A reduction in severe hypoglycaemia in type 1 diabetes in a randomized crossover study of continuous intraperitoneal compared with subcutaneous insulin infusion.

AIM: Continuous intraperitoneal insulin infusion (CIPII) with the DiaPort system using regular insulin was compared to continuous subcutaneous insulin infusion (CSII) using insulin Lispro, to investigate the frequency of hypoglycemia, blood glucose control, quality of life, and safety. METHODS: In this open, randomized, controlled, cross-over, multinational, 12-month study, 60 type 1 diabetic patients with frequent hypoglycemia and/or HbA1c > 7.0% with CSII were randomized to CIPII or CSII. The aim was to obtain the best possible blood glucose while avoiding hypoglycemia. RESULTS: The frequency of any hypoglycemia was similar (CIPII 118.2 (SD 82.6) events / patient year, CSII 115.8 (SD 75.7) p = 0.910). The incidence of severe hypoglycemia with CSII was more than twice the one with CIPII (CIPII 34.8 events / 100 patient years, CSII 86.1, p = 0.013). HbA1c, mean blood glucose, and glucose fluctuations were not statistically different. Treatment-related severe complications occurred mainly during CIPII: port infections (0.47 events / patient year), abdominal pain (0.21 events / patient year), insulin underdelivery (0.14 events / patient year). Weight gain was greater with CSII (+ 1.5 kg vs. - 0.1 kg, p = 0.013), quality of life better with CIPII. CONCLUSIONS: In type 1 diabetes CIPII with DiaPort reduces the number of severe episodes of hypoglycemia and improves quality of life with no weight gain. Because of complications, indications for CIPII must be strictly controlled. CIPII with DiaPort is an alternative therapy when CSII is not fully successful and provides an easy method of intraperitoneal therapy.

Multicentre, randomised, controlled study of the impact of continuous sub-cutaneous glucose monitoring (GlucoDay) on glycaemic control in type 1 and type 2 diabetes patients.

AIM: This randomised study was designed to investigate the impact of continuous glucose monitoring (CGM) for 48h on glycaemic control with a 3-month follow-up in patients with type 1 (T1D) or type 2 (T2D) diabetes. METHODS: A total of 48 patients with poor glycaemic control (HbA(1c): 8-10.5%) underwent CGM for 48h using the GlucoDay((R)) system (A. Menarini Diagnostics), after which they were randomly assigned to treatment adjustments based on either their CGM profile (CGM group) or their usual self-monitoring of blood glucose (SMBG group). HbA(1c) measurement and 48-h CGM were repeated 3 months later. RESULTS: Altogether, 34 patients with either T1D (n=9) or T2D (n=25) completed the study; seven patients chose to leave the study, and seven patients in the CGM group were excluded because their baseline CGM graphs were not interpretable. HbA(1c) levels decreased significantly in the CGM group (n=14, -0.63+/-0.27%; P=0.023), but not in the controls (n=20, -0.28+/-0.21%; P=0.30). In T2D patients, the improvement associated with CGM vs SMBG was due to HbA(1c) decreases (mean: -0.63+/-0.34%; P=0.05 vs -0.31+/-0.29%; P=0.18, respectively). However, HbA(1c) did not change significantly with CGM in T1D patients. Comparisons of CGM data at baseline and after 3 months showed no significant changes in glucose control, glucose variability or hypoglycaemia. No major adverse events related to the GlucoDay system were reported. CONCLUSION: This is the first randomised study showing that CGM improves glycaemic control in patients with T2D.

Implantable insulin pumps. A position statement about their clinical use.

AIM: To review clinical use of implantable insulin pumps and to suggest indications for this therapy. METHODS: The EVADIAC group performed a review of published reports on implantable insulin pumps for the last 15 years and analyzed its own centralized database. From this update, a position statement on indications of this therapy is drawn. RESULTS: Published papers mostly report safety and effectiveness data from observational cumulated experiences of 15-350 patient-years. While HbA(1c) reduction does not reach statistical significance in all reported studies, improvement of blood glucose stability and reduction of severe hypoglycaemia appear as constant characteristics of this therapy. When compared to subcutaneous insulin therapy in randomized controlled studies, implantable pumps allow significantly reduced blood glucose fluctuations and improved quality of life in both type 1 and type 2 diabetic patients, and a significant weight decrease in type 2 diabetic patients. While the EVADIAC registry shows the reduced occurrence of pump-pocket complications thanks to preventive measures and a lower incidence of catheter obstructions following improvements of catheter design, underdelivery due to insulin aggregation in pumps remains a recurrent although reversible issue. Determinants of increased anti-insulin antibody production in some patients remain elusive but impact on blood glucose control is limited in most cases. CONCLUSION: From analyzed data, the EVADIAC group states that implantable pumps can be safely indicated and provide metabolic improvements in type 1 diabetic patients who remain far from targeted HbA(1c) below 7% and/or experience large fluctuations of blood glucose including recurrent severe hypoglycaemia, in spite of intensive follow-up and education when treated by subcutaneous insulin.

What could be the reasons for giving up the implanted pump treatment?

The development of implanted insulin pump treatment has been particularly intense in France and French implanting centers joined to form an association called EVADIAC. The data collected by EVADIAC have clearly documented benefits as well possible problems with this treatment mode. In comparison with SC administration, intraperitoneal (IP) insulin infusion via an implanted pump achieves good metabolic control, improves long-term stability of diabetes and significantly reduces the risk of severe hypoglycemia. Problems can involve pump slowdown, catheter obstruction or local complication at the implantation site. With respect to the benefits, the rate of complications is highly acceptable. However, amongst the implanted diabetic patients, some elect to give up such a treatment mode. In a retrospective study we intended to examine their reasons for giving up this treatment. In our center, the patients who elected by themselves to give up the implanted pump account for 16% of all treated patients. This group of patients did not have, as compared to other implanted patients, less benefits nor more restrictions or incidents that could have impaired their well being. The reasons for giving up the implanted pump seem more often to be related to the refusal of a strict and institutional management linked to this treatment.

Reproducibility of plasma insulin kinetics during intraperitoneal insulin treatment by programmable pumps.

OBJECTIVE: To study the reproducibility of plasma insulin kinetics during intraperitoneal (IP) insulin therapy using an implanted programmable pump in patients with type 1, insulin dependent, diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: In a group of ten type 1 IDDM patients beginning chronic IP insulin treatment with an implanted pump, plasma free insulin profiles were determined from 12: 00 am to 12: 30 pm on two separate test days, one month apart. Anti-insulin antibody (AIA) levels were measured on each test day. RESULTS: From test day 1 to test day 2, no difference was observed in morning fasting free insulin levels (m +/- SD): 9.7 +/- 5.4 mU/L versus 9.8 +/- 5.3 mU/L, insulin peak values: 19.1 +/- 17 mU/L versus 20.8 +/- 9.9 mU/L, time to peak: 40 +/- 15 versus 42.8 +/- 16 minutes or post-bolus area under the plasma free insulin curve (AUC): 40.7 +/- 29 mU/L.h versus 45.5 +/- 29 mU/L.h. The intrapatient coefficient of variation was 14.4 +/- 13% for insulin peaks and 16.9 +/- 9.2% for post-bolus AUC. A significant increase in AIA levels (m +/- SD) was observed from 16.5 +/- 18% on test day 1 to 28.1 +/- 28% on test day 2. CONCLUSIONS: The reproducibility of plasma free insulin profiles is highly satisfactory during insulin delivery by the IP route using an implanted device.

Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience.

OBJECTIVE: To report a long-term multicentre experience with implantable insulin pumps in type 1 diabetic patients, and to test safety and accuracy of the systems following improvements in infused insulin solutions and peritoneal catheter. RESEARCH DESIGN AND METHODS: Forty MiniMed Implantable Pumps model 2001 were consecutively implanted over a two-month period in type 1 diabetic volunteers. The systems were equipped by a new compliant sideport catheter and were refilled at 45-day intervals with HOE 21 PH ETP insulin batches showing enhanced physical stability in vitro. Safety was assessed from the incidence of acute adverse events and effectiveness from quarterly HbA(1c) assays. Accuracy of delivery was measured at each pump refill by comparing residual insulin in the pump reservoir with expected amount according to programmed infusion. The study lasted until pump battery depletion or premature pump explantation. RESULTS: Cumulated experience was 106 patient-years. Premature explantations occurred in 3 cases, due to one electronic pump failure and two "pump-pocket" infections. Near-normal insulin delivery was sustained until expected battery depletion in 13 cases. Forty underdelivery events occurred in 24 pumps, but 36 among them were related to pump slowdowns due to insulin aggregation in pumps that were promptly solved by an outpatient NaOH rinse procedure. Only 4 underdeliveries were caused by catheter obstructions that required laparoscopy to remove peritoneal tissue overgrowth around the catheter. Over pump lifetime, HbA(1c) was 7.2 +/- 0.2% in the 13 patients with no underdelivery and 7.7 +/- 0.5% in the other ones. Only one severe hypoglycemia and one ketoacidosis occurred during the whole study. CONCLUSION: Our current experience with improved implantable pumps and insulin solutions shows both long-term safety and effectiveness of this treatment in type 1 diabetic patients following improvement in infused insulin solutions and catheter. This therapy may be a good alternative for patients that experience frequent severe hypoglycemia with intensive subcutaneous insulin therapy.

Improved metabolic control in diabetic adolescents using the continuous glucose monitoring system (CGMS).

OBJECTIVE: To determine the utility of the continuous glucose monitoring system (CGMS) as an outpatient procedure to improve management of diabetes in adolescents. RESEARCH DESIGN AND METHODS: Twelve adolescents (mean age: 16.2 +/- 3 years) with poorly controlled type 1 diabetes (HbA(1c) > 8%) were included in this trial. Mean HbA(1c) during the previous year was 10.1 +/- 1.2%. Insulin treatment consisted of 2 or 3 daily injections in 10 cases and CSII in 2. At the beginning of the study, HbA(1c) was determined and low blood glucose index (LBGI) was calculated. Continuous glucose monitoring was performed for three days. After downloading and analyzing data, results were discussed with the patient and insulin treatment was adjusted. Two months later testing was repeated and all parameters were reassessed. RESULTS: Initial CGMS profiles demonstrated glycemic excursions unrecognized by capillary measurements in all twelve patients. Glycemia before and after meals varied from<60 mg/dL to > 200 mg/dL in 2 patients (2 episodes). Postprandial hyperglycemia exceeded 200 mg/dL in 10 patients (24 episodes). Prolonged overnight hyperglycemia was observed in 5 patients (7 episodes), dawn phenomenon in 4 patients (6 episodes) and nighttime hypoglycemia in 4 patients (4 episodes). A day-to-day reproducibility of glycemic profiles was observed in 8 patients. Then insulin treatment was adjusted according to CGMS data. Changes involved dose levels in 3 patients, insulin type in 7, number of injections, i.e. 3 instead of 2, in 5 or change from insulin injection to CSII in 1. Reassessment two months later demonstrated a significant reduction of glycemic excursions in 8 patients. HbA(1c) (m +/- SD) decreased from 10.3 +/- 2.1% to 8.75 +/- 1.06% (p<0.05). LBGI increased from 1.7 +/- 0.9 to 2.4 +/- 1.4 but the difference was not significant. CONCLUSIONS: Use of CGMS in diabetic adolescent outpatients achieved a significant improvement in metabolic control not only by providing accurate data for adjustment of insulin treatment but also by promoting patient communication and motivation.