Abstract
Introduction
Differences in biochemical parameters of diabetic ketoacidosis in patients with end-stage kidney disease (ESKD) has not been established. Accordingly, we assessed the relationship between degree of metabolic acidosis and ß-hydroxybutyrate in patients with ESKD (eGFR < 15 mL/min/1.73 m2), moderate renal failure (eGFR 15–60), or preserved renal function (eGFR > 60).
Methods
This observational study included adults (18–80 years) with diabetes ketoacidosis (DKA), admitted to Emory University Hospitals between January 1, 2006 to December 31, 2016. DKA and renal stages were confirmed on admission laboratory values.
Results
Admission bicarbonate levels (13.9 ± 5 vs 13.4 ± 5.3 vs 13.8 ± 4.2 mmol/L, P = 0.7), and pH levels (7.2 ± 0.3 vs 7.2 ± 0.2 vs 7.2 ± 0.2, P = 0.8) were similar among groups. Patients with ESKD had lower mean ß-hydroxybutyrate level (4.3 ± 3.3 vs 5.6 ± 2.9 vs 5.9 ± 2.5 mmol/L, P = 0.01), but higher admission glucose (852 ± 340.4 vs 714.6 ± 253.3 mg/dL vs 518 ± 185.7 mg/dL, P < 0.01), anion gap (23.4 ± 7.6 vs 23 ± 6.9 vs 19.5 ± 4.7 mmol/L, P < 0.01), and osmolality (306 ± 20.6 vs 303.5 ± vs 293.1 ± 3.1mOsm/kg, P < 0.01) compared with patients with moderate renal failure and preserved renal function, respectively. The sensitivity of ß-hydroxybutyrate > 3 mmol/L for diagnosing DKA by bicarbonate level < 15 and <18 mmol/L was 86.9% and 72% in ESKD, 89.3% and 83.7% in moderate renal failure, and 96.2% and 88.3% in preserved renal function. In patients with ESKD, the corresponding ß-hydroxybutyrate with bicarbonate levels < 10, 10–15, <18 mmol/L were 5.5, 3.9, 3.0 mmol/L, respectively.
Conclusions
Significant metabolic differences were found among DKA patients with different levels of renal function. In patients with ESKD, a ß-hydroxybutyrate level > 3 mmol/L may assist with confirmation of DKA diagnosis.
Keywords: diabetes ketoacidosis, end-stage kidney disease, chronic kidney disease, hyperglycemic crises, diagnosis
The American Diabetes Association (ADA) diagnostic criteria for diabetes ketoacidosis (DKA) includes a triad of hyperglycemia, with a plasma glucose > 250 mg/dl; metabolic acidosis, with a pH of < 7.30, and a serum bicarbonate of ≤ 18 mmol/L; and elevated plasma and/or urinary ketones. The condition is classified as mild, moderate, or severe, depending on the extent of metabolic acidosis (1). The key diagnostic criterion is an elevation in the serum concentration of ketone bodies. Confirmation of increased ketone production has been performed using either the nitroprusside reaction for a semiquantitative estimation of acetoacetate and acetone levels in the plasma or urine, or by direct measurement of β-hydroxybutyrate, which is the predominant ketone body among patients with DKA (2, 3).
In adults, a ß-hydroxybutyrate concentration of 3.0 and 4.4 mmol/L corresponds to a bicarbonate of 18.0 and 15.0 mmol/L, respectively (4). Therefore, international guidelines have recommended a ß-hydroxybutyrate > 3 mmol/L and a bicarbonate level < 18 mmol/L as the prime diagnostic features of DKA (5, 6). These diagnostic criteria, however, may create challenges in the setting of mixed acid-based disorders, such as chronic renal failure, increased lactate production, and hyperchloremic acidosis (7, 8).
In a recent study, we reported that end-stage renal disease patients hospitalized with DKA presented with higher admission blood glucose, anion gap, and serum osmolality, but with lower ß-hydroxybutyrate compared with patients with preserved kidney function and estimated glomerular filtration rate (eGFR) > 60 mL/min/1.73 m (9). In addition, there is limited evidence on ß-hydroxybutyrate metabolism and clearance of ketones bodies in patients with chronic renal failure and end-stage kidney disease (ESKD) on dialysis. Because a potential discrepancy between severity of acidosis and ß-hydroxybutyrate concentration may complicate the diagnosis of DKA in ESKD patients, we assessed the association between metabolic acidosis and ß-hydroxybutyrate concentration in patients admitted with DKA according to kidney function in patients with preserved kidney function and progressively impaired kidney failure, including ESKD on dialysis.
Methods
Study population
We included adult hospitalized patients between 18 and 80 years of age, with at least 1 measured ß-hydroxybutyrate value, admitted with an International Classification of Diseases, 9th and 10th version (ICD-9/10) code for DKA and ESKD on chronic maintenance hemodialysis, to Emory University Hospitals between January 1, 2006 and December 31, 2016. We excluded pregnant patients, those with multiple hospitalizations, and patients not meeting the laboratory diagnosis criteria of DKA (1).
Cohort creation
We searched the Emory Clinical Data Warehouse for patients with admission diagnosis of DKA and ESKD on hemodialysis by prespecified ICD-9/10 criteria, as previously described (9, 10). We further included only the first admission, and then confirmed the diagnosis of DKA for all subjects by using prespecified laboratory diagnostic criteria set by the ADA (1). The diagnosis of ESKD was confirmed by laboratory data (estimated glomerular filtration rate [eGFR] < 15 mL/min/1.73 m2) on admission. For comparison, we divided patients into 3 groups based on eGFR (eGFR < 15 mL/min/1.73 m2 for ESKD, >15–60 mL/min/1.73 m2 for moderate renal failure, and > 60 mL/min/1.73 m2 for preserved renal function).
We also examined the correlation between ß-hydroxybutyrate concentration on admission and serum bicarbonate levels < 10, and between 10 and 15 and <18 mmol/L, corresponding to severe, moderate, and mild DKA based on the ADA’s guidelines (1). Patients were managed by their hospital teams with a nurse-driven protocol available across all Emory hospitals, based on the ADA guidelines for DKA management. The study was approved by the Institutional Review Board of Emory University.
Study variables
We collected the following patient demographics: age, gender, race, ethnicity, body mass index (BMI), admission, and inpatient laboratory values, including hemoglobin A1c (HbA1c), glucose, pH, ketones, serum osmolality, anion gap, serum sodium, serum potassium, and eGFR. ß-hydroxybutyrate was measured by a standard enzymatic method at Emory Laboratory.
Statistical analysis
Patient characteristics were summarized using mean and standard deviation for continuous variables and proportions for categorical variables. The comparisons among patients with ESKD, moderate renal failure, and preserved renal function were evaluated using Kruskal Wallis test or χ 2 test (or Fisher exact test), respectively. We further measured how serum bicarbonate levels correlated with ß-hydroxybutyrate within each group using Pearson’s correlation coefficient (r). Statistical tests were all performed with a two-sided significance level of 0.05. All analyses were conducted based on available cases and using SAS software, version 9.4 (SAS Institute Inc, Cary, NC, USA).
Results
Among the 504 patients meeting the inclusion criteria, a total of 49 (9.7%) patients had ESKD, 305 (60.5%) had moderate renal failure (eGFR 15–60 mL/min/1.73 m2), and 150 (29.8%) patients had preserved renal function (eGFR > 60 mL/min/1.73 m2). Baseline and biochemical parameters on admission are listed in Table 1.
Table 1.
Baseline and biochemical characteristics
| Characteristic | Preserved Renal Function (n = 150, 29.8%) | Moderate Renal Failure (n = 305, 60.5%) | End Stage Kidney Disease (n = 49, 9.7%) | P-value |
|---|---|---|---|---|
| Age | 35.6 ± 14.0 | 51.0 ± 16.8 | 50.5 ± 17.0 | <0.0001 |
| Gender, No. (%) | 0.27 | |||
| Female | 72 (48%) | 153 (50%) | 30 (61%) | |
| Male | 78 (52%) | 152 (50%) | 19 (39%) | |
| Race, No. (%) | 0.15 | |||
| African American | 118 (79%) | 214 (70%) | 41 (84%) | |
| Other | 3 (2%) | 12 (4%) | 0 (0%) | |
| White | 29 (19%) | 79 (26%) | 8 (16%) | |
| Ethnicity, No. (%) | 0.29 | |||
| Hispanic | 3 (2%) | 6 (2%) | 0 (0%) | |
| Non-Hispanic | 130 (87%) | 268 (88%) | 48 (98%) | |
| Unknown | 17 (11%) | 31 (10%) | 1 (2%) | |
| BMI | 26.5 ± 7.2 | 28.4 ± 7.9 | 26.5 ± 7.3 | 0.0083 |
| Insurance, No. (%) | <0.0001 | |||
| Commercial | 51 (34%) | 98 (32%) | 7 (14%) | |
| Government | 48 (32%) | 155 (51%) | 40 (82%) | |
| No Insurance | 51 (34%) | 51 (17%) | 2 (4%) |
Abbreviation: BMI, body mass index.
Patients with preserved renal function were younger (mean age in years: 35.6 ± 14 vs 50.5 ± 17 vs 51 ± 17 years, P ≤ 0.001) compared with patients with ESKD and moderate renal failure, respectively. There was no difference on sex, race, or ethnicity. Patients with moderate renal failure had a higher BMI (28.4 ± 8 vs 26.5 ± 7.2 vs 26.5 ± 7.2 kg/m2, P = 0.008) compared with those with ESKD and preserved renal function. Patients with ESKD were mostly covered by government-sponsored insurance (82%), while most uninsured patients were in the younger group with preserved renal function (34%).
While admission bicarbonate levels (13.9 ± 5 vs 13.4 ± 5.3 vs 13.8 ± 4.2 mmol/L, P = 0.7) and pH levels (7.2 ± 0.3 vs 7.2 ± 0.2 vs 7.2 ± 0.2, P = 0.8) were similar among groups, there were significant differences on multiple biochemical parameters. Patients with ESKD had lower mean ß-hydroxybutyrate (4.3 ± 3.3 vs 5.6 ± 2.9 vs 5.9 ± 2.5 mmol/L, P = 0.01), HbA1c (10.2 ± 2.1 vs 11.6 ± 2.7 vs 12.4 ± 2.5% P = 0.01), and plasma sodium (129.3 ± 7.6 vs 132 ± 6.9 vs 132.1 ± 5.2 mmol/L, P = 0.001) compared with patients with moderate renal failure and preserved renal function (Table 2). In addition, patients with ESKD had higher admission plasma glucose (852 ± 340.4 vs 714.6 ± 253.3 mg/dL vs 518 ± 185.7 mg/dL, P < 0.01), potassium (5.6 ± 1.3 vs 5.3 ± 1.1 vs 4.8 ± 0.9 mmol/L, P < 0.01), anion gap (23.4 ± 7.6 vs 23 ± 6.9 vs 19.5 ± 4.7 mmol/L, P < 0.01), and total serum osmolality (306 ± 20.6 vs 303.5± vs 293.1 ± 3.1 mOsm/kg, P < 0.01).
Table 2.
Biochemical parameters on admission
| Characteristic | Preserved Renal Function | Moderate Renal Failure | ESKD | P-value |
|---|---|---|---|---|
| Glucose, mg/dl | 518.6 ± 185.7 | 714.6 ± 253.3 | 852.0 ± 340.4 | <.0001 |
| HbA1c, % | 12.4 ± 2.5 | 11.6 ± 2.7 | 10.2 ± 2.1 | 0.01 |
| Sodium, mmol/L | 132.1 ± 5.2 | 132.0 ± 6.9 | 129.3 ± 7.6 | 0.001 |
| Potassium, mmol/L | 4.8 ± 0.9 | 5.3 ± 1.1 | 5.6 ± 1.3 | <0.001 |
| Bicarbonate, mmol/L | 13.8 ± 4.2 | 13.4 ± 5.3 | 13.9 ± 4.9 | 0.7 |
| Anion Gap, mmol/L | 19.5 ± 4.7 | 23.0 ± 6.9 | 23.4 ± 7.6 | <0.001 |
| pH | 7.2 ± 0.2 | 7.2 ± 0.2 | 7.2 ± 0.3 | 0.83 |
| ß-hydroxybutyrate, mmol/L | 5.9 ± 2.5 | 5.6 ± 2.9 | 4.3 ± 3.3 | 0.01 |
| Osmolarity, mOsm/kg | 293.1 ± 13.1 | 303.5 ± 18 | 306.0 ± 20.6 | <0.001 |
Abbreviations: ESKD, end-stage kidney disease; HbA1c, hemoglobin A1c.
Correlation between bicarbonate and ß -hydroxybutyrate levels across the spectrum of renal function
Pearson correlation analyses showed that bicarbonate and ß-hydroxybutyrate had a negative correlation in all groups independent of the severity of kidney function. The correlation between increases in ß-hydroxybutyrate and reduction in bicarbonate patients with ESKD, moderate renal failure, and preserved renal function were r = -0.48, P = 0.0005; r = -0.52, P < 0.0001; and r = -0.59, P < 0.0001, respectively. Among patients with ESKD, the mean values of corresponding ß-hydroxybutyrate in patients with bicarbonate levels < 10, 10–15, <18 mmol/L were 5.5 (95% confidence interval [CI] -0.40–11.5), 3.9 (CI -2.0–9.8), and 3.0 mmol/L (CI -3.0–8.9), respectively. Among patients with moderate renal failure, the corresponding ß-hydroxybutyrate concentration was 6.5 (CI 1. 5–11.5), 5.0 (CI -0.03–10), and 4.1 mmol/L (CI -0.9–9.1), respectively. Among patients with preserved renal function, the corresponding ß-hydroxybutyrate values were 7.2 (CI 3.3–11.2), 5.5 (CI 1.5–9.4), and 4.4 mmol/L (CI 4.0–4.9), respectively.
Diagnostic’s sensitivity and specificity according to ß-hydroxybutyrate levels
According to Sheik-Ali et al (4), ß-hydroxybutyrate levels > 3.0 and > 3.8 mmol/L are diagnostic of DKA in pediatric and adult populations, respectively (5). We performed analyses to identify the sensitivity and specificity analysis for different ß-hydroxybutyrate levels across the spectrum of renal function (Table 3).
Table 3.
Sensitivity and specificity of ß-hydroxybutyrate (> 3 mmol/L and > 3.8 mmol/L) in diagnosing DKA as defined by bicarbonate levels
| ß-hydroxybutyrate > 3.0 mmol/L | Sensitivity (%) | Specificity | Sensitivity | Specificity |
|---|---|---|---|---|
| Bicarbonate < 18 mmol/L | Bicarbonate < 15 mmol/L | |||
| End-stage renal disease | 72.2 | 84.6 | 86.9 | 69.2 |
| Moderate renal failure | 83.7 | 54.8 | 89.3 | 42.2 |
| Preserved renal function | 88.3 | 43.3 | 96.2 | 33.3 |
Abbreviation: DKA, diabetes ketoacidosis.
For patients with ESKD, a ß-hydroxybutyrate level of > 3 mmol/L has a sensitivity of 86% (CI 73–100%) and a specificity of 69% (51–86%) for detecting a bicarbonate level of < 15 mmol/L, and 72% (CI 58–86%) and a specificity of 84% (65–100%) for detecting a bicarbonate level of < 18 mmol/L. For patients with ESKD, a ß-hydroxybutyrate level of > 3.8 mmol/L has a sensitivity of 78% (CI 61–95%) and a specificity of 73% (56–90%) for detecting a bicarbonate level of < 15 mmol/L, and a sensitivity of 63% (CI 48–79%) and a specificity of 84% (65–100%) for detecting a bicarbonate level of < 18 mmol/L.
For patients with moderate renal failure, a ß-hydroxybutyrate level of > 3 mmol/L has a sensitivity of 89% (CI 84–93%) and a specificity of 42% (34–49%) for detecting a bicarbonate level of < 15 mmol/L, and a sensitivity of 83% (CI 79–88%) and a specificity of 54% (44–65%) for detecting a bicarbonate level of < 18 mmol/L. For patients with moderate renal failure, a ß-hydroxybutyrate level of > 3.8 mmol/L has a sensitivity of 87% (CI 82–92%) and a specificity of 50% (43–58%) for detecting a bicarbonate level of < 15 mmol/L, and a sensitivity of 80% (CI 75–84%) and a specificity of 64% (54–74%) for detecting a bicarbonate level of < 18 mmol/L.
For patients with preserved renal function, a ß-hydroxybutyrate level of > 3 mmol/L has a sensitivity of 96% (CI 91–100%) and a specificity of 33% (22–44%) for detecting a bicarbonate level of < 15 mmol/L, and a sensitivity of 88% (CI 82–94%) and a specificity of 43% (25–61%) for detecting a bicarbonate level of < 18 mmol/L. For patients with preserved renal function, a ß-hydroxybutyrate level of > 3 mmol/L has a sensitivity of 96% (CI 91–100%) and a specificity of 33% (22–44%) for detecting a bicarbonate level of < 15 mmol/L, and a sensitivity of 88% (CI 82–94%) and a specificity of 43% (25–61%) for detecting a bicarbonate level of < 18 mmol/L.
Discussion
Our results show that in patients with DKA, we found significant differences on several biochemical diagnostic parameters between patients with ESKD, moderate renal failure, and preserved renal failure. Patients with ESKD had lower ß-hydroxybutyrate, while bicarbonate and pH levels were similar between groups with various degrees of renal function. In addition, patients with ESKD had lower corresponding levels of ß-hydroxybutyrate for severe, moderate, and mild DKA episodes, per ADA criteria based on bicarbonate levels. Recently, we reported that patients with combined features of DKA and hyperosmolar state have an increased risk for poor outcomes (11). In this study, patients with ESKD presenting with DKA had higher serum osmolality, which may represent an additional marker of disease severity.
Diabetic ketoacidosis is an acute and preventable metabolic complication of diabetes; it is potentially life-threatening and associated with increased morbidity, healthcare utilization, and hospital readmissions (9, 12, 13). Traditionally, it occurred among patients with type 1 diabetes, but more recently also among patients with type 2 diabetes. While hospital mortality has improved significantly in recent years in the U.S. and U.K. (13–16), postdischarge mortality remains elevated up to 10%–23% in those with recurrent DKA episodes (17, 18), which represents up to 40% of all-cause 30-day readmissions in the U.S. (14). Moreover, patients with ESKD, a high comorbidity index, being discharged against medical advice, or with drug use, were the strongest predictors for readmissions (14).
We recently reported that patients admitted with DKA and ESKD experience increased treatment-related complications, including higher risk of hypoglycemia, volume overload, requirement for mechanical ventilation, and prolonged hospital stay (9). We also noticed that patients with ESKD had lower ß-hydroxybutyrate but similar bicarbonate levels. Insulin is a key factor for the formation of ketone bodies, with suppression of lipolysis and ketone bodies production at low circulating levels (8). However, in insulin deficiency states, there is activation of hormone sensitive lipase, resulting in triglyceride degradation, free fatty acid formation, and increased acetyl co-enzyme A levels. When the production of acetyl-CoA exceeds the rate of metabolism (tricarboxylic acid cycle-TCA) in the mitochondria, there is a shift towards the formation of ketone bodies in the liver, mostly ß-hydroxybutyrate and acetoacetate. In normal individuals, the production of ketone bodies is in a equimolar ratio (ie, 1:1 aceto-acetate:ß-hydroxybutyrate), but this ratio is shifted to 1:7–10 in DKA, with ß-hydroxybutyrate being the predominant ketone body in the circulation (8). In this study, we reported that levels of ß-hydroxybutyrate are lower in patients with ESKD compared with those with preserved renal function, while bicarbonate and pH values are similar. Hence, this raises questions on the current diagnostic biochemical criteria by the ADA, focused on specific cutoff values of bicarbonate, anion gap, and pH but not on specific ß-hydroxybutyrate levels (1). Several experts have suggested a need for updating these guidelines, and better standardization given differences in the definitions between U.K., U.S., and the International Society of Pediatric and Adolescent Diabetes (ISPAD) (2, 3, 5–7). The U.K. and ISPAD guidelines both recommend a threshold of ß-hydroxybutyrate > 3 mmol/L for the diagnosis and management of DKA, and discouraged relying uniquely on urine ketones given its limitations (5–7). Our sensitivity and specificity analysis confirmed these results across the spectrum of renal function and highlights the value of using ß-hydroxybutyrate for diagnosis confirmation. This is particularly important in patients with mixed acid-based disorders, such as chronic renal failure, in which anion gap and bicarbonate may not the most reliable diagnostic parameter for DKA.
Few studies have reported on ß-hydroxybutyrate metabolism and clearance of ketone bodies in patients with chronic renal failure and ESKD. In 1969, Levitt et al reported that the concentration of nonfasting β-hydroxybutyrate is significantly and comparably increased in patients with diabetes and uremia, compared with healthy individuals (19). Among 15 patients with ESKD (creatinine clearance < 10 ml/min/1.73 m2), the investigators reported that nonfasting ß-hydroxybutyrate concentrations were higher in ESKD (0.72 ± 0.55 mmol/L) compared with patient diabetes with preserved kidney function (0.59 ± 0.26 mmol/L) and nondiabetic controls (0.23 ± 0.21 mmol/L). Of note, these patients were not in ketoacidosis’ conditions. In the same study, the investigators reported a significant decrease of ß-hydroxybutyrate levels from predialysis to postdialysis (19). These reports are in agreement with our findings of reduced concentration of ß-hydroxybutyrate in patients with DKA on chronic dialysis compared with patients with preserved and normal kidney function.”
In clinical practice and some studies, clinicians and trainees rely heavily on high anion gap criteria for diagnosis, treatment modification, and resolution of DKA. Our results highlight the limitations of such an approach in patients with ESKD, in whom a low bicarbonate with high anion gap may not necessarily be just DKA. The measurement of serum ß-hydroxybutyrate, with levels > 3 mmol/L in adults, should be a better diagnostic criterion for diagnosis and management of these patients, with the consideration that levels are usually lower compared with patients with preserved renal failure and similar bicarbonate values. A potential explanation for the differences on ß-hydroxybutyrate levels and severity of DKA based on bicarbonate vales may be multifactorial. Osmotic diuresis is responsible for the profound fluid and electrolyte loss in DKA, but it’s not present in dialysis patients with ESKD (20–22). Hypertonicity in patients with ESKD is more related to high glucose levels, and less to osmotic diuresis, with suggestions that insulin alone may be adequate to manage DKA in these patients, with limited or without intravenous fluid resuscitation (21). It’s possible that since bicarbonate levels are chronically lower in the setting of ESKD, these cases have mild to moderate DKA if ß-hydroxybutyrate is used to define severity instead of the traditional approach by bicarbonate levels < 18, 15, 10 mmol/L. We suspect that higher circulating insulin levels due to a prolonged insulin half-life in patients with ESKD may provide some suppression of lipolysis and ketogenesis, resulting in a lower production of ß-hydroxybutyrate, and the severity of metabolic acidosis may be from the combination of increased ketosis and underlying chronic renal failure.
Our study has several limitations, including the small sample size of the ESKD cohort. While larger studies will be needed to confirm these findings, this is a rare scenario, and this cohort is the largest published at this time. Notably, our corresponding ß-hydroxybutyrate levels for each bicarbonate value are similar to those previously reported in patients with preserved renal function (5). Using ICD-9/10 codes to identify diabetes has been a limitation in prior DKA studies, but we further confirmed the diagnosis by admission biochemical data. We, however, are unable to accurately differentiate type of diabetes, and precipitant causes.
Conclusions
We identified several clinical and biochemical differences among patients admitted with DKA across the spectrum of renal function. Patients with ESKD had lower ß-hydroxybutyrate, while bicarbonate and pH levels were similar between groups with different renal functions. Moreover, patients with ESKD had lower corresponding levels of ß-hydroxybutyrate for severe, moderate, and mild DKA episodes, as per ADA criteria based on bicarbonate levels. Similarly, these results highlight the limitations of the current diagnosis and management of DKA in patients with ESKD, in whom a low bicarbonate with high anion gap may not necessarily be just DKA. The measurement of serum ß -hydroxybutyrate, with levels > 3 mmol/L, should be an alternative diagnostic criterion for diagnosis and the management of patients with DKA and advanced renal failure.
Acknowledgments
Author Contributions: RJG conducted the study, analyzed the data and results, and drafted the initial and final manuscript. FJP, PV, CZ, BA, MC, GEU conducted the study, reviewed the data and analysis, and critically reviewed and contributed to the manuscript. ZZ performed the statistical analysis. RJG is the guarantor of this work and, as such, had full access to the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis.
Additional Information
Disclosures: RJG is supported in part by grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institute of Health under Award Numbers P30DK111024 and 1K23DK123384-01. RJG received unrestricted research support (to Emory University) for investigator-initiated studies from Novo Nordisk and Dexcom, and consulting fees from Abbott Diabetes Care, Sanofi, Novo Nordisk, Eli Lilly and Valeritas. GEU is partly supported by research grants from the NIH/NATS UL1 TR002378 from the Clinical and Translational Science Award program, and 1P30DK111024-01 from NIH and National Center for Research Resources. GEU has received unrestricted research support for research studies (to Emory University) from Merck, Novo Nordisk, and Dexcom Inc. FJP and PV are supported by NIH grants: 1K23GM128221-01A1 and 3K12HD085850-03S1. FJP received consulting fees from Merck, Boehringer Ingelheim, Lilly, and AstraZeneca, and Sanofi, and research support from Merck and Dexcom Inc. PV has received consulting fees from Merck, and Boehringer Ingelheim. No other potential conflict of interest relevant to this article was reported.
Data Availability
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.
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Associated Data
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Data Availability Statement
Restrictions apply to the availability of some or all data generated or analyzed during this study to preserve patient confidentiality or because they were used under license. The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.