canadian diabetes association 2003 clinical practice guidelines for the prevention and management of...

Canadian Diabetes Association2003 Clinical Practice Guidelines

for the Prevention and Management of Diabetes in Canada



This material has been reviewed by the Canadian Diabetes Association for its medical and scientific accuracy.Presence of the Canadian Diabetes Association Partners in Progress mark does not constitute an endorsement of the products or services of GlaxoSmithKline Inc.

Getting to Goal in Type 2 Diabetes


1 Harris S, et al, The Diabetes in Canada Evaluation (DICE) Study, ADA 2003, 2162-PO2 Harris MI, et al. Diabetes Care 1999; 22:403–408.

Per

cen

tag

e o

f su

bje

cts

0

20

40

60

80

100

<7% > 7%

A1C (%)

US (1988-1994)2

Many patients have inadequate glycemic controlMany patients have inadequate glycemic control

38%

62%

Per

cen

tag

e o

f su

bje

cts

0

20

40

60

80

100

< 7% 7%

A1C (%)

CAN (2003)1

50% 50%

Years T2DM

Proportion of patients with A1C > 7.0 increases with duration of type 2 diabetes

Proportion of patients with A1C > 7.0 increases with duration of type 2 diabetes

<=2<=2 3-53-5 6-96-9 10-1410-14 15+15+

31%31%

42%42%

53%53%

67%67%

62%62%

Harris,S et al. CDA 2003; Type 2 Diabetes and Associated Complications in Primary Care in Canada: The Impact of Duration of Disease on Morbidity Load.

Proportion of patients with hypertension increases with duration of type 2 diabetesProportion of patients with hypertension

increases with duration of type 2 diabetes

Years T2DM

<=2<=2 3-53-5 6-96-9 10-1410-14 15+15+

53%53%57%57%

64%64%

71%71% 72%72%


Proportion of patients with dyslipidemia increases with duration of type 2 diabetes

Proportion of patients with dyslipidemia increases with duration of type 2 diabetes

Years T2DM

<=2<=2 3-53-5 6-96-9 10-1410-14 15+15+

55%55% 57%57% 58%58% 59%59%

66%66%


Proportion of patients with cardiovascular disease increases with duration of type 2 diabetes

Proportion of patients with cardiovascular disease increases with duration of type 2 diabetes

Years T2DM

<=2<=2 3-53-5 6-96-9 10-1410-14 15+15+

15%15%

21%21%24%24%

29%29%

48%48%


Proportion of patients with microvascular disease increases with duration of type 2 diabetes

Proportion of patients with microvascular disease increases with duration of type 2 diabetes

Years T2DM

<=2<=2 3-53-5 6-96-9 10-1410-14 15+15+

21%21%

32%32%

42%42% 44%44%

62%62%


The evolution of management guidelinesThe evolution of management guidelines

Studies including UKPDS have highlighted the importance of glycemic control in reducing complications

New guidelines include tighter targets for glycemic control

Guidelines recognize importance of treating all aspects of the condition

Current guidelines therefore include targets for

glycemic control

lipid levels

blood pressure

Studies including UKPDS have highlighted the importance of glycemic control in reducing complications

New guidelines include tighter targets for glycemic control

Guidelines recognize importance of treating all aspects of the condition

Current guidelines therefore include targets for

glycemic control

lipid levels

blood pressure

Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412.

UKPDS: decreased risk of diabetes-related complications associated with a 1% decrease in A1C

UKPDS: decreased risk of diabetes-related complications associated with a 1% decrease in A1C

Per

cen

tag

e d

ecre

ase

in r

ela

tive

ris

k co

rres

po

nd

ing

to

a 1

% d

ecre

ase

in H

bA

1C

**

Any diabetes-related endpoint

21%

**

Diabetes-related death

21% **

All cause

mortality

14%*

Stroke

12%

**

Peripheral vascular disease†

43%

**

Myocardial infarction

14%

**

Micro-vascular disease

37%

**

Cataract extraction

19%

Observational analysis from UKPDS study data

†Lower extremity amputation or fatal peripheral vascular disease*P = 0.035; **P < 0.0001

Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412.

UKPDS: the benefits of improved glycemic control

UKPDS: the benefits of improved glycemic control

Improved glycemic control significantly reduces risk of diabetes-related complications

UKPDS results indicated that a 1% reduction in A1C would reduce the risk of microvascular complications by 37%, but have less effect (16%) on macrovascular complications

Further improvement in sustained glycemic control and reduction in the burden of cardiovascular disease are needed

Improved glycemic control significantly reduces risk of diabetes-related complications

UKPDS results indicated that a 1% reduction in A1C would reduce the risk of microvascular complications by 37%, but have less effect (16%) on macrovascular complications

Further improvement in sustained glycemic control and reduction in the burden of cardiovascular disease are needed

06

7

8

9

2 4 6 8 10

A1

C (

%)

Years from randomization

Upper limit of of normal = 6.2%

ConventionalGlyburideChlorpropamideMetforminInsulin

0

UKPDS demonstrated loss of glycemic control with all agents studied

UKPDS demonstrated loss of glycemic control with all agents studied

UK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865.

Overweight patientsCohort, median values

Turner RC, et al. UKPDS 49. JAMA 1999; 281:2005–2012.

100

Years from randomization3 6 9

0

20

40

60

80

3 6 9 3 6 9 3 6 9

Diet Insulin MetforminSulfonylurea

Overweight patients

Pro

po

rtio

n o

f p

atie

nts

(%

)

50%

Proportion of patients with A1C < 7.0% on monotherapy at 3, 6 and 9 years

Proportion of patients with A1C < 7.0% on monotherapy at 3, 6 and 9 years

Error bars = 95% CI

The UKPDS demonstrated progressive decline of -cell function over time

The UKPDS demonstrated progressive decline of -cell function over time

100

80

60

40

P < 0.0001

HOMA model, diet-treated n = 376

Time from diagnosis (years)

100

-ce

ll f

un

ctio

n (

%) 80

60

40

20

0

Start of treatment

Adapted from Holman RR. Diabetes Res Clin Pract 1998; 40 (Suppl.):S21–S25.

–10 –9 –8 –7 –6 –5 –4 –3 –2 –1 1 2 3 4 5 6





Glycemic TargetsGlycemic Targets

CMAJ 1998; 159 (8 Suppl):S1-29

1998 CDA Treatment Targets1998 CDA Treatment Targets

Level

Ideal(normal

nondiabetic)

Optimal*(target goal)

Suboptimal †

(action maybe required)

Inadequate ‡

(actionrequired)

Glycated Hb(% of upperlimit)e.g., HbA1cassay

<100(.04-.06)

<115(<0.07)

116-140(.07-8.4)

>140(>0.084)

Fasting orpremeal glucoselevel (mmol/L)

3.8-6.1 4-7 7.1-10 >10

Glucose level1-2 h after meal(mmol/L)

4.4-7 5.0-11 11.1-14 >14

Hb = hemoglobin

*These levels are likely related to minimal long-term complications but may be impossible to achieve in most paients with type 1 diabetes with current therapies†Attainable in the majority of people with diabetes but may not be adequate to prevent compications‡These levels are related to a markedly increased risk of long-term complications, requiring a reassessment and readjustment of therapy

A1C**(%)

FPG/preprandial PG(mmol/L)

2-hour postprandial PG(mmol/L)

Target for most patients 7.0 4.0-7.0 5.0-10.0

Normal range (considered for patients in whom it can beachieved safely)

6.0 4.0-6.0 5.0-8.0

A1C = glycosylated hemoglobinDCCT = Diabetes Control and Complications TrialFPG = fasting plasma glucosePG = plasma glucose

2003 CDA Recommended Targets for Glycemic Control

2003 CDA Recommended Targets for Glycemic Control

Components of Glycemic ControlComponents of Glycemic Control

2 h. Postprandial Plasma Glucose

5-10 mmol/L5-8 mmol/L*

2 h. Postprandial Plasma Glucose


Fasting/PreprandialPlasma Glucose


Fasting/PreprandialPlasma Glucose


A1C

<7%, <6%* A1C

<7%, <6%*

*If can be achieved safely





Management of Hyperglycemiain Type 2 Diabetes

Management of Hyperglycemiain Type 2 Diabetes

Lifestyle InterventionLifestyle Intervention

The first step in treating type 2 diabetes

Nutrition therapy and exercise can improve glycemic control

Success of lifestyle intervention related to: patient’s initial fasting plasma glucose level amount of weight loss achieved by patient

Only a minority of patients are able to attain treatment targets using lifestyle intervention alone.

The first step in treating type 2 diabetes

Nutrition therapy and exercise can improve glycemic control

Success of lifestyle intervention related to: patient’s initial fasting plasma glucose level amount of weight loss achieved by patient

Only a minority of patients are able to attain treatment targets using lifestyle intervention alone.

UKPDS 7: Response of FPG to Diet Therapy in Newly Diagnosed PatientsUKPDS 7: Response of FPG to Diet Therapy in Newly Diagnosed Patients

N= 3044, newly diagnosed patients FPG at diagnosis 12.1+/- 3.7 mmol/L Diet counseling Patients with FPG 10-12 mmol/L needed reduction of 28% ideal body weight; to attain FPG <6 mmol/L 16% achieved FPG <6 after 3 months:

in the group presenting with FPGs of 6-8 mmol/L 50% met this target in the group presenting with FPGs of 16-22 mmol/L only 10% were successful

N= 3044, newly diagnosed patients FPG at diagnosis 12.1+/- 3.7 mmol/L Diet counseling Patients with FPG 10-12 mmol/L needed reduction of 28% ideal body weight; to attain FPG <6 mmol/L 16% achieved FPG <6 after 3 months:

in the group presenting with FPGs of 6-8 mmol/L 50% met this target in the group presenting with FPGs of 16-22 mmol/L only 10% were successful

Metabolism, 1990; 39(3): 905-912

Antihyperglycemic AgentsAntihyperglycemic Agents

Glucose (G)

Insulin

I

I

I

II

I

I

I

G

G

GG

G

G

G

GI

G

GG

Adipose tissue

Liver

Pancreas

Muscle

Gut

IG

Carbohydrate

Stomach -glucosidase inhibitors

Insulin secretagogues

Biguanides

Thiazolidinediones

Primary Sites of Action of Oral Antihyperglycemic Agents

Primary Sites of Action of Oral Antihyperglycemic Agents

Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.

Key RecommendationsKey Recommendations

• Antihyperglycemic agents should be initiated if glycemic targets not met after 2-3 months of lifestyle intervention

• Antihyperglycemic agents should be started concomitantly with lifestyle if A1C levels are greater than 9%

• The lag period before adding other agent(s) should be kept to a minimum to achieve glycemic targets within 6-12 months

• Unless contraindicated, metformin should be used first line; other agents should be considered in the order they appear in the treatment algorithm

• Insulin therapy should be initiated if targets cannot be achieved with lifestyle changes and oral therapy

• Antihyperglycemic agents should be initiated if glycemic targets not met after 2-3 months of lifestyle intervention

• Antihyperglycemic agents should be started concomitantly with lifestyle if A1C levels are greater than 9%

• The lag period before adding other agent(s) should be kept to a minimum to achieve glycemic targets within 6-12 months

• Unless contraindicated, metformin should be used first line; other agents should be considered in the order they appear in the treatment algorithm

• Insulin therapy should be initiated if targets cannot be achieved with lifestyle changes and oral therapy

Diet/exercise

Oralmonotherapy

Oral combination

Insulin

Early aggressivecombination therapy as required

Stepwise treatment

Oral +/- insulin

New Treatment Options for Type 2 Diabetes

New Treatment Options for Type 2 Diabetes

Management of Hyperglycemia in Type 2 Diabetes

Management of Hyperglycemia in Type 2 Diabetes

Clinical assessment and initiation of nutrition and physical activity

Overweight(BMI 25 kg/m2)

Non-overweight(BMI 25 kg/m2)

Mild to moderate hyperglycemia (A1C <9.0%) Marked hyperglycemia (A1C 9.0%)

Add a drug from a different classor

Use insulin alone or in combination with:• biguanide• insulin secretagogue• insulin sensitizer*• alpha-glucosidase inhibitor

Timely adjustments to and/or additions of oral antihyperglycemic agentsand/or insulin should be made to attain target A1C within 6 to 12 months

If not at target

* When used in combination with insulin, insulin sensitizers may increase the risk of edema or CHF. The combination of an insulin sensitizer and insulin is currently not an approved indication in Canada.

Overweight (BMI 25 kg/m2)

Mild to moderate hyperglycemia (A1C <9.0%)

Biguanide alone or in combination with 1 of:• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor

L

I

F

E

S

T

Y

L

E

Dose-Effect RelationshipDose-Effect RelationshipDose-Effect Relationship

Riddle M. Combining sulfonylureas and other oral agents. Am J of Med. 2000; 108(6A):15S-22S.

Graph of theoretical dose-effect relationship for many drugs, showing that half-maximal dosages yield far more than 50% of the therapeutic effects and that side effects can increase as the dosage nears maximal levels.

Maximal

Half-maximal

Half-maximal Maximal

Therapeutic effect

Side effect

Eff

ect

Dose

Dose-Response CurveDose-Response CurveDose-Response Curve

Riddle M. Combining sulfonylureas and other oral agents. Am J of Med. 2000; 108(6A):15S-22S.

Dose-response curve showing GI related effects

30

20

10

0 500 1000 1500 2000 2500

0

0.5

1.0

1.5

2.0

Dose

GI

Dis

tre

ss

Pa

tie

nts

(%

)

Re

du

cti

on

vs

. p

lac

eb

o,

Hb

A 1c

(%)

Non-overweight (BMI 25 kg/m2)


1 or 2† antihyperglycemic agents from different classes• biguanide• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor



Use insulin alone or in combination with:

• biguanide• insulin secretagogue• insulin sensitizer*• alpha-glucosidase inhibitor

If not at target

* When used in combination with insulin, insulin sensitizers may increase the risk of edema or CHF. The combination of an insulin sensitizer and insulin is currently not an approved indication in Canada.† May be given as a combined formulation: rosiglitazone and metformin (Avandamet TM)

L

I

F

E

S

T

Y

L

E

Marked hyperglycemia (A1C 9.0%)

2 antihyperglycemic agents from different classes †

• biguanide• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor

Add an oral antihyperglycemic agentfrom a different class or insulin*


If not at target


L

I

F

E

S

T

Y

L

E


Basal and/or preprandial insulin

* When used in combination with insulin, insulin sensitizers may increase the risk of edema or CHF. The combination of an insulin sensitizer and insulin is currently not an approved indication in Canada.* * If using preprandial insulin, do not add an insulin secretagogue.

L

I

F

E

S

T

Y

L

E

Intensify insulin regimen or add

• biguanide• insulin secretagogue**• insulin sensitizer*• alpha-glucosidase inhibitor


If not at target





Biguanide alone or incombination with 1 of:

• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor

1 or 2† antihyperglycemicagents from differentclasses


Add a drug from a different class orUse insulin alone or in combination with:



2 antihyperglycemic agentsfrom different classes †


Basal and/orpreprandial insulin

Add an oral

antihyperglycemic agentfrom a differentclass or insulin*

Intensify insulinregimen or add


If not at targetIf not at targetIf not at targetIf not at target


L

I

F

E

S

T

Y

L

E

• A1C <7% (< 6% if can be achieved safely)

• Aim to achieve targets within 6-12 months

• Start with combination therapy or insulin for patients with A1C > 9%

• Consider insulin at any stage of treatment

• Vascular protection to further reduce cardiovascular risk

• A1C <7% (< 6% if can be achieved safely)

• Aim to achieve targets within 6-12 months

• Start with combination therapy or insulin for patients with A1C > 9%

• Consider insulin at any stage of treatment

• Vascular protection to further reduce cardiovascular risk

Key ChangesKey Changes





This material has been reviewed by the Canadian Diabetes Association for its medical and scientific accuracy.Presence of the Canadian Diabetes Association Partners in Progress mark does not constitute an endorsement of the products or services of GlaxoSmithKline Inc.



Supplementary Slides:Key RecommendationsSupplementary Slides:Key Recommendations

In people with type 2 diabetes, if glycemic targets are not achieved using lifestyle management within 2 to 3 months, antihyperglycemic agents should be initiated [Grade A, Level 1A ]. In the presence of marked hyperglycemia (A1C > 9.0%), antihyperglycemic agents should be initiated concomitant with lifestyle counselling [Grade D, Consensus].

In people with type 2 diabetes, if glycemic targets are not achieved using lifestyle management within 2 to 3 months, antihyperglycemic agents should be initiated [Grade A, Level 1A ]. In the presence of marked hyperglycemia (A1C > 9.0%), antihyperglycemic agents should be initiated concomitant with lifestyle counselling [Grade D, Consensus].

Recommendation 1Recommendation 1

If glycemic targets are not attained when a single antihyperglycemic agent is used initially, an antihyperglycemic agent or agents from other classes should be added. The lag period before adding other agent(s) should be kept to a minimum, taking into account the pharmacokinetics of the different agents. Timely adjustments to and/or additions of antihyperglycemic agents should be made in order to attain target A1C within 6 to 12 months [Grade D, Consensus].

If glycemic targets are not attained when a single antihyperglycemic agent is used initially, an antihyperglycemic agent or agents from other classes should be added. The lag period before adding other agent(s) should be kept to a minimum, taking into account the pharmacokinetics of the different agents. Timely adjustments to and/or additions of antihyperglycemic agents should be made in order to attain target A1C within 6 to 12 months [Grade D, Consensus].



This choice of antihyperglycemic agent(s) should take into account the individual and the following factors:

Unless contraindicated, a biguanide (metformin) should be the primary drug used in overweight patients [Grade A, Level 1A]; and

Other classes of antihyperglycemic agents may be used either alone or in combination to attain glycemic targets, with consideration given to the information in Table 1 and Figure 1 [Grade D, Consensus for the order of antihyperglycemic agents listed in Figure 1].

This choice of antihyperglycemic agent(s) should take into account the individual and the following factors:

Unless contraindicated, a biguanide (metformin) should be the primary drug used in overweight patients [Grade A, Level 1A]; and

Other classes of antihyperglycemic agents may be used either alone or in combination to attain glycemic targets, with consideration given to the information in Table 1 and Figure 1 [Grade D, Consensus for the order of antihyperglycemic agents listed in Figure 1].


In people with type 2 diabetes, if individual treatment goals have not been reached with a regimen of nutrition therapy, physical activity and sulfonylurea [Grade A, Level 1A], sulfonylurea plus metformin [Grade A, Level 1A] or other oral antihyperglycemic agents [Grade D, Consensus], insulin therapy should be initiated to improve glycemic control.

In people with type 2 diabetes, if individual treatment goals have not been reached with a regimen of nutrition therapy, physical activity and sulfonylurea [Grade A, Level 1A], sulfonylurea plus metformin [Grade A, Level 1A] or other oral antihyperglycemic agents [Grade D, Consensus], insulin therapy should be initiated to improve glycemic control.


Combining insulin and the following oral antihyperglycemic agents (listed in alphabetical order) has been shown to be effective in people with type 2 diabetes:

alpha-glucosidase inhibitors (acarbose) [Grade A, Level 1A]

biguanide (metformin) [Grade A, Level 1A]

Insulin secretagogues (sulfonylureas) [Grade A, Level 1A]

Insulin sensitizers (thiazolidinediones) [Grade A, Level 1A] (The combination of an insulin sensitizer plus insulin is currently not an approved indication in Canada.)

Combining insulin and the following oral antihyperglycemic agents (listed in alphabetical order) has been shown to be effective in people with type 2 diabetes:

alpha-glucosidase inhibitors (acarbose) [Grade A, Level 1A]

biguanide (metformin) [Grade A, Level 1A]

Insulin secretagogues (sulfonylureas) [Grade A, Level 1A]

Insulin sensitizers (thiazolidinediones) [Grade A, Level 1A] (The combination of an insulin sensitizer plus insulin is currently not an approved indication in Canada.)


Insulin may be used as initial therapy in type 2 diabetes [Grade A, Level 1A], especially in cases of marked hyperglycemia (A1C > 9.0%) [Grade D, Consensus].

Insulin may be used as initial therapy in type 2 diabetes [Grade A, Level 1A], especially in cases of marked hyperglycemia (A1C > 9.0%) [Grade D, Consensus].


To safely achieve optimal postprandial glycemic control, mealtime insulin lispro or insulin aspart is preferred over regular insulin [Grade B, Level 2].

To safely achieve optimal postprandial glycemic control, mealtime insulin lispro or insulin aspart is preferred over regular insulin [Grade B, Level 2].


When insulin given at night is added to oral antihyperglycemic agents, insulin glargine may be preferred over NPH to reduce overnight hypoglycemia [Grade B, Level 2] and weight gain [Grade B, Level 2 ].

When insulin given at night is added to oral antihyperglycemic agents, insulin glargine may be preferred over NPH to reduce overnight hypoglycemia [Grade B, Level 2] and weight gain [Grade B, Level 2 ].


All individuals with type 2 diabetes currently using or starting therapy with insulin or insulin secretagogues should be counselled about the recognition and prevention of drug-induced hypoglycemia [Grade D, Consensus].

All individuals with type 2 diabetes currently using or starting therapy with insulin or insulin secretagogues should be counselled about the recognition and prevention of drug-induced hypoglycemia [Grade D, Consensus].

Supplementary Slides:Alternate Animation for

Treatment Algorithm

Supplementary Slides:Alternate Animation for

Treatment Algorithm















Add an oral






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If not at target





Add an oral


If not at targetIf not at target






If not at target


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Use insulin alone or in combination with:• biguanide• insulin secretagogue• insulin sensitizer*• alpha-glucosidase inhibitor

Overweight (BMI 25 kg/m2)



Biguanide alone or in combination with 1 of:• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor

If not at target

* When used in combination with insulin, insulin sensitizers may increase the risk of edema or CHF. The combination of an insulin sensitizer and insulin is currently not an approved indication in Canada.

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Add an oral






L

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Use insulin alone or in combination with:


Non-overweight (BMI 25 kg/m2)



1 or 2† antihyperglycemic agents from different classes• biguanide• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor

If not at target


L

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Add an oral






L

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Add an oral







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Add an oral antihyperglycemic agentfrom a different class or insulin*



2 antihyperglycemic agents from different classes †


If not at target


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Add an oral






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Add an oral







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Basal and/or preprandial insulin

If not at target

Intensify insulin regimen or add


* When used in combination with insulin, insulin sensitizers may increase the risk of edema or CHF. The combination of an insulin sensitizer and insulin is currently not an approved indication in Canada.* * If using preprandial insulin, do not add an insulin secretagogue.

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canadian diabetes association 2003 clinical practice guidelines for the prevention and management of...

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diabetes slide

diabetes control

management of diabetes

diabetes care

target a1c

glycemic control slide

postprandial plasma

fpgpreprandial pg mmoll