RECIPES FOR SUCCESS

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2003 CDA Clinical Practice Guidelines
J. Robin Conway M.D. Diabetes Clinic Smiths
Falls, ON www.diabetesclinic.ca
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Worldwide rates of diabetes mellitus predictions
80 70 60 50 40 30 20 10 0
Prevalence (millions)
Year 1995 2000 2025
North America
Europe
Southeast Asia
World Health Organization. 1997. Canadian
Diabetes Association, 1998 website.
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(No Transcript)
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2 Million Canadians Have Diabetes Mellitus
Frequency of diagnosed and undiagnosed diabetes
and IGT, by age (U.S. data - Harris)
Harris. Diabetes Care 199316642-52.
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Cardiovascular Disease Risk is Increased 2 to 4
Times
Framingham study diabetes and CAD mortalityat
20-year follow-up
Haffner Am J Cardiol 19998411J-4J.
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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 gt2 Risk Factors 79 tested
  7 Diabetes
  13 IGT or IFG
  74 No Treatment
  Advice

Leiter et al. Diabetes Care 2000
Strychar I et al. Cdn J Diab 2003(abs)
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T2DM in Family Practice

• 84 of patients had A1c in past year
• Average A1c 7.9 (goallt7)
• 88 had BP check
• 48 had lipid profiles
• 28 tested for microalbuminuria
• 15 had foot exams

Harris S et al. Cdn Fam Phys 2003
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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)
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Burden of Poor Control - Cost
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2003 CDA Guidelines

• Early Aggressive Screening
• FPG every 3yrs over age 40
• High Risk Groups
  
  
  Relatives of Diabetics
  Aboriginals Hispanics
  PCOS
  Schizophrenics
  Dyslipidemia

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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,

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PREVENTION Pre diabetes

• OGTT should be considered if BMIgt25 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.

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DIAGNOSIS

• FBS gt7 mmol/L symptoms
• RBS gt11 mmol/L symptoms
• PREDIABETES
• IFG FBS 6.1-7 mmol/L
• IGT 2 hr PC glucose on OGTT 7.8-11
• If FBS gt 5.7 mmol/L do OGTT

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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
?6.0
4.0-6.0
5.0-8.0
Normal range (considered for patients in whom
it can be achieved safely)
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
their A1C values to DCCT levels (reference range
0.040 to 0.060). However, as many laboratories
continue to use a different reference range, the
target A1C value should be adjusted based on the
specific reference range used by the laboratory
that performed 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 hemoglobin DCCT
Diabetes Control and Complications Trial FPG
fasting plasma glucose PG plasma glucose
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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 gt14 mmol/L

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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

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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

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Goals in Diabetes

• FBSlt7, PClt11, A1clt7
• BP lt130/80
• TC/HDL lt4, LDL lt2.5, Trig lt1.5
• ACR lt2 Male, lt2.8 Female

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Drugs in Type 2
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Need for Combination Therapy in UKPDS
of Patients
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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

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UKPDS Long-term Glucose Control



9
Conventional
8
HbA1c ()
Intensive
7
ULN 6.2
6
0
Years of treatment
UKPDS Study Group, Lancet, 1998352837-853.
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Progressive Loss of ?-cell Function in UKPDS

?-cell function ()
Conventional
Sulphonylurea
Metformin
Mean age at baseline 53 yrs.
UKPDS 16 Diabetes 1995 4412491258
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Type 2 Diabetes is Characterized by Insulin
Resistance and Progressive ß-cell Failure
100 75 50 25
Stages of Type 2 Diabetes in Relationship to
ß-cell Function
Beta Cell Function ()
Postprandial hyperglycemia
Type 2 diabetes phase I
Impaired glucose tolerance
Type 2 diabetes phase III
Type 2 diabetes phase II
-12 -10 -6 -2 0
2 6 10 14
Years from Diagnosis

• 50 of ß-cell function is already lost at
  diagnosis
• Elevated PPG occurs before diagnosis

Lebovitz HE. Diabetes Review 19997(3)139 153.
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Impaired Insulin Secretion in Type 2 Diabetes
Adapted from Polonsky KS et al. N Engl J Med
1996 334 777.
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Type 2 Diabetes Underlying Defects
Pathophysiology
? Beta-cell function
Insulin resistance
Type 2 diabetes
Other defects ? lipolysis release of NEFA ?
hepatic glucose production
Adapted from Matthaei et al. Endocrine Reviews
200021585-618. Adapted from Frayn. Br J Nutr
200083(suppl 1) S71-S77.
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Type 2 Diabetes - Dual Impairment
Insulin Secretion

• 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 Resistance
Lebovitz HE. Diabetes Review. 1999 7(3)139-153.
Polonsky KS, et al. NEJM 19883181231-9. Bonora
E, et al. Diabetes 1998471643-49.
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Issues to be Addressed whenSelecting Agents

• Degree of ?-cell deficiency
• Magnitude of insulin resistance
• Extent of fasting hyperglycemia
• Magnitude of postprandial hyperglycemia

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Epidemiological Evidence Linking PPG with
Cardiovascular Disease
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CHD Risk and Type 2 Diabetes
Db- No diabetes Db Diabetes MI- No prior MI
MI prior MI
MI
Stroke
CV death
plt0.001 for prior MI vs. no MI and diabetes vs.
no diabetes calculated with Cox
proportional-hazards models, adjusted for age and
sex
Haffner SM et al. N Engl J Med 339 229-234, 1998
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2-hour PPG, Not FPG, PredictedAll-cause Mortality
2.5 2.0 1.5 1.0 0.5 0.0
Hazard ratio
³11.1
7.8 11.0
2-hour PPG, 75g OGTT(mmol/L)
lt7.8
lt6.1 6.1 6.9 ³7.0
Fasting plasma glucose (mmol/L)
Adjusted for age, centre, sex
Adapted from DECODE Study Group. Lancet
1999354617.
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Epidemiological Evidence Linking High PPG with
CVD Risk Mortality
DECODE, 19991 High PPG is associated with
increased risk of death, independent of
FPG Pacific and Indian Ocean, 19992 High PPG with
normal FPG doubles the risk of
mortality Funagata Diabetes Study, 19993 IGT, but
not IFG, is a risk factor for CVD Whitehall,
Paris, Helsinki Study 19984 Men in upper 2.5 of
PPG distribution had significantly higher CHD
mortality The Rancho-Bernardo Study, 19985 PPG
more than doubles the risk of fatal CVD and
heart disease in older adults Diabetes
Intervention Study, 19966 PPG (1-hr
post-breakfast), but not FPG, is associated with
CHD
2-hour PPG after 75g OGTT, except where indicated
1DECODE Study Group. Lancet 1999354617. 2Shaw
JE et al. Diabetologia 1999421050. 3Tominaga M
et al. Diabetes Care 199922920. 4Balkau B et
al. Diabetes Care 199821360. 5Barrett-Connor E
et al. Diabetes Care 1998211236. 6Hanefeld M et
al. Diabetologia 1996391577.
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Intervention Studies to Control PPG and its
Effect on CV Disease
Manzella 20051 Type 2 Repaglinide had greater PPG lowering and a significantly greater improvement in endothelial function and a decline in oxidative stress compared to glyburide
Esposito 20042 Type 2 After 12 months, CIMT regression (decrease of gt 0.020 mm) was observed in 52 of the repaglinide group vs 18 in the glyburide group (plt0.01).
Hanefeld 20043 Type 2 Acarbose reduced relative risk of myocardial infarction by 64 (p0.012) and any CV event 35 (p0.0061)
Chiasson 20034 IGT Acarbose 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 200425(1)10-16.
3. Esposito K et al. Circulation 2004110. 4.
Manzella D et al. Diabetes Care 2005 28(2) 366.
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Sites of Action of Currently Available
Therapeutic Options
LIVER
MUSCLE
ADIPOSE TISSUE
PANCREAS
GLUCOSE PRODUCTION Biguanides Thiazolidinediones
PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones (Big
uanides)
INSULIN SECRETION Sulfonylureas Meglitinides Insul
in
INTESTINE
GLUCOSE ABSORPTION
Alpha-glucosidase inhibitors
Sonnenberg, Kotchen Curr Opin Nephrol Hypertens
19987551-5.
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Combination Antihyperglycemic Therapy

• Addition, rather than substitution recommended
• Agents from other classes should be added
• Diff sites of action
• Diff MOA

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Timeline for Therapy in Type 2 Diabetes
Metformin/Thiazolidinediones
Secretagogues
Lifestyle
IGT
Years
Modified from graphic developed by the IDC
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Canadian Diabetes Association 2003 Clinical
Practice Guidelines for the Prevention and
Management of Diabetes in Canada
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Individualized Treatment

• Metformin for overweight patients
• If control not achieved add another agent
• If A1c gt9 start with 2 agents
• Consider early insulin for hyperglycemia
• Bedtime intermediate insulin (NPH)

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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 gt9
• Early Insulin if decompensated
• Consider TZD

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Clinical assessment and initiation of nutrition
and physical activity
Marked hyperglycemia (A1C ?9.0)
Mild to moderate hyperglycemia (A1C lt9.0)

Basal and/or preprandial insulin
Non-overweight (BMI ?25 kg/m2)
Overweight (BMI ?25 kg/m2)
2 antihyperglycemic agents from different classes

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

L I F E S T Y L E
Biguanide alone or in combination with 1 of
1 or 2 antihyperglycemic agents from
different classes

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

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

Add an oral antihyperglycemic agent from a
different class of insulin
Add a drug from a different class or Use
insulin alone or in combination with
Intensify insulin regimen or add

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

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

Timely adjustments to and/or additions of oral
antihyperglycemic agents and/or insulin should be
made to attain target A1C within 6 to 12 months
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L I F E S T Y L E
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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Expected A1C Lowering with Oral Monotherapy
Metformin Repaglinide Sensitizers (pioglitazone, rosiglitazone) Sulfonylureas (glyburide, gliclazide, glimepiride) 1 1.5
Acarbose Nateglinide Orlistat 0.5 0.8
oral insulin secretagogue targets PPG
Adapted from Table 1. CDA 2003 Clinical Practice
Guidelines, Can J Diabetes 2003 27(Suppl 2) S38.
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Insulin Secretagogues Mechanisms of Action
Treatment
1. Intestineglucose absorption
2. Muscle and adipose tissueglucose uptake
Insulin resistance
Blood glucose
4. Liver hepatic glucose output
3. Pancreas Insulin secretion Sulfonylureas
? insulin secretion
Insulin resistance
Lebovitz HE. Joslins Diabetes Mellitus, Ch. 29,
508-529.
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Antihyperglycemic Agents
Acarbose Nateglinide Repaglinide Rapid-acting
insulin analogues
Postprandial hyperglycemia
12.5
10.0
glucose (mmol/l)
7.5
5.0
Metformin Sulfonylureas TZDs Basal insulin
Basal hyperglycemia
0
0600
1200
1800
2400
0600
hours
Adapted from Riddle et al. Diabetes Care.
199013676-686.
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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

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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

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Adding Repaglinide to Restore Mealtime Insulin
Secretion
If A1C 8 1 mg or 2 mg with meals

• If repaglinide is 1st line or A1C lt8, start 0.5
  mg with meals
• Double the dose every week until target achieved
• Maximum mealtime dose (4mg) Maximum daily dose
  (16mg)

GlucoNorm Product Monograph, Novo Nordisk Canada
Inc., 2005.
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Basal/Bolus Treatment Program with Rapid-acting
and Long-acting Analogs
Breakfast
Lunch
Dinner
Aspart Aspart Aspart
or
or
or
Lispro Lispro Lispro
Plasma insulin
Glargine or Detemir
400
1600
2000
2400
400
800
1200
800
Time