LONG TERM BENEFITS OF ORAL AGENTS

J. Robin Conway M.D.Diabetes ClinicSmiths Falls, ONwww.diabetesclinic.ca

Long Term Benefits of Oral Agents

Robin Conway M.D.

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

spread out over at least 3 non-consecutive days

gradually increase to 4 hours or more a week

sessions should be at least 10 minutes at a time

Brisk walking Biking Raking leaves Continuous swimming Dancing Water aerobics

Resistance – all persons with diabetes, including elderly

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

Weight lifting Exercise with weight machines

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

Nutrition Therapy

People 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

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

Clinical assessment and initiation of nutrition therapy and physical activity

Mild to moderate hyperglycemia (A1C<9.0%) Marked hyperglycemia (A1C 9.0%)

Basal and/or preprandial

insulin

Non-overweight Overweight 2 antihyperglycemic agents from different

classes1 or 2

antihyperglycemic agents from different

classes

Biguanide alone or in

combination

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

Add a drug from a different class or use insulin alone or in combination

Add an oral antihyperglycemic agent from a different class or

insulin

Intensify insulin regimen or add

antihyperglycemic agents

Management of Hyperglycemia in Type 2 Diabetes Patients

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

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

Burden of Poor Control - Cost

45004700490051005300550057005900610063006500

6 7 8 9 10

HbA1c

cost

/pat

ien

t/ye

ar

Diabetes only Diab, HT, Heart dis

Burden of Poor Control - Cost

Estimate annual cost to health plans by level of glycemic control

Determine effect of Improved Glycemic Control on Health Care Utilization and Costs

4500

9500

14500

19500

24500

6 7 8 9 10

HbA1c

cost

/pat

ien

t/ye

ar

Diabetes only Diab, HT, Heart dis

Meltzer et al CMAJ 1998;159(Suppl):S1-29.

Oral Antihyperglycemic Agents: Biguanides

• Decreases hepatic glucoseproduction, enhances peripheral glucose uptake

– May reduce insulin resistance in the periphery

– e.g., Metformin

– Contraindicated in renal/hepatic insufficiency

– May cause GI side effects

– Not associated with hypoglycemia, may promote weight loss

MUSCLELIVER

Plosker, Faulds Drugs 1999;57:410-32. Balfour, Plosker Drugs 1999;57:921-30.

MUSCLE

ADIPOSE TISSUE

LIVER

Oral Antihyperglycemic Agents: Thiazolidinediones (TZDs)

• Decrease insulinresistance– Increase insulin-dependent

glucose disposal, decrease hepatic glucose production– e.g., Pioglitazone, rosiglitazone– Pioglitazone has a positive effect on lipids– Not associated with hypoglycemia– Possible URI, headache, edema, weight gain and

reduction in hemoglobin

TZD

INSULIN

RECEPTOR

RNADNA

Saltiel, Olefsky Diabetes 1996;45:1661–9.

Thiazolidinediones: Mechanism of Insulin Sensitization

TZD

PPAR

INSULIN

GLUT-4

GLUCOSE

Durability of Glycemic Control with Pioglitazone Long Term

7.5

8

8.5

9

9.5

10

10.5

baseline endpoint week 12 week 24 week 36 week 48 week 60 week 72

rollover placebo

rollover pioglitazone

Einhorn D et al. Diabetes 2001;50 (suppl2):A111

Hb

A1c

(%

)

Metformin & Pioglitazone 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

Oral Antihyperglycemic Agents: Sulfonylureas

• Stimulate pancreatic insulin release

– e.g., First-generation: tolbutamide, chlorpropamide, acetohexamide

– e.g., Second-generation: Glyburide, gliclazide

– Secondary failure a problem– Weight gain, risk of hypoglycemia

Meltzer et al CMAJ 1998;159(Suppl):S1-29.

PANCREAS

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.

Oral Antihyperglycemic Agents: Alpha-glucosidase inhibitors

• Slows gut absorptionof starch and sucrose

– Attenuates postprandial increases in blood glucose levels

– e.g., Acarbose – GI side effects– Not associated with hypoglycemia or weight

gain

Salvatore, Giugliano Clin Pharmacokinet 1996;30:94-106.

INTESTINE

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

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

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