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Transcript of Www.diabetesclinic.ca Combination Therapy in Type 2 Diabetes.
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Combination Therapy in Type 2 Diabetes
www.diabetesclinic.ca
Combination Therapy for Type 2 Diabetes
J. Robin Conway M.D.Diabetes ClinicSmiths Falls, ONwww.diabetesclinic.ca
www.diabetesclinic.ca
Natural History of Type 2 Diabetes
Normal Impaired glucosetolerance
Type 2 diabetes
Time
Insulinresistance
Insulinproduction
Glucoselevel
-celldysfunction
Henry. Am J Med 1998;105(1A):20S-6S.
LifestyleLifestyle
Metformin/ThiazolidinedionesMetformin/Thiazolidinediones
SecretagoguesSecretagoguesInsulinInsulin
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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
Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Cdn J Diabetes 2003; 27 (suppl 2)
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Clinical assessment and initiation of nutrition and physical activity
Mild to moderate hyperglycemia (A1C <9.0%)
Overweight(BMI 25 kg/m2)
Non-overweight(BMI 25 kg/m2)
Biguanide alone or incombination with 1 of:
• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor
1 or 2† antihyperglycemicagents from differentclasses
• biguanide• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor
Add a drug from a different class orUse insulin alone or in combination with:
• biguanide• insulin secretagogue• insulin sensitizer*• alpha-glucosidase inhibitor
Marked hyperglycemia (A1C 9.0%)
2 antihyperglycemic agentsfrom different classes †
• biguanide• insulin sensitizer*• insulin secretagogue• insulin• alpha-glucosidase inhibitor
Basal and/orpreprandial insulin
Add an oral
antihyperglycemic agentfrom a differentclass of insulin*
Intensify insulinregimen or add
• biguanide• insulin secretagogue**• insulin sensitizer*• alpha-glucosidase inhibitor
If not at targetIf not at targetIf not at targetIf not at target
L
I
F
E
S
T
Y
L
E
Timely adjustments to and/or additions of oral antihyperglycemic agentsand/or insulin should be made to attain target A1C within 6 to 12 months
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Pharmacologic Management of Type 2 Diabetes
• Add anti-hyperglycemic agents if:Diet & exercise therapy do not achieve targets
after 2-3 month trialor
newly diagnosed and has an A1C of 9%
Intensify to reach targets in 6-12 months
A1C & 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
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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
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Need for Combination Therapy in UKPDS
50%
75%
0%
10%
20%
30%
40%
50%
60%
70%
80%
3 years 9 years
% of Patients
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Dose-Response CurveDose-Response CurveDose-Response Curve
Riddle M. Combining sulfonylureas and other oral agents. Am J of Med. 2000; 108(6A):15S-22S.
Dose-response curve showing GI related effects
30
20
10
0 500 1000 1500 2000 2500
0
0.5
1.0
1.5
2.0
Dose
GI
Dis
tre
ss
Pa
tie
nts
(%
)
Re
du
cti
on
vs
. p
lac
eb
o,
Hb
A 1c
(%)
Metformin
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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
2. Muscle and adipose tissue: glucose uptake Metformin glucose utilization
3. Pancreas: insulin secretion
4. Liver: hepatic glucose output Metformin HGO
Insulin resistance
Insulin resistanceBlood glucose
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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
Muscle and adipose tissue insulin resistance glucose uptake
Liver insulin resistance hepatic glucose
production
Bloodglucose
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
06
7
8
9
2 4 6 8 10
A1
C (
%)
Years from randomization
Upper limit of of normal = 6.2%
ConventionalGlyburideChlorpropamideMetforminInsulin
0
UKPDS demonstrated loss of glycemic control with all agents studied
UKPDS demonstrated loss of glycemic control with all agents studied
UK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865.
Overweight patientsCohort, median values
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-2
-1.5
-1
-0.5
0
0 (n=157) 16 (n=151) 28 (n=141) 40 (n=133)
Weeks
Me
an
Ch
an
ge
in H
BA
1c
fro
m
ba
se
line
(%
po
ints
)
Pioglitazone 30 mg plus SU
Double-blind phase
Open-label phase
Hanefeld M et al. Exp Clin Endocrinol Diabetes 2000;108 (suppl 2):S256-66
**
*
* p<0.05
Sulfonylurea Study - Long-term Mean Changes in HbA1C from Baseline
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Metformin 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
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Sulfonylureas: mechanism of action
1. Intestine:glucose absorption
2. Muscle and adipose tissue:glucose uptake
3. Pancreas: Insulin secretionSulfonylureasinsulin secretion
4. Liver: hepatic glucose output
Insulin resistance
Insulin resistanceBlood glucose
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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
Amatruda, Diabetes Mellitus, 1996.
Insulin resistance
1. Intestine:glucose absorption
2. Muscle and adipose tissue: glucose uptake
3. Pancreas: insulin secretion
4. Liver: hepatic glucose output
Insulin resistanceBlood glucose
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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
Lifestyle Change
Monotherapy Combination oral agents
Insulin + oral agents
Old Paradigm
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%)
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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