one-sided α of 0.05, and assuming an SD of 14% with correlation of 0.48 between the baseline and outcome time in range (based on data from the JDRF CGM randomized trial [8]), the required sample size was estimated to be 122. However, to better assess CGM-only safety, the sample size was selected to be 225 participants randomly assigned 2:1 to the CGM only group or CGM+BGM group.

Analyses followed the intention-to-treat principle. The primary analysis was a treatment group comparison of time in range (70–180 mg/dL) during the 26-week trial by using an ANCOVA model adjusted for baseline time in range and site as a random effect. Confounding was assessed by repeating the analysis with the inclusion of potential confounding variables as covariates. Prespecified exploratory analyses were conducted to assess for interaction between the treatment effect on the time in range (70–180 mg/dL) during the 26-week trial and baseline factors by including interaction terms in the ANCOVA models. For the remaining CGM outcomes, treatment group comparisons were made by using ANCOVA models based on van der Waerden score rankings if the metric was skewed and adjusted for the corresponding baseline value and clinical site as a random effect.

Change in HbA_1c from baseline was compared between groups by using an ANCOVA model adjusted for baseline HbA_1c and site as a random effect. The proportions of participants with both no worsening of HbA_1c by >0.3% (3.3 mmol/mol) and no severe hypoglycemic event were compared between treatment groups by using a logistic regression model adjusted for baseline HbA_1c and site as a random effect. The percentages of subjects with at least one blood ketone level ≥0.6 mmol/L (and ≥1.0 mmol/L) were compared between treatment groups by using a logistic regression model adjusted for site as a random effect. The mean scores on the Diabetes Technology Questionnaire were compared between treatment groups by using ANCOVA models adjusted for site as a random effect. For the Hypoglycemia Fear Survey, the overall total score, the total score for the low–blood glucose questions (1–10), and the total score for the worrying questions (11–23) were each compared between treatment groups by using an ANCOVA model adjusted for the baseline value and site as a random effect.

Analyses were conducted with SAS 9.4 software (SAS Institute, Cary, NC). All P values are two-sided.

Between 22 May 2015 and 11 March 2016, 226 participants were assigned to either the CGM-only group (n = 149) or the CGM+BGM group (n = 77). Mean age was 44 ± 14 years (35 [15%] ≥60 years old), mean diabetes duration was 24 ± 12 years, and mean baseline HbA_1c was 7.0 ± 0.7% (53 ± 7.7 mmol/mol); 107 (47%) were CGM users, and 119 (53%) were not using CGM when enrolled. Participant characteristics according to treatment group are listed in Table 1.

One participant in the CGM-only group was determined after randomization to have been ineligible (percentage of time <60 mg/dL during blinded baseline CGM wear was >10%). Seven participants in the CGM-only group and two in the CGM+BGM group withdrew from the trial. Thus, the trial was completed by 142 (95%) of the CGM-only group participants and by 75 (97%) of the CGM+BGM group participants (Supplementary Figs. 2 and 3).

Among participants completing the trial, all in both groups were using CGM in month 6. CGM use averaged 6.7 ± 0.5 and 6.8 ± 0.4 days/week in the CGM-only and CGM+BGM groups, respectively, over the 26-week trial (Table 2), with 91% and 95% averaging ≥6 days/week. All participants in the CGM+BGM group and all but one in the CGM-only group averaged ≥5 days/week over the entire 26 weeks. Among participants ≥60 years old who completed the study, 95% in the CGM-only group (n = 21) and 92% in the CGM+BGM group (n = 13) averaged ≥6 days/week, and among participants <60 years old, 90% (n = 121) and 95% (n = 62) averaged ≥6 days/week. Among the completers of the trial, BGM tests per day from meter downloads (including the two required daily BGM tests) averaged 2.8 ± 0.9 in the CGM-only group and 5.4 ± 1.4 in the CGM+BGM group (P < 0.001).

Mean time spent in the range of 70–180 mg/dL was 63 ± 13% at both baseline and 26 weeks in the CGM-only group and 65 ± 13% and 65 ± 11%, respectively, in the CGM+BGM group (adjusted difference 0%; one-sided 95% CI −2%). Other CGM metrics of glucose control for mean glucose, hyperglycemia, hypoglycemia, and glycemic variability also showed little change from baseline to 26 weeks and no significant differences between groups (Table 3). Mean change in HbA_1c was 0.0% (0.0 mmol/mol) in each group (P = 0.41) (Table 3). Results were similar in subgroups based on age, duration, education, CGM use before study enrollment, baseline HbA_1c, and baseline time in range (Table 4). CGM and HbA_1c results also were similar between groups in the subset ≥60 years old (Supplementary Table 2).

No severe hypoglycemic events occurred in the CGM-only group, and one occurred in the CGM+BGM group. No occurrences of DKA occurred in either group. Other serious adverse events, unrelated to the study intervention, occurred in four (3%) participants in the CGM-only group and three (4%) in the CGM+BGM group (Supplementary Table 3). A blood ketone level ≥0.6 mmol/L occurred at least once in 48 (32%) participants in the CGM-only group and 26 (34%) in the CGM+BGM group (P = 0.79); the ketone level was ≥1.0 mmol/L at least once in 27 (18%) and 15 (19%) participants, respectively (P = 0.84).

Mean scores on the Diabetes Technology Questionnaire were 3.6 ± 0.6 in the CGM-only group and 3.8 ± 0.6 in the CGM+BGM group at baseline and 3.6 ± 0.6 in each group at 26 weeks (P = 0.58). There also was no significant difference between groups on the section of the questionnaire inquiring about change from prestudy (P = 0.28) (Supplementary Table 4). On the Hypoglycemia Fear Survey, total scores were 29 ± 11 in the CGM-only group and 28 ± 9 in the CGM+BGM group at baseline and 32 ± 11 and 31 ± 11 at 26 weeks, respectively (P = 0.88) (Supplementary Table 5).

This multicenter randomized trial was conducted to determine whether using CGM alone to make insulin dosing decisions is as safe and effective as using CGM as an adjunct to BGM. For the primary outcome of CGM-measured time in the glucose range of 70–180 mg/dL, use of CGM alone was shown to be noninferior to using CGM and BGM together. For this metric and all other efficacy outcomes for CGM-measured hyperglycemia, hypoglycemia, and glucose variability, results in the CGM-only and CGM+BGM groups were virtually identical as were the HbA_1c results. Scores obtained from the Diabetes Technology Questionnaire and Hypoglycemia Fear Survey also were similar in the two groups. From a safety perspective, no DKA events or severe hypoglycemic episodes occurred in the CGM-only group. Comparable results were found in participants who were experienced CGM users at study entry, in those who were CGM naive, in older versus younger participants, and in those with higher and lower education levels. In both treatment groups, mean time in range was similar at baseline and during follow-up, likely reflecting the excellent glycemic control of most participants entering the trial.

To our knowledge, this randomized trial is the first to assess the effectiveness and safety of insulin dosing by using CGM alone in adults with T1D. In addition to randomization and multiple center participation, the strengths of this study include a high degree of participant retention, CGM use, and treatment group adherence. Notably, there was good separation between the treatment groups in the number of BGM tests per day, particularly when recognizing that two of the BGM measurements per day were required for CGM calibration and that according to the protocol, the calibrations were performed at times such that they would not influence insulin bolusing.

The major limitation of the trial relates to the generalizability of the results based on the participant inclusion and exclusion criteria. The trial cohort included adults with T1D who used an insulin pump and were well controlled (mean HbA_1c 7.0% [53 mmol/mol]) and likely to adhere to the study protocol and excluded individuals with significant hypoglycemia unawareness or a substantial amount of CGM-measured hypoglycemia. Although the trial only included pump users to be able to document when an insulin bolus was given, it seems reasonable to apply the results to individuals who use multiple daily injections of insulin who otherwise fit the profile of the study participants because the impact of sensor inaccuracy in determining the amount of a bolus should be similar in pump users and injection users (8,22). The results of this study support the need for future studies to assess the safety of CGM used without routine BGM testing in youth and in less-compliant adults than those included in this study, such as individuals with higher HbA_1c levels, who perform BGM testing fewer than four times a day, and with hypoglycemia unawareness (23).

The application of this trial’s results to clinical practice can benefit people with T1D by reducing their burden of multiple daily fingersticks when using CGM and can enhance the cost-effectiveness of CGM therapy by reducing the number of daily BGM test strips. Furthermore, the demonstration that insulin dosing based on CGM alone is safe has applicability to assessing risk involved with artificial pancreas systems that automate insulin delivery based on CGM sensor glucose measurements.

In conclusion, in adults with well-controlled T1D meeting the eligibility criteria for this trial, use of CGM without regular use of confirmatory BGM is as safe and effective as using CGM with a confirmatory BGM measurement for insulin dosing.

Funding. Funding was provided by the Leona M. and Harry B. Helmsley Charitable Trust. Dexcom provided the CGM systems used in the trial.

Duality of Interest. G.A. has served on a scientific advisory board for Diasend and Novo Nordisk and received consultancy payments from Dexcom. G.A.'s employer has received research support from Novo Nordisk and Bristol-Myers Squibb/AstraZeneca with no personal income to G.A. D.F.K. has served on a scientific advisory board for Novo Nordisk, Abbott, Eli Lilly, Sanofi, and Janssen. D.F.K. has received speaker fees from Janssen, Valeritas, AstraZeneca, Eli Lilly, Novo Nordisk, and Dexcom. D.F.K.'s employer has received research support from AstraZeneca, Eli Lilly, Novo Nordisk, Dexcom, and Lexicon. D.F.K. holds stock in Dexcom. A.L.P. has served on a scientific advisory board and consulted for Abbott, Becton Dickinson, Bigfoot Biomedical, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Intarcia, Janssen, Lexicon, Medtronic-MiniMed, Merck, Novo Nordisk, Omada Health, OptumRx, Sanofi, and UnitedHealthcare and received editorial fees from Medscape. A.L.P.'s employer has received research support from Dexcom. I.H. has received consultancy fees from Abbott Diabetes Care, Roche, and Intarcia. R.M.B. has served on a scientific advisory board and received consultancy fees from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb/AstraZeneca, Dexcom, Eli Lilly, Halozyme, Johnson & Johnson, Medtronic, Novo Nordisk, Roche, Sanofi, and Takeda. R.M.B.'s employer has contracts with the following companies for his services with no personal income to R.M.B.: Abbott, Boehringer Ingelheim, Bristol-Myers Squibb/AstraZeneca, Dexcom, Eli Lilly, Halozyme, Johnson & Johnson, Medtronic, Novo Nordisk, Roche, Sanofi, Takeda, and Merck. R.M.B. has inherited Merck stock. A.J.A. has received consultancy fees from Dexcom, Lexicon, Medtronic, and Novo Nordisk. A.J.A.'s nonprofit employer has received research support from Dexcom, Lexicon, Medtronic, and Novo Nordisk with no personal compensation to A.J.A. V.N.S. has received speaking fees from Dexcom. A.P.-T. has served on a scientific advisory board and received consultancy fees from Boehringer Ingelheim, Bristol-Myers Squibb/AstraZeneca, Dexcom, Eli Lilly, Halozyme, Lexicon, Merck, Medtronic, Mylan, Novo Nordisk, and Sanofi. A.P.-T.'s employer has contracts with the following companies for her services with no personal income to A.P.T.: Boehringer Ingelheim, Bristol-Myers Squibb/AstraZeneca, Dexcom, Eli Lilly, Halozyme, Lexicon, Merck, Medtronic, Mylan, Novo Nordisk, and Sanofi. H.R. has served on a scientific advisory board for Elli Lilly, Merck, Novartis, and Novo Nordisk. H.R. received research grant support from Bristol-Myers Squibb, Daiichi Sankyo, and Lexicon. H.R.'s employer has received research support from Medtronic and Merck. A.B. has served on a scientific advisory board for Abbott and Janssen and received speaker fees from AstraZeneca and Sanofi. A.B. has received research grant support from Novo Nordisk, Eli Lilly, AbbVie, MannKind Corporation, Orexigen Therapeutics, Inc., Sanofi, Jaeb, Merck, GlaxoSmithKline, University of Oxford, Bristol-Myers Squibb, Boehringer Ingelheim, Duke University Medical Center, Medtronic, AstraZeneca, and Halozyme. R.W.B.'s employer has received research support and study supplies from Dexcom and Abbott Diabetes Care. No other potential conflicts of interest relevant to this article were reported.

Author Contributions. G.A., K.J.R., and R.W.B. contributed to the data interpretation and wrote and edited the manuscript. T.D.R. performed statistical analyses and wrote and edited the manuscript. D.F.K., A.L.P., I.H., R.M.B., E.T., A.J.A., V.N.S., M.R.R., B.W.B., A.P.-T., R.P.-B., H.R., E.E., A.B., and C.K. contributed to the data interpretation and reviewed and edited the manuscript. R.W.B. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.

Detroit, Michigan, Henry Ford Health System (n = 27), Davida Kruger (PI), Terra Cushman (C); Los Angeles, California, University of Southern California Community Diabetes Initiatives (n = 19), Anne Peters (PI), Mark Harmel (C); Seattle, Washington, University of Washington Diabetes Care Center (n = 19), Irl Hirsch (PI), Dori Khakpour (C); Minneapolis, Minnesota, Park Nicollet International Diabetes Center Adult Endocrinology (n = 18), Richard Bergenstal (PI), Beth Olson (C); Chicago, Illinois, Northwestern University (n = 18), Grazia Aleppo (PI), Elaine Massaro (C), Teresa Pollack (C); Boston, Massachusetts, Joslin Diabetes Center Adult Diabetes (n = 16), Elena Toschi (PI), Astrid Atakov-Castillo (C); Portland, Oregon, Harold Schnitzer Diabetes Health Center at Oregon Health & Science University (n = 15), Andrew Ahmann (PI), Kristin Jahnke (C); Aurora, Colorado, University of Colorado/Denver, Barbara Davis Center for Childhood Diabetes (n = 15), Viral N. Shah (PI), Terra Thompson (C); Philadelphia, Pennsylvania, University of Pennsylvania Perelman School of Medicine Penn Rodebaugh Diabetes Center (n = 15), Michael Rickels (PI), Amy Peleckis (I), Shannon O’Brien (I), Cornelia Dalton-Bakes (C); Atlanta, Georgia, Atlanta Diabetes Associates (n = 14), Bruce Bode (PI), Siana Tyler (C); San Diego, California, Scripps Whittier Diabetes Institute (n = 14), Athena Philis-Tsimikas (PI), Rosario Rosal (C); Ann Arbor, Michigan, University of Michigan (n = 13), Rodica Pop-Busui (PI), Cynthia Plunkett (C); Tampa, Florida, University of South Florida Diabetes Center (n = 12), Henry Rodriguez (PI), Emily Eyth (C); Des Moines, Iowa, Iowa Diabetes and Endocrinology Research Center (n = 8), Anuj Bhargava (PI), Lisa Borg (C).