Combination Therapy in Type 2 Diabetes

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Combination Therapy for Type 2 Diabetes J. Robin Conway M.D.

Diabetes Clinic Smiths Falls, ON www.diabetesclinic.ca

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Lifestyle

Natural History of Type 2 Diabetes

Metformin/Thiazolidinediones Secretagogues Insulin Insulin resistance Glucose level Insulin production Normal Impaired glucose

b

-cell dysfunction Type 2 diabetes Time tolerance

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Henry.

Am J Med

1998;105(1A):20S-6S.

Oral Agents for Type 2 Diabetes

Class

Αlpha-glucosidase inhibitor Biguanide Insulin Insulin secretagogues Insulin sensitizers (TZDs) Combined rosiglitazone and metformin

Expected decrease in A1C with monotherapy

0.5 – 0.8 1.0 – 1.5 Depends on regimen 1.0 – 1.5 0.5 for nateglinide 1.0 – 1.5 1.0 – 1.5 Antiobesity agent (orlistat) 0.5 •

more rapid improvement of blood glucose

• Counsel patients about hypoglycemia prevention and treatment

SMBG is recommended at least once daily

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Canadian Diabetes Association 2003

Clinical assessment and initiation of nutrition and physical activity Mild to moderate hyperglycemia (A1C <9.0%) Marked hyperglycemia (A1C



9.0%) Overweight (BMI



25 kg/m 2 ) Biguanide alone or in combination with 1 of:

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

Non-overweight (BMI



25 kg/m 2 ) 1 or 2 † antihyperglycemic agents from different classes

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

2 antihyperglycemic agents from different classes †

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

Basal and/or preprandial insulin If not at target If 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 with:

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

Add an oral antihyperglycemic agent from a different class of insulin* 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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Intensify insulin regimen or add

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

•

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

BMI  25 Biguanide alone or in combination < 9% BMI < 25 1 or 2 agents from different classes  9% - 2 agents from different classes or insulin basal and/or preprandial www.diabetesclinic.ca

Intensify to reach targets in 6-12 months

Targets for Glycemic Control

Target for most patients

A1C (%)

 7.0 Normal range (if it can be safely achieved)  6.0

FPG/preprandial (mmol/L)

4.0 – 7.0 4.0 – 6.0

2h Postprandial (mmol/L)

5.0 – 10.0 5.0 – 8.0

* 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

Need for Combination Therapy in UKPDS

% of Patients

80% 70% 60% 50% 40% 30% 20% 10% 0%

50% 75%

3 years 9 years

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2.0

1.5

1.0

0.5

0 0 500 1000 Dose 1500 2000 2500 30 20 10

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Riddle M. Combiningsulfonylureas and other oral agents. .

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: www.diabetesclinic.ca

insulin or insulin analogues

Biguanides: mechanism of action

1. Intestine: glucose absorption 2.

Muscle and adipose tissue: glucose uptake Metformin



glucose utilization 4. Liver: hepatic glucose output Metformin



HGO Blood glucose Insulin resistance Insulin resistance 3. Pancreas: insulin secretion

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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 www.diabetesclinic.ca

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 www.diabetesclinic.ca

Thiazolidinediones: mechanism of action

Blood glucose Liver



insulin resistance



hepatic glucose production Muscle and adipose tissue



insulin resistance



glucose uptake 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 www.diabetesclinic.ca

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 www.diabetesclinic.ca

UKPDS demonstrated loss of glycemic control with all agents studied 9 8 7 6 0 0 2 4 6 8 Years from randomization UK Prospective Diabetes Study Group. UKPDS 34.

Lancet

1998; 352:854 –865.

Conventional Glyburide Chlorpropamide Metformin Insulin

Upper limit of of normal = 6.2% 10 Overweight patients Cohort, median values

*

p<0.05

Sulfonylurea Study - Long-term Mean Changes in HbA1C from Baseline

0 (n=157) 0 16 (n=151) Weeks 28 (n=141) 40 (n=133) -0.5

-1 -1.5

-2 * Double-blind phase * Pioglitazone 30 mg plus SU * Open-label phase

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Hanefeld M et al. Exp Clin Endocrinol Diabetes 2000;108 (suppl 2):S256-66

Metformin Study - Open Label Extension

-0.8

-1 -1.2

-1.4

0 end of DB STUDY -0.2

-0.4

-0.6

-1.6

Change in HbA1c (%)

week 24 week 48 week 72 0 -0.5

-1 -1.5

-2 -2.5

-3 -3.5

Hb1c fasting glucose -4 www.diabetesclinic.ca

Change in fasting glucose (mmol/L)

Einhorn et al. Clin Therapeutics 2000;12:1395-1409

Sulfonylureas: mechanism of action

1. Intestine: glucose absorption 2. Muscle and adipose tissue: glucose uptake Blood glucose Insulin resistance 4. Liver: hepatic glucose output Insulin resistance

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3. Pancreas: Insulin secretion Sulfonylureas



insulin secretion

Sulfonylureas - Advantages

• Improve a primary pathophysiologic impairment: insulin secretion • Physiologic route of insulin delivery • High initial response rate • No lag period before response www.diabetesclinic.ca

Sulfonylureas - Disadvantages

• Hypoglycemia – may be prolonged or severe • Weight gain • Drug interactions (especially 1 st generation) • Hyponatremia (with chlorpropamide) • Cannot use if allergic to sulfa compounds www.diabetesclinic.ca

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 www.diabetesclinic.ca

Insulin - Disadvantages

• Hypoglycemia • Weight gain • Need for injections • Non-physiologic route of administration (peripheral) • Patient and physician non-acceptance www.diabetesclinic.ca

Alpha-Glucosidase inhibitors: mechanism of action

1. Intestine: glucose absorption 2. Muscle and adipose tissue: glucose uptake 4.

Liver: hepatic glucose output Blood glucose Insulin resistance Insulin resistance

Amatruda, Diabetes Mellitus, 1996.

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3.

Pancreas: insulin secretion

Alpha-Glucosidase Inhibitors -

Advantages • Good safety profile • No weight gain or modest weight loss • Dose coupled to meals www.diabetesclinic.ca

Alpha-Glucosidase Inhibitors -

Disadvantages • Modest effect on fasting plasma glucose and HbA 1C • Flatulence, gastrointestinal side effects • Cannot treat hypoglycemia with sucrose, maltose, or starch – use glucose, fructose, or lactose www.diabetesclinic.ca

Changing Therapies to Address Diabetes Progression

Old Paradigm

Lifestyle Change Monotherapy Combination oral agents Insulin + oral agents

New Paradigm www.diabetesclinic.ca

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 www.diabetesclinic.ca

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

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(HbA 1c <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 factor for cardiovascular disease