Benefits gained through CSII application included a slower deterioration of HbA1c values, evidenced by an increasing difference in initial and final HbA1c levels depending on CSII or MDI treatment. Curiously, baseline characteristics of the presented study group suggest that the analysed patients could have been in fact better controlled than those in the STAR 3 trial [9
], (mean HbA1c levels 7.6 ± 1.5 vs. 8.5 ± 0.6) making it more difficult to obtain a statistically significant improvement of HbA1c. Stable HbA1c levels despite ageing and duration of diabetes observed in CSII-treated individuals in this trial do, however, mirror the beneficial effect of the STAR 3 participants. Final mean HbA1c levels in the paediatric group in STAR 3 equalled 7.7%, whereas in the presented cohort the final mean HbA1c reached 7.6%. Despite the methodological differences and application of different insulin pumps (the STAR 3 pumps were sensor-augmented), results confirming the overall benefit of CSII seem surprisingly convergent. Moreover, the difference in final HbA1c levels was similar to that reported in a recent meta-analysis by Monami et al. [17
] who showed a −0.3% reduction in favour of the CSII group. This may be interpreted as showing that CSII offers an advantage in terms of better metabolic control, but the improvement will seldom exceed 0.5% in long-term observation. Further improvements could theoretically be gained through the use of more sophisticated therapeutic approaches such as dual wave bolus (DWB) [18
]. However, due to the magnitude duration of observation, changing patient preferences in using DWB, the authors refrained from introducing this factor to stratify the CSII group.
Although CSII was shown to offer better metabolic control, this effect did not translate into the risk of acute hospitalizations. A lack of difference in this endpoint suggested that educational measures undertaken during the switching phase were adequate and did not result in shortened time to first hospital visit due to acute complications. Finally, rates of hospitalizations due to acute visits did not differ between the groups which confirmed that no additional risk of hypoglycaemia or ketoacidosis was created by CSII treatment, in contrast to earlier studies on that matter [20
The obviously non-random allocation of patients is the main limitation of the study and a potential for bias, but the lack of differences in baseline HbA1c and duration of diabetes justified this approach and made the groups comparable. The authors performed covariate matching for baseline HbA1c and duration of diabetes which lead to balanced group numbers, apart from the age difference, which was adjusted for in multivariate comparisons. The perfect design—a randomized study—for a group of such magnitude would be unfeasible from an organizational point of view. Recently published results of an ambitious project on the use of sensor-augmented CSII (the STAR 3 trial) [9
] covered 156 children allocated to either CSII or MDI. The observational approach with matching of MDI and CSII patients used in this study, although potentially biased by non-random selection, allowed the authors to include a study group of 454 individuals, yielding greater statistical power and robustness in terms of adjusted effects estimation. The fact that the differences in HbA1c persisted after correction for confounding factors further increased the credibility of presented findings.
Presented patients were followed for 3 years, which allowed the authors to evaluate the effect of CSII on hospitalization rates and variability of HbA1c. The latter effect of CSII may be clinically important, as lower SD of HbA1c is a result of reduced rates of prolonged periods glycaemia maintained alternatively within the high or low concentration range. CSII treatment was already reported to reduce blood glucose variability in a meta-analysis authored by Pickup et al. [21
]. Although variability of HbA1c is not yet considered an endpoint in diabetes trials, it was proven to increase the risk of long-term complications of diabetes in DCCT data analysis [22
]. Therefore, interventions aimed at its reduction could be perceived as being potentially beneficial and therefore worthy of further interest.
Results of this study in terms of HbA1c changes due to CSII treatment were in line with those obtained by Jakisch et al. [23
] who in a group of 434 matched pairs of patients with type 1 diabetes, showed an improvement of HbA1c during the first year of the study. In their study however, the difference disappeared after 3 years of observation, showing that the benefit could be attributed to the “novelty” effect. In the presented study, the effect seemed to persist throughout the observation period of similar duration (mean 3.05 years), possibly due to different educational approaches or changes in patients’ ability to cope with diabetes and its management.
Persistent residual function of the beta cells could also contribute to better metabolic control in CSII-treated patients. However, as only 12% of analysed patients had C-peptide levels within normal range and no difference was detected between the groups, it seems very unlikely that residual beta cell function contributed significantly to the observed outcomes.
Over 30% of patients required at least one hospitalization due to acute complications during the observation period. This could result in a bias of study results, as the older patients may have left the group after shorter observation periods before developing acute complications, while younger ones could be observed for longer periods of time increasing their chances of acute hospitalization. However, the rate of acute hospitalizations per 100 patient/years was nearly identical between CSII and MDI-treated patients, as was the case for risk of the first acute hospitalization, which allowed the authors to assume that the risk of being hospitalized due to acute conditions is the same with MDI or CSII treatment. CSII did, however, promote shorter overall hospital stays per year by nearly 25%, which could result in an economic benefit from this type of treatment.
The rate of severe hypoglycaemia in an outpatient setting among children with diabetes is hard to estimate, as reported rates range widely from 6.63 events per 100 patient-years, reported by the PedPump study which included patients from Poland [24
], to 62 per 100 patient-years reported earlier by Levine et al. [25
]. In the Hvidore study group, which formulated the criteria for assessment of hypoglycaemic events used in the above-mentioned studies, the rate of severe hypoglycaemia equalled 22 per 100 patient-years [26
]. Introduction of CSII treatment was shown to reduce the overall rate of hypoglycaemia [21
] and was expected to result in a reduction in hospitalizations due to this complication in the studied group. The observed lack of differences in this outcome could result from one of the limitations of the presented study—the authors were unable to objectively collect and analyse data from outpatient clinics and match them with those from the hospital database. All patients and their parents could contact their attending diabetologists by phone and did so in critical situations including severe hypoglycaemic episodes, but precise recall of the overall and individual numbers of such episodes was not possible. As a result, the authors were unable to determine actual rates of hypoglycaemia not resulting in hospital admission. Hospitalizations due to hypoglycaemia, however, constituted 25% of all acute diabetes-related hospital visits in our study group, which is a similar value range as that noted in an earlier study by Palta et al. [27
] The authors reported a rate of 1.9 per 100 patient-years hospital admissions due to hypoglycaemic events in patients with diabetes aged 0–29, which amounted to 21% of all hospital admissions of their cohort. Thus, it seemed that the group presented within this study did not deviate significantly from those reported in previous reports in terms of hypoglycaemia incidence, with no evident benefits gained through the introduction of CSII.
Confirmation of the fact that baseline HbA1c was the main risk factor for hospitalization due to acute complications may be one with considerable clinical implications. This association was previously reported in epidemiologic studies on children with diabetes [25
]. One could therefore assume that patients with initially worse metabolic control should be a group of particular interest for the physician, as any intervention leading to the improvement of HbA1c could yield beneficial effects in terms of reducing the risk of acute hospitalizations. The percentage of patients reaching the therapeutic goal of ADA for HbA1c (<7.0%) was considerably greater in the presented study in both CSII and MDI groups than in the STAR 3 cohort. The difference was particularly evident in MDI individuals (25.7% vs. 10% reported by STAR 3), undermining the beneficial effect of CSII and suggesting suboptimal diabetes management in the MDI group in the cited study.