insulin infusion (CSII) and NPH-based multiple daily insulin injections
(MDI) on glycaemic control and quality of life: Results of the 5-nations
trial. Diabetic Med 23(2):141-147.
Level of evidence
Level IICountry
Europe (11 centres in the Netherlands, UK, Spain, Italy, and Germany)Research
question/aims
The aim of the study was to compare CSII with MDI with respect to metabolic parameters in an adequately powered RCT with a crossover design.Study type/design
Multicentre, open, randomised crossover trial.The total study duration was 16 months, including 2 x 6-month treatment phases, each started with a 2-month run-in period, during which patients received education to optimise intensive insulin therapy. Study visits took place at baseline and every two months thereafter.
Patient group
Participants: adults with type 1 diabetes on MDI for at least 6 months.Inclusion criteria: Type 1 diabetes and absent C-peptide secretion, aged 18-65 years, on MDI for ≥6 months, able to manage intensive insulin therapy and the technical aspects of insulin pump usage.
Exclusion criteria: Hypoglycaemia unawareness, progressive retinopathy, renal insufficiency, acute coronary syndrome or cerebrovascular accident within the last 6 months, uncontrolled hypertension, autonomic neuropathy, planned or existing pregnancy, or other clinically significant concomitant disorders.
Subject disposition: 272 subjects were enrolled and randomised into two arms. 223 subjects (82%) completed the study. 31 subjects withdrew during the first treatment phase, 12 subjects completed the first phase but did not cross over into the second treatment phase, and 6 subjects withdrew during the second treatment phase.
CSII then MDI arm: N=127, 48% male, mean (± SD) age 35.3 (± 9.8) years, BMI 24.9 (± 3.3) kg/m2, duration of diabetes 14.4 (± 8.9) years, duration of MDI 7.6 (± 4.3) years, HbA1c 8.2% (± 1.4%), total daily insulin usage 53.4 (± 21.4) IU.
MDI then CSII arm: N=129, 47% male, mean (± SD) age 37 (± 10.6) years, BMI 24.8 (± 3.4) kg/m2, duration of diabetes 15.4 (± 10.1) years, duration of MDI 8.1 (± 6.2) years, HbA1c 8.3% (± 1.1%), total daily insulin usage 50.8 (± 18.5) IU.
Intervention
CSII using a H-TRON V100 or H-TRONplus V100 insulin pump (Disetronic Medical Systems) with insulin lispro (Eli Lilly Inc.).Comparator
MDI with ≥ 3 injections of insulin lispro before meals and ≥ 1 injection of insulin NPH to achieve optimal control.The glycaemic targets for both treatments were identical. Target blood glucose range: 4.0 – 7.0 mmol/L preprandially, 8.0 – 10.0 mmol/L postprandially, and 6.0 – 10.0 mmol/L at bedtime. Patients were advised to decrease or increase the dose of NPH insulin if fasting glucose was repeatedly < 4.0 or > 7.0 mmol/L and to decrease or increase the dose of rapid-acting insulin at meals if the 1hr postprandial blood glucose was repeatedly <8.0 or > 10.0 mmol/L.
Outcome definitions
Primary outcomes: (1) mean HbA1c values at the end of each treatment period (determined by HPLC with normal range 4.4 – 6.1%), (2) daily blood glucose fluctuation defined as the average SD of the mean daily blood glucose, using measurements taken during the 14 days prior to the final visit in each treatment period.Secondary outcomes: mean daily blood glucose values (determined from standardised 24 hr blood glucose profiles), the frequency and severity of hypoglycaemic episodes, quality of life (using the 46-item DQoL questionnaire, the SF-12, and an additional 4-item questionnaire related to lifestyle and therapy manageability), signs of discomfort at the injection or infusion site, serious AEs (especially severe hypoglycaemia graded according to DCCT criteria, and ketoacidosis). Blood glucose levels were checked at least 4 times per day (before meals and at bedtime).
with measurements before and 1 hr after meals, at bedtime, and between 2 and 3 am. Hypoglycaemic episodes were subject defined as mild (self-treated) or severe (requiring third- party help).
Data analyses &
statistics
As a result of the absence of a carry-over effect, the study was analysed as a crossover study. Run-in periods were excluded from the statistical analysis. The primary endpoint HbA1c was initially analysed for non-inferiority of CSII with respect to MDI. Non-inferiority was shown if the upper limit of the one-sided 97.5% CI was ≤ 0.7% in favour of MDI. The test of inferiority was based on the per-protocol crossover cohort of 212 subjects. In case of non-inferiority, the superiority of CSII and MDI was to be analysed using a one-sided student’s t test with a significance level of 2.5%, based on the ITT crossover cohort of 229 subjects.The second primary endpoint and the main secondary endpoints were analysed using a two- sided student’s t test with a significance level of 5%, based on the ITT cohort. Missing data was substituted using a last observation carried forward analysis.
The safety cohort comprised 256 subjects.
Study quality
A. Unknown. Details of the randomisation procedure were not provided. B. Unknown. No details of the concealment of randomisation were provided.C. Reported. The two treatment arms were comparable with respect to patients’ characteristics. The publication states that there were no significant differences with respect to concomitant diseases or medications but data were not shown.
D. Adequate. Inclusion and exclusion criteria were defined.
E. Adequate. Mean EOT HbA1c was reported and the SEM was shown graphically. The difference between treatment arms and 95% CIs were reported.
F. Adequate. Analyses were based on the ITT crossover cohort. Although 272 subjects were randomised, 43 subjects dropped out during or after the first treatment phase and were not included in the analyses.
G. Partial. The number of withdrawals was stated along with the main reason for withdrawal (refusal to start CSII for the MDI then CSII arm and refusal to leave CSII for the CSII then MDI arm). During the first treatment phase 16 subjects in the CSII-MDI arm and 15 subjects in the MDI-CSII arm withdrew from the study. After the first treatment phase, 10 subjects in the CSII- MDI arm and 2 subjects in the MDI-CSII arm did not crossover into the second treatment phase. Three subjects in each treatment arm withdrew during the second treatment phase.
Results (within
scope of systematic
review update)
The publication states that there was no carry-over effect. Data were not shown. Mean ± SEM HbA1c at 8 months:
CSII 7.45 ± ~0.065% (note: SEM estimated from figure) MDI 7.67 ± ~0.075% (note: SEM estimated from figure) CSII vs MDI P< 0.001
Difference 0.23% (upper 97.5% CI 0.104%) Mean ± SEM HbA1c at 6 months:
CSII ~7.51 ± ~0.065% (note: mean and SEM estimated from figure) MDI ~7.64 ± ~0.075% (note: mean and SEM estimated from figure) CSII vs MDI P< 0.05
Mean ± SEM HbA1c at 4 months:
CSII ~7.47 ± ~0.065% (note: mean and SEM estimated from figure) MDI ~7.57 ± ~0.075% (note: mean and SEM estimated from figure) Number of severe hypoglycaemic episodes:
CSII 0.2 events per patient per year MDI 0.5 events per patient per year CSII vs MDI P< 0.001
Number of ketoacidotic episodes:
4 episodes in total, 2 during the first CSII treatment phase and 2 during the run-in phase, resulting in a total frequency of 0.03 events per patient year. No episodes occurred during MDI therapy.
Quality of life (DQoL): CSII arm EOT score 75 MDI arm EOT score 71 CSII vs MDI P< 0.001
Whereas all scores deteriorated during MDI, an improvement in all categories was observed with CSII. There were significant improvements in treatment satisfaction (P< 0.001), treatment impact (P< 0.001) and a significant reduction in diabetes-related worry (P< 0.01) when using CSII compared with MDI.
Quality of life (SF-12): Physical health subscale
No difference when using CSII compared with MDI (no data provided) Mental health subscale
Significant improvement in perception of mental health when using CSII compared with MDI (P=0.05)
Quality of life (Lifestyle and manageability):
Patients perceived significantly more flexibility with regard to eating habits (P< 0.001) and significant improvement in lifestyle flexibility and sleep patterns (P< 0.001) when using CSII compared with MDI.
Authors
conclusions
The study demonstrated the superiority of CSII over an NPH-based MDI regimen with respect to HbA1c, reduced mean blood glucose levels, and blood glucose fluctuations, and a reduction in the incidence of severe as well as minor episodes of hypoglycaemia. In addition, CSII conferred significant advantages in terms of quality of life with improvements in treatment satisfaction, treatment impact, perception of mental health, flexibility of eating habits and lifestyle, and reduction in diabetes-related worry. There was no significant difference in treatment modalities with respect to incidence of diabetic ketoacidosis. However, CSII was uniquely associated with a small number of infusion-site problems, notably skin reactions and local pain. Despite this, once patients had experienced CSII they were much more likely to recommend it than an NPH-based MDI regimen.Reviewers notes
The second treatment phase was preceded by a 2-month run-in/washout period. The authors state that as a result of the absence of a carry-over effect, the study was analysed as a cross- over trial.Conflict of interest: The study was reported on behalf of the 5-Nation Study Group with grant support from Disetronic Medical Systems AG. One author was reimbursed by Disetronic/Roche for attending a conference, and received fees for speaking and membership of an advisory board. Another received honoraria from Roche/Disetronic for participating in advisory boards. A third author received fees for speaking to a symposium by Disetronic Medical Systems, Italy. One author was reimbursed by Disetronics for attending a conference. A fifth author has been employed by Disetronic Medical Systems.
Relevance to study
question
At study entry, participants were receiving ≥ 3 insulin injections per day (note: mean HbA1c 8.3% and 8.2% in the 2 treatment arms) Intervention and comparator appropriate (both rapid-acting analogues)Abbreviations: AE, adverse event; BMI, body mass index; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; DQoL, Diabetes Quality of Life; EOT, end of treatment; HPLC, high-performance liquid chromatography; ITT, intention to treat; MDI, multiple daily injections; NPH, neutral protamine hagedorn; SD, standard deviation; SF-12, 12-item Short Form Health Survey
The quality of the RCTs was assessed using the following questions: (A) Was the assignment to the treatment groups really random?; (B) Was the treatment allocation concealed?; (C) Were the groups similar at baseline in terms of prognostic factors?; (D) Were the eligibility criteria specified?; (E) Were the point estimates and measure of variability presented for the primary outcome measure?; (F) Did the analysis include an intention-to-treat analysis?; (G) Were withdrawals and dropouts completely described?