Insulin Pump Treatment In Type 2 Diabetes Mellitus – Literature Review Gina Botnariu1, Alina Popa2, Cristina Lacatusu1, Bogdan Mihai1 1.University of… [627732]

Insulin Pump Treatment In Type 2 Diabetes Mellitus – Literature Review Gina Botnariu1, Alina Popa2, Cristina Lacatusu1, Bogdan Mihai1 1.University of Medicine and Pharmacy “Gr. T. Popa” Iasi – Department of Diabetes, Nutrition and Metabolic Disease 2.University of Medicine and Pharmacy “Gr. T. Popa” Iasi – Department of Nursing Correspondent authors: Gina Botnariu: E-mail: [anonimizat] Alina Popa: E-mail: [anonimizat] Abstract: Progressive hyperglycemia in type 2 diabetes induced by progressive b-cell failure together with a state of insulin resistance may result in needing for exogenous insulin therapy,associated eventually to oral therapy. Continuous subcutaneous insulin infusion (CSII) by insulin pump may be much more advantageous compared with the conventional approach of insulin intensification by multiple daily injections (MDI). Many studies suggested that CSII in type 2 diabetes may be much more appropriated in obtaining a good metabolic control, together with maintaining body weight, avoiding severe hypoglycemia, increasing quality of life and level of satisfaction. !Keywords: insulin pump, type 2 diabetes, insulin treatment !Introduction: Insulin constitutes the mainstay for managing type 2 diabetes mellitus, when oral agents are not enough to maintain glycaemic control. Progressive hyperglycemia in type 2 diabetes results from a progressive b-cell failure together with a state of insulin resistance the result being the need for exogenous insulin therapy, associated eventually to oral therapy (1, 2). The use of external pumps in patients with type 2 diabetes is a recent practice, the rationale being first suggested by its use in case reports of type 2 diabetes with extreme insulin resistance and poor glycemic control (3). These beneficial effects of insulin pump using were attributed to increased insulin sensitivity assessed by the hyperinsulinemic- euglycemic clamp studies (4). All these obsevations generated the idea that continuous subcutaneous insulin infusion (CSII) insulin pump using may be much more advantageous compared with the conventional approach of insulin intensification by multiple daily injections (MDI) (3). Diabetes Control and Complications Trial indicated that intensive insulin therapy or continuous subcutaneous insulin infusion (CSII) via insulin pumps could achieve near-normoglycemia as well as delay the progression of longterm complications (5). The current American Diabetes Association (ADA) 2017/European Society for the Study of Diabetes consensus treatment algorithm for T2DM includes basal insulin therapy at Step 2 (Tier 1) and intensive insulin at Step 3 (Tiers 1 and 2). Given the increasing amounts of insulin required by people with T2DM and the failure of any single insulin regimen to obtain glycemic control over the long term, continuous subcutaneous insulin infusion (CSII) or insulin pump therapy has been explored as an alternative to conventional or intensive insulin therapy (6). !CSII as a Method Of Intensification Of Insulin Therapy In Type 2 Diabetes In the past few decades, CSII has become an attractive alternative to MDI. There are limited qualitative studies exploring adults’ experiences. Some of them encountered positive experiences with CSII as a tool that improves glycemic control and enhances quality of life. Two randomized crossover studies with small numbers of subjects have shown an advantage of CSII in comparison with MDI. In these studies, obese type 2 diabetic patients were successively treated by CSII and MDI for periods of 12 and 18 weeks, respectively (7, 8, 9). Intensification was offered in patients

failing to respond to two or more insulin injections per day (NPH or premixed NPH plus rapid-acting analog). These subjects exhibited a baseline HbA1c = 9% despite high insulin requirements (aprox.1 units/kg/day). For insulin intensification, a rapid-acting analog was used in CSII in both studies, and NPH plus a rapid-acting analog (7) or regular human insulin (8) was used in MDI basal bolus regimens. In these two studies, CSII was more effective than MDI for lowering HbA1c (21.2 vs. – 0.45%, P = 0.03, and 20.8 vs. 0.4%, P = 0.01, respectively). Singh et all (cited by 10) indicated that insulin pumps may act as a valuable new treatment option for type 2 diabetics, especially in patients failing on current injection regimen. In a randomized, controlled trial, with a duration of 6 months, Medtronic’s OPT2MISE of 331 patients who had not responded to multiple daily basal-bolus injection regimens, showed a 0.7-percentage-point. In another retrospective single-center chart review of 13 adults (10 men, three women) with a mean age 55 years (range, 43–71) and mean body mass index 34.5 kg/m2 not well controlled (HbA1c >7%) on insulin alone (n=11) or insulin plus metformin (n=2), there was seen an improvement in HbA1c with pump use. Study subjects who also had daily dose more than 200 units, more than four injections per day, wide glycemic excursions, and/or intractable hypoglycemia became well controlled with Medtronic pump, due to “bolus wizard” calculation and carbohydrates count. In 5 years, the average HbA1c for the group had dropped to 7.7% from an average 8.9% at baseline, a large statistically significant difference (P = 0.0076) (10, 11, 12). CSII and Body Weight Most prospective and observational studies evaluating CSII in type 2 diabetic patients were short-term studies, with aprox. 6 months’ or 1 year’s duration In the studies with aprox. 6 months’ duration a 1.7–1.9 kg weight gain was observed (8, 9). In 1-year duration studies, a weight gain of ; 2 kg (P < 0.01) was observed in one (9). In the four randomized studies comparing CSII with MDI, no significant difference in weight change was observed between the two treatments (8–12). Insulin Pump And Hypoglycaemia In Type 2 Diabetics Hypoglycemia is a major outcome. Most studies have found a very low incidence of severe hypoglycemia in type 1 and type 2 diabetic patients using CSII (13, 14). A metaanalysis showed an advantage of CSII versus MDI with an odds ratio of 0.48 for severe hypoglycemia (14). Insulin Pump Treatment During Pregnancy In Type 2 Diabetic Women International Diabetes Federation’s Global Diabetes in Pregnancy Guideline recommend insulin as optimal therapy, ideally initiated prior to pregnancy, because lack of comprehensive and intensive metabolic control of pregestational type 2 diabetic patients before and during gestation may induce serious adverse fetal outcome (15, 16). Intensification in the management of pregnancy in type 2 diabetes women would greatly improve pregnancy outcome. In such circumstances, CSII use may be one of the components in assisting patients with type 2 diabetes, ensuring a better glucose control than with MDI, allowance of temporary basal rates and flexible boluses, decrease in hypoglycemia rate and improvement in quality of life (17). Simple Insulin Dosing Regimen with CSII in Type 2 Diabetics There are some studies which provide the simplifying in insulin regimen in people with T2DM who still have some residual beta-cell. Parkner et al. (18) reported a study in which 21 subjects were randomized to receive equivalent doses of insulin via CSII or a once-daily injection of insulin

glargine followed by a crossover to the other therapy. The dose level for each treatment period was dictated by the subject’s baseline insulin glargine use. CSII use was associated with lower variability in exogenous fasting insulin levels and a lower area under the curve. Therefore, recent studies have investigated whether CSII for T2DM has long-term benefits and can improve glycemic control using a simple dosing regimen (19, 20). In a longitudinal pilot study with a duration of 4 months, mean HbA1c reduced in all three cohorts after 4 months of CSII from 8.4% to 7.2%; the mean daily basal, bolus, and total insulin doses at the end of the study significantly decreased (0.94U/kg). All three cohorts preferred their new therapy with the pump (21). Morera et al, demonstrated the sustained efficacy of insulin pump therapy in a cohort of 161 type 2 diabetic patients with MDI failure, after 9 years follow-up. Over 9 years of follow-up, HbA1c decrease was maintained (P < 0.05), daily insulin requirements did not change, and weight gain was stable over 7 years (22). Level of Satisfaction And Quality Of Life In Type 2 Diabetic Patients Insulin Pump Treated Raskin and Herman evaluated, in two randomized parallel-group studies, the treatment satisfaction, diabetes impact, and diabetes satisfaction scores improved over time with both CSII and MDI treatments (23, 24). The satisfaction score did not differ between MDI and pump in the older population. Conclusion: Despite limited data from randomized control studies, longitudinal data suggest that CSII may be preferred to MDI in type 2 diabetic patients with severe insulin resistance and poor glycemic control. The selection of candidates for pump therapy should be done considering patient’s ability to cope with the pump device, the absence of major cognitive or operative disability, adherence to self-monitoring glycaemia and personal willingness to use an insulin pump. Reference 1.Gerich JE. The genetic basis of type 2 diabetes mellitus: impaired insulin secretion versus impaired insulin sensitivity. Endocr Rev 1998;19:491–503 2.Gale, E.A.M.. The United Kingdom Prospective Diabetes Study [UKPDS] [internet]. 2014 Oct 20; Diapedia 1104085197 rev. no. 20. https://doi.org/10.14496/dia.1104085197.20 3.Gormley MJ, Hadden DR, Woods R, Sheridan B, Andrews WJ. One month’s insulin treatment of type II diabetes: the early and medium-term effects following insulin withdrawal. Metabolism 1986;35: 1029–1036 4.Pouwels MJ, Tack CJ, Hermus AR, Lutterman JA. Treatment with intravenous insulin followed by continuous subcutaneous insulin infusion improves glycaemic control in severely resistant Type 2 diabetic patients. Diabet Med 2003; 20:76–79. Diabetes Care. 1987 Jan-Feb;10(1):1-19. 5.The DCCT Research Group. Control and Complications Trial (DCCT): results of feasibility study. Diabetes Care. 1987 Jan-Feb;10(1):1-19. 6.Pharmacologic Approaches to Glycemic Treatment.American Diabetes Association. Standards of Medical Care in Diabetes 2017. Diabetes Care 2017, V ol 40, Suppl.1, 73 7.Berthe E, Lireux B, Coffin C, et al. Effectiveness of intensive insulin therapy by multiple daily injections and continuous subcutaneous infusion: a comparison study in type 2 diabetes with conventional insulin regimen failure. Horm Metab Res 2007;39:224–229

8.Wainstein J, Metzger M, Boaz M, et al. Insulin pump therapy vs. multiple daily injections in obese Type 2 diabetic patients. Diabet Med 2005;22:1037–1046 9.Charras L, Sanz C, Labrousse-Lhermine F, Cazals L, Hanaire H. Traitement par pompe à insuline dans le diabète de type 2 (DT2): 12 ans de suivi d’une cohorte de 50 patients (Abstract). Diabetes Metab 2012;38: 10.Tucker M.E. Insulin Pumps Help Some Type 2 Diabetes Patients for 5 yeahttp://www.medscape.com/viewarticle/851641_print 11.Herman WH, Ilag LL, Johnson SL, et al. A clinical trial of continuous subcutaneous insulin infusion versus multiple daily injections in older adults with type 2 diabetes. Diabetes Care 2005;28:1568– 1573 12.Johnson SL, McEwen LN, Newton CA, et al. The impact of continuous subcutaneous insulin infusion and multiple daily injections of insulin on glucose variability in older adults with type 2 diabetes. J Diabetes Complications 2011;25: 211–215 13.Jeitler K, Horvath K, Berghold A, et al. Continuous subcutaneous insulin infusion versus multiple daily insulin injections in patients with diabetes mellitus: systematic review and meta-analysis. Diabetologia 2008;51:941–951 14.Fatourechi MM, Kudva YC, Murad MH, Elamin MB, Tabini CC, Montori VM. Clinical review: Hypoglycemia with intensive insulin therapy: a systematic review and meta-analyses of randomized trials of continuous subcutaneous insulin infusion versus multiple daily injections. J Clin Endocrinol Metab 2009;94:729–740 15.Meltzer SJ. Prepregnancy care: a shared responsibility. Diabetes Care 2010;33: 2713–2715 16.National Institute for Health and Clinical Excellence. Diabetes in pregnancy; management of diabetes and its complications from pre-conception to the post-natal period, clinical guideline 63. 2008. www.nice.org. uk/nicemedia/pdf/CG063Guidance.pdf. 17.Owens LA, Avalos G, Kirwan B, Carmody L, Dunne F. ATLANTIC DIP: closing the loop: a change in clinical practice can improve outcomes for women with pre- gestational diabetes. Diabetes Care 2012; 35:1669–1671 18.Parkner T, Laursen T, Vestergaard ET, Hartvig H, Smedegaard JS, Lauritzen T, Christiansen JS: Insulin and glucose profiles during continuous subcutaneous insulin infusion compared with injection of a long-acting insulin in type 2 diabetes. Diabet Med 2008;25:585–591. Insulin Pump for Type 2 Diabetes 19.Reznik Y , Cohen O. and misuse of continuous subcutaneous insulin infusion in type 2 diabetes. Diabetes Care, V olume 36, Supplement 2, August 2013 S219-225 20.Bruce W. Bode. Insulin Pump Use in Type 2 Diabetes. DIABETES TECHNOLOGY & THERAPEUTICS, V olume 12, Supplement 1, 2010, S-17-S21 21.Edelman SV , Bode BW, Bailey TS, Kipnes MS, Frias JP: Continuous subcutaneous insulin infusion in patients with type 2 diabetes safely improved glycemic control using a simple insulin dosing regimen [abstract]. Diabetes 2009; 58 (Suppl 1):A113. 22.Morera J, Joubert M, Morello R, Rod A, Lireux B, Reznik Y .Sustained Efficacy of Insulin Pump Therapy in Type 2 Diabetes: 9-Year Follow-up in a Cohort of 161 Patients | Diabetes Care, 1-2. 23.Raskin P, Bode BW, Marks JB, et al. Continuous subcutaneous insulin infusion and multiple daily injection therapy are equally effective in type 2 diabetes: a randomized, parallel-group, 24-week study. Diabetes Care 2003;26:2598–2603 24.Herman WH, Ilag LL, Johnson SL, et al. A clinical trial of continuous subcutaneous insulin infusion versus multiple daily injections in older adults with type 2 di- abetes. Diabetes Care 2005;28:1568– 1573