2003 cda clinical practice guidelines oral agents

www.diabetesclinic.ca

2003 CDA Clinical Practice Guidelines ORAL AGENTS

J. Robin Conway M.D.Diabetes Clinic - Smiths Falls, ON

Options for Diabetes


Kingston April 17 2004


80

70

60

50

40

30

20

10

0

Prevalence (millions)

North America

Europe SoutheastAsia

Year199520002025

World Health Organization. 1997.Canadian Diabetes Association, 1998 website.

Worldwide rates of diabetes mellitus: predictions


Frequency of diagnosed and undiagnosed diabetes and IGT, by age (U.S. data - Harris)

2 Million Canadians Have Diabetes Mellitus

0

5

10

15

20

25

30

35

40

20-34 35-44 45-54 55-64 65-74

% ofpopulation

IGTUndiagnosed diabetesDiagnosed diabetes

Harris. Diabetes Care 1993;16:642-52.

www.diabetesclinic.caHaffner Am J Cardiol 1999;84:11J-4J.

Framingham study: diabetes and CAD mortalityat 20-year follow-up

Cardiovascular Disease Risk is Increased 2 to 4 Times

17.4

8.5

17.0

3.602468

101214161820

Annual CAD Deaths per 1,000

Persons

Men Women

Diabetics Nondiabetics


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 >2 Risk Factors, 79% tested 7% Diabetes , 13% IGT or IFG

74% No Treatment AdviceStrychar I et al. Cdn J Diab 2003(abs)

Leiter et al. Diabetes Care 2000


T2DM in Family Practice

• 84% of patients had A1c in past year

• Average A1c 7.9% (goal<7%)

• 88% had BP check

• 48% had lipid profiles

• 28% tested for microalbuminuria

• 15% had foot examsHarris S et al. Cdn Fam Phys 2003


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


Structured care

• ACLS

• ATLS

• Seattle Defibrillator Experience

• GREACE Study


Structured Care VS Usual Care

Αthyros VG et al. Curr Med Res Opin. 2002;18:220-228.

• 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 pt’s choice• All patients had access to any necessary medications,

including statins• Included lifestyle modifications (diet and exercise) as well

as lipid-lowering medications

Str

uctu

red

Car

e:U

sual

Car

e:


Reduction in Relative Risk of Primary Endpoints

-43

-59

-52 -51 -50-47-47

-60

-50

-40

-30

-20

-10

0Total Mortality

CoronaryMortality Nonfatal MI

UnstableAngina PTCA/CABG CHF Stroke

Αthyros VG et al. Curr Med Res Opin. 2002;18:220-228.

%% R

edu

ctio

n R

edu

ctio

n

PP==00.0021.0021 PP==00.001.00177 PP=0=0.00.001111 PP==00.0.03434PP==00.00.000101 PP==00.00.003232 PP=0=0.0.02121


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

Normal range (considered for patients in whom it can beachieved safely)

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.†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 theirA1C values to DCCT levels (reference range: 0.040 to 0.060). However, as many laboratories continue to use a differentreference range, the target A1C value should be adjusted based on the specific reference range used by the laboratory thatperformed 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 hemoglobinDCCT = Diabetes Control and Complications TrialFPG = fasting plasma glucosePG = plasma glucose


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

• 3 spread out over at least non- consecutive days

• 4 gradually increase to hours or more aweek

• 10 sessions should be at least minutes at a time

B risk walking Biking

Raking leaves Continuous swimming

Dancing Water aerobics

Resistance– all persons with, diabetes including elderly

• 3 times a week • 1 10start with set of-15 repetitions • 2 10progress to sets of-15 • 3 8then sets of

Weight lifting Exercis e with weight machines

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


Nutrition TherapyPeople 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


Drugs in Type 2


9

Hb

A1

c (

%)

UKPDS: Long-term Glucose Control

06

7

8

0 3 6 9 12 15Years of treatment

Conventional

Intensive

ULN = 6.2%

UKPDS Study Group, Lancet, 1998;352:837-853.


06

7

8

9

2 4 6 8 10

A1

C (

%)

Years from randomization

Upper limit of normal = 6.2%

ConventionalGlyburideChlorpropamideMetforminInsulin

0

UK Prospective Diabetes Study Group. UKPDS 34. Lancet 1998; 352:854–865.

Overweight patientsCohort, median values

UKPDS demonstrated loss of glycemic control

with all agents studied


-ce

ll f

un

ctio

n (

%)

Conventional Sulphonylurea Metformin

0

20

40

60

80

100

0 1 2 3 4 5 6 70

20

40

60

80

100

0 1 2 3 4 5 6 7

-ce

ll f

un

ctio

n (

%)

Years from randomization

Non obese Obese

UKPDS 16: Diabetes 1995; 44:1249–1258

Progressive Loss of -cellFunction in UKPDS

Mean age at baseline 53 yrs.


Natural History of Type 2 Diabetes

Normal Impaired glucosetolerance 10 yrs

Type 2 diabetes12-15 yrs

Time

Insulinresistance

Insulinproduction

Glucoselevel

-celldysfunction

Henry. Am J Med 1998;105(1A):20S-6S.

LifestyleMetformin/ThiazolidinedionesMetformin/Thiazolidinediones

SecretagoguesSecretagoguesInsulinInsulin


Sites of Action of Currently Available Therapeutic Options

GLUCOSE ABSORPTION

GLUCOSE PRODUCTION

BiguanidesThiazolidinediones

MUSCLE

PERIPHERAL GLUCOSE UPTAKE

Thiazolidinediones(Biguanides)

PANCREAS

INSULIN SECRETIONSulfonylureasMeglitinides

Insulin

ADIPOSE TISSUE

LIVER

Alpha-glucosidase inhibitors

INTESTINE

Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998;7:551-5.


Combination Antihyperglycemic Therapy

Site of action MOA Agents

Insulin

secretion

Sulfonylureas Meglitanides,

Insulin

Glucose

production Biguanides

Thiazolidinediones

Glucose

absorption Alpha-glucosidase

inhibitors

Peripheral glucose uptake

Thiazolidinediones (Biguanides)

Addition, rather than substitution recommended

Agents from other classes should be added

–Diff sites of action

–Diff MOA


Individualized Treatment

• Metformin for overweight patients

• If control not achieved add another agent

• If A1c >9 start with 2 agents

• Consider early insulin for hyperglycemia

• Bedtime intermediate insulin (NPH)


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 †


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

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

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


Clinical assessment and initiation of nutrition and physical activity


Overweight(BMI 25 kg/m2)

Biguanide alone or incombination with 1 of:• 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 †


Basal and/orpreprandial insulin

Add an oral

antihyperglycemic agentfrom a differentclass of insulin*

If not at targetIf not at target

Intensify insulinregimen or add

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

Non-overweight(BMI 25 kg/m2)

1 or 2† antihyperglycemicagents from differentclasses


If not at target


L

I

F

E

S

T

Y

L

E

If not at target


Add a drug from a different classor

Use insulin alone or in combination with:• biguanide• insulin secretagogue• insulin sensitizer*• alpha-glucosidase inhibitor



•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.

If not at target

Biguanide alone or in combination with 1 of:

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

Overweight (BMI 25 kg/m2)

L

I

F

E

S

T

Y

L

E


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


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 >9%

• Early Insulin if decompensated

• Consider TZD


-2.5

-2

-1.5

-1

-0.5

0

Glyburide

Hb

AH

bA

1C1C (

%)

(%

)

Metformin AcarboseGlitazoneRepaglinide

HbA1C in Diet-Treated PatientsEffects of Various Medications

(Difference from Placebo)(Difference from Placebo)

FDA approved Prescribing Information for various OADs


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

Álpha-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)


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


Need for Combination Therapy in UKPDS

50%

75%

0%

10%

20%

30%

40%

50%

60%

70%

80%

3 years 9 years

% of Patients


Dose-Response Curve

Riddle M. Combining sulfonylureasand other oral agents. Am J of Med2000; 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


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


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


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


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


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


Thiazolidinediones: mechanism of actions

Muscle and

adipose tissue insulin resistance glucose uptake

Liver insulin resistance hepatic glucose

production

Bloodglucose

Pancreas demand for insulin secretion ß-cell insulin content


Thiazolidinediones – Advantages –

• Corrects a primary pathophysiologic impairment: insulin resistance

• Possible once-daily dosing

• Improves Lipids, Lower serum triglyceride

• May be used in renal insufficiency


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


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


Sulfonylureas: mechanism of action


2. Muscle and adipose tissue: glucose uptake

3. Pancreas: Insulin secretionSulfonylureas insulin secretion

4. Liver: hepatic glucose output

Insulin resistance

Insulin resistanceBlood

glucose


Sulfonylureas – Advantages –

• Improve a primary pathophysiologic impairment: insulin secretion

• Physiologic route of insulin delivery

• High initial response rate

• No lag period before response


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


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


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


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


Therapeutic Need, 1988

““In general, older patients have more renal In general, older patients have more renal failure and cardiovascular and hepatic failure and cardiovascular and hepatic problems, as well as a tendency to skip problems, as well as a tendency to skip meals and snacks. For this reason, it is meals and snacks. For this reason, it is best to choose an agent with relatively best to choose an agent with relatively short duration of action, which is less short duration of action, which is less

likely to cause profound hypoglycemia.”likely to cause profound hypoglycemia.”

Physician’s Guide to Non-Insulin-Dependent (Type II) Diabetes. Physician’s Guide to Non-Insulin-Dependent (Type II) Diabetes. Diagnosis and Diagnosis and Treatment (Second Edition) p.39. ADA-CEP 1984,1988.Treatment (Second Edition) p.39. ADA-CEP 1984,1988.


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 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


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


Insulin – Disadvantages –

• Hypoglycemia

• Weight gain

• Need for injections

• Non-physiologic route of administration (peripheral)

• Patient and physician non-acceptance


Alpha-Glucosidase inhibitors mechanism of action

Amatruda, Diabetes Mellitus, 1996.

Insulin resistance


2. Muscle and adipose tissue: glucose

uptake

3. Pancreas: insulin secretion

4. Liver: hepatic glucose output

Insulin resistanceBlood glucose


Alpha-Glucosidase Inhibitors – Advantages –

• Good safety profile

• No weight gain or modest weight loss

• Dose coupled to meals


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


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


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


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


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%)


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


QUESTIONS?www.diabetesclinic.ca

2003 cda clinical practice guidelines oral agents

Documents

diabetes control

diabetes mellitusfrequency

undiagnosed diabetes

diabetes care 2000t2dm

canadian diabetes association

diabetes quebec screening

diabetes clinic smiths

a1c target