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ORAL AGENTS in T2DM MANAGMENT (OHAs)

If a patient is not optimally controlled by diet and exercise alone, oral hypoglycemic agents (OHA's) are usually the first line of drug therapy in the management of Type 2 diabetes.

DRUG OF CHOICE

Type 2 diabetes is characterized by three basic abnormalities that contribute to the development of hyperglycemia:

A) Impaired insulin secretion by the pancreas;
B) Peripheral insulin resistance; and
C) Excessive glucose production by the liver;

Type 2 patients would have a combination of these three mechanisms which cause the high blood glucose levels. The problem is that the extent and severity of each of these mechanisms varies in different individuals, and the oral agent which would be most optimal for any patient would depend on which of these three mechanism plays a major role in their hyperglycemia.

Although there is no hard and fast rule for this, it is widely accepted that in type 2 patients with low body weight, impaired insulin secretion is the predominant defect, while insulin resistance tends to be less severe than in the obese variety. Insulin resistance and hyperinsulinemia are the classic abnormalities of obese individuals with type 2 diabetes.

All the oral agents available do not have the same mechanism of action. Thus, one must know how a class of oral agent acts in order to choose the appropriate drug.

MAIN GROUPS OF OHAs

Oral Agents commonly used in the Treatment of Type 2 Diabetes

Agent Dose Duration of action Efficacy Major side effects Contraindications
Sulfonylureas

Increase insulin secretion by pancreas;

Metabolizedprimarily liver, excreted by kidney
    Average decrease in FPG 60-80 mg%

Average decrease in HbA1c: 0.8- 2%
Hypoglycemia; abdominal discomfort, nausea in around 1% to 3% patients; hyperacidity, metallic taste or change in taste; weight gain; Significant renal or hepatic dysfunction
Glipizide 2.5-20 mg/day 8-12 hours   Hypoglycemia risk
4-6%
 
Glibenclamide 2.5-20 mg/day 16-24 hours   Hypoglycemia risk
4-6%
 
Gliclazide 80-240mg/day 6-8 hours   Hypoglycemia risk
< 2%
 
Glimepiride 1-8 mg/day 24 hours   Hypoglycemia risk
< 2%
 
 
Biguanides
Decreases hepatic glucose production

Not metabolized, eliminated by kidneys
    Average decrease in FPG 65-75 mg%

Average decrease in HbA1c: 1 - 2%
Gastrointestinal discomfort, especially nausea; metallic taste in mouth, loss of appetite; vitamin B12 deficiency, rarely lactic acidosis; weight loss DKA, alcoholism, renal or hepatic dysfunction; congestive heart failure; acute illness; cardiovascular collapse (shock); acute myocardial infarction;septicemia; acute or chronic metabolic acidosis; respiratory insufficiency;
Metformin 500-1500 mg/ per day with meals 8 hours      
 
Alpha-glucosidase inhibitors

Delays absorption of complex carbohydrates in intestinesNot absorbed systemically
To be taken with first bite of the meal   Average decrease in FPG 25-30 mg%

Average decrease in HbA1c: 0.5 to1%
Abdominal discomfort, bloating, "gas" formation, nausea and diarrhea; liver disease, bowel or intestinal disease, intestinal obstruction
Acarbose 25-100 mg with each meal 4 Hours      
Miglitol 50-100mg. with each meal 4 Hours      
Voglibose 200mg with each meal        
 
Meglitinides

Increases pancreatic insulin secretion

Metabolized in the liver
    Average decrease in FPG 30-40 mg%

Average decrease in HbA1c: 0.5 to 0.7%
Average decrease in FPG 30-40 mg%

Average decrease in HbA1c: 0.5 to 0.7%

Hypoglycemia; gastrointestinal upsets; muscle aches, URTI and flu-like symptoms; body ache;
Type 1 DM; diabetic ketoacidosis, hepatic dysfuntion
Repaglinide 0.5-4 mg with each meal 3 hours      
Nateglinide 60-120 mg with each meal 3 hours      
 
Glitazones

Reduces insulin resistance at cellular level;

Metabolized in the liver
Taken with or without food   Average decrease in FPG 70-80 mg%

Average decrease in HbA1c: 1.5 - 2.5 %
Weight gain, edema;URTI; toothaches; sore throat; body ache; headaches Hepatic dysfunction; CHF, increasing edema
Rosiglitazone 4-8 mg/day 12 hours      
Pioglitazone 15-45 mg/day 24 hours      
Recently, questions have been raised about cardiovascular safety of rosiglitazone and it should be used with added caution. It should not be used in patients with established cardiovascular disease, elderly patients and along with insulin. Although, it is not clear whether this is a class effect of glitazones, it would appear prudent to be extra cautious even with the use of pioglitazone. If pioglitazone is used along with insulin, the dose should not exceed 30mg/day.

Recently, new agents known as incretin mimetics which act by increasing endogenous incretin hormone effects have become available.

For a table on these new class of drugs, see Appendix 5a

Protocols for OHA THERAPY

OHA THERAPY in a RELATIVELY non-obese Type 2 Diabetes patient


Protocol





Recently, questions have been raised about cardiovascular safety of rosiglitazone and it should be used with added caution. Although, it is not clear whether this is a class effect of glitazones, it would appear prudent to be extra cautious even with the use of pioglitazone. Rosiglitazone should not be used along wit insulin. The dose of pioglitazone should not be more than 30mg/day when used along with insulin.

In view of this, metformin may the drug of choice as a sensitizer

Managing the Overweight (Obese) Patient

Protocol

Recently, questions have been raised about cardiovascular safety of rosiglitazone and it should be used with added caution. Although, it is not clear whether this is a class effect of glitazones, it would appear prudent to be extra cautious even with the use of pioglitazone. Rosiglitazone should not be used along wit insulin. The dose of pioglitazone should not be more than 30mg/day when used along with insulin.

In view of this, metformin may the drug of choice as a sensitizer.

Many trials have shown that a 20 mg dose of rimobanant, which is used in the management of obese diabetics, can lead to an average weight loss of approximately 6 kg over a year when accompanied with lifestyle therapies. Importantly, it leads to a decrease in abdominal obesity and improves cardiovascular risk factors. The most common reported side effects include depression, anxiety, and nausea and should not be used in patients on anti-depressives. It is NOT accepted for use by the U.S. FDA.

GENERAL ASPECTS IN OHA THERAPY

Theoretically, most Type 2 patients should be given a trial with diet and exercise for an adequate period (usually 4-6 weeks) before using oral hypoglycemic agents. But practically speaking, patients with fasting blood glucose levels more than 200 mg%, or in patients with significant symptoms, OHA therapy can be started along with diet and exercise. This will allow a more rapid relief of symptoms.

The starting dose should be small as it is not possible to foretell how a patient will respond to the oral agent.

OHA increments must be made in small amounts (half to one tablet at one time) and gradually (every 1-2 weeks), till optimal control is reached.

In many patients, there will be a need to combine two or more oral agents or even insulin therapy with possibly insulin sensitizers.

Combinations of submaximal doses of different classes of OHAs may be equally effective as or more effective than maximum dose of monotherapy in improving glucose control with fewer adverse effects.

Once Optimal Control Is Achieved

Re-enforce importance of diet and exercise;

Efforts must be made to reduce the dose slightly to see if the control is maintained; the rationale for this is to try and obtain the optimal target level for the individual with the smallest possible dose.

Emphasize need or regular follow-ups.



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