Diabetes Ther (2016) 7:411–438
`DOI 10.1007/s13300-016-0180-0
`
`REVIEW
`
`Clinical Effectiveness of Liraglutide in Type 2 Diabetes
`Treatment in the Real-World Setting: A Systematic
`Literature Review
`
`Amrita Ostawal . Emina Mocevic . Nana Kragh . Weiwei Xu
`
`Received: May 10, 2016 / Published online: June 27, 2016
`Ó The Author(s) 2016. This article is published with open access at Springerlink.com
`
`ABSTRACT
`
`Introduction: In clinical trials, liraglutide has
`proven to be an effective drug for the treatment
`of
`type 2 diabetes mellitus
`(T2DM). The
`real-world effectiveness of liraglutide has been
`investigated in numerous studies. The aim of
`this systematic literature review is to collate
`evidence on the real-world clinical effectiveness
`of liraglutide.
`Methods: A review of publications
`from
`Medline, EMBASE, the Cochrane Library, and
`conference proceedings was
`conducted to
`identify observational studies that assessed the
`
`Enhanced content To view enhanced content for this
`article go to http://www.medengine.com/Redeem/
`DBD4F060387252C8.
`
`Electronic supplementary material The online
`version of this article (doi:10.1007/s13300-016-0180-0)
`contains supplementary material, which is available to
`authorized users.
`
`A. Ostawal
`Pharmerit GmbH, Berlin, Germany
`E. Mocevic N. Kragh
`Novo Nordisk A/S, Søborg, Denmark
`
`W. Xu (&)
`Pharmerit International, Rotterdam,
`The Netherlands
`e-mail: wxu@pharmerit.com
`
`clinical effectiveness of liraglutide in real-world
`clinical practice. This review was conducted
`according to the National Institute of Health
`and Care Excellence (NICE) guidance. No
`language or time limits were applied, except to
`the
`conference
`proceedings
`(2013–2015).
`Endpoints for data extraction were decided a
`priori. Study quality appraisal was done for
`full-text journal articles.
`Results: Of 124 publications included in the
`review, 43 were full-text articles. Liraglutide
`significantly
`reduces
`glycated hemoglobin
`(HbA1c) within
`6 months
`of
`initiating
`treatment
`(mean change
`in HbA1c
`from
`baseline: -0.9% to -2.2%; HbA1c \7.0%:
`29.5–65.0%). The NICE composite endpoint
`(HbA1c
`reduction C1%
`and
`weight
`reduction C3%) was met
`in 16.9–47.0% of
`patients with liraglutide treatment. Liraglutide
`therapy led to a mean change in absolute
`weight
`from baseline of -1.3 to -8.65 kg.
`Liraglutide treatment was well
`tolerated in
`patients with T2DM. The rate of occurrence of
`hypoglycemia with liraglutide monotherapy
`was B0.8%. Hypoglycemia was more common
`in patients
`taking antidiabetic medications
`(0.0–15.2%)
`together with liraglutide. The
`
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`Diabetes Ther (2016) 7:411–438
`
`effect of
`and weight
`beneficial glycemic
`liraglutide therapy in patients with T2DM was
`maintained for at least 12 months.
`Conclusion: Evidence
`from observational
`studies reflecting real-world clinical practice
`demonstrates that liraglutide therapy improves
`glycemic
`control with a
`low risk
`of
`hypoglycemia,
`and
`is
`associated with
`significant weight loss in patients with T2DM.
`These observations are consistent with clinical
`trial findings.
`Funding: Novo Nordisk A/S, Søborg, Denmark.
`
`Keywords: Effectiveness;
`HbA1c;
`Hypoglycemia; Liraglutide; Literature review;
`Real-world evidence; Safety; Type 2 diabetes;
`Weight
`
`INTRODUCTION
`
`Type 2 diabetes mellitus (T2DM) is a chronic
`metabolic disorder characterized by increased
`blood glucose levels, i.e., hyperglycemia, which
`over
`time
`can cause microvascular
`and
`macrovascular complications
`[1]. The main
`goal of T2DM treatment is to achieve and
`maintain patients’
`individual
`target blood
`glucose levels, thus reducing the occurrence of
`complications [2].
`the
`for
`guidelines
`There
`are
`several
`those
`management
`of
`T2DM including
`developed by
`the
`International Diabetes
`Federation (IDF) [3], the American Diabetes
`Association
`(ADA)
`[4],
`the
`American
`Association
`of
`Clinical
`Endocrinologists
`(AACE)/American College of Endocrinology
`(ACE) [5], and the National Institute of Health
`and Care Excellence (NICE) from the UK [6].
`The treatment recommendations are generally
`consistent but with some differences. For
`example,
`the ADA and
`the
`European
`
`Association for the Study of Diabetes (EASD)
`suggest a treatment algorithm for patients with
`T2DM [7] which suggests that patients with
`T2DM should initially be offered education in
`lifestyle changes, with advice to lose weight by
`changing dietary habits and increasing physical
`activity. If a patient’s blood glucose level is not
`decreased
`to,
`and maintained
`at,
`the
`individualized target
`glycated hemoglobin
`(HbA1c)
`levels [7],
`it is recommended that
`medical treatment with anti-diabetic drugs be
`initiated. Over the years, glucagon-like peptide
`(GLP-1) receptor agonists (RAs) have become
`integral as second- or third-line therapies in
`many treatment guidelines, such as the ADA/
`EASD, the AACE, and the IDF [3–7].
`GLP-1 RAs are one among many treatment
`options available for patients with T2DM.
`GLP-1 RAs mimic the effects of endogenous
`GLP-1, which regulates plasma glucose levels by
`stimulating the secretion and biosynthesis of
`insulin and by inhibiting the secretion of
`glucagon and by delaying the gastric emptying
`of food and reducing food intake [8, 9]. Based
`on this mechanism of action, GLP-1 RA has
`effects on controlling
`glucose
`level
`and
`reducing body weight. Liraglutide was
`the
`second GLP-1 RA that was approved for the
`treatment of T2DM by the European Medicines
`Agency (EMA) and the US Food and Drug
`Administration (FDA)
`in 2009 and 2010,
`respectively. Currently, liraglutide is the most
`used GLP-1 RA worldwide [10]. The efficacy and
`safety of liraglutide mono- and combination
`therapy have been evaluated in the Liraglutide
`Effect and Action in Diabetes (LEAD) clinical
`program which consisted of six clinical trials
`[11–16], and recently a clinical trial comparing
`liraglutide head-to-head with lixisenatide was
`finalized [17]. There exist a number of different
`clinical trials on the efficacy of
`liraglutide,
`among others comparative trials vs. albiglutide
`
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`Diabetes Ther (2016) 7:411–438
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`413
`
`[18], dulaglutide [19], exenatide [20], sitagliptin
`[21, 22], switching to GLP-1 RA from sitagliptin
`[23] and with other oral antidiabetic drugs
`(OADs;
`dipeptidyl
`peptidase-4
`inhibitors
`[DPP-4i], sulfonylurea [SU], glinide, metformin
`a-glucosidase
`[MET],
`inhibitor,
`or
`thiazolidinedione [TZD])
`[24]. Furthermore,
`one
`Japanese
`trial
`assessed liraglutide
`in
`combination with insulin [25]. Results from all
`these trials consistently showed that patients
`treated with liraglutide had significantly
`improved glycemic
`control
`(with a high
`proportion of patients reaching HBA1c\7.0%
`at the end of the trial) and achieved substantial
`reductions
`in
`absolute
`body
`weight.
`Importantly,
`these
`beneficial
`effects
`of
`liraglutide occurred with a
`low risk of
`hypoglycemia, and the drug was well tolerated
`in patients with T2DM [11–25].
`Established as a drug with robust clinical
`efficacy and safety profile in controlled settings,
`the clinical effectiveness and safety of liraglutide
`for the treatment of patients with T2DM have
`also been investigated in observational studies
`reflecting real-life clinical practice. We performed
`a systematic literature review to evaluate the
`effectiveness of liraglutide for the treatment of
`patients with T2DM in real-world clinical
`practice. The goal of the review is to provide a
`succinct overview of the evidence on the clinical
`effectiveness of
`liraglutide which could help
`guide
`clinical decision making and assist
`clinicians in deciding how different therapies fit
`into the current treatment algorithm, and help
`inform current and future treatment guidelines
`for the management of patients with T2DM.
`
`METHODS
`
`This systematic literature review was conducted
`in accordance with the NICE guidance to obtain
`
`consistent,
`a
`information using
`relevant
`reproducible, and transparent methodology
`[26]. According to this guidance, this process
`involves the development of a study protocol
`(see supplementary file 1), parallel review of
`retrieved publications by two independent
`researchers
`for
`the
`selection of
`relevant
`publications, followed by a full-evidence data
`extraction and quality assessment of study
`methodology,
`results,
`and implication of
`results to routine T2DM clinical practice.
`
`Search Strategy
`
`To collect evidence on the effectiveness of
`liraglutide, different databases were selected.
`These
`included Medline
`(1979–2016)
`and
`EMBASE (1974–2016; searched simultaneously
`via ProQuest), Cochrane (1992–2016; Cochrane
`Database
`of
`Systematic Reviews
`[CDSR];
`Database of Abstracts of Reviews of Effects
`[DARE]; Cochrane Methodology
`Register
`[CMR]; Health
`Technology
`Assessments
`Database [HTA]; and The National Health
`Services [NHS] Economic Evaluation Database
`[EED]), health technology assessment websites,
`and conference proceedings
`(International
`Society for Pharmacoeconomics and Outcomes
`Research [ISPOR], ADA, EASD, World Diabetes
`Congress-IDF [WDC-IDF]).
`The search terms included both free-text and
`Emtree/MeSH terms of
`indication, clinical
`effectiveness,
`comparative
`effectiveness,
`generic and brand name of liraglutide, and
`were designed to meet
`the requirements
`outlined in NICE guidelines for the methods
`of technology appraisal [26]. Complex search
`strings, combining extensive lists of search
`terms for indication and topic, were used to
`search the databases through ProQuest. For
`other databases,
`less complex search strings
`
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`414
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`Diabetes Ther (2016) 7:411–438
`
`were used as the search engines provided fewer
`options. In all databases, no language or time
`limits were applied to ensure that no relevant
`publications were missed. The annual meeting
`abstracts were only searched for the last 3 years
`(up until 2015), because it was assumed that
`after 3 years these would have been published as
`full publications in a peer-reviewed journal. The
`search terms that were applied per database are
`provided
`in
`the
`study
`protocol
`(see
`supplementary file 1).
`The database searches were executed on
`October 13, 2015 and an updated search in
`ProQuest was conducted on January 7, 2016.
`
`Eligibility Criteria
`
`the
`the searches were performed,
`After all
`results were screened (based on title and
`abstract
`followed by full-text
`review)
`in
`parallel by two independent researchers after
`the removal of duplicate publications. If the
`researchers could not reach agreement on the
`selection of a relevant publication, a third
`independent
`researcher was
`consulted to
`decide eligibility of the publication for the
`review. The inclusion and exclusion criteria for
`the screening and selection process are provided
`in Table 1.
`
`Data Extraction and Assessment of Study
`Quality
`
`The data extraction of selected studies was
`performed by one researcher (AO). A second
`researcher performed a thorough quality check
`to assure all relevant data were extracted to the
`correct parameter (WX). Endpoints for data
`extraction were decided a priori. These
`primarily
`included
`effectiveness
`(glucose
`control
`and weight)
`and if
`the
`studies
`identified in the literature search reported
`
`adverse
`(hypoglycemia,
`endpoints
`safety
`events [AEs], serious AEs) related to liraglutide
`treatment for patients with T2DM, then these
`were also included. No statistical analyses were
`performed.
`Following data extraction, a critical appraisal
`of the quality of selected studies was performed
`by a single researcher (AO), and reviewed by a
`second
`researcher
`(WX).
`This
`quality
`assessment was completed for all
`selected
`observational studies that were published in
`full text based on the recommendations of the
`Centre for Reviews and Dissemination (CRD)
`guidance for undertaking reviews in healthcare
`[27]. The quality of full-text publications was
`subjectively evaluated based on several criteria
`including completeness of
`reporting,
`study
`population and design, sample size, sampling
`procedure, study follow-up duration, treatment
`setting, patient inclusion and exclusion criteria
`and patient enrollment and study completion
`rates. In addition to this, quality appraisal was
`further informed by assessing potential sources
`of confounding and biases (e.g., patient baseline
`characteristics, misclassification, selection bias,
`reporting bias, etc.) which are known to be
`prominent
`in
`observation
`studies.
`The
`limitations described in the individual articles
`from the authors’ perspective were also used to
`guide
`the quality appraisal. The quality
`assessment of abstracts was not performed as
`study details were not adequately reported.
`
`Data Reporting
`
`section focuses mainly on the
`The results
`findings
`from full-text
`journal publications
`identified in the systematic literature review.
`These
`findings
`are
`supplemented with
`supportive
`evidence
`from the
`conference
`abstracts. This approach for presentation was
`chosen because full-text publications are peer
`
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`Diabetes Ther (2016) 7:411–438
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`415
`
`Table 1 Study eligibility criteria
`
`Item
`
`Inclusion criteria
`
`Population
`
`Patients with T2DM
`
`Exclusion criteria
`
`Type 1 diabetes mellitus
`
`Gestational diabetes
`
`Other diseases
`
`Intervention Treatment regimens including liraglutide
`
`Insulin therapy
`
`Comparator Treatment regimens including NIADs
`
`Insulin therapy
`
`NIADs
`
`TZD (e.g., pioglitazone)
`
`DPP-4i (e.g., sitagliptin or saxagliptin)
`
`SGLT2 inhibitor (e.g., dapagliflozin or
`canagliflozin)
`
`GLP-1 RA (e.g., exenatide, albiglutide, or
`dulaglutide)
`
`MET
`
`SU
`
`Other OADs
`
`Outcomes
`
`Clinical effectiveness and safety of liraglutide
`
`Comparative effectiveness and safety of
`liraglutide compared to other NIADs
`
`Study design Chart review
`
`Medical record analysis
`
`Database analysis
`
`Expert panel studies
`
`Prospective follow-up studies
`
`Post-marketing surveillance studies
`
`Studies not reporting the clinical effectiveness/safety of
`either liraglutide compared to other NIADs
`
`RCT
`
`Case-reports
`
`Letters to editor
`
`Location
`
`Language
`
`All
`
`All
`
`None
`
`None
`
`DPP-4i dipeptidyl peptidase-4 inhibitor, GLP glucagon-like peptide, MET metformin, NIAD non-insulin antidiabetic drug,
`OAD oral antidiabetic drug, RA receptor agonist, RCT randomized controlled trials, SGLT2 sodium-glucose cotransporter
`type-2, SU sulfonylurea, T2DM type 2 diabetes mellitus, TZD thiazolidinedione
`
`reviewed and considered to be of higher quality
`than
`abstracts
`from annual
`conference
`proceedings as complete methodological details
`and results are reported in full-text articles.
`
`Compliance with Ethics Guidelines
`
`This article is based on previously conducted
`studies and does not involve any new studies of
`
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`Diabetes Ther (2016) 7:411–438
`
`human or animal subjects performed by any of
`the authors.
`
`RESULTS
`
`Included Studies
`
`in 220
`resulted
`searches
`database
`The
`publications from Medline and EMBASE (via
`ProQuest). No publications were identified in
`the Cochrane
`library. A total
`of
`303
`publications were
`found from conference
`proceedings. After
`removing 88 duplicates
`from a total of 523 publications, the title and
`abstracts of 435 publications were screened for
`eligibility to a full-text
`screening. Of 435
`publications, 284 were excluded based on title
`and abstract screening. Of 151 publications, 81
`were abstracts from conference proceedings
`and, therefore, only 70 full-text publications
`were
`reviewed for
`eligibility by full-text
`screening based on the pre-defined study
`eligibility
`criteria. Of
`these
`70
`full-text
`publications, 27 were excluded: 5, 17, and 5
`records due to population, outcome, and study
`design irrelevance,
`respectively. Thus, 43
`full-text publications were included.
`One-hundred and twenty-four publications
`were eventually included in this
`literature
`review. Of
`these, 43 were full-text
`journal
`articles, and 81 were abstracts identified from
`databases of conference proceedings or from
`published
`supplements
`of
`conference
`proceedings.
`The
`search
`and
`selection
`is
`procedure
`shown
`in
`the
`PRISMA
`flowchart (Fig. 1).
`
`Study Characteristics
`
`More than half of the 43 full-text journal
`articles [28–70] had a study design which
`
`involved analyses of data that were previously
`collected
`from patient medical
`record/
`chart
`review from hospitals, or databases
`(53.5%; N = 23) [28, 30–33, 37, 39, 40, 43,
`44, 46, 49–51, 54–58, 61, 62, 65, 70]. The
`majority of the studies assessed the clinical
`effectiveness of liraglutide without an active
`(81.4%; N = 35)
`comparator
`[28, 29, 31,
`34, 36–39, 41–49, 51–55, 57, 60–64, 66–71].
`Real-world studies with comparators were less
`frequently observed (18.6%; N = 8); the most
`common comparators
`for
`liraglutide were:
`(N = 6)
`sitagliptin
`or
`any
`DPP-4i
`[32, 33, 35, 40, 56, 58], exenatide (N = 3)
`[33, 35, 50], glimepiride or any other SUs
`(N = 2) [30, 35], pioglitazone or other TZDs
`(N = 1) [35], and MET (N = 1) [35]; note: these
`numbers do not add up because some studies
`had more than one comparator. The most
`frequently observed follow-up duration from
`these publications was C12 months
`(46.5%;
`N = 20)
`[28–47],
`followed by 6–12 months
`and\6 months
`(34.9%; N = 15)
`[48–62],
`(18.6%; N = 8)
`[63–70]. Real-world studies
`frequently reported data on the effect of
`liraglutide from outpatient settings (30.2%;
`N = 13)
`[34,
`39,
`40,
`42–44,
`49,
`55, 58, 60, 61, 66, 67]. The geographical scope
`of the review included studies from Europe
`(N = 24),
`the USA (N = 5), and Asia–Pacific
`(N = 14; see supplementary file 2).
`Study characteristics
`from the abstracts
`(N = 81; see supplementary file 3 for the full
`list of conference abstracts included in this
`review) were similar to those reported from
`full-text
`publications.
`The majority
`of
`conference abstracts reported findings from
`studies involving analyses of already available
`data (60.5%; N = 49), followed by those based
`on prospective study designs (24.7%; N = 20).
`For the remaining abstracts (14.8%; N = 12),
`information on study design was not reported.
`
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`Diabetes Ther (2016) 7:411–438
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`417
`
`Fig. 1 PRISMA flow diagram. No studies were excluded
`due to intervention/comparator at the full-text screening
`stage. Other sources include publications from different
`conference proceedings (see supplementary file 1). aPa-
`tients were solid organ transplant recipients or had other
`
`serious comorbidities. bResults were reported for overall
`glucagon-like peptide-1 receptor agonist (no differentiation
`for liraglutide and exenatide); or data were unavailable in
`the full-text article. ti, ab title and abstract
`
`Most of the studies assessed liraglutide without
`an active comparator (75.3%; N = 61). The
`common comparators were exenatide (N = 9),
`(N = 8),
`sitagliptin or
`any DPP-4i
`and
`(N = 2).
`glimepiride
`The most
`frequent
`follow-up
`duration
`in
`the
`studies
`(N = 36),
`was C12 months
`followed
`and\6 months
`(N = 27),
`by C6–12 months
`(N = 13).
`Five
`studies
`did
`not
`have
`information on study duration. The treatment
`
`from outpatient and
`liraglutide
`effect of
`inpatient settings was reported in 16 and 2
`studies, respectively. The remaining abstracts
`did not specify the treatment setting.
`
`Quality Appraisal of Full-Text Articles
`
`from the quality appraisal of 43
`Findings
`full-text journal publications are presented in
`supplementary file 4. Generally,
`the study
`
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`Diabetes Ther (2016) 7:411–438
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`designs were appropriate to assess the clinical
`effectiveness of liraglutide in routine clinical
`practice.
`The
`review
`findings
`allow
`of
`understanding
`the
`outcomes
`from
`real-world clinical practice when liraglutide is
`prescribed according to local guidelines.
`Common limitations of some of the studies
`that were identified included small sample size,
`missing data, and limited generalizability to the
`patient setting or study country. Some studies
`did not adjust for potential confounding by
`measured
`and
`unmeasured
`factors
`like
`prescription bias. Confounding variables such
`as
`the use of other medications, baseline
`severity of disease and duration of diabetes,
`values
`of
`comorbidity
`indices,
`baseline
`prevalence of comorbidities, and body mass
`index (BMI) were also not addressed between
`intervention and comparator groups. Notably,
`these study limitations are typically reported in
`observational studies [72].
`
`Patient Baseline Characteristics
`
`In the full-text publications (N = 43), 7413
`patients were treated with liraglutide. The
`mean age of patients with T2DM on liraglutide
`treatment was between 43.6 and 63.5 years at
`baseline. The majority of publications (N = 22)
`included more male patients (50.5–74.4%) than
`female patients. In the remaining 21 studies,
`male patients comprised 29.0–49.4% of the
`total
`study population. Mean duration of
`T2DM ranged from 5 to 15.8 years. The mean
`baseline HbA1c level of patients with T2DM
`before liraglutide treatment was between 7.2%
`and 9.8%. Mean baseline weight and mean BMI
`24.7–38.6 kg/m2,
`were
`63.8–120 kg
`and
`respectively (see supplementary file 2).
`The average dosage of liraglutide varied by
`country (dosage information was not available
`for
`9 publications
`[32,
`35,
`46,
`49–51,
`
`56, 58, 70]). In all the studies from Japan,
`patients were started at a dosage of 0.3 mg per
`day and titrated up to 0.9 mg per day in
`increments of 0.3 mg per week [38, 40, 54,
`55, 61, 68, 70]. The recorded liraglutide dose
`used in real-world studies was higher in the USA
`than in Europe, as 1.8 mg was used more often
`than 1.2 mg [28, 49, 56, 73]. In Europe, the use
`of both 1.2 and 1.8 mg doses of liraglutide was
`documented. Notably, most of the patients
`from European studies
`received liraglutide
`1.2 mg, and a subgroup of patients in these
`studies had the dose escalated to 1.8 mg.
`In studies comparing liraglutide with active
`comparators, baseline patient characteristics
`were generally balanced between treatment
`groups. Some differences were observed in the
`baseline characteristics, especially regarding use
`of
`concomitant and previous
`antidiabetic
`therapy. Concomitant SU, MET, and, to an
`extent, basal/pre-mixed insulin use was similar
`in patients treated with exenatide or liraglutide.
`There was insufficient information on the use of
`concomitant medications
`in patients using
`DPP-4i or pioglitazone compared to liraglutide.
`Information on the use of prior therapies varied
`between the studies.
`from conference
`Patient
`characteristics
`abstracts largely showed a similar trend to
`those
`observed
`for
`patient
`baseline
`characteristics from full-text articles.
`
`Clinical Effectiveness
`
`Glucose Control
`HbA1c: Change in HbA1c Level The clinical
`effectiveness of antidiabetic drugs on blood
`glucose control is measured by HbA1c (which
`is widely used as a measure of average glucose
`level over the preceding months before the time
`of measurement) and/or plasma glucose level
`(either fasting or post-prandial) [6, 74].
`
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`
`The following measurements were reported
`by the identified observational studies regarding
`HbA1c level: change in mean HbA1c from
`baseline to end-of-study, and proportion of
`patients achieving widely accepted HbA1c
`targets for patients with T2DM (i.e., \7% or
`B6.5%).
`One-hundred and six publications reported
`the changes
`in HbA1c
`from baseline to
`end-of-study, for patients with T2DM treated
`with liraglutide. Of these, 38 were full-text
`articles
`[28–34,
`36–53,
`55–60,
`62,
`64,
`66, 67, 69, 70]. Study attributes and patient
`baseline
`characteristics
`from the
`included
`studies are provided in supplementary file 2.
`Of the 38 full-text publications, 18 studies
`reported an average follow-up duration of
`C12 months [29–33, 36–40, 42–47], followed
`by 15 studies with an average follow-up period
`of C6–12 months [34, 48, 49, 52–60, 62, 73].
`The remaining five studies had an average
`follow-up period of B6 months
`[64, 66,
`67, 69, 70].
`reported mean
`studies
`The
`identified
`baseline HbA1c in the range of 7.5–9.8% and
`end-of-study HbA1c ranging from \6% to 8.5%
`after
`liraglutide
`treatment
`[29–34, 36–50, 52–60, 62, 64, 66, 67, 69, 70]. It
`was reported that liraglutide therapy led to a
`mean HbA1c change from baseline of -0.6% to
`-2.26% (see Fig. 2). Mean changes in HbA1c
`from baseline to end-of-study from studies
`(N = 21),
`conducted in Europe
`the USA
`(N = 4), and Asia–Pacific (N = 13) were -0.8%
`to -1.9%, -0.8% to -0.99%, and -0.6% to
`-2.26%, respectively (see Fig. 2). Real-world
`studies demonstrate
`evidence of
`lowering
`blood glucose levels
`regardless of baseline
`HbA1c
`level
`and follow-up durations
`in
`patients with T2DM treated with liraglutide
`(Fig. 2)
`[28–34,
`36–53,
`55–60,
`62,
`64,
`66, 67, 69, 70].
`
`HbA1c: Proportion of Patients Achieving
`HbA1c Target of <7% and £6.5% The
`guidelines of the ADA (2015) [2] and Canadian
`Diabetes Association (CDA) suggest multiple
`goals of
`therapy,
`including attaining the
`of HbA1c\7%, no
`composite
`endpoint
`incidence of hypoglycemia, and/or no weight
`gain (or weight loss if obese) in patients with
`T2DM. More or less stringent targets may be
`appropriate if these can be achieved without
`significant hypoglycemia or AEs. The AACE
`recommend a stringent glycemic target of
`HbA1c B6.5% with low risk of hypoglycemia
`[75], which is further endorsed by NICE [74]. A
`total of 37 publications had data on the
`proportion of patients achieving the HbA1c
`targets of\7.0% and B6.5%.
`36,
`34,
`Overall,
`29.3–64.5% [28–32,
`39, 42, 43, 45, 46, 48, 49, 52–54, 56–58,
`70, 73] and 22.05–41.03% [28, 42, 45, 49,
`52, 53, 56] patients with T2DM treated with
`the\7% and B6.5% HbA1c
`liraglutide met
`targets, respectively (for baseline characteristics
`of
`study population in these studies;
`see
`supplementary file 2).
`
`Plasma
`Post-Prandial
`and
`Fasting
`Glucose Thirty-six publications reported data
`on the effect of liraglutide on fasting plasma
`glucose (FPG) and post-prandial plasma glucose
`(PPG). Of
`these, 20 were full-text articles.
`Baseline FPG and PPG levels in patients with
`T2DM treated in the real-world setting were
`114.4–201 mg/dL
`and
`167.57–252.5 mg/dL,
`respectively. Overall, the evidence indicated
`that
`liraglutide monotherapy
`and/or
`in
`combination with oral glucose-lowering agents
`was effective in reducing FPG and PPG levels.
`FPG and PPG reductions from baseline to
`end-of-study were in the range of 28.1–52.21
`and
`23.7–66.71 mg/dL,
`respectively.
`End-of-study
`FPG and
`PPG observations
`
`MPI EXHIBIT 1112 PAGE 9
`
`

`

`420
`420
`
`Diabetes Ther (2016) 7:411-438
`Diabetes Ther (2016) 7:411–438
`
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`MPI EXHIBIT 1112 PAGE 10
`
`MPI EXHIBIT 1112 PAGE 10
`
`€
`

`

`Diabetes Ther (2016) 7:411–438
`
`421
`
`b Fig. 2 Mean change in HbA1c from baseline in patients
`in a Europe
`with T2DM on liraglutide
`treatment
`(N = 21), b the USA (N = 4), and c Asia–Pacific
`a[11–25]. Note: data in the figures report
`(N = 13).
`findings from full-text publications (38 of the 43 articles
`that were included in the review). Data on HbA1c were
`not reported in five full-text publications. Numbers
`in
`parentheses on the x axis are references to the relevant
`publications. HbA1c glycated hemoglobin, T2DM type 2
`diabetes mellitus
`
`ranged from 99.1–144 and 100.9–180.7 mg/dL,
`which are close to the ADA-recommended
`glycemic
`target
`for non-pregnant
`adults
`(70–130 and \180 mg/dL, respectively) [76].
`
`Body Weight
`
`Reduction in body weight is associated with
`improved glycemic control, insulin sensitivity,
`and a reduced risk of developing cardiovascular
`disease in obese patients with diabetes [77].
`Seventy-four publications reported effect of
`liraglutide on body weight in patients with
`T2DM. Among
`these,
`28 were
`full-text
`publications [29–32, 34, 36, 37, 39, 40, 42, 43,
`46, 48, 49, 51–55, 57–59, 62, 63, 65, 67, 69].
`Only 4 studies had a
`follow-up period
`of\6 months [63, 65, 67, 69]. The remaining
`studies were equally divided between study
`follow-up durations of C6–12 months (N = 12)
`[34, 48, 49, 51–55, 57–59, 62] and C12 months
`(N = 12) [29–32, 36, 37, 39, 40, 42, 43, 46, 62].
`Overall,
`liraglutide
`treatment
`both as
`monotherapy and in combination with oral
`therapy led to significant weight loss in patients
`with T2DM (Fig. 3). In patients with T2DM who
`were prescribed liraglutide therapy baseline
`weight and BMI range were 63.8–120 kg/m2
`and 24.7–38.6 kg/m2, respectively.
`Liraglutide therapy, over time, led to a mean
`change in absolute weight from baseline of -1.3
`to -8.65 kg. Mean changes in weight from
`baseline in patients from Europe (N = 16), the
`USA (N = 1), and Asia–Pacific (N = 11) were
`
`-2.4 to -6.5 kg, -2.9 kg, and -1.3 to -8.7 kg,
`respectively (Fig. 3). A few studies showed mean
`weight reduction in patients with T2DM for up
`to 2 years after initiating liraglutide treatment
`[30, 40, 42, 43, 78].
`Two studies that included 3210 patients
`showed that patients experienced reduction in
`body weight regardless of their baseline BMI
`(25.0–40.0 kg/m2) after
`initiating liraglutide
`therapy [42, 49]. Importantly, higher baseline
`BMI was associated with larger absolute weight
`loss in patients [42, 49]. Chitnis et al. [49]
`(N = 3005 patients)
`reported larger weight
`reductions with increasing
`BMI
`at
`the
`6-month follow-up (BMI C 40 kg/m2: -4.0 kg;
`BMI 35–39.9 kg/m2: –3.0 kg; BMI 30–34.9 kg/
`m2: -1.9 kg; BMI 25–29.9 kg/m2: -1.5 kg;
`P\0.01 for trend) [49]. Ponzani et al.
`[42]
`(N = 205 patients) reported similar findings at
`(BMI C35 kg/m2:
`20 months
`-6.66 kg;
`BMI[30–35 kg/m2: -4.8 kg; BMI B30 kg/m2:
`-2.98 kg) [42]. Both these studies had good
`generalizability to real-world patients with
`T2DM and obesity [42, 49]. These findings
`reinforce that liraglutide could be beneficial,
`not only in avoiding weight gain, but also in
`helping patients with T2DM and obesity to lose
`weight.
`
`NICE Composite Endpoint: Percentage
`of Patients with HbA1c Reduction ‡1%
`and Weight Reduction ‡3%
`Treatment guidelines for the management of
`T2DM highlight the importance of not only
`improving
`glycemic
`control but
`also of
`managing obesity and hypertension [74].
`Thus, composite endpoints are increasingly
`reported in the assessment of novel diabetes
`therapies. The NICE guidelines recommend that
`GLP-1 mimetic therapy is continued if patients
`with T2DM have
`a beneficial metabolic
`response (a reduction of at least 11 mmol/mol
`
`MPI EXHIBIT 1112 PAGE 11
`
`

`

`Diabetes Ther (2016) 7:411-438
`Diabetes Ther (2016) 7:411–438
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