When it comes to managing type 1 diabetes, patient education and training in insulin delivery — rather than choosing between an insulin pump and injections — may be key, according to a study in The BMJ.
Over 250 adults with type 1 diabetes were randomized to receive multiple daily insulin injections or insulin pump therapy, plus structured group training on flexible insulin dosing based on diet, activity, and blood glucose levels. The training took place over five consecutive days. At baseline, over 90% of participants had hemoglobin A1c levels of 7.5% or higher.
At 24 months, both groups had achieved clinically significant reductions in mean HbA1c level, with no significant difference between the groups. In addition, about a quarter of patients in each group had HbA1c levels below 7.5%.
The authors write, “These results do not support a policy of providing insulin pumps to adults with poor glycemic control until the effects of training on participants’ level of engagement in intensive self management have been determined.”
Objective To compare the effectiveness of insulin pumps with multiple daily injections for adults with type 1 diabetes, with both groups receiving equivalent training in flexible insulin treatment.
Design Pragmatic, multicentre, open label, parallel group, cluster randomised controlled trial (Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial).
Setting Eight secondary care centres in England and Scotland.
Participants Adults with type 1 diabetes who were willing to undertake intensive insulin treatment, with no preference for pumps or multiple daily injections. Participants were allocated a place on established group training courses that taught flexible intensive insulin treatment (“dose adjustment for normal eating,” DAFNE). The course groups (the clusters) were then randomly allocated in pairs to either pump or multiple daily injections.
Interventions Participants attended training in flexible insulin treatment (using insulin analogues) structured around the use of pump or injections, followed for two years.
Main outcome measures The primary outcomes were a change in glycated haemoglobin (HbA1c) values (%) at two years in participants with baseline HbA1c value of ≥7.5% (58 mmol/mol), and the proportion of participants achieving an HbA1c value of <7.5%. Secondary outcomes included body weight, insulin dose, and episodes of moderate and severe hypoglycaemia. Ancillary outcomes included quality of life and treatment satisfaction.
Results 317 participants (46 courses) were randomised (156 pump and 161 injections). 267 attended courses and 260 were included in the intention to treat analysis, of which 235 (119 pump and 116 injection) had baseline HbA1c values of ≥7.5%. Glycaemic control and rates of severe hypoglycaemia improved in both groups. The mean change in HbA1c at two years was −0.85% with pump treatment and −0.42% with multiple daily injections. Adjusting for course, centre, age, sex, and accounting for missing values, the difference was −0.24% (−2.7 mmol/mol) in favour of pump users (95% confidence interval −0.53 to 0.05, P=0.10). Most psychosocial measures showed no difference, but pump users showed greater improvement in treatment satisfaction and some quality of life domains (dietary freedom and daily hassle) at 12 and 24 months.
Conclusions Both groups showed clinically relevant and long lasting decreases in HbA1c, rates of severe hypoglycaemia, and improved psychological measures, although few participants achieved glucose levels currently recommended by national and international guidelines. Adding pump treatment to structured training in flexible intensive insulin treatment did not substantially enhance educational benefits on glycaemic control, hypoglycaemia, or psychosocial outcomes in adults with type 1 diabetes. These results do not support a policy of providing insulin pumps to adults with poor glycaemic control until the effects of training on participants’ level of engagement in intensive self management have been determined.
Trial registration Current Controlled Trials ISRCTN61215213.
People with type 1 diabetes mellitus require lifelong treatment with insulin to prevent diabetic ketoacidosis and to optimise blood glucose levels to minimise vascular complications.1 Insulin is generally administered by multiple daily subcutaneous injections, using different insulins to cover background and meal requirements. Doses are adjusted according to eating, physical activity, and blood glucose level. This approach and its integration within flexible lifestyles is promoted in “dose adjustment for normal eating” (DAFNE)2 and similar structured training courses.3 Despite this training and best efforts, many people struggle to achieve glycaemic targets and a considerable proportion go on to develop serious complications, reducing both the length and the quality of their lives.1 4
In continuous subcutaneous insulin infusion, a pump delivers insulin continuously under the skin through a small plastic tube and cannula.5 6 Pumps are filled with quick acting insulin to supply both background insulin and insulin replacement after meals.
Potential advantages include more precise insulin delivery and the ability to adjust basal insulin levels. Observational studies have reported improved glucose control, reduced risk of hypoglycaemia, and enhanced quality of life. Pump treatment is more expensive than multiple daily injections, with pumps costing around £2500 ($3041; €2800) each plus £1500 a year for consumables (cannulas, reservoirs, and batteries).7
In the UK, pump use is approved in adults with type 1 diabetes who have high glycated haemoglobin (HbA1c) values (>8.5%) or an inability to achieve reasonable control without “disabling hypoglycaemia.”8 An estimated 6% of UK adults with type 1 diabetes use pumps, which is lower than in many comparable countries.9 Around 40% of people with type 1 diabetes in the USA use pumps,10 and proponents of pumps suggest that far more people should be offered them in the UK.11
One weakness of existing evidence is that patients allocated to pumps are likely to have received more training and attention than those using multiple daily injections. A recent observational study12 of pump treatment and injections, where both groups received intensive education in insulin usage, concluded that the training might have made the most difference. To our knowledge, no randomised trials in adults have compared pump treatment with multiple daily injections where the same structured training in insulin adjustment has been provided, so the added benefit of pump technology remains unclear.
In the Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial we assessed the effectiveness of adding pump treatment to high quality equivalent structured education in flexible intensive insulin treatment for people with type 1 diabetes, comparing pump plus education with multiple daily injections plus education. Our hypothesis was that much of the benefit of pump treatment might come from the re-training and education in insulin use given to enable patients to use pumps safely. We present the clinical effectiveness and quantitative psychosocial results of this pragmatic trial.
The study protocol has been previously published.13 In brief, we conducted a multicentre, parallel group, open label, confirmatory, cluster randomised controlled trial. Eight secondary care centres (three in Scotland and five in England) recruited up to 40 participants to three pump and three multiple daily injection courses (with five to eight patients on each course) over 11 months. Participants were allocated a place on a one week DAFNE skills training course, with a further visit at six weeks. The course groups (clusters) were randomly allocated in pairs to either pump or multiple daily injections. After the courses, participants received the trial treatment for two years. We collected outcome measures at baseline (up to three weeks before the DAFNE course) and at six, 12, and 24 months. A cluster design was chosen to address the challenge of randomising participants and then finding suitable times for their attendance on a course of the correct allocation. We believe this approach reduced both recruitment bias and attrition rates before the course.
We recruited adults with a diagnosis of type 1 diabetes for at least 12 months, and who were willing to undertake intensive insulin treatment with self monitoring of blood glucose levels, counting of carbohydrate intake, and insulin self adjustment, with no preference for either pump or multiple daily injections. Participants were those with clinical indications for structured education in insulin treatment to optimise diabetes control who had not participated previously in structured training. We excluded those with a strong desire for pump treatment, those already using optimised multiple daily injections and meeting the criteria of the National Institute for Health and Care Excellence for pump treatment, those needing a pump in the opinion of the investigator, those with serious diabetic complications, and those unable to communicate in English. Courses (clusters) required between five and eight participants to maintain optimal course dynamics.
Participants using multiple daily injections attended standard DAFNE structured education courses,2 which were conducted over five consecutive days and delivered to groups of five to eight adults as outpatients. The participants took insulin aspart, a quick acting insulin analogue, for meals, and twice daily injections of insulin detemir for background replacement. They used the Accu-Chek Aviva Expert Bolus Advisor System (Roche Diagnostics Ltd, Burgess Hill, UK) as a bolus calculator, as there is evidence that bolus advisers can improve glycaemic control, presumably by helping patients calculate the appropriate meal related bolus.14
Participants allocated to pump treatment attended a modified DAFNE course, previously validated in pump users.15That course maintained the five day structure and the principles of insulin dose adjustment in the standard DAFNE course, but also incorporated the practical skills and learning outcomes needed to use pumps successfully. This necessitated an additional group session, delivered one to three weeks before the main course. Standard DAFNE includes a rigorous quality assurance programme. For the pump courses, fidelity testing was undertaken to assess incorporation of appropriate pump training. Participants used a Minimed Paradigm Veo insulin pump (model X54; Medtronic, Watford, UK) with insulin aspart. The bolus wizard in the pumps was activated as part of the course.
The curriculum (and associated patient workbook) was adapted specifically to make better use of pump features, compared with standard (multiple daily injections) DAFNE. This included general pump management (infusion sets, cannulas, filling reservoirs, changing batteries, and troubleshooting). During the five day course participants were also taught use of the bolus wizard, basal testing and adjustment (including fasting during the day and overnight glucose profiles), use of temporary basal rates for physical activity or alcohol intake (reduced) and illness (increased), use of alternative bolus “waves” (extended, multiwave), prevention of diabetic ketoacidosis (“sick day rules” eg, when to use a pen to inject insulin in case of cannula/pump failure, how much insulin to give and how often).
All participants (multiple daily injections and continuous subcutaneous insulin infusion) were invited to the course follow-up session at six to eight weeks, and those who required additional input were offered further one-to-one appointments. These appointments were supported by meter or pump downloads (Diasend: www.glooko.com/diasend; CareLink: www.medtronicdiabetes.com/products/carelink-personal-diabetes-software), depending on local availability. Participants were encouraged to maintain paper record diaries to facilitate discussion and adjustments, according to the principles taught on the course and supported by the workbook. Some might have already sought additional help in between these planned appointments. We recorded diabetes related contact with educators outside the course and at the six week follow-up.
We specified two primary outcomes. One was the change in HbA1c (%, measured centrally) after two years in participants whose baseline HbA1c was ≥7.5% (58 mmol/mol). HbA1c is the accepted ideal surrogate measure of glycaemic control and provides a measure of efficacy and a means of modelling long term cost effectiveness. Our choice of this primary outcome was based on our concern that HbA1c values might not decrease in those who entered the trial with low baseline values, but who might be experiencing problematic hypoglycaemia. Success for such individuals would be an HbA1c value that was maintained or even increased but with a reduced frequency of severe hypoglycaemia (an important secondary endpoint).
The other primary endpoint was the proportion of participants reaching the 2004 NICE target of HbA1c ≤7.5% (58 mmol/mol).
Secondary biomedical outcomes measured at six, 12, and 24 months were moderate hypoglycaemia (an episode that could be treated by the individual, but where hypoglycaemia caused a significant interruption of current activity leading to impaired performance, or embarrassment, or being woken during nocturnal sleep); severe hypoglycaemia (an episode leading to cognitive impairment sufficient to cause either coma or requiring the assistance of another person to recover); total and high density lipoprotein cholesterol levels; proteinuria; insulin dose; and body weight. Diabetic ketoacidosis was recorded through the assessment of serious adverse events throughout the trial.
Quantitative psychosocial self completed questionnaires assessed generic and diabetes specific quality of life: SF-12 (12 item short form health survey); WHOQOL-BREF (World Health Organization quality of life–BREF); EQ-5D (EuroQol five dimensions questionnaire); DSQOL (diabetes specific quality of life), fear of hypoglycaemia (HFS: hypoglycaemia fear scale), satisfaction with treatment (DTSQ: diabetes treatment satisfaction questionnaire), and emotional wellbeing (HADS: hospital anxiety and depression scale) at the same time points.13
A health economic evaluation to address the question “What is the cost effectiveness of pump treatment compared with multiple daily injections in patients receiving the DAFNE structured education programme?” was undertaken. It has been submitted for publication. It included a within trial and a modelled patient lifetime analysis, the latter being the primary focus of the evaluation.
We calculated the sample size using a minimally clinically important difference of 0.5% (5.5 mmol/mol) in HbA1c values. To detect this difference with a standard deviation of 1% at 80% power and 5% two sided significance required 64 participants with an HbA1c of ≥7.5% in each group. To allow for clustering of educators, an average of seven participants per group, a within course intraclass correlation coefficient of 0.05, and a 10% dropout rate, we required a sample size of 93 in each group. In the DAFNE database,15 75% of participants had an HbA1c value ≥7.5%, so we required 124 participants per group. We planned to recruit 280 participants, which increased the power to 85% but allowed for some variation in dropout rates and the proportion of participants with HbA1c of ≥7.5%. However, monitoring of baseline data showed the actual proportion of participants with an HbA1c of ≥7.5% was around 90%. A modelling exercise undertaken during recruitment with conservative estimates of 85% (HbA1c ≥7.5%) and dropout rate of 15% suggested the trial would require at least 240 participants with primary outcome data at two years to preserve a power of at least 85%.
After providing consent, participants were allocated to a training course, depending on their availability. Courses were randomised in pairs either to DAFNE plus pump or to DAFNE plus multiple daily injections. Simple randomisation in a block size of two, stratified by centre, was used for the first four courses. Courses 5 onwards were allocated in pairs using minimisation; the number of participants with baseline HbA1c values ≥7.5% and the total number of participants were used as minimisation factors. A statistician within Sheffield Clinical Trials Research Unit conducted the randomisation by a user written Stata code produced to generate allocation. The trial coordinator revealed the allocation to study sites. Participants who were unable to attend their original course were allowed to attend a later course in the same treatment arm, to reduce selection bias.
Analyses were performed in Stata 13 after a prespecified approved statistical analysis plan. All analyses were by intention to treat, with participants analysed in the groups to which they were randomised, unless otherwise specified. Participants were included in the intention to treat analysis if they had at least one post-baseline HbA1c measure. Those who dropped out before receiving the intervention were substituted where possible, to ensure the courses were run with adequate numbers of participants, but these individuals were not included in the analysis. Statistical tests were two sided at the 5% significance level.
We analysed the change in HbA1c (%) at two years using a mixed effects model, with centre and baseline HbA1c treated as fixed effect covariates, and course (cluster) as a random intercept. For the primary analysis we used multiple imputation to impute missing HbA1c data for participants with at least one follow-up HbA1c measure but without two years outcome. We also performed a per protocol sensitivity analysis that excluded participants who had switched treatment. Changes in HbA1c values at six months and one year were analysed in the same way.
The proportion of participants reaching an HbA1c of <7.5% was compared between groups using a logistic regression model adjusted for baseline HbA1c, and centre and modelling separate courses within centre as random intercepts.
We used negative binomial mixed effects regression (to account for over-dispersion and clustering) on the number of moderate hypoglycaemic episodes in the four weeks before each follow-up, and occurrence of at least one moderate episode in the four weeks before courses as a covariate and the same covariates described previously. The number of severe hypoglycaemic episodes in two years was analysed as for moderate hypoglycaemic episodes, with the addition of study follow-up as the exposure. Incidence rate ratios were calculated using negative binomial random effects regression with participant as the random effect, adjusted for baseline HbA1c value and centre, based on the full intention to treat set (n=260).
Secondary continuous outcomes (insulin dose, body weight, high density lipoprotein and total cholesterol levels) were analysed as for the primary outcome. We categorised proteinuria as macroalbuminuria, microalbuminuria, or normal and analysed using mixed effects ordered logistic regression adjusted for clustering by course (random effect), centre, and baseline HbA1c (fixed effects).
Changes in psychological outcomes were analysed using a mixed model adjusted for course (random), centre, baseline HbA1c, and baseline score, with the exception of the diabetes treatment satisfaction questionnaire, which we compared between groups using a non-parametric Wilcoxon-Mann-Whitney U test. No adjustments for multiple testing were made to the significance level for all exploratory secondary objectives.
A retrospective subgroup analysis used mixed effects regression modelling with the primary outcome, change in HbA1c (%), including main effects of treatment group and subgroup, an interaction term between treatment and subgroup, and covariates of centre (fixed effect) and course (random effect). All categories for the subgroup analysis were prespecified in the statistical analysis plan but not in the original protocol, and are reported in full.
Fifteen people, who had previously attended DAFNE courses (including pilot courses on pump treatment) but were not participating in the trial, were recruited to act as a user group and contribute to different aspects of the work. We invited two members to join both the steering group and the other investigator meetings. In addition, one of the project team (a doctor) is a pump user. They provided input to the trial design, implementation, and dissemination, including all participant materials. This included a discussion of the most appropriate research questions and whether individuals who were willing to try pump treatment could be successfully recruited into a trial where they could be randomised to multiple daily injections.
Participants were recruited between November 2011 and April 2013. Follow-up continued until June 2015. The CONSORT flowchart (fig 1⇓) shows the flow of patients through the trial. Forty six courses were randomised. Of the 317 participants included in the randomisation, 50 were excluded from any analysis; 40 withdrew before giving baseline data and 10 before their course. All randomised courses were delivered. Of 267 participants randomised and attending the baseline assessment and the course, 260 (pump=132; injections=128) made up the intention to treat set. Two hundred and forty eight participants had complete primary outcome data at 24 months.
Table 1⇓ shows the baseline demographics and characteristics of the trial population stratified by treatment received. Baseline data were well balanced between treatment groups, with the exception of slightly higher baseline HbA1c in the pump group (9.3% v 9.0%). Just 9% had a baseline HbA1c <7.5%.
At 24 months in participants whose baseline HbA1c was ≥7.5% (n=119 in pump group; n=116 in multiple daily injections group) the mean change in the pump group was a decrease of 0.85% (9.3 mmol/mol) compared with 0.42% (4.5 mmol/mol) in the multiple daily injections group. After adjusting for centre, course, and baseline HbA1c, the mean difference in HbA1c change from baseline was −0.24% (95% confidence interval −0.53% to 0.05%) (−2.7 mmol/mol, −5.8 to 0.5) in favour of pump treatment (P=0.10). The treatment difference was larger for the per protocol analysis; mean difference −0.36% (−0.64% to −0.07%) (−3.9 mmol/mol, −7.0 to −0.8) in favour of pump treatment (P=0.02), although this point estimate was still smaller than the prespecified minimal clinically important difference. Estimate of the intraclass correlation coefficient was approximately 0.5%.
At 24 months, for the treatment groups combined (n=248), in all participants with complete HbA1c data there was a decrease of 0.54% (95% confidence interval 0.38% to 0.69%) (5.9 mmol/mol, 4.2 to 7.6) and for participants with baseline HbA1c ≥7.5% (n=224) the decrease was slightly greater, at 0.64% (95% confidence interval 0.48% to 0.80%) (7 mmol/mol, 5.2 to 8.8).
Proportion of participants reaching HbA1c ≤7.5% (58 mmol/mol)
The proportions of participants reaching an HbA1c ≤7.5% (58 mmol/mol) after two years, regardless of baseline HbA1c value, were 25.0% for the pump group and 23.3% for the multiple daily injections group (odds ratio 1.22, 95% confidence interval 0.62 to 2.39, P=0.57, table 2⇓). The results were similar at six and 12 months.
The primary analysis at 24 months was repeated for six and 12 month follow-up visits (table 3⇓). The results for these interim time points were consistent with the primary outcome analysis. The largest difference in HbA1c change from baseline was observed at six months, with an adjusted mean difference of −0.25% (95% confidence interval −0.52% to 0.02%) (−2.7 mmol/mol, −5.6 to 0.2), P=0.07. Figure 2 displays the change in HbA1c for participants with data at all four time points by treatment group.