Type 2 Diabetes: Avandia and Other Oral Medications

Unlike type 1 diabetes, the initial management of the type 2 form of the disease is not dependent on insulin. Due to the different pathology of the type 2 diabetes, the management of this condition revolves around a strict regimen of exercise and diet (non-pharmacological means) and agents that aid insulin sensitivity (pharmacological methods). Another fundamental difference between the treatment of type 1 and type 2 diabetes is the availability of oral hypoglycemic drugs to treat the latter condition.

An important landmark study provided valuable insights into the management of type 2 diabetes. The United Kingdom Prospective Diabetes Study (UKPDS) was the largest and longest study of type 2 diabetes ever conducted. The UKPDS recruited 5,102 patients with newly diagnosed type 2 diabetes in 23 centers around the U.K. between 1971 and 1991. The patients were followed for an average of 10 years. Numerous reports have been published from the study and a full list of these are given on the UKPDS website (http://www.dtu.ox.ac.uk/ukpds).

One of the primary aims of the study was to determine whether intensive use of oral medication to lower blood glucose levels would reduce diabetic complications. One significant observation to come from the UKPDS is the progressive nature of type 2 diabetes. In the course of the study, an increase in the dose of oral medication was often required. Additionally, combined therapy or additional insulin therapy was necessary in many of the patients as the study progressed.

There are several classes of oral hypoglycemic agents available for the treatment of type 2 diabetes. The leading categories are sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones (glitazones), pyramidal glucose regulators and glinides. The sulfonylureas, biguanides and alpha-glucosidase inhibitors are established hypoglycemic agents, while the glitazones and pyramidal glucose regulators are new classes of oral agents.

Sulfonylureas. Sulfonylureas were the first oral hypoglycemic drugs to become clinically available for the treatment of type 2 diabetes. These agents lower blood glucose by stimulating the pancreatic beta cells to secrete insulin. Sulfonylureas bind to the outer membrane of the beta cell and trigger a series of biochemical messengers to release insulin. Sulfonylureas are only effective when there is sufficient beta cell function. A common side effect of these agents is hypoglycemia, especially if the patient does not eat during the medication.

Biguanides. Biguanides were the next oral agents to be introduced. They came to be chosen as first-line treatment in obese type 2 diabetics. They reduce blood glucose levels by increasing the sensitivity of cells to insulin, thus promoting the uptake and storage of glucose. Biguanides also act directly on the liver to reduce the formation and release of glucose into the blood.

Alpha-glucosidase inhibitors. Alpha-glucosidase enzymes help to break down complex carbohydrates prior to the absorption in the small intestine. Alpha-glucosidase inhibitors block the activity of these enzymes, thus reducing the amount of glucose absorbed. Consequently, the surge of blood glucose levels normally seen after a meal is delayed and is smaller than usual.
Thiazolidinediones (glitazones). Glitazones are the newest established class of oral hypoglycemic agents. Their mechanism of action involves potentiation of insulin, thereby increasing glucose uptake and decreasing glucose output from the liver. It has been suggested that glitazones act by stimulating the PPAR-gamma isoform, which modulates the transcription of several insulin responsive genes involved in the control of glucose and lipid metabolism. The first glitazone was Warner-Lambert's Rezulin (troglitazone); it had to be withdrawn because of liver toxicity problems, and this had an inhibitory effect on uptake of the next glitazone products to be launched, by Eli Lilly/Takeda and Glaxo SmithKline.

Pyramidal glucose regulators. Pyramidal glucose regulators are another new class of oral anti-diabetes drugs. They stimulate the release of insulin from the beta cells but, unlike the sulfonylureas, they do not inhibit protein synthesis in the beta cells. In addition, pyramidal glucose regulators have the advantage of a quick onset and short duration of action. Therefore, if these agents are taken a sufficient time before a meal, glucose levels rise soon after eating and return to basal levels between meals, thereby mimicking the normal insulin regulation.

The exhibit below lists the main types of oral diabetes treatments, and leading brands.

Source: MedMarket Diligence, LLC; Report #D510, "Diabetes Management Worldwide."