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2003 CDA Clinical Practice Guidelines
ORAL AGENTS
Options for Diabetes
Kingston April
17 2004
J. Robin Conway M.D.
Diabetes Clinic - Smiths Falls, ON
www.diabetesclinic.ca
www.diabetesclinic.ca
Worldwide rates of diabetes
mellitus: predictions
80
70
60
50
Prevalence
(millions)
40
30
20
Year
1995
2000
2025
10
0
North
America
Europe
Southeast
Asia
World Health Organization. 1997.
www.diabetesclinic.ca
Canadian Diabetes
Association, 1998 website.
2 Million Canadians
Have Diabetes Mellitus
Frequency of diagnosed and undiagnosed diabetes
and IGT, by age (U.S. data - Harris)
40
35
30
% of
population
IGT
Undiagnosed diabetes
Diagnosed diabetes
25
20
15
10
5
0
20-34
35-44
45-54
Harris. Diabetes Carewww.diabetesclinic.ca
1993;16:642-52.
55-64
65-74
Cardiovascular Disease Risk
is Increased 2 to 4 Times
Framingham study: diabetes and CAD mortality
at 20-year follow-up
Haffner Am J Cardiolwww.diabetesclinic.ca
1999;84:11J-4J.
The burden of Diabetes
•
87% of Type 2 Diabetes is managed
in Primary Care
• Diascan Study: 23.5% of patients in our office
Leiter et al. Diabetes Care 2000
have diabetes
• Quebec 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)
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 exams
Harris S et al. Cdn Fam Phys 2003
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Organization and
Delivery of Care
• Diabetes should be organized using a DHC
(Diabetes Healthcare) team approach
• People with diabetes should be offered initial and
ongoing needs-based
diabetes education
• The role of diabetes nurse educators and other
DHC team members should be enhanced in
cooperation with the physician
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Structured care
•
•
•
•
ACLS
ATLS
Seattle Defibrillator Experience
GREACE Study
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Structured Care VS Usual Care
• Patients received atorvastatin 10 mg/d (titrated up to 80
mg/d) to reach the NCEP LDL-C goal
• Specialist care unit with a strict protocol to achieve NCEP
LDL-C target
• Treatment from a physician of pt’s choice
• All patients had access to any necessary medications,
including statins
• Included lifestyle modifications (diet and exercise) as well
as lipid-lowering medications
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Αthyros VG et al. Curr Med Res Opin. 2002;18:220-228.
Reduction in Relative Risk of
Primary Endpoints
Total Mortality
Coronary
Mortality
Nonfatal MI
Unstable
Angina
PTCA/CABG
CHF
-51
-50
Stroke
0
-10
-20
-30
-40
-50
-43
-47
-52
-60
-47
-59
P=0.0021 P=0.0017 P=0.0001 P=0.0032
Αthyros VG et al. Curr Med Reswww.diabetesclinic.ca
Opin. 2002;18:220-228.
P=0.0011 P=0.021 P=0.034
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 be
achieved 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.
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.
†Glycemic
A1C = glycosylated hemoglobin
DCCT = Diabetes Control and Complications Trial
FPG = fasting plasma glucose
PG = plasma glucose
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Physical Activity and
Diabetes
Type
Recommendation
Aerobic – especially type 2
Brisk walking
 150 minutes of moderate-intensity
Biking
exercise each week
Raking leaves
 spread out over at least 3 nonContinuous swimming
consecutive days
 gradually increase to 4 hours or more a Dancing
Water aerobics
week
 sessions should be at least 10 minutes
at a time
Weight lifting
 3 times a week
Exercise with weight
 start with 1 set of 10-15 repetitions
machines
 progress to 2 sets of 10-15
 then 3 sets of 8
Resistance – all persons with
diabetes, including elderly
Example
• For people who have not previously exercised regularly and are at
risk of CVD, an ECG stress test should be considered prior to starting
an exercise program
Testing is particularly important before, during
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and for many
hours after exercise.
Nutrition Therapy
People with diabetes should:
• Receive nutrition counseling by a
registered dietitian
• Receive individualized meal planning
• Follow Canada’s Guidelines for Healthy Eating
• People on intensive insulin should also be taught
to adjust the insulin for the amount of
carbohydrate consumed
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Drugs in Type 2
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UKPDS:
Long-term Glucose Control
9
HbA1c (%)
Conventional
8
Intensive
7
ULN = 6.2%
6
0 0
3
6
9
12
Years of treatment
www.diabetesclinic.ca
UKPDS Study Group,
Lancet, 1998;352:837-853.
15
A1C (%)
UKPDS demonstrated loss
of glycemic control
with all agents studied
9
8
Conventional
Glyburide
Chlorpropamide
Metformin
Insulin
7
6
0
Upper limit of
normal = 6.2%
0
2
4
6
8
Years www.diabetesclinic.ca
from randomization
UK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865.
10
Overweight
patients
Cohort, median
values
Progressive Loss of -cell
Function in UKPDS
Non obese
Obese
100
80
80
60
60
40
40
20
20
0
0
0
1
2
3
4 5 6 7
0 1 2
Years from randomization
Conventional
Sulphonylurea
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UKPDS 16: Diabetes 1995; 44:1249–1258
Mean
3
4
5
6
7
Metformin
age at baseline 53 yrs.
-cell function (%)
-cell function (%)
100
Natural History
of Type 2 Diabetes
Lifestyle
Metformin/Thiazolidinediones
Insulin
Insulin
resistance
Secretagogues
Glucose
level
-cell
dysfunction
Insulin
production
Time
Normal
Impaired glucose
tolerance 10 yrs
Type 2 diabetes
12-15 yrs
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Henry. Am J Med 1998;105(1A):20S-6S.
Sites of Action of Currently
Available Therapeutic Options
LIVER
ADIPOSE
TISSUE
PANCREAS
GLUCOSE
PRODUCTION
Biguanides
Thiazolidinediones
MUSCLE
PERIPHERAL
INSULIN SECRETION
Sulfonylureas
Meglitinides
Insulin
INTESTINE
GLUCOSE
ABSORPTION
Alpha-glucosidase inhibitors
GLUCOSE UPTAKE
Thiazolidinediones
(Biguanides)
Sonnenberg, Kotchen Curr Opin Nephrol
Hypertens 1998;7:551-5.
www.diabetesclinic.ca
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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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)
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Mild to moderate hyperglycemia (A1C <9.0%)
Non-overweight
(BMI 25 kg/m2)
Overweight
(BMI 25 kg/m2)
Biguanide alone or in
combination with 1 of:
• insulin sensitizer*
• insulin secretagogue
• insulin
• alpha-glucosidase
inhibitor
1 or 2† antihyperglycemic
agents from different
classes
Marked hyperglycemia (A1C 9.0%)
2 antihyperglycemic agents
from different classes †
Basal and/or
preprandial insulin
• biguanide
• insulin sensitizer*
• insulin secretagogue
• insulin
• alpha-glucosidase
inhibitor
• biguanide
• insulin sensitizer*
• insulin secretagogue
• insulin
• alpha-glucosidase
inhibitor
F
E
S
T
Y
L
E
Clinical assessment and initiation of nutrition and physical activity
If not at target
If not at target
If not at target
L
I
If not at target
Add a drug from a different class
or
Use insulin alone or in combination with:
• biguanide
• insulin secretagogue
• insulin sensitizer*
• alpha-glucosidase inhibitor
Add an oral
antihyperglycemic agent
from a different
class of insulin*
Timely adjustments to and/or additions
of oral antihyperglycemic agents
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and/or insulin should be made to attain target A1C within 6 to 12 months
Intensify insulin
regimen or add
• biguanide
• insulin
secretagogue**
• insulin sensitizer*
• alpha-glucosidase
inhibitor
Clinical assessment and initiation of nutrition and physical activity
Overweight
(BMI 25 kg/m2)
Biguanide alone or in
combination with 1 of:
• insulin sensitizer*
• insulin secretagogue
• insulin
• alpha-glucosidase
inhibitor
Non-overweight
(BMI 25 kg/m2)
1 or 2† antihyperglycemic
agents from different
classes
Marked hyperglycemia (A1C 9.0%)
2 antihyperglycemic agents
from different classes †
Basal and/or
preprandial insulin
• biguanide
• insulin sensitizer*
• insulin secretagogue
• insulin
• alpha-glucosidase
inhibitor
• biguanide
• insulin sensitizer*
• insulin secretagogue
• insulin
• alpha-glucosidase
inhibitor
If not at target
If not at target
If not at target
If not at target
L
I
F
E
S
T
Y
L
E
Mild to moderate hyperglycemia (A1C <9.0%)
Add a drug from a different class
or
Use insulin alone or in combination with:
• biguanide
• insulin secretagogue
• insulin sensitizer*
• alpha-glucosidase inhibitor
Add an oral
antihyperglycemic agent
from a different
class of insulin*
Timely adjustments to www.diabetesclinic.ca
and/or additions of oral antihyperglycemic agents
and/or insulin should be made to attain target A1C within 6 to 12 months
Intensify insulin
regimen or add
• biguanide
• insulin
secretagogue**
• insulin sensitizer*
• alpha-glucosidase
inhibitor
Mild to moderate hyperglycemia (A1C <9.0%)
Overweight (BMI 25 kg/m2)
• insulin sensitizer*
• insulin secretagogue
• insulin
• alpha-glucosidase inhibitor
Y
L
E
Biguanide alone or in combination with 1 of:
Add a drug from a different class
or
Use insulin alone or in combination with:
• biguanide
• insulin secretagogue
• insulin sensitizer*
• alpha-glucosidase inhibitor
L
I
F
E
S
T
If not at target
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
•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 notwww.diabetesclinic.ca
an approved indication in Canada.
Pharmacotherapy
•
•
•
•
•
•
•
•
Metformin
Insulin Sensitizer (TZD)
Insulin Secretagogue
Insulin
Alpha-glucosidase inhibitor
Anorexiant*
If not at target
Add an agent from another class
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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 >9%
• Early Insulin if decompensated
• Consider TZD
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HbA1C in Diet-Treated Patients
Effects of Various Medications
(Difference from Placebo)
0
HbA1C (%)
-0.5
-1
-1.5
-2
-2.5
Repaglinide Metformin
Glyburide Glitazone Acarbose
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FDA
approved Prescribing Information for various OADs
Oral Agents for Type 2 Diabetes
Αlpha-glucosidase inhibitor
Expected decrease in A1C
with monotherapy
0.5 – 0.8
Biguanide
1.0 – 1.5
Insulin
Depends on regimen
Insulin secretagogues
Insulin sensitizers (TZDs)
1.0 – 1.5
0.5 for nateglinide
1.0 – 1.5
Combined rosiglitazone and metformin
1.0 – 1.5
Antiobesity agent (orlistat)
0.5
Class
• Combination at less than maximal doses result in more
rapid improvement of blood glucose
• Counsel patients about hypoglycemia prevention and treatment
SMBG is recommended at least once daily
Canadian Diabetes Association
2003 Clinical Practice Guidelines for the Prevention and Management of
www.diabetesclinic.ca
Diabetes in Canada. Cdn J Diabetes 2003; 27 (suppl 2)
Pharmacologic Management
of Type 2 Diabetes
• Add anti-hyperglycemic agents if:
Diet & exercise therapy do not achieve targets after 2-3 month trial
or
newly diagnosed and has an A1C of  9
A1C
& BMI
Suggested starting agent
BMI  25 Biguanide alone or in combination
< 9%
 9%
BMI < 25 1 or 2 agents from different classes
--
2 agents from different classes or
insulin basal and/or preprandial
Intensify to reach
targets in 6-12 months
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Need for Combination
Therapy in UKPDS
% of Patients
80%
70%
60%
75%
50%
40%
30%
50%
20%
10%
0%
3 years
9 years
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Dose-Response Curve
1.5
1.0
30
20
0.5
GI Distress Patients (%)
Reduction vs. placebo, HbA1c (%)
2.0
10
0
0
500
1000
1500
2000
2500
Dose
Metformin
Dose-response curve showing GI related effects
Riddle M. Combining
sulfonylureasand other oral agents. Am J of Med2000;
www.diabetesclinic.ca
108(6A):15S-22S
.
Mechanisms To Lower Glucose
• Decrease glucose production:
biguanides (or thiazolidinediones)
• Increase muscle glucose uptake:
thiazolidinediones (or biguanides)
• Stimulate insulin secretion:
repaglinide or sulfonylureas
• Retard carbohydrate absorption:
alpha-glucosidase inhibitors
• Correct insulin deficiency:
insulin or insulin analogues
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Biguanides:
mechanism of action
1. Intestine:
glucose absorption
4. Liver: hepatic
Blood
glucose
2. Muscle and adipose
tissue: glucose uptake
Metformin  glucose
utilization
Insulin resistance

glucose output
Metformin  HGO
Insulin
resistance
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3. Pancreas:
insulin secretion
Metformin
– Advantages –
• Corrects a primary pathophysiologic
impairment: hepatic glucose production
• High initial response rate
• Long record of relative safety
• No weight gain or modest weight loss
• Advantageous lipid profile
www.diabetesclinic.ca
Metformin
– Disadvantages –
• GI side effects on initiation
• Must be held prior to, and after, radiologic studies
using intravascular iodinated contrast media
• Risk of lactic acidosis: caution in
–
–
–
–
impaired renal function
impaired hepatic function
pharmacologically treated CHF
alcoholism
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Metformin
Dosage
• 500-2500 mg/day, no benefit over 2000
mg/day. Divide dose into twice daily.
Tablets of 500 & 850 mg. 500 mg fully
covered by ODB, 850 mg (Glucophage) not
covered.
• Start low and titrate up slowly to avoid GI
side effects
www.diabetesclinic.ca
Thiazolidinediones:
mechanism of actions
Blood
glucose
Liver
 insulin resistance
 hepatic glucose
production
Muscle and
adipose tissue
 insulin resistance
 glucose uptake
Pancreas
demand for insulin secretion
ß-cell insulin content
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Thiazolidinediones
– Advantages –
• Corrects a primary pathophysiologic
impairment: insulin resistance
• Possible once-daily dosing
• Improves Lipids, Lower serum triglyceride
• May be used in renal insufficiency
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Thiazolidinediones
– Disadvantages –
• Delayed action (onset: 3 wks, full effect:
10-12 wks)
• Variable response in monotherapy
• Weight gain
• Increased LDL-cholesterol (short-term)
• Few long-term studies
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Thiazolidenedione
Dosage
• Pioglitazone (Actos), dosage range 15-45 mg
• Tablets of 15, 30 & 45 mg
• Rosiglitazone (Avandia) dose range 2-8 mg
Tablets of 2, 4, 8 mg
• May take 3 weeks to 3 mo to see effect
• ODB Section 8 with failure of max dose
Metformin & Glyburide
www.diabetesclinic.ca
Sulfonylureas:
mechanism of action
2.

1. Intestine:
glucose absorption
Insulin resistance
Blood
glucose
4. Liver: hepatic
glucose output
Muscle and
adipose
tissue:
glucose
uptake
3. Pancreas:
Insulin secretion
Sulfonylureas
insulin secretion
Insulin
resistance
www.diabetesclinic.ca
Sulfonylureas
– Advantages –
• Improve a primary pathophysiologic
impairment: insulin secretion
• Physiologic route of insulin delivery
• High initial response rate
• No lag period before response
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Sulfonylureas
– Disadvantages –
• Hypoglycemia
– may be prolonged or severe
•
•
•
•
Weight gain
Drug interactions (especially 1st generation)
Hyponatremia (with chlorpropamide)
Cannot use if allergic to sulfa compounds
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Sulphonylureas
Dosage
• Glyburide (Diabeta)dose range 2.5-20 mg, split into
twice daily. Tablets of 2.5 and 5 mg
Full ODB
Coverage
• Gliclazide (Diamicron) dose range 40-320 mg a day,
divided into 2 doses. Diamicron MR 30 mg from 1-4
tablets, once daily ODB section 8 if hypoglycemia
on Glyburide
• Glimepiride (Amaryl) dose 0.5-4 mg OD Tabs
0.5, 1 , 2, 4 mg. No ODB coverage
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MEGLITINIDES New Class of
Insulin Secretagogues
Physiologic Reasons
• Insulin secretion must be closely coupled to
fluctuations in plasma glucose with little or
no lag time
– Prevents early postprandial hyperglycemia
– Prevents late postprandial hypoglycemia
• Insulin secretion should not be stimulated
when plasma glucose is low
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Why is there a Need for New
Classes of Insulin Secretagogues?
Pharmacologic Reasons
• Chronic sulfonylurea treatment causes
desensitization of ß-cell insulin secretion
• High “secondary failure” rate with
sulfonylureas
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Therapeutic Need, 1988
“In general, older patients have more renal
failure and cardiovascular and hepatic
problems, as well as a tendency to skip
meals and snacks. For this reason, it is
best to choose an agent with relatively
short duration of action, which is less
likely to cause profound hypoglycemia.”
Physician’s Guide to Non-Insulin-Dependent (Type II) Diabetes. Diagnosis and
Treatment (Second Edition) p.39. ADA-CEP 1984,1988.
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Meglitinides
Efficacy Summary
• Rapid response
– Decline in 24-hr mean BG ( 2.2-4.4 mmol/L) within 1 week
• Good clinical response
– Improves glucose control D HbA1C ~ 1.6-2.1% (vs placebo)
• Glycemic control
– Documented HbA1C reductions sustained over 1 year
• Dose response
– Reductions in mean glucose seen at 0.5-4 mg ac
• Synergistic
– Incremental improvements when used in combination with metformin
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Meglitinides
Dosage
• Repaglinide (Gluconorm) 0.5 to 4 mg with
each meal. Tablets of 0.5, 1.0 and 2 mg ODB
Section 8 requires hypoglyhcemia on Glyburide
• Nateglinide (Starlix) 120 mg with each meal
ODB No Coverage
www.diabetesclinic.ca
Insulin
– Disadvantages –
•
•
•
•
Hypoglycemia
Weight gain
Need for injections
Non-physiologic route of administration
(peripheral)
• Patient and physician non-acceptance
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Alpha-Glucosidase inhibitors
mechanism of action
2. Muscle and
adipose
tissue: glucose
uptake
Insulin resistance
1. Intestine:
glucose absorption

Blood
glucose
4. Liver: hepatic
glucose output
Insulin
resistance
3. Pancreas:
insulin secretion
Amatruda, Diabetes Mellitus, 1996. www.diabetesclinic.ca
Alpha-Glucosidase Inhibitors
– Advantages –
• Good safety profile
• No weight gain or modest weight loss
• Dose coupled to meals
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Alpha-Glucosidase Inhibitors
- Disadvantages • Modest effect on fasting plasma glucose
and HbA1C
• Flatulence, gastrointestinal side effects
• Cannot treat hypoglycemia with sucrose,
maltose, or starch
– use glucose, fructose, or lactose
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Acarbose
Dosage
• Acarbose (Prandase) dose 50-100 mg with
the first bite of each meal.
High index of side effects, start low (25 mg
OD) and titrate up gradually.
• Not very effective for hyperglycemia 0.5%
A1c reduction.
• ODB Coverage on LU
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Anorexiants
Dosage
• Orlistat (Xenical) 120 mg tabs, one with the first
bite of each meal. Inhibits 30% of dietaryt fat
absorpton needs to be used with a low fat diet.
Lifestyle counseling essential. Prevented Diabetes
in XENDOS study.
• ODB Section 8 with failure of Metformin & SU in
the obese patient
• Sibutramine (Meridia) dose 10 or 15 mg caps
OD. No ODB Coverage
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Type 2 Diabetes
Key Concepts
• Dual impairment:
– ß-cell function: insulin secretion
– insulin action: insulin resistance
• “Glucose toxicity” aggravates both
impairments
• Multiple mechanisms to correct hyperglycemia
• Most patients require combination therapy
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Combination Therapy
Summary
• The magnitude of the diabetic epidemic dictates
more aggressive approaches to treatment
• Evidence clearly suggest that early intensive
treatment results in significant decrease in
complications
• To reduce macrovascular disease more strict
glucose control might be needed (HbA1c <6%)
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In Conclusion
• Prevalence of type 2 diabetes is increasing
dramatically
• Majority of patients are diagnosed and treated by
the family physician
• New paradigm: need to be much more aggressive
early in the treatment of these patients utilizing dual
therapies
• Hypoglycemia can be managed through proper
treatment choices and lifestyle management
• Glucose is a continuous progressive risk factor for
cardiovascular disease
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QUESTIONS?
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