Insulin Pen Use for Type 2 Diabetes—A Clinical Perspective
Timothy S. Bailey, M.D., F.A.C.E.1and Steven V. Edelman, M.D.2Abstract
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
I
t is time to deliverinsulin 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.1This 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 ade-quate glycemic control over time. Data from the United Kingdom Prospective Diabetes Study2support this concept, and current treatment recommendations from the American Diabetes Association=European Association for the Study of Diabetes3have institutionalized the notion of earlier insulin use in T2DM.
Treat-to-target studies, popularized by Riddle et al.,4have 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 ade-quate glucose control after consumption of nutrients.5While the kinetics of the insulin prescribed are important in ex-plaining 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 pro-tecting the insulin from light and heat, both forces of nature that affect the potency of insulin over time.6Because 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 sulin vial. If patients followed the insulin product package in-sert, 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 accurate7and associated with higher quality of life scores than traditional insulin vials and sy-ringes.8It is no wonder that they are preferred by patients9,10 and providers11,12alike.
In most parts of the developed world (see the article on pen demographics13 in this supplement), pen therapy has re-placed 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 pre-scribing. 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). The original pens were reusable and used a disposable insulin cartridge. In 1989 the first fully disposable prefilled insulin pen was developed (NovoLet) (also from Novo Nordisk). This eliminated the loading step and further reduced the complexity of insulin injection.
The Innovo 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 pro-viding the thinnest and shortest needle available for insulin 1AMCR Institute, Escondido, California.
2Department of Medicine, University of California San Diego, San Diego, California. DIABETES TECHNOLOGY & THERAPEUTICS
Volume 12, Supplement 1, 2010
ªMary Ann Liebert, Inc.
DOI: 10.1089=dia.2010.0032
Table 1. Current Insulin Pens Manufacturer a Model Dose (U) Capacity (U) Insulins b Note Lilly KwikPen 1–60 (by 1) 300 U H , M50, M75, LPS Prefilled HumaPen Luxura HD 1–30 (by 0.5) 3 m L = 300 U H c HumaPen Luxura 1–60 (by 1) 3 m L = 300 U H c HumaPen Memoir 1–60 (by 1) 3 m L = 300 U H c Memory Original prefilled 1–60 (by 1) 300 U H , M75, M50, N, 70 = 30, LPS HumaPen Ergo II 1–60 (by 1) 3 m L = 300 U H c Novo Nordisk FlexPen 1–60 (by 1) 300 U V , D , M70 Prefilled NovoPen Jr. 1–35 (by 0.5) 3 m L = 300 U V c NovoPen 3 2–70 (by 1) 3 m L = 300 U V c Echo (by 0.5) 3 m L = 300 U V c Memory NovoPen 4 1–60 (by 1) 3 m L = 300 U V c Sanofi-Aventis Solostar 1–80 (by 1) 300 U A , G Prefilled OptiClik 1–80 (by 1) 3 m L = 300 U A , G c ClikStar 1–80 (by 1) 3 m L = 300 U A , G c Owen Mumford Ltd Autopen Classic 1–21 (by 1) 3 m L = 300 U H , Hypurin c Auto-inject 2–42 (by 2) Autopen 24 1–21 (by 1) 3 m L = 300 U A , G c Auto-inject 2–42 (by 2) Color images avai lable online at w ww.lieb ertonline.c om = dia. a Lil ly, India napolis, IN; Novo Nor disk, Bags vaerd, Denm ark; San ofi-Aventis, Paris , Franc e; Owen Mum ford Ltd, Woods toc k, Oxfo rd, UK . bA, glul isine; D, dete mir, G, gl argine ; H , lispro; LPS, lisp ro protam ine suspension; N, NP H Hum ulin (Lilly ); M50, Hu malog (Lilly ) Mix 50 = 50; M7 0, Novolog (N ovo-Nord isk) Mix 70 = 30; M7 Humal og Mix 75 = 25; NA, not avai lable; V, aspart ; 70 = 30, 70 = 30 Hu mulin . cAvai lability of 3-mL pen cartri dges varies by country. S-87
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. intra-dermal 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.15Although 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 tradition-ally thought to require longer needles for reliable insulin de-livery.
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 develop-ment 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 to-wards 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 com-ponent.
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 gen-erally older and sicker and already receiving multiple medi-cations for indimedi-cations other than diabetes. Vision and dexterity may be limited. Insulin is typically added onto ex-isting 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 reluc-tance 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 miti-gated by enhanced legibility of the dose displayed. Magnifi-cation 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 fea-ture of pens that are useful to people with limited vision. Some pens have been deliberately designed to be larger (e.g., InnoLet[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 thor-oughness 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 an-alogs, which are provided as solutions. With a goal of re-ducing 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 other-wise 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 assis-tants. 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 self-injection may not be equally well suited for ‘‘other self-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 hypogly-cemia 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 wire-lessly 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 in-sulin 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.19Incorporating these into the pen itself would help with patient motivation as well as documenting
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.20Excessive air in the insulin chamber can affect the time course of insulin deliv-ery.21
Because of the thinness of the needle, higher doses take a significantly longer time to deliver. Patients sometimes re-move the pen needle from the injection site prematurely, leading to leakage from the pen needle and insulin under-delivery. Newer pens might offer assistance to patients by indicating when delivery has been completed.
More highly concentrated insulin preparations will poten-tially mitigate these concerns. The use of concentrated insulin (e.g., U-500) can also be very helpful and practical for insulin-resistant T2DM.22The currently available concentrated insu-lin (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 sev-eral 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 facil-itate 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, Sa-nofi Aventis, and Xoma. S.V.E. declares no competing finan-cial interests.
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Timothy S. Bailey, M.D., F.A.C.E. AMCR Institute 700 West El Norte Parkway, Suite 201 Escondido, CA 92026 E-mail:[email protected]
