Several new drugs have become available for the treatment of type 2 diabetes mellitus in the past few years, and among them the thiazolidinediones are probably the most promising and interesting. Their mechanism of action involves a reduction in insulin resistance while simultaneously improving some of the independent risk factors for cardiovascular disease frequently found in patients with type 2 diabetes mellitus. On the other hand, while they might have many advantages over the other available antihyperglycemic agents, there are still some concerns about their long-term safety. Consequently, while awaiting the results of the planned long-term cardiovascular outcome studies, which will help establish their true benefits and risks, physicians must remain skeptical about these drugs and consider not only their claimed advantages, but also their not-so-well-publicized risks. This article summarizes the known and/or presumed beneficial and toxic effects of these drugs.

Introduction

It is well accepted that the most important reason to treat type 2 diabetes mellitus aggressively is to prevent its chronic complications, both microvascular and macrovascular. It is also well known that the plasma glucose levels are causally and directly related to the microvascular complications (retinopathy, nephropathy, and neuropathy), and that the treatment of hyperglycemia, aimed at obtaining near-normoglycemia, prevents (or at least slows down) the progression of these complications, independent of the glucose-lowering agent used.[1-3]

Although these microvascular complications cause significant morbidity and cost, it is the macrovascular complications (coronary artery disease, cerebrovascular disease and peripheral vascular disease) that cause most of the excess mortality in patients with type 2 diabetes mellitus when compared with the rest of the population. The macrovascular complications are also responsible for a significant amount of morbidity and cost.[4-6] Moreover, the prevention of these macrovascular complications, particularly coronary artery disease, is not as simple as prevention of the microvascular complications. Although some evidence suggests that strict glycemic control does have a beneficial effect in terms of reduction of cardiovascular events, this benefit seems to be small.[3]

Consequently, to date, the prevention of the macrovascular complications in patients with type 2 diabetes mellitus is based on an aggressive approach to the modifiable, traditional risk factors for cardiovascular disease frequently present in these patients (ie, dyslipidemia, obesity, hypertension, and smoking). Furthermore, although several other potentially independent risk factors for the development of cardiovascular disease in these patients have recently been identified -- eg, Lp(a) lipoprotein, homocysteine, plasminogen activator inhibitor (PAI-1), fibrinogen, C-reactive protein, microalbuminuria, and others -- we have had few, if any, means to modify them.

Fortunately, in the past few years, the Food and Drug Administration (FDA) has approved several new drugs for the treatment of hyperglycemia in patients with type 2 diabetes mellitus. The most promising of these are the thiazolidinediones (TZDs), since evidence suggests that they might have a direct beneficial effect on several of these cardiovascular risk factors, traditional and novel, independent of their hypoglycemic effects. In this review, we summarize the accumulated scientific evidence to date regarding these therapeutic agents (Table). For logical reasons, we only use human studies for evidence when discussing their potential benefits, but we include both human and animal studies when reviewing their potential toxicity.

Thiazolidinediones

The TZDs are a new class of oral hypoglycemic agent. Currently, the only 2 drugs of this class on the market in the United States are rosiglitazone and pioglitazone. There is also clinical experience with a third TZD, troglitazone, which was withdrawn from the market in 2000 because of its hepatotoxicity. Several other drugs belonging to this class are currently in different stages of preclinical and clinical development in the drug industry.[7,8]

Mechanism of Action

The hypoglycemic effect of the TZDs is related to their ability to increase insulin sensitivity and, consequently, increase peripheral glucose utilization. Although the exact mechanism of action is not completely understood, the most widely-accepted hypothesis is that their effect on insulin sensitivity is related to their well-known ability to bind and activate the nuclear peroxisomal proliferator-activated receptors-gamma (PPAR-). These receptors, which are abundant in adipocytes and are also present (to a lesser extent) in myocytes and other tissues, stimulate the expression of a number of genes that encode proteins involved in the metabolism of glucose and lipids. Their main biologic effect in adipose tissue, besides promoting the differentiation of pre-adipocytes into adipocytes, is to increase the uptake of fatty acids and lipogenesis. This "fatty-acid steal" in turn stimulates the nonoxidative metabolism of glucose in muscle and suppresses hepatic gluconeogenesis.[7,8]

Benefits

Glycemic Effects
In this manuscript, we do not review the glycemic effects of these drugs, since they have been recently and extensively reviewed elsewhere. However, the blood-glucose-lowering effect of the currently available TZDs is similar; all of the TZDs lower the hemoglobin A1c (HbA1c) level by approximately 0.5% to 1.5%, depending on the circumstances in which they are being used and/or studied.[9,10]

Insulin Resistance/Hyperinsulinemia
Besides lowering plasma glucose, the TZDs also lower the circulating insulin levels and/or the insulin dose required to achieve appropriate glycemic control in patients with type 2 diabetes mellitus. This reduction in the degree of insulin resistance causes an increase in peripheral glucose uptake, and also, under certain circumstances, reduces hepatic basal-glucose production.[11-13]

Dyslipidemia
Most of the studies with TZDs have shown that these drugs increase the high-density lipoprotein (HDL) levels by approximately 5% to 15%, though it seems that this increase is only due to an increase in its HDL3 subfraction.[9,11,14-16] Their effects on triglyceride levels are more variable and controversial. Most (but not all) of the studies using troglitazone and pioglitazone have shown a trend toward a reduction of approximately 10% to 20% in the plasma triglyceride levels; rosiglitazone does not seem to share this triglyceride-lowering effect.[9,11,12] In general, TZDs lower levels of circulating free fatty acids, and this is thought to be one of the most important mechanisms contributing to their ability to lower insulin resistance.[12,17,18]

Hypertension
Several studies using troglitazone have shown reductions in blood pressure in hypertensive as well as normotensive patients with type 2 diabetes mellitus. These reductions have ranged from as little as 3 mm Hg to as high as 9 mm Hg in mean arterial pressure. Other studies, however, have not been able to reproduce these findings.[19-24]

Microalbuminuria
Studies using troglitazone and rosiglitazone in patients with type 2 diabetes mellitus and microalbuminuria have shown reductions in the urinary microalbumin-to-creatinine ratio of up to 60%, independent of their glucose-lowering and/or blood-pressure-lowering effects.[25-29]

Vascular Endothelium
In humans, troglitazone seems to have a potent inhibitory effect on the progression of early atherosclerotic lesions at 3 and 6 months after beginning therapy, as shown by ultrasound technique (B-mode) evaluating the thickness of the intimal and medial layers of the common carotid artery walls.[30] Moreover, troglitazone has shown the ability to inhibit coronary restenosis in patients with type 2 diabetes mellitus who have had coronary angioplasty with the use of stents.[31] Evidence shows that the TZDs increase muscular blood flow through a not-well-understood vasodilatation process[32]; however, other investigators have not been able to reproduce this vasodilatory effect.[33]

Thrombogenic Factors/Procoagulant State
The TZDs seem to cause a reduction in the blood levels of plasminogen activator inhibitor-1 (PAI-1) and fibrinogen, which are frequently found to be elevated in patients with type 2 diabetes mellitus and are thought to contribute to their increased risk for cardiovascular disease. All investigators, however, have not been able to reproduce these effects.[24,34-36]

Fat Tissue Distribution
Several studies using troglitazone have shown that it selectively reduces intra-abdominal (visceral) fat while increasing total body fat, mostly by means of increasing peripheral subcutaneous fat.[37-39] This quality is interesting and potentially important, since it has recently been shown that the intra-abdominal fat is the main fat tissue in the body responsible for the insulin resistance observed in obesity. Reductions in this intra-abdominal fat tissue by means of caloric restriction or exercise, are known to lower insulin resistance and other manifestations of the metabolic syndrome.[40,41]

Pancreatic Beta Cells/Insulin Secretion
Growing evidence in patients with impaired glucose tolerance and type 2 diabetes seems to indicate that the TZDs improve the secretory capacity of the pancreatic cells in the short term as well as in the long term.[42-44] The mechanism responsible for this effect is not well understood; nevertheless, a recent study showed that PPAR- receptors are highly expressed in human islet endocrine cells.[45]

Bone Turnover
One study suggests that the TZDs might decrease bone turnover independent of their effects on glucose metabolism, as evidenced by a decrease in bone-resorption markers in patients with type 2 diabetes mellitus. However, this finding needs to be validated by other investigators; moreover, whether this effect will translate into an increase in bone mineral density and a decrease in fracture risk in patients with type 2 diabetes mellitus remains to be seen.[46]

Other Beneficial Effects
Polycystic Ovary Syndrome. Since the TZDs lower insulin resistance, they would be expected to be of benefit in the treatment of other conditions associated with insulin resistance. They have been studied in patients with polycystic ovary syndrome and have shown the capacity to improve the metabolic and reproductive abnormalities associated with this syndrome, helping, among other things, to induce ovulation.[47,48]
Severe Insulin-Resistance Syndromes. The TZDs have been found effective in the treatment of Werner's syndrome, several genetic and/or autoimmune lipodystrophy syndromes, as well as the poorly-understood HIV-associated lipodystrophy-dysmetabolic syndrome.[49-51]
Neoplasms. Several in vitro studies and a few in vivo animal studies suggest that the TZDs might have antiproliferative effects in colon, prostate, breast, lung, and gastric cancer cell lines, as well as inhibitory effects on estrogen biosynthesis in breast adipose tissue.[52-61] However, the only evidence in humans for a potential therapeutic role of the TZDs in the treatment of cancers comes from a small, uncontrolled study (involving only 3 patients), which showed that TZDs can induce solid/terminal tumor differentiation in patients with malignant liposarcoma. Whether this will translate into any clinical benefit remains to be seen.[62]

Risks

In general, the TZDs are well tolerated with few side effects; nonetheless, potential adverse effects deserve some attention.

Hepatic Toxicity
The hepatotoxicity of troglitazone is well known and resulted in its withdrawal from the US market in early 2000; it has been reported to cause reversible abnormalities in liver function tests in 2% of patients, and severe, irreversible liver failure in approximately 1 in 50,000 patients.[51,63-70] The other TZDs currently available in the United States, rosiglitazone and pioglitazone, do not seem to share this problem. During premarketing and postmarketing clinical trials, the incidence of abnormal liver enzymes in patients treated with these drugs has been the same as that for the placebo/control groups. Only 2 cases of severe liver disease that developed in patients receiving rosiglitazone have been published; both were reversible and in both cases a causal association with rosiglitazone is not clear, since there were several confounding factors.[71-73] Nonetheless, until more long-term experience with these drugs is available, we must follow FDA recommendations for monitoring liver enzymes: check bimonthly for the first year that the drugs are prescribed, and periodically thereafter.[74,75]

Lipid Effects
The TZDs increase low-density lipoprotein (LDL) levels by approximately 5% to 15%. Although this increase seems to be due to an increase in the size and reduction in the density of the lipoprotein particles by making them larger and fluffy, and therefore presumably less atherogenic, this remains a reason for concern.[9,14] Additionally, evidence shows that troglitazone might increase the plasma levels of Lp(a) lipoprotein; however the magnitude and significance of this increment are not clear.[76,77]

Hematologic Effects
In general, during clinical studies, the TZDs have caused reductions of 2% to 4% in hematocrit level, and decreases of up to 1 g/dL in hemoglobin level; similarly, mild decreases in white blood cell counts and platelet counts have been noted.[9,11,63,74,75,78] Although the exact cause of these decreases is not known, the effects have been attributed to a hemodilutional effect from an increase in plasma volume. A toxic effect on the bone marrow cannot be completely ruled out, however, since bone marrow hypocellularity and increased bone marrow fat have been observed in animals.[78]

Fluid Retention/Edema
Edema (most frequently only lower-extremity edema) has been reported in approximately 5% of patients treated with TZDs, and in up to 15% of patients when used in combination with insulin during clinical trials.[9,63,74,75] This problem may be severe enough to warrant discontinuance of these agents. Furthermore, pulmonary edema has been documented in the literature.[79] Although the cause for this edema is not well understood, it may be related to the 6% to 8% increase in plasma volume that has been observed in clinical studies.[63]

Weight Gain/Obesity
As with any other hypoglycemic drug, with the exception of the biguanides, patients treated with TZDs gain weight. This is probably due to several factors, including the obvious increase in plasma volume that happens when correcting the state of chronic dehydration in which patients with chronic hyperglycemia live, and cessation of the caloric loss through the urine (glucosuria). In the case of the TZDs, it is probably also due to the increase in the total body fat that is known to happen in patients treated with these drugs.[8,37-39] During clinical trials, this weight gain has been reported to be from 2 to 6 kg during the first 6 months to 1 year of treatment, depending upon the circumstances in which the drugs are used.[9,66-68] In clinical practice, however, it is not rare to find patients who gain a much greater amount of weight, occasionally more than 20 kg, making it necessary to discontinue these medications.[80] Unfortunately, thus far there is no way to predict which patient will gain excessive weight. We also do not know if this increase in total body fat and weight is reversible, or if it can result in a "TZD-resistant state" due to an increase in insulin resistance that hypothetically could happen after a critical threshold in total-body-fat mass is reached.[8,17]

Cardiac Toxicity
Multiple studies in animals (mice, rats, dogs, and monkeys) have shown that some of the TZDs can cause cardiac hypertrophy, though this effect has not been shown thus far in human studies.[20,63,74,75,78,81] Nonetheless, because TZDs may cause an increase in plasma volume, they are contraindicated in patients with New York Heart Association Class III and Class IV heart failure. There have been reports of pulmonary edema developing after the addition of a TZD to the therapeutic regimen of patients with type 2 diabetes mellitus.[79]

Neoplastic Potential
Several studies, mostly in vitro, suggest that the TZDs might have antiproliferative effects on certain types of cancer cells; however, other studies, mostly in vivo animal studies, show that the TZDs may induce the formation of lipomas, benign and/or malignant urinary bladder (transitional cell) tumors, vascular tumors (hemangiomas and hemangiosarcomas), and the growth of uterine leiomyomas.[74,75,82,83] Furthermore, under certain circumstances, the TZDs can promote the development of colorectal cancer and/or polyps; because of this risk, it has been suggested that TZDs should not be prescribed to patients who are known to be at high risk for development of colon polyps (eg, those patients belonging to a family with adenomatous polyposis coli).[8,84,85] Some of these tumors were observed only after long-term administration of the TZD.[82]

Cost
Cost is also an important issue and a significant disadvantage of the TZDs. The currently available TZDs have been priced significantly higher than any of the other oral hypolycemic agents, with prices up to and above $150 for a 1-month supply of the higher doses.

Conclusion

When compared with the remainder of the drugs currently available for the treatment of hyperglycemia in patients with type 2 diabetes mellitus, the TZDs offer the advantage of simultaneously improving several of the independent cardiovascular risk factors commonly associated with the insulin-resistance syndrome. It would be expected then, at least hypothetically, that the TZDs would help prevent and/or slow down the progression of arteriosclerosis and cardiovascular disease in patients with type 2 diabetes mellitus. Because of their potential for adverse effects, unclear long-term safety, the not-so-well-established long-term benefits, and the considerable expense, however, we must be prudent with their use, remain skeptical, and wait for the results of the long-term cardiovascular outcome studies that are currently underway to help establish the true long-term safety and effectiveness of these drugs in preventing the macrovascular complications in patients with type 2 diabetes mellitus.

CME Information
The print version of this article was originally certified for CME credit. For accreditation details, contact the publisher. Southern Medical Association, 35 Lakeshore Dr, Birmingham, AL 35209, telephone: (205) 945-1840; fax (205) 945-1840.

*Thus far, only in vitro and/or in vivo animal studies have reported these risks.
HDL = High-density lipoprotein, LDL = low-density lipoprotein, PAI-1 = plasminogen activator inhibitor-1, PCOS = polycystic ovary syndrome.

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Sidebar: Key Points

• Thiazolidinediones are a new class of drugs available for the treatment of type 2 diabetes mellitus.
  
• Thiazolidinediones have the potential to reduce the development of cardiovascular disease.
  
• Thiazolidinediones have several side effects that need to be kept in mind when prescribing these drugs.
  

Reprint Address

Reprint requests to Fernando Ovalle, MD, University of Alabama at Birmingham School of Medicine, Division of Endocrinology and Metabolism, 1808 7th Ave S, BDB 813, Birmingham, AL 35294.