www.diabetesclinic.ca 2003 cda clinical practice guidelines j. robin conway m.d. diabetes clinic...
TRANSCRIPT
www.diabetesclinic.ca
2003 CDA Clinical Practice Guidelines
J. Robin Conway M.D.Diabetes ClinicSmiths Falls, ONwww.diabetesclinic.ca
www.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.
www.diabetesclinic.ca
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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)
www.diabetesclinic.ca
Burden of Poor Control - Cost
www.diabetesclinic.ca
2003 CDA Guidelines
• Early Aggressive Screening• FPG every 3yrs over age 40• High Risk Groups
Relatives of Diabetics Aboriginals & Hispanics PCOS Schizophrenics Dyslipidemia
www.diabetesclinic.ca
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,
www.diabetesclinic.ca
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.
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
Drugs in Type 2
www.diabetesclinic.ca
Need for Combination Therapy in UKPDS
50%
75%
0%
10%
20%
30%
40%
50%
60%
70%
80%
3 years 5 years
% of Patients
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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.
www.diabetesclinic.ca
-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.
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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.
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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.
www.diabetesclinic.ca
Issues to be Addressed when
Selecting Agents• Degree of -cell deficiency
• Magnitude of insulin resistance
• Extent of fasting hyperglycemia
• Magnitude of postprandial hyperglycemia
www.diabetesclinic.ca
Epidemiological Evidence Linking PPG with Cardiovascular Disease
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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.
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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.
www.diabetesclinic.ca
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.
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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)
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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.
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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
www.diabetesclinic.ca
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.
www.diabetesclinic.ca
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