Sometimes requires discontinuation Contraindicated in active hepatic renal and coronary artery disease

insulin levels and corrects many of the nontradi-tional risk factors that are associated with the insulin resistance syndrome [77].

Cardiovascular effects of metformin

In the UKPDS, treatment with metformin (another drug that decreases hyperinsulinemia and insulin resistance) produced greater reduction in cardiovascular disease events and mortality than sulfonylureas and insulin [8]. The latter drugs decreased blood glucose level to a similar degree as metformin but did not decrease plasma insulin concentrations. This effect may have been mediated through a decrease in insulin resistance, although other effects of metformin, such as improvement in lipid profile, improved fibrinoly-sis, and prevention of weight gain, may be important [8]. Metformin has a favorable, albeit modest, effect on plasma lipids, particularly in decreasing triglycerides and low-density lipopro-tein (LDL) cholesterol; however, it had little, if any, effect on HDL cholesterol levels [78]. Met-formin use was associated with decreased plas-minogen activator inhibitor (PAI-1) activity which led to improved endothelial dysfunction (see Table 1).

Thiazolidinediones

The thiazolidinediones are a relatively new class of compounds for the treatment of type 2 diabetes mellitus (Box 3). Troglitazone became available in the United States in 1997 but was withdrawn from the market in March 2000 because it caused severe idiosyncratic liver injury [79]. The thiazolidinediones have emerged as an important therapeutic drug class in the management of type 2 diabetes mellitus, and their efficacy in lowering plasma glucose is well established [80-

86]. Epidemiologic studies have demonstrated that hyperinsulinemia, a marker for insulin resistance, is an independent risk factor for cardiovascular disease [18]. Correction of insulin resistance may be clinically important in type 2 diabetes mellitus and may decrease risk for cardiovascular disease.

Mechanism of action

The glucose-lowering effects of the thiazolidi-nediones are mediated primarily by decreasing insulin resistance in muscle and fat and, thereby, increasing glucose uptake [19,87]. Thiazolidine-diones also increase glucose disposal and reduce hepatic glucose production [88]. The actions of the thiazolidinediones are mediated through binding and activation of the peroxisome proliferator-activated receptor (PPAR)-y receptor, a nuclear receptor that has a regulatory role in differentiation of cells, particularly adipocytes. This receptor also is expressed in several other tissues, including vascular tissue [89]. In addition, thiazolidine-diones decrease plasma free fatty acid concentrations and may improve insulin sensitivity indirectly by this decrease in free fatty acids [90]. Because free fatty acids are involved in lipid metabolism and also have deleterious effects on the vasculature [16], this reduction in plasma free fatty acids may have a beneficial effect on cardiovascular disease.

PPARs are members of the nuclear receptor superfamily and contain common structural elements that include a ligand-binding domain and a DNA-binding domain [91]. Three PPAR family members have been identified thus far, PPAR-y, PPAR-a, and PPAR-S (also known as PPAR-b or nucl). PPAR-y, a key mediator in metabolic syndromes such as diabetes mellitus and obesity, was identified first as a part of the transcrip-tional complex that is integral to adipocyte

Box 3. Advantages and disadvantages of thiazolidinediones

Advantages Potent insulin sensitizer Cardiovascular benefits Improves endothelial dysfunction

Disadvantages

Requires hepatic function monitoring every 2 months for first year after initiation of therapy May cause fluid retention

Contraindicated in patients who have New York Heart Association class III and IV congestive heart failure differentiation. Transient overexpression of PPAR-y in fibroblasts directs those cells toward an adipocyte-like phenotype [92] that is consistent with high adipose expression of PPAR-y [93,94]. PPAR-a and PPAR-y are expressed in the major cellular constituents of the vessel wall (endothelial cell, vascular smooth muscle cell [VSMC], and monocyte/macrophages) as well as in human atherosclerotic lesions [95,96].

The thiazolidinediones have the potential to alter metabolic conditions beyond the management of glycemia [20]. Because the thiazolidine-diones target insulin resistance, these agents may improve many of the risk factors that are associated with the insulin resistance syndrome. Although data on the impact of the thiazolidine-diones on cardiovascular outcomes are lacking, results of ongoing clinical trials are awaited eagerly [97] and are likely to support the use of these agents in minimizing adverse cardiovascular event. It seems that the thiazolidinediones exert numerous nonglycemic effects that may improve cardiovascular outcomes [19,20].

Lipid metabolism and oxidation

Several studies observed the effects of the thiazolidinediones on lipid metabolism [98,99]. Published data indicate that all of the thiazolidi-nediones increase HDL cholesterol, although only troglitazone and pioglitazone consistently decrease triglycerides [82,100-102]. Pioglitazone and rosiglitazone increase HDL and LDL cholesterol levels. Differences between the thiazolidine-diones with respect to their lipid effects may reflect the fact that populations that had different baseline values were studied; a randomized, comparative trial is needed to determine whether a true difference exists.

The effects of the thiazolidinediones on LDL cholesterol are complex. Patients who have type 2 diabetes mellitus (or individuals who are insulin resistant) are more likely than normal individuals to have small, dense, triglyceride-rich LDL cholesterol particles [103] that are highly susceptible to oxidation. Oxidative modification confers ath-erogenic properties on these small, dense, LDL cholesterol particles [20,104]. This characteristic is a key initial event in the progression of atherosclerosis and the presence of small, dense, LDL is an independent risk factor for cardiovascular disease [105-107]. In some studies, thiazolidine-diones increased total cholesterol or LDL cholesterol. Although there is an increase in LDL

cholesterol, this predominantly is in the larger, buoyant particles of LDL cholesterol which may be less atherogenic [90,98,108]. Concomitantly, the small, dense LDL cholesterol particles decreased with thiazolidinedione therapy [98,109]. Winkler et al [110] studied the effect of pioglita-zone on LDL subfractions in normolipidemic, nondiabetic patients who had arterial hypertension. They used a monocentric, double-blind, randomized, parallel-group study that compared 45 mg pioglitazone (n = 26) and a placebo (n = 28) that were given once daily for 16 weeks. Fifty-four moderately hypertensive patients (LDL cholesterol, 2.8 mmol/L ± 0.8 mmol/L; HDL cholesterol, 1.1 mmol/L ± 0.3 mmol/L; triglycerides, 1.4 mmol/L (median; range 0.5-7.1 mmol/L) were studied at baseline and on treatment. Pioglitazone reduced dense LDLs by 22% (P = 0.024).

There is evidence to suggest that PPAR-y may be an important regulator of foam cell gene expression and that oxidized LDL cholesterol regulates macrophage gene expression through activation of PPAR-y [111]. Chinetti and colleagues [112] demonstrated that activators of PPAR-a and PPAR-y receptors induce expression of the nuclear receptor liver x receptor-a and ATP-binding cassette subfamily-1 promoter genes, which are involved in the pathway that activates apolipoprotein AI-mediated cholesterol efflux from macrophages and macrophage-derived foam cells. Furthermore, PPAR-y promotes the uptake of oxidized LDL cholesterol by macrophages [113].

Blood pressure

If insulin resistance causes hypertension, then improving insulin sensitivity should have the potential to lower blood pressure. The effects of thiazolidinediones on blood pressure have been examined in several different experimental and clinical settings. A study of 24 nondiabetic, hypertensive patients who were treated with rosiglitazone demonstrated that rosiglitazone treatment added to the patient's usual antihyper-tensive medication resulted in a decline in systolic and diastolic blood pressure and improved insulin resistance [114]. Ogihara and associates [115] demonstrated significant reduction in blood pressure in hypertensive subjects who had type 2 diabetes mellitus and were treated with troglita-zone. In another study of 203 patients who had type 2 diabetes mellitus, treatment with rosiglita-zone significantly reduced ambulatory blood pressure [116]. Scherbaum and associates [117] also reported decreases in systolic blood pressure by pioglitazone in normotensive and hypertensive patients who had diabetes mellitus. Similar results were seen in nonhypertensive patients who had type 2 diabetes mellitus [82] and nondiabetic, obese persons [83,118].

Raji et al [114] examined the effect of rosigli-tazone on insulin resistance and blood pressure in patients who had essential hypertension. There were significant decreases in mean 24-hour systolic blood pressure; the decline in systolic blood pressure correlated with the improvement in insulin sensitivity. Rosiglitazone treatment of nondiabetic hypertensive patients improves insulin sensitivity, reduces systolic and diastolic blood pressure, and induces favorable changes in markers of cardiovascular risk.

A potential mechanism for thiazolidinedione-mediated decreases in blood pressure may be improved insulin sensitivity, which promotes insulin-mediated vasodilatation. Alternative hypotheses for the decrease in blood pressure include inhibition of intracellular calcium and myocyte contractility [119,120] and endothelin-1 expression and secretion. Pioglitazone inhibited renal artery proliferation in animal models [121,122] which generated reductions in blood pressure.

Endothelial function, vascular reactivity, and vascular wall abnormalities

Vascular endothelium is involved in the regulation of vascular tone, vessel permeability, and angiogenesis. Various paracrine vasodilatory and vasoconstrictor factors, most notably nitric oxide and endothelin-1, determine vascular tone [80,123]. The endothelium plays a vital role in the maintenance of blood fluidity, vascular wall tone, and permeability. Endothelial dysfunction is central to many vascular diseases, including atherosclerosis and diabetic microangiopathy. Endo-thelial function is disturbed by many of the individual features of the insulin resistance syndrome, including hypertension, dyslipidemia, and hyperglycemia [124].

In insulin-resistant, obese subjects and patients who have type 2 diabetes mellitus, this vaso-dilatory effect of insulin is decreased—an abnormality that might be attributable to impairment in the ability of the endothelium to produce nitric oxide or to enhanced inactivation of nitric oxide [122]. In addition, the action of endothelium-

derived nitric oxide is impaired in patients who have atherosclerosis and insulin resistance. This impairment has been attributed, in part, to increased vascular oxidative stress. Thiazolidine-diones improve endothelium-derived nitric oxide production and action, and hence, may be a potential agent in the treatment of patients who have coronary artery disease [125]. An antioxidant effect of the thiazolidinediones also inhibits the expression of adhesion molecules by the endothe-lial cells. Thiazolidinediones inhibit the expression of proinflammatory genes (nuclear factor KB [NFjB]-regulated genes) and suppresses factors that are responsible for plaque rupture and thrombosis (ie, early growth response transcription factor-1 and tissue factor), which could contribute to an antiatherogenic effect [126].

Avena and colleagues [127] demonstrated normalization of impaired brachial artery flow-mediated dilatation in troglitazone-treated human subjects who had peripheral vascular disease. Improvement of vascular reactivity in obese, nondiabetic patients after treatment with rosigli-tazone also was reported [128]. The thiazolidine-diones act on the endothelium by way of various mechanisms, namely their action on the nitric oxide synthesis; modulation of the nuclear receptor, PPAR-y; and effects on various cytokines, including adhesion molecules, that are involved in the atherosclerotic process [129-131]. Recently, metformin was shown to improve endothelial function [100]. Because the biguanides do not stimulate PPARs, other mechanisms are likely to be involved in the pathogenesis of endothelial dysfunction in insulin resistance.

The thiazolidinediones also may prevent the progression of atherosclerosis by inhibiting mono-cyte chemoattractant protein (MCP)-1 expression in endothelial cells. In addition to attenuated response to tumor necrosis factor (TNF)-a, other mediators of inflammation also are suppressed. Anti-inflammatory properties and antioxidant effects were observed in patients who had type 2 diabetes mellitus and were treated with thiazoli-dinediones; hence, these agents may be of benefit at the vascular level [125,129-132]. One study that evaluated troglitazone showed a profound reduction in the levels of NFkB, a molecule that induces inflammatory cytokines, such as TNF-a, MCP-1, adhesion molecules (soluble intercellular adhesion molecule-1), and reactive oxygen species. Thus, thiazolidinediones exert anti-inflammatory actions that may contribute to their putative anti-atherosclerotic effects [133].

PPAR-y ligands counter the effects of various inflammatory cytokines that are released after the endothelial injury. These agents also inhibit VSMC proliferation, down-regulate endothelial cell growth factor receptors, and suppress the movement of various other cells through inhibition of vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and MCP-1. A recent animal study demonstrated that pioglitazone had vasculoprotective effects in acute and chronic vascular injury [131]. Similarly, in a rat model, rosiglitazone reduced myocardial infarction and postischemic injury and improved aortic flow following reperfusion [134,135].

B-mode ultrasound is a noninvasive method for evaluating carotid intimal-medial complex thickness, which is an indicator for early atherosclerosis and is associated with insulin resistance [136,137]. This measurement may serve as a surrogate marker for atherosclerotic events because patients who have increased intimal-medial complex thickness have a higher rate of cardiovascular events over time. Treatment with troglitazone significantly decreases intima-medial thickness in patients who had type 2 diabetes mellitus [137]. Koshiyama and associates [138] recently reported a significant decrease in the intima-medial thickness in patients who had type 2 diabetes mellitus and were treated with pioglitazone. It is possible that the effects of the thiazolidinediones are direct cellular effects on the atherosclerotic process that are not linked to their effects on insulin resistance.

In acute coronary events, exposure of the highly thrombogenic lipid core to circulating coagulation factors can lead to a progressive cascade that results in occlusion of the vessel. Matrix metalloproteinases (MMPs) that are produced by monocyte-derived macrophages and vascular smooth muscle cells contribute to this process by causing plaque rupture, and thus, exposure of the lipid core. Troglitazone and rosiglitazone inhibited the expression and functional activity of MMP-9 in human monocyte-derived macrophages and human VSMC [96,139,140]. Patients with Type 2 diabetes are disproportionately affected by cardiovascular disease, and cardiovascular events are a major cause for morbidity and mortality in this population [141]. Following cardiovascular interventions such as balloon an-gioplasty, patients with diabetes appear to have a higher rate of restenosis [142]. Several recent human trials have demonstrated beneficial effects of thiazolidenediones in decreasing restenosis following angioplasty. Choi et al [143] have recently demonstrated that patients having a coronary stent implant who were randomized to receive rosiglitazone had a significant reduction in restenosis as well as artery diameter reduction compared to a control group who received equal glucose lowering therapy with other agents (Fig. 2). Similarly, pioglitazone has been demonstrated to reduce neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus [144]. Although small clinical studies discussed above are interesting, large multicenter studies are needed to confirm these findings before they can be translated into clinical practice [141].

In summary, thiazolidinediones improve endothelial nitric oxide synthesis, counter the effects of hyperinsulinemia-induced resistance, suppress various mediators of inflammation that are involved in atherosclerosis, and inhibit injury-induced VSMC migration; thereby, they potentially prevent restenosis and further occlusion.

Fibrinolysis, coagulation, and inflammation

Decreased fibrinolytic activity, in association with elevated plasma PAI-1, is associated with an

Stenosis (% of luminal diameter)

Fig. 2. Cumulative distribution curves for percent stenosis of the luminal diameter in the rosiglitazone and central groups. The distributions were similar at baseline and immediately after stent implantation. At 6 months the mean degree of stenosis in the rosiglitazone group was significantly lower than in the control group. (From Choi D, Kim SK, Choi SH. Preventative effects of rosiglitazone on restenosis after coronary stent implantation in patients with type 2 diabetes. Diabetes Care 2004;27:2654-60; with permission.)

Stenosis (% of luminal diameter)

Fig. 2. Cumulative distribution curves for percent stenosis of the luminal diameter in the rosiglitazone and central groups. The distributions were similar at baseline and immediately after stent implantation. At 6 months the mean degree of stenosis in the rosiglitazone group was significantly lower than in the control group. (From Choi D, Kim SK, Choi SH. Preventative effects of rosiglitazone on restenosis after coronary stent implantation in patients with type 2 diabetes. Diabetes Care 2004;27:2654-60; with permission.)

increased risk of atherosclerosis and cardiovascular disease [145,146]. PAI-1 is the primary inhibitor of endogenous tissue plasminogen activator and is elevated in patients who have diabetes mellitus and in insulin-resistant nondiabetic individuals. Increased PAI-1 levels are now recognized to be an integral part of the insulin resistance syndrome and correlate significantly with plasma insulin. Insulin infusion during infarction and postinfarction periods (which is known to improve outcomes) decreased plasma PAI-1 levels [147]. Immunohistochemical analysis of the coronary lesions from patients who had coronary artery disease demonstrated an imbalance of the local fibrinolytic system with increased coronary artery tissue PAI-1 levels in patients who had type 2 diabetes mellitus [148]. Impaired fibrinolysis also is noted in other insulin-resistant states, such as the polycystic ovary syndrome [138]. Fonseca and colleagues [149] demonstrated a decrease in plasma PAI-1 levels in patients who had diabetes mellitus who treated with a thiazoli-dinedione. This observation was confirmed in several studies [124,150]. The postulated mechanism for the effect of the thiazolidinediones is by way of the activation of PPAR-y and subsequent suppression of PAI-1.

In vitro studies with troglitazone demonstrated direct effect on the vessel wall that led to a decreased synthesis of PAI-1 and indirect effects on hepatic synthesis as a result of the attenuation of hyperinsulinemia [151]. Pioglitazone had a similar effect [132]. Treatment with rosiglitazone also decreased PAI-1 levels [152]. Therefore, PAI-1 reduction may well be a class effect of the insulin sensitizers. Although increases in PAI-1 levels are associated with an increased risk of myocardial infarction, no study demonstrated a diminution of this risk with reduction in plasma PAI-1 levels. Consequently, clinical trials are necessary to demonstrate such a benefit.

Like elevated PAI-1, increases in plasma concentrations of markers of inflammation, such as C-reactive protein (CRP), are associated with the insulin resistance syndrome and cardiovascular disease [153]. Fuell and colleagues [154] reported reductions in the proinflammatory markers, in-terleukin-6, CRP, and white blood cells, in patients who had type 2 diabetes mellitus that was treated with rosiglitazone. Haffner and colleagues [155] reported a reduction in levels of MMP-9 and CRP in patients who had type 2 diabetes mellitus and were treated with rosiglitazone. These effects may be related to the decrease in insulin resistance and may have beneficial consequences for long-term cardiovascular risk.

Mohanty et al [156] treated 11 nondiabetic obese subjects and 11 obese diabetic subjects with 4 mg of rosiglitazone daily for a period of 6 weeks. Blood glucose concentration changed significantly at 6 weeks only in the obese diabetic subjects after rosiglitazone treatment for 6 weeks, whereas insulin concentration decreased significantly at 6 weeks in both groups. Rosiglitazone treatment led to a significant reduction in NFjB-binding activity in mononuclear cells, plasma MCP-1, TNF-a, soluble MCP-1, CRP, and serum amyloid A were also lowered, particularly in the obese patients. Thus, rosiglitazone, a selective PPAR-y agonist, exerts an antiinflammatory effect at the cellular and molecular level, and in plasma.

Albuminuria

Urinary microalbuminuria is monitored routinely in clinical practice and is recognized as a marker of cardiovascular disease and diabetic nephropathy [157,158]. Current methods of reducing microalbuminuria include strict glycemic control and the use of angiotensin-converting enzyme inhibitors. Imano and colleagues [157] showed reductions in urinary microalbumin: creatinine ratio during a 12-week clinical trial when troglitazone was compared with metformin. Similar effects were noted with rosiglitazone. [116,159]. In a 52-week, open trial of patients who had type 2 diabetes mellitus who were given either rosiglitazone or glyburide, patients who were treated with rosiglitazone had a significant reduction in urinary albumin:creatinine ratio compared with baseline [116]. Laboratory work revealed that PPAR-y receptors are expressed in mesangial cells of animal models and inhibit mesangial cell proliferation and angiotensin II-induced PAI-1 expression [160]. Consequently, thiazolidinedione therapy may represent an alternate method for reducing proteinuria and subsequent nephropathy.

Body weight

Clinical trials suggest that thiazolidinediones may increase body weight; however, the weight gain is accompanied by improvement in glycemic control and also may be secondary to fluid retention [161-163]. Stimulation of adipogenesis through PPAR-y is another potential mechanism for weight gain [164]. This effect is site-specific; weight gain occurs from an increase in subcutaneous fat with a concomitant decrease in visceral fat content (ie, fat redistribution) [165— 167]. The clinical significance of increased body weight with the thiazolidinediones is unclear. Weight gain usually increases insulin resistance, which, in turn, increases glucose; however, thia-zolidinediones clearly decrease insulin resistance and glucose despite mild weight gain.

Thus, other mechanisms must be involved in the weight/insulin resistance relationship. For instance, increased intra-abdominal fat is associated with increased insulin resistance [168,169]. The redistribution of body fat that is mediated by the thiazolidinediones may be important; studies support this hypothesis. Kelly and associates [166] demonstrated that treatment with troglitazone in human subjects who had type 2 diabetes mellitus decreased intra-abdominal fat mass but did not affect total body fat or weight. Similar effects were observed in patients who had type 2 diabetes mellitus who were treated with rosiglitazone or pioglitazone [170,171]. Thus, the thiazolidine-diones may reduce fat accumulation in the visceral abdominal cavity by improving insulin sensitivity.

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