Patients with diabetes and end-stage kidney disease (ESKD) may experience “burnt-out diabetes,” defined as having an HbA1c value <6.5% without antidiabetic therapy for >6 months. We aim to assess glycemic control by continuous glucose monitoring (Dexcom G6 CGM) metrics and glycemic markers in ESKD patients on hemodialysis with burnt-out diabetes.
In this pilot prospective study, glycemic control was assessed by continuous glucose monitoring (CGM), HbA1c measures, and glycated albumin and fructosamine measurements in patients with burnt-out diabetes (n = 20) and without a history of diabetes (n = 20).
Patients with burnt-out diabetes had higher CGM-measured daily glucose levels, lower percent time in the range 70–180 mg/dL, higher percent time above range (>250 mg/dL), and longer duration of hyperglycemia >180 mg/dL (hours/day) compared with patients without diabetes (all P < 0.01). HbA1c and fructosamine levels were similar; however, patients with burnt-out diabetes had higher levels of glycated albumin than did patients without diabetes.
The use of CGM demonstrated that patients with burnt-out diabetes have significant undiagnosed hyperglycemia. CGM and glycated albumin provide better assessment of glycemic control than do values of HbA1c and fructosamine in patients with ESKD.
Diabetes is the leading cause of end-stage kidney disease (ESKD) and need for dialysis, accounting for approximately 45% of all ESKD cases in the United States (1,2). Glycosylated hemoglobin (HbA1c) has been the gold standard to assess glycemic control in patients with diabetes (3). Although HbA1c is associated with chronic complications of diabetes in patients with normal kidney function, its predictive value is uncertain in patients with ESKD (4,5). To overcome the limitations of HbA1c, alternative methods to assess glycemic control have been proposed, including using fructosamine and glycated albumin measurements (6–9). Continuous glucose monitoring (CGM) provides a more comprehensive glycemic control assessment than does intermittent capillary glucose monitoring and HbA1c in ambulatory patients (4) Although the accuracy of CGM in ESKD has not been established, a recent prospective study with patients with type 1 and type 2 diabetes reported an acceptable accuracy of CGM in patients with chronic kidney disease (10).
Approximately 20% of patients with diabetes and ESKD experience “burnt-out” diabetes, defined as having an HbA1c of <6.5% without antidiabetic therapy for >6 months (8,9,11). Whether patients with burnt-out diabetes are truly euglycemic or they continue to have hyperglycemia but are misdiagnosed due to limitations of HbA1c is unknown. To address this knowledge gap, we compared glycemic control as measured by CGM and glycemic markers (HbA1c, glycated albumin, and fructosamine) in patients with ESKD, in patients with burnt-out diabetes, and in patients with ESKD and without known history of diabetes. We hypothesized that the use of CGM would improve assessment of glycemic control compared with traditional glycemic markers.
Research Design and Methods
This pilot prospective study included 20 patients with ESKD who were undergoing hemodialysis and who had burnt-out diabetes and 20 patients with ESKD without a previous history of diabetes. Patients with burnt-out diabetes had a confirmed diagnosis of diabetes, had been undergoing hemodialysis for >3 months, and had an HbA1c <6.5% when not taking antidiabetic therapy for >6 months. Patients in the control group had no history of diabetes or use of antidiabetic therapy, had been undergoing hemodialysis for >3 months, and had an HbA1c <6.5%. Patients were enrolled from Emory dialysis centers in Atlanta, Georgia. The study protocol and informed consent were approved by the Emory University Institution Review Board.
All patients wore for 10 days a blinded Dexcom G6 CGM (Dexcom, San Diego, CA) placed by the study coordinator in the lower abdomen. Blood samples for routine chemistry values, HbA1c, and fructosamine, and glycated albumin levels were collected before a dialysis session.
The primary end point included differences in mean daily glucose level and time in range 70–180 mg/dL by CGM between groups. Secondary outcomes included differences in percentage of time above range >180 mg/dL and >250 mg/dL, and number of total hypoglycemic episodes per participant with glucose <70 mg/dL and <54 mg/dL. A hyperglycemic or hypoglycemic episode was defined by at least 15 min or three consecutive CGM readings. We also evaluated differences in nocturnal hyperglycemia and hypoglycemia, and differences in glycemic variability by mean amplitude glycemic excursion, coefficient of variation and SD.
Statistical Analysis
The data were summarized as mean ± SD for continuous variables and count (percentage) for discrete variables, unless otherwise specified. We made the comparisons using the nonparametric Wilcoxon test for continuous variables and χ2 tests (or Fisher exact tests) for discrete variables. A two-sided P value of <0.05 was considered statistically significant.
Results
Demographic and clinical characteristics are detailed in Table 1. There were no significant differences in age, sex, race, duration of diabetes and hemodialysis, HbA1c, or history of diabetic complications or comorbidities between the two groups (Table 1). Patients with burnt-out diabetes had a median duration of dialysis of 3.0 (interquartile range = 2.0–5.5) years, median duration of diabetes of 15.0 (interquartile range = 10.0–20.0) years, and had discontinued their glucose-lowering medications for an average of 2.2 years. Three patients with burnt-out diabetes stopped their antidiabetic medications before starting dialysis, 11 stopped them after starting hemodialysis, and 6 participants were unsure of the timeline but confirmed not taking them and had no diabetes medications listed in medical records. Patients with ESKD without history of diabetes had a median duration of dialysis of 6.0 (interquartile range = 2.4–8.5) years (Table 1).
Clinical characteristics in patients with ESKD and ether burnt-out diabetes or no known history of diabetes
. | Burnt-out diabetes (n = 20) . | No diabetes (n = 20) . | P value . |
---|---|---|---|
Age, years | 62.7 ± 8.3 | 60.1 ± 9.5 | 0.35 |
Sex, n (%) | 0.75 | ||
Male | 10 (50) | 12 (60) | |
Female | 10 (50) | 8 (40) | |
BMI, kg/m2 | 31.9 ± 5.5 | 23.5 ± 6.0 | <0.001 |
Black race, n (%) | 20 (100) | 20 (100) | |
Systolic BP, mmHg | 140.0 ± 28.2 | 139.8 ± 34.0 | 0.66 |
Diastolic BP, mmHg | 70.4 ± 15.9 | 82.4 ± 18.4 | 0.036 |
Duration of diabetes, median (Q1, Q3) | 15.0 (10–20) | NA | |
Duration of dialysis, median (Q1, Q3) | 3.0 (2.0–5.5) | 6.0 (2.4–8.5) | 0.23 |
Treatment and comorbidities | |||
Prior insulin use, n (%) | 14 (70) | 0 (0) | . |
EPO equivalent* | 26.5 ± 30 | 46.3 ± 49 | 0.40 |
Coronary artery disease, n (%) | 7 (35) | 3 (15) | 0.27 |
Heart failure, n (%) | 14 (70) | 15 (75) | 1.00 |
Hypertension, n (%) | 20 (100) | 18 (90) | 0.49 |
Laboratory values | |||
Hemoglobin, g/dL | 11.2 ± 0.9 | 10.8 ± 1.2 | 0.26 |
Hematocrit, % | 34.8 ± 2.2 | 33.7 ± 4.2 | 0.45 |
Ferritin, ng/mL | 631 ± 251 | 682 ± 322 | 0.40 |
TSAT, % | 36 ± 10 | 23 ± 10 | 0.70 |
Mean HbA1c, % | 5.5 ± 0.6 | 5.3 ± 0.5 | 0.22 |
HbA1c category, n (%) | 0.52 | ||
<5.7% | 10 (50) | 13 (65) | |
5.7% to <6.5% | 10 (50) | 7 (35) | |
Mean glycated albumin, % | 17.1 ± 3.6 | 14.5 ± 2.2 | 0.022 |
Glycated albumin level, n (%) | 0.10 | ||
<13.6% | 2 (11) | 7 (39) | |
13.6% to <16% | 4 (22) | 5 (28) | |
≥16% | 12 (67) | 6 (33) | |
Mean fructosamine, mmol/L | 330.7 ± 57.6 | 315.1 ± 36.6 | 0.69 |
Fructosamine level, mmol/L, n (%) | 0.69 | ||
<285 | 3 (17) | 5 (28) | |
≥285 | 15 (83) | 13 (72) |
. | Burnt-out diabetes (n = 20) . | No diabetes (n = 20) . | P value . |
---|---|---|---|
Age, years | 62.7 ± 8.3 | 60.1 ± 9.5 | 0.35 |
Sex, n (%) | 0.75 | ||
Male | 10 (50) | 12 (60) | |
Female | 10 (50) | 8 (40) | |
BMI, kg/m2 | 31.9 ± 5.5 | 23.5 ± 6.0 | <0.001 |
Black race, n (%) | 20 (100) | 20 (100) | |
Systolic BP, mmHg | 140.0 ± 28.2 | 139.8 ± 34.0 | 0.66 |
Diastolic BP, mmHg | 70.4 ± 15.9 | 82.4 ± 18.4 | 0.036 |
Duration of diabetes, median (Q1, Q3) | 15.0 (10–20) | NA | |
Duration of dialysis, median (Q1, Q3) | 3.0 (2.0–5.5) | 6.0 (2.4–8.5) | 0.23 |
Treatment and comorbidities | |||
Prior insulin use, n (%) | 14 (70) | 0 (0) | . |
EPO equivalent* | 26.5 ± 30 | 46.3 ± 49 | 0.40 |
Coronary artery disease, n (%) | 7 (35) | 3 (15) | 0.27 |
Heart failure, n (%) | 14 (70) | 15 (75) | 1.00 |
Hypertension, n (%) | 20 (100) | 18 (90) | 0.49 |
Laboratory values | |||
Hemoglobin, g/dL | 11.2 ± 0.9 | 10.8 ± 1.2 | 0.26 |
Hematocrit, % | 34.8 ± 2.2 | 33.7 ± 4.2 | 0.45 |
Ferritin, ng/mL | 631 ± 251 | 682 ± 322 | 0.40 |
TSAT, % | 36 ± 10 | 23 ± 10 | 0.70 |
Mean HbA1c, % | 5.5 ± 0.6 | 5.3 ± 0.5 | 0.22 |
HbA1c category, n (%) | 0.52 | ||
<5.7% | 10 (50) | 13 (65) | |
5.7% to <6.5% | 10 (50) | 7 (35) | |
Mean glycated albumin, % | 17.1 ± 3.6 | 14.5 ± 2.2 | 0.022 |
Glycated albumin level, n (%) | 0.10 | ||
<13.6% | 2 (11) | 7 (39) | |
13.6% to <16% | 4 (22) | 5 (28) | |
≥16% | 12 (67) | 6 (33) | |
Mean fructosamine, mmol/L | 330.7 ± 57.6 | 315.1 ± 36.6 | 0.69 |
Fructosamine level, mmol/L, n (%) | 0.69 | ||
<285 | 3 (17) | 5 (28) | |
≥285 | 15 (83) | 13 (72) |
Data are reported as mean ± SD. BP, blood pressure; EPO, erythropoietin; NA, not applicable; Q, quartile; TSAT, transferrin serum iron saturation.
Total EPO equivalent given during 30 days after placement of CGM device.
Patients with burnt-out diabetes had higher mean daily glucose level according to CGM (141.7 ± 22.3 vs. 126.7 ± 13.7 mg/dL; P = 0.009); lower percent time in range 70–180 mg/dL (80.4 ± 14.0 vs. 93.9 ± 6.4; P < 0.001); higher percent time above range >180 mg/dL (17.2 ± 14 vs. 4.6 ± 5.3; P < 0.001), >200 mg/dL (10.0% ± 11% vs.1.9% ± 2.9%; P < 0.001), and >250 mg/dL (1.99% ± 3.0% vs. 0.13% ± 0.4%, P = 0.015); and longer duration of hyperglycemia >180 mg/dL (4.1 ± 3.4 vs. 1.1 ± 1.3 h/day; P < 0.001) compared with patients without diabetes (Table 2). Duration of hypoglycemia <70 mg/dL did not vary between groups (P = 0.99).
Glycemic control metrics by CGM
. | Burn-out diabetes (n = 20) . | No diabetes (n = 18) . | P value . |
---|---|---|---|
Glycemic control | |||
% TIR 70–180 mg/dL | 80.4 ± 14.0 | 94.0 ± 6.4 | <0.001 |
% TAR >180 mg/dL | 17.2 ± 14.1 | 4.6 ± 5.3 | <0.001 |
% TAR >250 mg/dL | 2.0 ± 3.0 | 0.1 ± 0.4 | 0.015 |
Duration >180 mg/dL, hours/day | 4.1 ± 3.4 | 1.1 ± 1.3 | <0.001 |
Duration >250 mg/dL, hours/day | 0.5 ± 0.7 | 0.1 ± 0.1 | 0.015 |
% TBR <70 mg/dL | 2.5 ± 5.8 | 1.5 ± 5.0 | 0.99 |
% TBR <54 mg/dL | 1.3 ± 3.5 | 0.4 ± 1.7 | 0.11 |
Mean daily glucose, mg/dL | 141.7 ± 22.2 | 125.7 ± 13.7 | 0.009 |
Glycemic variability | |||
Mean amplitude glycemic excursion | 54.9 ± 18.2 | 42.4 ± 9.4 | 0.013 |
SD | 36.3 ± 10.2 | 24.9 ± 4.3 | <0.001 |
Coefficient of variation | 0.3 ± 0.1 | 0.2 ± 0.1 | 0.002 |
. | Burn-out diabetes (n = 20) . | No diabetes (n = 18) . | P value . |
---|---|---|---|
Glycemic control | |||
% TIR 70–180 mg/dL | 80.4 ± 14.0 | 94.0 ± 6.4 | <0.001 |
% TAR >180 mg/dL | 17.2 ± 14.1 | 4.6 ± 5.3 | <0.001 |
% TAR >250 mg/dL | 2.0 ± 3.0 | 0.1 ± 0.4 | 0.015 |
Duration >180 mg/dL, hours/day | 4.1 ± 3.4 | 1.1 ± 1.3 | <0.001 |
Duration >250 mg/dL, hours/day | 0.5 ± 0.7 | 0.1 ± 0.1 | 0.015 |
% TBR <70 mg/dL | 2.5 ± 5.8 | 1.5 ± 5.0 | 0.99 |
% TBR <54 mg/dL | 1.3 ± 3.5 | 0.4 ± 1.7 | 0.11 |
Mean daily glucose, mg/dL | 141.7 ± 22.2 | 125.7 ± 13.7 | 0.009 |
Glycemic variability | |||
Mean amplitude glycemic excursion | 54.9 ± 18.2 | 42.4 ± 9.4 | 0.013 |
SD | 36.3 ± 10.2 | 24.9 ± 4.3 | <0.001 |
Coefficient of variation | 0.3 ± 0.1 | 0.2 ± 0.1 | 0.002 |
TAR, time above range; TBR, time below range; TIR, time in range.
Hyperglycemia duration by CGM for >15 min.
The individual CGM glucose profiles during the 10 days of the study period in patients with burnt-out diabetes and those without a history of diabetes are shown in Fig. 1A and B. All patients with burnt-out diabetes experienced multiple episodes of glucose excursions >180 mg/dL, and 55% had glucose values >250 mg/dL. The mean CGM glucose level was lower in patients without a history of diabetes (P < 0.009); many patients had episodes of hyperglycemia >180 mg/dL; and 3 patients (17%) had hyperglycemic episodes measured by CGM >250 mg/dL (Fig. 1B).
Mean glucose among patients with burn-out diabetes measured by CGM over 10 days. A) Patients with burnt-out diabetes. B) Patients without a history of diabetes.
Mean glucose among patients with burn-out diabetes measured by CGM over 10 days. A) Patients with burnt-out diabetes. B) Patients without a history of diabetes.
The mean HbA1c in the burnt-out group was 5.5% ± 0.6%, with 50% of patients having an HbA1c <5.7% and 50% having an HbA1c between 5.7% and 6.5%. The mean HbA1c in patients without history of diabetes was 5.3% ± 0.5% (P = 0.22), with 65% of these having HbA1c <5.7% and 35% having an HbA1c between 5.7% and 6.5% (P = 0.52) (Table 1). There were no differences in fructosamine levels (330.7 ± 57.6 vs. 315.1 ± 36.6 mmol/L; P = 0.69). Levels of glycated albumin were higher among patients with burnt-out diabetes compared with those with no history of diabetes (17.1% ± 3.6% vs. 14.5% ± 2.2%; P = 0.02), with 67% of patients with burnt-out diabetes having high glycated albumin levels (>16%) compared with 33% of patients without history of diabetes (Table 1 and Supplementary Fig. 1).
Compared with patients without diabetes, those with burnt-out diabetes had higher glycemic variability (mean amplitude of glycemic excursion: 54.9 ± 18.2 vs. 42.4 ± 9.4, P = 0.013; coefficient of variation: 0.26 ± 0.06 vs. 0.20 ± 0.03, P = 0.13; and SD 36.3 ± 10.2 vs. 24.9 ± 4.3, P < 0.001) (Table 2).
Conclusions
Our pilot study using CGM demonstrated that patients with burnt-out diabetes have higher mean daily glucose levels with repeated episodes of hyperglycemia >180 mg/dL, and higher glycemic variability compared with patients with ESKD without a history of diabetes. The use of CGM and glycated albumin provided better assessment of glycemic control compared with HbA1c and fructosamine levels. Our findings indicate that CGM improves the assessment of glycemic control in patients with ESKD better than HbA1c and that the burnt-out status is a reflection of the inadequacy of using HbA1c rather than a “true” normalization of glycemic control.
Clinical guidelines have recommended using HbA1c to assess glycemic control and guide diabetes management in patients with ESKD (4,12,13). However, falsely low HbA1c levels in ESKD are commonly reported in the presence of anemia, use of erythropoietin-stimulating agents, reduced erythrocyte life span from uremia, and erythrocyte lysis during the hemodialysis procedure (2,14). Alternative glycemic markers such as fructosamine and glycated albumin have been developed. They reflect glycemia during the past 2–4 weeks and presumably are more reliable than the HbA1c (4,5,15). However, these biomarkers may be affected by altered albumin metabolism in the setting of ESKD (16). The lack of accurate glycemic markers represents a major challenge in assessing and optimizing glycemic management in patients with ESKD and dialysis (17).
Our study highlights the limitations of currently recommended indicators of glycemic control (i.e., HbA1c, fructosamine levels) in patients with ESKD who are undergoing dialysis. Despite having an HbA1c <6.5%, all patients with burnt-out diabetes had significant hyperglycemia by CGM (Figs. 1 and 2). Of interest, many patients without previous history of diabetes also experienced episodes of hyperglycemia by CGM, suggesting that they may have undiagnosed diabetes. In addition, our study confirms that measuring glycated albumin, but not fructosamine, may be a more useful tool for assessing glycemic control in patients with ESKD who are undergoing dialysis.
Markers of glycemic control (HbA1c, fructosamine, and glycated albumin) in patients with ESKD with burnt-out diabetes and without a history of diabetes. Red boxes indicate burnt-out diabetes. Blue boxes indicate no history of diabetes.
Markers of glycemic control (HbA1c, fructosamine, and glycated albumin) in patients with ESKD with burnt-out diabetes and without a history of diabetes. Red boxes indicate burnt-out diabetes. Blue boxes indicate no history of diabetes.
Limitations of the study include a small number of participants with only 10-day assessment with CGM. Thus, trends could be missed that would appear over a longer wear time. All participants were African American and undergoing hemodialysis, thus our results cannot be generalizable to other racial groups or those receiving peritoneal dialysis. We limited the assessment of glycemic control to HbA1c, fructosamine levels, and glycated albumin levels, which may not be accurate glycemic tools in this population, so we do not know if patients without a previous history of diabetes with detected hyperglycemia by CGM had a diagnosis of diabetes.
In summary, the use of CGM demonstrated that patients with burnt-out diabetes have significant undiagnosed hyperglycemia, and that HbA1c and fructosamine levels are not reliable markers for assessing glycemic control in patients with ESKD. CGM and glycated albumin provide better assessment of glycemic control than do HbA1c and fructosamine levels in patients with ESKD. Studies are needed to understand the possible utility of continued treatment of hyperglycemia in this population. The outcomes of this study show promise for more precise monitoring of glycemic control, providing insight to the best screening, monitoring, and treatment for those undergoing dialysis, via the use of CGM.
This article contains supplementary material online at https://doi.org/10.2337/figshare.24574531.
This article is featured in a podcast available at https://diabetesjournals.org/journals/pages/diabetes-core-update-podcasts.
Article Information
Funding. R.J.G. is partially supported by research grants from the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; grants P30DK111024 and 1K23DK123384-03). P.V. is supported in part by NIH grant 1K23DK113241. G.E.U. is partly supported by research grants from the NATS (grant UL 3UL1TR002378-05S2) from the Clinical and Translational Science Award program and from the NIH NIDDK and National Center for Research Resources (grant 2P30DK111024-06). R.G.M. received support from the NIDDK (grants K23DK114497, R03DK127010), the National Institute on Aging (grant R01AG079113), PCORI (grant DB-2020C2-20306), and National Center for Advancing Translational Sciences (grant UL1TR002377).
Dexcom provided CGM devices, a device reader, and adhesive patches to the study team. The Jacob’s Fund for Education provided the funds for the gift cards for the participants and the cost of research study.
Duality of Interest. R.J.G. received research support outside of this work via Emory University for investigator-initiated studies from Novo Nordisk, Dexcom, and Eli Lilly, and consulting fees from Abbott Diabetes Care, Dexcom, Sanofi, Eli Lilly, Bayer, and Novo Nordisk. PV has received consulting fees from Mitre. G.E.U. has received research support (to Emory University) from Bayer, Abbott, and Dexcom, and has served on advisory boards for Dexcom and Glycare. R.G.M. serves as a consultant to Emmi (Wolters Kluwer) on developing patient education materials related to diabetes. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. R.J.G. and G.E.U. designed the study and wrote the research proposal. C.Y.K. and G.E.U. researched the data and wrote the initial drafts of the manuscript. C.Y.K., Z.Z., B.M., and A.G. served as study coordinators, screening and randomizing research candidates, collecting data, and ensuring successful completion of the study protocol. R.J.G., J.E.N., R.G.M., M.F., P.V., and T.I. reviewed and edited the study proposal and manuscript. L.P. analyzed the data. G.E.U. wrote the research proposal and 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 the accuracy of the data analysis.
Prior Presentation. Part of this work was presented in a poster at the American Diabetes Association 83rd Scientific Sessions, San Diego, CA, 23–26 June 2023.