versus multiple daily injections in older adults with type 2 diabetes.
Diabetes Care; 28(7):1568-1573.
Level of evidence
Level IICountry
US (2 centres)Research
question/aims
The purpose of the study was to compare the efficacy and safety of CSII and MDI in older adults with insulin-treated type 2 diabetes.Study type/design
Two-centre, open, randomised, parallel-group trial.The total treatment duration was 12 months. Subjects were screened 4 weeks before
randomisation to allow for discontinuation of oral antidiabetic medications and study instruction. There was an additional 1 week between randomisation and treatment initiation where subjects monitored their diet, physical activity and blood glucose levels in order to estimate the initial total daily insulin dose. Study visits took place at baseline, weeks 1, 2, and 4, at 2 months, and every two months thereafter.
Patient group
Participants: older adults aged at least 60 years with insulin-treated type 2 diabetes.Inclusion criteria: age ≥ 60 years, clinical diagnosis of type 2 diabetes for ≥ 1 yr, taking ≥ 1 insulin injection per day for the past month (with or without oral antidiabetic medications), and had an HbA1c ≥ 7.0%.
Exclusion criteria: BMI > 45 kg/m2; severe impairment of cardiac, hepatic, or renal function; presence of any physical, psychological, or cognitive impairments that would interfere with adherence to an intensive insulin therapy program; ≥ 2 episodes of severe hypoglycaemia in the past year or a history of hypoglycaemia unawareness.
Subject disposition: Of 144 screened subjects, 107 were randomised into two treatment arms. The study was completed by 48/53 subjects (91%) in the CSII arm and 50/54 subjects (93%) in the MDI arm.
CSII arm: N=53, 72% male, mean (± SD) age 66.6 (± 5.9) years, BMI 32.5 (± 5.8) kg/m2, Caucasian 81%, duration of diabetes 16.9 (± 9.0) years, HbA1c 8.4% (± 1.1%), retinopathy 42%, nephropathy 17%, neuropathy 72%, prior insulin only 57%, prior insulin & oral agent(s) 43%, duration of insulin treatment 8.1 (± 8.3) years.
MDI arm: N=54, 44% male, mean (± SD) age 66.2 (± 4.5) years, BMI 31.8 (± 5.8) kg/m2, Caucasian 91%, duration of diabetes 15.4 (± 8.9) years, HbA1c 8.1% (± 1.2%), retinopathy 36%, nephropathy 13%, neuropathy 59%, prior insulin only 61%, prior insulin & oral agent(s) 39%, duration of insulin treatment 8.2 (± 7.7) years.
Intervention
CSII using a MiniMed 508 insulin infusion pump (Medtronic MiniMed) with insulin lispro (Humalog; Eli Lilly).The initial basal rate (units/hr) was calculated as 50% of the total daily insulin dose divided by 24 hr. The remaining 50% was administered as preprandial lispro boluses. Participants were instructed to adjust their premeal boluses based on their premeal capillary glucose readings and anticipated carbohydrate consumption.
Comparator
MDI (≥ 3 injections/day) with preprandial insulin lispro and once daily insulin glargine (Lantus, Aventis).Basal insulin was calculated as 50% of the total daily insulin dose and administered as glargine before bedtime. The remaining 50% was administered as for the CSII arm.
Outcome definitions
Mean HbA1c at study end, mean HbA1c over time, weight, infusion and injection site problems, hypoglycaemic episodes, quality of life (using DQOLCTQ and SF-36).
Minor hypoglycaemia was defined as capillary glucose < 65 mg/dL that was self-treatable or, if glucose was not measured, symptoms of hypoglycaemia that resolved with oral carbohydrate. Severe hypoglycaemia was defined as a capillary glucose < 50 mg/dL associated with confusion, loss of consciousness, or seizures, or, in the absence of a glucose determination, confusion, loss of consciousness, or seizures that resolved with the administration or oral carbohydrate, glucagon, or intravenous glucose by another person. Catastrophic hypoglycaemia was defined as
hospitalisation, and/or death.
Data analyses &
statistics
Analyses: Results are presented as mean ± SD. An ITT analysis employing repeated-measures ANOVA, adjusted for gender and baseline HbA1c, was used to test the change in mean HbA1c over time. Differences in proportions were compared using Fisher’s exact test (two-tailed), and number of events, adjusted for exposure time, were compared using Poisson regression. Results are presented as mean ± SD. The pre-randomisation DQOLCTQ scores were subtracted from those at the subsequent visits to create change scores. Repeated measures ANOVA was used to assess differences.Safety was assessed in 105/107 subjects.
Sample size calculation: Based on 180 subjects (90 in each arm), the study had 90% power to detect a difference in HbA1c of 0.5% between groups using a two-tailed Students’ t test, at 0.05% significance. Recruitment was halted early due to a recommendation from the data safety monitoring board due to an observed difference of 0.2% between treatment groups that was unlikely to become significant even if the study was continued.
Study quality
A. Unknown. However, randomisation was provided by a data-coordinating centre.B. Adequate. A block randomisation scheme was used at each site. Upon verification of eligibility, the study coordinator or investigator contacted the data-coordinating centre for the randomisation assignment.
C. Reported. The two treatment arms were generally comparable with respect to demographics and baseline disease characteristics. However, more men were randomised to the CSII arm compared with the MDI arm (72% vs 44%) and HbA1c levels at baseline tended to be higher in the CSII arm than the MDI arm (8.4% vs 8.1%).
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.
G. Partial. The number of withdrawals was stated but not the reason for withdrawal. 8 subjects, 4 from each arm withdrew from the study and one CSII subject died at 8 months due to cancer. 2 subjects in the CSII arm withdrew before initiation of therapy, 1 withdrew after 2 weeks, and the other after 4 months. In the MDI arm, 2 subjects withdrew after 2 months, 1 after 8 months, and 1 after 10 months.
Results (within
scope of systematic
review update)
Mean ± SD HbA1c at study end: CSII 6.6 ± 0.8%
MDI 6.4 ± 0.8% CSII vs MDI P= 0.19
Mean ± SD change in HbA1c from baseline to study end: CSII -1.7 ± 1.0%
MDI -1.6 ± 1.2%
Change in mean HbA1c over time:
In both treatment arms, HbA1c improved significantly over time (P< 0.0001). The mean difference between treatment groups was not significant (P= 0.19).
There was no interaction between treatment group and time. Gender, BMI, and study site were not significantly associated with HbA1c values.
Achievement of HbA1c < 7.0% at study end: CSII 75%
MDI 84%
CSII vs MDI P= 0.30
Incidence of severe hypoglycaemic episodes: CSII 4 episodes in 3 subjects
MDI 12 episodes in 6 subjects, including one episode classified as catastrophic CSII vs MDI P= 0.49
0.08 events per person-year 0.23 events per person-year CSII vs MDI P= 0.61
Not reported.
Quality of life (DQOLCTQ):
Diabetes impact score increased by 2 points over time in both arms, P< 0.01 CSII vs MDI P= 0.19
Worry scores improved by 3 points over time in both arms, P< 0.02 CSII vs MDI P= 0.62
Diabetes worry, social worry, treatment flexibility, and social stigma did not change over the course of the study and there were no differences between arms.
Quality of life (SF-36): Physical health subscale
CSII 40.5 at baseline to 41.1 at study end, ns MDI 40.6 at baseline to 41.0 at study end, ns CSII vs MDI ns
Mental health subscale
CSII 51.0 at baseline to 50.0 at study end, ns MDI 53.0 at baseline to 50.5 at study end, ns CSII vs MDI ns
Authors
conclusions
This study suggests that for highly functioning insulin-treated type 2 diabetics ≥ 60 years of age, intensive treatment with either MDI or CSII is feasible and safe. Both treatment groups had significant decreases in mean HbA1c to levels < 7.0% and were able to maintain HbA1c levels <7.0% with good safety and high treatment satisfaction. There was no difference in efficacy between CSII and MDI and no difference in efficacy by baseline HbA1c, gender, BMI, or study site. Although there was a trend toward a higher number of severe hypoglycaemic events in the MDI arm, this was largely related to one subject who experienced four events.Because MDI achieved results comparable to CSII and because MDI is less expensive than CSII, MDI may be preferred as an initial regimen for older patients with type 2 diabetes requiring intensive insulin therapy.
Reviewers notes
Long-acting analogue insulin glargine was used as basal insulin in the MDI arm.Conflict of interest: Insulin, syringes, monitoring equipment and supplies, and insulin infusion pumps and continuous blood glucose monitoring devices were donated by Eli Lilly, Aventis, Becton Dickinson, Roche Diagnostics, and Medtronic MiniMed.