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Combination Therapy in Type 2 Diabetes


Combination Therapy for Type 2 Diabetes

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


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)


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


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


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


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 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


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: insulin resistance

• 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


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


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

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


-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


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


Sulfonylureas: mechanism of action


2. Muscle and adipose tissue:glucose uptake

3. Pancreas: Insulin secretionSulfonylureasinsulin secretion

4. Liver: hepatic glucose output

Insulin resistance



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


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


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



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


Changing Therapies to Address Diabetes Progression

Lifestyle Change

Monotherapy Combination oral agents

Insulin + oral agents

Old Paradigm

New Paradigm


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

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