diabetic patients. Diabetic Med 22(8):1037-1046.
Level of evidence
Level IICountry
Israel (7 centres)Research
question/aims
To compare the efficacy of insulin pump treatment with MDI in the treatment of poorly controlled obese type 2 diabetic patients already receiving two or more daily injections of insulin plus metformin.Study type/design
Multicentre, open, randomised, crossover trial.After a 2-week single run-in period during which subjects were treated with insulin therapy plus metformin, patients were randomised and then treated in two 18-week treatment periods separated by a 12-week washout period during which they were treated with MDI plus metformin. Evaluations were conducted at weeks 0, 18, 30, and 48, after randomisation.
Changes in insulin dose were made according to similar rules and treatment guidelines. There was no specific protocol treatment; each investigator made recommendations based on clinical judgement. The treatment target was to achieve HbA1c < 7%. There was no upper limit for insulin dose.
Patient group
Participants: obese, uncontrolled, insulin-treated type 2 diabetic subjects.Inclusion criteria: obese (BMI 30-45 kg/m2) men or women, aged 30-70 years, suffering from uncontrolled type 2 diabetes (HbA1c > 8.5%), treated for ≥ 3 months with diet, metformin (850 mg 2-3 times daily) and high doses of insulin (> 1 unit/kg/day), divided into 2 or 3 daily injections. Exclusion criteria: New-onset diabetes (< 6 months), type 1 diabetes, or diabetes secondary to pancreatitis or other disease, history of ischaemic heart disease or CVA within the last 6 months, pre-proliferative or proliferative diabetic retinopathy, advanced nephropathy, liver enzymes twice above the upper limit of the normal range, HbA1c > 15% at screening.
Subject disposition: Of 58 screened subjects, 40 were randomised equally into two treatment arms and 29 subjects (14 in the CSII-MDI arm and 15 subjects in the MDI-CSII arm) completed the study per protocol. During the first treatment period, 3 subjects randomised to the CSII-MDI arm and 5 subjects randomised to the MDI-CSII arm dropped out. One subject from each arm discontinued during the washout period. In the second treatment period, 1 subject in the MDI- CSII arm discontinued.
CSII then MDI arm: N=20, weight 91.8 (±17.4) kg, HbA1c 10.2% (± 1.4%), insulin dose 99.3 (±24.5) units/day.
MDI then CSII arm: N=20, weight 94.01 (±12.4) kg, HbA1c 10.3% (± 1.2%), insulin dose 113.4 (±28.04) units/day.
Gender, age, and ethnicity were not reported for subjects in the two treatment arms. However, compared with subjects who completed the study protocol, subjects who dropped out of the study were similar in terms of age (both 56.8 years, P= 0.9) and gender (73% vs 60% female, P= 0.4). HbA1c was marginally significantly lower in subjects who completed the study protocol (8.9 ± 2.1% vs 9.5 ± 1.5%, P= 0.05).
Intervention
CSII using MiniMed with insulin lispro.Comparator
MDI (four injections daily) with regular insulin (Actrapid, Novo Nordisk; or Humulin R, Eli Lilly) and NPH (Insulatard-HM, Novo Nordisk; or Humulin N, Eli Lilly).Outcome definitions
Mean HbA1c at study end, insulin dose, weight, blood glucose (mean meal-test AUC), lipid profile, hypoglycaemic events.Patients performed 4-point daily self blood glucose monitoring on a regular basis and 7-point monitoring prior to study visits.
A minor hypoglycaemic event was defined as a blood glucose < 3.3 mmol/L that the subject handles without assistance from others. A major hypoglycaemic event was defined as one in which the patient was unable to self treat and either had a blood glucose < 2.8 mmol/L, symptoms remitted after intake of intravenous glucose, intramuscular glucagon or food intake.
Data analyses &
statistics
Analyses: Descriptive data were reported as mean ± SD. Distributions of continuous variables were tested using the Kolmogorov-Smirnov test. For distributions that varied significantly from normal, the Mann-Whitney U-test was used. Categorical variables were compared using the Chi- square test with 99% Monte Carlo CIs. Change from baseline was compared by treatment assignment using the t-test for independent samples or the Mann-Whitney U-test, as appropriate. Carry-over effects were determined by summing subjects’ values obtained at the end of each treatment period and comparing them by treatment arm using the t-test for independent samples. Period effect was estimated by subtracting second-period values from the first-period values and comparing by group using the t-test for independent samples. Direct treatment effects were estimated as the difference between the subject values at the end of each treatment period and compared by arm.In the ITT analysis of all enrolled subjects, the LOCF method was used to account for missing data. A completers analysis was also conducted.
Sample size calculation: The present study was designed to have 80% power to detect a true by- treatment group difference of 0.85% in HbA1c, assuming a two-sided alpha of 0.05, and a SD of the difference of 1.3%. Based on these assumptions, a sample size of 39 was required. Taking into consideration dropouts or assumption errors, a total of 58 subjects was recruited.
Study quality
A. Unknown. No details of random sequence generation were provided.B. Unknown. No details were provided to determine whether treatment allocation was concealed. C. Unknown. Gender, age, and ethnicity were not reported for the two treatment arms. However, HbA1c was similar between arms (10.2% in the CSII-MDI arm vs 10.3% MDI-CSII arm). D. Adequate. Inclusion and exclusion criteria were defined.
E. Adequate. Mean (±SD) HbA1c at study end was reported together with the mean (±SD) change from baseline to study end.
F. Adequate. Efficacy analyses were conducted on an ITT basis, in addition to a completers analysis.
G. Adequate. The number of withdrawals and reason for withdrawal were stated. During the first treatment phase, 3 subjects randomised to CSII then MDI dropped out (1 unable to use the pump, 1 with severe hypoglycaemia, and 1 with hyperglycaemia), and 5 subjects randomised to MDI then CSII dropped out (2 due to non-compliance, 2 for protocol violations, and 1 with diagnosis of carcinoma of the lung). During washout, 2 subjects withdrew, 1 in the CSII-MDI arm because of non-compliance and 1 in the MDI-CSII arm due to protocol violation. In the second treatment period, 1 subject in the CSII-MDI arm discontinued because of severe hypoglycaemia.
Results (within
scope of systematic
review update)
To test for a carry-over effect, the sum of the subject values obtained at the end of each treatment period was compared by treatment group. Inadequate evidence exists to reject that the carry-over effect in group 1 is equal to the carry-over effect in group 2. Equal carry-over effects can thus be assumed.
Mean ± SD HbA1c at end of first treatment period (18 weeks) [ITT cohort]: CSII-MDI arm 7.9 ± 1.0%
MDI-CSII arm 8.4 ± 1.3% CSII vs MDI P< 0.05
Mean ± SD HbA1c at end of second treatment period (18 weeks) [ITT cohort]: CSII-MDI arm 8.8 ± 1.4%
MDI-CSII arm 8.8 ± 1.5%
Mean ± SD change in HbA1c from baseline to study end [ITT cohort]: CSII -0.8 ± 1.5%
MDI 0.4 ± 1.3% CSII vs MDI P= 0.007
Mean ± SD change in HbA1c from baseline to study end [completers’ cohort]: CSII -0.8 ± 1.6%
MDI -0.2 ± 1.2% CSII vs MDI P= 0.4
Incidence of major hypoglycaemic episodes: CSII 3 subjects
MDI 2 subjects
Number of ketoacidotic episodes: Not reported.
Change from baseline in lipid profile (mmol/L): Total cholesterol CSII 0.1 ± 0.7 MDI -0.1 ± 1.1 CSII vs MDI P= 0.5 Triglycerides CSII 0.01 ± 0.7 MDI 0.5 ± 2.9 CSII vs MDI P= 0.5 HDL CSII -0.05 ± 0.2 MDI 0.01 ± 0.2 CSII vs MDI P= 0.4 LDL CSII 0.1 ± 0.4 MDI -0.1 ± 0.6 CSII vs MDI P= 0.1
Authors
conclusions
In the ITT analysis, CSII appeared to be superior to MDI in reducing HbA1c and glucose AUC values without significant change in weight or insulin dose in obese, uncontrolled, insulin-treated type 2 diabetic subjects. The number of major hypoglycaemic events were few and similar in both groups. However, the study was not powered to detect a difference in the frequency of major hypoglycaemic events by treatment groups.Reviewers notes
The second treatment phase was preceded by a 12-week washout period in which patients were treated with MDI plus metformin. The authors attempted to investigate evidence of a carry-over effect and found no evidence.Conflict of interest: None declared.
Relevance to study
question
At study entry, participants were uncontrolled on insulin (note: mean HbA1c 10.2% and 10.3% in the 2 treatment arms). Participants were required to be obese and aged 30-70 yrsParticipants with HbA1c >15% were excluded
Intervention and comparator inappropriate (CSII with rapid-acting analogue and MDI with short- acting insulin)
Abbreviations: AE, adverse event; AUC, area under the curve; BMI, body mass index; CI, confidence interval; CSII, continuous subcutaneous insulin infusion; ITT, intention to treat; MDI, multiple daily injections; NPH, neutral protamine hagedorn; ns, not significant; SD, standard deviation
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?