Options for Diabetes

1
2003 CDA Clinical Practice Guidelines ORAL AGENTS

• Options for Diabetes

J. Robin Conway M.D. Diabetes Clinic - Smiths
Falls, ON
Kingston April 17 2004
www.diabetesclinic.ca
2
Worldwide rates of diabetes mellitus predictions
80 70 60 50 40 30 20 10 0
Prevalence (millions)
Year 1995 2000 2025
North America
Europe
Southeast Asia
World Health Organization. 1997. Canadian
Diabetes Association, 1998 website.
3
2 Million Canadians Have Diabetes Mellitus
Frequency of diagnosed and undiagnosed diabetes
and IGT, by age (U.S. data - Harris)
Harris. Diabetes Care 199316642-52.
4
Cardiovascular Disease Risk is Increased 2 to 4
Times
Framingham study diabetes and CAD mortalityat
20-year follow-up
Haffner Am J Cardiol 19998411J-4J.
5
The burden of Diabetes

• 87 of Type 2 Diabetes is managed in Primary
  Care
• Diascan Study 23.5 of patients in our office
  have diabetes
• Quebec screening gt2 Risk Factors, 79 tested
  7 Diabetes , 13 IGT or IFG
  74 No
  Treatment Advice

Leiter et al. Diabetes Care 2000
Strychar I et al. Cdn J Diab 2003(abs)
6
T2DM in Family Practice

• 84 of patients had A1c in past year
• Average A1c 7.9 (goallt7)
• 88 had BP check
• 48 had lipid profiles
• 28 tested for microalbuminuria
• 15 had foot exams

Harris S et al. Cdn Fam Phys 2003
7
Organization and Delivery of Care

• Diabetes should be organized using a DHC
  (Diabetes Healthcare) team approach
• People with diabetes should be offered initial
  and ongoing needs-based diabetes education
• The role of diabetes nurse educators and other
  DHC team members should be enhanced in
  cooperation with the physician

8
Structured care

• ACLS
• ATLS
• Seattle Defibrillator Experience
• GREACE Study

9
Structured Care VS Usual Care

• Patients received atorvastatin 10 mg/d (titrated
  up to 80 mg/d) to reach the NCEP LDL-C goal
• Specialist care unit with a strict protocol to
  achieve NCEP LDL-C target
• Treatment from a physician of pts choice
• All patients had access to any necessary
  medications, including statins
• Included lifestyle modifications (diet and
  exercise) as well as lipid-lowering medications

Structured Care
Usual Care
?thyros VG et al. Curr Med Res Opin.
200218220-228.
10
Reduction in Relative Risk of Primary Endpoints
Reduction
P0.034
P0.0021
P0.0017
P0.0011
P0.0001
P0.0032
P0.021
?thyros VG et al. Curr Med Res Opin.
200218220-228.
11
Recommended targets for glycemic control
A1C ()
FPG/preprandial PG (mmol/L)
2-hour postprandial PG (mmol/L)
Target for most patients
?7.0
4.0-7.0
5.0-10.0
?6.0
4.0-6.0
5.0-8.0
Normal range (considered for patients in whom
it can be achieved safely)
Treatment goals and strategies must be tailored
to the patient, with consideration given to
individual risk factors. Glycemic targets for
children ?12 years of age and pregnant women
differ from these targets. Please refer to
Other Relevant Guidelines for further
details. An A1C of 7.0 corresponds to a
laboratory value of 0.070. Where possible,
Canadian laboratories should standardize
their A1C values to DCCT levels (reference range
0.040 to 0.060). However, as many laboratories
continue to use a different reference range, the
target A1C value should be adjusted based on the
specific reference range used by the laboratory
that performed the test. As a useful guide an
A1C target of 7.0 refers to a threshold that is
approximately 15 above the upper limit of
normal. A1C glycosylated hemoglobin DCCT
Diabetes Control and Complications Trial FPG
fasting plasma glucose PG plasma glucose
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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

Testing is particularly important before, during
and for many hours after exercise.
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Nutrition Therapy

• People with diabetes should
• Receive nutrition counseling by a registered
  dietitian
• Receive individualized meal planning
• Follow Canadas Guidelines for Healthy Eating
• People on intensive insulin should also be taught
  to adjust the insulin for the amount of
  carbohydrate consumed

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Drugs in Type 2
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UKPDS Long-term Glucose Control



9
Conventional
8
HbA1c ()
Intensive
7
ULN 6.2
6
0
Years of treatment
UKPDS Study Group, Lancet, 1998352837-853.
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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 normal 6.2
6
0
Overweight patientsCohort, median values
0
2
4
6
8
10
Years from randomization
UK Prospective Diabetes Study Group. UKPDS 34.
Lancet 1998 352854865.
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Progressive Loss of ?-cellFunction in UKPDS

?-cell function ()
Conventional
Sulphonylurea
Metformin
Mean age at baseline 53 yrs.
UKPDS 16 Diabetes 1995 4412491258
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Natural History of Type 2 Diabetes
Lifestyle
Metformin/Thiazolidinediones
Secretagogues
Henry. Am J Med 1998105(1A)20S-6S.
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Sites of Action of Currently Available
Therapeutic Options
LIVER
MUSCLE
ADIPOSE TISSUE
PANCREAS

• GLUCOSE PRODUCTION
• Biguanides
• Thiazolidinediones

• PERIPHERAL
• GLUCOSE UPTAKE
• Thiazolidinediones
• (Biguanides)

• INSULIN SECRETION
• Sulfonylureas
• Meglitinides
• Insulin

INTESTINE

• GLUCOSE ABSORPTION

Sonnenberg, Kotchen Curr Opin Nephrol Hypertens
19987551-5.
Alpha-glucosidase inhibitors
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Combination Antihyperglycemic Therapy

• Addition, rather than substitution recommended
• Agents from other classes should be added
• Diff sites of action
• Diff MOA

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Individualized Treatment

• Metformin for overweight patients
• If control not achieved add another agent
• If A1c gt9 start with 2 agents
• Consider early insulin for hyperglycemia
• Bedtime intermediate insulin (NPH)

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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

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

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

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

If not at target
If not at target
If not at target
If not at target

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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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

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

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

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

If not at target
If not at target
If not at target
If not at target

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
24
Overweight (BMI ?25 kg/m2)

Biguanide alone or in combination with 1 of

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

L I F E S T Y L E
If not at target

• When used in combination with insulin, insulin
  sensitizers may increase the risk of edema or
  CHF. The combination
• of an insulin sensitizer and insulin is
  currently not an approved indication in Canada.

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Pharmacotherapy

• Metformin
• Insulin Sensitizer (TZD)
• Insulin Secretagogue
• Insulin
• Alpha-glucosidase inhibitor
• Anorexiant
• If not at target
• Add an agent from another class

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Pharmacotherapy

• Treat the Predominant problem
• Each Drug will lower A1c 1-1.5
  (Acarbose Orlistat 0-5)
• Start with Metformin in Obese or High FBS
• Combination therapy if A1c gt9
• Early Insulin if decompensated
• Consider TZD

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HbA1C in Diet-Treated PatientsEffects of Various
Medications
(Difference from Placebo)
HbA1C ()
Glyburide
Metformin
Repaglinide
Acarbose
Glitazone
FDA approved Prescribing Information for various
OADs
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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)
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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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Need for Combination Therapy in UKPDS
of Patients
31
Dose-Response Curve
Metformin
Dose-response curve showing GI related effects
Riddle M. Combining sulfonylureasand other oral
agents. Am J of Med2000 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

33
Biguanides mechanism of action
1. Intestineglucose absorption
2. Muscle and adipose tissue glucose uptake
Metformin ? glucose utilization
Blood glucose
Insulin resistance
4. Liver hepatic glucose output Metformin HGO
?
Insulin resistance
3. Pancreas insulin secretion

34
Metformin Advantages

• Corrects a primary pathophysiologic impairment
  hepatic glucose production
• 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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Metformin Dosage

• 500-2500 mg/day, no benefit over 2000 mg/day.
  Divide dose into twice daily. Tablets of 500
  850 mg. 500 mg fully covered by ODB, 850 mg
  (Glucophage) not covered.
• Start low and titrate up slowly to avoid GI side
  effects

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Thiazolidinediones mechanism of actions
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

40
Thiazolidenedione Dosage

• Pioglitazone (Actos), dosage range 15-45 mg
• Tablets of 15, 30 45 mg
• Rosiglitazone (Avandia) dose range 2-8 mg
  Tablets of 2, 4, 8 mg
• May take 3 weeks to 3 mo to see effect
• ODB Section 8 with failure of max dose Metformin
  Glyburide

41
Sulfonylureas mechanism of action
1. Intestineglucose absorption
2. Muscle and adipose tissue
glucose 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

44
Sulphonylureas Dosage

• Glyburide (Diabeta)dose range 2.5-20 mg, split
  into twice daily. Tablets of 2.5 and 5 mg
  Full ODB Coverage
• Gliclazide (Diamicron) dose range 40-320 mg a
  day, divided into 2 doses. Diamicron MR 30 mg
  from 1-4 tablets, once daily ODB section 8
  if hypoglycemia on Glyburide
• Glimepiride (Amaryl) dose 0.5-4 mg OD Tabs
  0.5, 1 , 2, 4 mg. No ODB coverage

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MEGLITINIDES New Class of Insulin Secretagogues

• Physiologic Reasons
• Insulin secretion must be closely coupled to
  fluctuations in plasma glucose with little or no
  lag time
• Prevents early postprandial hyperglycemia
• Prevents late postprandial hypoglycemia
• Insulin secretion should not be stimulated when
  plasma glucose is low

46
Why is there a Need for New Classes of Insulin
Secretagogues?

• Pharmacologic Reasons
• Chronic sulfonylurea treatment causes
  desensitization of ß-cell insulin secretion
• High secondary failure rate with sulfonylureas

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Therapeutic Need, 1988
In general, older patients have more renal
failure and cardiovascular and hepatic problems,
as well as a tendency to skip meals and snacks.
For this reason, it is best to choose an agent
with relatively short duration of action, which
is less likely to cause profound hypoglycemia.
Physicians Guide to Non-Insulin-Dependent (Type
II) Diabetes. Diagnosis and Treatment (Second
Edition) p.39. ADA-CEP 1984,1988.
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Meglitinides Efficacy Summary

• Rapid response
• Decline in 24-hr mean BG (? 2.2-4.4 mmol/L)
  within 1 week
• Good clinical response
• Improves glucose control D HbA1C 1.6-2.1 (vs
  placebo)
• Glycemic control
• Documented HbA1C reductions sustained over 1 year
• Dose response
• Reductions in mean glucose seen at 0.5-4 mg ac
• Synergistic
• Incremental improvements when used in combination
  with metformin

49
Meglitinides Dosage

• Repaglinide (Gluconorm) 0.5 to 4 mg with each
  meal. Tablets of 0.5, 1.0 and 2 mg ODB
  Section 8 requires hypoglyhcemia on Glyburide
  
• Nateglinide (Starlix) 120 mg with each meal
  
  ODB No Coverage

50
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
2. Muscle and adipose tissue glucose
uptake
1. Intestineglucose absorption
Insulin resistance
Blood glucose
?
4. Liver hepatic glucose output
Insulin resistance
3. Pancreas insulin secretion
Amatruda, Diabetes Mellitus, 1996.
52
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

54
Acarbose Dosage

• Acarbose (Prandase) dose 50-100 mg with the first
  bite of each meal. High
  index of side effects, start low (25 mg OD) and
  titrate up gradually.
• Not very effective for hyperglycemia 0.5 A1c
  reduction.
• ODB Coverage on LU

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Anorexiants Dosage

• Orlistat (Xenical) 120 mg tabs, one with the
  first bite of each meal. Inhibits 30 of dietaryt
  fat absorpton needs to be used with a low fat
  diet. Lifestyle counseling essential. Prevented
  Diabetes in XENDOS study.
• ODB Section 8 with failure of Metformin SU in
  the obese patient
• Sibutramine (Meridia) dose 10 or 15 mg caps OD.
  No ODB Coverage

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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)

58
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

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QUESTIONS?

• www.diabetesclinic.ca