Combination Therapy in Type 2 Diabetes

1
Combination Therapy in Type 2 Diabetes
2
Combination Therapy for Type 2 Diabetes
J. Robin Conway M.D. Diabetes Clinic Smiths
Falls, ON www.diabetesclinic.ca
3
Natural History of Type 2 Diabetes
Metformin/Thiazolidinediones
Secretagogues
Lifestyle
Henry. Am J Med 1998105(1A)20S-6S.
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Oral Agents for Type 2 Diabetes

• 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 Diabetes in Canada. Cdn J Diabetes
2003 27 (suppl 2)
5
Clinical assessment and initiation of nutrition
and physical activity
Marked hyperglycemia (A1C ?9.0)
Mild to moderate hyperglycemia (A1C lt9.0)

Basal and/or preprandial insulin
Non-overweight (BMI ?25 kg/m2)
Overweight (BMI ?25 kg/m2)
2 antihyperglycemic agents from different classes

• biguanide
• insulin sensitizer
• insulin secretagogue
• insulin
• alpha-glucosidase
• inhibitor

L I F E S T Y L E
Biguanide alone or in combination with 1 of
1 or 2 antihyperglycemic agents from
different classes

• insulin sensitizer
• insulin secretagogue
• insulin
• alpha-glucosidase
• inhibitor

• biguanide
• insulin sensitizer
• insulin secretagogue
• insulin
• alpha-glucosidase
• inhibitor

Add an oral antihyperglycemic agent from a
different class of insulin
Add a drug from a different class or Use
insulin alone or in combination with
Intensify insulin regimen or add

• biguanide
• insulin secretagogue
• insulin sensitizer
• alpha-glucosidase inhibitor

• biguanide
• insulin
• secretagogue
• insulin sensitizer
• alpha-glucosidase
• inhibitor

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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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
lt 9 BMI ? 25 Biguanide alone or in combination
lt 9 BMI lt 25 1 or 2 agents from different classes
? 9 -- 2 agents from different classes or insulin basal and/or preprandial
Intensify to reach targets in 6-12 months
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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

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
of Patients
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Dose-Response Curve
Dose-Response Curve
Dose-Response Curve
Metformin
Dose-response curve showing GI related effects
Riddle M. Combining
sulfonylureas
and other oral agents.
Am J of Med
. 2000 108(6A)15S-22S
.
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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
2. Muscle and adipose tissue glucose uptake
Metformin ? glucose utilization
1. Intestineglucose absorption
Insulin resistance
Blood glucose
4. Liver hepatic glucose output Metformin HGO
?
3. Pancreas insulin secretion
Insulin resistance
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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
Bloodglucose
Muscle and adipose tissue? insulin resistance?
glucose uptake
Liver? insulin resistance ? hepatic glucose
production
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 effect10-12
  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


9
8
()
Conventional Glyburide Chlorpropamide Metformin In
sulin
A1C
7
Upper limit of of normal 6.2
6
0
0
2
4
6
8
10
Years from randomization
Overweight patientsCohort, median values
UK Prospective Diabetes Study Group. UKPDS 34.
Lancet 1998 352854865.
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Sulfonylurea Study - Long-term Mean Changes in
HbA1C from Baseline



Double-blind phase
Open-label phase
plt0.05
Hanefeld M et al. Exp Clin Endocrinol Diabetes
2000108 (suppl 2)S256-66
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Metformin Study - Open Label Extension
Change in HbA1c ()
Change in fasting glucose (mmol/L)
Einhorn et al. Clin Therapeutics 2000121395-1409
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Sulfonylureas mechanism of action
1. Intestineglucose absorption
2. Muscle and adipose tissueglucose uptake
Insulin resistance
Blood glucose
?
4. Liver hepatic glucose output
3. Pancreas Insulin secretionSulfonylureas??in
sulin 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. Intestineglucose absorption
2. Muscle and adipose tissue glucose uptake
Insulin resistance
Blood glucose
?
4. Liver hepatic glucose output
Insulin resistance
3. Pancreas insulin secretion
Amatruda, Diabetes Mellitus, 1996.
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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
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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 lt6)

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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