Diabetes Ther
`https://doi.org/10.1007/s13300-023-01499-x
`
`ORIGINAL RESEARCH
`
`Physician Perceptions of Dose Escalation for Type 2
`Diabetes Medications in the United States
`
`Kristina S. Boye . Jessica B. Jordan . Raleigh Malik . Louis S. Matza
`
`Received: July 25, 2023 / Accepted: October 17, 2023
`Ó The Author(s) 2023
`
`ABSTRACT
`
`Introduction: Medications used to treat type 2
`diabetes (T2D) often require dose escalation to
`optimize effectiveness. Physician and patient
`perceptions of treatment characteristics of T2D
`medications have previously been examined,
`but little is known about perceptions of escala-
`tion to the optimal dose for each patient. This
`study examined physicians’ perceptions of dose
`escalation for medications used to treat T2D.
`Methods: Data on dose escalation and other
`factors influencing decision-making for treat-
`ment of T2D were collected via an online survey
`of endocrinologists and primary care physicians
`in the USA.
`Results: The sample included 501 physicians
`(348
`primary
`care
`physicians
`and
`153
`
`Prior Presentation: Parts of these study results were
`presented in a poster format at the American Diabetes
`Association 83rd Annual Scientific Sessions in San Diego,
`CA from 23–26 June 2023. The citation for this work is as
`follows: Boye K, Jordan J, Malik R, Cyr RA, Matza LS.
`1054-P: A Physician Survey Focusing on Dose Escalation
`for Type 2 Diabetes Medications. Diabetes.
`2023;72(Supplement1) https://doi.org/10.2337/db23-
`1054-P.
`
`K. S. Boye R. Malik
`Eli Lilly and Company, Indianapolis, IN, USA
`J. B. Jordan L. S. Matza (&)
`Evidera, Bethesda, MD, USA
`e-mail: louis.matza@evidera.com
`
`endocrinologists). Dose escalation was not fre-
`quently considered by physicians as a primary
`factor keeping patients’ from reaching treatment
`goals (mentioned as a factor by only 7.6% of the
`sample) or a barrier to prescribing T2D medica-
`tion (16.2%). Factors more likely to keep patients
`from reaching treatment goals
`included an
`unhealthy diet (86.6%) and medication adher-
`ence (77.4%). The most common reasons that
`physicians reported for escalating dose levels were
`the need for better glycemic control (reported by
`89.8% of the sample), ability to decrease the total
`number of medications by increasing the dose of
`one medication (39.9%), and the need for the
`patient to lose weight (39.3%). Data reported by
`primary care physicians and endocrinologists
`followed similar patterns.
`Conclusions: Although common with T2D
`treatments, escalating the dose of T2D medica-
`tion was not perceived by physicians to be a
`significant barrier to attaining treatment goals
`or prescribing medication. Multiple factors
`contribute to the decision to escalate the dose of
`T2D medication.
`
`PLAIN LANGUAGE SUMMARY
`
`In early phases of initiating medication treat-
`ment for a patient with type 2 diabetes (T2D), it
`is common for physicians to increase from a
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`lower initial dose to a higher end dose to max-
`imize treatment benefit. This process is known
`as dose escalation. The purpose of this study was
`to examine physicians’ perceptions of dose
`escalation for medications used to treat T2D. An
`online survey was designed to identify reasons
`why physicians in the US may choose to esca-
`late or not escalate a dose of medication for
`T2D. In addition, physicians were asked about
`factors that keep patients from reaching treat-
`ment goals to identify whether the requirement
`for dose escalation is perceived to be a common
`barrier to successful treatment. The sample
`included 501 physicians (348 primary care, 153
`endocrinologists). Dose escalation was not fre-
`quently considered to be a primary factor
`keeping patients’ from reaching treatment goals
`or a barrier to prescribing medication for T2D.
`Dose escalation decisions are complex, driven
`by a range of factors such as glycemic control
`medication tolerability, the patient’s body mass
`index,
`treatment guidelines,
`comorbidities,
`characteristics of the patient’s entire treatment
`regimen, and potential cardiovascular benefits.
`
`Keywords: Type 2 diabetes; Dose escalation;
`Online
`survey;
`Primary
`care
`physician;
`Endocrinologist; Treatment goal; Prescribing
`barrier
`
`Key Summary Points
`
`Why carry out this study?
`
`Because dose escalation is a common
`attribute of medications used to treat type
`2 diabetes (T2D), it is important to
`understand its impact.
`
`Little is known about physicians’
`perceptions of escalation to the optimal
`dose for each patient.
`
`The purpose of this study was to conduct
`an online survey of endocrinologists and
`primary care physicians in the US to
`examine their perceptions of dose
`escalation for medications used to treat
`T2D.
`
`Diabetes Ther
`
`What was learned from the study?
`
`Results suggest that most physicians,
`including endocrinologists and primary
`care physicians, do not perceive dose
`escalation to be a significant challenge.
`
`Dose escalation was not perceived to be a
`significant barrier to attaining treatment
`goals or prescribing medication.
`
`Decisions to escalate a dose are complex,
`driven by a range of factors such as
`glycemic control, medication tolerability,
`the patient’s body mass index, treatment
`guidelines, comorbidities, characteristics
`of the patient’s entire treatment regimen,
`and potential cardiovascular benefits.
`
`INTRODUCTION
`
`A growing body of literature has focused on
`attributes of medications used to treat type 2
`diabetes (T2D). Attributes examined in previous
`research include dose frequency, dose flexibil-
`ity, glucose monitoring, adverse event profile,
`requirements for reconstituting the medication,
`and ease of preparing and using injection devi-
`ces [1–14]. Attributes of the treatment process
`have been shown to affect medication adher-
`ence, which can have an impact on treatment
`outcomes [15–21]. In addition to the impact on
`patients, these medication attributes can also
`affect physicians’ perceptions of treatments for
`T2D [22], which directly influence their choice
`of medications to prescribe for their patients.
`Relatively limited research has examined the
`impact of dose escalation. Dose escalation is the
`process of increasing a fixed dose of medication
`from a lower initial dose to a higher end dose to
`optimize the medication’s acceptability and
`efficacy [23]. Dose escalation is commonly
`required during the early phases of treatment
`with oral and injectable T2D therapies, such as
`metformin, liraglutide, tirzepatide, dulaglutide,
`and semaglutide [24–26]. Dose escalation is
`different
`from the
`individualized
`dose
`
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`Diabetes Ther
`
`adjustments in response to changes in a physi-
`ological parameter, often called ‘‘dose titration.’’
`For example, patients treated with multiple
`daily insulin injections regularly adjust their
`dose based on blood glucose levels [27].
`Because dose escalation is a common attri-
`bute of medications used to treat T2D, it is
`important to understand its impact. In a previ-
`ous study examining the patient perspective,
`dose escalation was perceived to be one of the
`least important characteristics of treatment for
`T2D [27]. However, physicians’ perceptions of
`dose
`escalation remain largely unknown.
`Therefore, the purpose of this study was to
`examine physicians’ perceptions of dose esca-
`lation for medications used to treat T2D. An
`online survey was designed to identify reasons
`why physicians may choose to escalate or not
`escalate a dose of medication for T2D. In addi-
`tion, physicians were asked about factors that
`keep patients from reaching treatment goals to
`identify whether
`the requirement
`for dose
`escalation is perceived to be a common barrier
`to successful treatment.
`
`METHODS
`
`Study Design
`
`In this cross-sectional study, physicians com-
`pleted an online survey designed to assess their
`perceptions of dose escalation. Before complet-
`ing the survey, physicians provided electronic
`consent and completed online screening ques-
`tions to determine whether they were eligible to
`participate. The online survey was designed to
`take approximately 20–30 min to complete, and
`physicians who completed the survey were
`reimbursed. Participants provided informed
`consent before completing the survey. All pro-
`cedures and materials were approved by a cen-
`tral
`institutional
`review board (22131-01A,
`Ethical and Independent Review Services),
`which was conducted in accordance with the
`Declaration of Helsinki. All surveys were com-
`pleted from July to September 2022.
`
`Participants
`
`Participants were primary care physicians and
`endocrinologists licensed to practice medicine
`in the USA. To be eligible for this study, physi-
`cians were required to have been in medical
`practice for C 1 year, treated an average of C 10
`patients with T2D per month, and prescribed
`injectable T2D medication (i.e., insulin or glu-
`cagon-like peptide-1 receptor agonists) for C 3
`patients in the 6 months prior to survey com-
`pletion. Physicians were excluded if they were
`practicing medicine in a state where the Sun-
`shine Act prohibits participation (i.e., Vermont
`and Massachusetts). An estimated sample size of
`approximately 400 to 500 physicians (approxi-
`mately 70% primary care physicians, 30%
`endocrinologists) was targeted, roughly equally
`distributed across four US regions (Northeast,
`Midwest, South, and West). As the planned
`analyses were descriptive without a key statis-
`tical comparison, no power analysis was con-
`ducted when determining the sample size
`target. The sample size target was determined
`on the basis of similar surveys published in the
`past as well as practical implications.
`Participants were
`recruited through a
`healthcare provider (HCP) panel built over a
`period of approximately 12 years by sourcing
`HCP contact data through direct physician
`outreach,
`conferences,
`LinkedIn outreach,
`ZoomInfo, institution websites, and PubMed.
`HCP status is confirmed at the time of opting
`into the panel by verifying their National Pro-
`vider Identifier and implementing other quality
`control metrics. Panelist data are periodically
`cross-checked against online databases
`to
`ensure profiling remains accurate as time passes.
`The recruitment strategy for most of the study
`was to conduct a spam-resistant continual email
`campaign, sending study invitations to verified
`primary care physicians and endocrinologists in
`the HCP panel. However, for the initial soft
`launch of 15 physicians, a controlled email
`campaign was used to avoid over-recruitment
`and pause data collection as needed to identify
`any potential issues with the survey prior to full
`launch. For the full launch, the continual email
`campaign was initiated, usually sending emails
`every 2 days during the study period. The email
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`invitation briefly described the study and how
`much time it would take. A link was provided in
`the email invitation for the participant to click
`and be screened. If the screening questions
`determined that the participant was eligible, the
`participant would continue by completing the
`online physician survey. For this study, a total of
`[ 30,000 email
`invitations were sent, and
`recruitment was discontinued when the sample
`size target was reached.
`
`Online Physician Survey
`
`To inform development of the survey, four
`clinical experts (three physicians with experi-
`ence treating T2D and one clinical researcher
`who designs trials of medication for T2D) were
`interviewed about dose escalation. They were
`asked about factors they consider when decid-
`ing whether to escalate the dose of T2D medi-
`cation, advantages and disadvantages of dose
`escalation, and the importance of dose escala-
`tion relative to other attributes of medication
`used to treat T2D. The content of the online
`survey was based on input provided during
`these qualitative interviews with physicians and
`a clinical researcher.
`for
`The survey began with instructions
`completion. Respondents were instructed to
`answer the questions while thinking about ‘‘the
`broad range of antihyperglycemic medications
`for type 2 diabetes, including oral treatment like
`metformin, empagliflozin, and oral semaglu-
`tide; basal and meal-time insulin; and non-in-
`sulin injectable medications like liraglutide,
`injectable semaglutide, and dulaglutide.’’ Then,
`a series of questions were administered to
`determine whether the physicians met study
`inclusion criteria. Physicians who met criteria
`continued by completing three additional
`background questions (see physician character-
`istics in Table 1). The next set of questions
`assessed the importance of dose escalation rel-
`ative to other medication attributes. These
`items asked physicians to select from a list of
`medication attributes (presented in Tables 2 and
`3) to indicate which attributes most commonly
`prevent patients from reaching treatment goals
`
`Diabetes Ther
`
`and which attributes were most commonly
`perceived as a barrier to prescribing medication.
`The final series of questions was designed to
`provide
`insight
`into physicians’ decisions
`regarding dose escalation. For example, one
`question asked physicians to select from among
`a list of factors (presented in Table 4) they
`consider when deciding whether to escalate a
`dose of medication for T2D. Another item asked
`physicians to report the most common reasons
`for escalating a dose over the past 6 months,
`again by selecting from a list of potential rea-
`sons (presented in Table 5).
`After each of the questions where physicians
`selected multiple responses
`from a list of
`options (i.e., Tables 2, 3, 4, 5), physicians were
`asked to rank their selections in order of
`importance. The exact wording of the key
`questions is presented in footnotes below the
`relevant tables.
`it was
`After completing the draft survey,
`formatted for online completion and adminis-
`tered to the first 15 participants (i.e., 10 primary
`care physicians and 5 endocrinologists). Data
`collection was paused after these initial 15 par-
`ticipants so that results could be examined to
`ensure that
`the survey was functioning as
`intended. Results of the interim analysis led to
`two edits prior to continuing with data collec-
`tion. First, the item assessing gender was moved
`to the screening section earlier in the survey so
`that gender could be considered as part of the
`screening criteria. Second, one question was
`deleted because it appeared to be potentially
`confusing. After making these two edits, the full
`data collection was allowed to proceed until the
`sample size target was met. Because no survey
`content was changed or added following the
`initial 15 completions, results from the pilot
`participants were included in the final dataset.
`
`Statistical Methods
`
`Descriptive statistics were used to summarize
`participants’ responses and to characterize the
`sample in terms of sociodemographic charac-
`teristics and clinical background. For continu-
`ous variables,
`the mean, median,
`standard
`deviation,
`and
`range were
`calculated.
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`Diabetes Ther
`
`Table 1 Physician background information
`
`Physician characteristics
`
`Years in medical practice (mean, SD)
`
`Years managing or treating patients with T2D (mean,
`SD)
`
`Practice setting description (n, %)
`
`Individual or small group practice
`
`Multi-specialty group practice
`
`Hospital setting
`
`Long-term care facility
`
`Other
`
`Gender (n, %)
`
`Male
`
`Female
`
`Decline to respond
`
`Region of practice in US (n, %)
`
`Northeast
`
`Midwest
`
`South
`
`West
`
`Total
`sample
`(N = 501)
`
`Primary care
`physicians
`(N = 348)
`
`18.7 (9.3)
`
`18.8 (9.4)
`
`18.9 (9.3)
`
`19.2 (9.4)
`
`208 (41.5%) 161 (46.3%)
`
`217 (43.3%) 135 (38.8%)
`
`57 (11.4%)
`
`36 (10.3%)
`
`6 (1.2%)
`
`6 (1.7%)
`
`13 (2.6%)
`
`10 (2.9%)
`
`320 (63.9%) 226 (64.9%)
`
`176 (35.1%) 120 (34.5%)
`
`5 (1.0%)
`
`2 (0.6%)
`
`130 (25.9%) 89 (25.6%)
`
`117 (23.4%) 85 (24.4%)
`
`139 (27.7%) 92 (26.4%)
`
`115 (23.0%) 82 (23.6%)
`
`Endocrinologists
`(N = 153)
`
`P valuea
`
`0.606
`
`0.369
`
`0.004
`
`0.303
`
`0.680
`
`18.4 (9.1)
`
`18.4 (9.2)
`
`47 (30.7%)
`
`82 (53.6%)
`
`21 (13.7%)
`
`0 (0.0%)
`
`3 (2.0%)
`
`94 (61.4%)
`
`56 (36.6%)
`
`3 (2.0%)
`
`41 (26.8%)
`
`32 (20.9%)
`
`47 (30.7%)
`
`33 (21.6%)
`
`SD standard deviation, T2D type 2 diabetes
`aP values are for analyses comparing the two subgroups of participants in this table. The statistical tests were t tests for
`continuous variables and chi-square analyses for categorical variables
`
`Categorical variables are reported as frequencies
`and percentages. Analyses were conducted with
`SAS software version 9.4 (SAS Institute, Cary,
`NC).
`
`RESULTS
`
`Sample Characteristics
`
`Of the 602 physicians who were screened, 501
`(83.2%) met
`criteria
`for
`study inclusion,
`including 348 (57.8%) primary care physicians
`and 153 (25.4%) endocrinologists (Fig. 1). The
`
`most common reasons for ineligibility were not
`being a primary care physician or endocrinolo-
`gist (n = 47, 46.5%) and not seeing a sufficient
`number of patients with T2D per month
`(n = 13, 12.9%). The majority of physicians
`were male (n = 320, 63.9% of those who com-
`pleted the survey), and most worked in either
`an individual or small group practice (n = 208,
`41.5%) or a multi-specialty group practice
`(n = 217, 43.3%). Participants were roughly
`evenly
`distributed
`across
`the Northeast
`(n = 130, 25.9%), Midwest (n = 117, 23.4%),
`South (n = 139, 27.7%), and West (n = 115,
`23.0%) regions of the US (Table 1).
`
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`Table 2 Factors preventing patients from reaching T2D treatment goalsa
`Factors that keep patients from reaching treatment goals (n, %)b Total
`sample
`(N = 501)
`
`Primary care
`physicians
`(N = 348)
`
`Endocrinologists
`(N = 153)
`
`Diabetes Ther
`
`Unhealthy diet
`
`Medication adherence problems (i.e.,
`not taking medication as directed or skipping doses)
`
`Lack of exercise
`
`Difficulty obtaining medication
`
`Medication adverse events
`
`Missing healthcare visits
`
`Difficulty titrating doses based on
`blood glucose levels (e.g., with insulin)
`
`Challenges with using an injection device
`
`Frequency of medication doses
`
`Difficulty accessing healthcare
`
`Dose timing requirements (like having to
`take medication at a specific time)
`
`Onset of new comorbidities
`
`Physical limitations
`
`Difficulty escalating to an effective dose
`
`Cognitive issues
`
`Other reason not listed here
`
`434 (86.6%)
`
`306 (87.9%)
`
`128 (83.7%)
`
`388 (77.4%)
`
`272 (78.2%)
`
`116 (75.8%)
`
`360 (71.9%)
`
`264 (75.9%)
`
`96 (62.7%)
`
`222 (44.3%)
`
`147 (42.2%)
`
`75 (49.0%)
`
`140 (27.9%)
`
`97 (27.9%)
`
`43 (28.1%)
`
`132 (26.3%)
`
`94 (27.0%)
`
`38 (24.8%)
`
`106 (21.2%)
`
`67 (19.3%)
`
`39 (25.5%)
`
`97 (19.4%)
`
`70 (20.1%)
`
`27 (17.6%)
`
`88 (17.6%)
`
`57 (16.4%)
`
`31 (20.3%)
`
`87 (17.4%)
`
`60 (17.2%)
`
`27 (17.6%)
`
`60 (12.0%)
`
`35 (10.1%)
`
`25 (16.3%)
`
`54 (10.8%)
`
`33 (9.5%)
`
`21 (13.7%)
`
`41 (8.2%)
`
`30 (8.6%)
`
`38 (7.6%)
`
`28 (8.0%)
`
`37 (7.4%)
`
`28 (8.0%)
`
`20 (4.0%)
`
`13 (3.7%)
`
`11 (7.2%)
`
`10 (6.5%)
`
`9 (5.9%)
`
`7 (4.6%)
`
`T2D type 2 diabetes
`aPhysicians responded to the following question: ‘‘What are the primary factors that keep your patients from reaching their
`type 2 diabetes treatment goals, such as maintaining good glycemic control, losing weight, and reducing cardiovascular risk?
`(Check up to five of the most important factors)’’
`bFactors are sorted by total N, with the most commonly cited factors appearing first
`
`Factors Preventing Attainment of T2D
`Treatment Goals
`
`Unhealthy diet (86.6%), medication adherence
`problems (77.4%), and lack of exercise (71.9%)
`were the factors most commonly cited by
`physicians as preventing patients from reaching
`T2D treatment goals (Table 2). In contrast, few
`physicians (7.6%) selected ‘‘difficulty escalating
`to an effective dose’’ as a factor that prevented
`patients from reaching treatment goals. Of the
`38 physicians (7.6%) who ranked ‘‘difficulty
`
`escalating to an effective dose’’ as one of the five
`most
`important
`factors preventing patients
`from reaching T2D treatment goals, only one
`(2.6%) ranked it as the most important factor.
`Reports of the primary care physicians and
`endocrinologists followed similar patterns.
`
`Barriers to Prescribing T2D Medication
`
`Over two-thirds of physicians (68.7%) reported
`that health plan formulary restrictions were a
`barrier
`to
`prescribing
`T2D medications
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`Diabetes Ther
`
`Table 3 Barriers to prescribing a medication for treatment of T2Da
`
`Barriers that most frequently keep physicians
`from prescribing any specific medication for T2D (n, %)b
`
`Total sample
`(N = 501)
`
`Primary care
`physicians
`(N = 348)
`
`Endocrinologists
`(N = 153)
`
`Patient health plan formulary restrictions
`
`344 (68.7%)
`
`240 (69.0%)
`
`104 (68.0%)
`
`Injectable route of administration
`
`230 (45.9%)
`
`177 (50.9%)
`
`53 (34.6%)
`
`Risk of medication-related adverse events
`
`200 (39.9%)
`
`141 (40.5%)
`
`59 (38.6%)
`
`Patient preference
`
`Tendency to cause weight gain
`
`Insufficient efficacy for glycemic control
`
`Frequency of medication doses
`
`Insufficient effect on weight loss
`
`Durability of glycemic effectiveness
`
`Warnings and precautions in the drug label
`
`Challenges associated with escalating to an effective dose
`
`Difficulty titrating doses based on blood glucose
`levels (e.g., insulin)
`
`My lack of familiarity or experience with
`a particular medication
`
`Lack of evidence on cardiovascular outcomes
`
`Inconveniences associated with oral medication
`(e.g., size of pill, dose timing, food restrictions)
`
`Time required to train patients on how to
`properly use medication
`
`Need for refrigeration of the medication
`
`Other reason not listed here
`
`186 (37.1%)
`
`131 (37.6%)
`
`55 (35.9%)
`
`161 (32.1%)
`
`102 (29.3%)
`
`59 (38.6%)
`
`140 (27.9%)
`
`82 (23.6%)
`
`118 (23.6%)
`
`83 (23.9%)
`
`110 (22.0%)
`
`72 (20.7%)
`
`83 (16.6%)
`
`82 (16.4%)
`
`81 (16.2%)
`
`80 (16.0%)
`
`47 (13.5%)
`
`61 (17.5%)
`
`53 (15.2%)
`
`54 (15.5%)
`
`58 (37.9%)
`
`35 (22.9%)
`
`38 (24.8%)
`
`36 (23.5%)
`
`21 (13.7%)
`
`28 (18.3%)
`
`26 (17.0%)
`
`78 (15.6%)
`
`69 (19.8%)
`
`9 (5.9%)
`
`53 (10.6%)
`
`50 (10.0%)
`
`35 (10.1%)
`
`32 (9.2%)
`
`18 (11.8%)
`
`18 (11.8%)
`
`46 (9.2%)
`
`35 (10.1%)
`
`11 (7.2%)
`
`38 (7.6%)
`
`32 (6.4%)
`
`26 (7.5%)
`
`24 (6.9%)
`
`12 (7.8%)
`
`8 (5.2%)
`
`T2D type 2 diabetes
`aPhysicians responded to the following question: ‘‘When choosing among treatment options for your patients with type 2
`diabetes, what are the barriers that most frequently keep you from prescribing any specific medication? (Check up to five of
`the most important barriers)’’
`bBarriers are sorted by total N, with the most commonly cited barriers appearing first
`
`(Table 3). Other commonly reported barriers
`included an injectable route of administration
`(45.9%), concerns about the risk of medication-
`related adverse events (39.9%), patient prefer-
`ence (37.1%), and the tendency of some T2D
`medications to cause weight gain (32.1%). In
`comparison, ‘‘challenges associated with esca-
`lating to an effective dose’’ was reported to be a
`
`barrier to prescription less frequently (16.2%).
`When physicians were asked to rank the factors
`they consider to be barriers to prescription,
`health plan formulary restrictions were most
`commonly cited (by 67.4% of the sample) as the
`most important factor. Dose escalation was
`reported to be the primary barrier by 9.9% of
`the sample.
`
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`Diabetes Ther
`
`Table 4 Factors considered by physicians when deciding whether to escalate a dose of medication for T2Da
`
`Factors considered by physicians when deciding
`whether to escalate a dose of medication to
`treat T2D (n, %)b
`
`Total
`sample
`(N = 501)
`
`Primary care
`physicians
`(N = 348)
`
`Endocrinologists
`(N = 153)
`
`Glycemic control and HbA1c
`
`446 (89.0%)
`
`312 (89.7%)
`
`134 (87.6%)
`
`Medication tolerability and adverse events
`
`303 (60.5%)
`
`207 (59.5%)
`
`96 (62.7%)
`
`Severity of the patient’s diabetes
`
`Patient’s current weight or BMI
`
`Treatment guidelines
`
`212 (42.3%)
`
`155 (44.5%)
`
`57 (37.3%)
`
`192 (38.3%)
`
`126 (36.2%)
`
`66 (43.1%)
`
`187 (37.3%)
`
`146 (42.0%)
`
`41 (26.8%)
`
`Comorbidities (e.g., hypertension, dyslipidemia, fatty liver)
`
`173 (34.5%)
`
`128 (36.8%)
`
`45 (29.4%)
`
`Escalating one antihyperglycemic medication dose may allow
`a patient to discontinue or decrease the dose
`of another medication
`
`Cardiovascular benefits of treatment
`
`Patient’s reaction to a dose increase (e.g., escalation may
`feel discouraging to some patients)
`
`112 (22.4%)
`
`65 (18.7%)
`
`47 (30.7%)
`
`105 (21.0%)
`
`71 (20.4%)
`
`81 (16.2%)
`
`52 (14.9%)
`
`34 (22.2%)
`
`29 (19.0%)
`
`Recommendations in the drug label
`
`74 (14.8%)
`
`44 (12.6%)
`
`30 (19.6%)
`
`Patient’s ability to make changes
`
`Patient’s cardiovascular history
`
`Escalating the dose of one antihyperglycemic medication
`may complicate polypharmacy because you may need
`to adjust the dose of another medication
`
`Patient’s age
`
`Difficulties for you and your office associated with
`changing from one dose to another (e.g., writing
`a new prescription, more follow-up appointments,
`patient training)
`
`Escalating a dose may be lower priority than other
`aspects of the patient’s care (e.g., managing blood
`pressure, adjusting cholesterol medications)
`
`Reluctance to waste medication (e.g., if patient just
`picked up a 90-day supply of a dose, they may not
`want to change to a new dose)
`
`74 (14.8%)
`
`60 (17.2%)
`
`14 (9.2%)
`
`70 (14.0%)
`
`49 (14.1%)
`
`58 (11.6%)
`
`40 (11.5%)
`
`21 (13.7%)
`
`18 (11.8%)
`
`39 (7.8%)
`
`35 (7.0%)
`
`29 (8.3%)
`
`23 (6.6%)
`
`10 (6.5%)
`
`12 (7.8%)
`
`28 (5.6%)
`
`22 (6.3%)
`
`6 (3.9%)
`
`26 (5.2%)
`
`17 (4.9%)
`
`9 (5.9%)
`
`Duration of the patient’s diabetes
`
`22 (4.4%)
`
`11 (3.2%)
`
`11 (7.2%)
`
`BMI body mass index, HbA1c glycated hemoglobin, T2D type 2 diabetes
`aPhysicians responded to the following question: ‘‘What are the factors you consider when deciding whether to escalate the
`dose of medication used to treat type 2 diabetes? (Check up to five of the most important factors)’’
`bFactors are sorted by total N, with the most commonly cited factors appearing first
`
`Novo Nordisk Exhibit 2382
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
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`Diabetes Ther
`
`Table 5 Reasons for escalating a dose of medication for their patients with T2Da
`
`Most common reasons physicians have escalated a dose for patients
`with T2D in the past 6 months (n, %)b
`
`Total
`sample
`(N = 501)
`
`Primary care
`physicians
`(N = 348)
`
`Endocrinologists
`(N = 153)
`
`Patient needed more HbA1c benefit or glycemic control
`
`450 (89.8%) 317 (91.1%)
`
`133 (86.9%)
`
`By increasing the dose of one medication, you were able to decrease the
`patient’s total number of pills or injections
`
`200 (39.9%) 126 (36.2%)
`
`74 (48.4%)
`
`Patient needed more weight loss
`
`There were no tolerability concerns at a lower dose, which made it
`possible to increase the dose
`
`197 (39.3%) 123 (35.3%)
`
`74 (48.4%)
`
`194 (38.7%) 130 (37.4%)
`
`64 (41.8%)
`
`You were trying to maximize cardiovascular benefits of treatment
`
`167 (33.3%) 126 (36.2%)
`
`41 (26.8%)
`
`A higher dose was recommended in treatment guidelines
`
`110 (22.0%) 88 (25.3%)
`
`22 (14.4%)
`
`A higher dose was recommended in the drug label
`
`40 (8.0%)
`
`22 (6.3%)
`
`18 (11.8%)
`
`Patient requested a higher dose
`
`15 (3.0%)
`
`11 (3.2%)
`
`4 (2.6%)
`
`Published previously in Boye et al. 1054-P: A Physician Survey Focusing on Dose Escalation for Type 2 Diabetes Medi-
`cations. Diabetes. 2023;72(Supplement_1). Copyright 2023 by the American Diabetes Association
`HbA1c glycated hemoglobin, T2D type 2 diabetes
`aPhysicians responded to the following question: ‘‘In the past 6 months, what are the most common reasons you have
`escalated a dose for your type 2 diabetes patients? (Check up to five reasons)’’
`bReasons are sorted by total N, with the most commonly cited reasons appearing first
`
`Factors Contributing to Decisions About
`Dose Escalation
`
`To identify factors that physicians consider
`when deciding whether to escalate a dose of
`medication for T2D, they were asked to select
`the five most important factors from the list of
`18 factors presented in Table 4.
`‘‘Glycemic
`control and HbA1c’’ were selected as one of the
`five most important factors by 446 physicians
`(89.0% of the sample). Of these 446, 74.9%
`reported that this was the most important factor
`contributing to dose
`escalation decisions.
`‘‘Medication tolerability and adverse events’’
`appears to be a second primary factor, selected
`by 60.5% of the sample. While no other factors
`were selected by a majority of the sample, the
`other common factors included severity of the
`patient’s diabetes (42.3%), the patient’s current
`weight or body mass index (BMI)
`(38.3%),
`treatment guidelines (37.3%), and comorbidi-
`ties (34.5%). Responses to this question fol-
`lowed similar patterns for the primary care
`physicians and endocrinologists (Table 4).
`
`Respondents were also asked about the most
`common reasons they have escalated a dose for
`patients during the past 6 months (Table 5).
`Consistent with results in Table 4, they reported
`most commonly escalating a dose because their
`patients
`required more
`glycemic
`control
`(89.8%). Other reasons that were somewhat
`commonly cited included the ability to decrease
`total medication burden by increasing the dose
`of one medication (39.9%), the need for more
`weight loss (39.3%), and the fact that there were
`no tolerability concerns at a lower dose, which
`made it possible to increase the dose (38.7%).
`Physicians were also asked about the factors
`that cause them not to escalate a dose for one of
`their patients. The most commonly cited rea-
`sons were the potential for adverse events at a
`higher dose (68.5%), additional glycemic con-
`trol was not needed (66.3%), dosing limitations
`associated with comorbidities such as chronic
`kidney disease (49.7%), and the patient’s age
`(25.0%). Reasons for escalating and not esca-
`lating a dose followed similar patterns for the
`primary care physicians and endocrinologists.
`
`Novo Nordisk Exhibit 2382
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00009
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`Diabetes Ther
`
`Fig. 1 Participant disposition. T2D, type 2 diabetes. *Excluding rescue medications
`
`DISCUSSION
`
`Previous research has examined patient and
`physician perceptions of a wide range of attri-
`butes of medications for treatment of T2D
`[9, 14]. For example, medication attributes
`shown to have an impact on patient preference
`include glycemic control, adverse event profile,
`dose frequency, injection device, dose flexibil-
`ity, and medication preparation requirements
`[14]. However, the current study is the first to
`focus on dose escalation for the treatment of
`T2D. Results of the current survey suggest that
`endocrinologists and primary care physicians
`may not perceive dose escalation to be a sig-
`nificant challenge. These findings add to a pre-
`vious study indicating that patients perceived
`dose escalation to be one of the least important
`characteristics of treatments for T2D [27].
`Only 16.2% of physicians in this sample
`reported that dose escalation was a potential
`barrier
`to prescribing medication for
`their
`patients with T2D. Furthermore, only 7.6%
`considered dose escalation requirements to be
`one of the top five factors preventing patients
`from reaching treatment goals. The factors that
`were most commonly believed to interfere with
`treatment goals tended to be related to patient
`
`behavior, such as unhealthy diet, medication
`adherence,
`lack of
`exercise, and missing
`healthcare visits. In addition, a range of treat-
`ment process attributes were perceived to
`interfere with treatment goals more commonly
`than dose escalation (e.g., the need to titrate
`doses based on glucose levels, dose frequency,
`dose timing requirements). In general, these
`results were similar across the subgroups of
`endocrinologists and primary care physicians.
`Overall, these findings help place dose escala-
`tion in context of other T2D medication attri-
`butes.
`From the
`physician
`perspective,
`requirements for dose escalation appear to be a
`less important concern than the effects of the
`medication as well as other treatment process
`attributes.
`Results also provide insight into physicians’
`decision-making regarding dose
`escalation.
`Responses to several questions in this survey
`indicate that decisions to escalate a dose are
`complex, driven by a range of factors. The need
`for increased glycemic control was the most
`commonly reported reason that physicians
`escalate a dose, but they reported considering
`multiple factors when making these decisions,
`including medication tolerability, the patient’s
`current weight or BMI, treatment guidelines,
`
`Novo Nordisk Exhibit 2382
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
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`Diabetes Ther
`
`comorbidities, characteristics of the patient’s
`entire treatment regimen, and potential car-
`diovascular benefits.
`Findings should be interpreted in the con-
`text of several limitations. First, the survey was
`conducted with a sample of physicians who
`treat T2D; therefore,