Type 2 patients that one sees in practice 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 lean type 2 patients, 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.

Before, we discuss the modalities of how to manage a patient using an oral agent, it would be worthwhile to understand the types of oral agents available for use.

MAIN GROUPS OF OHAs

SULFONYLUREAS

The sulfonylureas have been available since the 1950s and have historically been the first line of pharmacologic therapy for diabetes.

During World War II, French scientists working on the antibiotic potential of modified sulfonamides found that the mice that they were experimenting upon died unexpectedly. Such unexplained deaths also occurred amongst a few of the soldiers who had been administered these modified sulfonamides as an antibiotic. On closer examination, the cause of the deaths was found to be due to hypoglycemia. Unfortunately, in the milieu of the war scene, this effect of the sulfonamides was not paid much attention to and it was only as late as 1955 that the first oral sulfonylurea, carbutamide, was first introduced in the market as an oral hypoglycemic agent. The following year, tolbutamide and chlorpropamide were also introduced. In later years, the so-called "second generation" sulfonylureas, glibenclamide and glipizide amongst them, were brought into the market. Relative late comers on the sulfonyurea scene are gliclazide and glimepiride.

The sulfonylureas are often classified as belonging to the first or second generation. The first generation sulfonylureas are rarely used now.

Sulfonylureas work primarily by stimulating pancreatic insulin secretion, which in turn reduces hepatic glucose output and increases peripheral glucose disposal. There is some evidence that the newer sulfonylureas such as gliclazide and glimepiride may also have some action in reducing insulin resistance.

Biguanides

The precursors of the biguanides have been around for much longer. Way back in 1918, guanidine derivatives were used as oral hypoglycemic agents. Synthalin A, a homologue of guanidine, continued to be used for many years and would have been still more frequently used if insulin had not become available for routine use. Synthalin A is the precursor of the modern day biguanides, two of which are commonly used here being phenformin and metformin. Although some doctors continue to use phenformin, it's use has declined to such an extent that for most purposes, when one takes of biguanides, one is usually referring to metformin.

Metformin works primarily by inhibiting hepatic glucose production and improving insulin sensitivity. It does not stimulate insulin secretion from the pancreas and, when used alone, does not cause hypoglycemia or hyperinsulinemia. Metformin may increase glucose utilization in peripheral tissues to a lesser degree, by decreasing insulin resistance in muscle cells. Metformin may also improve glucose levels by reducing intestinal glucose absorption. Metformin should be started with a single daily dose of 500 mg, taken with a meal. The patient's response to therapy can be checked at one- to two-week intervals and will guide how the dosage should be increased. Metformin dosage can be increased by one tablet (500 mg) per day at one- to two-week intervals until glycemic control is obtained or a total daily dose of 2,000 mg is reached. The maximal daily dosage should not exceed 2,550 mg; most patients get little additional benefit from dosages of more than 2,000 mg per day.

Alpha-Glucosidase Inhibitors

Acarbose is an alpha-glucosidase inhibitor that slows down the breakdown of disaccharides and polysaccharides and other complex carbohydrates into monosaccharides. The enzymatic generation and subsequent absorption of glucose is delayed and the postprandial blood glucose values, which are characteristically high in patients with type II diabetes, are reduced with acarbose. AGIs do not prevent the absorption of carbohydrates and complex sugars, but they do delay their absorption.

Delaying the absorption of carbohydrates is a unique mechanism among oral diabetic medications for lowering HgbA1c levels. The effectiveness of this mechanism is one of the physiologic characteristics of type 2 diabetes. Patients with type 2 diabetes demonstrate a delayed or sluggish insulin response from the pancreas to a glucose (a meal) load. By delaying the absorption of glucose, the insulin response is more matched to the serum glucose, resulting in less postprandial hyperglycemia and a lowering of the HbA1c. The AGIs also demonstrate a lowering of total insulin output of the pancreas, increased insulin sensitivity, a variable but mild decrease in triglycerides, with no effect on patient weight.

One disadvantage with the use of acarbose is that it is to be taken along with the first bite of a meal. Moreover, it has to be taken three times daily with meals. These factors often lead to non compliance and a decrease in the efficacy of the drug. Acarbose may be started at 25 mg three times daily, taken at the beginning of each main meal. The dosage can be adjusted at four- to eight-week intervals. The maximal recommended dosage is 100 mg three times daily (50 mg three times daily if the patient's body weight is 132 lb [60 kg] or less).

Meglitinides

Repaglinide from the meglitinide drug class, acts like an extremely short-acting SU (an insulin secretagogue) and is potentially useful as a SU replacement. The effect of repaglinide on the pancreas is very similar to that of the SUs. Repaglinide, like the SUs, blocks the potassium channels on the pancreatic islet beta-cells, which causes an influx of calcium into the cell and increasing the secretion of insulin. There appears to be 2 similar potassium channels on islet beta-cells, one of which is predominantly affected by repaglinide and the other is predominantly affected by SUs.

The repaglinide-affected potassium channel appears to be glucose dependent, which may partially explain why repaglinide is associated with a much lower incidence of hypoglycemia.

What makes repaglinide clinically different from the SUs is its ultra-short half-life (1 hour). Repaglinide is taken just before or with meals, and the stimulation of the pancreas is limited only to a brief time around meals. Because of the short duration, the patient does not have continuous high levels of insulin and the resulting adverse effects.

Its biggest advantage over the other oral hypoglycemic medications is that it allows for flexible timing and missed meals.

Repaglinide stimulates the release of insulin from the pancreatic beta cells by closing ATP-sensitive potassium channels. It is rapidly absorbed, allowing for a rapid onset of action. It was found to be three to five times more potent in stimulating insulin release than the sulfonylurea glibenclamide. However, it does not stimulate the release of insulin in the absence of glucose. Repaglinide augments the early insulin response and decreases prandial and postprandial glucose excursions.

Repaglinide's rapid onset and short duration of action make multiple daily doses necessary. The physician can often turn this characteristic to good use by instructing patients to take repaglinide immediately before each meal. This approach is especially useful for patients who eat at irregular hours or sometimes skip meals altogether. For patients who are just beginning treatment with oral medications or whose HbA1c is less than 8 percent, the recommended starting dose is 0.5 mg taken 15 minutes before each meal. For patients who have previously been receiving oral medication for diabetes and who have an HbA1c of 8 percent or more, a starting dose of 1 or 2 mg taken 15 minutes before each meal is recommended. The maximal recommended dosage is 4 mg per meal, for a maximum of four meals (16 mg) a day. If a patient skips a meal, he or she should not take the tablet. If a patient adds a meal, a tablet should be added for that meal.