Continuous Glucose Monitoring in Patients With Diabetes on Peritoneal Dialysis

Background: Patients with chronic kidney disease (CKD) caused by diabetes mellitus (DM) experience metabolic alterations characterized by elevated blood glucose levels and associated cardiovascular complications, which increase morbidity and mortality. Therefore, adequate metabolic control is necessary to reduce the incidence of these complications. This task is challenging without icodextrin because insulin adjustment is complicated by the additional glucose supplied through dialysis bags and absorbed through the peritoneum.

Under this premise, continuous glucose monitoring is important for assessing patients' metabolic status. This approach will provide clinically relevant data to improve care, minimize healthcare system expenses, and support decision-making regarding adjustments to dialysis treatment.

Objective: To use continuous glucose monitoring to determine whether the type, dose, route of administration, and timing of insulin application are associated with glucose patterns identified through continuous glucose monitoring, including the magnitude and duration of periods of hyperglycemia and hypoglycemia during 24-hour periods of interstitial glucose monitoring.

Material and Methods: This is a cross-sectional, non-interventional study involving adult patients with type 2 diabetes mellitus receiving automated peritoneal dialysis who exhibit high or high-average peritoneal transport characteristics.

The inclusion criteria are patients older than 40 years, of any sex, diagnosed with diabetic nephropathy, who are insulin-dependent for metabolic control and have received peritoneal dialysis treatment for at least three months. The study will continuously evaluate patients' glycemic control, with automatic scanning and data recording every six hours during automated peritoneal dialysis infusion. According to the sample size calculation, 110 patients are required.

The Guardian 3 sensor will be placed subcutaneously in the upper posterior region of the patient's non-dominant arm using the One-press serter. This is a minimally invasive procedure that does not require surgical protocols. The sensor will be connected to the Guardian Connect transmitter for continuous communication with the Guardian Connect application.

The sensor has an approximate lifespan of seven days, corresponding to the duration of the enzymatic reaction that allows adequate measurement. Data will be transmitted every five minutes, 24 hours a day, for seven consecutive days. At the end of this period, participants will be scheduled for placement of a second sensor to complete 14 days of follow-up.

On day seven, participants will undergo removal of the first sensor and placement of a new sensor to complete the 14-day follow-up period. On day 14, the total 24-hour peritoneal dialysis drainage volume will be collected to measure glucose, urea, and creatinine concentrations. Peritoneal glucose absorption, the dialysate-to-plasma creatinine ratio (D/P creatinine), and Kt/V will be calculated. Dietary information will be collected to calculate caloric intake and meal timing. This information, together with subcutaneous insulin administration, will be recorded in the Guardian Connect application.

Statistical Analysis: The databases will be audited monthly through random sampling of blocks comprising 5% of their content. Semiannual reports will be prepared to monitor the records collected and the outcomes obtained up to each reporting date. These reports will contain basic descriptive information, including measures of central tendency and dispersion, according to the characteristics of the variables.

Patients will be classified according to the percentage of time that glucose measurements remain within the predefined range of 70-180 mg/dL. Patients who spend at least 70% of the time within this range will be classified as having "Adequate" glycemic control, whereas those who do not reach this target will be classified as having "Not Adequate" glycemic control.

Results will be reported using measures of central tendency and dispersion appropriate to the characteristics of the variables. Depending on the type of variable, the chi-square test, Student's t-test, or Mann-Whitney U test will be used to detect differences between the adequate and inadequate glycemic control groups.

Logistic regression analysis will be used to identify variables significantly associated with glycemic control within the recommended ranges, as assessed by continuous glucose monitoring. In the first stage, each independent variable will be analyzed separately. In the second stage, multivariable analysis will be performed, considering insulin type, route of administration, dose, and administration schedules. Potential confounding variables, including obesity, treatment adherence, diet, and physical activity prescribed by the treating physician, will also be included.

Detailed Description JUSTIFICATION The high prevalence of patients with end-stage chronic kidney disease (CKD) treated with peritoneal dialysis (PD) and the predominance of diabetes mellitus (DM) as a cause of CKD make it necessary to establish documented guidelines for metabolic control in patients with DM receiving PD.

These guidelines should consider insulin dosage in relation to glucose intake from food and glucose absorption through the peritoneum. They should also consider meal schedules, infusion schedules for PD solutions with higher glucose concentrations, and the route of insulin administration, since the intraperitoneal route requires up to twice the dose administered subcutaneously.

To develop these guidelines, monitoring metabolic control using conventional tools, such as blood glucose measurements with a portable glucometer or glycated hemoglobin, is insufficient because these methods do not allow identification of the times of day when insulin should be administered to optimize its use. Continuous glucose monitoring is the only practical tool available for this purpose.

Recent reports identify CKD as the third chronic degenerative disease with the greatest financial impact on the Mexican Social Security Institute (IMSS). Together with diabetes mellitus and hypertension, CKD accounts for a substantial proportion of healthcare expenditure for patients with chronic diseases. Moreover, patients with DM represent more than half of those enrolled in dialysis programs.

In this context, metabolic control and fluid balance in patients with DM receiving PD represent both clinical and economic challenges.

RESEARCH QUESTION Is continuous glucose monitoring an effective tool for detecting the effects of insulin type, dose, route of administration, and timing on metabolic control in patients with diabetes receiving peritoneal dialysis? OBJECTIVES

General Objective:

To use continuous glucose monitoring to determine whether insulin type, dose, route of administration, and timing are associated with glucose patterns identified through continuous glucose monitoring, including the magnitude and duration of periods of hyperglycemia and hypoglycemia during 24-hour periods of interstitial glucose monitoring.

Specific Objectives:

1. To identify insulin prescription patterns in patients with diabetes receiving PD, including insulin type, dose, administration schedule, and route of administration.
2. To compare daily glucose concentration profiles measured by continuous glucose monitoring with fasting blood glucose concentrations and glycated hemoglobin percentages.
3. To identify which insulin administration regimen is associated with shorter durations and lower magnitudes of hypoglycemia and hyperglycemia.
4. To measure peritoneal glucose absorption and its relationship with glucose concentrations measured by continuous glucose monitoring.

MATERIALS AND METHODS

Design:

Cross-sectional, non-interventional study.

Population:

Adult patients with type 2 diabetes mellitus (DM2) and end-stage CKD receiving peritoneal dialysis.

Inclusion Criteria: Patients older than 40 years, of any sex, diagnosed with diabetic nephropathy, who are exclusively insulin-dependent for metabolic control and have received PD treatment for at least three months.

Non-Inclusion Criteria: Patients with positive serology for human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus; acute complications; hospitalization for cardiovascular, metabolic, or infectious conditions during the month preceding study enrollment; cancer; pregnancy; or allergy.

OUTCOMES

Primary:

Average glucose concentration detected during 24-hour periods. Magnitude and duration of periods of hypoglycemia (<70 mg/dL) and hyperglycemia (>180 mg/dL) recorded during 24-hour periods.

Secondary:

Necessary adjustments in insulin dosage during the monitoring period. PROCEDURES A member of the research team will invite patients who meet the eligibility criteria, as identified in PD consultation records, to participate in the study. Eligible patients will receive information about the study objectives and procedures.

For patients who agree to participate and sign the informed consent form, the initial interview will collect demographic information (sex, age, marital status, educational level, economic activity, and income), clinical information (underlying disease, disease duration, previous hospitalizations, and comorbidities), and laboratory information (complete blood count, basic biochemical parameters, inflammatory markers, mineral metabolism, nutritional parameters, and cardiovascular parameters) available in their medical records.

Information will be collected by nursing staff trained in clinical research procedures (monitors). The data collected will correspond to established dialysis adequacy criteria and are specified in the attached forms.

Participants will be scheduled for blood sample collection for biochemical analysis, including glucose, urea, creatinine, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, glycated hemoglobin, and C-reactive protein.

Participants will receive training in the use of the glucose monitor, which will be placed on the non-dominant arm. Once the monitor has been calibrated, participants will undergo monitoring for seven days. The first sensor will then be removed and replaced with a second sensor, completing a total follow-up period of 14 days.

The recorded data will be collected by the investigators and documented in forms designed for this purpose.

Patient training will consist of face-to-face theoretical and practical instruction. Proper performance of calibration procedures, glucose measurement consultation, and understanding of warning signals will be verified to ensure safe use of the monitoring device.

If glucose concentrations above 250 mg/dL are recorded at any time or persist for more than seven hours (30%) per day, participants will be referred for a detailed evaluation by their treating physician, who will have been previously informed of the inadequate metabolic control.

LABORATORY All biochemical and laboratory tests will be used for routine monitoring of patients receiving PD and will be performed at the affiliated hospital using standard automated techniques.

CONTINUOUS GLUCOSE MONITORING Guardian 3 sensor, Guardian Connect Transmitter Kit, and Guardian Connect System, consisting of the Guardian Connect transmitter, One-Press serter, Guardian Connect smartphone application (App), and standard printing equipment.

The sensor will be connected to the Guardian Connect transmitter for continuous communication with the Guardian Connect application. A smartphone is required for this purpose. If participants do not have a smartphone, one will be provided to enable appropriate follow-up.

After proper functioning has been verified through calibration supported by a glucometer and capillary blood glucose test strips, data will be transmitted every five minutes, 24 hours a day, for seven consecutive days. This period corresponds to the duration of the enzymatic reaction that allows adequate measurement.

At the end of the seven-day period, participants will be scheduled for placement of a second sensor to complete the 14-day follow-up period.

The information provided by the Guardian Connect system can be downloaded in Excel format and analyzed by the clinician through the CareLink website. The clinician will analyze trends, glucose concentration patterns, and major alerts indicating values outside the established range.

On day seven, participants will be scheduled for sensor removal, and the total 24-hour PD drainage volume will be collected for glucose, urea, and creatinine measurements. Peritoneal glucose absorption, the dialysate-to-plasma creatinine ratio (D/P creatinine), and Kt/V will also be calculated.

Dietary information will be obtained to calculate caloric intake and meal timing. Subcutaneous insulin administration will be recorded in the Guardian Connect application.

STATISTICAL PLAN The databases will be audited monthly through random sampling of blocks comprising 5% of their content.

Semiannual reports will be prepared to monitor the records collected and the outcomes obtained up to each reporting date. These reports will contain basic descriptive information, including measures of central tendency and dispersion, according to the characteristics of the variables.

Patients will be classified according to the percentage of time that glucose measurements remain within the predefined range of 70-180 mg/dL (24). Patients who spend at least 70% of the time within this range will be classified as having "Adequate" glycemic control, whereas those who do not reach this target will be classified as having "Not Adequate" glycemic control.

Results will be reported using measures of central tendency and dispersion appropriate to the characteristics of the variables.

Depending on the type of variable, the chi-square test, Student's t-test, or Mann-Whitney U test will be used to identify differences between the adequate and inadequate glycemic control groups.

Logistic regression analysis will be used to identify variables significantly associated with glycemic control within the recommended ranges, as assessed by continuous glucose monitoring.

In the first stage, each independent variable will be analyzed separately. In the second stage, multivariable analysis will be performed, considering insulin type, route of administration, dose, and administration schedules.

Potential confounding variables, including obesity, treatment adherence, diet, and physical activity prescribed by the treating physician, will also be included.

According to the protocol, the independent variables considered will be daily glucose absorption, insulin dose, administration timing in relation to food intake and the PD solutions used, and route of administration.

All analyses will be performed using SPSS version 24. Statistical significance will be established at p<0.05.

SAMPLE SIZE The following assumptions were used to calculate the sample size:Statistical test: Logistic regression.

Dependent variable: Time spent with interstitial glucose concentrations within the target range, dichotomized as "Adequate" or "Not Adequate."Dominant covariate: Route of insulin administration, dichotomized as "Subcutaneous" or "Intraperitoneal."This variable is considered the most important covariate because it has been associated with better glycemic control in studies using individual blood glucose measurements obtained with a portable glucometer and glycated hemoglobin as indicators of metabolic control.α: 0.05.β: 0.9.OR: Risk of time outside the target range >85% (Intraperitoneal/Subcutaneous): 0.46/0.30.

Sample size: N = 110. ETHICAL ASPECTS The research will be conducted in accordance with the ethical principles and guidelines established in the Official Mexican Standard NOM-028-SSA2-1999, the General Health Law regarding research involving human participants, Articles 96 and 100 of Title V, and Technical Standard No. 313.

These regulations establish protections for participants' rights, dignity, well-being, and anonymity.

The following guidelines will be observed:An informed consent form is included and will be presented to participants by associated investigators duly accredited by the authorities of the participating medical units.

According to Article 21 of the Regulations of the General Health Law on Health Research (1984), informed consent requires that research participants or, when applicable, their legal representatives receive a clear and complete explanation that allows them to understand the relevant aspects of the study.

This research is considered minimal risk because it involves standard procedures used in routine physical examinations, diagnoses, or treatments. It also involves a device supported by published evidence that can provide additional parameters for metabolic control in patients with diabetes.

The use of this device does not involve venous bleeding or direct insulin administration, as the sensor is placed intradermally. The device may generate alerts that participants will be trained to recognize and manage appropriately.

According to clinical experience in the management of patients receiving PD, the observed glucose variations are within ranges that do not represent a risk to participants but may allow optimization of insulin administration.

If glucose concentrations above 250 mg/dL are recorded at any time or persist for more than seven hours (30%) per day, participants will be referred for a detailed evaluation by their treating physician, who will have been previously informed of the inadequate metabolic control.

The risk-benefit balance is considered favorable because the potential value of the information obtained is relevant and the study involves minimal risk.

None of the participating investigators has a conflict of interest regarding the use of the Guardian Connect device.

Samples will be handled by experienced personnel and prepared at each center, since only glycated hemoglobin measurements and clinical laboratory tests will be performed before participants' monthly consultations.

The research team acknowledges the General Health Law regarding research, as well as the applicable regulations and biosafety manuals. The following considerations will be observed:Installation of the Guardian Connect sensor requires trained personnel. The Latam Medtronic Academy provides training to minimize risks and ensure appropriate handling of installation materials.

No samples will be processed in a central laboratory because samples will be processed at each participating center to avoid transferring serum or plasma between centers.

The use of appropriate personal protective equipment is strongly recommended when installing sensors in patients receiving dialysis.

RESOURCES, FINANCING, AND FEASIBILITY The research team comprises a nephrologist with clinical experience in hospital-based patient care, a researcher specializing in nephrology, and two nurses. Electronic data collection will also be performed by trained personnel.

Additional anticipated costs are associated with the electronic devices required for continuous glucose monitoring, for which resources will be necessary.

The research group has demonstrated experience through various publications in the field of nephrology.