INTRODUCTION
Dialysis patients with diabetes have a very short life expectancy likely caused by a high
incidence of co-morbidities combined with an increased risk of hypoglycaemia and poor
glycaemic control. Glycaemic monitoring is a challenge in dialysis patients, and the
number of available glucose-lowering agents are reduced often necessitating the use of
insulin. Overall, this means that dialysis patients do not receive the same high quality
of treatment as the general diabetes population.
In the past decades various diabetes technologies have revolutionised treatment,
primarily in type 1 diabetes, but have also shown effect in type 2 diabetes. Continuous
glucose monitoring (CGM) is a device applied to the skin that provides a detailed glucose
profile which enables the endocrinologist to tailor and optimize diabetes treatment. We
hypothesise that intermittent and/or continuous utilization of CGM will significantly
improve glycaemic control for patients undergoing haemodialysis or peritoneal dialysis,
thereby potentially reducing complications associated with diabetes in this population.
OBJECTIVES
The primary objective is to assess whether the intermittent or continuous use of CGM can
enhance glycaemic control among dialysis patients with type 1 or type 2 diabetes, in
comparison to the standard-monitoring involving finger-prick glucose and HbA1c.
Secondary objectives include assessing the impact of CGM on hypoglycaemia incidence,
quality of life, and cardiovascular events.
BACKGROUND
The combination of diabetes and end-stage renal disease is associated with a high risk of
diabetic complications with a mean survival time of 3 to 4 years. To reduce the risk of
diabetic complications, glycaemic control is essential, where the aim is to avoid both
hypo- and hyperglycaemia. For patients undergoing dialysis, HbA1c is currently the most
widely used tool for glycaemic monitoring. However, several studies have found HbA1c to
be an unreliable glycaemic marker. In addition, glycaemic targets using HbA1c are not
provided in current guidelines as studies report conflicting results on the optimal HbA1c
target. Therefore, new approaches for glycaemic control are warranted to improve diabetes
treatment.
Continuous glucose monitoring (CGM):
CGM uses a subcutaneous sensor to measure glucose levels every 5 to 15 min depending on
the model. A CGM provides a detailed estimate of the glucose profile and studies in
patients with type 1 and type 2 diabetes have demonstrated that CGM-use improved
glycaemic control without increasing the risk of hypoglycaemic events.
A CGM provides several glycaemic indexes including mean sensor glucose, variables for
glucose variability, time-in-ranges and are used to adjust antidiabetic treatment.
Time-in-ranges is a relatively new tool in glycaemic control where the percentage time
spent in different glucose intervals is calculated from the measured CGM data, for a
period (typically 10 to 14 days). Time-in-ranges are defined as the percentage time spent
in time-below-range (<3.9 mmol/L); time-in-target-range (3.9 to 10.0 mmol/L);
time-above-range (>10.0 mmol/L) mmol/L). The advantage of using time-in-ranges for
glycaemic control is the ability to diminish the risk of hypoglycaemia while maintaining
glycaemic control by optimizing the time spent in the target-range.
Current use of CGM in dialysis patients:
Two minor studies have used CGM to adjust the antidiabetic treatment in patients
receiving dialysis. These studies reported that the use of CGM with subsequent adjustment
in antidiabetic treatment was associated with a reduction in HbA1c level and could
indicate a beneficial effect of CGMs in the dialysis population8. However, a CGM-based
approach to diabetes treatment is not well defined and is currently bases on a consensus
report recommending patients with high risk of hypoglycaemia (which includes dialysis
patients) achieving the following glycaemic targets using time-in-ranges:
More than 50% time within time-in-target-range (3.9-10.0 mmol/L) (>12 h per day)
Less than 1% spent below-range (<3.9 mmol/L) (<15 min per day)
Less than 50% above-range (>10.0 mmol/L) (<12 h per day)
Less than 10% above 13.9 mmol/L (<2 h and 24 min per day) However, these
recommendations have not been evaluated in dialysis patients and it remains unknown
if these targets provide sufficient glycaemic control, reduce complications,
improves quality of life or are practical feasible.
The technical aspects of daily CGM use could constitute a problem for some of the most
fragile dialysis patients. Intermittent use of CGMs could therefore be an alternative
approach and have, in non-dialysis patients with diabetes, lead to a lowering of elevated
HbA1c levels. Intermittent CGM usage could alleviate the practical burden on both
patients and medical staff, reduce expenses, and still equip endocrinologists with CGM
data for optimizing glycaemic control. However, recent advancements in CGM technology
have enhanced usability and continuous use of CGMs likely hold advantages over
intermittent usage.
DESIGN AND POPULATION
This multicentre, prospective, randomized controlled study will be conducted at
Rigshospitalet, Roskilde University Hospital, North Zealand Hospital Hillerød, Herlev
Hospital, and Holbæk Hospital, encompassing all dialysis centres in eastern Denmark.
The study will include a total of 96 participants with type 1 or type 2 diabetes
undergoing either haemodialysis or peritoneal dialysis. Participants will be randomly
assigned in a 1:1:1 ratio to either receive standard glycaemic monitoring (Group 1),
intermittent CGM (Group 2) or continuous CGM (Group 3).
METHODS
All participants will be monitored for 9 months and randomly assigned to one of three
groups (Figure 3). Group 1, the control group, will undergo standard monitoring (using
HbA1c and finger-prick glucose) along with double-blinded CGM sessions scheduled at
months 0, 3, 6, and 9. Group 2 will have intermittent access to open CGM during the same
time intervals. Meanwhile, Group 3 will have continuous access to open CGM throughout the
entire duration of the study.
All three groups will undergo a 10-day period of double-blinded CGM to assess their
baseline glucose profiles. Additionally, participants will have three consultations with
an endocrinologist or a diabetes nurse at months 0, 3, and 6 for adjustments in their
glucose-lowering treatment. At the final visit (month 9), Groups 1 and 2 will undergo a
10-day period of double-blinded CGM, while Group 3 will have an open CGM session.
The objective for the intervention groups (Group 2 and 3) is to adjust their
glucose-lowering treatment to ensure patients spend less than 1% of their time with
glucose levels below 3.9 mmol/L and more than 60% of the time within the target range
(3.9 to 10.0 mmol/L). Meanwhile, for the control group, CGM data will be double-blinded,
and adjustment of glucose lowering medicine will be based on usual monitoring of HbA1c
and finger-prick glucose.
STATISTICAL ANALYSIS
Statistical analysis is performed as intention-to-treat and will be conducted by the
investigators in close collaboration with an experienced statistician. All data will be
described including data-incompleteness as well as reasons for data-incompleteness. A
linear mixed model with a participant-specific random intercept is used to analyse the
effect of changes in mean sensor glucose, time in range and HbA1c. This analysis will
compare changes across the three study groups from baseline to end of the study.
ETHICAL CONSIDERATIONS
CGM is a well-tested technology that has significantly improved glucose management in the
general diabetes population. It is expected to be safe and well tolerated, in dialysis
patients as well. The many examinations are time consuming for the study participants.
The project, however, will likely yield important knowledge on how to optimize diabetes
management in dialysis patients, which expectedly will benefit both the study
participants and in general all dialysis patients with diabetes.
The study will be registered at ClinicalTrials.gov prior to initiation. The trial
protocol adheres to the principles of the Helsinki Declaration II, and the study will be
conducted in compliance with Good Clinical Practice, the Act on the Processing of
Personal Data, and the General Data Protection Regulation. Approval from the regional
Research Ethical Committees are underway. Participants are covered by The Patient
Compensation Association.
PERSPECTIVES
We expect that blood glucose regulation tailored to CGM, instead of HbA1c/finger prick
will improve blood glucose levels and reduce the incidence of hypoglycemia among dialysis
patients. We expect the project to contribute to rethinking diabetes treatment among
these patients, leading to increased survival, reduced diabetes complications and
hospitalizations, and improved quality of life.