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.

History

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 [1]. 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 [2].

Current use

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
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
Figure 2. Schematic representation of the position of the insulin pump and catheter in vivo

Pharmacokinetic properties

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 [3]. 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 [4]. 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 [5]. Other possible effects include improvement of the impaired glucagon secretion and hepatic glucose production in response to hypoglycaemia through alleviation of peripheral hyperinsulinaemia [6].

Clinical evidence

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 [7][8].
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 [9][10][11][12][13]. 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 [14]. 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 [15].

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.

References

  1. ^ Renard. Implantable insulin delivery pumps. Minim Invasive Ther Allied Technol. 2004 dec;13(5):328–35.

  2. ^ Gin H, Renard E, Melki V, Boivin S, Schaepelynck-Bélicar P, Guerci B, e.a. Combined improvements in implantable pump technology and insulin stability allow safe and effective long term intraperitoneal insulin delivery in type 1 diabetic patients: the EVADIAC experience. Diabetes Metab. 2003 dec;29(6):602–7.

  3. ^ Schade DS, Eaton RP, Davis T, Akiya F, Phinney E, Kubica R, e.a. The kinetics of peritoneal insulin absorption. Metab. Clin. Exp. 1981 feb;30(2):149–55.

  4. ^ Nathan DM, Dunn FL, Bruch J, McKitrick C, Larkin M, Haggan C, e.a. Postprandial insulin profiles with implantable pump therapy may explain decreased frequency of severe hypoglycemia, compared with intensive subcutaneous regimens, in insulin-dependent diabetes mellitus patients. Am. J. Med. 1996 apr;100(4):412–7.

  5. ^ Selam JL, Bergman RN, Raccah D, Jean-Didier N, Lozano J, Charles MA. Determination of portal insulin absorption from peritoneum via novel nonisotopic method. Diabetes. 1990 nov;39(11):1361–5.

  6. ^ Wan CK, Giacca A, Matsuhisa M, El-Bahrani B, Lam L, Rodgers C, e.a. Increased responses of glucagon and glucose production to hypoglycemia with intraperitoneal versus subcutaneous insulin treatment. Metab. Clin. Exp. 2000 aug;49(8):984–9.

  7. ^ Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, van Ballegooie E, e.a. Improved glycemic control with intraperitoneal versus subcutaneous insulin in type 1 diabetes: a randomized controlled trial. Diabetes Care. 2009 aug;32(8):1372–7.

  8. ^ Logtenberg SJ, Kleefstra N, Houweling ST, Groenier KH, Gans RO, Bilo HJ. Health-related quality of life, treatment satisfaction, and costs associated with intraperitoneal versus subcutaneous insulin administration in type 1 diabetes: a randomized controlled trial. Diabetes Care. 2010 jun;33(6):1169–72.

  9. ^ Schaepelynck P, Renard E, Jeandidier N, Hanaire H, Fermon C, Rudoni S, e.a. A recent survey confirms the efficacy and the safety of implanted insulin pumps during long-term use in poorly controlled type 1 diabetes patients. Diabetes Technol. Ther. 2011 jun;13(6):657–60.

  10. ^ Hanaire-Broutin H, Broussolle C, Jeandidier N, Renard E, Guerci B, Haardt MJ, e.a. Feasibility of intraperitoneal insulin therapy with programmable implantable pumps in IDDM. A multicenter study. The EVADIAC Study Group. Evaluation dans le Diabète du Traitement par Implants Actifs. Diabetes Care. 1995 mrt;18(3):388–92.

  11. ^ Broussolle C, Jeandidier N, Hanaire-Broutin H. French multicentre experience of implantable insulin pumps. The EVADIAC Study Group. Evaluation of Active Implants in Diabetes Society. Lancet. 1994 feb 26;343(8896):514–5.

  12. ^ Selam JL, Micossi P, Dunn FL, Nathan DM. Clinical trial of programmable implantable insulin pump for type I diabetes. Diabetes Care. 1992 jul;15(7):877–85.

  13. ^ DeVries JH, Eskes SA, Snoek FJ, Pouwer F, Van Ballegooie E, Spijker AJ, e.a. Continuous intraperitoneal insulin infusion in patients with “brittle” diabetes: favourable effects on glycaemic control and hospital stay. Diabet. Med. 2002 jun;19(6):496–501.

  14. ^ Selam JL, Raccah D, Jean-Didier N, Lozano JL, Waxman K, Charles MA. Randomized comparison of metabolic control achieved by intraperitoneal insulin infusion with implantable pumps versus intensive subcutaneous insulin therapy in type I diabetic patients. Diabetes Care. 1992 jan;15(1):53–8.

  15. ^ Hedman CA, Frystyk J, Lindström T, Chen J-W, Flyvbjerg A, Ørskov H, e.a. Residual beta-cell function more than glycemic control determines abnormalities of the insulin-like growth factor system in type 1 diabetes. J. Clin. Endocrinol. Metab. 2004 dec;89(12):6305–9.

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