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GUIDELINES ON THE USE OF ORAL DRUG TREATMENT FOR TYPE 2 DIABETES (April 2007)

Introduction:

The prevalence of type 2 diabetes mellitus is increasing all over the world, especially in Asia¹. Both insulin deficiency and resistance contribute to the development of hyperglycaemia². Numerous studies prove that good glycaemic control can reduce diabetic microangiopathy and probably also macroangiopathy^3,4.

Diet and lifestyle modifications, such as exercise and weight reduction, are important steps for the control of hyperglycaemia, but most patients require oral anti-diabetic drugs (OAD)*, either as monotherapy or in combination, in order to attain target blood glucose level.

Several new OADs have been approved in recent years, so that more options are now available.

Currently there are 5 different classes of effective OAD (table 1), which differ in their modes of actions, pharmacokinetic and pharmacodynamic properties, side effect profiles, clinical effectiveness (monotherapy or in combination with others) and extra-glycaemic effects.

1. Drug initiation and monotherapy

1. Diabetes education should be given once the patient is diagnosed to have type 2 diabetes. This includes diet and lifestyle modification and self-monitoring of glucose^5-7 (refer to DHK Position Statement 2).

2. OAD should be initiated if the patient fails to attain target blood glucose level (refer to DHK Position Statement 3) after diet and lifestyle modification within three months. Nevertheless, early initiation should be considered if the patient is found to be symptomatic, has high blood glucose (random 14 mmol/L or HbA1c > 8.5%) or diabetic complications during the consultation.

3. Metformin, an insulin sensitizer that reduces hepatic glucose output, should be considered as first-line therapy especially in overweight patients (BMI 23) in order to have less weight gain, less hypoglycaemia and less long term DM morbidity and mortality^8,9. Side effects like diarrhea and abdominal discomfort, though common¹⁰, can often be alleviated by slow dosage titration. Use of metformin should be avoided in patients whose serum creatinine is higher than 150 μmol/L¹¹ or who have significant heart or liver failure, since lactic acidosis may be more common in these groups^12,13. Metformin should also be stopped during the peri-operative period and before contrast study.

4. SU bind to the sulphonylurea receptor subtype 1 (SUR-1) in islet cells and stimulate insulin secretion. The major side effects of SU are weight gain and hypoglycaemia (particularly with chlorpropamide and glibenclamide) especially in the elderly and in those with renal and liver disease. They are also contraindicated in patients with sulphonamide allergy. Thus, SU should usually be used as second -line agents.

5. TZD (Rosiglitazone & Pioglitazone) act on the specific nuclear receptors peroxisome proliferator-activated receptors gamma subtype (PPARγ) and target against insulin resistance¹⁴. They decrease HbA1c by approximately 1-2%, and do not cause hypoglycemia. Recent studies suggest potential beneficial non-glycaemic effects like reduction of inflammatory markers and progression of intima-media thickness of common carotid artery^15,16, as well as more sustainable glycaemic control¹⁷ . Side effects like weight gain and fluid retention are common but clinically significant heart failure and liver failure are rare. TZD should not be used in patients who have heart failure¹⁸ (NYHA class 3 and 4) or active liver diseases

6. Meglitinides (Repaglinide) and alpha-glucosidase inhibitor (Acarbose) may be advantageous if post-prandial hyperglycaemia is the main problem^19-21. Meglitinides are short acting insulin secretagogues which can be used in patients who have sulphonamide allergy, and hypoglycaemia may be less frequent than SU. Alpha-glucosidase inhibitor reduces carbohydrate absorption and should be taken at the beginning of each meal to maximize its effect. Gastrointestinal side effects like flatulence, bloating, abdominal discomfort and diarrhea are common (up to 30%). It is contraindicated in patients who have a history of intestinal obstruction, inflammatory bowel diseases, colonic ulceration, liver cirrhosis or chronic renal failure.

7. At present, OADs are not recommended in pregnancy and lactation.

Recommendations:

• Initiate OAD if lifestyle modification fails or in the presence of symptoms, significant hyperglycaemia or diabetic complications.

• In selecting OAD, attention should be paid to cost-effectiveness, efficacy, safety, compliance and patient’s preference.

• Metformin should be initiated as first line treatment, particularly in overweight patients unless contraindicated.

• TZD can be an effective alternative in patients intolerant to metformin.

• SU can achieve more rapid glycaemic control but with significant risk of hypoglycaemia.

• Meglitinides or alpha-glucosidase inhibitor may be advantageous if post-prandial hyperglycaemia is the main problem.

2. Combination therapy

8. If monotherapy fails to achieve the target HbA1c within two to three months, one should add another class of oral drug , except that the combination of SU and Meglitinides is unlikely to be useful, because of similar mechanisms of actions.

9. The combinations of metformin, TZD and SU have been shown to be useful^22-25 However, this regimen tends to be more costly and less effective than addition of insulin.

10. If oral drug combinations fail, insulin should be started early. Please consider referral to specialists for initiation of insulin treatment.

Recommendations:

• TZD, sulphonylureas or insulin should be added when metformin alone is not able to achieve the therapeutic target HbA1c.

• If two oral drug combinations failed to achieve target glucose control, insulin should be started. Combination of three oral drugs may be considered as an alternative.

3. Treatment adherence

11. It is important to realize that the treatment benefits of OAD may be limited by a lack of compliance. Studies show that the treatment adherence of OAD is only 65 to 85%^{26, 27}. Factors influencing compliance like comprehension and understanding of regimen and side effects, and perception of benefits should be well-addressed.

Recommendations:

• The compliance of patients taking OAD should be enhanced and monitored through education and improvement of provider-patient relationship.

4. Special consideration²⁸

12. In patients with decompensated diabetes such as FBG > 14 mmol/L, random blood glucose level > 17 mmol/L, HbA1c > 10% or in the presence of significant ketonuria, insulin therapy is the treatment of choice. Please consider referring the patient for specialist care.

* Oral anti-diabetic drug (OAD) is equivalent to oral hypoglycaemic agent (OHA)

Those who are interested in further reading could refer to the following websites:

IDF Global Guideline for Type 2 Diabetes: http://www.idf.org/home/index.cfm?node=1457
ADA Clinical Practice Recommendation 2007: http://www.diabetes.org/for-health-professionals-and-scientists/cpr.jsp

Table 1: Summary of the characteristics of different oral hypo-glycemic agents

References:

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