Combination Therapy in
Type 2 Diabetes
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Combination Therapy for Type 2 Diabetes
J. Robin Conway M.D.
Diabetes Clinic
Smiths Falls, ON
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Natural History
of Type 2 Diabetes
Metformin/Thiazolidinediones
Lifestyle
Secretagogues
Insulin
Insulin
resistance
Glucose
level
b -cell
dysfunction
Normal
Impaired glucose
tolerance
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Henry. Am J Med 1998;105(1A):20S-6S.
Insulin
production
Time
Type 2 diabetes
Oral Agents for Type 2 Diabetes
C lass
E x p ected d ecrease in A 1 C
w ith m o n o th era py
Α lph a-g lu co sid ase inh ib ito r
0 .5 – 0 .8
B igu anid e
1 .0 – 1 .5
In sulin
D ep ends on reg im en
In sulin secretag ogu es
In sulin sensitizers (T Z D s)
1 .0
– 1 .5
0 .5 fo r nateglinid e
1 .0 – 1 .5
C o m b in ed ro siglitazon e an d m etfo rm in
1 .0 – 1 .5
A n tiob esity ag ent (o rlistat)
0 .5
• 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
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Clinical assessment and initiation of nutrition and physical activity
Marked 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
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
I
F
E
S
T
Y
L
E
Mild to moderate hyperglycemia (A1C <9.0%)
If not at target
If not at target
If not at target
L
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
and/or insulin should be made to attain target A1C within 6 to 12 months
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Intensify insulin
regimen or add
• biguanide
• insulin
secretagogue**
• insulin sensitizer*
• alpha-glucosidase
inhibitor
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
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Intensify to reach targets in 6-12 months
Targets for Glycemic Control
A 1C
(% )
F P G /p rep ra n d ia l
(m m o l/L )
2 h P o stp ra n d ia l
(m m o l/L )
T arg et fo r m o st p atien ts
 7 .0
4 .0 – 7 .0
5 .0 – 1 0 .0
N o rm al ran g e
(if it can b e safely ach iev ed )
 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, preprandialwww.diabetesclinic.ca
and postprandial PG targets
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
10
0
0
500
1000
1500
2000
2500
Dose
Metformin
Dose-response curve
showing GI related effects
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Riddle M. Combiningsulfonylureas and other oral agents.Am J of Med. 2000; 108(6A):15S-22S.
GI Distress Patients (%)
Reduction vs. placebo, HbA1c (%)
2.0
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:
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insulin or insulin analogues
Biguanides: mechanism of action
1. Intestine:
glucose absorption
2. Muscle and adipose
tissue: glucose uptake
Metformin  glucose
utilization

Insulin resistance
Blood
4. Liver: hepatic
glucose output glucose
Metformin 
HGO
Insulin
resistance
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3. Pancreas:
insulin secretion
Metformin - Advantages
• Corrects a primary pathophysiologic
impairment: insulin resistance
• High initial response rate
• Long record of relative safety
• No weight gain or modest weight loss
• Advantageous lipid profile
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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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Thiazolidinediones:
mechanism of action
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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UKPDS demonstrated loss of glycemic
control with all agents studied
A1C (%)
9
8
Conventional
Glyburide
Chlorpropamide
Metformin
Insulin
7
Upper limit of of normal = 6.2%
6
0
0
2
4
6
8
Years from randomization
UK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865.
10
Overweight patients
Cohort, median values
Mean Change in HBA1c from
baseline (% points)
Sulfonylurea Study - Long-term Mean
Changes in HbA1C from Baseline
0 (n=157)
Weeks
16 (n=151)
28 (n=141)
40 (n=133)
0
-0.5
*
-1
Pioglitazone 30 mg
plus SU
*
*
-1.5
-2
Double-blind
phase
Open-label
phase
* p<0.05
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Hanefeld M et al. Exp Clin Endocrinol Diabetes 2000;108 (suppl 2):S256-66
Metformin 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)
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Einhorn et al. Clin Therapeutics 2000;12:1395-1409
Sulfonylureas: mechanism of action
1. Intestine:
glucose absorption
2. Muscle and adipose
tissue:
glucose uptake

Blood Insulin resistance
glucose
4. Liver: hepatic
glucose output
3. Pancreas:
Insulin secretion
Sulfonylureas
insulin secretion
Insulin
resistance
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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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Insulin - Advantages
•
•
•
•
Will control virtually all patients
Can be used to overcome glucose toxicity
Flexibility in dosing and lifestyle
Multiple preparations with different action
profiles
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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
1. Intestine:
glucose absorption
Blood Insulin resistance
glucose
Insulin
resistance
Amatruda, Diabetes Mellitus, 1996.

4. Liver: hepatic
glucose output
2. Muscle and adipose
tissue: glucose uptake
3. Pancreas:
insulin secretion
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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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Changing Therapies to Address
Diabetes Progression
Old Paradigm
Lifestyle
Change
Monotherapy Combination
oral agents
Insulin +
oral agents
New Paradigm
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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%) www.diabetesclinic.ca
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
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• Glucose is a continuous
progressive risk