b. Thiazolidinediones -  Drugs of this class of antihyperglycemic agents sensitize peripheral tissues to insulin. They bind a nuclear receptor called peroxisome proliferator-activated receptor gamma (PPAR-γ) and affect the expression of a number of genes and regulate the release of the adipokines - resistin and adiponectin - from adipocytes. Adiponectin secretion is stimulated, which sensitizes tissues to the effects of insulin, and resistin secretion is inhibited, which reduces insulin resistance. Observed effects of thiazolidinediones include increased glucose transporter expression (GLUT 1 and GLUT 4), decreased free fatty acid levels, decreased hepatic glucose output, and increased differentiation of preadipocytes into adipocytes. Like the biguanides, this class of drugs does not cause hypoglycemia. Troglitazone, the first drug in this class to go into widespread clinical use, has been withdrawn from clinical use because of drug-associated fatal liver failure.

Two other drugs in the same class are available for clinical use: rosiglitazone and pioglitazone. Both are effective as monotherapy and in combination with sulfonylureas or metformin or insulin. When used as monotherapy, these drugs lower HbA1c by about 1 or 2 percentage points. When used in combination with insulin, they can result in a 30-50% reduction in insulin dosage, and some patients can come off insulin completely. The combination of a thiazolidinedione and metformin has the advantage of not causing hypoglycemia. Patients inadequately managed on sulfonylureas can do well on a combination of sulfonylurea and rosiglitazone or pioglitazone. About 25% of patients in clinical trials fail to respond to these drugs, presumably because they are significantly insulinopenic.

The thiazolidinediones not only lower glucose but also have effects on lipids and other cardiovascular risk factors. Rosiglitazone therapy is associated with increases in total cholesterol, LDL-cholesterol (15%), and HDL-cholesterol (10%). There is a reduction in free fatty acids of about 8-15%. The changes in triglycerides were generally not different from placebo. The increase in the LDL-cholesterol need not necessarily be detrimental - studies with troglitazone showed that there is a shift from the atherogenic small dense LDL particles to larger, less dense LDL particles. Pioglitazone in clinical trials lowered triglycerides (9%) and increased HDL-cholesterol (15%) but did not cause a consistent change in total cholesterol and LDL-cholesterol levels. A prospective randomized comparison of the metabolic effects of pioglitazone and rosiglitazone on patients who had previously taken troglitazone showed similar effects on HbA1c and weight gain. Pioglitazone-treated subjects, however, had lower total cholesterol, LDL-cholesterol, and triglycerides when compared with rosiglitazone. The thiazolidinediones have also been demonstrated to decrease levels of plasminogen activator inhibitor type 1, matrix metalloproteinase 9, C-reactive protein, and interleukin 6. Small prospective studies have also demonstrated that treatment with these drugs lead to improvements in the biochemical and histologic features of nonalcoholic fatty liver disease. These effects make these drugs particularly beneficial for patients with the metabolic syndrome. The thiazolidinediones also may limit vascular smooth muscle proliferation after injury, and there are reports that troglitazone and piogliotazone reduce neointimal proliferation after coronary stent placement. Also, in one double-blind, placebo-controlled study, rosiglitazone was shown to be associated with a decrease in the ratio of urinary albumin to creatinine excretion.

Anemia occurs in 4% of patients treated with these drugs, but this effect may be due to a dilutional effect of increased plasma volume rather than a reduction in red cell mass. Weight gain occurs especially when the drug is combined with a sulfonylurea or insulin. Edema occurs in about 3-4% of patients receiving monotherapy with rosiglitazone or pioglitazone. The edema occurs more frequently (10-15%) in patients receiving concomitant insulin therapy and may result in congestive heart failure. The drugs are contraindicated in diabetic individuals with New York Heart Association class III and IV cardiac status. Rosiglitazone has recently been reported as being associated with new onset or worsening macular edema. Apparently, this is a rare side effect and most of these patients also had peripheral edema. The macular edema resolved or improved once the drug was discontinued. The dosage of rosiglitazone is 4-8 mg daily and of pioglitazone 15-45 mg daily, and the drugs do not have to be taken with food. Rosiglitazone is primarily metabolized by the CYP 2C8 isoenzyme and pioglitazone is metabolized by CYP 2C8 and CYP 3A4.

These two agents have so far not (unlike troglitazone) caused drug-induced hepatotoxicity. The FDA has, however, recommended that patients should not initiate drug therapy if there is clinical evidence of active liver disease or the alanine aminotransferase (ALT) level is 2.5 times greater than the upper limit of normal. Obviously, caution should be used in initiation of therapy in patients with even mild ALT elevations. Liver function tests should be performed prior to initiation of treatment and periodically thereafter.