Low-dose Pioglitazone Research Articles

Pioglitazone attenuates atrial remodeling and vulnerability to atrial fibrillation in alloxan-induced diabetic rabbits.

Recent evidence indicates that peroxisome proliferator-activated receptor (PPAR)-γ activators exert anti-inflammatory and antioxidant actions. However, the underlying mechanisms by which these agents prevent atrial remodeling in diabetes are not completely elucidated. We sought to investigate the potential effects of pioglitazone, a PPAR-γ activator, on atrial remodeling and atrial fibrillation (AF) inducibility in diabetic rabbits. Alloxan-induced diabetic rabbits were randomly divided into three groups: diabetes only, diabetes treated with low-dose pioglitazone (4mg/day/kg), or diabetes treated with high-dose pioglitazone (8mg/day/kg) (n=24 for each group). A total of 24 healthy rabbits served as controls. Eight weeks later, hemodynamic, echocardiographic, and electrophysiological parameters were recorded. Left atrial whole-cell patch-clamp studies, histological examination, and Western blot analysis were also performed. In the DM group (6/8 vs 1/8, P<.05), higher AF inducibility, increased amount of fibrosis, lower INa , and higher ICaL were observed in the DM group compared to controls. Western blot analysis showed that DM increased the expression of extracellular signal-regulated kinase 2 (ERK2), phosphorylation ERK, transforming growth factor beta-1, Toll-like receptor 4, nuclear factor-κB p50, and heat-shock protein 70. All of these electrophysiological, histological, ion current density, and protein expression changes were all reduced by pioglitazone. Pioglitazone attenuates diabetes-induced structural and electrophysiological remodeling in the atria, thereby reducing the vulnerability to AF.

The Low-Dose (7.5 mg/day) Pioglitazone Therapy.

Pioglitazone is one of thiazolidinedione derivatives, which stimulates nuclear peroxisome proliferator-activated receptor gamma and improves glucose and lipid metabolism and insulin sensitivity. A recent systematic review and meta-analysis showed that pioglitazone therapy was associated with a lower risk of major adverse cardiovascular events in patients with pre-diabetes and diabetes. Further, in a cohort study of patients with type 2 diabetes, pioglitazone therapy was associated with a statistically significant decrease in the risk of all-cause mortality. Despite these beneficial effects, the meta-analysis showed that pioglitazone therapy had higher risks of heart failure, bone fractures, edema and weight gain. To find out the efficacy and safety of the low-dose (7.5 mg/day) pioglitazone therapy, we reviewed the dose-response of pioglitazone on favorable effects and adverse effects due to pioglitazone, by searching the reports on effects of daily dose of 7.5 mg and/or 15 mg and/or 30 mg of pioglitazone. The low-dose pioglitazone therapy may show the same degree of improvements in glucose and lipid metabolism, fatty liver, insulin resistance, and adiponectin as the standard- and high-dose pioglitazone therapy. Furthermore, the low-dose pioglitazone therapy may also show less adverse effects on weight gain, edema and heart failure as compared with the standard- and high-dose pioglitazone therapy.

CHARACTERIZATION OF THE SCREENED POPULATION FOR THE TOMMORROW STUDY: A PHARMACOGENETICS-SUPPORTED CLINICAL TRIAL TO DELAY THE ONSET OF MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER’S DISEASE

In order to address the unmet burden of Alzheimer’s disease (AD), there is a growing interest in delaying symptom onset by initiating treatment in individuals at risk for disease but without overt evidence of cognitive deficits. To identify asymptomatic individuals at risk for disease, a biomarker risk assignment algorithm (BRAA) that includes the apolipoprotein E (APOE) and translocase of outer mitochondrial membrane 40 (TOMM40) genotypes [polyT homopolymer, rs10524523] and age has been developed. The TOMMORROW study will simultaneously qualify the BRAA for assigning risk of developing mild cognitive impairment (MCI) due to AD and evaluate the efficacy of low-dose pioglitazone (0.8 mg SR) for delaying the onset of MCI due to AD in individuals identified by the BRAA to be high-risk. A global, phase 3, double-blind, placebo-controlled trial was initiated in 2013 and has now been fully enrolled. The time-to-onset study operationalizes the core clinical diagnostic criteria (Albert et al. 2011) for MCI due to AD as the primary endpoint event. The study will be completed when 202 events in the high risk subjects have been reached; the treatment period is anticipated to be approximately 5 years. The TOMMORROW study (NCT01931566 clinicaltrials.gov) completed enrollment in December 2015 with 3494 subjects randomized. Screening was carried out on >24,000 individuals between ages 65–83 years (inclusive) at 59 study sites in five countries. At screening, <3% of the subjects self-identified as cognitively normal primarily failed due to not meeting the cognitive threshold for inclusion (age- and education-adjusted MMSE ≥25). The regional composition was 67% US, 20% UK, 11% AU, and 2% Germany and Switzerland. The gender split was approximately 56% female and 44% male. Genetic data for APOE and TOMM40’523were generated on >22,000 subjects. The demographic description, genetic characteristics (including APOE distribution of genotype status), and screening characteristics for this screening cohort of elderly, cognitively normal subjects will be presented. The experience of recruiting this study cohort provides valuable insights into the characteristics of healthy adults interested in clinical trials to delay symptomatic AD. The results may facilitate recruitment efforts for subsequent studies along the AD continuum.

The bioflavonoid quercetin synergises with PPAR-γ agonist pioglitazone in reducing angiotensin-II contractile effect in fructose-streptozotocin induced diabetic rats.

This study investigated the effects of combined minimal concentrations of quercetin and pioglitazone on angiotensin II-induced contraction of the aorta from fructose-streptozotocin (F-STZ)-induced type 2 diabetic rats and the possible role of superoxide anions (O2(-)) and nitric oxide (NO) in their potential therapeutic interaction. Contractile responses to Ang II of aortic rings from Sprague-Dawley (SD) and F-STZ rats were tested following pre-incubation of the tissues in the vehicle (DMSO; 0.05%), quercetin (Q, 0.1μM), pioglitazone (P, 0.1μM) or their combination (P+Q; 0.1μM each). The amount of superoxide anion was evaluated by lucigenin-enhanced chemiluminescence and dihydroethidium fluorescence, and NO by assay of total nitrate/nitrite, and 4-Amino-5-Methylamino-2',7'-Difluorofluorescein (DAF-FM) diacetate. The synergistic reduction of Ang II-induced contraction of diabetic but not normal aorta with minimally effective concentrations of P+Q occurs through inhibiting O2(-) and increasing NO bioavailability. This finding opens the possibility of maximal vascular protective/antidiabetic effects with low dose pioglitazone combined with quercetin, thus minimizing the risk of adverse effects.

Pharmacodynamic Effects of Low-Dose Pioglitazone in Patients with the Metabolic Syndrome without Diabetes Mellitus.

To determine the effects of low-dose pioglitazone on plasma adipocyte-derived cytokines, high-sensitivity C-reactive protein (hs-CRP), and components of the metabolic syndrome in adults with the metabolic syndrome without diabetes mellitus. Prospective, randomized, double-blind, placebo-controlled study. University of Colorado Clinical and Translational Research Center. Thirty-two men and women, aged 30-60 years, without diabetes who had a clinical diagnosis of the metabolic syndrome, as defined by the American Heart Association/National Heart, Lung, and Blood Institute criteria. Patients were randomly assigned to receive oral pioglitazone 7.5 mg daily or matching placebo for 8 weeks. The primary end point was the change in plasma high-molecular-weight (HMW) adiponectin level from baseline to week 8. Other end points were changes in plasma total adiponectin, omentin, and hs-CRP levels, and changes in components of the metabolic syndrome (e.g., insulin sensitivity) from baseline to week 8. Pioglitazone was associated with a significant increase in plasma HMW adiponectin from baseline to week 8 compared with placebo (+47% vs -10%, p<0.001). Insulin sensitivity increased significantly from baseline to week 8 in the pioglitazone group (+88%, p=0.02) but not in the placebo group (+15%, p=0.14). Change in HMW adiponectin was significantly correlated with the change in insulin sensitivity in the pioglitazone group (r = 0.784, p=0.003). No significant differences in mean percentage changes in plasma total adiponectin, omentin, and hs-CRP levels were observed between the pioglitazone and placebo groups. Likewise, changes in body weight, insulin sensitivity, glucose, lipids, and blood pressure did not differ significantly between the groups. Low-dose pioglitazone favorably modulates plasma HMW adiponectin, which was associated with an improvement in insulin sensitivity, in patients with the metabolic syndrome without diabetes.

Effects of Low-Dose Pioglitazone on Serum Levels of Adiponectin, Dehydroepiandrosterone, Amyloid Beta Peptide, and Lipid Profile in Elderly Japanese People with Type 2 Diabetes

This study was performed to see how pioglitazone at low doses could affect blood biomarkers related to atherosclerosis and aging. The effects of an add-on treatment with pioglitazone (15 mg for males and 7.5 mg for females) for 6 months were assessed in 24 outpatients (12 males, 12 females) with type 2 diabetes aged ≥ 70 years. As doses of sulfonylurea were reduced in 10 patients, no significant differences in HbA1c and glucose levels were seen. After the treatment, serum levels of HDL cholesterol, arachidonic acid (predominant in males), and high-molecular-weight adiponectin significantly increased. The level of dehydroepiandrosterone sulfate significantly decreased. No significant changes were seen in those of small dense LDL cholesterol, high-sensitivity C-reactive protein, and amyloid beta peptides 1–40 and 1–42. There was a slight but significant increase in body weight, but apparent adverse effects were not observed. In conclusion, pioglitazone at low doses increased serum adiponectin, HDL cholesterol, and arachidonic acid levels but decreased serum dehydroepiandrosterone level, not associated with glycemia, in elderly Japanese people with type 2 diabetes. An optimal dose of pioglitazone should be sought for to minimize its adverse effects and to fully exert its pleiotropic effects such as antiatherosclerotic and antiaging effects.

Progress in the tommorrow study: A pharmacogenetics supported clinical trial to delay onset of mild cognitive impairment due to Alzheimer’s disease with low-dose pioglitazone

Progress in the tommorrow study: A pharmacogenetics supported clinical trial to delay onset of mild cognitive impairment due to Alzheimer’s disease with low-dose pioglitazone

Effect of low dose pioglitazone on glycemic control and insulin resistance in Type 2 diabetes: A randomized, double blind, clinical trial

This study shows that pioglitazone 7.5mg/day as an add-on therapy in Southeast Asian patients with Type 2 diabetes is safer and equally efficacious as the 15- and 30-mg doses of pioglitazone. Hence it is prudent to start pioglitazone therapy at a lower dose of 7.5mg/day.

Effects of low doses of pioglitazone on resting-state functional connectivity in conscious rat brain.

Pioglitazone (PIO) is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist in clinical use for treatment of type 2 diabetes (T2DM). Accumulating evidence suggests PPARγ agonists may be useful for treating or delaying the onset of Alzheimer’s disease (AD), possibly via actions on mitochondria, and that dose strengths lower than those clinically used for T2DM may be efficacious. Our major objective was to determine if low doses of pioglitazone, administered orally, impacted brain activity. We measured blood-oxygenation-level dependent (BOLD) low-frequency fluctuations in conscious rats to map changes in brain resting-state functional connectivity due to daily, oral dosing with low-dose PIO. The connectivity in two neural circuits exhibited significant changes compared with vehicle after two days of treatment with PIO at 0.08 mg/kg/day. After 7 days of treatment with a range of PIO dose-strengths, connections between 17 pairs of brain regions were significantly affected. Functional connectivity with the CA1 region of the hippocampus, a region that is involved in memory and is affected early in the progression of AD, was specifically investigated in a seed-based analysis. This approach revealed that the spatial pattern of CA1 connectivity was consistent among all dose groups at baseline, prior to treatment with PIO, and in the control group imaged on day 7. Compared to baseline and controls, increased connectivity to CA1 was observed regionally in the hypothalamus and ventral thalamus in all PIO-treated groups, but was least pronounced in the group treated with the highest dose of PIO. These data support our hypothesis that PIO modulates neuronal and/or cerebrovascular function at dose strengths significantly lower than those used to treat T2DM and therefore may be a useful therapy for neurodegenerative diseases including AD.

Low Dose Pioglitazone Attenuates Oxidative Damage in Early Alzheimer's Disease by Binding mitoNEET

Oxidative damage (OD) is considered to be a central component in the progression of Alzheimer's disease (AD). 8-hydroxyguanosine (8-OHG), a readily oxidized ribonucleic acid found in AD, was used as a biomarker to investigate the role of OD in the progression of the disease. A disruption in two critical Thioredoxin-Dependent Peroxiredoxin System components, peroxiredoxin-3 (Prx-3) and thioredoxin (Trx), may serve as a source of the increased accumulation of OD observed in AD. We demonstrate that OD, in the form of 8-OHG, was quantitatively most significant during the earliest stage of AD [F (3, 25) = 5.08, p &lt; .01]. A drastic decline in mitochondrial protein levels of Prx-3 [F (3, 25) = 8.74, p. &lt; 01] and Trx [F (3, 25) = 4.33, p. &lt; 05] were also observed across the progression of the disease. We then tested the efficacy of pioglitazone, a thiazolidinedione class drug aimed to delay onset of AD by acting on mitoNEET. Our results showed a significant reduction in the oxidized variant of mitoNEET within the incipient population when a 0.8mg dose was simulated in silico (p = 0.0242; a. &lt; 05).

Efficacy of pioglitazone on erectile function recovery in a rat model of cavernous nerve injury.

To examine the effect of pioglitazone on erectile function in a rat model of postprostatectomy erectile dysfunction. Twenty adult rats were divided into 4 groups: (a) sham, (b) control--bilateral cavernosal nerve crush injury (BCNI), (c) BCNI + low-dose pioglitazone (PioL), and (d) BCNI + high-dose pioglitazone (PioH). Sham and control rats were administered phosphate-buffered saline, whereas PioL and PioH rats received 0.65 and 6.5 mg/kg of pioglitazone, respectively. All treatments were administered by oral gavage for 14 days. After treatment, animals underwent surgery for endpoint cavernosal response to define hemodynamic parameters of erectile function, reported as the ratio of intracavernosal pressure to mean arterial pressure. Corporal tissue was retrieved for histologic and molecular analysis. Animals treated with pioglitazone experienced dose-dependent improvements in the ratio of intracavernosal pressure to mean arterial pressure, with the PioH group achieving results similar to the sham group: sham, 0.774; BCNI, 0.421; PioL, 0.616; PioH, 0.758 (P = .0006). PioH animals demonstrated increased expression of endothelial nitric oxide (eNOS) and neuronal nitric oxide (nNOS), whereas both PioL and PioH animals had increased staining for anti--smooth muscle actin antibody and nonsignificant increases in cyclic guanosine monophosphate (cGMP). Pioglitazone improves erectile function in rats undergoing BCNI via a nitric oxide--mediated pathway.

Protective effects of pioglitazone against immunoglobulin deposition on heart of streptozotocin-induced diabetic rats

Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have immunomodulatory and anti-inflammatory effects. The study investigated the autoimmune injuries of diabetic cardiomyopathy (DCM) and tested the hypothesis that PPAR-γ agonists suppress disordered immune responses in diabetic heart, thereby preventing evolution of DCM. STZ-induced diabetic rats were assigned to five groups: DM group, given no treatment; INS group, given insulin (4 U kg(-1) d(-1)); PIL group, given low dose pioglitazone (4 mg kg(-1) d(-1)); PIL/INS group, given both low dose pioglitazone and insulin; PIH group, given high dose pioglitazone (20 mg kg(-1) d(-1)). Normal rats (CON group) were also monitored as control. The pathologic abnormalities of hearts were observed. The immunoglobulin deposition was examined by immunohistochemistry and immunofluorescence. At 16 weeks, interstitial fibrosis was shown in diabetic heart which was accompanied by plenty of inflammatory cells infiltrated. Pioglitazone therapy could ameliorate the cardiac injuries. Shown by immunohistochemistry, the difference of integrated optical density (IOD) of immunoglobulin deposition among each group had statistic significance. No obvious immunoglobulins were deposited in the intercellular substance of heart in CON group (IgA 290.8 ± 88.1, IgG 960.4 ± 316.0 and IgM 341.3 ± 67.9). But the deposition of immunoglobulins increased significantly in DM group (IgA 7,047.5 ± 1,328.3, P < 0.05; IgG 28,945.9 ± 5,160.7, P < 0.05 and IgM 8,580.8 ± 1,336.8, P < 0.05). Administration of pioglitazone greatly reduced the increased deposition in a dose-dependent fashion. Moreover, the statistical significance was the same with immunofluorescence analysis as with immunohistochemical examination. The data suggest that disordered immune responses play an important role in the pathogenesis of DCM. Pioglitazone showed protective effects by inhibiting the immunoglobulin deposition on diabetic myocardium.

Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone—a factorial study

To evaluate the efficacy and safety of initial combination therapy of sitagliptin 100 mg/day coadministered with all marketed doses of pioglitazone in patients with type 2 diabetes. Patients with A1c ≥7.5 and ≤11.0% were randomized among seven arms that received, once daily, 100 mg sitagliptin alone; 15, 30 or 45 mg pioglitazone alone, or 100 mg sitagliptin plus 15, 30 or 45 mg pioglitazone for 54 weeks. The primary endpoint was change from baseline in A1c at week 24. Protocol-specified analyses compared combination therapies with monotherapies at respective dose-strengths and combination of sitagliptin plus pioglitazone 30 mg with pioglitazone 45 mg monotherapy. Post-hoc analyses compared sitagliptin plus pioglitazone 15 mg with pioglitazone monotherapy at the two higher doses. Initial combination therapy with sitagliptin and pioglitazone provided significantly greater reductions in A1c (0.4-0.7% differences) and other glycaemic endpoints than either monotherapy at the same doses. Combining sitagliptin with low-dose pioglitazone generally produced greater glycaemic improvements than higher doses of pioglitazone monotherapy (0.3-0.4% differences in A1c). Combination therapy was generally well tolerated; adverse events (AEs) of hypoglycaemia were reported with similar incidence (7.8-11.1%) in all treatment groups over the 54 weeks of study; oedema was reported in 0.5% of patients in the sitagliptin monotherapy group and 2.7-5.3% among pioglitazone-treated groups. Significant weight gain was observed in all combination-treated groups compared with the sitagliptin monotherapy group. Initial combination therapy with sitagliptin and pioglitazone provided better glycaemic control than either monotherapy and was generally well tolerated.

Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3–TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study

Pioglitazone (PIO) is a peroxisome proliferator-activated receptor (PPAR)γ agonist insulin-sensitiser with anti-inflammatory and anti-atherosclerotic effects. Our objective was to evaluate the effect of low-dose PIO (15 mg/day) on glucose metabolism and inflammatory state in obese individuals with type 2 diabetes. A randomised, double-blind, placebo-controlled, mechanistic trial was conducted on 29 patients with type 2 diabetes treated with metformin and/or sulfonylurea. They were randomised to receive PIO or placebo (PLC) for 6 months, in a 1:1 ratio. Participants were allocated to interventions by central office. All study participants, investigators and personnel performing measurements were blinded to group assignment. At baseline and after 6 months patients underwent: (1) OGTT; (2) muscle biopsy to evaluate expression of TNF-α, tissue inhibitor of metalloproteases 3 (TIMP-3) levels, TNF-α converting enzyme (TACE) expression and enzymatic activity; (3) euglycaemic-hyperinsulinaemic clamp; (4) measurement of plasma high-sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor type-1 (PAI-1), TNF-α, IL-6, monocyte chemotactic protein-1 (MCP-1), adiponectin and fractalkine (FRK). The interventions were PIO 15 mg/day vs placebo and the main outcomes measured were absolute changes in whole-body insulin sensitivity, insulin secretion and inflammatory state. Fifteen participants were randomized to receive PIO and 14 participants were randomized to receive PLC. Eleven participants completed the study in the PIO group and nine participants completed the study in the PLC group and were analysed. Fasting plasma glucose and HbA1c decreased modestly (p < 0.05) after PIO and did not change after PLC. M/I (insulin-stimulated whole-body glucose disposal), adipose tissue insulin resistance (IR) index, insulin secretion/IR (disposition) index and insulinogenic index improved significantly after PIO, but not after PLC. Circulating MCP-1, IL-6, FRK, hsCRP and PAI-1 levels decreased in PIO- as compared with PLC-treated patients, while TNF-α did not change. TNF-α protein expression and TACE enzymatic activity in muscle were significantly reduced by PIO but not PLC. Adiponectin levels increased significantly after PIO as compared with PLC treatment. Given that the mean TACE enzymatic activity level at baseline in the PIO group was 0.29 ± 0.07 (fluorescence units [FU]), and at end of study decreased to 0.05 vs 0.14 in the PLC group, the power to reject the null hypothesis that the population means of the PIO and PLC groups are equal after 6 months is greater than 0.80. Given that M/I was 2.41 ± 0.35 μmol kg(-1) min(-1) (pmol/l)(-1) at baseline and increased by 0.55 in the PIO and 0.17 in the PLC groups, the power to reject the null hypothesis that the population means of the PIO and PLC groups are equal after 6 months is greater than 0.85. The type I error probability associated with this test of this null hypothesis is 0.05. No serious adverse events occurred in either group. Low-dose PIO (15 mg/day) improves glycaemic control, beta cell function and inflammatory state in obese patients with type 2 diabetes. Clinical.Trial.gov NCT01223196. This study was funded by TAKEDA.

Combined treatment with low-dose pioglitazone and beraprost sodium improves glucose intolerance without causing body weight gain

Pioglitazone (PIO) is widely used as an insulin-sensitizing agent in the treatment of type 2 diabetes, but it also causes an increase in body weight in a dose-dependent manner. Beraprost sodium (BPS), a stable prostaglandin I2 analog, is used clinically for the treatment of peripheral arterial disease and primary pulmonary hypertension. BPS has recently been demonstrated to promote insulin-induced glucose uptake by skeletal muscle. In this study, we examined whether low-dose PIO (PIO-L; 3 mg/kg/day) plus BPS treatment might exert antidiabetic effects without causing body weight gain in obese/diabetic KKAy mice. Treatment with PIO-L plus BPS tended to improve the hepatic insulin resistance and significantly improved the skeletal muscle insulin resistance, yielding a similar degree of hyperglycemia improvement to that obtained with high-dose PIO (PIO-H; 30 mg/kg/day) treatment. Moreover, the increase in body weight observed following PIO-H treatment was not observed following PIO-L plus BPS treatment. An increase in plasma adiponectin levels, which have been shown to be negatively correlated with hepatic glucose production, but not with the glucose disappearance rate during hyperinsulinemic-euglycemic clamp, was observed in the animals treated with PIO-L, PIO-L plus BPS, and PIO-H. This suggests that the improvement in hepatic insulin resistance was associated, at least in part, with an increase in the plasma adiponectin levels observed during PIO treatment. In contrast, treatment with BPS, which failed to increase the plasma adiponectin levels, ameliorated skeletal, but not hepatic insulin resistance. PIO-L plus BPS treatment may represent efficacious treatment for insulin resistance and type 2 diabetes without causing body weight gain.

Effects of Low Dose Pioglitazone on Restenosis and Coronary Atherosclerosis in Diabetic Patients Undergoing Drug Eluting Stent Implantation

PurposeThiazolidinediones are insulin-sensitizing agents that reduce neointimal proliferation and the adverse clinical outcomes associated with percutaneous coronary intervention (PCI) in patients with diabetes mellitus (DM). There is little data on whether or not low dose pioglitazone reduces adverse clinical outcomes.Materials and MethodsThe study population included 121 DM patients with coronary artery disease and they were randomly assigned to 60 patients taking 15 mg of pioglitazone daily in addition to their diabetic medications and 61 patients with placebo after the index procedure with drug-eluting stents (DESs). The primary end points were rate of in-stent restenosis (ISR) and change in atheroma volume and in-stent neointimal volume. The secondary end points were all-cause death, myocardial infarction (MI), stent thrombosis and re-PCI.ResultsThere were no statistical differences in the clinical outcomes and the rate of ISR between the two groups [all-cause death; n=0 (0%) in the pioglitazone group vs. n=1 (1.6%) in the control group, p=0.504, MI; n=2 (3.3%) vs. n=1 (1.6%), p=0.465, re-PCI; n=6 (10.0%) vs. n=6 (9.8%), p=0.652, ISR; n=4 (9.3%) vs. n=4 (7.5%), p=1.000, respectively]. There were no differences in changes in neointimal volume, percent neointimal volume, total plaque volume and percent plaque volume between the two groups on intravascular ultrasonography (IVUS) study.ConclusionOur study demonstrated that low dose pioglitazone does not reduce rate of ISR, neointimal volume nor atheroma volume in DM patients who have undergone PCI with DESs, despite the limitations of the study.

Effects of low-dose pioglitazone on glucose control, lipid profiles, renin-angiotensin-aldosterone system and natriuretic peptides in diabetic patients with coronary artery disease

Pioglitazone ameliorates insulin resistance, but has an adverse effect of oedema that may result in subsequent heart failure, especially in diabetic patients with coronary artery disease. In this study, we evaluated the effects of low-dose pioglitazone on glucose control, lipid profiles, renin-angiotensin-aldosterone (RAA) system and natriuretic peptides in diabetic patients with coronary artery disease. and results: We studied 22 diabetic patients with coronary artery disease and more than 40% of left ventricular ejection fraction (LVEF). Patients were treated with 15 mg of pioglitazone for 12 weeks, in addition to their other hypoglycaemic agents. Pioglitazone significantly decreased fasting blood glucose (155.2±52.9 mg/dl to 131.1±38.4 mg/dl, p<0.01) and haemoglobin A1C (7.13±0.44 to 6.69±0.47, p<0.001). It did not affect low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, but significantly decreased triglyceride (115.6±28.8 mg/dl to 99.4±30.0 mg/dl, p<0.05) and atherogenic index of plasma (0.28±0.17 to 0.19±0.16, p<0.05). Pioglitazone did not affect plasma renin activity, plasma aldosterone, human atrial natriuretic peptide or N-terminal pro-brain natriuretic peptide. Our data suggested that low-dose pioglitazone was a safe and useful agent at least in diabetic patients with coronary artery disease and preserved LVEF.

The effect of pioglitazone treatment on 15-epi-lipoxin A4 levels in patients with type 2 diabetes

ObjectivesArachidonic acid-derived eicosanoids (lipoxins and 15-epilipoxins) have a major role in resolution of inflammation. 15-epi-lipoxin A4 (15-epi-LXA4) is a lipid mediator with strong anti-inflammatory and inflammation-resolving effects. We examined the effect of pioglitazone therapy on plasma 15-epi-LXA4 in patients with type 2 diabetes (T2DM). MethodsT2DM patients (Age = 56 ± 2 y, BMI = 33 ± 1.8, HbA1c = 7.8 ± 0.3%) not on thiazolidinedione therapy for at least 12 months were randomized to receive either pioglitazone 15 mg/daily for two months (PIO 15) or pioglitazone 15 mg/day for one month followed by a dose escalation to 30 mg/day for an additional one month (PIO 30). ResultsPIO 15 increased plasma 15-epi-LXA4 levels (0.63 ± 0.06–1.05 ± 0.08 ng/mL, p < 0.01) and adiponectin levels (6.4 ± 0.3–10.1 ± 0.7 μg/mL, p < 0.001) and decreased fasting plasma glucose (125 ± 8–106 ± 9 mg/dL, p < 0.05), free fatty acids (FFA) (414 ± 46–320 ± 38 μmol/l, p < 0.05) and HOMA-IR (5.3 ± 0.4 to 4.0 ± 0.4, p < 0.05). Body weight (Δ = 0.2 kg) and HbA1c (7.4 ± 0.2–7.1 ± 0.2%) did not change significantly. PIO 30 treated patients had similar increase in plasma 15-epi-LXA4 (0.64 ± 0.10–1.08 ± 0.09 ng/mL, p < 0.01), and decrease in plasma FFA (423 ± 42–317 ± 40 μmol/l, p < 0.05) despite a greater increase in plasma adiponectin (6.5 ± 0.4–15.5 ± 0.7 ug/mL, p < 0.001) and a greater reduction in HbA1c (8.7 ± 0.5–7.4 ± 0.3%, p < 0.01), FPG (159 ± 16–120 ± 10 mg/dL, p < 0.01), and HOMA-IR (6.6 ± 0.8–4.4 ± 0.4, p < 0.005). Furthermore, PIO 30 treated patients had a significant increase in body weight (Δ = 1.7 kg, p < 0.02). ConclusionIn T2DM, low dose pioglitazone (15 mg/day) increases 15-epi-LXA4 and adiponectin levels in the absence of significant changes in body weight. Dose escalation of pioglitazone to 30 mg/day is associated with a similar increase in 15-epi-LXA4 despite a greater increase in plasma adiponectin concentrations.

TCT-428: Effects of Low Dose Pioglitazone on Restenosis and Atheroma Plaques in Patients with Diabetes Mellitus Undergoing Percutaneous Coronary Intervention

TCT-428: Effects of Low Dose Pioglitazone on Restenosis and Atheroma Plaques in Patients with Diabetes Mellitus Undergoing Percutaneous Coronary Intervention

PDB70 LOW-Dose Pioglitazone Utilisation in Patients with Type 2 Diabetes Mellitus in the United Kingdom

To evaluate the distribution of pioglitazone (PIO) daily dose prescribed by physicians for patients with type 2 diabetes mellitus (T2DM). In a retrospective cohort study using the UK MediPlus database, patients with diagnosed T2DM who received PIO prescription between July 2008– June 2009 (observation period) were included. Medical records from 07/2007–06/2008 were used to assess baseline conditions. Patients were grouped, according to prescriptions in the observation period, as low-dose users who received PIO prescriptions of 15-mg daily dose only or were down-titrated to 15 mg from a higher daily dose, and high-dose users for the rest who received a 30 mg or higher daily dose. Of 1813 patients with T2DM who received a PIO prescription, 48% received at least one 15 mg prescription during the observation period. Among all PIO prescriptions, 39%, 40%, and 21% were in 15, 30, and 45 mg or higher daily dose, respectively. Per study definitions 38% of the patients were classified as low-dose users and 62% as high-dose users. Low-dose users were more likely to be female (56% vs. 40%) and had a lower baseline prevalence of diabetic nephropathy (0% vs. 1%), compared to high-dose users (p<0.05). Low-dose PIO use was not associated with baseline prevalence of congestive heart failure, coronary artery disease, or bone fractures. Low-dose PIO was prescribed in greater than one-third of PIO prescriptions, regardless of patient age and major comorbidities. The reason(s) why patients received low-dose PIO warrants further investigation.