CIPII Intraperitoneal insulin (shortcut)
Almost all patients with T1DM need insulin treatment permanently. Most patients use insulin subcutaneously, either as injections or as continuous subcutaneous insulin infusion (CSII). Alternatively, intraperitoneal (IP) administration of insulin with an insulin pump can be used. Continuous intraperitoneal insulin infusion (CIPII) has been available for more than 30 years but is used in very few patients around the world. In addition to the implantable insulin pump, an external device using a catheter that is placed in the abdomen to deliver IP insulin is available: the ‘DiaPort’ system. In this topic, the main focus will be on IP insulin administration using an implantable pump. In succession, a brief history, pharmacokinetic properties, clinical evidence and the current use and future prospects of CIPII will be discussed in this topic.
With the development of microelectronics in the 1970s, a remotely controlled implantable pump became theoretically feasible. In the 1980s the first implantable pump was used for patients with non insulin dependent diabetes mellitus. In the first trials with the implantable pump both the IP and/or intravenous (IV) mode of insulin administration were tested. However, the pulsatile mode of insulin delivery of the IV pumps was associated with a high incidence of IV catheter obstructions and thus the IP mode was promoted. The clinical experience with implantable pumps remained limited for a period of time until the development of a stable insulin, U400 Insulin by Hoechst (semi-synthetic human insulin at neutral pH, stabilized adding genapol). This led the way for several manufacturers to develop implantable insulin pumps, such as the Infusaid M1000, Siemens ID1 / ID3 and Minimed PIMS/MIP (later Medtronic). Subsequently, a series of clinical trials were undertaken to assess the efficacy and safety of continuous intraperitoneal insulin infusion . As the clinical experience increased over the years, so did the number of adverse events. The most frequent adverse events were complications at the implantation site, i.e. infection, and catheter obstructions, i.e. due to insulin aggregates or encapsulation of the tip of the catheter. This raised questions about the risk to benefit ratio of CIPII. And although changes in both pump technology and procedures decreased the number of complications, many manufacturers decided to cease the development of IP insulin pumps .
Due to relative high costs and a lack of experience with IP treatment CIPII is currently used in only a few individuals around the world. Most of these patients have so called ’brittle diabetes’, i.e. failure to reach adequate glycaemic control despite intensive insulin therapy with multiple daily injections (MDI) or CSII and/or having frequent hypoglycaemic episodes.
Use of CIPII is largely restricted to Europe, especially France, The Netherlands and Sweden. At the present only one implantable pump (MIP 2007C, Medtronic/Minimed, Northridge, CA, USA) is still available for use in patients.(figure 1)
Figure 1. The insulin pump and patient-pump-communicator
Implantation of the pump is performed under general anaesthesia. Usually, the pump is located in a subcutaneous pocket in a lower abdominal quadrant (figure 2). From this pocket, the peritoneum is opened and the tip of the catheter is carefully inserted and directed towards the liver. After implantation, the pump reservoir is refilled at the outpatient clinic transcutaneously at least every 3 months, depending on the individual insulin requirement.
Figure 2. Schematic representation of the position of the insulin pump and catheter in vivo
With CIPII insulin is directly infused in the intraperitoneal space and absorbed into the portal system, thus yielding a more physiologic mode of insulin administration compared to subcutaneous insulin administration . Insulin delivered through the IP route is rapidly absorbed and allows blood glucose values to return to baseline values more rapidly with more predictable insulin profiles compared to SC injections of insulin . Furthermore, since IP insulin is almost entirely absorbed by the portal system, it leads to a more physiological insulin distribution with a high hepatic uptake and relatively low peripheral plasma insulin concentrations compared with systemic administration . Other possible effects include improvement of the impaired glucagon secretion and hepatic glucose production in response to hypoglycaemia through alleviation of peripheral hyperinsulinaemia .
Several studies have validated the effectiveness and safety of CIPII. In 2008, a randomized cross-over study compared the effects of CIPII and SC (MDI or CSII) insulin in 24 patients with ‘brittle’ T1DM. Glycaemic control improved with CIPII compared with SC treatment; the absolute mean difference in HbA1c was -0.76% in favor of CIPII. In addition, the mean time spent in euglycaemia, health related quality of life and treatment satisfaction all improved during CIPII treatment .
These findings are in line with previous reports on glycaemic control in people with T1DM treated with CIPII; in all of the three other randomized prospective studies comparing IP with SC (MDI and/or CSII) insulin in T1DM the glycaemic regulation improved and the frequency of hypoglycaemia decreased. However not all of these results reached statistical significance. Observational studies, performed mainly by the French ‘Evaluation dans le diabète des implants actifs’ (EVADIAC) group, showed a decrease in HbA1c and lower levels of hypoglycaemic events . Clinical and metabolic parameters such as weight, lipid spectrum, systolic and diastolic blood pressure and total insulin dose are unaffected by IP compared to SC insulin . IP administration of insulin increases the concentration of insulin-like growth factor 1 (IGF-1), possibly due to lowering the hepatic resistance to growth hormone by minimising portal insulinopenia .
Future prospects of CIPII
As mentioned above, currently only one implantable pump is available for clinical use. The availability will partly depend on continued commitment of the present single supplier to the production and further development of intraperitoneal pumps. Also, and very important, both regulatory and medical authorities need to acknowledge this treatment as a valid treatment modality for a selected group of individuals with T1DM. Furthermore, insurance companies will have to start reimbursing this expensive form of treatment for selected patient category. In the future, IP delivery could be linked to a kind of permanent sensor, and with a logarithm between this sensor and pump, one could create a closed loop in the future, without frequent self control, without multiple injections. Because of its physiological route and immediate effects opposed to the 15 minutes delay with sc insulin injection, IP insulin is in theory the ideal candidate for insulin infusion in the future.
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