www.diabetesclinic.ca 2003 cda clinical practice guidelines j. robin conway m.d. diabetes clinic...

www.diabetesclinic.ca

2003 CDA Clinical Practice Guidelines

J. Robin Conway M.D.Diabetes ClinicSmiths Falls, ONwww.diabetesclinic.ca


Worldwide rates of diabetes mellitus: predictions

Worldwide rates of diabetes mellitus: predictions80

70

60

50

40

30

20

10

0

Prevalence (millions)

North America

Europe Southeast

Asia

Year199520002025

World Health Organization. 1997.Canadian Diabetes Association, 1998 website.


Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris)

2 Million Canadians Have Diabetes Mellitus

0

5

10

15

20

25

30

35

40

20-34 35-44 45-54 55-64 65-74

% ofpopulation

IGTUndiagnosed diabetesDiagnosed diabetes

Harris. Diabetes Care 1993;16:642-52.

www.diabetesclinic.caHaffner Am J Cardiol 1999;84:11J-4J.

Framingham study: diabetes and CAD mortalityat 20-year follow-up

Cardiovascular Disease Risk is Increased 2 to 4 Times

17.4

8.5

17.0

3.602468

101214161820

Annual CAD Deaths per 1,000

Persons

Men Women

Diabetics Nondiabetics


THE BURDEN OF DIABETES

• 87% of Type 2 Diabetes is managed in Primary Care

• Diascan Study: 23.5% of patients in our office have diabetes

• Que screening >2 Risk Factors 79% tested 7% Diabetes 13% IGT or IFG 74% No Treatment Advice

Strychar I et al. Cdn J Diab 2003(abs)

Leiter et al. Diabetes Care 2000


T2DM in Family Practice

• 84% of patients had A1c in past year

• Average A1c 7.9% (goal<7%)

• 88% had BP check

• 48% had lipid profiles

• 28% tested for microalbuminuria

• 15% had foot examsHarris S et al. Cdn Fam Phys 2003


Cardiovascular Risk

Sask Smiths Falls

• Statin 19.9% 70%

• ACE 48.9% 91%

• ASA 23.5% 70%

Brown L et al. Cdn J Diab 2003(abs)Nozek L et al. Cdn J Diab 2003(abs)Conway R et al. Cdn J Diab 2003(abs)


Burden of Poor Control - Cost


2003 CDA Guidelines

• Early Aggressive Screening• FPG every 3yrs over age 40• High Risk Groups

Relatives of Diabetics Aboriginals & Hispanics PCOS Schizophrenics Dyslipidemia


SCREENING & PREVENTION

• All individuals should be evaluated annually for Diabetes risk on the basis of history, clinical and demographic criteria.

• Screening for Diabetes using a fasting plasma glucose should be performed every 3 years for individuals over 40 years of age.

• More frequent or earlier testing with either a fasting plasma glucose or OGTT in people with additional risk factors for Diabetes,


PREVENTION Pre diabetes

• OGTT should be considered if BMI>25 and FPG between 5.7 & 7 to identify IGT or Diabetes

• With IGT a program of lifestyle mod that includes wt loss & exercise to prevent T2D

• With IGT treatment with Metformin or Acarbose should be considered.


DIAGNOSIS

• FBS >7 mmol/L + symptoms

• RBS >11 mmol/L + symptoms

• PREDIABETES

• IFG FBS 6.1-7 mmol/L

• IGT 2 hr PC glucose on OGTT 7.8-11

• If FBS > 5.7 mmol/L do OGTT


Recommended targets for glycemic control*

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

*Treatment goals and strategies must be tailored to the patient, with consideration given to individual risk factors.†Glycemic targets for children 12 years of age and pregnant women differ from these targets. Please refer to “Other Relevant Guidelines” for further details.**An A1C of 7.0% corresponds to a laboratory value of 0.070. Where possible, Canadian laboratories should standardize theirA1C values to DCCT levels (reference range: 0.040 to 0.060). However, as many laboratories continue to use a differentreference range, the target A1C value should be adjusted based on the specific reference range used by the laboratory thatperformed the test. As a useful guide: an A1C target of 7.0% refers to a threshold that is approximately 15% above the upper limit of normal.

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


Monitoring

• A1c every 3 months• Self Monitor Glucose, interpret results,alter

food choices, physical activity, frequency of testing & medications

• Type 1 should test at least 3 times a day• Type 2 should test at least daily• Type 1 in acute illness should test ketones if

glucose >14 mmol/L


Exercise

• 150 minutes of moderate intensity aerobic exercise over 3 nonconsecutive days of the week or if willing 4 hrs/week

• Encourage resistance exercise 3 times/week


Nutrition

• Nutrition Counselling• Canada Food Guide• For PPG control Amnt

& source of CHO, Glycemic Index

• Sucrose to 10% Cal• Discuss Alcohol• Intensive Insulin do

CHO counting


Goals in Diabetes

• FBS<7, PC<11, A1c<7%

• BP <130/80

• TC/HDL <4, LDL <2.5, Trig <1.5

• ACR <2 Male, <2.8 Female


Drugs in Type 2


Need for Combination Therapy in UKPDS

50%

75%

0%

10%

20%

30%

40%

50%

60%

70%

80%

3 years 5 years

% of Patients


Pathophysiology of Type 2 Diabetes

• Decreased insulin secretion

• Loss of ‘first-phase’ insulin secretion

• Increased insulin resistance, resulting in:– Decreased glucose and fat uptake– Increased free fatty acid release– Increased hepatic glucose output


9

Hb

A1

c (

%)

UKPDS: Long-term Glucose Control

06

7

8

0 3 6 9 12 15Years of treatment

Conventional

Intensive

ULN = 6.2%

UKPDS Study Group, Lancet, 1998;352:837-853.


-ce

ll f

un

ctio

n (

%)

Conventional Sulphonylurea Metformin

0

20

40

60

80

100

0 1 2 3 4 5 6 70

20

40

60

80

100

0 1 2 3 4 5 6 7

-ce

ll f

un

ctio

n (

%)

Years from randomization

Non obese Obese

UKPDS 16: Diabetes 1995; 44:1249–1258

Progressive Loss of -cell Function in UKPDS

Mean age at baseline 53 yrs.


Type 2 Diabetes is Characterized by Insulin Resistance and Progressive ß-cell Failure

• 50% of ß-cell function is already lost at diagnosis

• Elevated PPG occurs before diagnosis

Impairedglucosetolerance

100

75

50

25

Years from Diagnosis

Beta

Cell F

un

cti

on

(%

)

-12 -10 -6 -2 0 2 6 10 14

Postprandial hyperglycemia

Type 2 diabetes phase I Type 2

diabetes phase II

Type 2 diabetes phase III

Lebovitz HE. Diabetes Review 1999;7(3):139 153.

Stages of Type 2 Diabetes in

Relationship to ß-cell Function


Impaired Insulin Secretion in Type 2 Diabetes

Time

6 am 10 am 2 pm 6 pm 10 pm 2 am 6 am

800

600

400

200

Insu

lin s

ecr

eti

on (

pm

ol/m

in)

0

Type 2 diabetes

healthy

Adapted from Polonsky KS et al. N Engl J Med 1996; 334: 777.


Type 2 Diabetes: Underlying Defects

Type 2 diabetes

Beta-cell functionInsulin resistance

Other defects:

lipolysisrelease of NEFA

hepatic glucose production

Adapted from Matthaei et al. Endocrine Reviews 2000;21:585-618.Adapted from Frayn. Br J Nutr 2000;83(suppl 1): S71-S77.

Pathophysiology


Type 2 Diabetes - Dual Impairment

• Impaired insulin secretion from pancreatic ß-cells• A sluggish and inadequate response to the glucose

load imposed by meals• Characteristic only of Type 2 diabetes• 100% of patients have impaired secretion at diagnosis

• Approx. 84% have insulin resistance• Also associated with other metabolic conditions

Insulin Secretion

Insulin Resistance

Lebovitz HE. Diabetes Review. 1999; 7(3):139-153. Polonsky KS, et al. NEJM 1988;318:1231-9. Bonora E, et al. Diabetes 1998;47:1643-49.


Issues to be Addressed when

Selecting Agents• Degree of -cell deficiency

• Magnitude of insulin resistance

• Extent of fasting hyperglycemia

• Magnitude of postprandial hyperglycemia


Epidemiological Evidence Linking PPG with Cardiovascular Disease


CHD Risk and Type 2 Diabetes

Haffner SM et al. N Engl J Med 339: 229-234, 1998

Db- No diabetes; Db+ Diabetes; MI- No prior MI; MI+ prior MI

p<0.001 for prior MI vs. no MI and diabetes vs. no diabetescalculated with Cox proportional-hazards models, adjusted for age and sex

MIStroke CV death


2-hour PPG, Not FPG, Predicted2-hour PPG, Not FPG, PredictedAll-cause MortalityAll-cause Mortality

Adjusted for age, centre, sex

<6.1 6.1– 6.9 7.0

11.1

7.8 –11.0

<7.8

Fasting plasma glucose (mmol/L)

2-ho

ur P

PG, 7

5g O

GTT

(mm

ol/L

)

2.5

2.0

1.5

1.0

0.5

0.0

Haza

rd r

ati

o

Adapted from DECODE Study Group. Lancet 1999;354:617.


Epidemiological Evidence Linking High PPG* with CVD Risk & Mortality

DECODE, 1999DECODE, 199911 High PPG is associated with increased risk of death, independent of FPG

Pacific and Indian Ocean, 1999Pacific and Indian Ocean, 199922 High PPG with normal FPG doubles the risk of mortality

Funagata Diabetes Study, 1999Funagata Diabetes Study, 199933 IGT, but not IFG, is a risk factor for CVD

Whitehall, Paris, Helsinki Study 1998Whitehall, Paris, Helsinki Study 19984

Men in upper 2.5% of PPG distribution had significantly higher CHD mortality

The Rancho-Bernardo Study, 1998The Rancho-Bernardo Study, 199855 PPG more than doubles the risk of fatal CVD and heart disease in older adults

Diabetes Intervention Study, 1996Diabetes Intervention Study, 199666 PPG (1-hr post-breakfast), but not FPG, is associated with CHD

1DECODE Study Group. Lancet 1999;354:617. 2Shaw JE et al. Diabetologia 1999;42:1050.3Tominaga M et al. Diabetes Care 1999;22:920. 4Balkau B et al. Diabetes Care 1998;21:360.5Barrett-Connor E et al. Diabetes Care 1998;21:1236. 6Hanefeld M et al. Diabetologia 1996;39:1577.

*2-hour PPG after 75g OGTT, except where indicated


Intervention Studies to Control PPG and its Effect on CV Disease

Manzella 20051

Type 2Repaglinide had greater PPG lowering and a significantly greater improvement in endothelial function and a decline in oxidative stress compared to glyburide

Esposito 20042

Type 2After 12 months, CIMT regression (decrease of > 0.020 mm) was observed in 52% of the repaglinide group vs 18% in the glyburide group (p<0.01).

Hanefeld 20043

Type 2Acarbose reduced relative risk of myocardial infarction by 64% (p=0.012) and any CV event 35% (p=0.0061)

Chiasson 20034

IGTAcarbose reduced relative risk of CV events by 49% and new cases of hypertension by 34% compared to placebo

1. Chiasson et al. JAMA 2003; 290: 486. 2. Hanefeld M, et al. Eur Heart J 2004;25(1):10-16. 3. Esposito K et al. Circulation 2004;110. 4. Manzella D et al. Diabetes Care 2005; 28(2): 366.


Sites of Action of Currently Available Therapeutic Options

GLUCOSE ABSORPTION

GLUCOSE PRODUCTION

BiguanidesThiazolidinediones

MUSCLE

PERIPHERAL GLUCOSE UPTAKE

Thiazolidinediones(Biguanides)

PANCREAS

INSULIN SECRETIONSulfonylureasMeglitinides

Insulin

ADIPOSE TISSUE

LIVER

Alpha-glucosidase inhibitors

INTESTINE

Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998;7:551-5.


Combination Antihyperglycemic Therapy

Site of action MOA Agents

Insulin

secretion

Sulfonylureas Meglitanides,

Insulin

Glucose

production Biguanides

Thiazolidinediones

Glucose

absorption Alpha-glucosidase

inhibitors

Peripheral glucose uptake

Thiazolidinediones (Biguanides)

Addition, rather than substitution recommended

Agents from other classes should be added

–Diff sites of action

–Diff MOA


Normal Blood Normal Blood GlucoseGlucose

Normal Normal Insulin Insulin

YearsYears

Timeline for Therapy in Type 2 Diabetes

IGTIGT DiabeteDiabetess

Avg Avg DxDx

6.5 yrs 6.5 yrs

Fasting Fasting Blood Blood

GlucoseGlucose

Postprandial Postprandial Blood GlucoseBlood Glucose

Insulin Insulin ResistanceResistance

Endogenous InsulinEndogenous Insulin

Modified from graphic Modified from graphic developed by the IDCdeveloped by the IDC

LifestyleLifestyle

Metformin/ThiazolidinedionesMetformin/Thiazolidinediones

SecretagoguesSecretagoguesInsulinInsulin


Canadian Diabetes Association2003 Clinical Practice Guidelines

for the Prevention and Management of Diabetes in Canada

Canadian Diabetes Association2003 Clinical Practice Guidelines

for the Prevention and Management of Diabetes in Canada


Individualized Treatment

• Metformin for overweight patients

• If control not achieved add another agent

• If A1c >9 start with 2 agents

• Consider early insulin for hyperglycemia

• Bedtime intermediate insulin (NPH)


Pharmacotherapy

• Treat the Predominant problem

• Each Drug will lower A1c 1-1.5% (Acarbose & Orlistat 0-5%)

• Start with Metformin in Obese or High FBS

• Combination therapy if A1c >9%

• Early Insulin if decompensated

• Consider TZD


Clinical assessment and initiation of nutrition and physical activity

Mild to moderate hyperglycemia (A1C <9.0%)

Overweight(BMI 25 kg/m2)

Non-overweight(BMI 25 kg/m2)

Biguanide alone or incombination with 1 of:

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

1 or 2† antihyperglycemicagents from differentclasses

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

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

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

Marked hyperglycemia (A1C 9.0%)

2 antihyperglycemic agentsfrom different classes †

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

Basal and/orpreprandial insulin

Add an oral

antihyperglycemic agentfrom a differentclass of insulin*

Intensify insulinregimen or add

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

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

L

I

F

E

S

T

Y

L

E

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


L

I

F

E

S

T

Y

L

E

Add a drug from a different classor

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

Overweight (BMI 25 kg/m2)

Mild to moderate hyperglycemia (A1C <9.0%)

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

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.


Expected A1C Lowering with Oral Monotherapy

Metformin

Repaglinide*#

Sensitizers (pioglitazone, rosiglitazone)

Sulfonylureas# (glyburide, gliclazide, glimepiride)

1 – 1.5 %

Acarbose*

Nateglinide*#

Orlistat0.5 – 0.8 %

Adapted from Table 1. CDA 2003 Clinical Practice Guidelines, Can J Diabetes 2003; 27(Suppl 2): S38.

#oral insulin secretagogue *targets PPG


Insulin Secretagogues: Mechanisms of Action

1. Intestine:glucose absorption

2. Muscle and adipose tissue:glucose uptake

3. Pancreas: Insulin secretionSulfonylureas

insulin secretion

4. Liver: hepatic glucose output

Insulin resistance

Insulin resistanceBlood glucose

Lebovitz HE. Joslin’s Diabetes Mellitus, Ch. 29, 508-529.

Treatment


Adapted from Riddle et al. Diabetes Care. 1990;13:676-686.

glu

cose

(m

mol/l)

10.0

5.0

00600 1200

hours1800 2400 0600

7.5

12.5

Postprandial hyperglycemia

Basal hyperglycemia

Antihyperglycemic Agents

MetforminSulfonylureas TZD’s

Basal insulin

AcarboseNateglinide Repaglinide

Rapid-acting insulin analogues


Attributes of Meglitinides Gluconorm (repaglinide)

Starlix (nateglinide)• Increases early-phase insulin release• Physiologic response to meals (rapid

onset and elimination)• Significant improvement in key blood

glucose parameters (PPG, FPG, and HbA1c)

• Low risk of hypoglycemia• Weight neutral


Hypoglycemia: Why is it Important?

• Annually, about 5 - 20% of patients on oral agents have hypoglycemia

• Under-recognized and under-reported

• Substantial impact:– Social embarrassment– Emotional toll – “found dead in bed”– Work restrictions (e.g. operating machinery)– Devastating to elderly patients

www.diabetesclinic.ca 47

Adding Repaglinide to Restore Mealtime Insulin Secretion

• If repaglinide is 1st line or A1C <8%, start 0.5 mg with meals

• Double the dose every week until target achieved

• Maximum mealtime dose (4mg); Maximum daily dose (16mg)

If A1C ≥8%

1 mg or 2 mgwith meals

GlucoNorm® Product Monograph, Novo Nordisk Canada Inc., 2005.


4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Glargineor

Detemir

Pla

sma

insu

lin

Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs

Lispro Lispro Lispro

Aspart Aspart Aspartor oror

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