Cardiovascular Effects

The thiazolidinediones have multiple beneficial effects on the cardiovascular system and these are detailed below and in Table 2.

Effects on Cardiac Structure and Function

Left ventricular hypertrophy (LVH) and LV diastolic dysfunction are both common cardiac consequences of hypertension and independently predict cardiovascular morbidity and mortality. In early rodent studies, troglitazone caused reversible increases in heart weight at high doses (62). However, in later animal studies, thiazolidinedione treatment inhibited LVH and improved LV function (63,64). In humans, treatment with troglitazone 800 mg for 48 weeks produced no significant changes in left ventricular mass index. Indeed, compared to the control glyburide group, troglitazone-treated patients demonstrated significant increases in cardiac stroke volume and cardiac index and decreases in diastolic pressure and peripheral vascular resistance (62). Another study

TABLE 2 Cardiovascular Risk Factor Reduction with Thiazolidinedione Treatment

Improve dyslipidemia (THDL-C,J.TG, J.LDL density) Decrease microalbuminuria, blood pressure

Decrease vascular inflammation, C-reactive protein, endothelin-1, MMP-9, MCP-1 levels Improve vascular reactivity, endothelial function Increase thrombolysis, decrease PAI-1 activity

Reduce neointimal/vascular smooth muscle cell proliferation, macrophage migration Reduce carotid intimal medial thickness assessed the effects of long-term treatment with rosiglitazone versus glyburide on cardiac structure/function and glycemic control in patients with type 2 diabetes. After 52 weeks of treatment, although small significant increases from baseline in left ventricular mass index (LVMI) were observed in the rosiglitazone group, these changes occurred primarily by week 28 and did not progress further at week 52 (65). In addition, the change in LVMI in the rosiglitazone group was not statistically significantly different to that in the glyburide group.

In a recent study in non-diabetic, insulin-resistant hypertensive patients, pioglita-zone treatment significantly improved LV diastolic function without LV mass regression, in proportion to the amelioration of insulin resistance in these patients (66).

Effects on Myocardial Metabolism

Glucose is an important substrate for the myocardial cells, especially during ischemia and an improvement in myocardial metabolic function may play a role in improved cardiac function in diabetic patients treated with thiazolidinediones. A study using positron emission tomography scanning demonstrated that 26 weeks of rosiglitazone treatment significantly increased insulin-stimulated myocardial glucose uptake by 38% and whole-body glucose uptake by 36%, while metformin treatment had no significant effect on these parameters. In this study, myocardial glucose uptake correlated inversely with FFA concentrations and interleukin (IL)-6 concentrations (67). Similar findings were reported in another study in which rosiglitazone therapy significantly increased insulin sensitivity and improved myocardial glucose uptake in type 2 diabetic patients with CAD (68). However, in a study in subjects with insulin-requiring type 2 diabetes and no CAD, pioglitazone treatment for 12 weeks had no demonstrable effect on myocardial blood flow despite metabolic improvements. The lack of any effect in this study may be due to differences in study subject selection and study duration (12 weeks vs. 16-26 weeks) (69).

Effects of Blood Pressure

The prevalence of hypertension in patients with diabetes is up to twofold higher than in non-diabetic individuals (70). In type 2 diabetes and other insulin-resistant states there is blunted insulin-mediated vasodilation caused by several factors including endothelial dysfunction, increased activation of sympathetic nervous system and enhancement of renal sodium reabsorption (71). It is possible that by improving insulin sensitivity, the thiazolidinediones enhance the tonic vasodilator response to insulin pressure, leading to reduced peripheral vascular resistance and BP. Further, by reducing hyperinsulinemia and plasma insulin levels, it is possible that the thiazolidinediones attenuate the potential BP-raising actions of insulin, such as renal sodium retention (72) and increased sympathetic activity. In a study using 123I-meta-iodobenzylguanidine cardiac imaging to evaluate cardiac sympathetic nervous function, troglitazone had a beneficial effect on cardiac sympathetic nervous function through a decrease in insulin resistance in patients with essential hypertension (73).

In most clinical studies so far, the thiazolidinedione have consistently been shown to lower both systolic and diastolic BP. In a meta-analysis of 37 clinical trials, when compared with baseline, the thiazolidinediones lowered systolic BP by 4.70 mmHg [95% confidence interval (CI), -6.13 to -3.27] and diastolic BP by 3.79 mmHg (95% CI, -5.82 to -1.77). When compared with placebo, thiazolidinediones lowered systolic BP by 3.47 mmHg (95% CI, -4.91 to -2.02) and diastolic BP by 1.84 mmHg (95% CI, -3.43 to -0.25) (74).

Effects on Glomerular Function and Albuminuria

Microalbuminuria (urinary albumin excretion rate between 30 and 300mg/24hr) is widely regarded as a marker of impaired vascular integrity in type 2 diabetic patients and is not only considered to be an early indicator of renal and cardiovascular disease risk, but also confers an increased risk for all-cause mortality (75). The presence of microalbuminuria is an indication for aggressive intervention to improve glycemic and BP control and reduce cardiovascular risk factors.

In a study from Japan (76), 45 type 2 diabetes patients with microalbuminuria were randomized to either pioglitazone 30 mg, glibenclamide 5mg or voglibose 0.6 mg (an alpha-glucosidase inhibitor). After 3 months, only pioglitazone was effective in reducing urinary albumin excretion and urinary endothelial-1 (ET-1) concentrations. An increase in circulating ET-1 is known to precede microalbuminuria in diabetic patients. In another 52-week, open-label study, patients with type 2 diabetes were randomized to treatment with rosiglitazone 4mg b.i.d. or glyburide. At week 28, significant reductions from baseline in albumin/creatinine ratio (ACR) were observed in both treatment groups. However, at week 52, only the rosiglitazone group showed a significant reduction from baseline. For patients with microalbuminuria at baseline, reductions in ACR did not correlate strongly with glycemic control, but showed strong correlation with changes in mean 24-h systolic and diastolic BP in rosiglitazone-treated patients (77). Of note, PPAR-y receptors are present in the renal mesangial cells and in cultured mesangial cells, PPAR-y activation by thiazolidinediones attenuates TGF-p (l)-induced fibronectin accumulation observed in the glomerular mesangium in cases of glomerulosclerosis (78).

Anti-Atherogenic Effects

The vascular endothelial cells, the monocyte/macrophage cells and the vascular smooth muscle cells all play a crucial role in the development of accelerated atherosclerosis (79). There is growing evidence from both in vitro and animal studies that the thiazolidine-diones as PPAR-y agonists modify the risk of atherosclerosis progression through beneficial effects on all these components. Several studies have documented that the thiazolidinediones inhibit the expression of the endothelial cellular adhesion molecules (MCP-1, ICAM-1 and VCAM-1) (80), negatively regulate macrophage activation (81,82); regulate macrophage lipid homeostasis through activation of the ABCA-1-mediated reverse cholesterol pathway (83); and reduce the expression and release of tissue factors (84). Through these effects, the thiazolidinediones modify the vascular pathology and thrombogenicity associated with atherosclerosis and improve the stability of the atherosclerotic plaque. The effects of these changes on biochemical markers and surrogate markers of atherosclerosis progression like carotid intimal medial thickening have been favorable (84,85). Cardiac intravascular ultrasound studies have also shown a significant reduction in neointimal tissue proliferation after coronary stent implantation in diabetic patients treated with thiazolidinediones (86).

However, the "gold standard" to determine the cardiovascular benefits of a drug is a randomized, double-blind, placebo-controlled study. In the Prospective Pioglitazone Clinical Trial in Macrovascular Events Study (PROactive Study), 5238 patients with type 2 diabetes and evidence of pre-existing cardiovascular disease were randomized to pioglitazone 45 mg daily, or placebo in addition to their usual glucose-lowering medications (87). In order to assess the effect of pioglitazone on CAD, independent of its glucose lowering effects, all patients were treated to optimal glucose, lipid and BP goals. After an average follow up of ~ 3 years, pioglitazone treatment was associated with a modest 10% (not statistically significant, P = 0.09), reduction in the risk of the primary composite endpoint, which consisted of all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, and revascularization or amputation. However, the "main secondary endpoint" (defined before the unblinding of the data) and consisting of certain of the primary outcome measures, namely all-cause mortality, myocardial infarction, and stroke, was significantly reduced by 16%. Of note, pioglitazone treatment was associated with an increase in CHF and hospitalization for CHF. However, the criteria for heart failure were not clearly defined and it is unclear whether the frequency of this diagnosis was confounded by an increased presence of peripheral edema in the pioglitazone group. On the other hand, it is reassuring that mortality from heart failure was not increased.

Although the PROActive study results demonstrated a reduction in all-cause mortality, myocardial infarction, and stroke with pioglitazone, the study was not designed to determine the mechanism(s) for this benefit. This could have resulted from the lower HbA1c of 0.5% in the pioglitazone group, a small but significant reduction in BP, or changes in the lipid profile. Given the multiple beneficial effects of the thiazolidine-diones on improving insulin sensitivity and on traditional and non-traditional risk factors, it is tempting to speculate that these anti-atherogeneic effects contributed to the results. Also, it is not known if thiazolidinediones reduce vascular events in the setting of optimal BP, lipid and glucose control. This is being studied in the National Institutes of Health funded ACCORD study, a 7-year, 10,000-patient study designed to evaluate the effects of tight BP, lipid and glucose control (using insulin sensitizers, insulin secretagogues and insulin), on cardiovascular events in patients with type 2 diabetes (88); and the RECORD study, a 6-year study designed to evaluate whether rosiglitazone, in combination with metformin or sulfonylurea, affects CAD outcomes and progression of diabetes in the long term (89).

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