Journal of Diabetes Science and Technology
`Volume 4, Issue 5, September 2010
`© Diabetes Technology Society
`
`ORIGINAL ARTICLES
`
`Correct Use of a New Reusable Insulin Injection Pen by Patients
`with Diabetes: A Design Validation Study
`
`Sherwyn Schwartz, M.D.
`
`Abstract
`
`Background:
`Insulin pen devices are currently being used by approximately half of insulin users worldwide. ClikSTAR®
`(sanofi-aventis) is a novel reusable insulin pen for injecting either long-acting insulin glargine or short-acting
`insulin glulisine. The objective of this study was to demonstrate that individuals with diabetes could use the
`ClikSTAR pen correctly.
`
`Methods:
`In this open-label, single-center study, people with diabetes delivered three 40 U insulin doses after receiving
`training from a diabetes specialist (group A, n = 256) or after self-training (group B, n = 47). Administration of
`a dose of 75-115% of the intended dose was considered successful. Adverse events (AEs) and product technical
`complaints (PTCs) were recorded.
`
`Results:
`In group A (68% females, 93% Hispanic ethnicity, 97% type 2 diabetes mellitus, mean ± standard deviation
`age 52 ± 11 years, diabetes duration 11 ± 7 years), half of the participants had prior experience in using insulin
`pen devices. All except one participant (99.6%) in group A successfully delivered three insulin doses. The lower
`one-tailed 95% confidence limit for the success rate (98.2%) was higher than the predefined target of 90%.
`Demographic/baseline characteristics were similar in group B, but 70% had not previously used an injection pen.
`Group B also showed success; 93.6% of participants successfully completed three dose deliveries. No AEs were
`reported, although one participant (0.4%) in group A reported one PTC during the training period that was
`due to a blocked needle.
`
`Conclusions:
`This study successfully validated the ClikSTAR pen for use by individuals with diabetes.
`
`J Diabetes Sci Technol 2010;4(5):1229-1235
`
`Author Affiliation: Diabetes and Glandular Disease Research Associates, San Antonio, Texas
`
`Abbreviations: (AE) adverse event, (PTC) product technical complaint, (TlDM) type 1 diabetes mellitus, (T2DM) type 2 diabetes mellitus
`
`Keywords: design validation, reusable insulin pen device, type 2 diabetes mellitus
`
`Corresponding Author: Sherwyn Schwartz, M.D., Diabetes and Glandular Disease Research Associates, 5107 Medical Dr., San Antonio, TX 78229;
`email address slschwartz@dgdclinic.com
`
`1229
`
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`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Correct Use of a New Reusable Insulin Injection Pen by Patients
`with Diabetes: A Design Validation Study
`
`Schwartz
`
`Introduction
`
`E ffective management of type 1 diabetes mellitus
`(TlDM) and type 2 diabetes mellitus (T2DM) relies on
`maintaining glycemic control within the normal range
`and keeping the hemoglobin Ale level below 7% or,
`preferably, 6.5%.1 Insulin therapy is essential in TlDM and
`is becoming more commonly used in T2DM, particularly
`in light of the American Diabetes Association/European
`Association for the Study of Diabetes position statement,
`which describes that insulin therapy is the most effective
`method of lowering blood glucose levels and is capable
`of achieving glycemic control at any disease stage in
`T2DM.2 Insulin can be administered via several methods
`such as vial and syringe, insulin pump, and insulin pen.
`In particular, insulin pens have increased the convenience
`and flexibility of insulin therapy compared with the
`traditional vial and syringe administration method.3A
`
`Despite the continuing advances in insulin administration
`technology, the potency of insulin therapy means that
`dosing errors can have adverse consequences for the
`health of patients with diabetes, whereas the accurate
`insulin dosing associated with insulin delivery devices
`has the potential to lead to better long-term outcomes.
`Insulin pen devices have repeatedly been demonstrated to
`exhibit greater dose accuracy compared with syringes. 5,6
`Ongoing development to achieve further improvements
`in insulin pens and facilitate insulin injection is a major
`focus. In particular, developments have focused on
`prefilled pens such as SoloSTAR®
`(sanofi-aventis),7,8
`KwikPen® (Eli Lilly),9- 11 and FlexPen® (Novo Nordisk),12,13
`which have provided improvements in terms of ease of
`use, injection force, and patient preference. However, it
`is also important to acknowledge that 29% of insulin users
`worldwide administer insulin with a reusable pen,14 for
`reasons that might include individual preference, cost or
`environmental impact, and that the advances made in
`prefilled pen technology are transferred to reusable pens.
`
`clinical setting after receiving active training from a
`diabetes specialist.
`
`Methods
`
`Participants
`Individuals aged 13-79 years who had been diagnosed
`with TlDM or T2DM for at least 1 year and who were
`able to read and understand English were eligible for this
`study. Exclusion criteria included individuals who had
`unsuccessfully used, or attempted to use, insulin pens
`within the past 2 years; current addiction/abuse of
`alcohol or drugs; diagnosis of dementia or another mental
`condition rendering them incapable of understanding
`the nature, scope, and possible consequences of the study;
`severe visual or dexterity
`impairment;
`individuals
`unlikely to comply with the protocol; and participation
`in a clinical trial and/or device validation study within
`the past 3 months. All participants provided written,
`informed consent. Participants could voluntarily withdraw
`at any time before study completion, irrespective of
`the reason, or could be withdrawn at the investigator's
`discretion. Participants who showed extreme difficulty
`in handling the insulin pen or who were not able to
`remove the cap, insert the cartridge, or attach the needle
`during the initial training periods were excluded from
`the study before entering the validation phase, because
`they would generally be excluded from using insulin
`pens in clinical practice.
`
`Study Design
`(Diabetes and
`single-site
`This was an open-label,
`Glandular Disease Clinic, San Antonio, TX), single-visit,
`two-arm, design validation study. The participants included
`in the study were either trained by a diabetes specialist
`(group A) or self-trained (group B) before performing the
`validation tests. The study design is presented in Figure 1.
`
`ClikSTAR® (sanofi-aventis) is a novel, reusable insulin pen
`device developed as part of the ongoing development of
`insulin pens aimed at improving ease of use, injection
`force, differentiating features, and dose accuracy.7,15
`ClikSTAR insulin pens are fitted with cartridges for the
`injection of either the long-acting insulin glargine or the
`short-acting insulin glulisine. The aim of this study was
`to demonstrate that individuals with diabetes could use
`the ClikSTAR device correctly in a simulated real-world
`
`Participants in group A were given a face-to-face training
`session over 30-60 minutes, which was delivered by
`a trained diabetes specialist. The training could be
`performed in groups with no more than four patients per
`educator. During the training session, the participants
`were given a demonstration of the ClikSTAR device
`and instructions on how to insert the cartridge and
`needle, set and deliver a safety dose, and set and deliver
`a standard dose of insulin (40 U). The safety test involved
`
`J Diabetes Sci Technol Vol 4, Issue 5, September 2010
`
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`

`Correct Use of a New Reusable Insulin Injection Pen by Patients
`with Diabetes: A Design Validation Study
`
`expelling 2 U of insulin into the air with the tip of the
`needle pointing upward to ensure that the device was
`set up correctly and that air bubbles that may disrupt
`the test had been removed. The participants were then
`asked to perform two assistance-free demonstrations of
`using the ClikSTAR device, which included insertion of
`the insulin cartridge, attachment of the needle, execution
`of the safety test and dose delivery, and a review of
`the instructional leaflet. This scenario was designed to
`mimic clinical practice for people starting insulin pen
`injections (or switching to a different pen) in which a
`health care provider provides the patient with training
`on how to use the new pen correctly.
`
`Participants in group B were given the instructional
`leaflet, the insulin pen, a cartridge, needles, and a
`telephone helpline number and were instructed to learn
`how to use the ClikSTAR device in the absence of direct
`training. This self-directed
`learning session
`lasted
`approximately 30 minutes. This scenario was designed
`to mimic a less likely practice environment, where the
`participant receives the insulin pen and instructional
`leaflet without any training by a diabetes specialist and
`learns how to use the device on their own. The participants
`in this group were allowed to telephone the diabetes
`specialist to request additional information. Participants
`were enrolled into group B once group A enrollment had
`been completed. Inclusion in both groups was not possible.
`
`For device validation, after the appropriate training
`sessions, all participants were asked to insert a pen
`needle, perform a safety test, and inject a 40 U dose
`of insulin glargine into a receptacle, rather than as an
`actual injection. This procedure was to be repeated
`three times. The investigators were not allowed to assist
`or guide the participants, except to ensure that nobody
`injected themselves with insulin. The doses delivered
`were assessed by the investigator who visually inspected,
`weighed, and photographed the device on the weighing
`scale before and after each procedure. All digital
`photographs of the pen were evaluated by an independent
`expert reviewer to determine whether any errors were
`made by the investigator.
`
`Participants were disqualified from the dose delivery
`demonstration according
`to
`the
`following criteria:
`(1) participant error-the participant was unable
`to
`remove the insulin pen cap or to attach the needle to
`permit a dosing measurement; (2) investigator error-the
`study investigator made a critical mistake that affected
`the conduct of the test or the system being tested, such
`as weighing the pen with the inner or outer cap attached,
`
`Training period
`
`Dosing period
`
`Schwartz
`
`Group A Face-to-face training by
`diabetes specialist with
`access to pen and
`instructional leaflet
`(30-60 min)
`
`~ Assessment of dose delivery using injection pad
`
`1. Insert pen needle
`2. Perform safety test
`3. Inject 40 units of insulin into pad
`
`Group B Self-training with
`access to pen,
`instructional leaflet, and
`phone line to diabetes
`specialist (30 min)
`
`I/
`
`, Three separate assessments (60 min)
`
`Observational period (1 single day)
`
`Figure 1. Study design.
`
`as identified by photograph; (3) scale malfunction(cid:173)
`malfunction of the scale used to weigh the pen device
`to calculate the insulin dose delivered; and (4) pen
`disqualification-if participants observed that a device
`was malfunctioning, they could request a new one.
`The malfunctioning pen together with the attached needle
`was sent for investigation following the product technical
`complaint (PTC) process. Since a visibly malfunctioning
`pen would normally be replaced in real practice before
`any injections were carried out, all dosing measurements
`with this pen were excluded from the analysis.
`
`The primary analysis variable was the proportion of
`participants delivering a successful dose on all three dose
`delivery repetitions after active training by a diabetes
`specialist (group A). The main secondary analysis variable
`was the proportion of participants delivering a successful
`dose on all three dose delivery repetitions after self-training
`(group B). Additional secondary endpoints included
`correct insulin dose (75-115% of intended dose, i.e., 30 to
`46 U for an intended dose of 40 U-based on advisory
`board recommendations); safety endpoints [adverse events
`(AEs) and PTCs]; the proportion of participants who
`requested additional instructions by calling the diabetes
`specialist during the training period (for the self-trained
`participants), who performed the safety test correctly
`before each of the three dose delivery repetitions, and
`who used the instructional leaflet during the dosing
`period; the proportion of dose delivery repetitions for
`which a successful dose was delivered; and the accuracy
`and precision of the device based on the three dose
`injections per participant.
`
`Statistical Analyses
`A total of 321 participants were planned for inclusion
`in this study (266 in group A and 55 in group B).
`Sample sizes were determined based on a 90% success
`
`J Diabetes Sci Technol Vol 4, Issue 5, September 2010
`
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`

`Correct Use of a New Reusable Insulin Injection Pen by Patients
`with Diabetes: A Design Validation Study
`
`rate (considered uninteresting) and 95% success rate
`(considered interesting), such that 239 participants should
`ensure that the one-sided 95% lower confidence bound
`would exclude 90% with a statistical power of 90%.
`Given an expected dropout rate or ineligible results of 5%,
`266 participants were to be included in group A to
`provide 239 evaluable participants. For group B, only a
`descriptive analysis was planned, and with a success rate
`expected to range from 60-80%. Fifty participants were
`deemed sufficient to allow calculation of a one-sided 95%
`confidence interval with a precision of 9.3-11.4%, and
`55 participants were
`to be
`included
`to ensure 50
`evaluable participants. The lower limit of the one-sided
`95% confidence
`intervals for
`the success rates was
`calculated according to the Clopper-Pearson method.
`Statistical analyses were performed using all evaluable
`participants, while safety was assessed in all included
`participants.
`
`Results
`
`Study Population
`A total of 345 participants were enrolled in the study,
`276 in group A and 69 in group B. In group A,
`10 participants who experienced difficulties during the
`training period were withdrawn after training, and a
`further 10 participants were disqualified because of
`investigator error (for 1 participant, the printed weight
`was lost, and for 9 participants, photographs of the
`device taken during the validation session were missing).
`Consequently, 256 participants were included in the
`evaluation of group A. In group B, of the 69 participants
`enrolled, 1 participant did not wish to continue the
`study after self-training, 3 participants were disqualified
`due to investigator error (missing photographs), and
`18 participants were disqualified because of participant
`errors (15 participants were unable to attach the needle,
`2 participants performed only one dose assessment, and
`1 participant was unable to insert the insulin cartridge
`or attach the needle). Therefore, 47 participants were
`included
`in the evaluation of group B;
`the safety
`population included all 276 participants in group A and
`all 69 participants in group B. The characteristics of the
`evaluable populations are shown in Table 1 and were
`broadly comparable between both groups. In group A,
`2.7% (n = 7) and 97.3% (n = 249) had TlDM and T2DM,
`respectively, and the respective proportions in group B
`were 6.4% (n = 3) and 93.6% (n = 44). However, a greater
`proportion of participants in group A versus group B
`reported that they had prior experience of using an insulin
`injection pen [46.5%
`(n = 119) versus 29.8%
`(n = 14),
`respectively; Table 1].
`
`Schwartz
`
`Table 1.
`Participant Characteristics
`
`Statistics
`
`Mean±
`standard
`deviation,
`range
`
`n (%)
`n (%)
`n (%)
`n (%)
`
`n (%)
`n (%)
`
`n (%)
`n (%)
`
`Mean±
`standard
`deviation,
`range
`
`n (%)
`n (%)
`
`n (%)
`n (%)
`
`Group A
`n = 256
`
`Group B
`n = 47
`
`52.1 ± 10.7,
`23-73
`
`49.7 ± 13.6,
`19-69
`
`0
`36 (14.1)
`188 (73.4)
`32 (12.5)
`
`0
`9 (19.1)
`31 (66.0)
`7 (14.9)
`
`83 (32.4)
`173 (67.6)
`
`22 (46.8)
`25 (53.2)
`
`237 (92.6)
`19 (7.4)
`
`42 (89.4)
`5 (10.6)
`
`10.9 ± 7.4,
`1.1-39.4
`
`8.9 ± 6.6,
`1.5-26.5
`
`7 (2.7)
`249 (97.3)
`
`3 (6.4)
`44 (93.6)
`
`119 (46.5)
`137 (53.5)
`
`14 (29.8)
`33 (70.2)
`
`Age (years)
`
`Age
`<18 years
`18-40 years
`40-65 years
`e".65 years
`
`Gender
`Male
`Female
`
`Ethnicity
`Hispanic
`Not Hispanic
`
`Duration of diabetes
`(years)
`
`Type of diabetes
`Type 1
`Type 2
`
`Experience with
`injection pen
`Yes
`No
`
`Assessment of Dose Delivery after Diabetes
`Specialist Training
`The majority of participants in group A delivered three
`successful doses of 40 U (i.e., between 30 and 46 U)
`after diabetes specialist
`training
`[99.6%
`(n = 255);
`95% lower bound: 98.2%; Figure 2]; only one subject did not
`deliver all three doses correctly (Table 2). This individual,
`a 52-year-old Hispanic female who had previously used
`an injection device, successfully delivered the first two
`doses (39.0 and 39.6 U) but not the third dose, delivering
`a dose of 48.8 U instead of 40 U. Overall, 767 of 768
`individual doses (99.9%) were within the predefined
`target range of 30-46 U.
`
`Assessment of Dose Delivery after Self-Training
`As in group A, the majority of participants in group B
`delivered three successful doses after self-training
`[93.6%
`(n = 44); 95%
`lower bound: 84.3%; Figure 2].
`Meanwhile, 3 participants (6.4%) did not deliver all
`three doses correctly (Table 2), with seven dose delivery
`failures. Of these 3 participants, 2 did not use the
`instruction leaflet during the insulin pen set up and
`did not dial the correct target dose of 40 U during each
`
`J Diabetes Sci Technol Vol 4, Issue 5, September 2010
`
`1232
`
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`

`100
`
`100
`
`99.6
`
`Schwartz
`
`■ Dose 1
`■ Dose 2
`Dose 3
`
`Group A
`(diabetes-specialist trained)
`
`Group B
`(sett-trained)
`
`g>~ 100
`·c~
`80
`Cl> Cl>
`Q) .g
`.:?: "'
`"O _
`"' ::::,
`........
`~ :ll
`.e- ~
`.2 (J
`t: ::::,
`n,"'
`a. n,
`
`0
`
`60
`
`40
`
`20
`
`Correct Use of a New Reusable Insulin Injection Pen by Patients
`with Diabetes: A Design Validation Study
`
`of the three dose assessments. The third participant
`used the instruction leaflet, correctly performed the
`safety
`test, and successfully delivered
`the required
`dose during the first and second dose assessments, but
`failed the safety test and dose delivery during the third
`assessment. Overall, 134 of 141 doses (95%) were within
`the predefined target range of 30-46 U.
`
`Safety
`None of the enrolled participants (n = 345) reported an
`AE during the study. One participant reported one PTC
`during the study. This PTC was investigated and was
`found to be due to a blocked needle rather than a fault
`with the pen.
`
`Discussion
`
`The results of this study demonstrate that the majority of
`participants were able to deliver three consecutive doses
`of insulin in a simulated clinical setting after receiving
`training from a diabetes specialist (group A) or after
`self-training (group B). Indeed, 99.6% of participants in
`group A correctly administered three doses with the
`ClikSTAR device after training from a diabetes specialist,
`and the 95% lower bound was 98.2%, which was above
`the predefined limit of 90%. Participants in group B
`appeared to be slightly underdosing, and the resulting
`success rate in group B was lower. This was to be
`expected because the participants relied on instruction
`manuals, a helpline, or their own experience and were
`not given feedback on whether their use of the device
`was correct before the validation test.
`
`Figure 2. Participants delivering a successful dose.
`
`Notably, there were no AEs reported in this study and
`no insulin pen malfunctions; the only PTC reported
`was subsequently attributed to a blocked needle rather
`than to the device itself. In actual clinical use, people
`using insulin pen devices are recommended to set and
`deliver a safety dose, thus confirming that the full
`system (device and needle) is functioning correctly, as
`demonstrated by the appearance of insulin at the tip
`of the needle. If no insulin is seen, the user should
`replace the needle and repeat the test before injecting,
`in addition to checking that there is sufficient insulin
`left in the cartridge. Performing such safety tests before
`injecting is an integral part of good treatment practice
`and can help to ensure that the dose will be delivered
`instead of no dose being delivered.
`
`for
`requirement
`is a key
`Accurate dose delivery
`insulin delivery devices because of the potential for
`hypoglycemia with excessively high doses and for
`
`Table 2.
`Dose Delivery
`
`Safety test performed correctly
`
`No, n (%)
`
`Yes, n (%)
`
`Units displayed prior to the dose
`
`Dose 1
`n = 256
`
`Group A
`
`Dose 2
`n = 256
`
`Dose 3
`n = 256
`
`Dose 1
`n = 47
`
`Group B
`
`Dose 2
`n = 47
`
`Dose 3
`n = 47
`
`2 (0.8)
`
`2 (0.8)
`
`2 (0.8)
`
`9 (19.1)
`
`8 (17.0)
`
`9 (19.1)
`
`254 (99.2)
`
`254 (99.2)
`
`254 (99.2)
`
`38 (80.9)
`
`39 (83.0)
`
`38 (80.9)
`
`Mean ± standard deviation
`
`40 ± 0.2
`
`40 ± 0.2
`
`40 ± 0.2
`
`38 ± 7.3
`
`38 ± 7.2
`
`38 ± 7.3
`
`Minimum/maximum
`
`Dose delivered (U)
`
`39/41
`
`39/40
`
`39/40
`
`4/40
`
`4/40
`
`4/40
`
`Mean ± standard deviation
`
`39.4 ± 0.81
`
`39.6 ± 0.57
`
`39.6 ± 0.83
`
`37.4 ± 7.61
`
`38.0 ± 7.20
`
`37.2 ± 9.09
`
`Minimum/maximum
`
`32.9/40.9
`
`36.9/42.3
`
`35.1/48.8
`
`1.7/40.5
`
`3.6/40.5
`
`0.0/40.3
`
`Participants delivering a successful
`dose (30-46 U), n (%)
`
`256 (100.0)
`
`256 (100.0)
`
`255 (99.6)
`
`45 (95.7)
`
`45 (95.7)
`
`44 (93.6)
`
`J Diabetes Sci Technol Vol 4, Issue 5, September 2010
`
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`

`Correct Use of a New Reusable Insulin Injection Pen by Patients
`with Diabetes: A Design Validation Study
`
`hyperglycemia with low doses. On a day-to-day basis,
`hypoglycemia is probably the complication most feared
`by people with diabetes. Therefore, the upper limit
`of the dose range was set at 115% of the target dose
`(46 U for a 40 U dose).
`
`It should be noted that this study was designed to
`validate the proposal that the ClikSTAR device could
`be used successfully in a clinical setting by patients
`following specialist or self-training and was not designed
`to compare these two training methods. Interpretation
`of the relative merits of specialist versus self-training is
`limited by the markedly greater number of patients in
`group A compared with group B and by the fact that a
`larger proportion of participants in group B had no prior
`experience in using insulin pen devices (70.2% for group B
`versus 53.5% for group A). There were also differences
`in the number of enrolled patients who were excluded
`from the study due to extreme difficulty in using the
`ClikSTAR device. In total, 10 of 276 (3.6%) enrolled patients
`in group A and 18 of 69 (26%) in group B were excluded.
`Patient exclusion was intended to eliminate individuals
`who were unlikely to be candidates for insulin pens
`in clinical practice, but patient exclusion may have
`resulted in selection bias in both groups. The findings
`of this study should also be interpreted in light of the
`small number of individuals with TlDM included in the
`analysis (<10%) and by the lack of comparison with other
`pen types. Further studies are warranted to address
`these points.
`
`Continual development of insulin pen devices is an
`important consideration to aid the treatment of diabetes.
`For example, many of the earlier reusable insulin devices,
`such as OptiPen Pro and NovoPen 3, had maximum doses
`of only 60 U. However, the trend toward higher insulin
`doses of basal insulin in particular has prompted the
`introduction of pens such as SoloSTAR and ClikSTAR
`with 80 U maximum doses. In the LANMET study,16 for
`example, the average insulin doses of insulin glargine
`and neutral protamine Hagedorn insulin were 68 and
`70 U/day, respectively, which would require multiple
`injections for pens with 60 U maximum doses. Similarly,
`the introduction of multiple body colors for SoloSTAR
`was reported to aid the differentiation between insulin
`pens17 and is likely to be advantageous for the increasing
`number of patients using intensive basal and prandial
`insulin regimens. Accordingly, ClikSTAR was developed
`to incorporate these advantages into a reusable device,
`thus providing an advanced device option for individuals
`with diabetes.
`
`Schwartz
`
`Conclusions
`
`Overall, this study has validated the assertion that it is
`easy for diabetes patients to correctly use the ClikSTAR
`pen to deliver insulin accurately, as demonstrated by
`the finding that the majority of participants in group A
`(99.6%) delivered three insulin doses successfully after
`receiving training from a diabetes specialist. Although a
`high level of success was also achieved after self-training,
`face-to-face training is recommended to ensure that people
`with diabetes can use insulin pens correctly before
`starting insulin therapy.
`
`Funding:
`
`This study was supported by sanofi-aventis.
`
`Acknowledgments:
`
`Editorial support was provided by Anisha Mehra, Ph.D., Medicus
`International and funded by sanofi-aventis.
`
`References:
`
`1. American Diabetes Association. Standards of medical care in
`diabetes--2010. Diabetes Care. 2010;33 Suppl l:Sll-61.
`
`2. 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
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`Sanofi Exhibit 2119.006
`Mylan v. Sanofi
`IPR2018-01675
`
`

`

`Schwartz
`
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`www.iournalofdst.org
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`Sanofi Exhibit 2119.007
`Mylan v. Sanofi
`IPR2018-01675
`
`