Embryonic Stem Cell Use

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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

Today continuous subcutaneous insulin infusion (CSII) is frequently used in children and adolescents with type 1 diabetes mellitus. The present cross-sectional trial aimed to document current practice, quality of diabetes control and incidence of acute complications in different age-groups under CSII vs. multiple daily insulin injection therapy (MIT). Moreover the survey analyzed socio-demographic backgrounds of the patients. A total of 901 patients (age 11.5±4.0, diabetes duration 4.0±3.6 years) was entered in the database. Clinical data, laboratory parameters and, using a standardized questionnaire, socio-demographic data were assessed. For age-related analyses patients were allocated to 4 groups: pre-school children (< 6 years), pre-adolescents (≥ 6 and<11 years), adolescents (≥ 11 and<16 years) and young adults (≥ 16 and<22 years). Of the cohort n=194 had a CSII, n=707 had a MIT. Patients with CSII vs. MIT had a longer diabetes duration, they used more frequently insulin analogues, performed more frequently blood-glucose self-tests and had a lower insulin dosage per kilogram body weight. In respect of HbA1c, the mean amplitude of blood-glucose excursions, but also of lipids, creatinine, microalbuminuria and blood pressure, there were no differences in neither age-group between patients with CSII and MIT. In patients with CSII and MIT, there was a tendency (p<0.05) towards an increase in HbA1c in adolescents and young adults and there was a decrease (p<0.05 for tendency) in the frequency of hypoglycaemia from the age group of young adults to pre-school children. Adolescents and young adults with CSII had a higher educational level. Pre-adolescents, adolescents and young adults with CSII have also better diabetes-related knowledge. Moreover, in all age-groups, the parents of patients with CSII had mostly a lower unemployment rate and higher educational levels. The present analyses demonstrate that in all age-groups CSII provides convenient and flexible insulin delivery during routine treatment of type 1 diabetes. There is reasonable quality of diabetes control accompanied by a low incidence of hypoglycaemia and ketoacidosis. However, under CSII and MIT there is an increase of HbA1c towards adolescence. It must also highlighted that CSII seems to be expansive and that CSII is more frequently used in patients with better educational levels and deriving from higher social classes.

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.

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.

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Type 1 diabetes is a metabolic disorder resulting from a defect in insulin secretion. Onset of type 1 diabetes mellitus may occur at any age and it is one of the most common chronic diseases of childhood and adolescence. Since there are no interventions known to prevent onset, it is vital that effective treatment regimes are available. Glycaemic control is maintained by replacement of insulin and may be in the form of 'conventional' insulin therapy (multiple injections per day) or continuous subcutaneous insulin infusion (CSII). To assess the effects of CSII compared to multiple insulin injections (MI) in people with type 1 diabetes mellitus. Studies were obtained from electronic searches of The Cochrane Library, MEDLINE, EMBASE and CINAHL. Studies were included if they were randomised controlled trials comparing CSII with three or more insulin injections per day (MI) in people with type 1 diabetes mellitus. Two authors independently assessed risk of bias and extracted characteristics of included studies. Authors contacted study investigators to obtain missing information. Generic inverse variance meta-analyses using a random-effects model were performed. Twenty three studies randomised 976 participants with type 1 diabetes to either intervention. There was a statistically significant difference in glycosylated haemoglobin A1c (HbA1c) favouring CSII (weighted mean difference -0.3% (95% confidence interval -0.1 to -0.4). There were no obvious differences between the interventions for non-severe hypoglycaemia, but severe hypoglycaemia appeared to be reduced in those using CSII. Quality of life measures suggest that CSII is preferred over MI. No significant difference was found for weight. Adverse events were not well reported, no information is available on mortality, morbidity and costs. There is some evidence to suggest that CSII may be better than MI for glycaemic control in people with type 1 diabetes. Non-severe hypoglycaemic events do not appear to be reduced with CSII. There is insufficient evidence regarding adverse events, mortality, morbidity and costs.

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Recent meta-analyses in the published medical literature have found improved glycaemic control with continuous subcutaneous insulin infusion (CSII) compared with multiple daily injections (MDI) of insulin for patients with diabetes mellitus. In Australia, CSII is predominantly used in type 1 diabetes mellitus (T1DM) patient populations. OBJECTIVE/INTERVENTION: To project long-term costs and outcomes of CSII (Novorapid or Humalog) compared with MDI (NPH insulin plus Novorapid or Humalog) in adult and adolescent T1DM patients in Australia. The study was a modelling analysis utilising a lifetime horizon in adult and adolescent specialty care T1DM patient populations from Australia. Published Australian diabetes complication costs (adjusted to Australian dollars [$A], year 2006 values), treatment costs and discount rates of 5.0% per annum were applied to costs and clinical outcomes. A lifetime horizon was taken, considering only direct medical costs and excluding indirect and non-medical costs. The validated CORE diabetes model employs standard Markov/Monte Carlo simulation techniques. It was used to simulate diabetes progression in Australian adult (mean age 43 years, duration of diabetes 17 years, mean glycosylated haemoglobin [HbA(1c)] 8.2%) and adolescent (mean age 17 years, duration of diabetes 6 years, mean HbA(1c) 8.9%) patients with baseline characteristics taken predominantly from Australian National Diabetes Information Audit and Benchmarking (ANDIAB) in Australia. The main outcome measures were incremental costs and effectiveness of CSII compared with MDI in Australian adult and adolescent patients with T1DM. Mean direct lifetime costs were $A34,642 higher with CSII treatment than with MDI for adult patients and $A41,779 higher for adolescent patients. Treatment with CSII was associated with an improvement in life expectancy of 0.393 years for adults compared with MDI and 0.537 years for adolescents. The corresponding gains in QALYs were 0.467 QALYs and 0.560 QALYs for adults and adolescents, respectively. This produced incremental cost effectiveness ratios (ICERs) of $A88,220 and $A77,851 per life-year gained for CSII compared with MDI for adult and adolescent T1DM patients, respectively, in Australia. These data also produced corresponding ICERs of $A74,147 per QALY and $A74,661/QALY for adult and adolescent T1DM patients, respectively. Sensitivity analyses suggested that our base-case assumptions were mostly robust with improvements in ICERs for reduction in hypoglycaemic events with CSII treatment and worse ICERs for lower HbA(1c) changes associated with CSII treatment compared with MDI. Our analysis suggests that CSII is associated with ICERs in the range of $A53,022-259,646 per QALY gained, with most ICERs representing good value for money in Australia under the majority of scenarios explored.

Objective To evaluate the efleet of continuous subcutaneous insulin infusion (CSII)combined with mefformin hydroehloride( Met H)on type 2 diabetic patients. Methods 240 patients with type 2 diabetes melli-tus (T2DM) were divided into 3 groups randomly: CSII combined with Met H ( A group: n=80) ; simple CSII ( B group:n=80) ; multiple deliver insulin (MDI) ( C group: n=80). The levels of blood glucose, HbA1 e, therapeutic time, a-mount of insulin, Fins ,C-P, HOMA-IR and IAI were compared among them before and after 10d of treatment. Results GroupA, B eornpared with group C, the levels of HbA1 e significantly deeroased in other two groups [ ( 8.0±3.2)%vs. (6.9±1.4)% and(7.0±1.2)% ] (aU P<0.05),so did the therapeutic time[(6.0±1.9)d vs. (3.0±1.4) and(3.5±1.5) d] and insulin dose[ (55.0±17.0) U/d vs. (38.0±15.0) U/d and(45.0±16) U/d] (all P<0.05). The insulin dose was much less in group A than in group B. Versus group B and C,the HOMA-IR of group A (0.8±0.3 vs. 1.5±0.4 and 1.6±0.4)decreased(P<0.05) ,and IAI(-2.0±4.3 vs. -3.6±4. 2 and -4.1±4.3) increased (all P<0.05), without the function impairments of heart, liver or kidney. Conclusion CSII in combi-nation with mefformin hydreehloride can significantly enhance the treatment effect of the patients with type 2 diabetes mellitns; reduce blood glucose and HbA1 e, improve insulin resistenee,lessen insulin need. Key words: Diabetes mellitus,type2; Insulin infusion systems; Insulin resistanee; Mefformin

Objective Continuous subcutaneous insulin infusion (CSII) is on the rise among pediatric patients with type 1 diabetes mellitus. Metabolic effects alone cannot explain this rising popularity. From the patient's perspective, the main benefits of CSII may be found in subjective psychosocial health outcomes (patient-reported outcomes [PRO]). Subjects and methods In a multicenter open randomized controlled trial, children and adolescents aged 6 to16 years currently treated with multiple daily injections (MDI) were randomized 1:1, stratified by center, to either starting with CSII immediately after the baseline interview or to continuing MDI while waiting 6 months for transmission to CSII. The primary outcomes were patient-reported diabetes-specific health-related quality of life (DHRQOL) and diabetes burden of the main caregiver. Secondary outcomes were caregiver stress, fear of hypoglycemia, satisfaction with treatment, and HbA1c. Results Two-hundred and eleven patients were randomized between February 2011 and October 2014, and 186 caregivers and 170 patients were analyzed using the intention-to-treat principle for primary outcomes. Children 8 to 11 years in the CSII group reported improved DHRQOL at follow-up compared to MDI (median difference [MD] 9.5, 95% confidence interval [CI] 3.6-16.7, P = 0.004). There were no treatment differences in the adolescent age-group 12 to 16 years (MD 2.7; 95% CI -3.2-9.5; P = 0.353). The main caregivers of the CSII group reported a significant decline of overall diabetes burden at follow-up compared to the MDI group (MD 0; 95% CI -1-0; P = 0.029). Secondary PROs also were in favor of CSII. Conclusions CSII has substantial psychosocial benefits. PROs demonstrate these benefits. Registered as NCT01338922 at clinicaltrials.gov.

Satisfaction of adult patients using continuous subcutaneous insulin infusion or multiple daily injections with type 1 diabetes mellitus.

Continuous subcutaneous insulin infusion (CSII) is an effective method of intensive therapy for patients with type 1 diabetes; however, most studies have not examined long-term glycemic control. We evaluated the long-term efficacy of CSII in a cohort of adult patients with type 1 diabetes. This was a retrospective observational study of 200 patients with type 1 diabetes who initiated CSII at a single outpatient clinic in Kingston, ON, Canada between January 1998 and December 2012. Data were collected from 3 months prior to and up to 15 years after initiation of CSII and included glycated hemoglobin (HbA1c) level and demographic factors potentially associated with glycemic control. Mean age and duration of diabetes at CSII initiation were 35.4 years and 22.4 years, respectively. Mean duration of CSII at the time of analysis was 6 years. Mean HbA1c at initiation of CSII was 8.7% and decreased to a nadir of 7.5% 6 months post-initiation (SD = 1.0) (P < 0.001). This increased over time (range, 7.8-8.2%) but remained lower than the pre-CSII HbA1c (P < 0.001). Shorter duration of diabetes prior to CSII initiation, history of missed appointments, mental illness, and active smoking were predictors of higher HbA1c on CSII. Pre-CSII HbA1c predicted long-term HbA1c on CSII. The data demonstrate that in a clinic setting, patients on CSII maintain lower HbA1c values over a 1-10-year period compared with pre-CSII values. Poor pre-CSII HbA1c, history of missed appointments, mental illness, and active smoking are predictors of those less likely to achieve an HbA1c target of ≤ 7.0%.

Advances in exercise, physical activity, and diabetes mellitus.

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.