CLINICAL INTEREST AND CRITICAL ANALYSIS OF EXTERNAL INSULIN PUMPS AND CONTINUOUS GLUCOSE MONITORING
The main objective of the management of type 1 diabetes is to restore a closed loop of glucose homeostasis. In the present work, we will focus our attention on two technological advances that may be used to address this goal in the future: the insulin therapy using a continuous subcutaneous insulin infusion (CSII), on the one hand, and the interstitial glucose continuous monitoring, on the other hand.
Our personal contribution in the field of CSII consists of a systematic review of the literature focusing on several topics of interest with this mode of insulin administration (use of ultra-short insulin analogues, desensitization in case of allergy to insulin, occurrence and influence of anti-insulin antibodies, development of lipodystrophies), on the one hand, a retrospective study of more than 500 patient-years of CSII treatment among type 1 diabetic patients followed at the CHU Liège, on the other hand.
1) Systematic review of the literature
This first part of the work does not contain original experiments. However, it deals with 4 systematic reviews of the literature about common or specific topics relative to CSII:
1) the comparison of the use of an ultra-short insulin analogue versus regular human insulin on both overall glucose control (glycated haemoglobin or HbA1c and hypoglycaemic episodes) and the risk of ketoacidosis (in case of CSII interruption);
2) the use of an external pump as a method of desensitization in case of insulin allergy; of note, this review follows the publication of an original personal observation also briefly reported in the present work;
3) the development of antiinsulin antibodies (AIA) when using CSII (and even more intraperitoneal continuous insulin infusion) and the impact of these AIA on the metabolic control and glucose instability;
and 4) the occurrence of skin lipohypertrophies or lipoatrophies when using CSII in the abdominal subcutaneous tissue
An exhaustive analysis of the literature demonstrates a significant advantage of using an ultra-short insulin analogue instead of human regular insulin. Indeed, we demonstrated a modest, although significant, reduction in HbA1c level, without increasing the incidence of hypoglycaemic episodes and apparently without aggravating the risk of ketoacidosis episodes in case of CSII interruption. The risk of developing AIA seems to be rather low with CSII, and indeed lower than what has been reported with the use of implantable pump and continuous peritoneal insulin infusion. The consequences of higher AIA levels with CSII on glucose control seem rather modest, at least when clinical events are taking into account such as glucose instability, despite well demonstrated pharmacokinetic interferences. Lipodystrophies during CSII therapy may occur, especially lipohypertrophies due to the anabolic effect of insulin that is infused continuously in the same subcutaneous abdominal area. Lipoatrophies, of immunological origin with an inflammatory component, raise less problems with CSII, and such lipoatrophies have even been treated successfully with CSII infusing an ultra-short insulin analogue. CSII may also be helpful for the management of allergic reactions that may occur with classical insulin therapy. Indeed, CSII may offer a “desensitization” strategy, such as reported in a clinical case when a young type 1 diabetic woman was remarkably improved with the use of CSII infusion of lispro insulin. An exhaustive review of the literature reveals the description of 10 such cases, which demonstrates the potential interest of CSII in this very specific indication.
2) Retrospective study on > 500 patient-years
This study analyzes both the indications and the results obtained with CSII therapy in 97 patients with type 1 diabetes treated with CSII and a mean follow up of 5 years (CHU Liège).
HbA1c levels before CSII (8.6 ± 1.3 %) decreased after 6 months of CSII (8.0 ± 1.2 %; p<0.05). However, results of HbA1c were quite heterogeneous, with a minority of well controlled patients. Among the 68 patients who had HbA1c levels above 8 % (mean 9.16 ± 1.02 %) before initiating CSII, HbA1c levels decreased to 8.5 ± 1.07 % at the last visit. HbA1c level averaged 6.8 ± 1.35 % in 15 women with unstable diabetes and who achieved 25 pregnancies. The incidence of comas or severe hypoglycaemic episodes averaged 0.2 episodes/patient.year. These events were observed in 31 different patients; among them, 7 were treated with CSII because of a high hypoglycaemic risk. Nevertheless, generally speaking, the patients with such a high risk of hypoglycaemia had a lower such risk during CSII. The total number of ketoacidosis was 29 (incidence of 0.05 event/patient.year), among which 5 were related to an identified technical problem.
These results demonstrate that CSII therapy improves metabolic control, with a reduction of HbA1c level and a diminution of the incidence of severe hypoglycaemia.
Three types of devices for continuous glucose monitoring in the subcutaneous interstitial milieu were used: CGMS® (« Continuous Glucose Monitoring System »), Guardian® and Navigator®. This part of our work comprises five original studies. We will first analyze the accuracy of these sensors in two specific studies: CGMS® in patients with type 1 diabetes (in- and out-patients) and Guardian® in type 1 diabetic patients submitted to a standardized physical exercise. Thereafter, we will report an original clinical application with the Guardian® in type 1 diabetic patients at high risk of hypoglycaemia. Afterwards, we describe the recent results of a one-year international randomised control trial called Capteur-Evadiac. This trial wanted to evaluate the best strategy (sensors used as the patients want or based on a strategy prescribed by the physicians).
Finally, the last original trial, with the CGMS®, aimed of detecting unrecognized hyperglycaemia in non diabetic patients hospitalized in coronary care unit.
1) Study of glucose sensor accuracy
The experiment concerning the assessment of GCMS® comprised 3 different parts : an in-patient study during 3 days in 12 hospitalized patients ; an out-patient study during 6 days (with 2 consecutive sensors) in 21 patients ; and an outpatient of only 3 days in 20 patients. Capillary glucose measurements (7 to 8 per day) were used as comparison. The glucose data were analyzed with correlation methods, Clarke error grid and the calculation of mean absolute differences using the Bland and Altman method. Our conclusion is that CGMS® may be used to appreciate “glucose trends », even if its accuracy was closer to that of glucometers rather than well-validated laboratory devices. Its use in the hospital was more accurate than in outpatients and a 6-day monitoring was more useful to appreciate inter-daily glucose reproducibility than a 3-day monitoring in such outpatient conditions.
The experiment concerning Guardian® involved 10 patients with type 1 diabetes treated with CSII for more than one year. They were submitted to a standardized physical exercise at a constant high workload of 30 minutes on a bicycle. The glucose concentration recorded by the sensor was noticed every 5 minutes from T-10 to T+30 min, and then every 10 minutes during the recovery phase from T+30 to T+90 min, and compared to concomitant glucose concentrations in blood drawn from a peripheral venous catheter. The results demonstrate that the glucose reduction observed during an intensive muscular exercise in diabetic patients treated with CSII can be estimated in real time with a clinically acceptable accuracy by the mean of a glucose sensor. A good calibration of the sensor before the effort is a prerequisite to obtain such objective.
2) Role of the Guardian® in glucose control and risk of hypoglycaemia in patients treated with CSII
Thirteen patients with type 1 diabetes treated with CSII and having more than 6 capillary glucose measurements below 60 mg/dl for the last 14 days were evaluated in the trial. They were randomized in a cross over design to two successive periods of 12 weeks with either a continuous glucose monitoring (Guardian RT®), or classical home blood glucose monitoring only. HbA1c levels decreased from 8.3 ± 0.7% (baseline) to 7.7 ± 0.6 % with the use of Guardian (p=0.049) vs. 8.0 ± 0.8% with home blood glucose monitoring alone. On average, the number of glucose values below 60 mg/dl decreased from 13.9 ± 9.2 (baseline) to 7.6 ± 6.8 with the Guardian® (p=0.011) vs. 11.1 ± 4.5 with home blood glucose monitoring alone based on the last 14 days. The results of this pilot study support the hypothesis that the use of a continuous glucose monitoring with a subcutaneous sensor (here the Guardian®) is able to significantly improve overall glucose control, as assessed by the changes in HbA1c levels, while reducing the incidence of hypoglycaemic episodes in type 1 diabetic patients prone to present such hypoglycaemic complications.
3) Multicentric trial CAPTEUR-EVADIAC
CAPTEUR-EVADIAC is a multicentric randomised trial performed by EVADIAC association, a French-Belgian group of leaders in the fields of technological advances in the treatment of diabetes. Our aim was to assess and compare the effect of two approaches to use CGM for one year in poorly-controlled type 1 diabetic patients.
Patients with type 1 diabetes, age ≥8yrs, HbA1c ≥8% were randomly assigned into 3 groups (1:1:1). Outcomes on glucose control were assessed according to two modes of using CGM (G 1: patient-led, G 2: physician-driven) vs. conventional Self Blood Glucose Monitoring (G 3: control).
Out of the 180 patients, 178 patients completed the study. At one year, the HbA1c level improved similarly in both CGM groups, and was reduced when compared with the control group: G1 vs. G3: -0.52 %, p = 0.0006, G2 vs. G3: -0.47 %, p = 0.0008, G1+G2 vs. G3: -0.50 %, p < 0.0001). Occurrence of hypoglycaemia was similar in the 3 groups. Patient satisfaction (DQoL) and physical health (SF36) scores improved in both experimental CGM groups (respectively p=0.004 and p=0.04). Consumption of sensors was 34% lower in group 1 when compared with group 2.
In conclusion, a long-term use of CGM resulted in a significant improvement in glucose control and quality of life in poorly-controlled type 1 diabetic patients on intensified insulin therapy.
4) Use of a CGMS® glucose sensor in intensive care unit
Patients hospitalized in intensive care units are exposed to hyperglycaemia, which may be harmful. The detection of hidden hyperglycaemic phases in order to treat them appropriately, without exposing the patient to an unacceptable risk of hypoglycaemia, represents a major objective. We evaluated the ability of identifying the time period above 140 mg/dl with a continuous monitoring of glucose in the interstitial milieu (CGMS®) in 21 non diabetic patients hospitalized for acute coronary syndrome in intensive care unit. The secondary objective was the search for predictive factors of hyperglycaemia in such circumstances. The calibration of the sensor was performed by using the 4 daily capillary glucose measurements routinely made in the intensive care. On a cumulative period of more than 50,000 min of recording, sensor data revealed a time period with glucose values >140 mg/dl lasting more than 9,500 min (i.e. 17 % of cumulative time). Despite the fact that there exists a significant relationship between the number of capillary glucose measurements above 140 mg/dl and the time with a glucose level > 140 mg/dl recorded by the sensor (r=0.93 ; p<0.001), only 22/136 capillary glucose measurements were > 140 mg/dl among the 17 patients showing such hyperglycaemic phases. Our results demonstrate the better ability to detect hidden hyperglycaemic periods with the use of a continuous glucose monitoring (CGMS®) than with iterative capillary glucose measurements in patients with unknown diabetes and without hyperglycaemia at admission in the coronary care unit. The absence of predictive factors of such hyperglycaemia should promote the systematic use of such intensive glucose monitoring in these patients. The availability of a continuous measure of interstitial glucose concentration with a real-time display may contribute to improve the benefits/risk ratio of the control of hyperglycaemia (without inducing severe hypoglycaemia) in such critical situations as hospitalisation in intensive care units.
Technological advances were registered in both the delivery of insulin and the glucose monitoring. However, caution is mandatory, and a critical evaluation is needed before the use of any new device in routine practice. Nevertheless, the glucose sensor is an attractive tool already widely used in specialized diabetes centres after numerous attempts to validate it. Furthermore, the efficacy of CSII for treating type 1 diabetes is well recognized. Thus, it seems to be realistic that a combination of these two techniques will be possible in a near future, allowing to restore normoglycaemia without exposing the patient to a significant risk of hypoglycaemia. Such an objective would result in a drastic reduction in the complications due to chronic hyperglycaemia while improving the quality of life of type 1 diabetic patients. Hopefully, the various pieces of our work would have, modestly, contributed to this wonderful adventure trying to restore the closed loop of glucose homeostasis, a major advance in the field of diabetes care.