It is time to deliver insulin via a safe, usable, and simple

DIABETES TECHNOLOGY & THERAPEUTICS Volume 12, Supplement 1, 2010 ª Mary Ann Liebert, Inc. DOI: 10.1089=dia.2010.0032 Insulin Pen Use for Type 2 Diabetes A Clinical Perspective Timothy S. Bailey, M.D., F.A.C.E. 1 and Steven V. Edelman, M.D. 2 Abstract While insulin delivery technology continues to progress, its adoption in the clinic lags behind, particularly in people with type 2 diabetes. In this article the authors present their clinical perspective regarding insulin pen therapy in this population. Introduction It is time to deliver insulin via a safe, usable, and simple device for all persons with diabetes. This article will present the case for this in type 2 diabetes mellitus (T2DM). Elsewhere in this supplement the use of insulin pumps with T2DM was discussed. 1 This review focuses on greater use of the insulin pen, an improved method of insulin delivery for patients that lies between insulin syringe and insulin pump technologies. Insulin therapy is currently believed to be an inevitable component in the therapy of T2DM in order to achieve adequate glycemic control over time. Data from the United Kingdom Prospective Diabetes Study 2 support this concept, and current treatment recommendations from the American Diabetes Association=European Association for the Study of Diabetes 3 have institutionalized the notion of earlier insulin use in T2DM. Treat-to-target studies, popularized by Riddle et al., 4 have provided evidence for the rapid effectiveness of long-acting insulins in lowering hemoglobin A1c in patients with T2DM. There is also a body of literature that, as endogenous insulin production diminishes over time in these patients, they will require premeal doses of fast-acting insulin to maintain adequate glucose control after consumption of nutrients. 5 While the kinetics of the insulin prescribed are important in explaining the results achieved, the ability to utilize this strategy outside the research setting relies significantly on the insulin delivery method. Insulin pens provide significant advantages, including ease of training by healthcare professionals and use by patients, that have made them commonplace where their use has been encouraged. They also have advantages in protecting the insulin from light and heat, both forces of nature that affect the potency of insulin over time. 6 Because most insulins have a shelf life of 1 month, patients using less than 33 units daily would waste some of the 1,000 units that are in each insulin vial. If patients followed the insulin product package insert, they would be throwing out the remaining insulin and starting a new vial. Insulin pens help to avoid this waste of resources because they contain only 300 units of insulin. There is a convincing literature that shows insulin pens to be simpler, easier to learn, more discreet, more convenient, more portable, and more accurate 7 and associated with higher quality of life scores than traditional insulin vials and syringes. 8 It is no wonder that they are preferred by patients 9,10 and providers 11,12 alike. In most parts of the developed world (see the article on pen demographics 13 in this supplement), pen therapy has replaced vials and syringes. The United States is unique in its high persistence of obsolete syringe technology. This artifact is due in large part to health plan disincentives to pen prescribing. While perceptions linger, most patients now have reasonable, but not universal, access to pen technology as most but not all health plans have removed or reduced prior cost barriers. A Brief History Insulin pens were first introduced in 1985 by Novo Nordisk (Bagsvaerd, Denmark) (NovoPen Ò ). The original pens were reusable and used a disposable insulin cartridge. In 1989 the first fully disposable prefilled insulin pen was developed (NovoLet Ò ) (also from Novo Nordisk). This eliminated the loading step and further reduced the complexity of insulin injection. The Innovo Ò pen, introduced in 1999 by Novo Nordisk, was the first to provide a memory of when insulin was last delivered. This addressed this important and not uncommon dilemma of patients not recalling whether they had taken their insulin injection or not. Although this model is no longer available, newer pens with a memory function are available (see Table 1 for a list of currently available pens and features). Insulin pen needles should not be taken for granted. They have maintained a technological lead over syringes in providing the thinnest and shortest needle available for insulin 1 AMCR Institute, Escondido, California. 2 Department of Medicine, University of California San Diego, San Diego, California. S-86

S-87 1 35 0.5) 2 70 1) 0.5) 1 80 1) 1 80 1) 1 80 1) 1 21 2 42 1 21 2 42 Original prefilled HumaPen Ergo II FlexPen NovoPen Jr. NovoPen 3 Echo NovoPen 4 Solostar OptiClik ClikStar Autopen Classic Autopen 24 HumaPen Luxura HumaPen Memoir 1) 2) 1) 2) 1 30 0.5) HumaPen Luxura HD Dose (U) KwikPen Model Capacity (U) H, Hypurin c A, G V, D, M70 H, M75, M50, N, 70=30, LPS H, M50, M75, LPS Insulinsb Table 1. Current Insulin Pens Auto-inject Auto-inject Memory Memory Note Color images available online at www.liebertonline.com=dia. a Lilly, Indianapolis, IN; Novo Nordisk, Bagsvaerd, Denmark; Sanofi-Aventis, Paris, France; Owen Mumford Ltd, Woodstock, Oxford, UK. b A, glulisine; D, detemir, G, glargine; H, lispro; LPS, lispro protamine suspension; N, NPH Humulin (Lilly); M50, Humalog (Lilly) Mix 50=50; M70, Novolog (Novo-Nordisk) Mix 70=30; M75, Humalog Mix 75=25; NA, not available; V, aspart; 70=30, 70=30 Humulin. c Availability of 3-mL pen cartridges varies by country. Owen Mumford Ltd Sanofi-Aventis Novo Nordisk Lilly Manufacturer a

S-88 BAILEY AND EDELMAN delivery. Pen needles have also maintained a relatively large lumen diameter to allow an easy and low-force injection. 14 Not surprisingly, their diminutive appearance contributes significantly to the favorable perception of insulin initiation in a person with T2DM. New data are becoming available regarding the needle length required to deliver insulin subcutaneously (vs. intradermal or intramuscular delivery, where kinetics may be different). A study of dermal thickness showed remarkable consistency across subject gender, age, ethnicity, and body mass index. 15 Although the study was performed to assess feasibility of intradermal vaccine administration, one could extrapolate that a needle with a length of 3 mm would reach the subcutaneous space in all patients at all sites. This has relevance for patients with T2DM, who have been traditionally thought to require longer needles for reliable insulin delivery. All manufacturers of insulin currently have pens as an important part of their portfolio. Other injected peptides for diabetes namely, exenatide, liraglutide, and pramlintide are currently only available via insulin pens. A product for osteoporosis (teriparatide) is available only in a pen based on the same technology used by the company for one of their insulins. Injectable diabetes products currently in development are likely to become available in a pen format only. Traditionally, insulin pens have been durable devices. That is to say that the patient would continue to use the primary device for many months or even years. The insulin cartridge would be replaced weekly to monthly. The pen needle has always been intended for single use. The current trend is towards fully disposable devices where no component is used for more than 1 month. The integration of drug with device eliminates the loading step, making use of the device easier. From a regulatory perspective insulin pens are classed as combination products, having both a device and drug component. Pen Benefits in T2DM Patient safety is the most basic rationale for insulin pen use to become the standard of insulin care for T2DM. Insulin, commonly regarded as a complicated and dangerous drug, is being administered to a rapidly growing number of patients. Unlike patients with type 1 diabetes, these patients are generally older and sicker and already receiving multiple medications for indications other than diabetes. Vision and dexterity may be limited. Insulin is typically added onto existing oral diabetes therapy and intimidates patients and providers alike. Patients are exposed to hyperglycemia for years prior to being placed on insulin. The clinical inertia that this reflects is in part due to patient and provider reluctance to initiate unnecessarily complex therapy. 16 Ease of use is important for all users of medical devices. However, for patients with T2DM, additional factors may add to usability. Poor visual acuity in some patients can be mitigated by enhanced legibility of the dose displayed. Magnification of a digital display provides far greater discrimination than that of reading a fluid level with analog graduations of a syringe. Audible and tactile clicks are an additional feature of pens that are useful to people with limited vision. Some pens have been deliberately designed to be larger (e.g., InnoLet Ò [Novo Nordisk, but this product is no longer available]) so that persons with less dexterity can operate them easily. Pens have eliminated the possibility of mixing, a complex process with potential risks of damaging rapid-acting insulins from contamination. 17 Older intermediate-acting insulins (e.g., NPH) that required resuspension have been reported to exhibit variable kinetic properties, depending on the thoroughness of the mixing of the delivered insulin. Insulin pens with suspensions have a small ball to help with resuspension; insulin vials do not have this feature. However, the need for resuspension has been obviated by today s soluble basal analogs, which are provided as solutions. With a goal of reducing confusion, newer insulin pens have distinctive appearances and tactile properties to reduce the chance of confusion between insulin types. Patients with T2DM require higher doses than needed with type 1 diabetes. In the treat-to-target trials doses between 40 and 50 units were typically utilized. Therefore, a pen useful for T2DM should deliver at least this volume. Most marketed pens can deliver up to 60 80 units at a time. However, many patients require higher dosing, and concentrated insulin (i.e., U-500 regular insulin) has been a useful tool for these patients. However, the need to use U-100 syringes to deliver this added an additional point of confusion (i.e., 20 units by syringe markings of U-500 was really 100 units delivered). With the use of insulin pens, more concentrated insulin preparations could be unambiguously dosed by the same digital displays as currently used with standard insulin preparations. The sheer volume of patients with T2DM overwhelms the relatively scarce pool of diabetes educators. Insulin pens free up time for other aspects of diabetes care that would otherwise be consumed by teaching how to correctly administer insulin by vial and syringe. Instead, the teaching of use of insulin pens can be competently delegated to medical assistants. Not only are these lower-skilled workers competent to teach insulin injection by insulin pens, but they gain increased job satisfaction as they have a greater ability to interact with patients. A recent study suggested that pens suitable for selfinjection may not be equally well suited for other injection. 18 Disabled people whose diabetes management requires a caretaker may therefore require special consideration in choosing an insulin pen. New Possibilities There is no reason why patients using a pen should not have most of the advantages of a smart insulin pump. Pens should have a memory to document the last dose and have an insulin on board feature to reduce the danger of hypoglycemia with stacking. Patients should be able to input their carbohydrate to insulin ratios and correction factors so that when a blood glucose value is inputted or picked up wirelessly from a paired home glucose monitor, a suggested dose shows up on the digital readout of the pen. This information could be inputted directly to the pen or via a computer that has a connection to the pen. These advances may inspire insulin companies to come up with newer shapes and designs that allow for this already developed technology that is availble in most of the currently marketed insulin pumps. Patient-driven algorithms have been validated for titrating basal insulin doses. 19 Incorporating these into the pen itself would help with patient motivation as well as documenting

INSULIN PEN USE FOR TYPE 2 DIABETES S-89 adherence with timely and appropriately adjusted insulin doses. Development of a pen that would display results from a continuous glucose monitor (CGM) that is also worn by the patients would be extremely helpful and would make CGM devices more useful. Newer insulin pens should incorporate an indicator of time elapsed since prior insulin injection and have a reminder to take injection alarm. This may reduce the frequency of missed and duplicate injections. The force required for injection should remain low. Many patients forget to remove the pen needle between injections. This can lead to increased cellular debris in the cartridge and an accumulation of air. 20 Excessive air in the insulin chamber can affect the time course of insulin delivery. 21 Because of the thinness of the needle, higher doses take a significantly longer time to deliver. Patients sometimes remove the pen needle from the injection site prematurely, leading to leakage from the pen needle and insulin underdelivery. Newer pens might offer assistance to patients by indicating when delivery has been completed. More highly concentrated insulin preparations will potentially mitigate these concerns. The use of concentrated insulin (e.g., U-500) can also be very helpful and practical for insulinresistant T2DM. 22 The currently available concentrated insulin (U-500) would be easier and safer to administer if it were available in pen form. Conclusions Insulin pens have improved since their introduction to the diabetes marketplace in 1985. Insulin pens offer just as many advantages to patients with insulin requiring T2DM as they do to those with type 1 diabetes and should be the standard of care for all insulin-using patients. Insulin pens improve several safety concerns relating to self-administration of insulin by end users. As a growing number of patients with T2DM use multiple daily injection regimens, including concentrated insulin such as U-200 and U-500, pens will become more important to deliver insulin safely and easily. They also help to protect the insulin from light and heat, both important factors in maintaining potency over time. Lastly, new pens should have smart features, similar to those that are standard features of currently available insulin pumps. These would assist in calculating insulin dose according to personalized insulin to carbohydrate ratios and correction factors or facilitate adherence with a treat-to-target insulin algorithm. Author Disclosure Statement T.S.B. has received consulting honoraria from Animas, BD, Medtronic, and Roche, speaking honoraria from Amylin, Dexcom, Lilly, and Novo Nordisk, and research support from Animas, Amylin, Bayer, BD, Biodel, Corcept, CPEX, Bristol Myers Squibb, Dexcom, GlaxoSmithKline, Incyte, Lifescan, Lilly, Medtronic, Merck, Novo Nordisk, Resmed, Roche, Sanofi Aventis, and Xoma. S.V.E. declares no competing financial interests. References 1. Bode BW: Insulin pump use in type 2 diabetes. Diabetes Technol Ther 2010;12(Suppl 1):S-00 S-00. 2. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837 853. 3. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B; American Diabetes Association; European Association for Study of Diabetes: Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32:193 203. 4. Riddle MC, Rosenstock J, Gerich J: The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26:3080 3086. 5. Edelman SV, Henry RR: Diagnosis and Management of Type 2 Diabetes, 9 th ed. Greenwich, CT: Professional Communications, Inc., 2007. 6. Grajower MM, Fraser CG, Holcombe JH, Daugherty ML, Harris WC, De Felippis MR, Santiago OM, Clark NG: How long should insulin be used once a vial is started? Diabetes Care 2003;26:2665 2669. 7. Asakura T, Seino H, Nakano R, Muto T, Toraishi K, Sako Y, Kageyama M, Yohkoh N: A comparison of the handling and accuracy of syringe and vial versus prefilled insulin pen (FlexPen). Diabetes Technol Ther 2009;11:657 661. 8. Rubin RR, Peyrot M: Quality of life, treatment satisfaction, and treatment preference associated with use of a pen device delivering a premixed 70=30 insulin aspart suspension (aspart protamine suspension=soluble aspart) versus alternative treatment strategies. Diabetes Care 2004;27:2495 2497. 9. Jefferson IG, Marteau TM, Smith MA, Baum JD: A multiple injection regimen using an insulin injection pen and prefilled cartridged soluble human insulin in adolescents with diabetes. Diabet Med 1985;2:493 495. 10. Korytkowski M, Bell D, Jacobsen C, Suwannasari R; FlexPen Study Team: A multicenter, randomized, open-label, comparative, two-period crossover trial of preference, efficacy, and safety profiles of a prefilled, disposable pen and conventional vial=syringe for insulin injection in patients with type 1 or 2 diabetes mellitus. Clin Ther 2003;25:2836 2848. 11. Davis EM, Bebee A, Crawford L, Destache C: Nurse satisfaction using insulin pens in hospitalized patients. Diabetes Educ 2009;35:799 809. 12. Asamoah E: Insulin pen the ipod for insulin delivery (why pen wins over syringe). J Diabetes Sci Technol 2008;2: 292 296. 13. Perfetti R: Reusable and disposable insulin pens for the treatment of diabetes: understanding the global differences in user preference and an evaluation of inpatient insulin pen use. Diabetes Technol Ther 2010;12(Suppl 1):S79 S85. 14. Siegmund T, Blankenfeld H, Schumm-Draeger PM: Comparison of usability and patient preference for insulin pen needles produced with different production techniques: thin-wall needles compared to regular-wall needles: an open-label study. Diabetes Technol Ther 2009;11:523 528. 15. Laurent A, Mistretta F, Bottigioli D, Dahel K, Goujon C, Nicolas JF, Hennino A, Laurent PE: Echographic measurement of skin thickness in adults by high frequency ultrasound to assess the appropriate microneedle length for intradermal delivery of vaccines. Vaccine 2007;25:6423 6430.

S-90 BAILEY AND EDELMAN 16. Nichols GA, Alexander CM, Girman CJ, Kamal-Bahl SJ, Brown JB: Treatment escalation and rise in HbA1c following successful initial metformin therapy. Diabetes Care 2006;29:504 509. 17. American Diabetes Association: Insulin administration. Diabetes Care 2004;27(Suppl 1):S106 S109. 18. Yakushiji F, Fujita H, Terayama Y, Yasuda M, Nagasawa K, Shimojo M, Taniguchi K, Fujiki K, Tomiyama J, Kinoshita H: The best insulin injection pen device for caregivers: results of injection trials using five insulin injection devices. Diabetes Technol Ther 2010;12:143 148. 19. Davies M, Storms F, Shutler S, Bianchi-Biscay M, Gomis R: Improvement of glycemic control in subjects with poorly controlled type 2 diabetes. Diabetes Care 2005;28:1282 1288. 20. Le Floch JP, Herbreteau C, Lange F, Perlemuter L: Evidence of non-inert material in needles and cartridges following a single insulin injection with a pen. Diabetes Metab 1997;23: 228 229. 21. Ginsberg BH, Parkes JL, Sparacino C: The kinetics of insulin administration by insulin pens. Horm Metab Res 1994;26: 584 587. 22. Cochran E, Gorden P: Use of U-500 insulin in the treatment of severe insulin resistance. Insulin 2008;3:211 218. Address correspondence to: Timothy S. Bailey, M.D., F.A.C.E. AMCR Institute 700 West El Norte Parkway, Suite 201 Escondido, CA 92026 E-mail: tbailey@amcrinstitute.com