Influence of Dialysis on the Glucose Profile in Patients ...

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810 Endocrine Care

Authors

F. Chantrel1, H. Sissoko1, L. Képénékian2, A. Smagala3, L. Meyer4, O. Imhoff4, L. Serb5, D. Fleury6, F. Dorey7, T. Krummel8, J. P. Le Floch9, L. Kessler2

Affiliations

Affiliation addresses are listed at the end of the article

Key words ▶ diabetes ● ▶ hemodialysis ● ▶ continuous glucose ● monitoring

Abstract



We sought to investigate the impact of dialysis on glucose profiles of diabetic patients using continuous glucose monitoring (CGM). The study included 33 hemodialyzed patients with diabetes (14 females and 19 males; mean age: 66 ± 8 years; patients with type 2 diabetes: 30; mean duration of dialysis: 3.8 ± 2.6 years) who were under insulin treatment. After a run-in period, CGM was performed for 48 h, including a dialysis session. Three CGM sessions were proposed for each patient over a 3-month period. CGM results were analyzed during and after dialysis at 6 different time points. Moreover, data were analyzed in 7 different day periods according to meals. Of the 99 CGM available, 21 were

Introduction received 02.10.2013 accepted 12.02.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1370963 Published online: March 13, 2014 Horm Metab Res 2014; 46: 810–813 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence L. Kessler, MD, PhD Department of Endocrinology and Diabetology University Hospital 1, Place de l’Hôpital 67091 Strasbourg – Cedex France Tel.: + 33/3/88 11 62 67 Fax: + 33/3/88 11 67 51 laurence.kessler@ chru-strasbourg.fr



Because of increased incidence of diabetes mellitus (DM), end-stage renal disease (ESRD) due to diabetic nephropathy has emerged as a major public health issue [1]. Notably, hemodialyzed patients with diabetes face an increased risk of cardiovascular morbidity and mortality [2, 3] and DM is an independent predictor of deaths in ESRD patients [4]. Although several studies have reported a benefit of strict glycemic control on morbidity and mortality outcomes in type 1 and type 2 DM [5, 6], data are conflicting as to its efficacy in hemodialyzed patients with diabetes. One study demonstrated that tight glycemic control may improve quality of life and reduce the need for hospitalizations and lower limbs amputations in hemodialyzed patients with diabetes [7]. However, another report has warned against the potential dangers of intensive treatment regimens and strict glycemic control (glycated hemoglobin [HbA1c] < 53 mmol/mol [7 %]) that may increase the risk of hypoglycemic events in this group of

Chantrel F et al. Continuous Glucose Monitoring … Horm Metab Res 2014; 46: 810–813

excluded because of technical issues or patient refusal. The CGM results indicated that mean glucose values (7.5 ± 2.5 mmol/l vs. 9.4 ± 1.9 mmol/l; p < 0.001) and variability indices (p < 0.001) were lower, whereas the frequency of hypoglycemia (4.4 ± 9.6 % vs. 2.1 ± 7.9 %; p < 0.001) was higher during hemodialysis sessions. Significant differences were observed in glucose values only before and 2 h after breakfast (p < 0.001). Compared with other day periods, glucose values were lower during the second half of the night and higher before and after dinner (p < 0.001). In summary, CGM allows the identification of a particular glucose profile in hemodialyzed diabetic patients. CGM seems feasible and clinically useful for the analysis of glucose profiles in this group of patients.

patients [8, 9]. Control of blood glucose in ESRD patients is challenging because both uremia and dialysis can affect insulin secretion and tissue sensitivity to insulin. Such factors contribute to wide fluctuations in blood glucose levels and exogenous insulin requirements. Moreover, the hormonal regulation of hepatic glucose production in ESRD patients may increase the risk of hypoglycemic episodes [10–12]. Measurements of blood glucose levels and HbA1c are routinely used as indices of glycemic control in hemodialyzed patients with diabetes. However, single measurements of HbA1c and random blood glucose values are not always useful to help a greater proportion of ESRD patients to achieve long-term metabolic control [13]. In this scenario, continuous glucose monitoring (CGM) may offer significant benefits over traditional intermittent blood glucose testing in reducing the risks of developing long-term complications associated with DM [14]. In order to achieve optimal glycemic control in a high-risk population like hemodialyzed patients with diabetes, it is crucial to be able to alert the patient promptly in

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Influence of Dialysis on the Glucose Profile in Patients with Diabetes: Usefulness of Continuous Glucose Monitoring

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Subjects and Methods



Study population This prospective multicenter study was conducted in 5 nephrology centers located in France. All hemodialyzed patients with diabetes consecutively admitted to the participating centers were considered eligible for study. The exclusion criteria were as follows: history of severe anemia or blood transfusions in the previous 2 months; life expectancy of less than 1 year; presence of chronic inflammatory disorders; previous treatment with steroids; history of malignancies requiring surgery, chemotherapy or radiotherapy; and unwillingness to participate in the study. Of a total of 38 eligible patients, 4 did not provide consent and 1 died of severe respiratory insufficiency during the followup. The final study group consisted of 33 hemodialyzed diabetic patients (14 females and 19 males; mean age: 66 ± 8 years; body mass index: 33.2 ± 6.5 kg/m2; patients with type 2 DM: 30; mean duration of dialysis: 3.8 ± 2.6 years; mean duration of DM: 23 ± 11 years; HbA1c: 65 ± 13 mmol/mol). The prevalence of diabetic complications was as follows: 39 % coronary heart disease, 68 % retinopathy, and 14 % amputations. All of the patients were being treated with insulin [12 (36 %) with a premixed insulin regimen and 21 (64 %) with a basal-bolus regimen]. The study protocol was approved by the local ethics committee, and written informed consent was obtained from all participants.

Continuous glucose monitoring Three CGM sessions were proposed for each patient over a 3-month period. Each CGM device (Navigator®, Abbott Diabetes Care, Rungis, France) was used for a total of 54 h, including 2 consecutive dialysis sessions. The probe was inserted subcutaneously at the beginning of the first dialysis session. During this session, the device was calibrated and patients were informed about its management (run-in period). Interstitial glucose values were recorded every 5 min during the following 48 h, including a second dialysis session. The probe was removed after completion of the second dialysis session. CGM sessions were considered to be valid if at least 200 of the 576 possible glucose measurements were available for analysis.

Statistical analysis Continuous data are expressed as means ± standard deviations (SD), whereas categorical variables are given as counts and percentages. The following CGM data were used for analysis: mean glucose values, within-subject variability [within-subject SD and coefficient of variation (CV), mean amplitude of glycemic excursion (MAGE)], percentage and mean value of hypoglycemia (< 3.3 mmol/l). CGM parameters were compared during and after the dialysis session using one-way analysis of variance (ANOVA). ANOVA for repeated measures was used to compare the differences between mean glucose values measured by CGM before and 2 h after each meal. We also compared mean glucose levels measured in 7 different periods, that is, 1) 3 h after breakfast; 2)

before lunch; 3) 3 h after lunch; 4) before dinner; 5) 3 h after dinner; 6) first part of the night (between 3 h after dinner and 4 h before breakfast); and 7) second part of the night (4 h before breakfast) using ANOVA for repeated measures.

Results



Of the 99 CGM available, 21 were excluded because of technical issues: displacement of the probe or loss of wireless signals coming from the CGM monitor (n = 14) or patient refusal to perform multiple CGM (n = 7). The CGM results indicated that mean glucose values and variability indices were significantly lower (p < 0.001). The frequency of glucose levels < 3.3 mmol/l was significantly greater during dialysis (4.4 ± 9.6 % vs. 2.1 ± 7.9 %, p < 0.001), with a parallel increase in mean glucose values (2.7 ± 0.5 mmol/l vs. 2 ± 1.3 mmol/l, p < 0.001). Significant differences in glucose values were observed only before and 2 h after breakfast (8 ± 2.4 mmol/l vs. 9.4 ± 3.3 mmol/l, ▶ Table 1). p < 0.001; ● Both before and after dinner, glucose values were higher (10.6 ± 3.4 mmol/l and 10.5 ± 3.3 mmol/l, p < 0.001) than those measured before and after breakfast (8 ± 2.4 mmol/l and 9.4 ± 3.3 mmol/l) as well as before and after lunch (8.6 ± 3 mmol/l and 8.9 ± 2.2 mmol/l). Compared with other day periods, glucose values were lower during the second half of the night and higher ▶ Fig. 1). before and after dinner (p < 0.001; ●

Discussion



The results from our study using CGM suggest that hemodialyzed diabetic patients are characterized by higher glucose levels at the end of afternoon and lower glucose values in the second part of the night. Another intriguing finding is the evidence of an improved glucose variability during dialysis sessions. Our results demonstrate that CGM is feasible in hemodialyzed patients with diabetes. Of a total of 99 CGM traces obtained in our sample of 33 patients, 78 were available for the final analysis. The remaining 21 traces were missing because of technical issues or patient withdrawal. Performing CGM in patients who are already undergoing dialysis 3 times a week may pose an additional burden that can not be acceptable to every subject, ultimately resulting in drop-outs. Conversely, technical issues were due the displacement of the probe or loss of wireless signals coming from the CGM monitor. Because of the frailty of the study population, we deemed eligible for the final analysis all of the CGM traces with at least 200 of the 576 possible blood glucose values (i. e., 35 %). Notably, the number of useful glucose values available for analy▶ Table 1). This result was not unexsis was markedly higher (● pected because we used a run-in period that may be helpful to select the most well-motivated patients [15]. In this scenario, patient’s motivation and treatment engagement must be considered as a key component for the successful use of CGM. Notably, an inherent advantage of this technique is the repeatability of CGM data in patients with type 2 diabetes − who are characterized by relatively lower glucose excursions compared with those with type 1 diabetes. Single-spot glycemic measurements and HbA1c levels are known to be of only limited value in hemodialyzed patients with diabetes [13] and optimizing glycemic control in these subjects requires accurate assessment [16, 17]. Ongoing studies are

Chantrel F et al. Continuous Glucose Monitoring … Horm Metab Res 2014; 46: 810–813

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order to allow time to the therapeutic actions to be effective. Moreover, the use of CGM in this patient group may allow tracking the physiological glucose dynamics with finer detail both in relation to meals and hemodialysis sessions. Therefore, we designed the current study to investigate the impact of dialysis on glucose profiles of diabetic patients both during and after hemodialysis sessions by means of CGM.

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During dialysis

Outside dialysis

p

48

6–8

40–42

282 ± 49 256–308 9.4 ± 2 3.2 ± 1 34 ± 9 5.7 ± 3.2

53 ± 10 40–96 7.5 ± 2.5 1.2 ± 0.6 16 ± 9 2.7 ± 2.4

229 ± 40 216–252 9.4 ± 1.9 3.2 ± 1.1 36 ± 10 5.8 ± 3.1

< 0.001 < 0.001 < 0.001 < 0.001

2.1 ± 7.9 2.14 ± 1.1

4.4 ± 9.6 2.7 ± 0.5

1.8 ± 8.2 2.03 ± 1.3

< 0.001 < 0.001

Table 1 Continuous glucose monitoring and laboratory data of the 33 hemodialyzed patients with diabetes enrolled in the study.

8 ± 2.4 9.4 ± 3.3 8.6 ± 3 8.9 ± 2.2 10.6 ± 3.4 10.5 ± 3.3 8.9 ± 3.3 8.1 ± 1.0

SD: Standard deviation; MAGE: Mean amplitude of glycemic excursions p-Values for comparisons during and outside the dialysis sessions

Fig. 1 Results of 24-h CGM in 33 hemodialyzed patients with diabetes. Mean glucose levels were measured in 7 different periods, i. e., 1) 3 h after breakfast (3hB); 2) before lunch (BL); 3) 3 h after lunch (3hL); 4) before dinner (BD); 5) 3 h after dinner (3hD); 6) first part of the night (between 3 h after dinner and 4 h before breakfast); and 7) second part of the night (4 h before breakfast) using ANOVA for repeated measures (***p < 0.001).

examining the effects of CGM on the prevention of hypoglycemic events and their consequences in ESRD patients [9]. Indeed, enthusiasm for tight glycemic control in hemodialysis patients has been tempered by the concern that treatment-induced hypoglycemia may increase mortality [16, 17]. In our study, CGM results indicated that hypoglycemic events were more frequent but less severe during dialysis sessions. This phenomenon can be explained by the presence of glucose in the dialysate (5.5 mmol/l) which can move freely to the blood following its concentration gradient [18]. Moreover, the results of CGM demonstrated that mean glucose values and within-subject variability were lower during dialysis sessions. Standard laboratory assays would miss

such variations, which are consistent with those reported in previous studies [19–22]. Another interesting finding of this study is that CGM results demonstrated significant differences in pre- and post-meal glucose values among hemodialyzed diabetic patients, with concentrations being the highest before and after dinner. Such a profile differs significantly from the one observed in patients with type 2 DM, who reached the lowest levels of glucose before dinner [23]. In this study, hemodialyzed patients with diabetes showed the lowest glucose values during the night. Such differences can be due to specific alterations of glucose metabolism occurring in this patient population characterized by a decreased in glycogen storage, abnormal liver gluconeogenesis together with the abnormalities in clearance and peripheral tissue sensitivity of insulin due to ESRD [11]. This may require adjustment or titration of the insulin doses according to CGM glucose profiles. In conclusion, CGM allowed the identification of a particular glucose profile in hemodialyzed diabetic patients. CGM seems to be feasible and clinically useful for the analysis of glucose profiles in this group of patients, potentially providing valuable information for clinical management.

Acknowledgements



This study was financially supported by Novo Nordisk. Continuous glucose monitoring devices were kindly provided by Abbott.

Conflict of Interest



J. P. Le Floch has served as a consultant for, and has received financial support from Abbott Diabetes Care and Novo Nordisk. F. Chantrel, L. Képénékian, A. Smagala, L. Meyer, O. Imhoff, A. Sissoko, L. Serb, D. Fleury, F. Dorey, M. Pinget, T. Krummel, and L. Kessler have no conflicts of interest to disclose.

Chantrel F et al. Continuous Glucose Monitoring … Horm Metab Res 2014; 46: 810–813

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CGM duration (h) CGM glucose levels n Range Mean (mmol/l) Within-subject SD (mmol/l) Coefficient of variation ( %) MAGE (mmol/l) Glucose values < 3.3 mmol/l Frequency ( %) Mean ± SD (mmol/l) Glucose levels according to meals Before breakfast (mmol/l) 2 h after breakfast (mmol/l) Before lunch (mmol/l) 2 h after lunch (mmol/l) Before dinner (mmol/l) 2 h after dinner (mmol/l) Routine indices Glucose levels (mean of 3 values; mmol/l) HbA1c (mmol/mol)

All study periods

Affiliations Department of Nephrology, Regional Hospital, Mulhouse, France 2 Department of Diabetology, University Hospital, University of Strasbourg, France 3 Department of Diabetology, Regional Hospital, Colmar, France 4 Department of Nephrology, St Anne Hospital, Strasbourg, France 5 Department of Diabetology, Regional Hospital, Mulhouse, France 6 Department of Nephrology, Regional Hospital, Valenciennes, France 7 Department of Diabetology, Regional Hospital, Valenciennes, France 8 Department of Nephrology, University Hospital, University of Strasbourg, France 9 Diabetology-Endocrinology, Clinique de Villecresnes, Villecresnes, France 1

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Endocrine Care 813

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