Circulating insulin antibodies: influence of continuous subcutaneous or intraperitoneal insulin infusion,and impact on glucose control

The purification of animal insulin preparations and the use of human recombinant insulin have markedly reduced the incidence, but not completely suppressed, the development of anti‐insulin antibodies (IAs). Advances in technologies concerning the mode of delivery of insulin, i.e. continuous subcutaneous insulin infusion (CSII), continuous peritoneal insulin infusion (CPII) and more recently inhaled insulin administration, appear to significantly increase circulating levels of immunoglobulin G (IgG) anti‐IAs in diabetic patients. However, the increase is usually moderate and mostly transient as compared to previous observations with poorly purified animal insulin preparations. The clinical impact of these circulating anti‐IAs remains unclear. Nevertheless, several studies have suggested that antibodies could retard insulin action, leading to a worsening of postprandial hyperglycaemia and/or serve as a carrier, thus leading to unexpected hypoglycaemia. CPII may be associated with more marked and sustained increase in IAs levels, possibly related to the use of an unstable insulin and the formation of immunogenic aggregates of insulin. The possible clinical consequences of these high levels of IAs remain to be evaluated because a low‐glucose morning syndrome or severe insulin resistance with ketone bodies production have been reported in some cases. In conclusion, even if CSII and CPII may promote the development of circulating IAs, this increase does not lead to immunological insulin resistance, compared to that previously described with animal non‐purified insulin preparations, and seems to have only marginal influence on blood glucose control or complications in most diabetic patients. Copyright © 2009 John Wiley & Sons, Ltd.     

Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based multiple daily insulin injections (MDI) on glycaemic control and quality of life: results of the 5-nations trial.

AIMS: The goal of the study was to determine whether continuous subcutaneous insulin infusion (CSII) differs from a multiple daily injection (MDI) regimen based on neutral protamine hagedorn (NPH) as basal insulin with respect to glycaemic control and quality of life in people with Type 1 diabetes. METHODS: The 5-Nations trial was a randomized, controlled, crossover trial conducted in 11 European centres. Two hundred and seventy-two patients were treated with CSII or MDI during a 2-month run-in period followed by a 6-month treatment period, respectively. The quality of glycaemic control was assessed by HbA(1c), blood glucose values, and the frequency of hypoglycaemic events. For the evaluation of the quality of life, three different self-report questionnaires have been assessed. RESULTS: CSII treatment resulted in lower HbA(1c) (7.45 vs. 7.67%, P < 0.001), mean blood glucose level (8.6 vs. 9.4 mmol/l, P < 0.001) and less fluctuation in blood glucose levels than MDI (+/- 3.9 vs. +/- 4.3 mmol/l, P < 0.001). There was a marked reduction in the frequency of hypoglycaemic events using CSII compared with MDI, with an incidence ratio of 1.12 [95% confidence interval (CI): 1.08-1.17] and 2.61 (95% CI: 1.59-4.29) for mild and severe hypoglycaemia, respectively. The overall score of the diabetes quality of life questionnaire was higher for CSII (P < 0.001), and an improvement in pump users' perception of mental health was detected when using the SF-12 questionnaire (P < 0.05). CONCLUSION: CSII usage offers significant benefits over NPH-based MDI for individuals with Type 1 diabetes, with improvement in all significant metabolic parameters as well as in patients' quality of life. Additional studies are needed to compare CSII with glargine- and detemir-based MDI.     

Determinants of glycaemic control in type 1 diabetes during intensified therapy with multiple daily insulin injections or continuous subcutaneous insulin infusion: importance of blood glucose variability

BACKGROUND AND METHODS: We investigated the factors that determine the best glycaemic control on multiple daily insulin (MDI) injections and continuous subcutaneous insulin infusion (CSII), and the hypothesis that blood glucose variability is a major determinant of control and that the resultant HbA(1c) on MDI correlates with the improvement achieved by CSII. We studied 30 type 1 diabetic subjects already receiving MDI. Renewed attempts to improve control on MDI were made for a median of five months, and then the subjects were switched to CSII. The variability of within-day and between-day blood glucose concentrations was calculated from blood glucose self-monitoring data. RESULTS: HbA(1c) during MDI varied from 5.7 to 11.7% (mean +/- SD, 8.5 +/- 1.4%). Within- and between-day blood glucose variability correlated with HbA(1c) on MDI (r = 0.59, p < 0.001; r = 0.48, p < 0.03). Within-day variability remained an independent predictor of HbA(1c) on MDI. Mean HbA(1c) improved with CSII (to 7.3 +/- 0.9%, p < 0.001), but reduction in HbA(1c) was variable and was related to the HbA(1c) on MDI (r = 0.79, p < 0.001) and within-day variability (r = 0.56, p < 0.01). Similar results were observed for subjects treated only with glargine-based MDI. CONCLUSIONS: The best glycaemic control achievable on MDI is related to blood glucose variability-those with the largest swings in blood glucose retaining the highest HbA(1c). The improvement in control achieved by CSII is related to HbA(1c) and blood glucose variability on MDI. Pump therapy is most effective in those worst controlled on MDI.     

Continuous subcutaneous insulin infusion (CSII) in the Veneto region: efficacy,acceptability and quality of life

Aim To study the effect of continuous subcutaneous insulin infusion (CSII) on metabolic control and well‐being in patients with Type 1 diabetes. Methods Efficacy, safety and interference with everyday life associated with CSII were studied retrospectively in 138 diabetic patients from the Veneto region treated for 7.4 ± 0.4 years. Results Glycosylated haemoglobin decreased during the first year of CSII from 9.3 ± 0.2% to 7.9 ± 0.1% (P < 0.0001), and then remained unchanged. Serious hypoglycaemia decreased from 0.31 ± 0.07/year to 0.09 ± 0.02/year (P < 0.003), as did ketoacidosis (from 0.41 ± 0.12/year to 0.11 ± 0.03/year, P < 0.013). During the first year of therapy daily insulin requirement decreased from 49 ± 1 to 42 ± 2 U/day (P < 0.0001) and did not change thereafter. The number of out‐patient consultations and hospital admissions per year also decreased significantly. CSII was associated with a progressive increase of body weight (P < 0.05) and with 0.2 ± 0.04 infections/patient per year at the infusion site. Infection was rated as mild in 72%, moderate in 18%, severe in 10%. Patients reported that CSII improved metabolic control (71%), sense of well‐being (41%), and allowed more freedom (40%). Quality of life, assessed using the DQOL, after 7 years of CSII was rated as good by patients (score of 73.0 ± 1.8 on a scale from 0 to 100). Conclusions This retrospective analysis suggests that CSII improves metabolic control in Type 1 diabetic patients, reduces hypoglycaemic and ketoacidotic events, is well accepted, allows a good quality of life and decreases out‐patient consultations and hospital admissions.     

Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta‐analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion

Aims Continuous subcutaneous insulin infusion (CSII) is a recommended treatment for reducing severe hypoglycaemia in Type 1 diabetes, but the change in hypoglycaemia compared with multiple daily insulin injections (MDI) is unclear. We therefore conducted a meta‐analysis comparing severe hypoglycaemia and glycaemic control during CSII and MDI. Methods Databases and literature (1996–2006) were searched for randomized controlled trials (RCTs) and before/after studies of ≥ 6 months’ duration CSII and with severe hypoglycaemia frequency > 10 episodes/100 patient years on MDI. Results In 22 studies (21 reports), severe hypoglycaemia during MDI was related to diabetes duration (P = 0.038) and was greater in adults than children (100 vs. 36 events/100 patient years, P = 0.036). Severe hypoglycaemia was reduced during CSII compared with MDI, with a rate ratio of 2.89 (95% CI 1.45 to 5.76) for RCTs and 4.34 (2.87 to 6.56) for before/after studies [rate ratio 4.19 (2.86 to 6.13) for all studies]. The reduction was greatest in those with the highest initial severe hypoglycaemia rates on MDI (P < 0.001). The mean difference in glycated haemoglobin (HbA_1c) between treatments was less for RCTs [0.21% (0.13–0.30%)] than in before/after studies [0.72% (0.55–0.90%)] but strongly related to the initial HbA_1c on MDI (P < 0.001). Conclusions The severe hypoglycaemia rate in Type 1 diabetes was markedly less during CSII than MDI, with the greatest reduction in those with most severe hypoglycaemia on MDI and those with the longest duration of diabetes. The biggest improvement in HbA_1c was in those with the highest HbA_1c on MDI.     

Continuous subcutaneous insulin infusion in patients with diabetes mellitus

During the last quarter of a century continuous subcutaneous insulin infusion (CSII) with external portable insulin pumps has been increasingly used in selected type 1 diabetic subjects and also in some patients with type 2 diabetes mellitus. The treatment of diabetes mellitus with insulin pumps has become more and more popular and accepted by diabetic patients as well as by medical professionals worldwide. Published trials have shown that, in most patients, mean blood glucose concentration and glycated hemoglobin (HbA1c) percentages are either slightly lower or similar on CSII versus an optimized therapy with multiple daily insulin injections. Hypoglycemic episodes seem to be less frequent and ketoacidoses occur at a comparable rate to that during intensive injection therapy. Moreover, nocturnal glycemic control can be improved with insulin pumps, and automatic basal rate changes help to minimize a prebreakfast blood glucose increase (often called 'the dawn phenomenon'). For many patients, CSII provides greater flexibility in timing of meals with the result of better quality of life and higher treatment satisfaction. However, despite these promising data, and although many patients with diabetes mellitus with well-defined clinical problems are likely to benefit substantially from CSII, either in respect to glycemic control, acute complications or quality of life and treatment satisfaction, we are still far away from reaching'dream diabetes management', the fully automatic closed-loop system. Presently, the most difficult problem concerns not the design of an 'optimal' insulin pump, but rather the development of a system which is able to provide continuous and reliable blood glucose monitoring. Hence, because this problem has not been solved with maximum satisfaction, the development of a feedback-controlled 'artificial pancreas' is one of the main goals in diabetes management in the new millennium.     

Insulin allergy in a patient with Type 2 diabetes successfully treated with continuous subcutaneous insulin infusion.

BACKGROUND: Patients with poor control of Type 2 diabetes on maximum oral hypoglycaemic therapy invariably need insulin therapy. Insulin allergy is uncommon, particularly in patients with Type 2 diabetes. Management of the condition can be difficult, and here we report the case of a patient with Type 2 diabetes and insulin allergy successfully managed with a continuous subcutaneous insulin infusion (CSII). CASE REPORT: A 60-year-old man was referred with insulin allergy. He had poorly controlled Type 2 diabetes (glycated haemoglobin 10.4%), on maximum doses of sulphonylurea and metformin, with osmotic symptoms. He was compliant with diet and tablets. His diabetes was complicated by retinopathy, nephropathy, coronary heart disease, obstructive sleep apnoea, obesity, depression and hypertension. He commenced on twice daily mixed insulin and, shortly after, developed pain, itching and erythema at the injection sites. The sites became indurated and tender, and he had constitutional symptoms. The insulin was changed to other preparations, including short- and long-acting analogues, with similar responses. Triple therapy with rosiglitazone was tried, with no improvement in control. Skin-prick testing confirmed allergy to insulin rather than additives. The patient was reluctant to undergo desensitization. He was commenced on an insulin pump in addition to his oral hypoglycaemics, and achieved fair control (glycated haemoglobin 8.3%) on 88 units of lispro per day, with little or no skin or systemic reaction. CONCLUSION: This is the first case report of insulin allergy in Type 2 diabetes being successfully managed by CSII.     

Quality of life and treatment satisfaction in adults with Type 1 diabetes: a comparison between continuous subcutaneous insulin infusion and multiple daily injections

Aims The aim of this case–control study was to compare quality of life (QoL) and treatment satisfaction in adults with Type 1 diabetes (T1DM) treated with either continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI). Methods Consecutive patients aged between 18 and 55 years, and attending diabetes clinics for a routine visit, completed the Diabetes‐Specific Quality‐of‐Life Scale (DSQOLS), the Diabetes Treatment Satisfaction Questionnaire (DTSQ) and the SF‐36 Health Survey (SF‐36). Case (CSII) and control subjects (MDI) were recruited in a 1 : 2 ratio. Results Overall, 1341 individuals were enrolled by 62 diabetes clinics; 481 were cases and 860 control subjects. Cases had a longer diabetes duration and were more likely to have eye and renal complications. Age, school education, occupation and HbA_1c were similar. Of control subjects, 90% followed glargine‐based MDI regimens and 10% used NPH‐based MDI regimens. On multivariate analysis, after adjusting for socioeconomic and clinical characteristics, scores in the following areas of the DSQOLS were higher in cases than control subjects: diet restrictions (β = 5.96; P < 0.0001), daily hassles (β = 3.57; P = 0.01) and fears about hypoglycaemia (β = 3.88; P = 0.006). Treatment with CSII was also associated with a markedly higher DTSQ score (β = 4.13; P < 0.0001) compared with MDI. Results were similar when CSII was compared separately with glargine‐ or NPH‐based MDI regimens. Conclusions This large, non‐randomized, case–control study suggests quality of life gains deriving from greater lifestyle flexibility, less fear of hypoglycaemia, and higher treatment satisfaction, when CSII is compared with either glargine‐based or NPH‐based MDI regimens.     

Continuous subcutaneous insulin infusion in diabetes: patient populations,safety, efficacy,and pharmacoeconomics

The level of glycaemic control necessary to achieve optimal short‐term and long‐term outcomes in subjects with type 1 diabetes mellitus (T1DM) typically requires intensified insulin therapy using multiple daily injections or continuous subcutaneous insulin infusion. For continuous subcutaneous insulin infusion, the insulins of choice are the rapid‐acting insulin analogues, insulin aspart, insulin lispro and insulin glulisine. The advantages of continuous subcutaneous insulin infusion over multiple daily injections in adult and paediatric populations with T1DM include superior glycaemic control, lower insulin requirements and better health‐related quality of life/patient satisfaction. An association between continuous subcutaneous insulin infusion and reduced hypoglycaemic risk is more consistent in children/adolescents than in adults. The use of continuous subcutaneous insulin infusion is widely recommended in both adult and paediatric T1DM populations but is limited in pregnant patients and those with type 2 diabetes mellitus. All available rapid‐acting insulin analogues are approved for use in adult, paediatric and pregnant populations. However, minimum patient age varies (insulin lispro: no minimum; insulin aspart: ≥2 years; insulin glulisine: ≥6 years) and experience in pregnancy ranges from extensive (insulin aspart, insulin lispro) to limited (insulin glulisine). Although more expensive than multiple daily injections, continuous subcutaneous insulin infusion is cost‐effective in selected patient groups. This comprehensive review focuses on the European situation and summarises evidence for the efficacy and safety of continuous subcutaneous insulin infusion, particularly when used with rapid‐acting insulin analogues, in adult, paediatric and pregnant populations. The review also discusses relevant European guidelines; reviews issues that surround use of this technology; summarises the effects of continuous subcutaneous insulin infusion on patients' health‐related quality of life; reviews relevant pharmacoeconomic data; and discusses recent advances in pump technology, including the development of closed‐loop ‘artificial pancreas’ systems. © 2015 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.     

Continuous subcutaneous insulin infusion (CSII) 30 years later: still the best option for insulin therapy

Thirty years after its introduction, the use of continuous subcutaneous insulin infusion (CSII) keeps increasing, especially among children and adolescents. The technique, when used properly, is safe and effective. Compared with traditional NPH‐based multiple daily injections (MDI), CSII provides a small but clinically important reduction of HbA_1c levels, diminishes blood glucose variability, decreases severe hypoglycaemic episodes and offers a better way to cope with the dawn phenomenon. Insulin analogues have improved the treatment of diabetes, eroding part of the place previously occupied by CSII, but CSII still remains the first option for patients experiencing severe hypoglycaemic episodes, high HbA_1c values or marked glucose variability while being treated with optimized MDI. Furthermore CSII is better than MDI considering the effects on quality of life and the possibility to adjust insulin administration according to physical activity or food intake. CSII may be limited by cost. Present estimates suggest that CSII may be cost‐effective just for patients experiencing a marked improvement in HbA_1c or a decrease in severe hypoglycaemic episodes, but the effects on quality of life are difficult to measure. CSII does not merely imply wearing an external device; it requires a multidisciplinary team, intensive patient education and continuous follow up. Copyright © 2009 John Wiley & Sons, Ltd.     

Optimization of basal insulin delivery in Type 1 diabetes: a retrospective study on the use of continuous subcutaneous insulin infusion and insulin glargine.

AIMS: To compare the effects on glycaemic control after using continuous subcutaneous insulin infusion (CSII) or insulin glargine. METHODS: Data were obtained from 17 diabetes outpatient clinics in Sweden, employing the same diabetes data management system. Type 1 diabetic patients using multiple dose injections were included prior to starting on either CSII (n = 563) or glargine (n = 513). The median duration of therapy was 25 months for CSII and 6 months for glargine. The comparison between the treatment modalities was carried out by multiple regression analysis and logistic regression analysis in an attempt at reducing the influence of confounding factors. RESULTS: The mean HbA1c decrease was 0.59 +/- 1.19% for CSII and 0.20 +/- 1.07% for glargine (P < 0.001, when assessed by logistic regression). An additional 0.1% lower HbA1c would be expected if glargine had been optimized with basal insulin 40-60% of the daily dose. The more pronounced effect of CSII was achieved with a lower daily dosage of insulin. In a multiple regression analysis with a change of HbA1c as the dependent variable, the following variables were significant: choice of treatment (P < 0.001), HbA1c prior to treatment (P < 0.001) and BMI prior to treatment (P < 0.01). CONCLUSION: Both regimes improved metabolic control, but CSII resulted in significantly higher reduction in HbA1c than after insulin glargine treatment, particularly in those individuals who had higher levels of HbA1c at baseline.     

In Type 1 diabetic patients with good glycaemic control,blood glucose variability is lower during continuous subcutaneous insulin infusion than during multiple daily injections with insulin glargine

Aims The superiority of continuous subcutaneous insulin infusion (CSII) over multiple daily injections (MDI) with glargine is uncertain. In this randomized cross‐over study, we compared CSII and MDI with glargine in patients with Type 1 diabetes well controlled with CSII. The primary end‐point was glucose variability. Methods Thirty‐nine patients [38.1 ± 9.3 years old (mean ± sd ), diabetes duration 16.6 ± 8.2 years, glycated haemoglobin (HbA_1c) 7.6 ± 0.8%], already on CSII for at least 6 months, were randomly assigned to CSII with lispro or MDI with lispro and glargine. After 4 months they were switched to the alternative treatment. During the last month of each treatment blood glucose variability was analysed using glucose standard deviation, mean amplitude of glycaemic excursions (MAGE), lability index and average daily risk range (ADRR). As secondary end‐points we analysed blood glucose profile, HbA_1c, number of episodes of hypo‐ and hyperglycaemia, lipid profile, free fatty acids (FFA), growth hormone and treatment satisfaction. Results During CSII, glucose variability was 5–12% lower than during MDI with glargine. The difference was significant only before breakfast considering glucose standard deviation (P = 0.011), significant overall using MAGE (P = 0.016) and lability index (P = 0.005) and not significant using ADRR. Although HbA_1c was similar during both treatments, during CSII blood glucose levels were significantly lower, hyperglycaemic episodes were fewer, daily insulin dose was less, FFA were lower and treatment satisfaction was greater than during MDI with glargine. The frequency of hypoglycaemic episodes was similar during both treatments. Conclusions During CSII, glucose variability is lower, glycaemic control better and treatment satisfaction higher than during MDI with glargine.     

Effect of insulin infusion on electrocardiographic findings following acute myocardial infarction: importance of glycaemic control

Aims To determine the effects of insulin infusion and blood glucose levels during acute myocardial infarction (AMI) on electrocardiographic (ECG) features of myocardial electrical activity. Methods ECGs at admission and 24 h were examined in a randomized study of insulin infusion vs. routine care for AMI patients with diabetes or hyperglycaemia. Results were analysed according to treatment allocation and also according to average blood glucose level. Results ECG characteristics were similar at admission in both groups. Patients allocated to conventional treatment had prolongation of the QT interval (QTc) after 24 h but those receiving infused insulin did not. In patients with a mean blood glucose in the first 24 h > 8.0 mmol/l, new ECG conduction abnormalities were significantly more common than in patients with mean blood glucose ≤ 8.0 mmol/l (15.0% vs. 6.0%, P < 0.05). Conclusions Prevention of QTc prolongation by administration of insulin may reflect a protective effect on metabolic and electrical activity in threatened myocardial tissue. Abnormalities of cardiac electrical conduction may also be influenced by blood glucose.     

Continuous basal insulin infusion without premeal boluses in insulin-dependent diabetes mellitus therapy

Summary Six insulin-dependent diabetic patients, poorly controlled on conventional insulin therapy (CIT), underwent continuous basal insulin infusion (CBII) and continuous subcutaneous insulin infusion (CSII) during 2 subsequent periods of 1 month each, employing a Betatron II insulin infusion pump (Lilly, CPI). During CSII, insulin was infused at a continuous basal rate with 3 premeal boluses. During CBII, from 22⁰⁰ to 06⁰⁰ a continuous basal nocturnal insulin infusion rate and from 06⁰⁰ to 22⁰⁰ a diurnal one, which was approximately twice the former, were maintained and total daily calorie intake was subdivided into 6 isoglycidic and isocaloric meals, taken at regular intervals. We obtained better blood glucose control both by CSII and CBII than by CIT, with significant reduction of HbA₁ values. Mean blood glucose levels were lower during CBII than during CSII, while M-index, number of hypo- and hyperglycemic events and insulin requirement were not different. However, daily blood glucose excursions were narrower and percent blood glucose increment after the noon meal was reduced during CBII. CBII insulin profile was characterized by a plateau trend with lower levels at meals in comparison with CSII. Our data show that the subdivision of daily calorie intake into 6 isocaloric and isoglycidic meals allows to achieve good metabolic control by continuous basal insulin infusion without need for premeal boluses and could be especially useful in brittle diabetic patients, whose brittle condition may be caused by erratic absorption of subcutaneous boluses of insulin.     

Longitudinal study on glycaemic control and quality of life in patients with Type 2 diabetes mellitus referred for intensified control.

AIM: The aim of our study was to describe investigate and association between improved glycaemic control on quality of life (QoL) during 1 year of treatment in a sample of 94 Type 2 diabetic patients referred for insulin therapy to an outpatient department (OPD). Treatment was aimed at achieving acceptable glycaemic control by means of maximizing oral therapy, if necessary switching over to insulin therapy, and information and education provided by a diabetes specialist nurse and dietitian. METHODS: QoL was measured using a disease-specific (Diabetes Health Profile (DHP)) and a generic questionnaire (RAND-36). After 1 year the medical examination and QoL measurements were repeated. The association between 1-year changes in QoL and achievement of good metabolic control (final glycosylated haemoglobin (HbA1c) < or = 8%), switch to insulin therapy, and presence of hyperglycaemic complaints at baseline was analysed after adjustment for appropriate confounders. RESULTS: After 1 year, mean HbA1c was reduced from 10.4% to 7.8%. Also QoL improved in the total group. Patients who achieved good glycaemic control after 1 year (61%) improved in a similar manner as the others. Patients switched over to insulin (65%) improved in a similar manner as the others, but at the final examination they experienced more problems with social functioning and pain. Patients with hyperglycaemic complaints at baseline (49%) improved more in QoL than those without, especially in physical functioning, vitality and health change, but at the final examination still scored lower on a majority of the DHP and RAND-36 dimensions. CONCLUSION: Symptoms of hyperglycaemia predict the strength of an association between improvements of glycaemic control and QoL.