Diabetes Collaborative

1
Diabetes Collaborative Learning Session 1 Workshop
Targets, Tools and Techniques
Marshall Dahl MD, PhD, FRCPC
2
Introduction

• Targets
• CDA 2003 Clinical Practice Guidelines
• Management of Diabetes and related conditions
• Tools
• Interventions and Medications
• Pathophysiologic Approach
• Techniques
• Practical Suggestions for apply tools to
  individual patients

3
Many patients have inadequate glycemic control
CAN (2003)1
US (1988-1994)2
100
100
80
80
62
60
60
50
50
Percentage of subjects
Percentage of subjects
38
40
40
20
20
0
0
? 7
lt 7
gt 7
lt7
A1C ()
A1C ()
1 Harris S, et al, The Diabetes in Canada
Evaluation (DICE) Study, ADA 2003, 2162-PO 2
Harris MI, et al. Diabetes Care 1999 22403408.
4
UKPDS decreased risk of diabetes-related
complications associated with a 1 decrease in A1C
Observational analysis from UKPDS study data
Any diabetes- related endpoint
Diabetes- related death
All cause mortality
Peripheral vascular disease
Micro- vascular disease
Myocardial infarction
Cataract extraction
Stroke
Percentage increase in relative risk
corresponding to a 1 rise in HbA1C
12
14
14

19

21
21




37
43


Adapted from Stratton IM, et al. UKPDS 35. BMJ
2000 321405412.
5
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

Stratton IM, et al. UKPDS 35. BMJ 2000
321405412.
6
2003 CDA 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)
A1C glycosylated hemoglobin DCCT Diabetes
Control and Complications Trial FPG fasting
plasma glucose PG plasma glucose
7
Components of Glycemic Control
A1C lt7, lt6
2 h. Postprandial Plasma Glucose 5-10 mmol/L 5-8
mmol/L
Fasting/Preprandial Plasma Glucose 4-7
mmol/L 4-6 mmol/L
If can be achieved safely
8
Pathophysiology of blood glucose control

• Type 1 diabetes
• Pancreatic ?-cell destruction with insulin
  deficiency
• Absolute insulin secretory defect
• Immune-mediated
• 10 of people with diabetes

9
Pathophysiology of blood glucose control

• Type 2 diabetes
• Increased insulin resistance
• Increased hepatic glucose secretion
• Diminished muscle and adipose tissue glucose
  uptake
• Relative insulin secretory defect
• 90 of people with diabetes

10
Diabetes and other Dysglycemic Categories

• Diabetes Diagnosis, any of
• Fasting Plasma Glucose 7.0
• Casual Plasma Glucose 11.1 with symptoms
• 2 hr 75 g OGTT 11.1
• Prediabetes Diagnosis
• FPG 6.1-6.9 Impaired Fasting Glucose
• 2 hr Glucose 7.8-11.0 Impaired Glucose
  Tolerance
• Higher cardiovascular risk and risk of
  progression to diabetes

11
Natural History of Type 2 Diabetes
Glucose
Post-prandial glucose
mmol/L
Fasting glucose
At risk for diabetes
Beta-cell dysfunction
Relative to normal
Insulin resistance
250
200
()
150
100
Insulin level
50
0
25
30
0
5
10
15
20
-10
-5
Years
R.M. Bergenstal, International Diabetes Center
12
The UKPDS demonstrated progressive decline of
?-cell function over time
100
100
Start of treatment
80
80
60
60
?-cell function ()
40
40
P lt 0.0001
20
0
10
9
8
7
6
5
4
3
2
1
1
2
3
4
5
6
Time from diagnosis (years)
HOMA model, diet-treated n 376
Adapted from Holman RR. Diabetes Res Clin Pract
1998 40 (Suppl.)S21S25.
13
Proportion of patients with A1C gt 7.0 increases
with duration of type 2 diabetes
lt2
3-5
6-9
10-14
15
Years T2DM
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.
14
UKPDS demonstrated loss of glycemic control with
all agents studied


9
8
()
Conventional Glyburide Chlorpropamide Metformin In
sulin
A1C
7
Upper limit of of normal 6.2
6
0
0
2
4
6
8
10
Years from randomization
Overweight patientsCohort, median values
UK Prospective Diabetes Study Group. UKPDS 34.
Lancet 1998 352854865.
15
Proportion of patients with A1C lt 7.0 on
monotherapy at 3, 6 and 9 years
Overweight patients
100
Diet
Insulin
Metformin
Sulfonylurea
80
60
Proportion of patients ()
50
40
20
0
3
6
9
3
6
9
3
6
9
3
6
9
Years from randomization
Error bars 95 CI
Turner RC, et al. UKPDS 49. JAMA 1999
28120052012.
16
Using the Right Tools

• Every patient differs
• Pattern of hyperglycemia pre vs post- meal
• Insulin secretory ability
• Co-morbidity

17
Activity

• Insulin-independent glucose uptake by muscles
• Increased muscle mass improves glycemia long-term
• Cardiovascular fitness
• Weight loss
• 150 min/ week plus resistance training

18
Lifestyle Intervention

• The first step in treating type 2 diabetes
• Nutrition therapy and exercise can improve
  glycemic control
• Success of lifestyle intervention related to
• patients 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.

19
Food Choices
20
UKPDS 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 lt6 mmol/L
• 16 achieved FPG lt6 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
21
Mechanisms of Type 2 Diabetes
Receptor postreceptor defects
Glucose
Insulin resistance
Liver
Increased glucose production
Peripheral Tissues (Muscle and Adipose)
Pancreas
Impaired insulin secretion
Adapted from Saltiel et al. Diabetes 1996
451661-1669.
22
Natural History of Type 2 Diabetes
Glucose
Post-prandial glucose
mmol/L
Fasting glucose
At risk for diabetes
Beta-cell dysfunction
Relative to normal
Insulin resistance
250
200
()
150
100
Insulin level
50
0
25
30
0
5
10
15
20
-10
-5
Years
R.M. Bergenstal, International Diabetes Center
23
Duration of the Postprandial, Postabsorptive, and
Fasting Stages
Breakfast
Lunch
Dinner
0.00am
4.00am
Breakfast
Monnier L. Eur J Clin Invest 20030(suppl. 2)311
24
Mechanisms of Action of Diabetes Medications
Decreased digestion of complex sugars
Alpha-glucosidase inhibitors
Sulfonylureas and CBAs
Blood Glucose
Biguanides Thiazolidinediones
Increased insulin secretion
Decrease in hepatic glucose production
Thiazolidinediones Biguanides
Increase in glucose uptake
25
Glucose

• Blood Glucose is derived from dietary
  disaccharides and starch
• Carbohydrates are a more important source than
  table sugar

26
Complex Carbohydrates

• Starch is composed of many molecules of sugar

27
Alpha-Glucosidase InhibitorsMechanisms of Action
1. Intestine glucose absorption
2. Muscle and adipose tissue glucose uptake
Insulin resistance
Blood glucose
4. Liver hepatic glucose output
3. Pancreas insulin secretion
Insulin resistance
28
Diabetes Medicines Acarbose

• (Prandase)
• Acts in the intestine
• Slows the breakdown of starch to simple sugars
• Slows rise of blood glucose after eating
• GI upset if dose increased too quickly
• Try 50 mg increments at two week intervals

29
Biguanides Mechanisms of Action
2. Muscle and adipose tissueBiguanides ?
glucose utilization
1. Intestine glucose absorption
Insulin resistance
Blood glucose
4. Liver Biguanides ? hepatic glucose output
3. Pancreas insulin secretion
Insulin resistance
30
Metformin

• Used as single agent or in combination with other
  medicines
• Potential for GI upset but usually well-tolerated
• Cant be used in the face of liver or kidney
  disease
• Risk of lactic acidosis if renal clearance
  becomes impaired.

31
ThiazolidinedionesMechanisms of Action
Treatment
Bloodglucose
Muscle andadipose tissue? insulin resistance?
glucose uptake
Liver? insulin resistance ? hepatic
glucose production
Pancreas ? demand for insulin secretion ?
beta-cell insulin content
32
from Sheppard and Kahn. NEJM341248-255.
33
Thiazolidinediones Mechanism of Insulin
Sensitization
Inzucchi, 1999 Yale University, unpublished
34
Thiazolidinediones Mechanism of Insulin
Sensitization
Inzucchi, 1999 Yale University, unpublished
35
Thiazolidinediones Mechanism of Insulin
Sensitization
Inzucchi, 1999 Yale University, unpublished
36
Thiazolidinediones

• Pioglitazone and Rosiglitazone
• (Actos and Avandia)
• PPAR-? receptor
• A1C reduction as individual agents or in
  combination

37
Thiazolidinediones Dosing
Treatment

• Pioglitazone
• Starting dose 15 mg od or 30 mg od
• Maximum dose 45 mg od
• Rosiglitazone
• Starting dose 4 mg od or 2 mg bid
• Maximum dose 8 mg od or 4 mg bid

Rosiglitazone product monograph Pioglitazone
product monograph
38
Thiazolidinediones Safety Considerations
Treatment

• Edema - small number of patients
• CHF - rare, need to watch for signs of fluid
  retention
• Contraindicated in NYHA Class (II),III,IV
• Anemia - relates to hemodilution from fluid
  retention
• May cause ovulation to resume in anovulatory women

Rosiglitazone product monograph Pioglitazone
product monograph
39
Natural History of Type 2 Diabetes
Glucose
Post-prandial glucose
mmol/L
Fasting glucose
At risk for diabetes
Beta-cell dysfunction
Relative to normal
Insulin resistance
250
200
()
150
100
Insulin level
50
0
25
30
0
5
10
15
20
-10
-5
Years
R.M. Bergenstal, International Diabetes Center
40
Insulin Secretagogues Mechanisms of Action
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
41
Insulin Secretagogues

• Sulfonylureas
• Glyburide, gliclazide
• (DiaBeta, Diamicron)
• Long-acting, powerful
• Can cause low sugars
• Carbamoyl Benzoic Acids
• Repaglinide (GlucoNorm)
• Nateglinide (Starlix)
• Shorter-acting
• Low sugars less likely

42
Insulin Secretagogues

• Watch for hypoglycemia potential
• Any patient with low-normal sugars
• Long-acting agents combined with decreased oral
  intake
• Chlorpropamide (Diabinase)
• Gliclazide SR (Diamicron MR)
• Intermediate agents with mild hyperglycemia
• Glyburide

43
Dose-Effect Relationship
Dose-Effect Relationship
Dose-Effect Relationship
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.
Riddle M. Combining
sulfonylureas
and other oral agents.
Am J of Med
. 2000 108(6A)15S-22S
.
44
Dose-Response Curve
Dose-Response Curve
Dose-Response Curve
Dose-response curve showing GI related effects
Riddle M. Combining
sulfonylureas
and other oral agents.
Am J of Med
. 2000 108(6A)15S-22S
.
45
Primary Sites of Action of Oral
Antihyperglycemic Agents
Stomach
Gut
I
Glucose (G)
G
I
Adipose tissue
I
G
Insulin
G
I
G
G
I
Pancreas
G
I
G
I
G
I
G
I
Muscle
G
I
G
G
Liver
Adapted from Kobayashi M. Diabetes Obes Metab
1999 1 (Suppl. 1)S32S40.Nattrass M Bailey
CJ. Baillieres Best Pract Res Clin Endocrinol
Metab 1999 13309329.
46
Natural History of Type 2 Diabetes
Glucose
Post-prandial glucose
mmol/L
Fasting glucose
At risk for diabetes
Beta-cell dysfunction
Relative to normal
Insulin resistance
250
200
()
150
100
Insulin level
50
0
25
30
0
5
10
15
20
-10
-5
Years
R.M. Bergenstal, International Diabetes Center
47
Insulin 2004

• All people with Type 1 Diabetes
• Some people with Type 2 Diabetes
• Many types with different times of onset and
  duration

48
Insulin Types
49
Insulin Injection
50
(No Transcript)
51
Key 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

52
New Treatment Options for Type 2 Diabetes
Stepwise treatment
Diet/exercise
Oralmonotherapy
Oral combination
Insulin
Oral /- insulin
53
Key Changes

• A1C lt7 (lt 6 if can be achieved safely)
• Aim to achieve targets within 6-12 months
• Start with combination therapy or insulin for
  patients with A1C gt 9
• Consider insulin at any stage of treatment
• Vascular protection to further reduce
  cardiovascular risk

54
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

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

L I F E S T Y L E

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
55
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

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

L I F E S T Y L E
If not at target
If not at target
If not at target

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
56
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

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

L I F E S T Y L E

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
57
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

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

L I F E S T Y L E
If not at target
If not at target
If not at target

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
58
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

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

L I F E S T Y L E

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
59
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

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

L I F E S T Y L E
If not at target
If not at target
If not at target
If not at target

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
60
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

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

L I F E S T Y L E

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
61
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

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

L I F E S T Y L E
If not at target
If not at target
If not at target
If not at target

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
62
Tools

• Goal
• intelligent active self-management by patients
  and physicians
• System Tools
• Resources for patients and physicians
• A practice structure that supports systematic
  care of Chronic Disease
• Interventions and medications
• Glycemia, Blood Pressure, Lipids, Proteinuria
• Eyes, nerves, feet

63
Customizing Therapy

• Define the individuals glucose profile
• Try a week of intensive testing ac, 2hr pc and
  hs
• Work from the morning first
• Normalize fasting sugars
• Metformin late in day,Type 2
• N insulin at bedtime, Types 1 and 2
• TZD drugs, Type 2

64
Customizing Therapy

• Look for post-prandial status next
• Marked rise (gt3mmol)
• Short acting agent
• Acarbose,
• CBA (GlucoNorm, Starlix)
• Short-acting insulin analogue (Humalog,
  Novo-Rapid)

65
Customizing Therapy

• High pre-prandial, despite controlled
  post-prandial
• longer acting agents
• glyburide, gliclizide,
• TZDs,
• daytime insulin

66
The Dilemma of the Overweight Patient
67
Customizing Therapy

• Overweight patients
• avoid overinsulinizing
• 30/70 insulin or glyburide
• lots of weight gain, same sugars.
• emphasize sensitizers (exercise, metformin, TZDs)
• Use short-acting secretagogues or short acting
  insulin with meals

68
Customizing Therapy

• Lean type 2 patients
• Secretagogues if early in disease course
• Insulin if advanced in course

69
Starting Insulin

• Diabetes Education Centres (and some pharmacies)
  can do this on short notice
• 30-45 minutes
• Includes device training, hypoglycemia advice,
  testing protocols, availablity of follow-up
• Issues like needle length, insulin-mixing
  techniques

70
More About Insulin

• Type 2 on pills (high fasting, other sugars often
  OK)
• Daytime orals, bedtime insulin
• Add NPH insulin 10 U qhs
• Increase by 5 U daily until FBS lt 9
• Additional doses of insulin can be added during
  the day, when required

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Still More About Insulin

• Type 1 Diabetes, or Type 2 Diabetes where
  appropriate
• Intensive approach
• Basal insulin Daily or BID NPH (Bedtime and/or
  Breakfast)
• Rapid acting insulin analogue with meals
• Need training for carbohydrate counting
• Eg. NPH 10/0/0/10 to start and adjust quickly
• Humalog or NovoRapid 1U per 10g CHO
• Additional 1 U for every glucometer reading of 2
  mmol gt 7.0

72
Still More and More About Insulin

• Patient on NPH at supper with hypos over-night?
• Move NPH to bedtime
• If on a pre-mix (ie 30/70) you may need to split
  supper 30/70 and give R at supper and NPH at
  bedtime
• Eg 30 units of 30/70 at supper becomes
• 10 units R at supper and 20 units NPH at bedtime

73
Insulin Whats New

• Long-acting basal insulins
• Insulin delivery devices

74
On the Horizon

• Non-invasive glucose monitoring
• Inhaled insulin
• Islet Cell transplants for Type 1 diabetes

75
Proportion of patients with cardiovascular
disease increases with duration of type 2 diabetes
lt2
3-5
6-9
10-14
15
Years T2DM
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.
76
Hyperglycemia and Vascular Disease Pathogenesis

• Non-enzymatic glycosylation of vascular wall
  structures
• Advanced Glycosylation End products (AGE)
• Endothelial dysfunction in hyperglycemia

77
Hyperglycemia and Vascular Disease Pathogenesis

• Many aspects of coagulation impaired
• Platelet behaviour abnormal
• Hypersensitive to stimuli
• Clot lysis inhibited
• Higher Plasminogen activator inhibitor 1 levels
• Fibrinogen levels elevated Disordered kinetics
• Correct with normoglycemia or heparin (aTIII
  lesion)

78
VASCULAR AND RENAL PROTECTION
VASCULAR PROTECTION Lifestyle modification ACE
inhibitors Antiplatelet therapy Dyslipidemia
therapy Glycemic control Smoking cessation
79
TARGETS OF TREATMENT BLOOD PRESSURE
The following are recommended as initial drug
choices (alphabetical order) ACE inhibitor,
ARB, Cardioselective beta-blocker, Thiazide-l
ike diuretic.
80
Treatment Threshold

• Not a target because normalization may not be
  possible
• Albumin Creatinine Ratio (ACR)

81
SCREENING FOR NEPHROPATHY
WHEN Type 1 annually after puberty and 5 years
of DM Type 2 at diagnosis and then annually
WHAT Urine dip or urine RM for non-diabetic
renal disease Random urine ACR for diabetic
nephropathy

• ACR Abnormal
• gt 20 mg/mmol men
• gt 28 mg/mmol women
• Diabetic nephropathy
• diagnosed

ACR Normal lt 2.0 mg/mmol men lt 2.8 mg/mmol
women Re-screen in 1 year
ACR Equivocal 2.0 - 20 mg/mmol men 2.8 - 28
mg/mmol women
Up to 2 repeat random urines for ACR performed 1
week to 2 months apart
2 or 3 abnormal ACRs
Only 1 abnormal ACR re-screen in 1 year
Diabetic nephropathy
82
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83
Back to Work!

• Real-world tasks
• Identification of people in your practice with
  diabetes
• Planned diabetes visits to organize care
• Start tracking outcomes
• Apply techniques and tools to approach targets

84
Surprise Quiz!
Big Horn Sheep
Wapiti
Pacific Dogwood
Cornus nuttallii
Cyanacitta stelleri
Stellars Jay
Western Red Cedar
Thuja plicata donn