Pioglitazone Improves Myocardial Blood Flow and Glucose Utilization in Nondiabetic Patients With Combined Hyperlipidemia (original) (raw)
Related papers
2010
This study's aim was to examine whether treatment with pioglitazone, added to conventional lipid-lowering therapy, would improve myocardial glucose utilization (MGU) and blood flow (MBF) in nondiabetic patients with familial combined hyperlipidemia (FCHL). Background Thiazolidinediones were found to improve insulin sensitivity and MGU in type 2 diabetes and MBF in Mexican Americans with insulin resistance. Familial combined hyperlipidemia is a complex genetic disorder conferring a high risk of premature coronary artery disease, characterized by high serum cholesterol and/or triglyceride, low high-density lipoprotein (HDL) cholesterol, and insulin resistance. Methods We undertook a randomized, double-blind, placebo-controlled study in 26 patients with FCHL, treated with pioglitazone or matching placebo 30 mg daily for 4 weeks, followed by 45 mg daily for 12 weeks. Positron emission tomography was used to measure MBF at rest and during adenosine-induced hyperemia and MGU during euglycemic hyperinsulinemic clamp at baseline and after treatment. Results Whereas no change was observed in the placebo group after treatment, patients receiving pioglitazone showed a significant increase in whole body glucose disposal (3.93 Ϯ 1.59 mg/kg/min to 5.24 Ϯ 1.65 mg/kg/min; p ϭ 0.004) and MGU (0.62 Ϯ 0.26 mol/g/min to 0.81 Ϯ 0.14 mol/g/min; p ϭ 0.0007), accompanied by a significant improvement in resting MBF (1.11 Ϯ 0.20 ml/min/g to 1.25 Ϯ 0.21 ml/min/g; p ϭ 0.008). Furthermore, in the pioglitazone group HDL cholesterol (ϩ28%; p ϭ 0.003) and adiponectin (ϩ156.2%; p ϭ 0.0001) were increased and plasma insulin (Ϫ35%; p ϭ 0.017) was reduced. Conclusions In patients with FCHL treated with conventional lipid-lowering therapy, the addition of pioglitazone led to significant improvements in MGU and MBF, with a favorable effect on blood lipid and metabolic parameters. (A study to investigate the effect of pioglitazone on whole body and myocardial glucose uptake and myocardial blood flow/coronary vasodilator reserve in patients with familial combined hyperlipidaemia; http://www.controlledtrials.com/mrct/trial/230761/ISRCTN78563659; ISRCTN78563659) (
Atherosclerosis, 2007
Familial combined hyperlipidaemia (FCHL) is a complex genetic disorder conferring high risk of premature atherosclerosis, characterized by high cholesterol and/or triglyceride, low high density lipoprotein (HDL) cholesterol and insulin resistance. We examined whether pioglitazone, added to conventional lipid-lowering therapy, would favourably affect metabolic parameters and alter body fat content. We undertook a randomized, double blind, placebo-controlled study in 22 male patients with FCHL treated with pioglitazone or matching placebo 30 mg daily for 4 weeks, increasing to 45 mg for 12 weeks. Magnetic resonance imaging and proton magnetic resonance spectroscopy were performed to measure adipose tissue (AT) body content as well as intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL) at baseline and after treatment. Significantly improved in the pioglitazone group were: triglyceride/HDL (atherogenic index of plasma) −32.3% (p = 0.002), plasma glucose −4.4% (p = 0.03), alanine-aminotransferase (ALT) −7.7% (p = 0.005) and adiponectin 130.1% (p = 0.001). Pioglitazone treatment resulted in a significant increase in total (5.3%, p = 0.02) and subcutaneous (7.1%, p = 0.003) adipose tissue as well as in soleus-IMCL levels (47.4%, p = 0.02) without alteration in intra-abdominal AT or IHCL. Changes in ALT and AST and IHCL were strongly correlated (r = 0.72, p < 0.01; r = .0.86, p < 0.01, respectively).
BACKGROUND: Previous evidence indicates that pioglitazone may improve dyslipidemia in patients with Type 2 diabetes mellitus (T2DM). AIM: The primary objective of this study was to evaluate the effect of either pioglitazone or placebo with metformin on levels of serum HDL cholesterol (HDL-C) in patients with T2DM. A secondary objective evaluated changes in metabolic syndrome (MS)-specific parameters. SUBJECTS AND METHODS: This multicenter, double-blind, randomized study was performed in patients with T2DM treated with metformin and hemoglobin A1c (HbA1c) levels between 6-8%, central obesity and reduced HDL-C. MS was evaluated from global changes in parameter values and expressed as a single factorial score following multivariate analysis of each parameter. 213 patients (110 in the pioglitazone group and 103 in the placebo group) were available for intention-to-treat analysis. RESULTS: Pioglitazone-treated patients showed a significant increase in HDL-C compared to placebo group (6.3 mg/dl vs 3.0 mg/dl; p<0.01) in addition to a greater reduction in the extent of MS (-13.2 vs -4.9; p=0.0055). Upon study completion, patients treated with pioglitazone had lower levels of HbA1c (6.41±0.65 vs 6.96±0.74%; p<0.001) and homeostasis model assessment-insulin resistance (HOMA-IR) (2.88±1.95 vs 4.68±3.63; p=0.013) and a reduction of the atherogenic LDL subfraction (pattern B) (-5.7%). CONCLUSIONS: The beneficial effects observed in pioglitazone-treated patients in the present study, (i.e. the increase in HDL-C and the reduction of insulin resistance and atherogenic LDL subfractions), support findings from the PROactive trial, where pioglitazone showed pleiotropic effects and reduced death, fatal myocardial infarction (MI) and non-fatal MI in T2DM patients with MS. Furthermore, medication used in this study showed good tolerability.
Circulation, 2009
Background-Cardiac disease is the leading cause of mortality in type 2 diabetes mellitus (T2DM). Pioglitazone has been associated with improved cardiac outcome but also with an elevated risk of heart failure. We determined the effects of pioglitazone on myocardial function in relation to cardiac high-energy phosphate, glucose, and fatty acid metabolism and triglyceride content in T2DM patients. Methods and Results-Seventy-eight T2DM men without structural heart disease or inducible ischemia as assessed by dobutamine stress echocardiography were assigned to pioglitazone (30 mg/d) or metformin (2000 mg/d) and matching placebo for 24 weeks. The primary end point was change in cardiac diastolic function from baseline relative to myocardial metabolic changes, measured by magnetic resonance imaging, proton and phosphorus magnetic resonance spectroscopy, and [ 18 F]-2-fluoro-2-deoxy-D-glucose and [ 11 C]palmitate positron emission tomography. No patient developed heart failure. Both therapies similarly improved glycemic control, whole-body insulin sensitivity, and blood pressure. Pioglitazone versus metformin improved the early peak flow rate (Pϭ0.047) and left ventricular compliance. Pioglitazone versus metformin increased myocardial glucose uptake (PϽ0.001), but pioglitazone-related diastolic improvement was not associated with changes in myocardial substrate metabolism. Metformin did not affect myocardial function but decreased cardiac work relative to pioglitazone (Pϭ0.006), a change that was paralleled by a reduced myocardial glucose uptake and fatty acid oxidation. Neither treatment affected cardiac high-energy phosphate metabolism or triglyceride content. Only pioglitazone reduced hepatic triglyceride content (PϽ0.001). Conclusions-In T2DM patients, pioglitazone was associated with improvement in some measures of left ventricular diastolic function, myocardial glucose uptake, and whole-body insulin sensitivity. The functional changes, however, were not associated with myocardial substrate and high-energy phosphate metabolism.
Pioglitazone reduces atherogenic index of plasma in patients with type 2 diabetes
Clinical chemistry, 2004
Background: Insulin resistance is often associated with increased triglyceride (TG) and decreased HDL-cholesterol (HDL-C) concentrations and increased small LDL particles. The Atherogenic Index of Plasma (AIP) has recently been proposed as a marker of plasma atherogenicity because it is increased in people at higher risk for coronary heart disease and is inversely correlated with LDL particle size. We studied the effect of pioglitazone, a thiazolidinedione that reduces insulin resistance, on the AIP of patients with type 2 diabetes. Methods: The data for the analysis of AIP in this report were obtained from four randomized, double-blind, multicenter, parallel-group, placebo-controlled clinical trials. Pioglitazone was used as monotherapy in one study and in combination therapy in three studies. Fasting glucose, insulin, HDL-C, and TGs plus glycohemoglobin (HbA 1C) were measured at baseline and various points during each study. Results: Patients in this study population with type 2 diabetes had high AIP values at baseline. Pioglitazone treatment significantly decreased AIP from baseline in each of the study groups. Pioglitazone treatment groups had a significantly lower AIP compared with their respective placebo controls. Finally, AIP was inversely and significantly correlated with measures of insulin sensitivity, such as the homeostasis model assessment and quantitative insulin sensitivity check index. In contrast, AIP was not significantly correlated with HbA 1C. Conclusions: Pioglitazone reduced AIP when used as monotherapy or in combination therapy with sulfonylurea, metformin, or insulin. AIP was inversely correlated with measures of insulin sensitivity.
Canadian Journal of Physiology and Pharmacology, 2007
The objective of the study was to demonstrate the effect of pioglitazone and pioglitazone in combination with statin on East Indian patients with hyperinsulinemia and hyperlipidemia. It was a randomized, placebo-controlled, doubleblind study with a parallel-group design comprising 83 patients. Patients of either sex with cardiac complications, including hyperlipidemia and (or) diabetes mellitus with or without hyperinsulinemia, were enrolled. Patients over 70 years of age, with renal or hepatic failure, or with severe diabetes mellitus (total glucose >400 mg/dL) were excluded from the study. Enrolled patients were randomly assigned to 4 groups that received placebo, pioglitazone, atorvastatin, or both. Blood samples were collected before and after treatment for analysis of serum glucose, insulin, lipid profile, apolipoprotein (apo) A1, apo B, and fibrinogen. Data were compared with that of patients with normal insulin or hyperinsulinemia. The patients with hyperinsulinemia receiving only pioglitazone showed a significant decrease in insulin levels compared with those with normal insulin levels. These patients also showed a significant increase in HDL levels. However, no significant change was observed in patients treated with both atorvastatin and pioglitazone. Pioglitazone was also found to increase significantly the apo A1 levels in patients with hyperinsulinemia, but there was no significant increase in patients given both atorvastatin and pioglitazone. Our data suggests that pioglitazone should be given preferably to the patients with hyperinsulinemia and statin should not be coadministered.
Dyslipidaemia in Type 2 diabetes: effects of the thiazolidinediones pioglitazone and rosiglitazone
Diabetic Medicine, 2005
This meta-analysis includes 23 randomized controlled trials in patients with Type 2 diabetes, which compared pioglitazone or rosiglitazone with placebo for 12 weeks. Both thiazolidinediones improved glycaemic control, HbA 1c reductions being 1.0-1.5%, and resulted in weight gain of about 3.0 kg. Pioglitazone significantly lowered triglycerides (− 0.45 mmol / l), increased high-density lipoprotein cholesterol (HDL-C) (+0.12 mmol / l), and showed neutral effects on low-density lipoprotein cholesterol (LDL-C) and total cholesterol levels. Rosiglitazone significantly increased HDL-C (+0.07 mmol/l) and had a neutral effect on triglycerides (− 0.12 mmol/l, 95% confidence intervals − 0.16 mmol / l to +0.14 mmol / l), while there were increases in LDL-C (+0.39 mmol / l) and total cholesterol (+0.54 mmol/l). Thiazolidinediones have similar effects upon glycaemic control and weight gain, but pioglitazone produces a more favourable lipid profile. The results of head-to-head clinical trials of these two thiazolidinediones are awaited, and long-term studies with cardiovascular end-points are ongoing.
Cardiovascular Diabetology, 2011
Background: Type 2 diabetes (T2D) is strongly associated with cardiovascular risk and requires medications that improve glycemic control and other cardiovascular risk factors. The authors aimed to assess the relative effectiveness of pioglitazone (Pio), metformin (Met) and any sulfonylurea (SU) combinations in non-insulin-treated T2D patients who were failing previous hypoglycemic therapy. Methods: Over a 1-year period, two multicenter, open-labeled, controlled, 1-year, prospective, observational studies evaluated patients with T2D (n = 4585) from routine clinical practice in Spain and Greece with the same protocol. Patients were eligible if they had been prescribed Pio + SU, Pio + Met or SU + Met serving as a control cohort, once they had failed with previous therapy. Anthropometric measurements, lipid and glycemic profiles, blood pressure, and the proportions of patients at microvascular and macrovascular risk were assessed. Results: All study treatment combinations rendered progressive 6-month and 12-month lipid, glycemic, and blood pressure improvements. Pio combinations, especially Pio + Met, were associated with increases in HDL-cholesterol and decreases in triglycerides and in the atherogenic index of plasma. The proportion of patients at high risk decreased after 12 months in all study cohorts. Minor weight changes (gain or loss) and no treatment-related fractures occurred during the study. The safety profile was good and proved similar among treatments, except for more hypoglycemic episodes in patients receiving SU and for the occurrence of edema in patients using Pio combinations. Serious cardiovascular events were rarely reported. Conclusions: In patients with T2D failing prior hypoglycemic therapies, Pio combinations with SU or Met (especially Pio + Met) improved blood lipid and glycemic profiles, decreasing the proportion of patients with a high microvascular or macrovascular risk. The combination of Pio with SU or Met may therefore be recommended for T2D second-line therapy in the routine clinical practice, particularly in patients with dyslipidemia.