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Pioglitazone: heart disease, lipids, diabetes
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Several studies were presented at recent DDW conference showing pioglitazone improved fatty liver & reduced liver inflammation & perhaps fibrosis as a result. You can have fatty liver, which can cause liver damage, without having viral hepatitis (HCV, HBV). Elevated lipids & glucose can cause fatty liver, also called NASH (nonalcoholic steatohepatitis). You can read these study results in the DDW Reports section on the NATAP website. Jules Levin
"Pioglitazone therapy does not affect coronary flow in diabetics"
"...Thiazolidinediones have demonstrated significant benefits on both glycemic control and associated cardiovascular risk factors including hypertension (17) and biochemical markers of risk... The effect of thiazolidinediones on human coronary circulation has not yet been defined and the absence of a significant effect after pioglitazone treatment found here may suggest that thiazolidinediones (or other insulin sensitizers used under standard conditions) may not improve coronary microvascular function, within the limits of this study......Twelve weeks may be an insufficient exposure to the active drug to demonstrate changes in MBF, especially for one that acts by modulating gene transcription, as predicted for a PPAR-{gamma} agonist. ......Several large-scale clinical trials are underway to test the effect of thiazolidinediones on clinical cardiovascular events.."
NEW YORK (Reuters Health) - Although pioglitazone therapy improves several cardiovascular risk factors in patients with insulin-requiring type 2 diabetes, it does not affect coronary flow, according to a report in the May issue of Diabetes Care.
Previous reports have suggested that insulin resistance may impair coronary endothelial function. Thus, treatment with a pioglitazone, an insulin-sensitizing agent, could, in theory, improve coronary flow.
To investigate, Dr. Marcelo F. DiCarli, from the Brigham and Women's Hospital in Boston, and colleagues used positron emission tomography to assess myocardial blood flow in 16 subjects with insulin-treated type 2 diabetes who were randomized to receive pioglitazone or placebo for 3 months.
Pioglitazone-treated patients experienced a drop in HbA1c levels, whereas control patients experienced an increase (p = 0.009), the researchers note. In addition, pioglitazone therapy was linked to a significant improvement in triglyceride and HDL concentrations.
Despite these beneficial effects, pioglitazone therapy did not alter resting or adenosine-stimulated myocardial blood flow, or have an effect on coronary flow reserve.
On regression analysis, lower glucose levels at the time of the study were linked to higher coronary flow reserve, the researchers point out.
Further studies are currently underway to clarify the beneficial effect that pioglitazone and other thiazolidinediones have on clinical cardiovascular events.
Diabetes Care 2005;28:1145-1150.
Effect of a Peroxisome Proliferator-Activated Receptor-{gamma} Agonist on Myocardial Blood Flow in Type 2 Diabetes
Diabetes Care 28:1145-1150, May 2005
Graham T. McMahon, MB, BCH1, Jorge Plutzky, MD2, Edouard Daher, MD3, Tammy Bhattacharyya, MD4, George Grunberger, MD4 and Marcelo F. DiCarli, MD5
1 Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
2 Department of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
3 Division of Cardiology, Wayne State University School of Medicine, Detroit, Michigan
4 Division of Endocrinology, Diabetes, and Metabolism, Wayne State University School of Medicine, Detroit, Michigan
5 Department of Nuclear Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
ABSTRACT
OBJECTIVE-The relationship between coronary endothelial function and insulin resistance remains speculative. We sought to determine whether pioglitazone, an insulin-sensitizing peroxisome proliferator-activated receptor (PPAR)-{gamma} agonist, improves cardiac endothelial function in individuals with type 2 diabetes.
RESEARCH DESIGN AND METHODS-Sixteen subjects with insulin-treated type 2 diabetes and without overt cardiovascular disease were randomly assigned to receive either 45 mg of pioglitazone or matching placebo for 3 months. Rest and adenosine-stimulated myocardial blood flow (MBF) were quantified with [13N]ammonia and positron emission tomography at baseline and study conclusion.
RESULTS-After 3 months, HbA1c levels dropped by 0.68% in the pioglitazone group and increased by 0.17% in the placebo group (P = 0.009 for difference between groups). Triglyceride (-93 vs. -39 mg/dl, P = 0.026) and HDL concentrations (+4.8 vs. -6.0 mg/dl, P = 0.014) improved significantly in the pioglitazone group compared with placebo. Despite these favorable changes, there was no demonstrable change in baseline MBF (-0.05 ± 0.24 vs. -0.09 ± 0.24 ml - min-1 - g-1, P = 0.45), adenosine-stimulated MBF (0.10 ± 0.75 vs. 0.14 ± 0.31 ml - min-1 - g-1, P = 0.25), or coronary flow reserve (0.45 ± 1.22 vs. 0.35 ± 0.72 ml - min-1 - g-1, P = 0.64) after 12 weeks of exposure to pioglitazone or placebo, respectively. Regression analysis revealed that lower glucose concentration at the time of the study was associated with higher coronary flow reserve (P = 0.012).
CONCLUSIONS-Pioglitazone treatment for 12 weeks in subjects with insulin-requiring type 2 diabetes had no demonstrable effect on coronary flow reserve despite metabolic improvements. Higher ambient glucose levels contribute to impaired vascular reactivity in individuals with diabetes.
Abbreviations: MBF, myocardial blood flow - PET, positron emission tomography - PPAR, peroxisome proliferator-activated receptor
INTRODUCTION
Atherosclerotic vascular disease and its sequelae remain the primary causes of mortality in patients with diabetes, accounting for 65-75% of deaths (1). Recent attention has focused on functional abnormalities of the endothelium as an early step in the pathogenesis of diabetic heart disease (2,3). Notably, studies on individuals with diabetes have demonstrated a consistently higher myocardial blood flow (MBF) at rest and impaired myocardial vasodilation capacity (4).
Endothelial dysfunction occurs when endogenous vasoconstrictors such as endothelin and angiotensin II dominate the action of naturally occurring vasodilators such as nitric oxide, an imbalance linked to known cardiovascular risk factors (5-7). Importantly, measures of endothelial dysfunction predict subsequent cardiovascular events (8). Insulin resistance has emerged as a putative common link between diabetes and endothelial dysfunction. Those with insulin resistance demonstrate impaired endothelial function (7,9) even before diabetes is diagnosed, and insulin induces vasodilation via endothelial nitric oxide release (10,11).
Thiazolidinediones activate the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-{gamma} to improve postreceptor insulin signaling and insulin sensitivity. Thiazolidinediones may also limit inflammation and atherosclerosis (12,13). We compared the effect of pioglitazone versus placebo on coronary blood flow, vascular resistance, and flow reserve using positron emission tomography (PET) at rest and after induced hyperemia. Concurrently, we characterized the effects of thiazolidinedione on serum markers of vascular relevance and predictors of coronary flow in 16 individuals with insulin-requiring type 2 diabetes.
AUTHOR DISCUSSION
The major finding of this pilot study was that subjects with insulin-requiring type 2 diabetes showed no significant change in coronary flow reserve after pioglitazone treatment, despite significant improvements in known or postulated cardiovascular risk factors (specifically HDL, glucose, and triglycerides). After a 12-week treatment course, patients assigned to high-dose pioglitazone had similar changes in adenosine-stimulated coronary blood flow and vascular resistance compared with those in the placebo group. An association was noted between coronary flow reserve and ambient glucose levels.
Insulin resistance has a central role in type 2 diabetes, as well as its associated complications of obesity, hypertension, dyslipidemia and atherosclerotic heart disease. Thiazolidinediones have demonstrated significant benefits on both glycemic control and associated cardiovascular risk factors including hypertension (17) and biochemical markers of risk (18). Some of these vascular benefits may derive from changes in the endothelium where PPAR-{gamma} is known to be expressed (19,20). Indeed, numerous in vitro studies reveal changes in PPAR-{gamma}-regulated target genes (21) that would be expected to limit atherosclerosis and/or inflammation, including nitric oxide synthetase (22). Consistent with this, troglitazone inhibited the development of atherosclerosis in mice fed high-fat diets (23) and rosiglitazone decreased aortic atheroma formation in apolipoprotein E-deficient mice (24). Early human studies noted a reduction in carotid intimal media thickness after 12 weeks of treatment with troglitazone or pioglitazone (25,26). Although improvements in flow-mediated vasodilation were reported with troglitazone (12,27), a thiazolidinedione now withdrawn from the market, its structure contains the antioxidant {alpha}-tocopherol. Antioxidant benefits are implicated as one potential mechanism for troglitazone's effects (13). The effect of thiazolidinediones on human coronary circulation has not yet been defined and the absence of a significant effect after pioglitazone treatment found here may suggest that thiazolidinediones (or other insulin sensitizers used under standard conditions) may not improve coronary microvascular function, within the limits of this study.
Although changes in arteriolar resistance in response to adenosine are largely mediated by direct vascular smooth muscle relaxation, reflecting primarily endothelium-independent vasodilation, there is evidence that 20-40% of the maximal vasodilator response caused by adenosine is related to nitric oxide release from the endothelium in response to shear stress (28,29). Thus, the vasodilator response to adenosine reflects the integrated effects of both vascular smooth muscle and endothelial cell function. Consequently, our findings suggest insulin resistance may not be related to either endothelium-dependent or independent coronary microvascular function.
Our results extend prior studies that examined the relationship between insulin resistance, diabetes, and endothelial function. Using high resolution brachial ultrasound, Tack et al. (30) demonstrated that troglitazone treatment for 8 weeks did not alter endothelium-dependent or independent vascular responses as measured by nitroglycerin-mediated brachial artery dilation in nondiabetic insulin-resistant subjects. Caballero et al. (27) also found no improvements in forearm blood flow using either flow or nitroglycerin-mediated dilation after 12 weeks of troglitazone in patients with established type 2 diabetes; flow-mediated dilation in the forearm did improve in a subgroup of individuals with recently diagnosed type 2 diabetes. After 16 weeks of rosiglitazone, one study noted a significant improvement in skin nitric oxide production without a significant change in skin perfusion (31). Our findings extend these observations by examining the coronary circulation in individuals who have progressed from insulin resistance to diabetes, demonstrating minimal difference between placebo- and pioglitazone-treated subjects in adenosine-stimulated coronary flow reserve.
Several factors should be considered in interpreting the results of this initial pilot study. As is often encountered in such studies, the total patient number is limited (to 16 patients in this case). This cohort may not be fully representative of the spectrum of individuals with insulin-requiring diabetes. Indeed, despite randomization, more females received pioglitazone (6 of 8) whereas more males received placebo (7 of 8). This sex difference could have resulted in confounding, although we note that within these small numbers, sex was not a predictor of MBF in the regression model. In addition, some of these patients were receiving insulin, which itself can contribute to variability in glucose concentrations, another potentially important variable in MBF that may have interfered with our ability to conclusively determine a relationship between glucose and MBF. Of note, although an inverse relationship was found between mean glucose and coronary blood flow, no relationship was apparent between HbA1c and MBF.
Twelve weeks may be an insufficient exposure to the active drug to demonstrate changes in MBF, especially for one that acts by modulating gene transcription, as predicted for a PPAR-{gamma} agonist. Nevertheless, prior studies have noted significant improvements in hepatic and peripheral insulin sensitivity to thiazolidinediones within similar time frames (32). Interestingly, lipid-lowering agents have been reported to rapidly alter MBF (33). The effect of pioglitazone on MBF may have been less than the predicted 20% change in myocardial perfusion used to power the study. PET-estimated coronary flow reserve is thought to be sufficiently precise to argue against test variability as accounting for the lack of change in MBF seen here. It is also worthwhile noting that the trend for improved blood flow did not reach statistical significance; perhaps a larger study may have demonstrated a thiazolidinedione benefit.
Consistent evidence exists (and is growing) for hyperglycemia as a key modulator of coronary vasodilator function in diabetes. An infusion of 50% dextrose in the brachial artery significantly attenuated the forearm blood flow response to methacholine in healthy humans without diabetes independent of their systemic insulin concentration (34). Kawano et al. (35) showed impaired flow-mediated brachial artery dilation after an oral glucose loading in subjects with normal and impaired glucose tolerance.
Several large-scale clinical trials are underway to test the effect of thiazolidinediones on clinical cardiovascular events. Several lines of evidence suggest that PPAR-{gamma} agonists may reduce atherosclerosis and cardiovascular morbidity. Within the limits of this study, the data presented here suggest that reductions in biochemical risk factors and blood pressure may be the dominant contributors to such vascular benefits rather than changes in insulin resistance. Data suggest that pioglitazone and other thiazolidinediones decrease C-reactive protein levels (18), microalbuminuria (36), arterial pulse-wave velocity (18), systolic and diastolic blood pressure (17), and increase adiponectin levels (18), each of which is associated with cardiovascular risk reduction. These data provide rationale for ongoing research to determine the nature of the effect of this class of agents on the cardiovascular system.
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