1012-P: Study of Insulin Stability Impact on Pump Therapy: Test Model Development

Background: Ultra rapid lispro (URLi) is a new insulin lispro formulation that has accelerated absorption and improved postprandial glucose control compared with insulin lispro (Humalog®). The compatibility and safety of URLi versus lispro were evaluated in patients with type 1 diabetes using continuous subcutaneous insulin infusion (insulin pump). Methods: In this phase 3, double-blind, crossover study, 49 patients were randomized to two 6-week treatment periods, after a 2-week lead-in period on lispro. The primary endpoint was the rate of infusion set failures due to a pump occlusion alarm, or unexplained hyperglycemia with blood glucose >13.9 mmol/L (250 mg/dL) that did not decrease within 1 h after a correction bolus. Results: There was no significant difference in the rate of infusion set failures between URLi and lispro (0.03 vs. 0.05 events/30 days, P = 0.375). A higher rate of premature infusion set changes was observed with URLi (1.13 vs. 0.78 events/30 days; P = 0.028), translating to one additional infusion set change approximately every 3 months. A trend toward improved glycemic control was observed with URLi treatment: Time in range 3.9-10.0 mmol/L (71-180 mg/dL) was 65.7% ± 1.3% versus 63.0% ± 1.3%. Treatment-emergent adverse events (TEAEs) were reported by 46.9% of patients on URLi treatment and 18.8% on lispro. This difference was driven by an increase in infusion site reactions-more than 90% were mild. Incidence of all other TEAEs and severe hypoglycemia was similar between treatments. Conclusions: URLi was compatible with insulin pump use with a safety profile similar to lispro.

### Adverse Event Our patient was 13 years and 2 months old, a white boy with type 1 diabetes diagnosed 2 years and 5 months before this adverse event (AE). He had no other significant medical history. His A1C was 7.6% 1 month before the insulin infusion needle break event. The patient had started on the t-slim insulin pump (Tandem Diabetes Care, San Diego, Calif.) 1 year and 6 days before the AE occurred. He was using the contact Detach (Unomedical, Inc., Bridgewater, N.J.) infusion set and lispro insulin. The contact Detach infusion set features a very fine, 29-gauge, 90° steel needle. With its additional adhesive pad, contact Detach provides extra security against needle dislodging. Its simplicity and security make it a good choice for active young children, pregnant women, and adults for whom soft cannula sets do not work well. The contact Detach set is available in 6- and 8-mm needle lengths and 23- and 32-inch tubing lengths (1). There were no reported previous pump AEs, emergency department visits, or diabetes ketoacidosis episodes related to continuous subcutaneous insulin infusion (CSII) therapy. The patient’s BMI was 18.65 kg/m2. The patient’s mother reported changing the pump site, per usual, on 16 July 2014. When she went to remove the infusion set, the needle was not attached to it. The parents could not find the needle. The patient did not feel any pain or discomfort where the infusion set had been placed. At the time the 8-mm needle broke off from the infusion site, it had been placed on the upper left buttock area at a 90° angle with IV3000 1-HAND adhesive dressing (Smith & …

It is now generally agreed that to achieve optimal glycemic control, patients with type 1 diabetes should be treated with intensive insulin therapy. This can be achieved by a continuous subcutaneous insulin infusion (CSII) or by multiple daily injections (MDI) using a combination of long-acting basal insulin (glargine or detemir) and a short-acting insulin (lispro, aspart, or glulisine) to control postprandial hyperglycemia. However, it remains controversial whether these two modalities are equally effective or if one is superior to the other. One meta-analysis1 and the 5-nations trial2 concluded that CSII resulted in better glycemic control compared to MDI. However, older insulins (neutral protamine Hagedorn or regular) and outdated pump technologies were used in these studies. Other studies have shown CSII to be equally effective3 or CSII being superior4 to MDI. Although a more recent meta-analysis also showed that the frequency of severe hypoglycemia in type 1 diabetes was reduced markedly in trials during CSII compared with MDI based on isophane and lente insulins, the authors acknowledged that they did not find any trials comparing CSII and MDI based on the newer long-acting insulin analogs where severe hypoglycemia could be analyzed. Moreover, their conclusions on hemoglobin A1c (HbA1c) were based on a relatively small number of trials concerning glargine and none using detemir.5 In addition, it is not clear if one of these two treatment modalities is superior to the other in routine clinical practice. We therefore compared the degree of glycemic control achieved, frequency and severity of hypoglycemic episodes, and perception of quality of life achieved by CSII versus MDI in our practice. We sent letters inviting all patients being treated with CSII or MDI in our practice that had been followed for at least 2 years—113 letters were sent to pump patients and 137 to patients on MDI. Fifty-three patients treated with CSII using insulin lispro or aspart and 54 patients treated with MDI therapy (glargine and either insulin lispro or aspart) agreed to participate. Hypoglycemic episodes were self-reported as mild or severe (requiring third-party help). Life satisfaction, impact, and worry related to diabetes were assessed by the diabetes quality of life questionnaire.6 The patient demographics and results of the study are shown in Table 1. Table 1. Demographics and Results Comparing CSII with MDI The mean HbA1c was significantly lower in the CSII group. Episodes of severe hypoglycemia were less frequent, and overall satisfaction was greater in the CSII group compared to the MDI group. These findings are similar to those seen in randomized controlled trials.1,2,4,5 We acknowledge that our sample was not a randomized sample and although we did not evaluate the socioeconomic status of patients, it is apparent that only those who could afford the pumps would have been on CSII therapy. We conclude that CSII therapy is associated with better glycemic control, fewer episodes of severe hypoglycemia, and higher life satisfaction compared to MDI in patients with type 1 diabetes in a routine clinical practice.

Persistent glucose variability is a frequent condition in type 1 diabetes. Continuous subcutaneous insulin infusion (CSII) is a rational option to overcome this clinical issue; however, no comparative studies have been reported for aspart and lispro insulin when used in CSII. This study compare the effects of aspart and lispro delivered by CSII on glycemic stability as measured using a continuous glucose monitoring system. This single-center, randomized, controlled, 3-day crossover trial included 17 patients with type 1 diabetes. Patients were randomized to receive insulin aspart or insulin lispro. The next day, they received a standard meal at breakfast and lunch and a bolus of insulin aspart or lispro based on insulin:carbohydrate ratio. Patients were monitored for 8 h, after which they received a crossover treatment with insulin aspart or insulin lispro followed by the same procedure as previously. Postprandial blood glucose was more stable with insulin aspart than insulin lispro (absolute Deltaglucose 7.04 +/- 3.16 vs. 9.04 +/- 4.2, P < 0.0019). Daily blood glucose variability profiles (coefficient of variation and mean amplitude of glucose excursion) and frequency of hypoglycemic episodes (area under the curve <72 mg/dL) were similar with both treatments. Postprandial glucose was more stable when insulin aspart was infused as a pre-meal bolus compared with insulin lispro, indicating a more favorable effect of insulin aspart on postprandial glucose. No differences in overall daily glucose stability were observed between insulin aspart and insulin lispro when infused as basal rate insulin.

This was a randomized double blinded study of a novel infusion set with and without heparin, hypothesizing that small doses of heparin would decrease thrombosis and subcutaneous inflammation. The MiniMed™ Quick-set™ infusion set was modified with a new tubing connector from current P-Cap. The P-Cap was modified to contain a foam (F) or a foam with heparin (F+H) connector. Visibly the sets appeared identical. Each participant wore two F and two F + H sets for 7 days or until set failure. The order of infusion set wear was randomly assigned. Infusion set failure was determined by unexplained hyperglycemia &amp;gt;250mg/dL with a failed correction dose, ketones &amp;gt;0.6mmol/L, evidence of infection, occlusion alarms, or adhesive failure. Infused set survival was compared to similar published 1-week studies using standard Quick-sets. There were 20 participants (mean age 29.5±8 years). Each set was worn 40 times. Length of wear and causes of failure are shown below. Length of wear was not different between the F and F+H groups, but both had improved length of wear compared to historical Quick-sets (p&amp;lt;0.05). There was no significant increase in insulin requirements or mean glucose values throughout the seven days of wear in any group. There was no difference in overall duration of wear between the F and F+H groups. Both infusion set groups intended for extended wear had significantly better survival than the historical Quick-Set™ group. Further studies are planned with the F group. Disclosure B.A. Buckingham: Advisory Panel; Self; ConvaTec Inc., Medtronic. Research Support; Self; Beta Bionics, Inc., Dexcom, Inc., Insulet Corporation, Medtronic, Tandem Diabetes Care. T. Marcal: None. L. Hoffman: None. G. Musolino: None. L. Ekhlaspour: None. G. Zhang: None. S. Chattaraj: Employee; Self; Medtronic. Funding Medtronic Diabetes

This article reviews the performance of our hospital's inpatient insulin pump policy. Twenty-five hospital admissions of 21 unique patients receiving outpatient insulin pump therapy were reviewed. Between November 1, 2005, and November 30, 2006, there were 25 hospital admissions involving 21 patients receiving outpatient insulin pump therapy. The average age and duration of diabetes among these 21 patients was 50 and 29 years, respectively; 67% were women, 90% had type 1 diabetes, and all were white. The mean length of hospital stay was 4 days, and the average reported length of insulin pump therapy was 4 years. Patients in 16 of the admissions were identified as candidates for continued use of the insulin pump during the hospital stay. Over 90% of patients remaining on the insulin pump had documentation by nursing of the presence of the pump at the time of admission; 100% of the patients had an admission glucose recorded; 88% had a record of signed patient consent; 81% had evidence of completed preprinted insulin pump orders; 75% received a required endocrine consultation; and 75% of cases had documentation of completed bedside flow sheet. A high frequency of both hypoglycemic and hyperglycemic events occurred in the patients; however, no adverse events were related directly to the insulin pump. Insulin pump therapy can be safely continued in the hospital setting. While staff compliance with required procedures was high, there was still room for improvement. More data are needed, however, on whether this method of insulin delivery is effective for controlling hyperglycemia in hospitalized patients.

The National Institute for Health and Clinical Excellence (NICE) was reviewing its previous guidance on continuous subcutaneous insulin infusion (CSII). The review provided an assessment of evidence which had been published since the previous NICE appraisal (TA 151) in 2007. To examine the clinical effectiveness and cost-effectiveness of using CSII to treat diabetes. To update the previous assessment report by reviewing evidence that has emerged since the last appraisal, and to take account of developments in alternative therapies, in particular the long-acting analogue insulins, which cause fewer problems with hypoglycaemia. A systematic review of the literature and an economic evaluation were carried out. The bibliographic databases used were MEDLINE and EMBASE, 2002 to June 2007. The Cochrane Library (all sections), the Science Citation Index (for meeting abstracts only) and the website of the 2007 American Diabetes Association were also searched. The primary focus for type 1 diabetes mellitus (T1DM) was the comparison of CSII with multiple daily injection (MDI), based on the newer insulin analogues, but trials of neutral protamine Hagedorn (NPH)-based MDI that had been published since the last assessment were identified and described in brief. For type 2 diabetes mellitus (T2DM), all trials of MDI versus CSII were included, whether the long-acting insulin was analogue or not, because there was no evidence that analogue-based MDI was better than NPH-based MDI. Trials that were shorter than 12 weeks were excluded. Information on the patients' perspectives was obtained from four sources: the submission from the pump users group--Insulin Pump Therapy (INPUT); interviews with parents of young children who were members of INPUT; some recent studies; and from a summary of findings from the previous assessment report. Economic modelling used the Center for Outcomes Research (CORE) model, through an arrangement with the NICE and the pump manufacturers, whose submission also used the CORE model. The 74 studies used for analysis included eight randomised controlled trials (RCTs) of CSII versus analogue-based MDI in either T1DM or T2DM, eight new (since the last NICE appraisal) RCTs of CSII versus NPH-based MDI in T1DM, 48 observational studies of CSII, six studies of CSII in pregnancy, and four systematic reviews. The following benefits of CSII were highlighted: better control of blood glucose levels, as reflected by glycated haemoglobin (HbA1c) levels, with the size of improvement depending on the level before starting CSII; reduction in swings in blood glucose levels, and in problems due to the dawn phenomenon; fewer problems with hypoglycaemic episodes; reduction in insulin dose per day, thereby partly off-setting the cost of CSII; improved quality of life, including a reduction in the chronic fear of severe hypoglycaemia; more flexibility of lifestyle--no need to eat at fixed intervals, more freedom of lifestyle and easier participation in social and physical activity; and benefits for the patients' family. The submission from INPUT emphasised the quality of life gains from CSII, as well as improved control and fewer hypoglycaemic episodes. Also, there was a marked discrepancy between the improvement in social quality of life reported by successful pump users, and the lack of convincing health-related quality of life gains reported in the trials. With regard to economic evaluation, the main cost of CSII is for consumables, such as tubing and cannulas, and is about 1800-2000 pounds per year. The cost of the pump, assuming 4-year life, adds another 430-720 pounds per annum. The extra cost compared with analogue-based MDI averages 1700 pounds. Most studies, assuming a reduction in HbA1c level of 1.2%, found CSII to be cost-effective. The most important weakness of the evidence was the very small number of randomised trials of CSII against the most modern forms of MDI, using analogue insulins. Based on the totality of evidence, using observational studies to supplement the limited data from randomised trials against best MDI, CSII provides some advantages over MDI in T1DM for both children and adults. However, there was no evidence that CSII is better than analogue-based MDI in T2DM or in pregnancy. Further trials with larger numbers and longer durations comparing CSII and optimised MDI in adults, adolescents and children are needed. In addition, there should be a trial of CSII versus MDI with similar provision of structured education in both arms. A trial is also needed for pregnant women with pre-existing diabetes, to investigate using CSII to the best effect.

Use of rapid-acting insulin analogues in the treatment of patients with type 1 and type 2 diabetes mellitus: Insulin pump therapy versus multiple daily injections

Insulin pumps have become increasingly available to children, young people, and adults with diabetes across the UK. The recently published National Institute for Health and Care Excellence (NICE) guidance (2015a; 2015b) for type 1 diabetes in adults and children and young people (NG17 and NG18) highlights the use of insulin pumps as the chosen treatment option for many people across all age groups living with type 1 diabetes. An insulin pump is a computerised, portable, external insulin-delivery device. Insulin is delivered via a small cannula on a preprogrammed continuous basis using a basal insulin delivery. The user instructs the pump to deliver bolus insulin in accordance with the food eaten. Insulin pumps are either attached via an infusion set connected to a cannula or via patch-pump technology, which has no infusion set attached (Figures 1 and 2). With new pumps continually being introduced, regular education and updates for practitioners and people using insulin pumps is essential for safe practice.

This survey collected and evaluated user responses about routine tasks and preferences regarding insulin pumps and infusion sets (IIS) with comparison of intercountry differences between the United States (US) and Germany (GER), chosen for their large insulin pump populations. A total of 985 subjects (534 US, 451 GER; 60% female) with type 1 diabetes on pump therapy anonymously answered 20 pump-related questions. US subjects also answered 11 questions about continuous glucose monitoring (CGM) usage. Length of use of insulin cartridges is shorter in US than in GER, mean (SD) 4.3 (5.0) versus 5.3 (3.2) days (P < .001), while the IIS is used longer: 3.3 (1.0) versus 2.7 (1.1) days (P < .001). Lower self-reported HbA1c levels were associated with longer use of insulin cartridges (7.3% for >3 days vs. 7.7% for <3 days; P < .01), and with use of an auto-insertion device (vs. manual IIS insertion) in the US (7.2% vs. 6.9%), but not in GER (7.7% vs. 7.9%). Only 47% of pump wearers stated that they were "very satisfied" with their pump (49% US vs. 45% GER, ns). However, 98% would recommend the pump to others (95% vs. 93%, ns). Analysis of CGM questions showed that 297 (60%) of 496 US responders currently wore one. Of these, 84% said they would recommend CGM to others. CGM wearers who stated they were "very satisfied" with their CGM had lower HbA1c than those who said they were "partly satisfied" (6.9% vs. 7.2%). This survey shows interesting differences in real-world use of insulin pumps in 2 large markets, and suggests areas where insulin pumps and CGMs might be improved.

Continuous subcutaneous insulin infusion (CSII), popularly called insulin pump therapy, has evolved from its invention in the 1970s as an experimental treatment designed to test the relationship between glycemic control and diabetic tissue complications (1) to its present status as a routine therapy for selected type 1 diabetic patients (2). However, the use of insulin pump therapy varies markedly throughout the world; there are some notable high-use countries, e.g., the U.S. and Israel, where it is estimated that ∼20% of type 1 diabetic patients use CSII (manufacturers’ estimates), whereas in other countries, such as the U.K. and Denmark, ∼1% use pump therapy (3). The reasons for this variation include the availability of financial resources and health care professionals to supervise CSII and a lack of knowledge on the effectiveness of CSII (3), but there is also disagreement on which diabetic subjects should be treated with CSII, as evidenced by both the different intercountry usage and the large number of reasons for starting insulin pump therapy (4–6). As noted by Schade and Valentine (7), “the challenge for the health care provider is to select the diabetic patients who will really benefit from pump usage.” What proportion and what types of type 1 diabetic patients should then be offered a trial of CSII on clinical grounds alone, leaving aside the legitimate issues of supply on the basis of patient preference and restrictions due to availability of funding and staffing? I shall argue that the target proportion best treated by CSII, or offered a trial of CSII, can be derived from an estimate of the effectiveness of this therapy compared with the best insulin injection treatment for particular clinical problems in type 1 diabetes. Most current guidelines (4,6) or reviews of the evidence base on CSII (2 …

61-Year-Old Man With Nausea and Vomiting

To investigate the effect of DAFNE and continuous subcutaneous insulin infusion in clinical practice. Within NHS Lothian, continuous subcutaneous insulin infusion started in 2004 and DAFNE education began in 2006. We extracted anonymized data from the national database for all those aged > 18 years with type 1 diabetes having a Dose Adjustment For Normal Eating course or continuous subcutaneous insulin infusion start date (n = 4617). In total, 956 persons received DAFNE education, and 505 had received an insulin pump, 208 of whom had DAFNE education followed by insulin pump. Mean (SD) HbA1c before DAFNE education was 68 (15) mmol/mol (8.4% [1.4%]) and 66 (13) mmol/mol (8.2% [1.2%]) before continuous subcutaneous insulin infusion. In the year following DAFNE education, the mean fall in within-person HbA1c was 3.8 mmol/mol (95% CI 4.0 to 3.4; 0.3% [0.4% to 0.3%]). Those with the poorest control (HbA1c ≥ 85 mmol/mol [9.9%]) experienced the largest decline (15.7 mmol/mol [1.4%]). Those in the lowest HbA1c band at initiation (< 53 mmol/mmol [7.0%]) experienced a rise. In the year following continuous subcutaneous insulin infusion initiation there was a mean fall in within-person HbA1c of 6.6 mmol/mol (6.8 to 6.4; 0.6% [0.6% to 0.6%]). In those with the poorest control (HbA1c ≥ 85 mmol/mol [9.9%]), the mean fall in HbA1c was 22.2 mmol/mol (23 to 21; 2.0% [2.1% to 1.9%]). Continuous subcutaneous insulin infusion effectiveness was not different with or without DAFNE education. The effects of both interventions were sustained over 5 years. Both DAFNE education and insulin pump therapy had the greatest effect on HbA1c in those with higher baseline values. There was little difference to attained HbA1c when Dose Adjustment For Normal Eating education was introduced before insulin pump therapy.

Portable insulin infusion devices are effective and safe insulin delivery systems for managing diabetes mellitus, especially type 1 diabetes. Rapidly absorbed insulin analogues, such as insulin lispro or insulin aspart, may offer an advantage over regular human insulin for insulin pumps. Several open-label randomised crossover trials demonstrated that continuous subcutaneous insulin infusion (CSII) with insulin lispro provided a better control of postprandial hyperglycaemia and a slightly but significantly lower glycated haemoglobin level, with lower daily insulin requirement and similar or even less hypoglycaemic episodes. A CSII study comparing insulin lispro and insulin aspart demonstrated similar results with the two analogues, and better results than those with regular insulin. Because these analogues have a quicker onset and a shorter duration of action than regular insulin, one might expect an earlier and greater metabolic deterioration in case of CSII interruption, but a more rapid correction of metabolic abnormalities after insulin boluses when reactivating the pump. These expectations were confirmed in randomised protocols comparing the metabolic changes occurring during and after CSII interruption of various durations when the pump infused either insulin lispro or regular insulin. The extra cost resulting from the use of CSII and insulin analogues in diabetes management should be compensated for by better metabolic control and quality of life. In conclusion, CSII delivering fast-acting insulin analogues may be considered as one of the best methods to replace insulin in a physiological manner by mimicking meal and basal insulin requirements, without higher risk of hypoglycaemia or ketoacidosis in well-educated diabetic patients.

Diabet. Med. 29, 971 (2012) Insulin therapy using an insulin injection was introduced in 1922. Progress towards a more physiological approach to insulin replacement has been painfully slow. One advance has been the use of continuous subcutaneous insulin infusion (CSII or insulin pumps) with or without glucose sensor augmentation. However, this therapeutic option is expensive and requires a trained multidisciplinary team to deliver an insulin pump service. It is therefore important to consider who would most benefit from such therapy and its cost-effectiveness. The availability of insulin pumps as a therapeutic option for the treatment of diabetes varies both between and within countries depending on the health system and its affordability for that country. In this month’s issue, Carlsson and colleagues (page 1055) examine the availability of insulin pump therapy in people with Type 1 diabetes attending 10 hospital outpatient clinics in Sweden. The use of insulin pumps varied between clinics and women were 1.5-fold more likely to use such therapy. Other features associated with pump use were a higher HbA1c at baseline, lower creatinine, high and low insulin doses, and younger age. People with Type 1 diabetes aged 20–30 years were two times more likely to begin to use insulin pumps than those aged 40–50 years. In the UK there are national guidelines (the National Institute for Health and Clinical Excellence; NICE) that recommend consideration of pump therapy in people with Type 1 diabetes on multiple daily injections with HbA1c > 69 mmol/mol (8.5%) despite the person trying to improve their diabetes control or in those in whom target HbA1c cannot be reached because of hypoglycaemia. The recommendations are even more relaxed in children. NICE also states that insulin pump therapy should only be started by a trained team that includes a doctor who specializes in insulin pump therapy, a diabetes nurse and a dietician. It is then recommended that the therapy should only be continued if there is a sustained improvement in HbA1c and/or less hypoglycaemia; quality of life should also be added to this list. An audit of pump services is currently being undertaken in the UK but it is likely to find that access is variable between sites, with some regions still not having access to a pump service as the commissioners of health care will not fund the service that requires not only the cost of the pump and its consumables but all members of the pump team, including the funding of educational packages. The availability of an insulin pump for a person with Type 1 diabetes then becomes a post-code lottery. This is an unacceptable state of affairs. Some patients with Type 1 diabetes do not want to use an insulin pump, but would consider the use of a continuous glucose monitoring system (CGMS). Unfortunately, there is no formal guidance on this issue in many countries, which makes it even more difficult for this to be considered an option, despite the wishes of those living with diabetes and health professionals advising on best practice.