Thiazolidinediones
The thiazolidinedione (TZD) class of oral hypoglycemics ( popularly known as glitazones) was developed in 1997 and offers a new mechanism for treatment of type 2 diabetes. The first, troglitazone was taken off the market in 1999 because of its association with hepatic toxicity. Rosiglitazone and pioglitazone have been available since 1999.

The primary effect of TZDs is peripheral, with increasing insulin sensitivity and increased glucose uptake. The TZDs have some effect on hepatic glucose uptake and sensitivity to a lesser degree. They do not stimulate the pancreas to produce more insulin.

The glitazones work well only when the major factor is insulin resistance. If you have excess abdominal weight ( high waist to hip ratio), low HDL, high triglycerides, or high blood pressure, these would be good indicators that the glitazones would be good for you possibly in association with metformin, or by themselves.

Because they work on insulin resistance, they have their greatest effect on the blood glucose after eating rather than the blood glucose upon waking. These drugs are better absorbed when taken with a meal. They can be dosed once daily, although rosiglitazone works better with twice-daily dosing.

With use of glitazones, patience is required. Blood sugar levels may show a significant reduction statistically in as little as two to four weeks, but the maximum effects are not seen until two or three months have passed.

Although they normally do not cause hypoglycemia when used by themselves, if used in combination with a sulfonylurea or insulin, low blood sugars may occur. Less insulin is required to control blood sugars when glitazones are used so your doctor may reduce the doses of any other diabetes tablets or insulin which you may be taking.

The glitazones are associated with side effects such as water retention and swelling of the ankles, especially in older people. Other possible side effects include weight gain, muscle weakness, and fatigue. Although they have not been shown to cause liver damage, your doctor may ask that you check your liver functions regularly. Call your doctor right away if you have any signs of liver disease, which include nausea, vomiting, stomach pain, lack of appetite, tiredness, yellowing of the skin or whites of the eyes, or dark-colored urine.

If you take birth control pills, glitazones might make your birth control pills less effective in preventing pregnancy.

Glitazones have additional benefits. Besides their effect in lowering the blood glucose levels, both drugs also have notable effects on lipids. The current data show that pioglitazone has a minimal effect on low-density lipoprotein (LDL) cholesterol levels and a favorable effect on high-density lipoprotein (HDL) cholesterol and triglyceride levels. Rosiglitazone has a favorable effect on HDL cholesterol levels but a negative effect on LDL cholesterol levels. They also lead to a slight reduction in the high blood pressure levels.

Meglitinides
Repaglinide and nateglinide are the two drugs which are used in this, the meglitinide group of drugs.

Their action is similar to that of sulfonylureas in the sense that they increase the secretion of insulin from the pancreas and are ineffective if the pancreas does not have enough capacity to secrete insulin.

Then how are they different from the sulfonylureas?
We discussed before that one of the problems in Type 2 diabetes was that there was a lag period between the increase in the blood glucose levels following a meal and the release of insulin from the pancreas. This caused the immediate post meal blood glucose to be very high and also could possibly lead to late hypoglycemia.

The meglitinides are different from the sulfonylureas in that they raise the insulin levels acting on the pancreas but through a different mechanism. This allows more insulin to be secreted earlier, removing the lag period between the rise in the blood glucose levels and the rise in the insulin levels in the blood. They act over a short period of time by increasing first-phase insulin release from the pancreas. They respond to the glucose level, so hypoglycemia is milder and less frequent than with sulfonylureas.

Their peak action of an hour and short duration of action of about three hours is ideal for matching meals.

They are ideally taken 10 to 15 minutes before meals, the dose should be skipped if a meal is skipped.

They can cause low blood sugars, but because they stimulate insulin production only if the blood sugar is high, the risk of lows is reduced. Like sulfonylureas, they do not work in Type 1 diabetes and require beta cells capable of producing insulin. If sulfonylureas have failed to control your blood glucose levels, the meglitinides would rarely be effective.

One difficulty with these medications is identifying those who would benefit from them. Most people do not check their blood sugars after meals to see how high it is going. Those whose blood sugar are spiking more than 40 or 50 mg/dl after meals may benefit from these drugs, so post-meal testing is critical for identifying these individuals. They are ideal for people whose fasting blood sugar is not that high, but whose HbA1c is elevated and whose blood sugars spike after meals so testing at this time is critical.

A minor problem is that people treat when they eat, so doses are taken several times a day and has to use eating as a reminder for taking the medication. Conversely, they are very useful in people who show high post meal levels and also have a very erratic eating timings, as they can be taken just with a meal rather than one having to take the sulfonylurea tablet some time before the meal.

They have been used in combination with metformin and the glitazones with good results.