Thiazolidinediones
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.
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.
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. 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.
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.
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.
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.
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. 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.
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.