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A Publication of the Professional

Sections of the Canadian Diabetes Association

Une publication des sections professionnellesde l'Association canadienne du diabete

CONTENTS: April 2013 - Volume 37 - Supplement 1

S1 Introduction

S4 Methods

S8 De

nition, Classi

cation and Diagnosis of Diabetes, Prediabetes and Metabolic SyndromeS12 Screening for Type 1 and Type 2 Diabetes

S16 Reducing the Risk of Developing Diabetes

Management

S20 Organization of Diabetes Care

S26 Self-Management Education

S31 Targets for Glycemic Control

S35 Monitoring Glycemic Control

S40 Physical Activity and Diabetes

S45 Nutrition Therapy

S56 Pharmacotherapy in Type 1 Diabetes

S61 Pharmacologic Management of Type 2 Diabetes

S69 Hypoglycemia

S72 Hyperglycemic Emergencies in Adults

S77 In-hospital Management of Diabetes

S82 Weight Management in Diabetes

S87 Diabetes and Mental Health

S93 Inuenza and Pneumococcal Immunization

S94 Pancreas and Islet Transplantation

S97 Natural Health Products

Macrovascular and Microvascular Complications

S100 Vascular Protection in People with Diabetes

S105 Screening for the Presence of Coronary Artery Disease

(continued)Publication Mail Agreement 41536048 Return undeliverable Canadian addresses to:Transcontinental Printing, 737 Moray St, Winnipeg, MB R3J 3S9 Printed in Canada

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S110 Dyslipidemia

S117 Treatment of Hypertension

S119 Management of Acute Coronary Syndromes

S124 Management of Stroke in Diabetes

S126 Treatment of Diabetes in People with Heart Failure

S129 Chronic Kidney Disease in Diabetes

S137 Retinopathy

S142 Neuropathy

S145 Foot Care

S150 Erectile Dysfunction

Diabetes in Children

S153 Type 1 Diabetes in Children and Adolescents

S163 Type 2 Diabetes in Children and Adolescents

Diabetes in Special Populations

S168 Diabetes and Pregnancy

S184 Diabetes in the Elderly

S191 Type 2 Diabetes in Aboriginal Peoples

AppendicesS197 Appendix 1: Etiologic Classication of Diabetes Mellitus

S198 Appendix 2: Sample Diabetes Patient Care Flow Sheet for Adults

S200 Appendix 3: Examples of Insulin Initiation and Titration Regimens in People with Type 2Diabetes

S202 Appendix 4: Self-Monitoring of Blood Glucose (SMBG) Recommendation Tool forHealthcare Providers

S204 Appendix 5: Approximate Cost Reference List for Antihyperglycemic Agents

S207 Appendix 6: Therapeutic Considerations for Renal Impairment

S209 Appendix 7: Sick Day Medication List

S210 Appendix 8: Rapid Screening for Diabetic Neuropathy

S211 Appendix 9: Diabetes and Foot Care: A Patient’s Checklist

S212 Appendix 10: Diabetic Foot Ulcers: Essentials of Management

S212 Appendix 11: A1C Conversion Chart

CONTENTS (continued): April 2013 - Volume 37 - Supplement 1

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Can J Diabetes 37 (2013) A3–A13

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Acknowledgment / Can J Diabetes 37 (2013) A3–A13

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A Publication of the

Professional Sections of theCanadian Diabetes Association

Une publication des

sections professionnelles de

l'Association canadienne du diabete

Editor-in-Chief

David Lau MD PHD FRCPC

Editor Emeritus

Heather J. Dean MD FRCPC

Associate Editors

Lori Berard RN CDE

Sarah Capes MD MSC FRCPC

Alice Y.Y. Cheng MD FRCPC

J. Robin Conway MD

Carol Fawcett RD CDE

Rejeanne Gougeon PHD

Timothy J. Kieffer PHD

Sora Ludwig MD FRCPC

Gail MacNeill RN, MED CDE

Sara Meltzer MD FRCPC

Daniele Pacaud MD FRCPC

Rémi Rabasa-Lhoret MD PHD

Michael Riddell PHD

Elizabeth Sellers MD MSC FRCPC

Diana Sherifali RN PHD CDE

Scot H. Simpson BSP PHARMD MSC

T. Michael Vallis PHD R.PSYCH

National Editorial Board

Gillian Booth MD MSC FRCPC

Peter E. Light PHD

Peter A. Senior MBBS PHD

Arya M. Sharma MD PHD FRCPC

Garry X. Shen MD PHD

International Editorial Board

Stephanie Amiel MD FRCP

Barbara J. Anderson PHD

Alan Baron MD

Stuart J. Brink MD

Suad Efendic MD PHD

George Eisenbarth MD PHDMartha Funnell RN MS CDE

Diana Guthrie PHD RN CDE

Phillipe Halban PHD

Len Harrison MD DSC FRACP

FRCPA

Robert Henry MD

Cheri Ann Hernandez RN PHD CDE

Ryuzo Kawamori MD PHDKarmeen Kulkarni RD MS CDE

Willy Malaisse MD PHD

Kathy Mulcahy RN MSN CDE

Stephen O'Rahilly MD FRCOI FRCF

Daniel Porte, Jr. MD

Paul Robertson MD

Alicia Schiffrin MD

Meng Tan MD FACP FRCPCVirginia Valentine RN MS CDE

Paul Zimmett AM

Managing Editor

Ryan Moffat

[email protected]

Publications Coordinator

Alarica Fernandes

[email protected]

mailto:[email protected]:[email protected]:[email protected]:[email protected]

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Notes to Readers

Overview

The Canadian Diabetes Association 2013 Clinical Practice Guide-

lines for the Prevention and Management of Diabetes in Canada are

intendedto guidepractice and are not intended to serve as a compre-

hensive text of diabetes management, nor are they intended to set

criteria for research protocols. These guidelines are intended to

inform general patterns of care. These guidelines are also intended

to enhance diabetes prevention efforts in Canada and to reduce the

burden of diabetes complications in people living with this disease.

As per the Canadian Medical Association Handbook on Clinical

Practice Guidelines (Davis D, et al. Ottawa, ON: Canadian Medical

Association; 2007), guidelines should not be used as a legal

resource in malpractice cases as “their more general nature renders

them insensitive to the particular circumstances of the individual

cases.” Healthcare professionals must consider the needs, values

and preferences of individual patients, use clinical judgement andwork with available human and healthcare service resources in

their settings. These guidelines were developed using the best

available evidence. It is incumbent upon healthcare professionals

to stay current in this rapidly changing eld.

Unless otherwise specied, these guidelines pertain to the care

of adults with diabetes. Two chaptersdType 1 Diabetes in Children

and Adolescents and Type 2 Diabetes in Children and Adoles-

centsdare included to highlight aspects of care that must be

tailored to the pediatric population.

Suggested Citation

To cite as a whole:Canadian Diabetes Association Clinical Practice Guidelines

Expert Committee. Canadian Diabetes Association 2013 Clinical

Practice Guidelines for the Prevention and Management of Diabetes

in Canada. Can J Diabetes 2013;37(suppl 1):S1-S212.

To cite a specic chapter:

Last, First M. "Chapter Title." Journal Year;Vol(Number):XX-XX.

Example:

Harper W, Clement M, Goldenberg R, et al. Canadian Diabetes

Association 2013 Clinical Practice Guidelines for the Prevention

and Management of Diabetes in Canada: pharmacologic

management of type 2 diabetes. Can J Diabetes 2013;37(suppl 1):

S61-S68.

Reproduction of the Guidelines

Reproduction of the Canadian Diabetes Association 2013 Clinical

Practice Guidelines for the Prevention and Management of Diabetes

in Canada, in whole or in part, is prohibited without written

consent of the publisher.

Extra Copies

Copies of this document may be ordered, for a nominal fee, at

orders.diabetes.ca.

To order 50 or more copies for educational, commercial or

promotional use, contact Zoe Aarden, Elsevier Canada, 905 King

St. W, Toronto, ON M6K 3G9; E-mail: [email protected].

Website

These guidelines are available at guidelines.diabetes.ca.

mailto:[email protected]:guidelines.diabetes.camailto:guidelines.diabetes.camailto:[email protected]

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Clinical Practice Guidelines

Introduction

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee

The initial draft of this chapter was prepared by Alice Y.Y. Cheng MD, FRCPC

Every 5 years,since 1992,the Clinical & Scientic Section (C&SS) of

the Canadian Diabetes Association has published comprehensive,

evidence-based recommendations for healthcare professionals to

consider in the prevention and management of diabetes in Canada.They have served as a helpful resource and aid for anyone caring for

people with diabetes and are recognized, not only in Canada but also

internationally, as high-quality, evidence-based clinical practice

guidelines (1). In fact, an analysis by Bennett et al (1) demonstrated

that the Canadian Diabetes Association clinical practice guidelines

are among the best in the world with respect to quality, rigour and

process (1). For these 2013 Clinical Practice Guidelines for the

Prevention and Management of Diabetes in Canada, volunteer

members of the Clinical Practice Guidelines Expert Committee

assessed the peer reviewed evidence published since 2008 relevant

to the prevention and management of diabetes. They then incorpo-

rated the evidence into revised diagnostic, prognostic and thera-

peutic recommendations for the care of Canadians living with

diabetes, as well as recommendations for measures to delay theonsetof diabetes for populations at high risk of developing type 2 diabetes.

A number of important changes have occurred in the develop-

ment of the 2013 clinical practice guidelines:

Expansion of the Expert Committee to include 120 healthcare

professional volunteers from across Canada; Expert Committee

members bring expertise from diverse practice settings and

include professionals from family medicine, endocrinology,

internal medicine, infectious disease, neurology, nephrology,

cardiology, urology, psychology, obstetrics, ophthalmology, pedi-

atrics,nursing,dietetics, pharmacy, exercisephysiologyand others.

Inclusion and active participation of people with diabetes on

the Expert Committee to ensure that their views and prefer-

ences informed the guideline development process and therecommendations.

Update and expansion of previous chapters and, in some cases,

amalgamation of previous chapters into others to increase

utility and relevance.

Inclusion of a drug cost appendix for pharmacological thera-

pies as a reference for clinicians.

Update and expansion of our Methodology process (e.g.

updated literature searches throughout the guideline devel-

opment process, expansion of the Duality of Interest policy)

(see Methods chapter, p. S4).

Inclusion of a “Practical Tips” box, where appropriate, to facil-

itate implementation of the recommendations.

Expanded harmonization of recommendations through

collaboration with other organizations, including the Canadian

Hypertension Education Program (CHEP), the Society of Obste-

tricians and Gynecologists of Canada (SOGC), the CanadianCardiovascular Society (CCS) and the Canadian Cardiovascular

Harmonization of National Guidelines Endeavour (C-CHANGE).

Expanded dissemination and implementation strategy with

increased use of technology.

It is hoped that primary care physicians and other healthcare

professionals who care for people with diabetes or those at risk of

diabetes will continue to nd the evidence compiled in these

guidelines a vital aid and resource in their efforts. We are condent

that, ultimately, if applied properly, these guidelines will lead to

improved quality of care, reduced morbidity and mortality from

diabetes and its complications, and a better quality of life for people

living with this chronic disease.

The Challenge of Diabetes

Diabetes mellitus is a serious condition with potentially devas-

tating complications that affects all age groups worldwide. In 1985,

an estimated 30 million people around the world were diagnosed

with diabetes; in 2000, that gure rose to over 150 million; and, in

2012, the International Diabetes Federation (IDF) estimated that

371 million people had diabetes (2). That number is projected to

rise to 552 million (or 1 in 10 adults) by 2030, which equates to 3

new cases per second (2). Although the largest increase is expected

to be in countries with developing economies, Canada also will be

impacted signicantly. As of 2009, the estimated prevalence of

diabetes in Canada was 6.8% of the populationd2.4 million Cana-

dians (3)d

a 230% increase compared to prevalence estimates in1998. By 2019, that number is expected to grow to 3.7 million (3).

Diabetes is the leading cause of blindness, end stage renal disease

(ESRD) and nontraumatic amputation in Canadian adults. Cardio-

vascular disease is the leading cause of death in individuals with

diabetes and occurs 2- to 4-fold more often than in people without

diabetes. People with diabetes are over 3 times more likely to be

hospitalized with cardiovascular disease, 12 times more likely to be

hospitalized with ESRD and over 20 times more likely to be

hospitalized for a nontraumatic lower limb amputation compared

to the general population (3). Diabetes and its complications

increase costs and service pressures on Canada’s publicly funded

healthcare system. Among adults aged 20 to 49 years, those with

Contents lists available at SciVerse ScienceDirect

Canadian Journal of Diabetesj o u r n a l h o m e p a g e :

w w w . c a n a d i a n j o u r n a l o f d i a b e t e s . c o m

1499-2671/$ e see front matter 2013 Canadian Diabetes Association

http://dx.doi.org/10.1016/j.jcjd.2013.01.009

Can J Diabetes 37 (2013) S1eS3

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diabetes were 2 times more likely to see a family physician and 2 to

3 times more likely to see a specialist (3). Also, peoplewith diabetes

were 3 times more likely to require hospital admission in the

preceding year with longer lengths of stay (3). Therefore, the

impact of diabetes is signicant not only for individuals but also for

their families and for society as a whole.

Delaying the Onset of Type 2 Diabetes

Prevention of type 1 diabetes has not yet been successful, butremains an active area of research. However, there is good evidence

that delayingthe onsetof type 2 diabetesresultsin signicant health

benets, including lower rates of cardiovascular disease and renal

failure (4). In 2007, the IDF releaseda “Consensuson Type 2 Diabetes

Prevention” and called upon the governments of all countries to

develop and implementa National Diabetes Prevention Plan (4). The

IDF proposed that strategies be implemented for 2 separate groups:

those at high risk of developing type 2 diabetes, and the entire

population at large. Among those at high risk, the proposed 3-step

approach was to A) identify those who may be at higher risk, B)

measure therisk,and C) intervene to delay/preventthe onsetof type

2 diabetes usingpredominantly health behaviourstrategies to affect

the modiable risk factors for type 2 diabetes. As of 2013, Canada

does not have such a strategy in place. There remains an urgent andincreasing need for governments to invest in research to dene

effective strategies andprogramsto prevent andtreatobesityand to

encourage physical activity. In addition, Canada’s diverse pop-

ulation, with some ethnic groups disproportionally affected by

diabetes, requires that health promotion, and disease prevention

and management strategies be culturallyappropriateand tailored to

specic populations. They also should include policies aimed at

addressing poverty and other systemic barriers to healthcare (5).

Optimal Care of Diabetes

Effectivediabetes careshould be delivered within the framework

of the Chronic Care Model and centred around the individual who is

practicing, and supported in, self-management (see Organization of Care chapter, p. S20). To achieve this, an interprofessional team with

the appropriate expertise is required, and the system needs to

support and allow for sharing and collaboration between primary

care and specialist care as needed. A multifactorial approach

utilizing an interprofessional team addressing healthy behaviours,

glycemic control, blood pressure control, lipid management and

vascular protection measures has been shown to effectively and

dramatically lower the risk of development and progression of

serious complications for individuals with diabetes (6e9). In addi-

tion, individuals with diabetes must be supported in the skills of

self-management sincetheir involvementin disease management is

absolutely necessary for success. People with diabetes require

training in goal setting, problem solving and health monitoring, all

of which are critical components of self-management. They alsoneed accessto a broad rangeof tools,including medications,devices

andsupplies to help them achieve therecommended blood glucose,

cholesterol and blood pressure targets. Health outcomes depend on

managing the disease effectively, and, without access to the neces-

sary tools and strategies, Canadians living with diabetes will not be

able to achieve optimal results. All levels of government should

commit to investingin chronic care management andsupport of the

tools needed for successful self-management to ensure that optimal

care can be delivered.

Research

Canada continues to be a world leader in diabetes research. This

researchis essential forcontinued improvement in thelivesof people

withdiabetes. Regulatory agencies should not apply these guidelines

in a rigid way with regard to clinical research in diabetes. It is sug-

gested that study protocols may include guideline recommenda-

tions, but individual decisions belong in the domain of the patient-

physician relationship. The merits of each research study must be

assessed individually so as to not block or restrict the pursuit of new

information. The Canadian Diabetes Association welcomes the

opportunity to work withregulatory agencies to enhance researchin

Canada and, ultimately, to improve the care of people with diabetes.

Cost Considerations

When it comes to the issue of cost, caution is required when

identifying direct, indirect and induced costs for treating diabetes

(10). In fact, the 2011 Diabetes in Canada report from the Public

Health Agency of Canadacouldnot reportthe total economic burden

of diabetes, but concluded that the costs will only increase

substantiallyas the prevalence of the disease increases overtime (3).

Nonetheless, in 2009, the Canadian Diabetes Association commis-

sioned a report to evaluate the economic burden of diabetes using

a Canadian Diabetes Cost Model, which utilizes the data from the

Canadian National Diabetes Surveillance System (NDSS) and the

Economic Burden of Illness in Canada (EBIC) (11). In this report, the

estimatedeconomicburdenof diabetes was$12.2billionin 2010 andprojected to increase by another $4.7 billion by 2020. It is certainly

the hope and expectation of all stakeholders that the evidence-

based prevention and management of diabetes in a multifactorial

fashion will reduce the economic burden of the disease (3,6,12).

These clinical practice guidelines, like those published before,

have purposefully not taken into account cost effectiveness in the

evaluation of the evidencesurrounding best practice. The numerous

reasons forthis have been outlined in detailpreviously (13). Someof

these reasons include the paucity of cost-effectiveness analyses

using Canadian data, the dif culty in truly accounting for all the

important costs (e.g. hypoglycemia) in any cost-effectiveness

analysis, the lack of expertise and resources to properly address

the cost-effectiveness analyses needed for all the clinical questions

within these clinical practice guidelines and, perhaps more impor-tantly, the philosophical question of which is more important:

clinical benet to the patient or cost to the system? At what level of

cost effectiveness should one consider a therapy worth recom-

mending?For these2013 clinical practice guidelines, the questionof

whether the committee should incorporate cost considerations was

discussed again, and a Cost Consideration Working Group, consist-

ing of health economists and health outcomes researchers, was

convened. Themandateof thegroup was todevelopa proposalto the

Clinical Practice Guidelines SteeringCommitteedescribing how cost

issues might be incorporated into the guidelines, considering

feasibility and impact. Based on issues of feasibility and philosoph-

icalconsiderations of our roleas recommendation developers, it was

decided that cost would not be included in the recommendations to

ensure that they reect the best available clinical evidence for thepatient. The issue of evidence-based vs. cost-effective healthcare is

an ethical debate that should involve all citizens because the

outcome of thisdebateultimately impacts every Canadian.However,

it is recognized and acknowledged that both the healthcare profes-

sional and the patient should consider cost when deciding on ther-

apies.Therefore, drug costs areincluded in Appendix 5, allowing for

easy reference for both clinicians and patients alike.

Other Considerations

In Canada, the glycated hemoglobin (A1C) continues to be re-

ported using National Glycohemoglobin Standardization Program

(NGSP) units (%). In 2007, a consensus statement from the American

Diabetes Association, the European Association for the Study of

A.Y.Y. Cheng / Can J Diabetes 37 (2013) S1eS3S2

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Diabetes and the IDF called for A1C reporting worldwide to change

to dual reportingof A1Cwith the International Federation of Clinical

Chemistry and Laboratory Medicine (IFCC) SI units (mmol/mol) and

derived NGSP units (%)with the hope of fullyconverting to exclusive

reporting in SI units (14). However, this has not been adopted

worldwide, with both Canada and the United States still using the

NGSP units (%) (15). Although there are some advantages to

reporting in SI units, the most notable disadvantage is the massive

education effort that would be required to ensure recognition and

adoption of the new units. At this time, Canada is not performingdual reporting. Therefore, throughout this document, the A1C will

still be written in NGSP units (%). For those who wish to convert

NGSP units to SI units, the following equation can be used: (16)

IFCC ¼ 10.93(NGSP) e 23.50.

Dissemination and Implementation

Despite the strength of the evidence supporting the multifacto-

rial treatment of people with diabetes to reduce complications,

a recent national cross-sectional survey conducted around World

Diabetes Day (November 14, 2012) demonstrated that only 13% of

5123 patients with type 2 diabetes had achieved all 3 metabolic

targets (glycemia, lipids and blood pressure) (17). Therefore, a care

gap remains and the effectivedissemination andimplementationof these 2013 clinical practice guidelines is critical. A Dissemination &

Implementation Chair was appointed at the beginning of the

guidelines process. Strategies were developed to increase practi-

tioner implementation and to improve patient care and health

outcomes. A Dissemination & Implementation Committee was

created to develop a strategic plan to be implemented at the launch

of the guidelines and to continue for years thereafter. These volun-

teers from across Canada are involved in creating a 3-year plan to

translate the evidence compiled in the guidelines into community

practice. An Executive Summary will be distributed to healthcare

professionals in Canada. The full guidelines will continue to be

available online, and summary articles will be strategically placed in

journals and newsletters. In addition, key messages and tools sup-

porting specic themes from the guidelines will be highlighted intechnology-based and paper-based awareness campaigns over the

next few years. Primary care physicians, healthcare providers,

government of cials, Canadiansliving with diabetes and the general

public continue to be the audiences for these campaigns.

Clinical Practice Guidelines and Clinical Judgement

“ Neither evidence nor clinical judgment alone is suf cient.

Evidence without judgment can be applied by a technician. Judgment

without evidence can be applied by a friend. But the integration of

evidence and judgment is what the healthcare provider does in order

to dispense the best clinical care.” (Hertzel Gerstein, 2012)

People with diabetes are a diverse and heterogeneous group;

therefore, it must be emphasized that treatment decisions need to

be individualized. Guidelines are meant to aid in decision making

by providing recommendations that are informed by the best

available evidence. However, therapeutic decisions are made at the

level of the relationship between the healthcare professional and

the patient. That relationship, along with the importance of clinical

judgement, can never be replaced by guideline recommendations.

Evidence-based guidelines try to weigh the benet and harm of

various treatments; however, patient preferences are not always

included in clinical research, and, therefore, patient values and

preferences must be incorporated into clinical decision making

(18). For some of the clinical decisions that we need to make with

our patients, strong evidence is available to inform those decisions,

and these are reected in the recommendations within these

guidelines. However, there are many other clinical situations where

strong evidence may not be available, or may never become

available, for reasons of feasibility. In those situations, the

consensus of expert opinions, informed by whatever evidence is

available, is provided to help guide and aid the clinical decisions

that need to be made at the level of the patient. It is also important

to note that clinical practice guidelines are not intended to be

a legal resource in malpractice cases as outlined in the Canadian

Medical Association Handbook on Clinical Practice Guidelines (19).

Conclusions

Diabetes is a complex and complicated disease. The burgeoning

evidence on new technologies and therapeutic treatments is

rapidly expanding our knowledge and ability to manage diabetes

and its complications; at the same time, however, it is challenging

for physicians and other healthcare professionals who care for

people with diabetes. These 2013 clinical practice guidelines

contain evidence-based recommendations that provide a useful

reference tool to help healthcare professionals translate the best

available evidence into practice. The hope is that these guidelines

will provide government of cials with the evidence they need

when rationalizing access to healthcare so that the potentially

benecial health outcomes are maximized for people living with

diabetes. Healthcare professionals are encouraged to judge inde-pendently the value of the diagnostic, prognostic and therapeutic

recommendations published in the 2013 Clinical Practice Guide-

lines for the Prevention and Management of Diabetes in Canada.

References

1. Bennett WL, Odelola OA, Wilson LM, et al. Evaluation of guideline recom-mendations on oral medications for type 2 diabetes mellitus. Ann Intern Med2012;156:27e36.

2. International Diabetes Federation. IDF Diabetes Atlas. 5th ed. Brussels: Inter-national Diabetes Federation, www.idf.org/diabetesatlas; 2012. AccessedFebruary 21, 2013.

3. Public Health Agency of Canada. Diabetes in Canada: Facts and Figures froma Public Health Perspective. Ottawa; 2011.

4. Alberti KGMM, Zimmet P, Shaw J. International Diabetes Federation:a consensus on type 2 diabetes prevention. Diabet Med 2007;24:451e63.

5. McManus R. Time for action: a Canadian proposal for primary prevention of type 2 diabetes. Can J Diabetes 2012;36:44e9.

6. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med1993;329:977e86.

7. Nathan DM, Cleary PA, Backlund JY, et al. Diabetes Control and ComplicationsTrial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC)Study Research Group. Intensive diabetes treatment and cardiovascular diseasein patients with type 1 diabetes. N Engl J Med 2005;353:2643e53.

8. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovasculardisease in patients with type 2 diabetes. N Engl J Med 2003;348:383e93.

9. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorialintervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580e91.

10. Ettaro L, Songer TJ, Zhang P, Engelgau MM. Cost of illness studies in diabetesmellitus. Pharmacoeconomics 2004;22:149e64.

11. Canadian Diabetes Association. An Economic Tsunami: The Cost of Diabetes inCanada. Toronto: Canadian Diabetes Association; 2009.

12. Gaede P, Valentine WJ, Palmet AJ, et al. Cost-effectiveness of intensied versusconventional multifactorial intervention in type 2 diabetes. Diabetes Care2008;31:1510e5.

13. Harris SB, McFarlane P, Lank CN. Consensus, cost-effectiveness and clinicalpractice guidelines: author’s response. Can J Diabetes 2005;29:376e8.

14. Consensus Committee. Consensus statement on the worldwide standardizationof the hemoglobin A1C measurement: the American Diabetes Association,European Association for the Study of Diabetes, International Federation of Clinical Chemistry and Laboratory Medicine, and the International DiabetesFederation. Diabetes Care 2007;30:2399e400.

15. Sacks D. Measurement of hemoglobin A1c: a new twist on the path toharmony. Diabetes Care 2012;35:2674e80.

16. Weykamp C, John WG, Mosca A, et al. The IFCC reference measurement systemfor HbA1c: a 6-year progress report. Clin Chem 2008;54:240e8.

17. Leiter LA, Berard L, Bowering K, et al. Type 2 diabetes mellitus management inCanada: Is it improving? Can J Diabetes 2013: in press.

18. McCormack JP, Loewen P. Adding “value” to clinical practice guidelines. CanFam Physician 2007;53:1326e7.

19. Davis D, Goldman J, Palda VA. Canadian Medical Association Handbook onClinical Practice Guidelines. Ottawa: Canadian Medical Association; 2007.

A.Y.Y. Cheng / Can J Diabetes 37 (2013) S1eS3 S3

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Methods


The initial draft of this chapter was prepared by Gillian Booth MD, MSc, FRCPC,Alice Y.Y. Cheng MD, FRCPC

Process

Following the process used to develop previous Canadian Dia-

betes Association clinical practice guidelines (1,2), an ExecutiveCommittee, Steering Committee and Expert Committee with broad

expertise and geographic representation were assembled. In total,

120 volunteers,including health professionals fromfamilymedicine,

endocrinology, internal medicine, infectious disease, neurology,

nephrology, cardiology, urology, psychology, obstetrics, ophthal-

mology, pediatrics, nursing, dietetics, pharmacy, exercise physiology

and others, as well as people with diabetes, participated in the

guideline development process.

The following basic principles were adopted to ensure that the

values and empirical basis underlying each recommendation were

explicitly identied andto facilitate thecriticalscrutiny and analysis

of each recommendation by other organizations and individuals.

Elements covered by the Appraisal of Guidelines for Research

and Evaluation (AGREE) II instrument were incorporated into theguideline development process.

Each recommendation had to address a clinically important

question related to 1 or more of the following: detection,

prognosis, prevention or management of diabetes and its

sequelae. Health benets, risks and side effects of interventions

were considered in formulating the recommendations. Patient

preferences and values were sought from expert panel

members with diabetes and the literature (where available).

Whenever possible, each recommendation had to be justied

by the strongest clinically relevant, empirical evidence that

could be identied; the citation(s) reporting this evidence had

to be noted adjacent to the relevant guideline.

The strength of this evidence, based on prespecied criteriafrom the epidemiological literature and other guidelines

processes, had to be noted (3e8).

Each recommendation had to be assigned a grade based on the

available evidence, its methodological strength and its appli-

cability to the Canadian population.

Each recommendation had to be approved by the Steering

Committee and Executive Committee, with 100% consensus.

Guidelines based on biological or mechanistic reasoning,

expert opinion or consensus had to be explicitly identied and

graded as such; harmonization was sought with other Cana-

dian guideline bodies, including the Canadian Cardiovascular

Society (CCS), the Canadian Hypertension Education Program

(CHEP), the Canadian Cardiovascular Harmonization of

National Guidelines Endeavour (C-CHANGE) and the Society of

Obstetricians and Gynecologists of Canada (SOGC).

Identifying and Appraising the Evidence

Authors for each chapter were assembled based on their relevant

elds of expertise. Each chapter had 1 lead author, 1 or 2 “evidence

resource” persons trained or experienced in clinical epidemiology or

clinical research methodology, and additional authors, as needed. At

the outset of the process, committee members from each section of

the guidelines attended a workshop on evidence-based method-

ology,in order to ensure a consistent approachto the development of

recommendations. Committee members identied clinically impor-

tant questions related to diagnosis, prognosis, prevention and treat-

ment of diabetes andits complications,which were used as a basis for

our literature search strategy (outlined below).

Authors were to explicitly dene A) the population to whicha guidelinewould apply; B) thetest,risk factoror interventionbeing

addressed; C) the “gold standard” test or relevant intervention to

which thetest or interventionin questionwascompared; andD) the

clinically relevant outcomes being targeted. This information was

used to develop specic, clinically relevant questions that were the

focus of literature searches. For each question, individual strategies

were developed combining diabetes terms with methodological

terms. A librarian with expertise in literature reviews performed

a comprehensive search of the relevant English-language, pub-

lished, peer-reviewed literature using validated search strategies

(http://hiru.mcmaster.ca/hiru/) of electronic databases (MEDLINE,

EMBASE, CINAHL, the Cochrane Central Register of Trials, and

PsycINFO [where appropriate]). This was complemented by the

authors’ own manual and electronic searches.

Fortopics that werecovered in the2008 guidelines, theliterature

searches focused on new evidence published since those guidelines,

including literature published in September 2007 or later. For new

topics, the search time frame included the literature published since

1990 or earlier, where relevant. Updated literature searches were

performed at regular intervals throughout the development process.

Key citations retrieved from the literature searches were then

reviewed. Each citation that was used to formulate or revise

a recommendationwas assigned a levelof evidence accordingto the

prespecied criteria in Table 1, reecting the methodological quality

of the paper. When evaluating papers, authors were required to use

standardized checklists that highlighted the most important







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elements of a well-conducted study. The level of evidence was then

determined by the cited paper’s objectives, methodological rigour,

susceptibility to bias and generalizability (Table 1). Becausethey could not be critically appraised, meeting abstracts, narrative

review articles, news reports and other sources could not be used

to support recommendations. Papers evaluating the cost effective-

ness of therapies or diagnostic tests also were not included.

A number of considerations were made when evaluating the

evidencewithina given area. Forexample, peoplewith diabetes areat

high risk for several sequelae that are not exclusive to diabetes (e.g.

cardiovasculardisease, renalfailure and erectile dysfunction).As such,

some evidence relating to these problems was identied that either

excluded, did not report on or did not focus on people with diabetes.

Whenever such evidence was identied, a level was assigned

using the approach described above. Higher levels were assigned if

A) people with diabetes comprised a predened subgroup; B) the

results in the diabetes subgroup were unlikely to have occurred by

chance; andC) the evidence was generated in responseto questions

that were formulated prior to the analysis of the results. Lower

levels (than those indicated in Table 1) were assigned to evidence

that did not meet these criteria.

Guideline Development

Expert Committee members evaluated the relevant literature,

and guidelines were developed and initially reviewed by the Expert

Committee. In the absence of new evidence since the publication of the 2008 clinical practice guidelines, recommendations from the

2008 document were not changed.

The studies used to develop and support each recommendation

are cited beside the level of evidence. In some cases, key citations

that inuenced the nal recommendation were not assigned the

same level of evidence but ratherwere of varying levelsof evidence.

In those circumstances, all relevant studies were cited, regardless of

the grading assigned to the recommendation. The nal grading

depended on the overall evidence available, including the relative

strengths of the studies from a methodological perspective and the

studies’ ndings. Studies with conicting outcomes were also

considered and cited in the nal recommendation where relevant.

Further details on the grading process are described below.

Finally, several treatment recommendations were based onevidence generated from the use of one therapeutic agent from

a given class (e.g. one of the statins). Whenever evidence relating to

1 or more agents from a recognized class of agents was available,

the recommendation was written so as to be relevant to the class,

but specically studied therapeutic agents were identied within

the recommendation and/or cited reference(s). Only medications

with Health Canada Notice of Compliance granted by February 15,

2013 were included in the recommendations.

Grading the Recommendations

After formulating new recommendations or modifying existing

ones based on new evidence, each recommendation was assigned

a grade from A through D (Table 2). The highest possible grade that

a recommendation could have wasbased on thestrengthof evidence

that supported the recommendation (i.e. the highest level of

evidence assigned to studies on which the recommendation was

based). However, the assigned grading was lowered in some cases,

for example, if the evidence was found not to be applicable to the

Canadianpopulation or, if based on the consensusof the Steering and

Executive Committees, there wereadditional concerns regarding the

recommendation. In some situations, the grading also was lowered

for subgroups that were not well represented in the study or in

whom the benecial effectof an interventionwas less clear. Grading

also was lowered if thendings fromrelevant (and equally rigorous)

studies on thetopicwereconicting. Thus,a recommendationbased

on Level 1 evidence, deemed to be very applicable to Canadians

and supported by strong consensus, was assigned a grade of A.

A recommendation not deemed to be applicable to Canadians, or

judged to require further supporting evidence,was assigned a lower

grade. Where available,the number of patients that would needto be

treated in order to prevent 1 clinical event (number needed to treat

[NNT])or to causean adverse event(number needed toharm[NNH])

was considered in assessing the impact of a particular intervention.

Table 1

Criteria for assigning levels of evidence to the published studies

Level Criteria

Studies of diagnosis

Level 1 a) Independent interpretation of test results (without

knowledge of the result of the diagnostic or gold standard)

b) Independent interpretation of the diagnostic standard

(without knowledge of the test result)

c) Selection of people suspected (but not known) to have

the disorder

d) Reproducible description of both the test and diagnosticstandard

e) At least 50 patients with and 50 patients without the

disorder

Level 2 Meets 4 of the Level 1 criteria

Level 3 Meets 3 of the Level 1 criteria

Level 4 Meets 1 or 2 of the Level 1 criteria

Studies of treatment and prevention

Level 1A Systematic overview or meta-analysis of high quality RCTs

a) Comprehensive search for evidence

b) Authors avoided bias in selecting articles for inclusion

c) Authors assessed each article for validity

d) Reports clear conclusions that are supported by the data

and appropriate analyses

OR

Appropriately designed RCT with adequate power to answer

the question posed by the investigators

a) Patients were randomly allocated to treatment groups

b) Follow-up at least 80% complete

c) Patients and investigators were blinded to the treatment*

d) Patients were analyzed in the treatment groups to which

they were assigned

e) The sample size was large enough to detect the outcome

of interest

Level 1B Nonrandomized clinical trial or cohort study with indisputable

results

Level 2 RCT or systematic overview that does not meet Level 1 criteria

Level 3 Nonrandomized clinical trial or cohort study; systematic

overview or meta-analysis of level 3 studies

Level 4 Other

Studies of prognosis

Level 1 a) Inception cohort of patients with the condition of interest

but free of the outcome of interestb) Reproducible inclusion/exclusion criteria

c) Follow-up of at least 80% of subjects

d) Statistical adjustment for extraneous prognostic factors

(confounders)

e) Reproducible description of outcome measures

Level 2 Meets criterion a) above, plus 3 of the other 4 criteria

Level 3 Meets criterion a) above, plus 2 of the other criteria

Level 4 Meets criterion a) above, plus 1 of the other criteria

RCT , randomized, controlled trial.

* In cases where such blinding was not possible or was impractical (e.g. intensive

vs. conventional insulin therapy), the blinding of individuals who assessed and

adjudicated study outcomes was felt to be suf cient.

Table 2

Criteria for assigning grades of recommendations for clinical practice

Grade Criteria

Grade A The best evidence was at Level 1

Grade B The best evidence was at Level 2

Grade C The best evidence was at Level 3

Grade D The best evidence was at Level 4 or consensus

G. Booth, A.Y.Y. Cheng / Can J Diabetes 37 (2013) S4eS7 S5

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The degree to which evidence derived from other populations was

felt to be relevant to diabetes also was reected in the wording and

grading of the recommendation. Finally, in the absence of Level 1, 2

or 3 supportingevidence,or if the recommendation wasbased on the

consensus of the Steering and Executive Committees, the highest

grade that could be assigned was D.

Interpreting the Assigned Grade of a Recommendation

The grade assigned to each recommendation is closely linked tothe methodological rigour and robustness of the relevant clinical

research. Therefore, as noted above, a high grade reects a high

degree of condence that following the recommendation will lead

to the desired outcome. Similarly, a lower grade reects weaker

evidence and a greater possibility that the recommendation will

change when more evidence is generated in the future. Of note, the

assigned grade contains no subjective information regarding the

importance of the recommendation or how strongly members of

the committee felt about it; it only contains information regarding

the evidence upon which the recommendation is based. Thus,

many Grade D recommendations were deemed to be very impor-

tant to the contemporary management of diabetes, based on

clinical experience, case series, physiological evidence and current

concepts of disease pathophysiology. However, the paucity of clinical evidence addressing the areas of therapy, prevention,

diagnosis or prognosis precluded the assignment of a higher grade.

Clearly, clinicians need to base clinical decisions on the best

available relevant evidence that addresses clinical situations.

However, they also frequently are faced with having to act in the

absence of clinical evidence, and there are many situations where

good clinical evidence may be impossible, impractical or too

expensive to generate (which implies that it would be impossible to

develop Grade A recommendations). For example, it took

the United Kingdom Prospective Diabetes Study (UKPDS) Group

>20 years to collect and publish Level 1 evidence leading to a Grade

A recommendation in support of the role of tight glycemic control

to reduce microvascular disease in people with type 2 diabetes.

Prior to the publication of the UKPDS results, the recommendationfor glycemic control to prevent microvascular consequences was

a Grade B recommendation (9).

Varying grades of recommendations, therefore, reect varying

degrees of certainty regarding the strength of inference that can be

drawn from the evidence in support of the recommendation.

Therefore, these evidence-based guidelines and their graded

recommendations are designed to satisfy 2 important needs: 1) the

explicit identication of the best research upon which the recom-

mendation is based and an assessment of its scientic relevance

and quality (captured by the assignment of a level of evidence to

each citation); and 2) the explicit assignment of strength of the

recommendation based on this evidence (captured by the grade). In

this way, they provide a convenient summary of the evidence to

facilitate clinicians in the task of “weighting” and incorporatingever increasing evidence into their daily clinical decision making.

They also facilitate the ability of clinicians, healthcare planners,

healthcare providers and society, in general, to critically examine

any recommendation and arrive at their own conclusions regarding

its appropriateness. Thus, these guidelines facilitate their own

scrutiny by others according to the same principles that they use to

scrutinize the literature.

It is important to note that the system chosen for grading

recommendations differs from the approach used in some other

guideline documents, such as the one pertaining to the periodic

health examination in Canada, in which harmful practices were

assigned a grade of D (8). In this Canadian Diabetes Association

guidelines document, recommendation to avoid any harmful

practices would be graded in the same manner as all other

recommendations. However, it should be noted that the authors of

these guidelines focused on clinical practices that were thought to

be potentially benecial and did not seek out evidence regarding

the harmfulness of interventions.

External Peer Review and Independent Methodological

Review

In May 2012, a draft document was circulated nationally and

internationally for review by numerous stakeholders and experts in

relevant elds. This input was then considered by the Executive and

Steering Committees, and revisions were made accordingly.

Subsequently, a panel of 6 methodologists, who were not directly

involved with the initial review and assessment of the evidence,

independently reviewed each recommendation, its assigned grade

and supportive citations. Based on this review, the wording,

assigned level of evidence and grade of each recommendation were

reassessed and modied as necessary. Revised recommendations

were reviewed and approved by the Executive and Steering

Committees. Selected recommendations were presented at a public

forum at the Canadian Diabetes Association/Canadian Society of

Endocrinology and Metabolism Professional Conference and Annual

Meetings in Vancouver, British Columbia, on October 13, 2012.

Disclosure of Duality of Interest

Committee members were volunteers and received no remu-

neration or honoraria for their participation. Members of all

committees signed an annual duality of interest form listing all

nancial interests or relationships with manufacturer(s) of any

commercial product(s) and/or provider(s) of commercial services.

Dualities of interest were discussed during deliberations where

relevant. In the case of a potential duality or outright conict of

interest, committee members removed themselves from discus-

sions. Funding for the development of the guidelines was provided

from the general funds of the Canadian Diabetes Association and

from unrestricted educational grants from Novo Nordisk CanadaInc, Eli Lilly Canada Inc, Merck Canada Inc, Bristol-Myers Squibb

and AstraZeneca, and Novartis Pharmaceuticals Canada Inc. These

companies were not involved in any aspect of guideline develop-

ment, literature interpretation, the decision to publish or any other

aspect related to the publication of these guidelines, and they did

not have access to guideline meetings, guideline drafts or

committee deliberations.

Guideline Updates

A process to update the full guidelines will commence within

5 years and will be published in 2018. Updates to individual

chapters may be published sooner in the event of signicant

changes in evidence supporting the recommendations. The Exec-utive and Steering Committees of the 2013 revision will continue to

remain intact to deliberate any potential updates to individual

chapters until such time as the Executive and Steering Committees

for the 2018 revision have been created.

Other Relevant Guidelines

Introduction, p. S1

References

1. Canadian Diabetes Association Clinical Practice Guideline Expert Committee.Canadian Diabetes Association 2003 clinical practice guidelines for the preven-tion and management of diabetes in Canada. Can J Diabetes 2003;27(suppl 2):S1e152.


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2. Canadian Diabetes Association Clinical Practice Guideline Expert Committee.Canadian Diabetes Association 2008 clinical practice guidelines for theprevention and management of diabetes in Canada. Can J Diabetes 2008;32-(suppl 1):S1e201.

3. Straus SE,McAlisterFA. Whatis theprognosis?In: GersteinHC, Haynes RB,editors.Evidence-based Diabetes Care. Hamilton, ON: BC Decker Inc; 2001. p. 6 e12.

4. American Medical Association. Users’ Guides to the Medical Literature: Essentials of Evidence-based Clinical Practice. Chicago, IL: American Medical Association; 2001.

5. Jaeschke R, Guyatt GH. How should diagnostic tests be chosen and used? In:Gerstein HC, Haynes RB, editors. Evidence-based Diabetes Care. Hamilton, ON:BC Decker Inc; 2001. p. 13e23.

6. Holbrook AM, Clarke J-A, Raymond C, et al. How should a particular problem bemanaged? Incorporating evidence about therapies into practice. In: Gerstein HC,Haynes RB, editors. Evidence-based Diabetes Care. Hamilton, ON: BC Decker Inc;2001. p. 24e47.

7. Harris SB, Webster-Bogaert SM. Evidence-based clinical practice guidelines. In:Gerstein HC, Haynes RB, editors. Evidence-based Diabetes Care. Hamilton, ON:BC Decker Inc; 2001. p. 48e61.

8. Goldbloom R, Battista RN. The periodic health examination: 1. Introduction.CMAJ 1986;134:721e3.

9. Meltzer S, Leiter L, Daneman D, et al. 1998 clinical practice guidelines for themanagement of diabetes in Canada. CMAJ 1998;159(suppl 8):S1e29.


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Denition, Classication and Diagnosis of Diabetes, Prediabetes

and Metabolic Syndrome


The initial draft of this chapter was prepared by Ronald Goldenberg MD, FRCPC, FACE,Zubin Punthakee MD, MSc, FRCPC

KEY MESSAGES

The chronic hyperglycemia of diabetes is associated with signicant long-

term microvascular and macrovascular complications.

A fasting plasma glucose level of 7.0 mmol/L, a 2-hour plasma glucose

value in a 75 g oral glucose tolerance test of 11.1 mmol/L or a glycated

hemoglobin (A1C) value of 6.5% can predict the development of reti-

nopathy. This permits the diagnosis of diabetes to be made on the basis of

each of these parameters.

Theterm “prediabetes” refers to impaired fasting glucose, impaired glucose

tolerance or an A1C of 6.0% to 6.4%, each of which places individuals at

high risk of developing diabetes and its complications.

Denition of Diabetes and Prediabetes

Diabetes mellitus is a metabolic disorder characterized by the

presence of hyperglycemia due to defective insulin secretion,

defective insulin action or both. The chronic hyperglycemia of

diabetes is associated with relatively specic long-term microvas-

cular complications affecting the eyes, kidneys and nerves, as well

as an increased risk for cardiovascular disease (CVD). Thediagnostic

criteria for diabetes are based on thresholds of glycemia that are

associated with microvascular disease, especially retinopathy.

“Prediabetes” is a practical and convenient term referring to

impaired fasting glucose (IFG), impaired glucose tolerance (IGT) (1)

or a glycated hemoglobin (A1C) of 6.0% to 6.4%, each of which

places individuals at high risk of developing diabetes and its

complications.

Classication of Diabetes

The classication of type 1 diabetes, type 2 diabetes and

gestational diabetes mellitus (GDM) is summarized in Table 1.

Appendix 1 addresses the etiologic classication of diabetes.

Distinguishing between type 1 and type 2 diabetes is important

because management strategies differ, but it may be dif cult at the

time of diagnosis in certain situations. Physical signs of insulin

resistance and autoimmune markers, such as anti-glutamic acid

decarboxylase (GAD) or anti-islet cell antibody (ICA) antibodies,

may be helpful, but have not been adequately studied as diagnostic

tests in this setting. While very low C-peptide levels measured after

months of clinical stabilization may favour type 1 diabetes (2), theyare not helpful in acute hyperglycemia (3). Clinical judgement with

safe management and ongoing follow-up is a prudent approach.

Diagnostic Criteria

Diabetes

The diagnostic criteria for diabetes are summarized in Table 2

(1). These criteria are based on venous samples and laboratory

methods.

A fasting plasma glucose (FPG) level of 7.0 mmol/L correlates

most closely with a 2-hour plasma glucose (2hPG) value of 11.1

mmol/L in a 75 g oral glucose tolerance test (OGTT), and each

predicts the development of retinopathy (5e

11).The relationship between A1C and retinopathy is similar to that

of FPG or 2hPG with a threshold at around 6.5% (5e7,11,12).

Although the diagnosis of diabetes is based on an A1C threshold for

developing microvascular disease, A1C is also a continuous

cardiovascular (CV) risk factor and a better predictor of macro-

vascular events than FPG or 2hPG (13,14). Although many people

identied by A1C as having diabetes will not have diabetes by

traditional glucose criteria and vice versa, there are several

advantages to using A1C for diabetes diagnosis (15). A1C can be

measured at any time of day and is more convenient than FPG

or 2hPG in a 75 g OGTT. A1C testing also avoids the problem of

day-to-day variability of glucose values as it reects the average

plasma glucose (PG) over the previous 2 to 3 months (1).

In order to use A1C as a diagnostic criterion, A1C must bemeasured using a validated assay standardized to the National

Glycohemoglobin Standardization Program-Diabetes Control and

Complications Trial reference. It is important to note that A1C may

be misleading in individuals with various hemoglobinopathies, iron

deciency, hemolytic anaemias, and severe hepatic and renal

disease (16). In addition, studies of various ethnicities indicate that

African Americans, American Indians, Hispanics and Asians have

A1C values that are up to 0.4% higher than those of Caucasian

patients at similar levels of glycemia (17,18). The frequency of

retinopathy begins to increase at lower A1C levels in American

blacks than in American whites, which suggests a lower threshold

for diagnosing diabetes in black persons (19). Research is required







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to determine if A1C levels differ in African Canadians or Canadian

First Nations. A1C values also are affected by age, rising by up to

0.1% per decade of life (20,21). More studies may help to determine

if age- or ethnic-specic adjusted A1C thresholds are required for

diabetes diagnosis. Also, A1C is not recommended for diagnostic

purposes in children, adolescents, pregnant women or those with

suspected type 1 diabetes.

Thedecision ofwhichtestto usefor diabetesdiagnosis (Table2) is

left to clinical judgement. Each diagnostic test has advantages and

disadvantages (Table 3). In the absence of symptomatic hypergly-

cemia, if a single laboratory test result is in the diabetes range,

a repeat conrmatory laboratory test (FPG,A1C, 2hPG ina 75g OGTT)

must be done on another day. It is preferable that the same test be

repeated (in a timely fashion) for conrmation, but a random PG in

the diabetes range in an asymptomatic individual should be

conrmed with an alternate test. In the case of symptomatic

hyperglycemia,the diagnosishas been made anda conrmatory test

is not required before treatment is initiated. In individuals in

whom type 1 diabetes is likely (younger or lean or symptomatic

hyperglycemia, especially with ketonuria or ketonemia), conrma-

tory testing should not delay initiation of treatment to avoid rapid

deterioration. If results of 2 different tests are available and both are

above the diagnostic cutpoints, the diagnosis of diabetes is

conrmed.Whenthe results ofmorethan1 test are available (among

FPG,A1C,2hPGina75gOGTT)andtheresultsarediscordant,thetest

whose result is above the diagnostic cutpoint should be repeated

and the diagnosis made on the basis of the repeat test.

Prediabetes

The term “prediabetes” refers to IFG, IGT or an A1C of 6.0% to

6.4% (Table 4), each of which places individuals at high risk of developing diabetes and its complications. Not all individuals with

prediabetes will necessarily progress to diabetes. Indeed, a signi-

cant proportion of people who are diagnosed with IFG or IGT will

revert to normoglycemia. People with prediabetes, particularly in

the context of the metabolic syndrome, would benet from CV risk

factor modication.

While people with prediabetes do not have the increased risk

for microvascular disease as seen in diabetes, theyare at risk for the

development of diabetes and CVD (23). IGT is more strongly

associated with CVD outcomes than is IFG. Individuals identied as

having both IFG and IGT are at higher risk for diabetes as well as

CVD. While there is no worldwide consensus on the denition of

IFG (24,25), the Canadian Diabetes Association denes IFG as an

FPG value of 6.1 to 6.9 mmol/L due to the higher risk of developingdiabetes in these individuals compared to dening IFG as an FPG

value of 5.6 to 6.9 mmol/L (25).

While there is a continuum of risk for diabetes in individuals

with A1C levels between 5.5% and 6.4%, population studies

demonstrate that A1C levels of 6.0% to 6.4% are associated with

Table 1

Classication of diabetes (1)

Type 1 diabetes* encompasses diabetes that is primarily a result of

pancreatic beta cell destruction and is prone to ketoacidosis. This form

includes cases due to an autoimmune process and those for which the

etiology of beta cell destruction is unknown.

Type 2 diabetes may range from predominant insulin resistance with

relative insulin deciency to a predominant secretory defect with insulin

resistance.

Gestational diabetes mellitus refers to glucose intolerance

with onset or rst recognition during pregnancy. Other specic types include a wide variety of relatively uncommon

conditions, primarily specic genetically dened forms of diabetes or

diabetes associated with other diseases or drug use (Appendix 1).

* Includes latent autoimmune diabetes in adults (LADA); the term used to

describe the small number of people with apparent type 2 diabetes who appear to

have immune-mediated loss of pancreatic beta cells (4).

Table 2

Diagnosis of diabetes

FPG ‡7.0 mmol/L

Fasting ¼ no caloric intake for at least 8 hours

or

A1C ‡6.5% (in adults)

Using a standardized, validated assay in the absence of factors that affect the

accuracy of the A1C and not for suspected type 1 diabetes (see text)

or

2hPG in a 75 g OGTT ‡11.1 mmol/L

orRandom PG ‡11.1 mmol/L

Random ¼ anytime of theday, without regardto theinterval since thelast meal

In the absence ofsymptomatic hyperglycemia,if a singlelaboratory test resultis

in the diabetes range, a repeat conrmatory laboratory test (FPG, A1C, 2hPG in

a 75 g OGTT) must be done on another day. It is preferable that the same test be

repeated (in a timely fashion) for conrmation, but a random PG in the diabetes

range in an asymptomaticindividual shouldbe conrmed with an alternatetest.

In the case of symptomatic hyperglycemia, the diagnosis has been made and

a conrmatory test is notrequiredbefore treatmentis initiated. In individuals in

whom type 1 diabetes is likely (younger or lean or symptomatic hyperglycemia,

especially with ketonuria or ketonemia), conrmatory testing should not delay

initiation of treatment to avoid rapid deterioration. If results of 2 different tests

are available and both are above the diagnostic cutpoints, the diagnosis of

diabetes is conrmed.

2hPG, 2-hour plasma glucose; A1C , glycated hemoglobin; FPG, fasting plasma

glucose; OGTT , oral glucose tolerance test; PG, plasma glucose.

Table 3

Advantages and disadvantages of diagnostic tests for diabetes* (22)

Parameter Advantages Disadvantages

FPG Established standard

Fast and easy

Single sample

Predicts microvascular

complications

Sample not stable

High day-to-day variability

Inconvenient (fasting)

Reects glucose homeostasis

at a single point in time

2hPG in

a 75 gOGTT

Established standard

Predicts microvascularcomplications

Sample not stable

High day-to-day variability Inconvenient

Unpalatable

Cost

A1C Convenient (measure any

time of day)

Single sample

Predicts microvascular

complications

Better predictor of macro-

vascular disease than FPG

or 2hPG in a 75 g OGTT

Low day-to-day variability

Reects long-term glucose

concentration

Cost

Misleading in various

medical conditions (e.g.

hemoglobinopathies, iron

deciency, hemolytic

anaemia, severe hepatic or

renal disease)

Altered by ethnicity and

aging

Standardized, validated

assay required

Not for diagnostic use in

children, adolescents, preg-

nant women or those withsuspected type 1 diabetes


glucose; OGTT , oral glucose tolerance test.

* Adapted from Sacks D. A1C versus glucose testing: a comparison. Diabetes Care.

2011;34:518e523.

Table 4

Diagnosis of prediabetes

Test Result Prediabetes category

FPG (mmol/L) 6.1e6.9 IFG

2hPG i n a 75 g OGTT ( mm ol /L ) 7.8e11.0 IGT

A1C (%) 6.0e6.4 Prediabetes


glucose; IFG, impaired fasting glucose; IGT , impaired glucose tolerance; OGTT , oral

glucose tolerance test.

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a higher risk for diabetes compared to levels between 5.5% and 6.0%

(26). While the American Diabetes Association denes prediabetes

as an A1C between 5.7% and 6.4%, the Canadian Diabetes Associa-

tion has based the denition on a higher risk group and includes an

A1C of 6.0% to 6.4% as a diagnostic criterion for prediabetes (1).

However, A1C levels below 6.0% can indeed be associated with an

increased risk for diabetes (26). The combination of an FPG of 6.1 to

6.9 mmol/L and an A1C of 6.0% to 6.4% is predictive of 100%

progression to type 2 diabetes over a 5-year period (27).

Metabolic syndrome

Prediabetes and type 2 diabetes are often manifestations of

a much broader underlying disorder (28), including the metabolic

syndromeda highly prevalent, multifaceted condition charac-

terized by a constellation of abnormalities that include abdominal

obesity, hypertension, dyslipidemia and elevated blood glucose.

Individuals with the metabolic syndrome are at signicant risk of

developing CVD. While metabolic syndrome and type 2 diabetes

often coexist, those with metabolic syndrome without diabetes

are at signicant risk of developing diabetes. Evidence exists to

support an aggressive approach to identifying and treating

people, not only those with hyperglycemia but also those with

the associated CV risk factors that make up the metabolic

syndrome, such as hypertension, dyslipidemia and abdominal

obesity, in the hope of signicantly reducing CV morbidity and

mortality.

Various diagnostic criteria for the metabolic syndrome have

been proposed. In 2009, a harmonized denition of the metabolic

syndrome was established, with at least 3 or more criteria required

for diagnosis (Table 5) (29).

Other Relevant Guidelines

Screening for Type 1 and Type 2 Diabetes, p. S12

Reducing the Risk of Developing Diabetes, p. S16

Type 1 Diabetes in Children and Adolescents, p. S153

Type 2 Diabetes in Children and Adolescents, p. S163

Relevant Appendix

Appendix 1. Etiologic Classication of Diabetes Mellitus

References

1. American Diabetes Association. Diagnosis and classication of diabetesmellitus. Diabetes Care 2012;35(suppl 1):S64e71.

2. Patel P, Macerollo A. Diabetes mellitus: diagnosis and screening. Am FamPhysician 2010;81:863e70.

3. Unger RH, Grundy S. Hyperglycemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for themanagement of diabetes. Diabetologia 1985;28:119e21.

4. Turner R, Stratton I, Horton V, et al. UKPDS 25: autoantibodies to islet-cellcytoplasm and glutamic acid decarboxylase for prediction of insulin require-ment in type 2 diabetes. UK Prospective Diabetes Study Group. Lancet 1997;350:1288e93.

5. McCance DR, Hanson RL, Charles MA, et al. Comparison of tests for glycatedhemoglobin and fasting and two hour plasma glucose concentrations asdiagnostic methods for diabetes. BMJ 1994;308:1323e8.

6. Engelgau MM, Thompson TJ, Herman WH, et al. Comparison of fasting and2-hour glucose and HbA1c levels for diagnosing diabetes. Diagnostic criteriaand performance revisited. Diabetes Care 1997;20:785e91.

7. The Expert Committee on the Diagnosis and Classication of Diabetes Mellitus.Report of the expert committee on the diagnosis and classication of diabetesmellitus. Diabetes Care 1997;20:1183e97.

RECOMMENDATIONS

1. Diabetes should be diagnosed by any of the following criteria:

FPG 7.0 mmol/L [Grade B, Level 2 (11)] A1C 6.5% (for use in adults in the absence of factors that affect the

accuracy of A1C and not for use in those with suspected type 1 dia-

betes) [Grade B, Level 2 (11)]

2hPG in a 75 g OGTT 11.1 mmol/L [Grade B, Level 2 (11)]

Random PG 11.1 mmol/L [Grade D, Consensus]

2. In the absence of symptomatic hyperglycemia, if a single laboratory test

result is in the diabetes range, a repeat conrmatory laboratory test (FPG,

A1C, 2hPG in a 75 g OGTT) must be done on another day. It is preferable

that the same test be repeated (in a timely fashion) for conrmation, but

a random PG in the diabetes range in an asymptomatic individual should

be conrmed with an alternate test. In the case of symptomatic hyper-

glycemia, the diagnosis has been made and a conrmatory test is not

required before treatment is initiated. In individuals in whom type 1

diabetes is likely (younger or lean or symptomatic hyperglycemia, espe-

cially with ketonuria or ketonemia), conrmatory testing should not delay

initiation of treatment to avoid rapid deterioration. If results of twodifferent tests are available and both are above the diagnostic cutpoints,

the diagnosis of diabetes is conrmed [Grade D, Consensus].

3. Prediabetes (dened as a state which places individuals at high risk of

developing diabetes and its complications) is diagnosed by any of the

following criteria:

IFG (FPG 6.1e6.9 mmol/L) [Grade A, Level 1 (23)]

IGT (2hPG in a 75 g OGTT 7.8e11.0 mmol/L) [Grade A, Level 1 (23)]

A1C 6.0%e6.4% (for usein adults in theabsence of factorsthat affect the

accuracy of A1C and not for use in suspected type 1 diabetes) [Grade B,

Level 2 (26)].

Abbreviations:

2hPG, 2-hour plasma glucose; A1C , glycated hemoglobin; FPG, fasting

plasma glucose; IFG, impaired fasting glucose; IGT , impaired glucose

tolerance; OGTT , oral glucose tolerance test; PG, plasma glucose.

Table 5

Harmonized denition of the metabolic syndrome: 3 measures to make the diagnosis of metabolic syndrome* (29)

Measure Categorical cutpoints

Men Women

Elevated waist circumference (population- and country-specic cutpoints):

Canada, United States

Europid, Middle Eastern, sub-Saharan African, Mediterranean

Asian, Japanese, South and Central American

102 cm

94 cm

90 cm

88 cm

80 cm

80 cm

Elevated TG (drug treatment for elevated TG is an alternate indicator y) 1.7 mmol/L

Reduced HDL-C (drug treatment for reduced HDL-C is an alternate indicator

y

) <

1.0 mmol/L in males,

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8. Ito C, Maeda R, Ishida S, et al. Importance of OGTT for diagnosing diabetesmellitus based on prevalence and incidence of retinopathy. Diabetes Res ClinPract 2000;49:181e6.

9. Miyazaki M, Kubo M, Kiyohara Y, et al. Comparison of diagnostic methods fordiabetes mellitus based on prevalence of retinopathy in a Japanese population:the Hisayama Study. Diabetologia 2004;47:1411e5.

10. Tapp RJ, Zimmett PZ, Harper CA, et al. Diagnostic thresholds for diabetes: theassociation of retinopathy and albuminuria with glycaemia. Diabetes Res ClinPract 2006;73:315e21.

11. The DETECT-2 Collaboration Writing Group. Glycemic thresholds for diabetesspecic retinopathy. Diabetes Care 2011;34:145e50.

12. International Expert Committee. International Expert Committee report on therole of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327e34.

13. Sarwar N, Aspelund T, Eiriksdottir G, et al. Markers of dysglycaemia and risk of coronary heart disease in people without diabetes: Reykjavik ProspectiveStudy and systematic review. PLoS Med 2010;7:e1000278.

14. Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes,and cardiovascular risk in nondiabetic adults. N Engl J Med 2010;362:800e11.

15. Report of a World Health Organization Consultation. Use of glycatedhaemoglobin (HbA1C) in the diagnosis of diabetes mellitus. Diabetes Res ClinPract 2011;93:299e309.

16. Gallagher EJ, Bloomgarden ZT, Roith D. Review of hemoglobin A1c in themanagement of diabetes. J Diabetes 2009;1:9e17.

17. Herman WH, Ma Y, Uwaifo G, et al. Differences in A1C by race and ethnicityamong patients with impaired glucose tolerance in the Diabetes PreventionProgram. Diabetes Care 2007;30:2453e7.

18. Ziemer DC, Kolm P, Weintraub WS, et al. Glucose-independent, black-white differences in hemoglobin A1c levels. Ann Intern Med 2010;152:

770e

7.

19. Tsugawa Y, Mukamal K, Davis R, et al. Should the HbA1c diagnostic cutoff differbetween blacks and whites? A cross-sectional study. Ann Intern Med 2012;157:153e9.

20. Davidson MB, Schriger DL. Effect of age and race/ethnicity on HbA1c levels inpeople without known diabetes mellitus: implications for the diagnosis of diabetes. Diabetes Res Clin Pract 2010;87:415e21.

21. Pani L, Korenda L, Meigs JB, Driver C, Chamany S, Fox CS, et al. Effect of agingon A1C levels in persons without diabetes: evidence from the FraminghamOffspring Study and NHANES 2001-2004. Diabetes Care 2008;31:1991e6.

22. Sacks D. A1C versus glucose testing: a comparison. Diabetes Care 2011;34:518e23.

23. Santaguida PL, Balion C, Morrison K, et al. Diagnosis, prognosis, and treatment of impairedglucose tolerance and impairedfasting glucose.Evidence report/technologyassessment no. 128. Agency Healthcare Research and Quality Publication No05-E026-2. Rockville, MD: Agency for Healthcare Research and Quality; September2005.

24. Shaw JE,Zimmet PZ,Alberti KG.Point: impaired fastingglucose:the case forthenew American Diabetes Association criterion. Diabetes Care 2006;29:1170e2.

25. Forouhi NG, Balkau B, Borch-Johnsen K, et al, EDEG. The threshold fordiagnosing impaired fasting glucose: a position statement by the EuropeanDiabetes Epidemiology Group. Diabetologia 2006;49:822e7.

26. Zhang X, Gregg E, Williamson D, et al. A1C level and future risk of diabetes:a systematic review. Diabetes Care 2010;33:1665e73.

27. Heianza Y, Arase Y, Fujihara K, et al. Screening for pre-diabetes to predict futurediabetes usingvarious cut-off points forHbA1c and impaired fastingglucose: theToranomon Hospital Health Management Center Study 4 (TOPICS 4). DiabeticMed 2012;29:e279e85.

28. Reaven GM. Banting Lecture 1988. Role of insulin resistance in human disease.Diabetes 1988;37:1595e607.

29. Alberti KGMM, Eckel R, Grundy S, et al. Harmonizing the metabolic syndrome.

Circulation 2009;120:1640e

5.

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Screening for Type 1 and Type 2 Diabetes


The initial draft of this chapter was prepared by Jean-Marie Ekoé MD, CSPQ, PD,Zubin Punthakee MD, MSc, FRCPC, Thomas Ransom MD, MSc, FRCPC,Ally P.H. Prebtani BScPhm, MD, FRCPC, Ronald Goldenberg MD, FRCPC, FACE

KEY MESSAGES

In the absence of evidence for interventions to prevent or delay type 1

diabetes, screening for type 1 diabetes is not recommended.

Screening for type 2 diabetes using a fasting plasma glucose (FPG) and/or

glycated hemoglobin (A1C) should be performed every 3 years in indi-

viduals40 yearsof ageor in individualsat high risk usinga risk calculator.

Diabetes will be diagnosed if A1C is 6.5% (see Denition, Classication

and Diagnosis chapter, p. S8).

Testing with a 2-hour plasma glucose (2hPG) in a 75 g oral glucose

tolerance test (OGTT) should be undertaken in individuals with an FPG of

6.1e6.9 mmol/Land/or an A1Cof 6.0%e6.4% in order to identify individuals

with impaired glucose tolerance (IGT) or diabetes.

Testing with a 2hPG in a 75 g OGTT may be undertaken in individuals with

anFPG5.6e6.0mmol/L and/orA1C 5.5%e5.9% and1 riskfactorin order to

identify individuals with IGT or diabetes.

The clinical spectrum of diabetes ranges from a low-risk to

a higher-risk individual or to the symptomatic patient who needs

immediate treatment. Screening for diabetes implies testing for

diabetes in individuals without symptoms who are unaware of

their condition. Screening for diabetes will also detect individuals

at increased risk for diabetes (prediabetes) or individuals with less

severe states of dysglycemia who may still be at risk for type 2

diabetes. Screening strategies vary according to the type of diabetes

and evidence of effective interventions to prevent progression of

prediabetes to diabetes and/or reduce the risk of complications

associated with diabetes. The growing importance of diabetes

screening is undeniable (1).

In contrast to other diseases, there is no distinction between

screening and diagnostic testing. Therefore, to screen for diabetesand prediabetes, the same tests would be used as for diagnosis

of both medical conditions (see Denition, Classication and

Diagnosis chapter, p. S8).

Screening for Type 1 Diabetes

Type1 diabetes mellitus is primarily a resultof pancreatic beta cell

destruction due to an immune-mediated process that is likely incited

by environmental factors in genetically predisposed individuals. An

individual’s risk of developing type 1 diabetes can be estimated by

considering family history of type 1 diabetes with attention to age of

onset and sex of the affected family members (2) and proling

immunity and genetic markers (3). The loss of pancreatic beta cells in

the development of type 1 diabetes passes through a subclinicalprodrome that can be detected reliably in rst- and second-degree

relatives of persons with type 1 diabetes by the presence of pancre-

atic islet autoantibodies in their sera (4). However, in a recent large

study, one-time screening for glutamic acid decarboxylaseantibodies

(GADAs) and islet antigen-2 antibodies (IA-2As) in the general

childhood population in Finland would identify 60% of those indi-

vidualswho willdeveloptype 1 diabetes over thenext27 years.Initial

positivity for GADAs and/or IA-2As had a sensitivity of 61% (95%

condence interval [CI] 36e83%) for type 1 diabetes. The combined

positivity for GADAs and IA-2As had both a specicity and a positive

predictive value of 100% (95% CI 59e100%) (5). Ongoing clinical

studies are testing different strategies for preventing or reversing

early type1 diabetes in the presence of positive autoimmunity.Given

that the various serological markers are not universally available andin theabsence of evidence for interventionsto prevent or delay type1

diabetes, no widespread recommendations for screening for type 1

diabetes can be made.

Screening for Type 2 Diabetes

Adults

Undiagnosed type 2 diabetes may occur in >2.8% of the general

adult population (6), and the number increases to >10% in some

populations (7,8). Tests for hyperglycemia can identify these

individuals, many of whom will have, or will be at risk for,

preventable diabetes complications (5,6). To be effective,

population-based screening would have to involve wide coverageand would have the goal of early identication and subsequent

intervention to reduce morbidity and mortality. Using various

multistaged screening strategies, the ADDITION-Europe study

showed that 20% to 94% of e

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