a systematic literature review of real world evidence ...10.1007/s13300-016-0180... · a systematic...

A systematic literature review of real world evidence studies of liraglutide (Victoza™) in

type 2 diabetes

Study protocol

Date: June 8, 2016

Status: Study protocol (Final)

Prepared for: Emina Mocevic

Novo Nordisk

Prepared by: Amrita Ostawal ([email protected])

Weiwei Xu ([email protected])

Pharmerit BV

Marten Meesweg 107

3068 AV Rotterdam

the Netherlands

www.pharmerit.com

+31 (0) 88 4400100

mailto:[email protected]

mailto:[email protected]

Copyright © 2016 Pharmerit International page 2 of 23

VERSION CONTROL

Version Date

(DD/MM/YY

YY)

Author(s) Summary of Changes/Comments

Version 1.0 6/8/2016 Pharmerit Original version


Table of Contents

LIST OF TABLES AND FIGURES 4

1 BACKGROUND 5

1.1 TYPE 2 DIABETES 5

1.2 GLP-1 AGONISTS 5

1.3 VICTOZA™ (LIRAGLUTIDE) 6

2 OBJECTIVES 7

2.1 OBJECTIVES 7

2.2 RESEARCH QUESTIONS 7

3 STUDY DESIGN 8

3.1 PICOS 8

3.2 DATABASES 9

3.3 APPROACH AND SEARCH TERMS 10

3.3.1 ProQuest 10

3.3.2 Cochrane 12

3.3.3 HTA websites 13

3.3.4 Conference Proceedings 14

3.4 SEARCH AND SELECTION PROCEDURE 15

3.5 DATA-EXTRACTION PROCEDURE 17

3.6 QUALITY ASSESSMENT 18

3.7 REPORTING AND PUBLICATION 19

3.7.1 Technical report 19

3.7.1 Slide-deck 19

3.7.2 Publication of findings in a peer-reviewed biomedical journal 19

4 ABBREVIATIONS 21

5 REFERENCES 22


List of Tables and Figures

List of Tables

Table 1: PICOS 8

Table 2: Included databases 9

Table 3: Search terms ProQuest (searched on 30/09/2015) 10

Table 4: Search terms Cochrane (searched on 30/09/2015) 12

Table 5: HTA websites searched (30/09/2015) 13

Table 6: Search terms for ISPOR 14

Table 7: Search terms for ADA 14

Table 8: Search terms for EASD 15

Table 9: Search terms for IDF 15

Table 10: Inclusion and exclusion criteria 15

Table 11: Evidence Quality Assessment Checklist 19

List of Figures

Figure 1: PRISMA Flow Diagram (2009) 17


1 Background

1.1 Type 2 Diabetes

In 2014, there were 387 million people with diabetes and 4.9 million deaths. The number of people

with diabetes has been increasing due to rising prevalence of obesity, increase in life expectancy, and

decreased physical activity. Consequently, treatment costs for diabetes have been increasing

worldwide. In 2014, around 612 billion USD was spent worldwide for diabetes (1).

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterised by increased blood

glucose levels (hyperglycaemia), which over time can cause microvascular complications such as

retinopathy, nephropathy, and neuropathy, and macrovascular complications such as ischemic heart

disease and stroke. Patients with T2DM are usually overweight or obese, leading to insulin

resistance. Initially, there is increased insulin production to counter this, but over time insulin

production falls. The main aim of treatment of patients with T2DM is to achieve and maintain blood

glucose levels and thereby reduce the occurrence of complications (2).

People with T2DM are initially managed by education on lifestyle changes, with advice to lose weight

by changing dietary habits and increasing physical activity. If patients fail to improve their blood

glucose level to the glycated haemoglobin (HbA1c) level of <7%, suggested as adequate glucose

control by the American Diabetes Association (ADA) and the European Association for the Study of

Diabetes (EASD) (3,4), and maintain it, then they are usually started on metformin. A sulfonylurea

(SU) is considered when patients cannot tolerate metformin or if it is contraindicated. However,

other antidiabetic drugs such as dipeptidyl peptidase-4 (DPP-4) inhibitors, a thiazolidinediones, or

sodium glucose transport 2 (SGLT2) inhibitors may be considered according to individual patients’

need (4). If patients fail to achieve satisfactory control on metformin, another oral glucose-lowering

drug is added, usually SU added to metformin (dual therapy). When dual therapy fails, a third drug is

added (triple therapy). The third drug could be an oral glucose-lowering drug of another class such

as pioglitazone, DPP-4 inhibitors (such as sitagliptin or saxagliptin), or a SGLT2 inhibitor (such as

dapagliflozin or canagliflozin), or an injectable glucagon-like peptide-1 (GLP-1) analogue (liraglutide

or exenatide, albiglutide, and dulaglutide). Some GLP-1 receptor agonists are now available in long-

acting form given only once a week. In T2DM, postprandial hyperglycaemia is common. The rise in

blood glucose level may be partly because of high glucagon levels. The incretin-based drugs reduce

the increased postprandial glucagon level. There are two types of incretin-based drugs, DPP-4

inhibitors and GLP-1 receptor agonists.

1.2 GLP-1 agonists

GLP-1 receptor agonists are glucose-lowering drugs that have to be injected. The GLP-1 receptor

agonists act like the naturally occurring incretin hormone GLP-1, a gastrointestinal hormone that is


secreted by the body following consumption of food, that regulates plasma glucose levels by

delaying gastric emptying of food and reducing hunger, by inhibiting secretion of glucagon, and by

stimulating secretion and biosynthesis of insulin (5,6). GLP-1 receptor agonists thus leads to glucose

control and reduces weight.

There are now five GLP-1 receptor agonists available in the market: exenatide in twice daily form

(Byetta™, AstraZeneca plc, London, UK) and as the long-acting, once-weekly version (Bydureon™,

AstraZeneca), once-daily liraglutide (Victoza™, Novo Nordisk A/S, Bagsværd, Denmark), once-daily

lixisenatide (Lyxumia™, Sanofi-Aventis, Bridgewater, NJ, USA), weekly albiglutide (Tanzeum™,

GlaxoSmithKline plc, London, UK), and recently, weekly dulaglutide (Trulicity™, Eli Lilly and Company,

Indianapolis, IN, USA).

1.3 Victoza™ (Liraglutide)

The efficacy and safety of Novo Nordisk’s Victoza™ (liraglutide given in both regimens - as mono-

and combination therapy) have been evaluated in the Liraglutide Effect and Action in Diabetes

(LEAD) program, where liraglutide induced a decrease of HbA1c between 0.8% and 1.5% (7–11). In

addition, liraglutide leads to a reduction in weight, blood pressure and lipids (12). Due to its

additional effects on glycaemic control, liraglutide is associated with an improvement in life

expectancy and in quality-adjusted life expectancy. It is also associated with a reduced cost in

diabetes-related complications, so it is more cost-effective versus a DPP-4 inhibitor (13).

Liraglutide was approved for treatment of T2DM by the European Medicines Agency (EMA) on July 3,

2009, and by the U.S. Food and Drug Administration (FDA) on January 25, 2010. Since then, the

market for GLP-1 treatment has steadily expanded liraglutide and now accounts for 72% of global

GLP-1 agonist sales. Victoza™ is available in around 80 markets and is used by an estimated 900,000

people worldwide (14).

https://en.wikipedia.org/wiki/European_Medicines_Agency

https://en.wikipedia.org/wiki/U.S._Food_and_Drug_Administration


2 Objectives

2.1 Objectives

To support the development of a publication on the clinical effectiveness of Victoza™ and a report

regarding costs and resource utilization of VictozaTM treatment, a systematic literature review (SLR)

will be conducted in accordance with widely accepted guidance to obtain relevant information using

a consistent, reproducible and transparent methodology.

• Main objective: To survey the real-world evidence (clinical effectiveness, resource utilisation

and costs) for Victoza™ use in patients with T2DM

2.2 Research questions

To meet the objective of this SLR the following research questions will be answered by identifying the relevant publications and completing data-extraction:

– What is the clinical effectiveness of Victoza™, including long-term effectiveness up to

2 years?

– What is the comparative effectiveness of Victoza™ compared to other non-insulin

antidiabetic drugs (NIADs)?

– What is the effectiveness of Victoza in patient subgroups?

– What is the effect of Victoza™ use on the health care resource utilisation in patients

with T2DM?

– What is the effect of Victoza™ use on the costs associated with healthcare use in

patients with T2DM?


3 Study design

The systematic literature review design is detailed below in the following sections:

PICOS: defining the search in terms of population, interventions, comparators, outcomes

and study design; these also form the eligibility criteria for the studies to be eventually

considered for data extraction

Databases: providing an overview of all databases which will be searched;

Approach and search terms: providing the overall strategy and search strings per

database;

Search and Selection procedure and quality assessment: details on the title/abstract and

full-text screening process are provided and the quality control process is described;

Data-extraction procedure: the extraction parameters for the top-line data-extraction

form are presented;

Reporting and Publication: description of topics which will be covered by the technical

report, slide-deck and manuscript for publication.

3.1 PICOS

In Table 1, details on relevant population, interventions, comparators, outcomes and study designs

(PICOS) are clarified. These will be used to guide the eligibility of studies for this SLR to consolidate the

evidence base on real world use of liraglutide/Victoza™.

Table 1: PICOS

Item Details

Population T2DM

Note: No limit will be applied while performing the searches

Interventions Victoza™ (liraglutide)

Note: Mono, dual and triple therapy will be included

Comparators For clinical effectiveness studies investigating liraglutide only, no comparator

is relevant

For clinical effectiveness studies comparing liraglutide to other treatments,

comparators are non-insulin antidiabetics drugs.

Outcomes Clinical effectiveness

– Blood sugar levels

• Fasting serum glucose

• 8-point self-monitored plasma glucose profile

– HbA1c

– Weight loss (change in kg or BMI; number of people reaching a set

target)


– Systolic blood pressure

– Lipids

– β-cell function, insulin sensitivity index and fasting glucagon

Comparative effectiveness to NIADs

Healthcare Resource Utilisation

– Hospitalisation

– HCP/GP visits

– Drug utilisation

Treatment cost (direct and indirect medical costs) per patient

Study design All but RCTs

Conventional trials will be included at first and will be discussed with the Novo

Nordisk team to agree upon final inclusion/exclusion

Note: For the purpose of the review; and in line with Novo Nordisk definition of

RWE; evidence not collected through conventional randomised controlled trials

will be considered for data extraction

Abbreviations: T2DM=type 2 diabetes mellitus; BMI=body mass index; HbA1c=glycated haemoglobin;

HCP=health care practitioner; GP=general practitioner; RCT=randomised controlled trial

3.2 Databases

The databases to be searches are provided in Table 2.

Table 2: Included databases

Search engine (website) Databases

ProQuest Medline®

EMBASE®

Cochrane Cochrane Database of Systematic Reviews (CDSR)

Database of Abstracts of Reviews of Effects (DARE)

Cochrane Methodology Register (CMR)

Health Technology Assessments Database (HTA)

NHS Economic Evaluation Database (EED)

HTA websites Single Technology Assessments (STA)

Guidelines (Multi technology assessments [MTA])

Conference Proceedings International Society for Pharmacoeconomics and Outcomes Research (ISPOR)

American Diabetes Association (ADA)

European Association for the Study of Diabetes (EASD)

World Diabetes Congress – International Diabetes Foundation (IDF)

Svensk Förenings för Diabetologis (SFD)

http://www.proquest.com/

http://www.cochrane.org/

http://www.cochrane.org/editorial-and-publishing-policy-resource/database-abstracts-reviews-effects-dare

http://www.ispor.org/

http://www.ispor.org/

http://professional.diabetes.org/Meeting_ListByType.aspx?ctyp=1

http://www.easd.org/

http://www.idf.org/worlddiabetescongress

http://www.idf.org/worlddiabetescongress

http://www.diabetolognytt.se/


3.3 Approach and search terms

The approach and search strings for ProQuest, Cochrane, HTA websites and the conference

proceedings are described in detail in the following sections. Search strategy includes the description

of search terms for indication and topics used, sources for search filters and limits applied.

The search terms have been designed to meet the requirements outlined in NICE’s guidelines for the

methods of technology appraisal, to ensure that all necessary papers are identified. Using the

ProQuest search engine (for Embase and Medline) complex search strings can be used, combining

extensive lists of search terms for indication and topic. For the other databases less complex search

strings are used as the search engines provide less options. In all databases, no language or time limits

are applied, to assure no relevant publications are missed. The annual meeting abstracts are only

searched for the last three years, as it can be assumed that after three years relevant abstract have

been published as full publication in a peer-reviewed journal.

3.3.1 ProQuest

ProQuest is used to search Medline, Medline In-Process and Embase (see search terms and results in

Table 3). To identify papers reporting on T2DM free text terms, Emtree terms and MESH terms for this

indication were combined. No time or language limits were applied.

Table 3: Search terms ProQuest (searched on 30/09/2015)

Topic Search Search terms # hits

S1 MESH.EXACT("Diabetes Mellitus, Type 2") OR EMB.EXACT("non

insulin dependent diabetes mellitus") OR TI,AB("type 2 diabetes"

OR "diabetes mellitus type 2" OR T2DM) OR TI,AB(non pre/0

insulin* pre/0 depend* OR noninsulin* pre/0 depend* OR

noninsulin?depend* OR non pre/0 insulin?depend*) OR

TI,AB((typ* pre/0 2 OR typ* pre/0 II) n/3 diabet*)

338042*

S2 (liraglutide OR victoza) OR EMB.EXACT("liraglutide") 5221*

S3 S1 AND S2 3119°

S4 (comparative effectiveness) OR (clinical effectiveness) OR efficacy

OR effect OR MESH.EXACT("Treatment Outcome") OR

MESH.EXACT("Comparative Effectiveness Research") OR

EMB.EXACT("comparative effectiveness") OR EMB.EXACT("drug

efficacy")

14582883*

S5 S3 AND S4 2639°

S6 (resource AND (utili*ation OR use)) OR EMB.EXACT("health care

utilization") OR EMB.EXACT.EXPLODE("health care utilization")

253210*

S7 S3 AND S6 28°

S8 TI,AB(low NEAR/5 cost) OR TI,AB(high NEAR/5 cost) OR

TI,AB(health?care NEAR/5 cost?) OR TI,AB(fiscal OR funding OR

financial OR finance) OR TI,AB(cost NEAR/5 estimate?) OR

TI,AB(cost NEAR/5 variable) OR TI,AB(unit NEAR/5 cost?) OR

TI,AB(economic? OR pharmacoeconomic? OR price? OR pricing)

1408522*

http://www.nice.org.uk/article/pmg9/chapter/Foreword


OR EMB.EXACT(“socioeconomics”) OR EMB.EXACT(“cost benefit

analysis”) OR EMB.EXACT(“cost effectiveness analysis”) OR

EMB.EXACT(“cost of illness”) OR EMB.EXACT(“cost control”) OR

EMB.EXACT(“economic aspect”) OR EMB.EXACT(“financial

management”) OR EMB.EXACT(“health care cost”) OR

EMB.EXACT(“health care financing”) OR EMB.EXACT(“health

economics”) OR EMB.EXACT(“hospital cost”) OR

EMB.EXACT(“cost minimization analysis”) OR

MESH.EXACT(“Economics”) OR MESH.EXACT(“Costs and Cost

Analysis”) OR MESH.EXACT(“Cost Allocation”) OR

MESH.EXACT(“Cost-Benefit Analysis”) OR MESH.EXACT(“Cost

Control”) OR MESH.EXACT(“Cost Savings”) OR MESH.EXACT(“Cost

of Illness”) OR MESH.EXACT(“Cost Sharing”) OR

MESH.EXACT(“Deductibles and Coinsurance”) OR

MESH.EXACT(“Medical Savings Accounts”) OR

MESH.EXACT(“Health Care Costs”) OR MESH.EXACT(“Direct

Service Costs”) OR MESH.EXACT(“Drug Costs”) OR

MESH.EXACT(“Employer Health Costs”) OR

MESH.EXACT(“Hospital Costs”) OR MESH.EXACT(“Health

Expenditures”) OR MESH.EXACT(“Capital Expenditures”) OR

MESH.EXACT(“Value of Life”) OR MESH.EXACT(“Economics,

Hospital”) OR MESH.EXACT(“Economics, Medical”) OR

MESH.EXACT(“Economics, Nursing”) OR

MESH.EXACT(“Economics, Pharmaceutical”) OR

MESH.EXACT(“Fees and Charges”) OR MESH.EXACT(“Budgets”)

S9 S3 AND S8 258°

S10 (EMB.EXACT("case control study") OR EMB.EXACT("family study")

OR EMB.EXACT("longitudinal study") OR EMB.EXACT("prospective

study") OR EMB.EXACT("retrospective study") OR

EMB.EXACT("observational study") OR EMB.EXACT("cohort

analysis") OR ("medical record review")) OR

(TI,AB(epidemiologic* pre/1 stud*) OR TI,AB(“case control”) OR

TI,AB(cohort pre/1 stud*) OR TI,AB(“cohort analy*”) OR

TI,AB(Follow Up pre/1 stud*) OR TI,AB(observational pre/1 stud*)

OR TI,AB(longitudinal) OR TI,AB(retrospective) OR TI,AB(“cross

sectional”) OR TI,AB("chart review") OR TI,AB("medical record

review")) OR (MESH.EXACT("Case-Control Studies") OR

MESH.EXACT("Cohort Studies") OR MESH.EXACT("Cross-Sectional

Studies") OR MESH.EXACT("Observational Study") OR

MESH.EXACT("Prospective Studies") OR

MESH.EXACT("Retrospective Studies") OR

MESH.EXACT("Longitudinal Studies"))

3760021*

S11 S3 AND S10 285°

S12 S3 AND (S4 OR S6 OR S8) AND S10 242° hits

* Duplicates are removed from the search in Embase/Medline, but included in the result count.

° Duplicates are removed from the search in Embase/Medline and from the result count.

Abbreviations: AB = search in abstract; EMB = search as Emtree term; MESH = search as Mesh term; TI = search

in title.


3.3.2 Cochrane

Cochrane search engine is used to search CDSR, DARE, CMR, HTA and EED. The search terms that will

be applied for the Cochrane search are provided in Table 4. No further limits were applied.

Table 4: Search terms Cochrane (searched on 30/09/2015)

Topic # Search terms # hits

Population 1 MeSH descriptor: [Diabetes Mellitus, Type 2] explode all

trees 9,256

2 diabetes:ti,ab and (type 2:ti,ab or II:ti,ab or 2ti,ab) 16,166

3 #1 OR #2 18,145

Intervention/comparators

4 (liraglitude OR victoza):ti,ab 10

5 #3 AND #4 9

Comparative

effectiveness 6 “comparative effectiveness”:ti,ab 1,030

7 “clinical effectiveness”:ti,ab 2,634

8 MeSH descriptor: [Treatment Outcome] explode all trees 98,028

9 MeSH descriptor: [Comparative Effectiveness Research]

explode all trees 164

10 #6 OR #7 OR #8 OR #9 101,038

11 #5 AND #10 1

Resource Utilisation 12 (resource and (utili*ation or use)):ti,ab 2,216

13 MeSH descriptor: [Patient Acceptance of Health Care]

explode all trees 20,189

14 #12 OR #13 22,259

15 #5 AND #14 0

Cost (-effectiveness) 16

((low near/5 cost) or (high near/5 cost) or (health?care

near/5 cost?) or (fiscal or funding or financial or finance)

or (cost near/5 estimate?) or (cost near/5 variable) or

(unit near/5 cost?) or (economic? or

pharmacoeconomic? or price? or pricing)):ti,ab

9,002

17 MeSH descriptor: [Cost-Benefit Analysis] explode all trees 17,181

18 MeSH descriptor: [Cost of Illness] explode all trees 1,186

19 MeSH descriptor: [Health Care Costs] explode all trees 6,879

20 MeSH descriptor: [Drug Costs] explode all trees 1,708

21 MeSH descriptor: [Employer Health Costs] explode all

trees 18

22 MeSH descriptor: [Hospital Costs] explode all trees 1,427

23 #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 28,047

24 #5 AND #23 2

Study design 25

((epidemiologic* pre/1 stud*) or ("case control") or

(cohort pre/1 stud*) or ("cohort analy*") or (Follow Up

pre/1 stud*) or (observational pre/1 stud*) or

20,024


(longitudinal) or (retrospective) or ("cross sectional") or

("chart review") or ("medical record review")):ti,ab

26 MeSH descriptor: [Case-Control Studies] explode all trees 11,755

27 MeSH descriptor: [Longitudinal Studies] explode all trees 15,235

28 MeSH descriptor: [Prospective Studies] explode all trees 69,188

29 MeSH descriptor: [Retrospective Studies] explode all

trees 7,700

30 MeSH descriptor: [Observational Study] explode all trees 0

31 MeSH descriptor: [Cohort Studies] explode all trees 114,785

32 #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 130,971

TOTAL 33 (#11 OR #15 OR #24) AND #32 0 hits

Abbreviations: MESH = search as Mesh term.

3.3.3 HTA websites

The HTA websites will be searched for STAs and Guidelines (i.e. MTAs) relevant for the T2DM

indication. Only these document types are searches as they provide the outcomes of the original

health technology assessments (HTA) performed.

The search will be performed through the search engine provided on the main page. The searches will

be performed using the search string “type 2 diabetes and liraglutide”. No limits will be applied.

Table 5: HTA websites searched (30/09/2015)

Europe Germany

– Gemeinsamer Bundesausschuss (G-BA)

– Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG)

France

– Haute Autorité de Santé (HAS)

Italy*

Spain*

Sweden

– Tandvårds- och läkemedelsförmånsverket (TLV)

UK

– National Institute for Health and Care Excellence (NICE)

North

America

US – The Food and Drug Administration (FDA)

Canada – The Canadian Agency for Drugs and Technologies in Health (CADTH)

Oceania Australia – Australian Government - Department of Health

Asia Japan*

*Spain, Italy and Japan do not publish HTA reports and their HTA bodies are therefore not listed above

Note: For HTA reports in other languages separate Pharmerit employees who speak the language, or an online translation

tool will be used. If this does not suffice, Pharmerit will request the Novo Nordisk team to translate or let the documents be

translated by a translation agency.

https://www.g-ba.de/

https://www.iqwig.de/

http://www.tlv.se/-/sok/?q=diabetes&tlvso=1&resid=310668711&uaid=13442AF5AF96DFC496928A1235508542%3A37392E3234352E3137392E323339%3A5247478448927223609&tlvst=true&tlvff=0&tlva=0&tlvl=-2

https://www.nice.org.uk/

http://www.fda.gov/

https://www.cadth.ca/

http://www.health.gov.au/internet/hta/publishing.nsf/Content/home-1


3.3.4 Conference Proceedings

Abstracts from the annual Meetings or scientific sessions presented from 2013 through 2015 will be

searched through the individual conference websites.

ISPOR

The ISPOR website will be searched for conference abstracts from 2013 to 2015. Only search terms

for “T2DM” and “liraglutide” will be used in the advanced search field (see Table 6Error! Reference

source not found.), no additional limits were applied to the search string. All results for the annual

meeting in 2013, 2014 and 2015 will be screened. This link will directly lead to the search engine of

the ISPOR website. On the website in disease/disorder the disease term diabetes is selected;

thereafter the search term is entered to be searched in the tile. In contrast to full-text, abstracts are

unlikely to report relevant evidence as a subtopic. Therefore, Pharmerit assumes that the title of the

abstract should contain one the applied search term liraglutide (main topic of interest) in order to be

included. Table 6 displays the search terms that will be used.

Table 6: Search terms for ISPOR

Search Year Search terms # hits

#1 2015 In Disease: Diabetes In Title: liraglutide 61



Total 79

ADA

The ADA website will be searched for conference abstracts from 2013 to 2015. The search term

“liraglutide” will be used to perform the search (see Table 7). This link will lead to a webpage with links

to conference abstracts for each year for the ADA conference meetings. For the year 2014 and 2015

search terms are inserted in the search bar. The search for 2013 is performed in the advanced search

with the search terms in abstract title search bar, similar to the ISPOR abstract search.

Table 7: Search terms for ADA

Search Year Search terms # hits

#1 2015 In Title: liraglutide 120



Total 187

EASD

The EASD website will be searched from 2013 to 2015. This link leads to the search engine of the EASD,

which can be used to select and search the three years of interest simultaneously. Search terms

“diabetes” and “liraglutide” were used in the right-top search bar, moreover in the left column

overview the specific meetings (2013, 2014 and 2015) are selected (Table 8). For result type the only

the option title was selected; for publication type abstracts and ePosters options were checked in the

options.

http://www.ispor.org/RESEARCH_STUDY_DIGEST/research_index.asp

http://professional.diabetes.org/Meeting_ListByType.aspx?ctyp=1

http://www.easdvirtualmeeting.org/resourcegroups#~searches/diabetes%20TYPE%202%20LIRAGLUTIDE/filters/resourcetype=1&tag=*&event=2,8,9&in=scene_texts&order=primary_event_starts_at


Table 8: Search terms for EASD

Search Search terms # hits

#1 diabetes AND liraglutide 143

Total 143

IDF

The IDF website will be searched from 2013 to 2015. Only 1 conference took place between this time

period (World Diabetes Congress Melbourne 2013). This link leads to the search engine of the IDF.

Search term for liraglutide was used in the search bar on the left-middle of the page (Table 9).

Table 9: Search terms for IDF

Search Search terms # hits

#1 liraglutide 48

Total 48

SFD

As there is no direct link to the previous congress archives, we will look for information on the website

archives through a keyword search using “liraglutide”. Alternatively we will contact SFD directly to

obtain the information/links to the relevant congress archives.

3.4 Search and Selection procedure

A search and selection file (1 single file in MS Excel) will be developed recording all identified hits and

the result of the selection process. This file will be used to remove duplicates between different

databases and to record the reasons for inclusion and exclusion. Duplicates will be identified using

Excel functions to match titles and authors from different data sources.

The selection of articles (based on title/abstract and full-text) will be done according to NICE

requirements with two reviewers and quality assessment for the extracted studies will be completed

using the following requirements by NICE:

1. Both reviewers perform the title/abstract selection. The results of each review are discussed

between the reviewers and a selection is made of the articles for the first review round. The

full-text selection round follows the same process.

2. In case the reviewers cannot find agreement on the selection of papers, a third reviewer

(senior team member) will be consulted.

The inclusion and exclusion criteria for the search and selection process to be applied is shown in

Error! Reference source not found.11). In case of doubt whether a publication should be included,

the reviewer will consult a third reviewer.

Table 10: Inclusion and exclusion criteria

Item Inclusion criteria Exclusion criteria

http://conference2.idf.org/MEL2013/World%20Diabetes%20Congress%202013/data/HtmlApp/main.html#open-sessions

http://diabetolognytt.se/


Population Patients with T2DM Patient with type 1 diabetes

mellitus

Gestational diabetes

Other diseases

Intervention Liraglutide Insulin therapy

NIADs

Comparator NIADs Insulin therapy

Outcomes Clinical effectiveness and safety of Victoza™

and NIADs

Comparative effectiveness and safety of

Victoza™ compared to other NIADs

Healthcare resource utilisation of T2DM

treatment using VictozaTM

Costs of T2DM treatment using VictozaTM

Studies not reporting the clinical

effectiveness/safety of either

VictozaTM or VictozaTM compared

to other NIADs

Studies not reporting costs and

resource utilization on an

individual patient level

Study design Chart review

Medical record analysis

Database analysis

Expert panel studies

Prospective follow-up studies

Post-marketing surveillance studies

Any type of interventional studies

• E.g. RCTs*

Case-reports

Letters to editor

Studies reporting resource utilisation or

costs based on modelling

Location All None

Language

All based on the Abstract None

Abbreviations: T2DM=Type 2 diabetes mellitus; NIAD=non-insulin antidiabetic drug; RCT=randomised controlled

trials

*Conventional trials will be included at first and will be discussed with the Novo Nordisk team to agree upon

final inclusion/exclusion

Note: For the purpose of the review; and in line with Novo Nordisk definition of RWE; evidence not collected

through randomised controlled trials will be considered for data extraction

Eligibility of non-English publications will be assessed based on their English abstracts. For publications

without English abstracts and for full text screening phase articles will be screened by separate

Pharmerit employees who speak the language, or an online translation tool will be used. If this does

not suffice, Pharmerit will request the Novo Nordisk team to translate or let the documents be

translated by a translation agency.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram (see

Figure 1) will be completed at the end of the selection phase. The PRISMA diagram will report the

number of studies initially retrieved, the number of studies excluded at each selection step after

implementing inclusion and exclusion criteria, and the number of studies eventually included in the

systematic review. This flow chart will be included in the report in a later stage.


Figure 1: PRISMA Flow Diagram (2009)

3.5 Data-extraction procedure

After selection of all articles, a data-extraction file (in MS Excel) will be constructed in order to assist

in selecting the relevant papers for data extraction. An empty Excel data extraction file will be

developed and shared with Novo Nordisk for one formal review round before data is extracted from

selected articles. Data extraction will be completed by one reviewer; the second reviewer will perform

a thorough quality check to assure all relevant data has been extracted to the correct parameter. For

non-English publications data will be extracted with help from Pharmerit employees who speak the

language, or an online translation tool will be used. If this does not suffice, Pharmerit will request the

Novo Nordisk team to translate or let the documents be translated by a translation agency.

The database will cover at least the following information:

Publication details: o Study title o Publication year o Author o Journal


o Data year o Country of data o Study sponsor

Study description o Study objective (as stated in the introduction) o Main and secondary topics of the study o Study type o Study design o Duration of study o Database name o Treatment setting o Inclusion/Exclusion criteria

Patient population

Medical treatment (i.e. liraglutide, regimen [monotherapy, dual or triple])

Outcomes: o Single arm studies: clinical effectiveness of liraglutide comparted to baseline, e.g.

Blood sugar levels HbA1c Weight loss (change in kg or BMI; number of people reaching a set target) Systolic blood pressure Lipids 8-point self-monitored plasma glucose profile β-cell function, insulin sensitivity index and fasting glucagon

o Comparative effectiveness of liraglutide compared to other NIADs o Resource Utilisation, e.g.

Hospitalisation HCP visits Drug utilisation

o Costs (direct, indirect, etc.)

Main conclusion (as reported in the publication’s conclusion section)

Limitations (as described in the publication’s discussion)

Future research (as described in the publication’s discussion)

3.6 Quality Assessment

Following the data-extraction process, a critical appraisal of the quality of selected studies will be

performed by a single researcher. This quality assessment is primarily required for the evidence

submission to NICE from 2015 (15). Thus the methodology will be adopted from the guidance for

evidence submission published by NICE. Table 11 will be completed for all selected observational

studies based on the recommendations of The Centre for Reviews and Dissemination (CRD’s) guidance

for undertaking reviews in health care (16).


Table 11: Evidence Quality Assessment Checklist

Study (author, date) Study 1 Study 2 Etc.

What is the study design of this study? (cohort study/ case-control

study/ case series)

(cohort study/ case-

control study/ case series) …

Was the study a prospective study or a

retrospective study?

(prospective/

retrospective)

(prospective/

retrospective)

In case of a case-control study, were the

groups similar at the outset of the study

in terms of prognostic factors?

(yes/no/not clear/NA) (yes/no/not clear/NA)

Was the intervention used

appropriately? (yes/no/not clear/NA) (yes/no/not clear/NA)

Were the outcome measures in the

study reliable? (yes/no/not clear/NA) (yes/no/not clear/NA)

Were the outcome measures in the

study valid? (yes/no/not clear/NA) (yes/no/not clear/NA)

Was the statistical analysis conducted

appropriately in the study? (yes/no/not clear/NA) (yes/no/not clear/NA)

Was the quality of reporting appropriate

in the study? (yes/no/not clear/NA) (yes/no/not clear/NA)

Can the study results be generalized to

routine practice? (yes/no/not clear/NA) (yes/no/not clear/NA)

Adapted from Centre for Reviews and Dissemination (2008) Systematic reviews. CRD’s guidance for

undertaking reviews in health care. York: Centre for Reviews and Dissemination

3.7 Reporting and Publication

3.7.1 Technical report

A report of size 50 pages on the evidence base for Victoza™ will be prepared using MS Word. The

report will comprise an introduction, the methodology, an overview of search results (including a

PRISMA flow diagram (see

Slide-deck

), the relevant results reported in included studies and review conclusions. The data tables (as

extracted) and full texts (annotated PDF) will be provided alongside the technical report.

3.7.1 Slide-deck

A slide-deck of size 30 slides comprising key results and highlights from the technical report will be

developed in MS Power Point.

3.7.2 Publication of findings in a peer-reviewed biomedical journal

Pharmerit will synthesise the research findings from the SLR on RWE of Victoza into a manuscript for

publication. The manuscript will be developed based on the target journal considered for publication.


4 Abbreviations

Abbreviation Full form

ADA American Diabetes Association

BMI Body Mass Index

CDSR Cochrane Database of Systematic Reviews

CRD Centre for Reviews and Dissemination

CENTRAL Cochrane Central Register of Controlled Trials

CMR Cochrane Methodology Register

CRD Centre for Reviews and Disseminations

EASD European Association for the Study of Diabetes

EED NHS Economic Evaluation Database

DPP-4 Dipeptidyl Peptidase-4

EMA Europeans Medicines Agency

FDA The Food and Drug Administration

GLP-1 Glucagon Like Peptide 1

GP General Practitioner

HbA1c Glycated Haemoglobin

HCP Health Care Professional

HTA Health Technology Assessments

LEAD Liraglutide Effect and Action in Diabetes

MTA Multi Technology Assessment

NIADs Non-insulin antidiabetic drugs

NICE National Institute for Health and Care Excellence

PICOS Population, interventions, comparators, outcomes and study designs

RCT Randomised Controlled Trial

RWE Real World Evidence

SGLT 2 Sodium Glucose Transporter 2

SLR Systematic Literature Review

SU Sulfonyl urea

STA Single Technology Assessment

T2DM Type 2 Diabetes Mellitus


5 References

1. Internation diabetes federation (IDF). Diabetes Atlas. 6th ed. Brussels, Belgium: IDF; 2013.

Available from: http://www.idf.org/diabetesatlas. Accessed October 1, 2015.

2. Gurung T, Shyangdan DS, O’Hare JP, Waugh N. A novel, long-acting glucagon-like peptide

receptor-agonist: dulaglutide. Diabetes Metab Syndr Obes. New Zealand; 2015;8:363–86.

3. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, et al. Management of

hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of

therapy. A consensus statement from the American Diabetes Association and the European

Association for the Study of Diabetes. Diabetologia. Germany; 2006 Aug;49(8):1711–21.

4. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of

hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position

statement of the American Diabetes Association and the European Association for the Study

of Diabetes. Diabetes Care. United States; 2015 Jan;38(1):140–9.

5. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting

hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-

dependent) diabetic patients. Diabetologia. GERMANY; 1993 Aug;36(8):741–4.

6. Baggio LL, Huang Q, Brown TJ, Drucker DJ. A recombinant human glucagon-like peptide (GLP)-

1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent

pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes.

United States; 2004 Sep;53(9):2492–500.

7. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, et al. Efficacy and safety of the

human glucagon-like peptide-1 analog liraglutide in combination with metformin and

thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care. United

States; 2009 Jul;32(7):1224–30.

8. Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs insulin glargine

and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes

mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia. Germany; 2009

Oct;52(10):2046–55.

9. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al.

Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised,

52-week, phase III, double-blind, parallel-treatment trial. Lancet (London, England). England;

2009 Feb;373(9662):473–81.


10. Marre M, Shaw J, Brandle M, Bebakar WMW, Kamaruddin NA, Strand J, et al. Liraglutide, a

once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater

improvements in glycaemic and weight control compared with adding rosiglitazone or placebo

in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. England; 2009 Mar;26(3):268–78.

11. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety

comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type

2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. United

States; 2009 Jan;32(1):84–90.

12. Rigato M, Fadini GP. Comparative effectiveness of liraglutide in the treatment of type 2

diabetes. Diabetes Metab Syndr Obes. New Zealand; 2014;7:107–20.

13. Mezquita Raya P, Perez A, Ramirez de Arellano A, Briones T, Hunt B, Valentine WJ. Incretin

therapy for type 2 diabetes in Spain: a cost-effectiveness analysis of liraglutide versus

sitagliptin. Diabetes Ther. United States; 2013 Dec;4(2):417–30.

14. Novo Nordisk. Novo Nordisk Annual Report 2014. 2015.

a systematic literature review of real world evidence ...10.1007/s13300-016-0180... · a systematic...

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