Continuous Intraperitoneal Insulin Infusion in T1DM
After 6 years of treatment with CIPII, HbA1c leveled with the value these T1DM patients had during intensive SC therapy, prior to starting CIPII. Nevertheless, patients experienced significant less grade 2 hypoglycaemic events and remained much more satisfied with CIPII compared to the SC treatment.
During the previous cross-over trial in which CIPII was commenced there was a significant decrease in HbA1c compared to the SC treatment phase from 70 to 58 mmol/mol. Compared to the SC treatment phase, the decrease in that study was significantly greater with CIPII with a mean difference of 8.4 mmol/mol. During the follow-up period described in the present study HbA1c stabilized at a level of 65 mmol/mol, which was not different to the levels prior and shortly after starting CIPII 6 years before. Several studies have described the effect of CIPII, as compared to SC insulin therapy, on glycaemic control. In all 3 short-term randomized studies, HbA1c improved with CIPII. In contrast to the findings in the present study, HbA1c improvement persisted over the years in subsequent long-term observational studies. Nevertheless, follow-up duration (45 days to 7.3 years) varied substantially between studies and, importantly, not all patients in those studies had intermediately or poorly controlled T1DM (HbA1c 63 to 83 mmol/mol).
In line with previous studies, the number of grade 2 hypoglycaemic events decreased during CIPII in the present cohort as compared to prior SC therapy. This may well be the result of a slightly more hyperglycaemic profile. Although speculative, the restoration of the portal to peripheral insulin gradient with CIPII treatment, known to improve glucagon secretion and hepatic glucose production in response to hypoglycaemia, may also help to explain this finding.
The HbA1c course in the current cohort may be partly explained by the effect of being under strict study conditions during the cross-over study, which diminishes after the end of the study. Several other explanations may be taken into account. First, complications of CIPII may also have a negative influence on glycaemic regulation. Second, it should be mentioned that from 2010 onwards all CIPII patients switched to another insulin (Insuman® Implantable 400 IU/mL) because the previous insulin batch (U-400 HOE 21PH, Insuplant® 400 IU/mL) was no longer available. The effect of the change in insulin formulation remains to be determined from an on-going study (clinical trials identifier NCT01194882).
The switch from SC insulin to CIPII increases HRQOL, which stabilizes over time. In the present study the level of HRQOL among CIPII treated subjects perpetuated. Nevertheless, as found in other studies and underlined by the fact that 42% of all patients had a WHO-5 score indicating poor emotional well-being, the HRQOL of these individuals remains poor. We found the SF-36 subscales role-physical and vitality to be comparable to patients with a minor (uncomplicated) chronic disease and the other subscales similar to patients with complicated diabetes or complicated coronary artery disease. Still, it is likely that the short duration of hospital admissions found in the present study, compared to 45 days per year before implantation of the pump previously described in a similar population, positively influence HRQOL and treatment satisfaction.
Since CIPII is used as a last treatment option in the Netherlands, the population in the present study is complex, strictly selected, and has a small size. On the other hand this limitation reflects general practice nowadays where CIPII is limited to a small number of patients in a small number of centers. Furthermore, when interpreting the comparisons between CIPII and previous SC therapy made in this study one should take differences in treatment periods (e.g. a duration of 6 months of the SC phase during a controlled study versus 6.4 years of subsequent CIPII therapy) into account. Prospective, long-term and large-scale studies with respect to i.e. glycaemic control, HRQOL and cost-effectiveness to compare SC and CIPII therapy for T1DM are imperative.
Discussion
After 6 years of treatment with CIPII, HbA1c leveled with the value these T1DM patients had during intensive SC therapy, prior to starting CIPII. Nevertheless, patients experienced significant less grade 2 hypoglycaemic events and remained much more satisfied with CIPII compared to the SC treatment.
During the previous cross-over trial in which CIPII was commenced there was a significant decrease in HbA1c compared to the SC treatment phase from 70 to 58 mmol/mol. Compared to the SC treatment phase, the decrease in that study was significantly greater with CIPII with a mean difference of 8.4 mmol/mol. During the follow-up period described in the present study HbA1c stabilized at a level of 65 mmol/mol, which was not different to the levels prior and shortly after starting CIPII 6 years before. Several studies have described the effect of CIPII, as compared to SC insulin therapy, on glycaemic control. In all 3 short-term randomized studies, HbA1c improved with CIPII. In contrast to the findings in the present study, HbA1c improvement persisted over the years in subsequent long-term observational studies. Nevertheless, follow-up duration (45 days to 7.3 years) varied substantially between studies and, importantly, not all patients in those studies had intermediately or poorly controlled T1DM (HbA1c 63 to 83 mmol/mol).
In line with previous studies, the number of grade 2 hypoglycaemic events decreased during CIPII in the present cohort as compared to prior SC therapy. This may well be the result of a slightly more hyperglycaemic profile. Although speculative, the restoration of the portal to peripheral insulin gradient with CIPII treatment, known to improve glucagon secretion and hepatic glucose production in response to hypoglycaemia, may also help to explain this finding.
The HbA1c course in the current cohort may be partly explained by the effect of being under strict study conditions during the cross-over study, which diminishes after the end of the study. Several other explanations may be taken into account. First, complications of CIPII may also have a negative influence on glycaemic regulation. Second, it should be mentioned that from 2010 onwards all CIPII patients switched to another insulin (Insuman® Implantable 400 IU/mL) because the previous insulin batch (U-400 HOE 21PH, Insuplant® 400 IU/mL) was no longer available. The effect of the change in insulin formulation remains to be determined from an on-going study (clinical trials identifier NCT01194882).
The switch from SC insulin to CIPII increases HRQOL, which stabilizes over time. In the present study the level of HRQOL among CIPII treated subjects perpetuated. Nevertheless, as found in other studies and underlined by the fact that 42% of all patients had a WHO-5 score indicating poor emotional well-being, the HRQOL of these individuals remains poor. We found the SF-36 subscales role-physical and vitality to be comparable to patients with a minor (uncomplicated) chronic disease and the other subscales similar to patients with complicated diabetes or complicated coronary artery disease. Still, it is likely that the short duration of hospital admissions found in the present study, compared to 45 days per year before implantation of the pump previously described in a similar population, positively influence HRQOL and treatment satisfaction.
Since CIPII is used as a last treatment option in the Netherlands, the population in the present study is complex, strictly selected, and has a small size. On the other hand this limitation reflects general practice nowadays where CIPII is limited to a small number of patients in a small number of centers. Furthermore, when interpreting the comparisons between CIPII and previous SC therapy made in this study one should take differences in treatment periods (e.g. a duration of 6 months of the SC phase during a controlled study versus 6.4 years of subsequent CIPII therapy) into account. Prospective, long-term and large-scale studies with respect to i.e. glycaemic control, HRQOL and cost-effectiveness to compare SC and CIPII therapy for T1DM are imperative.
Source...