Insulin Pen Use for Type 2 Diabetes—A Clinical Perspective

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<ul><li><p>Insulin Pen Use for Type 2 DiabetesA Clinical Perspective</p><p>Timothy S. Bailey, M.D., F.A.C.E.1 and Steven V. Edelman, M.D.2</p><p>Abstract</p><p>While insulin delivery technology continues to progress, its adoption in the clinic lags behind, particularly inpeople with type 2 diabetes. In this article the authors present their clinical perspective regarding insulin pentherapy in this population.</p><p>Introduction</p><p>It is time to deliver insulin via a safe, usable, and simpledevice for all persons with diabetes. This article will presentthe case for this in type 2 diabetes mellitus (T2DM). Elsewherein this supplement the use of insulin pumps with T2DM wasdiscussed.1 This review focuses on greater use of the insulinpen, an improved method of insulin delivery for patients thatlies between insulin syringe and insulin pump technologies.</p><p>Insulin therapy is currently believed to be an inevitablecomponent in the therapy of T2DM in order to achieve ade-quate glycemic control over time. Data from the UnitedKingdom Prospective Diabetes Study2 support this concept,and current treatment recommendations from the AmericanDiabetes Association=European Association for the Study ofDiabetes3 have institutionalized the notion of earlier insulinuse in T2DM.</p><p>Treat-to-target studies, popularized by Riddle et al.,4 haveprovided evidence for the rapid effectiveness of long-actinginsulins in lowering hemoglobin A1c in patients with T2DM.There is also a body of literature that, as endogenous insulinproduction diminishes over time in these patients, they willrequire premeal doses of fast-acting insulin to maintain ade-quate glucose control after consumption of nutrients.5 Whilethe kinetics of the insulin prescribed are important in ex-plaining the results achieved, the ability to utilize this strategyoutside the research setting relies significantly on the insulindelivery method. Insulin pens provide significant advantages,including ease of training by healthcare professionals and useby patients, that have made them commonplace where theiruse has been encouraged. They also have advantages in pro-tecting the insulin from light and heat, both forces of nature thataffect the potency of insulin over time.6 Because most insulinshave a shelf life of 1 month, patients using less than 33 unitsdaily would waste some of the 1,000 units that are in each in-sulin vial. If patients followed the insulin product package in-sert, they would be throwing out the remaining insulin and</p><p>starting a new vial. Insulin pens help to avoid this waste ofresources because they contain only 300 units of insulin.</p><p>There is a convincing literature that shows insulin pens tobe simpler, easier to learn, more discreet, more convenient,more portable, and more accurate7 and associated with higherquality of life scores than traditional insulin vials and sy-ringes.8 It is no wonder that they are preferred by patients9,10</p><p>and providers11,12 alike.In most parts of the developed world (see the article on pen</p><p>demographics13 in this supplement), pen therapy has re-placed vials and syringes. The United States is unique in itshigh persistence of obsolete syringe technology. This artifactis due in large part to health plan disincentives to pen pre-scribing. While perceptions linger, most patients now havereasonable, but not universal, access to pen technology asmost but not all health plans have removed or reduced priorcost barriers.</p><p>A Brief History</p><p>Insulin pens were first introduced in 1985 by Novo Nordisk(Bagsvaerd, Denmark) (NovoPen). The original pens werereusable and used a disposable insulin cartridge. In 1989 thefirst fully disposable prefilled insulin pen was developed(NovoLet) (also from Novo Nordisk). This eliminated theloading step and further reduced the complexity of insulininjection.</p><p>The Innovo pen, introduced in 1999 by Novo Nordisk,was the first to provide a memory of when insulin was lastdelivered. This addressed this important and not uncommondilemma of patients not recalling whether they had takentheir insulin injection or not. Although this model is no longeravailable, newer pens with a memory function are available(see Table 1 for a list of currently available pens and features).</p><p>Insulin pen needles should not be taken for granted. Theyhave maintained a technological lead over syringes in pro-viding the thinnest and shortest needle available for insulin</p><p>1AMCR Institute, Escondido, California.2Department of Medicine, University of California San Diego, San Diego, California.</p><p>DIABETES TECHNOLOGY &amp; THERAPEUTICSVolume 12, Supplement 1, 2010 Mary Ann Liebert, Inc.DOI: 10.1089=dia.2010.0032</p><p>S-86</p></li><li><p>Ta</p><p>bl</p><p>e1.</p><p>Cu</p><p>rr</p><p>en</p><p>tIn</p><p>sul</p><p>inP</p><p>en</p><p>s</p><p>Man</p><p>ufa</p><p>ctu</p><p>rera</p><p>Mod</p><p>elD</p><p>ose</p><p>(U)</p><p>Cap</p><p>acit</p><p>y(U</p><p>)In</p><p>suli</p><p>nsb</p><p>Not</p><p>e</p><p>Lil</p><p>lyK</p><p>wik</p><p>Pen</p><p>1</p><p>60(b</p><p>y1)</p><p>300</p><p>UH</p><p>,M</p><p>50,</p><p>M75</p><p>,L</p><p>PS</p><p>Pre</p><p>fill</p><p>ed</p><p>Hu</p><p>maP</p><p>en</p><p>Lu</p><p>xu</p><p>ra</p><p>HD</p><p>130</p><p>(by</p><p>0.5)</p><p>3m</p><p>L=30</p><p>0U</p><p>Hc</p><p>Hu</p><p>maP</p><p>en</p><p>Lu</p><p>xu</p><p>ra</p><p>160</p><p>(by</p><p>1)3</p><p>mL=30</p><p>0U</p><p>Hc</p><p>Hu</p><p>maP</p><p>en</p><p>Mem</p><p>oir</p><p>160</p><p>(by</p><p>1)3</p><p>mL=30</p><p>0U</p><p>Hc</p><p>Mem</p><p>ory</p><p>Ori</p><p>gin</p><p>alp</p><p>refi</p><p>lled</p><p>160</p><p>(by</p><p>1)30</p><p>0U</p><p>H,</p><p>M75</p><p>,M</p><p>50,</p><p>N,</p><p>70=30</p><p>,L</p><p>PS</p><p>Hu</p><p>maP</p><p>en</p><p>Erg</p><p>o</p><p>II1</p><p>60(b</p><p>y1)</p><p>3m</p><p>L=30</p><p>0U</p><p>Hc</p><p>No</p><p>vo</p><p>No</p><p>rdis</p><p>kF</p><p>lex</p><p>Pen</p><p>1</p><p>60(b</p><p>y1)</p><p>300</p><p>UV</p><p>,D</p><p>,M</p><p>70P</p><p>refi</p><p>lled</p><p>No</p><p>vo</p><p>Pen</p><p>Jr</p><p>.1</p><p>35(b</p><p>y0.</p><p>5)3</p><p>mL=30</p><p>0U</p><p>Vc</p><p>No</p><p>vo</p><p>Pen</p><p>3</p><p>270</p><p>(by</p><p>1)3</p><p>mL=30</p><p>0U</p><p>Vc</p><p>Ech</p><p>o</p><p>(by</p><p>0.5)</p><p>3m</p><p>L=30</p><p>0U</p><p>Vc</p><p>Mem</p><p>ory</p><p>No</p><p>vo</p><p>Pen</p><p>4</p><p>160</p><p>(by</p><p>1)3</p><p>mL=30</p><p>0U</p><p>Vc</p><p>San</p><p>ofi</p><p>-Av</p><p>enti</p><p>sS</p><p>olo</p><p>star</p><p>1</p><p>80(b</p><p>y1)</p><p>300</p><p>UA</p><p>,G</p><p>Pre</p><p>fill</p><p>ed</p><p>Op</p><p>tiC</p><p>lik</p><p>180</p><p>(by</p><p>1)3</p><p>mL=30</p><p>0U</p><p>A,</p><p>Gc</p><p>Cli</p><p>kS</p><p>tar</p><p>180</p><p>(by</p><p>1)3</p><p>mL=30</p><p>0U</p><p>A,</p><p>Gc</p><p>Ow</p><p>enM</p><p>um</p><p>ford</p><p>Ltd</p><p>Au</p><p>top</p><p>en</p><p>Cla</p><p>ssic</p><p>121</p><p>(by</p><p>1)3</p><p>mL=30</p><p>0U</p><p>H,</p><p>Hy</p><p>pu</p><p>rin</p><p>cA</p><p>uto</p><p>-in</p><p>ject</p><p>242</p><p>(by</p><p>2)A</p><p>uto</p><p>pen</p><p>24</p><p>121</p><p>(by</p><p>1)3</p><p>mL=30</p><p>0U</p><p>A,</p><p>Gc</p><p>Au</p><p>to-i</p><p>nje</p><p>ct2</p><p>42(b</p><p>y2)</p><p>Co</p><p>lor</p><p>imag</p><p>esav</p><p>aila</p><p>ble</p><p>on</p><p>lin</p><p>eat</p><p>ww</p><p>w.l</p><p>ieb</p><p>erto</p><p>nli</p><p>ne.</p><p>com=d</p><p>ia.</p><p>aL</p><p>illy</p><p>,In</p><p>dia</p><p>nap</p><p>oli</p><p>s,IN</p><p>;N</p><p>ov</p><p>oN</p><p>ord</p><p>isk</p><p>,B</p><p>agsv</p><p>aerd</p><p>,D</p><p>enm</p><p>ark</p><p>;S</p><p>ano</p><p>fi-A</p><p>ven</p><p>tis,</p><p>Par</p><p>is,</p><p>Fra</p><p>nce</p><p>;O</p><p>wen</p><p>Mu</p><p>mfo</p><p>rdL</p><p>td,</p><p>Wo</p><p>od</p><p>sto</p><p>ck,</p><p>Ox</p><p>ford</p><p>,U</p><p>K.</p><p>bA</p><p>,g</p><p>luli</p><p>sin</p><p>e;D</p><p>,d</p><p>etem</p><p>ir,</p><p>G,</p><p>gla</p><p>rgin</p><p>e;H</p><p>,li</p><p>spro</p><p>;L</p><p>PS</p><p>,li</p><p>spro</p><p>pro</p><p>tam</p><p>ine</p><p>susp</p><p>ensi</p><p>on</p><p>;N</p><p>,N</p><p>PH</p><p>Hu</p><p>mu</p><p>lin</p><p>(Lil</p><p>ly);</p><p>M50</p><p>,H</p><p>um</p><p>alo</p><p>g</p><p>(Lil</p><p>ly)</p><p>Mix</p><p>50=50</p><p>;M</p><p>70,</p><p>No</p><p>vo</p><p>log</p><p>(No</p><p>vo</p><p>-No</p><p>rdis</p><p>k)</p><p>Mix</p><p>70=30</p><p>;M</p><p>75,</p><p>Hu</p><p>mal</p><p>og</p><p>Mix</p><p>75=25</p><p>;N</p><p>A,</p><p>no</p><p>tav</p><p>aila</p><p>ble</p><p>;V</p><p>,as</p><p>par</p><p>t;70=30</p><p>,70</p><p>=30</p><p>Hu</p><p>mu</p><p>lin</p><p>.c A</p><p>vai</p><p>lab</p><p>ilit</p><p>yo</p><p>f3-</p><p>mL</p><p>pen</p><p>cart</p><p>rid</p><p>ges</p><p>var</p><p>ies</p><p>by</p><p>cou</p><p>ntr</p><p>y.</p><p>S-87</p></li><li><p>delivery. Pen needles have also maintained a relatively largelumen diameter to allow an easy and low-force injection.14</p><p>Not surprisingly, their diminutive appearance contributessignificantly to the favorable perception of insulin initiation ina person with T2DM.</p><p>New data are becoming available regarding the needlelength required to deliver insulin subcutaneously (vs. intra-dermal or intramuscular delivery, where kinetics may bedifferent). A study of dermal thickness showed remarkableconsistency across subject gender, age, ethnicity, and bodymass index.15 Although the study was performed to assessfeasibility of intradermal vaccine administration, one couldextrapolate that a needle with a length of 3 mm would reachthe subcutaneous space in all patients at all sites. This hasrelevance for patients with T2DM, who have been tradition-ally thought to require longer needles for reliable insulin de-livery.</p><p>All manufacturers of insulin currently have pens as animportant part of their portfolio. Other injected peptides fordiabetesnamely, exenatide, liraglutide, and pramlintideare currently only available via insulin pens. A product forosteoporosis (teriparatide) is available only in a pen based onthe same technology used by the company for one of theirinsulins. Injectable diabetes products currently in develop-ment are likely to become available in a pen format only.</p><p>Traditionally, insulin pens have been durable devices. Thatis to say that the patient would continue to use the primarydevice for many months or even years. The insulin cartridgewould be replaced weekly to monthly. The pen needle hasalways been intended for single use. The current trend is to-wards fully disposable devices where no component is usedfor more than 1 month. The integration of drug with deviceeliminates the loading step, making use of the device easier.From a regulatory perspective insulin pens are classed ascombination products, having both a device and drug com-ponent.</p><p>Pen Benefits in T2DM</p><p>Patient safety is the most basic rationale for insulin pen useto become the standard of insulin care for T2DM. Insulin,commonly regarded as a complicated and dangerous drug, isbeing 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 indications other than diabetes. Vision anddexterity may be limited. Insulin is typically added onto ex-isting oral diabetes therapy and intimidates patients andproviders alike. Patients are exposed to hyperglycemia foryears prior to being placed on insulin. The clinical inertiathat this reflects is in part due to patient and provider reluc-tance to initiate unnecessarily complex therapy.16</p><p>Ease of use is important for all users of medical devices.However, for patients with T2DM, additional factors may addto 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 discriminationthan that of reading a fluid level with analog graduations ofa 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</p><p>available]) so that persons with less dexterity can operatethem easily.</p><p>Pens have eliminated the possibility of mixing, a complexprocess with potential risks of damaging rapid-acting insulinsfrom contamination.17 Older intermediate-acting insulins(e.g., NPH) that required resuspension have been reported toexhibit variable kinetic properties, depending on the thor-oughness of the mixing of the delivered insulin. Insulin penswith suspensions have a small ball to help with resuspension;insulin vials do not have this feature. However, the need forresuspension has been obviated by todays soluble basal an-alogs, which are provided as solutions. With a goal of re-ducing confusion, newer insulin pens have distinctiveappearances and tactile properties to reduce the chance ofconfusion between insulin types.</p><p>Patients with T2DM require higher doses than needed withtype 1 diabetes. In the treat-to-target trials doses between 40and 50 units were typically utilized. Therefore, a pen usefulfor T2DM should deliver at least this volume. Most marketedpens can deliver up to 6080 units at a time. However, manypatients 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 addedan additional point of confusion (i.e., 20 units by syringemarkings of U-500 was really 100 units delivered). With theuse of insulin pens, more concentrated insulin preparationscould be unambiguously dosed by the same digital displaysas currently used with standard insulin preparations.</p><p>The sheer volume of patients with T2DM overwhelms therelatively scarce pool of diabetes educators. Insulin pens freeup time for other aspects of diabetes care that would other-wise be consumed by teaching how to correctly administerinsulin by vial and syringe. Instead, the teaching of use ofinsulin pens can be competently delegated to medical assis-tants. Not only are these lower-skilled workers competent toteach insulin injection by insulin pens, but they gain increasedjob satisfaction as they have a greater ability to interact withpatients. A recent study suggested that pens suitable for self-injection may not be equally well suited for other injection.18</p><p>Disabled people whose diabetes management requires acaretaker may therefore require special consideration inchoosing an insulin pen.</p><p>New Possibilities</p><p>There is no reason why patients using a pen should nothave most of the advantages of a smart insulin pump. Pensshould have a memory to document the last dose and have aninsulin on board feature to reduce the danger of hypogly-cemia with stacking. Patients should be able to input theircarbohydrate to insulin ratios and correction factors so thatwhen a blood glucose value is inputted or picked up wire-lessly from a paired home glucose monitor, a suggested doseshows up on the digital readout of the pen. This informationcould be inputted directly to the pen or via a computer thathas a connection to the pen. These advances may inspire in-sulin companies to come up with newer shapes and designsthat allow for this already developed technology that isavailble in most of the currently marketed insulin pumps.Patient-driven algorithms have been validated for titratingbasal insulin doses.19 Incorporating these into the pen itselfwould help with patient motivation as well as documenting</p><p>S-88 BAILEY AND EDELMAN</p></li><li><p>adherence with timely and appropriately adjusted insulindoses. Development of a pen that would display results froma continuous glucose monitor (CGM) that is also worn by thepatients would be extremely helpful and would make CGMdevices more useful.</p><p>Newer insulin pens should incorporate an indicator of timeelapsed since prior insulin injection and have a reminder totake injection alarm. This may reduce the frequency of missedand duplicate injections. The force required for injectionshould remain low.</p><p>Many patients forget to remove the pen needle betweeninjections. This can lead to increased cellular debris in thecartridge and an accumulation of air.20 Excessive air in theinsulin chamber can affect the time course of insulin deliv-ery.21</p><p>Because of the thinness of the needle, higher doses take asignificantly 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 byindicating when delivery has been completed.</p><p>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.22 The currently available concentrated insu-lin (U-500) would be easier and safer to administer if it wereavailable in pen form.</p><p>Conclusions</p><p>Insulin pens have improved since their introduction to thediabetes marketplace in 1985. Insulin pens offer just as manyadvantages to patients with insulin requiring T2DM as theydo to those with type 1 diabetes and should be the standard ofcare for all insulin-using patients. Insulin pens improve sev-eral safety concerns relating to self-administration of insulinby end users. As a growing number of patients with T2DMuse multiple daily injection regimens, including concentratedinsulin such as U-200 and U-500, pens will become moreimportant to deliver insulin safely and easily. They also helpto protect the insulin from light and heat, both importantfactors in maintaining potency over tim...</p></li></ul>

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