long term benefits of oral agents

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
•
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
Type Recommendation Example
Aerobic – especially
type 2



•
150 minutes of moderate-intensity
exercise each week
•
spread out over at least 3 non-
consecutive days
•
gradually increase to 4 hours or
more a week
•
sessions should be at least 10
minutes at a time

Brisk walking
Biking
Raking leaves
Continuous swimming
Dancing
Water aerobics
Resistance – all
persons with diabetes,
including elderly
•
3 times a week
•
start with 1 set of 10-15 repetitions
•
progress to 2 sets of 10-15
•
then 3 sets of 8
Weight lifting
Exercise with weight
machines


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
or
newly diagnosed and has an A1C of ≥ 9%
Intensify to reach targets in 6-12 months
A1
C
& BMI Suggested starting agent
<
9%
BMI ≥
25
Biguanide alone or in combination
BMI <
25
1 or 2 agents from different classes
≥
9%

2 agents from different classes or
insulin basal and/or preprandial
Clinical assessment and initiation of nutrition therapy and physical activity
Mild to moderate hyperglycemia (A1C<9.0%) Marked hyperglycemia (A1C ≥ 9.0%)
Basal and/or
preprandial
insulin
Non-overweight Overweight 2 antihyperglycemic
agents from different
classes
1 or 2
antihyperglycemic
agents from different
classes
Biguanide alone
or in
combination
If not at targetIf not at target If not at target If not at target
Add a drug from a different class or
use insulin alone or in combination
Add an oral
antihyperglycemic agent
from a different class or
insulin
Intensify insulin
regimen or add
antihyperglycemic
agents
Management of Hyperglycemia in Type 2
Diabetes Patients

Oral Agents for Type 2 Diabetes
SMBG is recommended at least once daily
•
Combination at less than maximal doses result in
more rapid improvement of blood glucose
•
Counsel patients about hypoglycemia prevention
and treatment
Class
Expected decrease in A1C
with monotherapy
Αlpha-glucosidase inhibitor 0.5 – 0.8
Biguanide 1.0 – 1.5
Insulin Depends on regimen
Insulin secretagogues 1.0 – 1.5
0.5 for nateglinide
Insulin sensitizers (TZDs) 1.0 – 1.5
Combined rosiglitazone and metformin 1.0 – 1.5
Antiobesity agent (orlistat) 0.5


Targets for Glycemic Control
* Treatment goals and strategies must be tailored to the patient, with consideration
given to individual risk factors
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


To achieve an A1C ≤ 7.0%, patients should aim for
FPG, preprandial and postprandial PG targets
Burden of Poor Control - Cost
4500
4700
4900
5100
5300
5500
5700
5900
6100
6300
6500
6 7 8 9 10
HbA1c
cost/patient/year
Diabetes only Diab, HT, Heart dis
Burden of Poor Control - Cost


Estimate annual
cost to health
plans by level of
glycemic control

Determine effect
of Improved
Glycemic Control
on Health Care
Utilization and
Costs
4500
9500
14500
19500
24500
6 7 8 9 10
HbA1c
cost/patient/year
Diabetes only Diab, HT, Heart dis
Meltzer et al CMAJ 1998;159(Suppl):S1-29.
Oral Antihyperglycemic Agents:
Biguanides
•
Decreases hepatic glucose
production, enhances
peripheral glucose uptake
–
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
MUSCLE
LIVER
Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.
MUSCLE
ADIPOSE
TISSUE
LIVER
Oral Antihyperglycemic Agents:
Thiazolidinediones (TZDs)
•
Decrease insulin
resistance
–
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
TZD
INSULIN
RECEPTOR
RNADNA
Saltiel, Olefsky Diabetes 1996;45:1661–9.
Thiazolidinediones: Mechanism of
Insulin Sensitization
TZD
PPARγ
INSULIN
GLUT-4
GLUCOSE
Durability of Glycemic Control
with Pioglitazone Long Term
7.5
8
8.5
9
9.5
10
10.5
baseline endpoint week 12 week 24 week 36 week 48 week 60 week 72
rollover placebo
rollover pioglitazone
Einhorn D et al. Diabetes 2001;50 (suppl2):A111
HbA1c (%)
Metformin & Pioglitazone Study

- Open Label Extension
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
end of DB STUDY week 24 week 48 week 72
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
0
Hb1c
fasting glucose
Change in HbA1c (%) Change in fasting glucose (mmol/L)
Einhorn et al. Clin Therapeutics 2000;12:1395-1409
Oral Antihyperglycemic Agents:
Sulfonylureas
•
Stimulate pancreatic
insulin release
–

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.
PANCREAS
Natural History
of Type 2 Diabetes
Normal
Impaired glucose
tolerance
Type 2 diabetes
Time
Insulin
resistance
Insulin
production
Glucose
level
β
-cell
dysfunction
Henry. Am J Med 1998;105(1A):20S-6S.
Oral Antihyperglycemic Agents:
Alpha-glucosidase inhibitors
•
Slows gut absorption

of starch and sucrose
–
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.
INTESTINE
Oral Agents for Type 2 Diabetes
SMBG is recommended at least once daily
•
Combination at less than maximal doses result in
more rapid improvement of blood glucose
•
Counsel patients about hypoglycemia prevention
and treatment
Class
Expected decrease in A1C
with monotherapy
Αlpha-glucosidase inhibitor 0.5 – 0.8
Biguanide 1.0 – 1.5
Insulin Depends on regimen
Insulin secretagogues 1.0 – 1.5
0.5 for nateglinide
Insulin sensitizers (TZDs) 1.0 – 1.5
Combined rosiglitazone and metformin 1.0 – 1.5
Antiobesity agent (orlistat) 0.5

Natural History
of Type 2 Diabetes
Normal
Impaired glucose
tolerance
Type 2 diabetes
Time
Insulin
resistance
Insulin
production
Glucose
level
β
-cell
dysfunction
Henry. Am J Med 1998;105(1A):20S-6S.


Lifestyle
Lifestyle
Metformin/Thiazolidinediones
Metformin/Thiazolidinediones
Secretagogues
Secretagogues
Insulin
Insulin
Targets for Glycemic Control

* Treatment goals and strategies must be tailored to the patient, with consideration
given to individual risk factors
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


To achieve an A1C ≤ 7.0%, patients should aim for
FPG, preprandial and postprandial PG targets