Journal of Diabetes Science and Technology
`Volume 4, Issue 3, May 2010
`© Diabetes Technology Society
`
`SYMPOSIUM
`
`Evolution of Diabetes Insulin Delivery Devices
`
`Jean-Louis Selam, MD.
`
`Abstract
`
`The first manufactured insulin pump was introduced in the 1970s and the first insulin pens in 1985; since
`then, many improvements have been made to both devices. The advantages of pens over syringes have been
`confirmed in numerous studies and include greater accuracy, ease of use, patient satisfaction, quality of life,
`and adherence. United States claims database analyses indicate that the improved adherence made possible
`by use of an insulin pen has the potential to reduce diabetes care costs when compared with using a vial
`and syringe. Features of certain advanced pump models include the ability to connect wirelessly to a blood
`glucose meter or to a subcutaneous interstitial glucose sensor for semicontinuous glucose-driven insulin rate
`adjustment. A new trend in the design of insulin pumps is the tubing-free patch pump that adheres directly
`to the skin. The low rate of insulin pen usage in the United States compared with European countries and the
`fact that many patients report that they are not offered the option of an insulin pen by their physician
`suggest that there is a need to increase patient and provider awareness of the currently available devices for
`insulin administration.
`
`J Diabetes Sci Technol 2010;4(3):505-513
`
`Introduction
`
`The publication of the results of the landmark Diabetes
`
`Control and Complications Trial (DCCD in 1993 clearly
`demonstrated the need for intensified methods of blood
`glucose (BG) control in type 1 diabetes to prevent
`complications such as retinopathy, nephropathy, and
`neuropathy.1 Five years later, the importance of intensive
`glycemic control to prevent microvascular complications
`in type 2 diabetes was shown by the United Kingdom
`Prospective Diabetes Study (UKPDS).2 However, the need
`for more convenient, safer, and more effective methods
`of
`insulin administration had been apparent
`long
`
`before the DCCT and UKPDS results were published. 3
`When insulin was first discovered in the early 1920s,
`the method of delivery used large glass syringes and
`reusable needles, both of which needed sterilization
`by boiling after each use. Needles were sharpened with
`a pumice stone so they could be reused. For over
`50 years, vial and syringe remained the only delivery
`option available for
`routine clinical use. The first
`manufactured
`insulin pump was introduced in the
`1970s, while the first manufactured insulin pen, the
`NovoPen® (Novo Nordisk), was introduced in 1985.4
`
`Author Affiliation: Diabetes Research Center, Tustin, California
`
`Abbreviations: (AlC) glycated hemoglobin, (BG) blood glucose, (CI) confidence interval, (CSII) continuous subcutaneous insulin infusion,
`(DCCT) Diabetes Control and Complications Trial, (DKA) diabetic ketoacidosis, (FDA) Food and Drug Administration, (MDI) multiple daily
`injections, (MPR) medication possession ratio, (OR) odds ratio, (QALY) quality-adjusted life year, (RCT) randomized controlled
`trial,
`(UKPDS) United Kingdom Prospective Diabetes Study
`
`Keywords: continuous subcutaneous insulin infusion, diabetes, insulin delivery, insulin pen, insulin pump
`
`Corresponding Author: Jean-Louis Selam, M.D., Diabetes Research Center, 2492 Walnut Ave, Suite 130, Tustin, CA 92780; email address
`ilselam@cox.net
`
`505
`
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`IPR2018-01676
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`

`Evolution of Diabetes Insulin Delivery Devices
`
`Selam
`
`Since then, many improvements and innovations have
`been made to both insulin pumps and pen devices.
`Furthermore, insulin analogs have become available that
`enable both continuous subcutaneous insulin infusion
`(CSII) using an insulin pump and insulin therapy using
`multiple daily injections (MDI) to more closely match
`physiologic insulin patterns.5- 8
`
`For various reasons that are unrelated to the scientific
`evidence base, the rate of adoption of insulin pens and
`pumps has differed greatly between the United States
`and Europe. Insulin pumps are more widely used on the
`American side of the Atlantic than on the European
`side, whereas insulin pens are used as an alternative to
`syringes by the majority of diabetes patients in Europe
`but by only approximately 15% of diabetes patients in
`the United States.9,10 The faster development of insulin
`pumps in the United States may be due to the fact
`that the United States was the country where the first
`manufactured insulin pump was invented.10 Additionally,
`the publication of the DCCT results greatly contributed
`to the rapid growth of CSII use in the United States,
`because almost half of the DCCT patients in the intensive
`treatment arm had been treated with CSII. As initial
`instruction for use of CSII takes considerably longer
`than that for an insulin pen, the use of CSII in the
`United States may also be facilitated by the availability of
`certified diabetes educators, who have the time and
`expertise to educate patients in the correct use of this
`technology.
`
`Both insulin pens and insulin pumps can offer benefits
`to patients, including the potential for improved clinical
`outcomes. However, in a survey of 600 patients using
`insulin for the treatment of type 2 diabetes in the United
`States, many patients reported that they had not been
`offered the option of an insulin pen by their physician.11
`Together with the low rate of insulin pen use in the
`United States compared with European countries, this
`suggests that there is a need to increase provider awareness
`of the benefits and limitations of the currently available
`devices for insulin administration in type 2 diabetes
`so that patients are informed of the range of options
`available and are thus able to choose the device that
`best suits their individual circumstances. Therefore, this
`article reviews the benefits and limitations of insulin
`pens and pumps in the treatment of diabetes.
`
`Methods
`
`This review is based on a literature search of the
`PubMed database using the following search strategy:
`
`"(diabetes or insulin or insulins) and (pen or pens or
`pump or pumps or CSII or continuous subcutaneous
`insulin infusion)". Health economic papers were identified
`by adding the search term "cost or economic." Searches
`were limited to articles published in English between
`January 1, 1985, and September 29, 2009. Priority was given
`to meta-analyses, systematic reviews, practice guidelines,
`and controlled clinical trials. Additional articles were
`identified from the reference lists of review articles.
`
`Benefits and Limitations of Insulin Pens
`Versus Vial and Syringe
`
`Insulin injection using vial and syringe delivery has the
`potential for several problems, including the inconvenience
`of carrying several materials and preparing the syringe,
`the adverse psychological and social impact of using a
`syringe (because syringes are associated with sickness
`and drug abuse), use of the incorrect insulin product, and
`failure to administer accurate doses. The development of
`insulin pens has therefore focused on ways to counter
`such problems. Several disposable and reusable pen devices
`have been developed that provide options for delivering
`rapid- and
`long-acting
`insulins and
`insulin premixes.
`Table 1 lists the pen devices that are currently available
`in the United States. The advantages of insulin pens over
`syringes have been confirmed in numerous studies.12- 22
`
`Table 1.
`Insulin Pen Delivery Devices Available in the
`United Statesa
`
`Refillable pens
`(manufacturer)
`
`Prefilled disposable pens
`(manufacturer)
`
`Autopen® 24 (Owen Mumford)
`
`FlexPen (Novo Nordisk)
`
`Autopen Classic AN3800
`(Owen Mumford)
`
`Autopen Classic AN3810
`(Owen Mumford)
`
`Humalog® KwikPen™ (Eli Lilly)
`
`Humalog Pen (Eli Lilly)
`
`HumaPen LUXURA HD (Eli Lilly)
`
`SoloSTAR® (sanofi-aventis)
`
`HumaPen MEMOIR (Eli Lilly)
`
`NovoPen 3 (Novo Nordisk)
`
`NovoPen 4 (Novo Nordisk)
`
`NovoPen Junior (Novo Nordisk)
`
`OptiClik® (sanofi-aventis)
`
`a Compatible insulin analogs for pen devices: Novo Nordisk = insulin
`detemir,
`insulin aspart, and biphasic
`insulin aspart 70/30;
`Eli Lilly = insulin lispro, insulin lispro mix 75/25, and insulin lispro
`mix 50/50; and sanofi-aventis = insulin glargine, insulin glulisine.
`The Autopen Classic takes Eli Lilly insulin cartridges, and the
`Autopen 24 takes sanofi-aventis insulin cartridges. The NovoPen
`models use 3 ml PenFill® cartridges.
`
`J Diabetes Sci Technol Vol 4, Issue 3, May 2010
`
`506
`
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`Evolution of Diabetes Insulin Delivery Devices
`
`Selam
`
`These advantages, which include greater accuracy,
`convenience, patient preference, and adherence, are
`discussed here.
`
`Accuracy, Ease of Use, and Patient
`Preference
`
`In a study of syringes and pens used by children with
`type 1 diabetes, pens were more accurate than syringes
`in measuring out insulin at low insulin doses (<5 U).20
`At doses above 5 U, pens and syringes had similar
`accuracies. In another study, pens were found to be more
`accurate than syringes at doses of 1 and 2 U.16 In a
`survey of 507 insulin users, 89% of 479 respondents (not
`all patients answered all survey questions) considered
`an insulin pen to be more socially acceptable than a vial
`and syringe; 86% of 475 respondents indicated that a pen
`was easier to use; and 86% of 488 respondents said that
`it took less time to prepare and administer injections
`with a pen.14 Similar responses were found in a survey
`of nurses in a community hospital after implementation
`of insulin pen devices.22 The majority of nurses stated that
`insulin pens were more convenient than vials/syringes.
`In addition, implementation of insulin pen devices did
`not increase the nurses' time spent to teach patients to
`self-inject insulin and did not increase insulin-related
`needle stick injuries.
`
`Korytkowski and colleagues17 assessed patient preference
`for an
`insulin pen versus vial and syringe in a
`randomized, open-label, crossover study in 121 adults with
`type 1 or type 2 diabetes. Patients were randomized to
`use either a prefilled pen or vial/ syringe to administer
`an insulin analog premix regimen for
`four weeks,
`followed by four weeks' use of the other injection device.
`In summary, 74% of patients indicated a preference
`for the pen over the vial/syringe (compared with 20%
`who preferred the vial/syringe), 85% considered the pen
`more discreet for use in public (compared with 9%
`for the vial/syringe), 74% considered it easier to use
`overall (compared with 21% for the vial/syringe), and 85%
`found the insulin dose scale on the pen easier to read
`(compared with 10% for the vial/syringe). The quality-of(cid:173)
`life benefits of insulin pens compared with syringes
`have also been confirmed in other studies using generic
`quality-of-life scales.18,21
`
`Adherence
`
`Adherence to the appropriate insulin therapy is a major
`element of good glycemic control, and there is evidence that
`insulin pens can improve patient adherence compared
`
`with vial and syringe delivery.12,19 Lee and associates19
`analyzed U.S. managed care claims data for 1156 subjects
`with type 2 diabetes. This study found that medication
`adherence (measured by the medication possession ratio
`[MPR]) significantly improved from 62% to 69% (p < .01)
`after conversion from regular human or analog insulin
`injection using a vial and syringe to a prefilled insulin
`analog pen (containing either insulin aspart or biphasic
`insulin aspart 70/30). In a similar study by Cobden and
`coworkers12 of 486 subjects who switched from vial and
`syringe to an insulin pen prefilled with biphasic insulin
`aspart 70/30, the MPR increased from 59% to 68% (p < .01).
`However, it should be noted that, although the MPR is
`a well-established measure of adherence, it is not possible
`to confirm with claims data that patients are correctly or
`accurately administering their drugs, and it is also not
`possible to include factors such as drug sharing or wastage.
`
`Health Economics of Insulin Pens
`
`Insulin analogs supplied in cartridges or prefilled pens
`have a higher per unit of insulin cost than do insulin
`analogs supplied in vials. For example, one vial (1000 U)
`of insulin glulisine costs $105.95, which equates to a cost
`of 10.6 cents per unit of insulin. Five prefilled insulin
`pens containing insulin glulisine (total of 1500 U) have a
`total cost of $201.01, equating to a cost of 13.4 cents per
`unit of insulin (26% more than the cost of insulin glulisine
`supplied in a vial). (Prices are the retail prices available to
`consumers at www.drugstore.com as of March 18, 2010.
`These prices are without health insurance coverage.
`Co-pays for pens and vials are similar for most health
`insurance plans.) However, most pen devices now have good
`formulary coverage, so cost should not be a limitation to
`the patient or physician. Data from the two studies that
`analyzed U.S. managed care claims data indicate that the
`improved adherence made possible by use of an insulin
`pen has the potential to reduce diabetes care costs (not
`including the cost of insulin) when compared with vial/
`syringe delivery, despite higher prescription costs for
`pen delivery.12,19
`
`In the study by Lee and colleagues,19 in addition to
`improved medication adherence in patients who converted
`from vial/syringe therapy to a prefilled insulin analog
`pen, the likelihood of experiencing a hypoglycemic event
`significantly decreased after conversion (odds ratio [OR]
`= 0.50; 95% confidence interval [CI], 0.37-0.68; p < .05).
`There were also significant decreases in hypoglycemia(cid:173)
`attributable emergency department visits (OR = 0.44;
`95% CI, 0.21-0.92; p < .05) and physician visits (OR= 0.39;
`95% CI, 0.24-0.64; p < .05). Total mean all-cause annual
`
`J Diabetes Sci Technol Vol 4, Issue 3, May 2010
`
`507
`
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`Evolution of Diabetes Insulin Delivery Devices
`
`Selam
`
`treatment costs were reduced by $1590 per patient
`(from $16,359 to $14,769; p < .01). Annual hypoglycemia(cid:173)
`attributable costs were reduced by $788 per patient
`(from $1415 to $627; p < .01), predominantly as a result
`of decreased hospitalization costs (from $857 to $288;
`p < .01). Annual diabetes-attributable costs were reduced
`by $600 per patient (from $8827 to $8227; p <
`.01).
`There were similar findings in the study by Cobden and
`associates,12 with significant decreases observed in the
`likelihood of hypoglycemic events and in treatment
`costs after conversion to a prefilled pen containing an
`insulin analog premix.
`
`Another study assessed patients with type 2 diabetes
`enrolled in the North Carolina Medicaid program and
`found that initiating insulin therapy with an insulin
`pen was associated with significant reductions in health
`care resource utilization and associated costs compared
`with starting insulin therapy using a vial and syringe. 23
`In this study, diabetes-related medication adherence was
`comparable with the two delivery methods, with an
`adherence rate of 53% for patients initiating insulin with
`a pen compared with a rate of 50% in patients using a
`syringe. However, total annualized health care costs
`were significantly lower for patients using an insulin
`pen than for those using a syringe ($14,857.42 versus
`$31,764.78; p < .05). Cost reductions with pen therapy
`compared with vial/syringe use were seen in hospital costs
`($1195.93 versus $4965.31; p < .05), diabetes-related costs
`($7324.37 versus $13,762.21; p < .05), and outpatient costs
`($7795.98 versus $13,103.51; p < .05).
`
`Glycated Hemoglobin
`
`Although two studies have reported that switching from
`vial/ syringes to prefilled insulin analog pens improved
`adherence as measured by
`the MPR, no rigorous,
`controlled studies to date have shown that insulin pen
`use is associated with greater reductions in glycated
`hemoglobin (AlC) as compared with vial and syringe
`use. One small study in 23 homeless patients found that
`switching from vial and syringe to a reusable insulin
`pen improved glycemic control at 3 and 6 months. 24
`In a study in 72 patients with type 1 diabetes who
`switched from vial and syringe injections to four or five
`injections per day with an insulin pen, glycemic control
`improved at follow-up (9-13 months after the switch)
`only in those patients who has previously been receiving
`one or two injections per day.25 When these patients were
`followed up for a further five years, metabolic control
`was found to deteriorate over time.26 However, the lack
`
`of a control group in these studies means that the effects
`of the natural history of the disease and of regression to
`the mean cannot be excluded.
`
`As mentioned earlier (in the Accuracy, Ease of Use, and
`Patient Preference section), in the randomized, open-label,
`crossover study conducted by Korytkowski et al.,17
`patients with type 1 or type 2 diabetes were randomized
`to use either a prefilled pen or vial/syringe to administer
`biphasic insulin aspart 70/30 for four weeks, followed
`by four weeks' use of the other injection device.
`No statistically significant differences were found between
`the two devices in mean fasting plasma glucose, serum
`fructosamine, or four-point glucose profile.
`
`Other Refinements
`
`Over the past 20 years, insulin pens have been constantly
`refined, with certain newer models offering advantages
`over older ones. For example,
`the
`latest improved
`FlexPen® (Novo Nordisk) requires a lower injection force
`while maintaining dose accuracy when compared with
`the older, original FlexPen. 27 Another example
`is
`the inclusion of a memory function in the HumaPen®
`MEMOIR™ device (Eli Lilly), which records the date,
`time, and amount of the previous 16 doses (including
`priming doses), so that patients and healthcare providers
`can see exactly how much insulin the patient last
`took and when. Finer needles and safety needles that
`are associated with reduced pain perception have
`also been developed for use with insulin pens. 28,29
`Disposable prefilled pens (which many patients find
`more convenient than the reusable cartridge-type pens)
`are now available for all insulin analogs. Many current
`insulin pen models also allow backward dialing to correct
`misdialed doses without wasting insulin. Two models
`allow the dose to be adjusted in half-unit increments
`(HumaPen LUXURA™ HD [Eli Lilly] and NovoPen Junior
`[Novo Nordisk]).
`
`Limitations Versus Vial and Syringe
`
`Apart from their higher prescription cost, the main
`limitation of pens compared with syringes is the inability
`for patients to mix their own insulin formulations
`(i.e., neutral protamine Hagedorn insulin mixed with
`regular
`insulin). However,
`three different premixed
`biphasic insulin analogs are available for use in prefilled
`and reusable pens. Furthermore, the mixing of insulin
`preparations is known to be highly inaccurate when
`performed by elderly patients. 30
`
`J Diabetes Sci Technol Vol 4, Issue 3, May 2010
`
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`
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`Evolution of Diabetes Insulin Delivery Devices
`
`Selam
`
`Benefits and Limitations of Insulin Pumps
`
`Improvements in insulin pump technology are also
`having an impact in providing an alternative option for
`insulin delivery in patients failing to achieve glycemic
`control using a MDI regimen and in other selected
`patients. The brick-sized devices of decades past have
`been replaced by small pumps no bigger than a pager.
`Modern external insulin pumps weigh less than 4 oz
`and consist of an insulin reservoir, a small battery(cid:173)
`operated pump, and a computerized control mechanism.
`Pumps deliver a continuous infusion of insulin (usually a
`rapid-acting insulin analog) via a cannula that is placed
`subcutaneously. Pumps are programmed to deliver both
`basal and bolus doses. Premeal or snack bolus doses can
`be selected to cover the user's estimated carbohydrate
`intake at mealtime and to correct for out-of-range BG
`readings. All pumps have occlusion and near-empty
`alarms. Pumps are also supplied with multiple basal
`delivery profiles that allow the patient to select different
`basal infusion rates based on differences in daily or
`weekly schedules. For example, a patient might require
`a different basal pattern on weekdays compared with
`weekends, or a schoolchild might need to adjust if the
`school day involves sporting activities.
`
`Table 2 provides an overview of the features of currently
`available insulin pumps. Many advanced models (e.g.,
`OneTouch® Ping™, OmniPod®, and MiniMed Paradigm®)
`can connect wirelessly to BG meters. The MiniMed
`Paradigm can also connect wirelessly to a disposable sub(cid:173)
`cutaneous interstitial-glucose sensor for semicontinuous
`glucose-driven insulin rate adjustment; this system is
`currently the only integrated pump and continuous
`glucose monitoring system available. Currently available
`continuous interstitial glucose monitoring systems are
`not as accurate as current home glucose meters but are
`useful for providing patients with the ability to monitor
`changes in glucose levels between finger stick readings.
`
`A new trend in the design of insulin pumps is the
`tubing-free "patch" pump. The only currently available
`patch pump is the OmniPod. The OmniPod pump/
`reservoir unit adheres directly to the skin and contains
`an
`integrated
`infusion set and automated
`inserter.
`The pump/reservoir unit communicates wirelessly with
`a separate controller that includes an integrated BG
`meter. Benefits of this patch pump design that have
`been reported by patients include the ability to wear
`the pump in the shower and the greater convenience of
`a tubing-free system. In one small study, 90% of patients
`
`(18 of 20) preferred using the OmniPod's automated
`cannula insertion system versus inserting with their
`current infusion sets. 31 Use of a patch pump may be
`particularly beneficial in adolescents, as 52% of 48
`adolescents in one study reported that they disconnected
`their (conventional design) pump for exercise. 32
`
`the OneTouch Ping also comes
`the OmniPod,
`Like
`with a separate wireless controller that includes an
`integrated BG meter and integrated food database for
`bolus calculations. The OneTouch Ping, which uses
`a conventional (i.e., nonpatch) pump design, can be
`controlled from both the pump itself as well as from the
`wireless controller.
`
`It is expected that more patch pumps will come onto the
`market in the future. The Solo™ MicroPump (Medingo, Ltd.)
`is a patch pump that has already received U.S. Food and
`Drug Administration (FDA) approval but, as of the time
`of this writing, is not yet available for sale. Another likely
`future advance in the development of CSII technology
`is the development of more accurate continuous glucose
`monitoring systems for use in combination with insulin
`pumps.
`
`Continuous Subcutaneous Insulin
`Infusion in Type 1 Diabetes
`
`Among patients with type 1 diabetes, the principal
`indications for CSII include patients who are unable to
`achieve acceptable glycemic control using MDI, patients
`with histories of frequent or severe hypoglycemia,
`and patients who need more intensive management
`because of microvascular complications.33,34 Since the
`introduction of long-acting insulin analogs, the "dawn
`phenomenon" has become a less frequent indication for
`CSil.34 However, pump therapy is not only costly, but
`requires a high level of motivation and commitment to
`diabetes self-management, with frequent checks of BG
`levels throughout the day, a responsibility that not all
`patients with diabetes are willing or able to undertake.
`In addition, some patients, particularly adolescents, may
`be self-conscious about being attached to a foreign object. 35
`
`When used in CSII, rapid-acting insulin analogs have
`been shown to produce a modest but significantly
`greater reduction in AlC compared with regular human
`insulin and are preferred by patients.5 Table 3 provides
`an overview of the insulins approved for pump therapy,
`including the maximum time allowed in the insulin
`reservoir.
`
`J Diabetes Sci Technol Vol 4, Issue 3, May 2010
`
`509
`
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`Evolution of Diabetes Insulin Delivery Devices
`
`Selam
`
`Table 2.
`Key Features of Insulin Pumps Available in the United Statesa
`
`Insulin pump model Accu-Chek® Spirit
`
`OneTouch Ping
`
`Manufacturer
`
`Animas
`Disetronic
`Medical Systems Corporation
`AG
`
`MiniMed
`Paradigm
`522/722
`
`DANA
`Diabecare IIS
`
`OmniPod Insulin
`Management
`System
`
`Nipro Amigo®
`
`Medtronics, Inc.
`
`Sooil
`Development
`
`lnsulet
`
`Nipro Diabetes
`Systems
`
`Basal programs
`
`Basal range
`
`Five profiles
`with 24-hourly
`basal rates each;
`temporary basal
`rate in 10%
`increments from
`0% to 200%,
`and 15 min
`increments from
`15minto24h
`
`0.1-25 U/h in
`0.1 U increments
`
`Smallest bolus
`
`0.1 U
`
`Overdelivery alarm No
`
`0.025-25 U/h
`in 0.025 U
`increments
`
`0.05 U
`
`Yes
`
`Three profiles
`12 basal rates in
`four personalized with up to 48
`programs;
`rates each
`temporary rate
`from 30 min to
`24 h in 30 min
`intervals or 10%
`increments
`
`Four profiles
`with 24 rates
`per profile;
`temporary basal
`rate in 25%
`increments
`±100%
`
`0.05-35 U/h
`
`0.00-16 U/h
`
`Seven profiles with Four profiles
`24 rates each
`with 48 rates
`available per
`profile; temporary
`basal rate in 10%
`increments from
`10% to 200% or
`15 min increments
`from 15 min to
`24 h
`
`0.05-30 U/h in
`0.05 U increments
`
`0-30 U/h in
`0.05 U increments
`
`0.05 U
`
`0.1 U
`
`0.05 U
`
`0.05 U
`
`Yes, self-tests
`and safeguards
`help prevent
`overdelivery
`
`Yes, internal
`cross checks
`
`No, safety systems Yes, internal
`monitor delivery
`processors
`and perform safety continually monitor
`checks on pod
`pump function
`and PDM
`to prevent
`overinfusion and
`underinfusion
`
`Reservoir size
`
`315 U
`
`200 U
`
`176 or 300 U
`
`300 U
`
`200 U
`
`Display features
`
`Reversible
`display; backlit
`display
`
`Color screen
`
`Backlight
`
`Backlight;
`energy-saving
`sleep mode
`
`Color screen on
`PDM controller
`
`300 U
`
`Backlight
`
`Connection
`
`Standard luer-lock Standard luer-
`lock
`
`Proprietary
`
`Proprietary
`
`Integrated infusion Standard luer-lock
`set with no tubing
`required
`
`Waterproof
`
`IPX8
`(60 min at 2.5 m)
`
`Waterproof (up to Splash resistant
`12 ft for 24 h)
`
`IPX8
`
`IPX8
`(30 min at 8 ft)
`
`IPX8
`(35 min at 1 m)
`
`Icon-based
`interface
`
`Includes a meter/
`Additional features Standard,
`remote that
`advanced, or
`custom selectable works wirelessly
`user menus;
`with the pump;
`side-mounted
`audible or
`tactile buttons;
`vibrating pump
`audible or
`alerts; integrated
`vibrating bolus
`food database
`confirmation and
`alerts;
`supports infrared
`wireless data
`transfer
`
`Interacts
`wirelessly with
`continuous
`glucose monitor
`as part of
`the MiniMed
`Paradigm
`REAL-Time
`System; optional
`remote control
`at additional
`cost; audible or
`vibrating alerts
`
`Pump casing is
`shatter resistant;
`audible or
`vibrating alerts
`and button
`feedback
`
`Tube-free,
`disposable system
`device applied
`directly to body
`with adhesive;
`uses wireless
`PDM for managing
`insulin delivery;
`integrated food
`database; built-in
`BG meter in PDM
`
`a The Solo MicroPump (Medingo, Ltd.) has received FDA approval but, as of the time of this writing, is not yet available for sale. PDM,
`personal diabetes manager
`
`The benefits of providing continuous delivery of a rapid(cid:173)
`acting insulin analog may be substantial for selected
`patients.36 Compared with MDI, the potential advantages
`of insulin pump therapy in type 1 diabetes include a
`
`lower AlC, a reduced total daily insulin dose, a reduced risk
`of hypoglycemia, lower BG variability, elimination of the
`need for daily injections, and increased flexibility in meal
`timing and size.s,37- 39 A meta-analysis of 11 randomized
`
`J Diabetes Sci Technol Vol 4, Issue 3, May 2010
`
`510
`
`www.iournalofdst.org
`
`Sanofi Exhibit 2160.006
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`Evolution of Diabetes Insulin Delivery Devices
`
`Selam
`
`controlled trials (RCTs) comparing CSII (using rapid(cid:173)
`acting insulin analogs) with MDI in type 1 diabetes
`found that CSII was associated with a significantly
`lower AlC compared with MDI (standardized difference
`in mean: 0.3 percentage points in favor of CSII; 95%
`CI, 0.1-0.4; p <
`.001).40 No significant difference was
`observed in the rate of severe hypoglycemia. All 11 RCTs
`included in this meta-analysis enrolled patients failing
`on MDI who were randomized to continue with the
`same MDI regimen or switch to CSIL The results of this
`meta-analysis therefore support the principal indication
`of CSII as being patients unable to achieve acceptable
`glycemic control using MDL
`
`Another meta-analysis included three RCTs that compared
`CSII and optimized MDI therapy using rapid-acting
`analogs in adults with type 1 diabetes.41 The pooled
`estimated AlC reduction with CSII compared with
`MDI was 0.35 percentage points in favor of CSII (95% CI,
`-Q.10 to 0.80; p = .08). There was no significant difference
`between CSII and MDI
`in the rate of hypoglycemic
`events. Importantly, a greater relative benefit of CSII was
`observed in patients with higher baseline AlC, suggesting
`that CSII may be particularly beneficial in patients with
`the poorest initial glycemic control.42
`
`Continuous Subcutaneous Insulin
`Infusion in Type 2 Diabetes
`
`Another meta-analysis assessed CSII versus MDI in
`type 2 diabetes. This meta-analysis included four RCTs
`that were of at least 12 weeks' duration and found that
`CSII did not produce any significant improvement of AlC
`compared with MDI (standardized difference in mean:
`0.09 percentage points; 95% CI, -0.08 to 0.26; p = .31).43
`Current evidence thus shows no clear benefits of CSII
`over MDI in the general type 2 diabetes population.
`Further research is required to investigate whether CSII
`may be useful in specific groups of type 2 diabetes
`patients, such as patients with marked insulin resistance;
`after failure of other intensified insulin regimens; during
`preconception, pregnancy,
`and
`lactation;
`following
`transplantation; and in cases of insulin allergy.44
`
`Complications of Insulin Pump Therapy
`
`Insulin pumps may undermedicate or overmedicate if
`they malfunction or are used improperly. Device problems
`that have been reported to the FDA include alarm problems,
`loosening and/or occlusion of the catheters, bent cannula,
`and screen display problems.45 Potential complications of
`CSII therapy therefore include diabetic ketoacidosis (DKA)
`and hypoglycemia.46 However, more reliable pumps and
`
`Table 3.
`Types of Insulin Used in Pump Therapy
`
`Insulin
`
`U.S. brand
`name
`(manufacturer)
`
`Approved age
`groups in the
`United States
`
`Maximum
`time allowed
`in reservoir
`
`Rapid-acting
`insulin analogs
`
`Insulin aspart
`
`NovoLog®
`(Novo Nordisk)
`
`Children and
`adults
`
`Six days
`
`Insulin
`glulisine
`
`Apidra®
`(sanofi-aventis)
`
`Children and
`adults
`
`Insulin lispro
`
`Regular human
`insulin
`
`Humalog
`(Eli Lilly)
`
`Humulin® R
`(Eli Lilly)
`Novolin® R
`(Novo Nordisk)
`
`Children and
`adults
`
`Children and
`adults
`Children and
`adults
`
`48 h
`
`48 h
`
`48 h
`
`48 h
`
`improved patient education have greatly reduced these
`risks. As with MDI therapy, DKA should be preventable
`through the use of published DKA prevention guidelines
`that recommend frequent monitoring of urine or serum
`ketones and BG, with appropriate intervention when ill.47
`
`While infusion-site infections are uncommon, irritation
`or
`inflammation at
`the
`infusion site are common
`complications of using an insulin pump,48 though their
`incidence has been reduced by the introduction of more
`modern infusion sets (for example, sets that use a Teflon
`cannula) and by better patient education. Adherence with
`the advised infusion site preparation and cannula insertion
`techniques, and with the recommended site duration
`and site rotation schedule, may minimize dermatologic
`complications.49
`
`Health Economics of Continuous
`Subcutaneous Insulin Infusion
`
`To date, only one cost-effectiveness analysis comparing CSII
`with MDI in patients with diabetes in the United States
`has been published. 50 A previously validated health
`economic model (the CORE Diabetes Model) was used to
`determine the incremental cost-effectiveness ratio of CSII
`compared with MDI using published clinical and cost
`d