LONG TERM BENEFITS OF ORAL AGENTS
J. Robin Conway M.D.
Diabetes Clinic
Smiths Falls, ON
www.diabetesclinic.ca
Long Term Benefits of Oral
Agents
Robin Conway M.D.
Physical Activity and Diabetes
Type
Recommendation
Aerobic – especially
type 2
Resistance – all
persons with diabetes,
including elderly
Example
 150 minutes of moderate-intensity Brisk walking
Biking
exercise each week
Raking leaves
 spread out over at least 3 nonContinuous swimming
consecutive days
Dancing
 gradually increase to 4 hours or
Water aerobics
more a week
 sessions should be at least 10
minutes at a time
Weight lifting
 3 times a week
 start with 1 set of 10-15 repetitions Exercise with weight
machines
 progress to 2 sets of 10-15
 then 3 sets of 8
• 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
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
Pharmacologic Management of
Type 2 Diabetes
• Add anti-hyperglycemic agents if:
Diet & exercise therapy do not achieve targets
after 2-3 month trial
orstarting agent
A1 & BMI Suggested
Cnewly diagnosed and has an A1C of  9%
<
9%
BMI 
25
BMI <
25

9%
2 agents from different classes or
-Intensify
to
reachbasal
targets
in 6-12
months
insulin
and/or
preprandial
Biguanide alone or in combination
1 or 2 agents from different classes
Management of Hyperglycemia in Type 2
Diabetes Patients
Clinical assessment and initiation of nutrition therapy and physical activity
Mild to moderate hyperglycemia (A1C<9.0%)
Overweight
Non-overweight
Biguanide alone
or in
combination
1 or 2
antihyperglycemic
agents from different
classes
If not at target
If not at target
Add a drug from a different class or
use insulin alone or in combination
Marked hyperglycemia (A1C  9.0%)
2 antihyperglycemic
agents from different
classes
If not at target
Add an oral
antihyperglycemic agent
from a different class or
insulin
Basal and/or
preprandial
insulin
If not at target
Intensify insulin
regimen or add
antihyperglycemic
agents
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
Targets for Glycemic Control
A1C
(%)
FPG/preprandial
(mmol/L)
2h Postprandial
(mmol/L)
Target for most patients
 7.0
4.0 – 7.0
5.0 – 10.0
Normal range
(if it can be safely achieved)
 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
To achieve an A1C  7.0%, patients should aim for
FPG, preprandial and postprandial PG targets
cost/patient/year
Burden of Poor Control - Cost
6500
6300
6100
5900
5700
5500
5300
5100
4900
4700
4500
6
7
8
9
HbA1c
Diabetes only
Diab, HT, Heart dis
10
 Estimate annual
cost to health
plans by level of
glycemic control
 Determine effect
of Improved
Glycemic Control
on Health Care
Utilization and
Costs
cost/patient/year
Burden of Poor Control - Cost
24500
19500
14500
9500
4500
6
7
8
9
HbA1c
Diabetes only
Diab, HT, Heart dis
10
Oral Antihyperglycemic Agents:
Biguanides
• Decreases hepatic glucose
production, enhances
peripheral glucose uptake
–
–
–
–
–
LIVER
MUSCLE
May reduce insulin resistance in the periphery
e.g., Metformin
Contraindicated in renal/hepatic insufficiency
May cause GI side effects
Not associated with hypoglycemia, may promote weight
loss
Meltzer et al CMAJ 1998;159(Suppl):S1-29.
Oral Antihyperglycemic Agents:
Thiazolidinediones (TZDs)
• Decrease insulin
resistance
MUSCLE
LIVER
ADIPOSE
TISSUE
– Increase insulin-dependent
glucose disposal, decrease hepatic glucose production
– e.g., Pioglitazone, rosiglitazone
– Pioglitazone has a positive effect on lipids
– Not associated with hypoglycemia
– Possible URI, headache, edema, weight gain and
reduction in hemoglobin
Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.
Thiazolidinediones: Mechanism of
Insulin Sensitization
INSULIN
INSULIN
TZD
RECEPTOR
GLUCOSE
TZD
GLUT-4
PPAR
DNA
Saltiel, Olefsky Diabetes 1996;45:1661–9.
RNA
Durability of Glycemic Control
with Pioglitazone Long Term
10.5
10
HbA1c (%)
9.5
rollover placebo
9
8.5
rollover pioglitazone
8
7.5
baseline
endpoint
week 12
week 24
week 36
week 48
week 60
week 72
Einhorn D et al. Diabetes 2001;50 (suppl2):A111
Metformin & Pioglitazone Study
- Open Label Extension
0
0
end of DB STUDY
week 24
week 48
week 72
-0.2
-0.5
-0.4
-1
-0.6
-1.5
-0.8
-2
-1
fasting glucose
-2.5
-1.2
-3
-1.4
-3.5
-1.6
-4
Change in HbA1c (%)
Hb1c
Change in fasting glucose (mmol/L)
Einhorn et al. Clin Therapeutics 2000;12:1395-1409
Oral Antihyperglycemic Agents:
Sulfonylureas
• Stimulate pancreatic
insulin release
PANCREAS
– e.g., First-generation: tolbutamide, chlorpropamide,
acetohexamide
– e.g., Second-generation: Glyburide, gliclazide
– Secondary failure a problem
– Weight gain, risk of hypoglycemia
Meltzer et al CMAJ 1998;159(Suppl):S1-29.
Natural History
of Type 2 Diabetes
Insulin
resistance
Glucose
level
Insulin
production
b-cell
dysfunction
Normal
Impaired glucose
tolerance
Henry. Am J Med 1998;105(1A):20S-6S.
Type 2 diabetes
Time
Oral Antihyperglycemic Agents:
Alpha-glucosidase inhibitors
• Slows gut absorption
of starch and sucrose
INTESTINE
– Attenuates postprandial increases in blood
glucose levels
– e.g., Acarbose
– GI side effects
– Not associated with hypoglycemia or weight
gain
Salvatore, Giugliano Clin Pharmacokinet 1996;30:94-106.
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
Natural History
of Type 2 Diabetes
Metformin/Thiazolidinediones
Lifestyle
Secretagogues
Insulin
Insulin
resistance
Glucose
level
b -cell
dysfunction
Normal
Impaired glucose
tolerance
Henry. Am J Med 1998;105(1A):20S-6S.
Insulin
production
Time
Type 2 diabetes
Targets for Glycemic Control
A1C
(%)
FPG/preprandial
(mmol/L)
2h Postprandial
(mmol/L)
Target for most patients
 7.0
4.0 – 7.0
5.0 – 10.0
Normal range
(if it can be safely achieved)
 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
To achieve an A1C  7.0%, patients should aim for
FPG, preprandial and postprandial PG targets