Low-dose Pioglitazone Research Articles

Cost-Utility Analysis of Low-Dose Pioglitazone in a Population With Prediabetes and a History of Stroke or Transient Ischemic Attack.

Pioglitazone significantly reduces the risk of stroke in people with diabetes, and in those with prediabetes, it markedly reduces the risk of stroke/myocardial infarction and new-onset diabetes. Low-dose pioglitazone provides most of the clinical benefits of high-dose pioglitazone, with fewer adverse effects. We report an economic evaluation of the cost-effectiveness of low-dose pioglitazone versus placebo from a Canadian public payer perspective in 2023 Canadian dollars. A Markov model was developed at a lifetime horizon with an annual cycle length and 5 health states (event-free, myocardial infarction, stroke, new-onset diabetes, and death). Transition probabilities were extracted from the IRIS (Insulin Resistance Intervention in Stroke) trial. Health state costs and utilities were based on public sources. Annual discount rates of 1.5% were applied in the reference-case analysis. Probabilistic analyses were conducted to deal with parameter uncertainty through 5000 simulations. The costs were estimated as $24 887 (interquartile range [IQR], $14 632-$41507) for low-dose pioglitazone and $57 301 (IQR, $48 730-$67368) for placebo, resulting in a cost saving of -$30 287 (IQR, -$43 374 to -$14 587) in favor of low-dose pioglitazone. Quality-adjusted life years were estimated as 25.99 (IQR, 24.56-26.81) for the low-dose pioglitazone and 19.44 (IQR, 18.68-20.13) for placebo, resulting in a difference of 6.37 (IQR, 5.07-7.36) in favor of low-dose pioglitazone. Consistent findings were observed from scenario analyses and 1-way probability sensitivity analyses. Holding across a wide range of values in modeling parameters, low-dose pioglitazone is found as the dominant strategy versus a placebo.

Anti-steatotic effects of PPAR-alpha and gamma involve gut-liver axis modulation in high-fat diet-fed mice

AimTo evaluate the effects of PPARα and PPARγ activation (alone or in combination) on the gut-liver axis, emphasizing the integrity of the intestinal barrier and hepatic steatosis in mice fed a high saturated fat diet. MethodsMale C57BL/6J were fed a control diet (C) or a high-fat diet (HF) for ten weeks. Then, a four-week treatment started: HF-α (WY14643), HF-γ (low-dose pioglitazone), and HF-αγ (combination). ResultsThe HF caused overweight, insulin resistance, impaired gut-liver axis, and marked hepatic steatosis. Treatments reduced body mass, improved glucose homeostasis, and restored the gut microbiota diversity and intestinal barrier gene expression. Treatments also lowered the plasma lipopolysaccharide concentrations and favored beta-oxidation genes, reducing macrophage infiltration and steatosis in the liver. ConclusionTreatment with PPAR agonists modulated the gut microbiota and rescued the integrity of the intestinal barrier, alleviating hepatic steatosis. These results show that these agonists can contribute to metabolic-associated fatty liver disease treatment.

Adolescent polycystic ovary syndrome without obesity: HOTAIR rs1443512 genotype relates to fat mass and to the redistribution of fat mass on low-dose pioglitazone.

Adolescent polycystic ovary syndrome (PCOS) is characterized by androgen excess and oligo-amenorrhea, and often results from ectopic lipid storage due to a mismatch between early adipogenesis and later lipogenesis. Endogenous HOX transcript antisense RNA (HOTAIR) and exogenous pioglitazone are enhancers of subcutaneous adipogenesis, particularly in the gluteofemoral region. The A allele of HOTAIR rs1443512 is an equivalent of a natural knock-down and is, thus, a candidate to influence the distribution of fat mass, and also the redistribution of fat mass by pioglitazone in adolescent PCOS-without-obesity. We performed two post hoc analyses by HOTAIR rs1443512 genotype. In the first, we analyzed the pooled pre-treatment data (auxology; endocrinology; body composition by dual X-ray absorptiometry; abdominal fat distribution by magnetic resonance imaging) of 65 adolescent girls with PCOS-without-obesity in three reported studies (ISRCTN45546616; ISRCTN29234515; ISRCTN11062950). In the second, we analyzed the results of 24 adolescent girls with PCOS-without-obesity, who received pioglitazone (7.5 mg/d for 1 year) as part of a randomized combination treatment (with spironolactone and metformin) in two reported studies (ISRCTN29234515; ISRCTN11062950). All data had been obtained in a blinded-to-genotype way. The pre-treatment data disclosed that the girls-with-A-allele of HOTAIR rs1443512 had developed PCOS with a lower BMI (22.3 ± 2.3 kg/m2; N = 17) than the other girls (24.1 ± 2.7 kg/m2; N = 48), this difference being essentially attributable to a lower fat mass (mean difference 4.6 kg; P < 0.01). On low-dose pioglitazone, girls-with-A-allele (N = 12) raised their fat mass while the other girls (N = 12) did not (total fat mass + 2.2 ± 1.8 kg vs - 0.9 ± 2.2 kg; P < 0.001), particularly in the gynoid area (gluteofemoral fat + 0.6 ± 0.4 kg vs - 0.1 ± 0.5 kg; hip circumference + 2.3 ± 1.9 cm vs - 1.7 ± 3.1 cm; both P < 0.001). The present findings suggest that the HOTAIR rs1443512 genotype influences not only the distribution of fat mass in adolescent girls with PCOS-without-obesity but also the redistribution of fat mass during prolonged treatment with low-dose pioglitazone. ISRCTN45546616 ( https://doi.org/10.1186/ISRCTN45546616 ). ISRCTN29234515 ( https://doi.org/10.1186/ISRCTN29234515 ). ISRCTN11062950 ( https://doi.org/10.1186/ISRCTN11062950 ).

Efficacy of 3months of additional pioglitazone treatment in type 2 diabetes patients with alcoholic fatty liver disease.

Pioglitazone ameliorates liver dysfunction in type 2 diabetes (T2D) patients with non-alcoholic fatty liver disease (NAFLD); however, its efficacy in T2D patients with alcoholic fatty liver disease (AFLD) is unclear. Here, we conducted a retrospective single-center trial investigating whether pioglitazone ameliorates liver dysfunction in T2D patients with AFLD. T2D patients (n = 100) receiving 3months of additional pioglitazone were divided into those with or without fatty liver (FL), and those with FL were further classified into AFLD (n = 21) and NAFLD (n = 57) groups. The effects of pioglitazone were compared across groups using medical record data on body weight changes; HbA1c, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyl transpeptidase (γ-GTP) levels; and fibrosis-4 (FIB-4) index. The pioglitazone dose (mean dose: 10.6 ± 4.6mg/day) did not affect weight gain but significantly decreased the HbA1c level in patients with or without FL (P < 0.01 and P < 0.05, respectively). The decrease in HbA1c level was significantly more pronounced in patients with FL than in those without FL (P < 0.05). In patients with FL, the HbA1c, AST, ALT, and γ-GTP levels significantly decreased after pioglitazone treatment than before (P < 0.01). The AST and ALT levels, but not the γ-GTP level, and the FIB-4 index significantly decreased after pioglitazone addition in the AFLD group, similar to that in the NAFLD group (P < 0.05 and P < 0.01, respectively). Similar effects were observed following low-dose pioglitazone treatment (≤ 7.5mg/day) (P < 0.05) in T2D patients with AFLD and NAFLD. These results suggest that pioglitazone may be also an effective treatment option for T2D patients with AFLD.

ODP426 SPIOMET4HEALTH: a 4-Arm Trial to Test the Effects of Lifestyle Intervention plus either Placebo, or Pioglitazone (PIO), or Spironolactone-Pioglitazone (SPIO), or Spironolactone-Pioglitazone-Metformin (SPIOMET) in Adolescent Girls and Young Women with PCOS

Abstract Introduction PCOS in adolescent girls and young women is nowadays thought to be, in essence, an epiphenomenon of ectopic fat accumulation. By definition, "adolescent PCOS" is characterized by androgen excess (as well clinical as biochemical) and oligo-anovulation (often judged by oligo-amenorrhea) (1) presenting between 2 and 8 years after menarche. There is no FDA-approved treatment for "adolescent PCOS". In SPIOMET4HEALTH (a project funded by the European Commission under Grant Agreement 899671), we aim at reducing ectopic fat in an early phase of PCOS, with a standardized lifestyle intervention plus a pharmacological addendum consisting of either placebo, or PIO, or SPIO, or SPIOMET. In "adolescent PCOS", low-dose pioglitazone (7.5 mg/d) may exert insulin-sensitizing and gonadotropin-normalizing effects, in part by raising the circulating concentrations of high-molecular-weight adiponectin; low-dose spironolactone (50 mg/d) may not only act as an anti-androgen but also exert anti-mineralocorticoid effects that raise energy expenditure by activating brown adipose tissue; low-dose metformin (850 mg/d) is known to act through multiple mechanisms and was recently shown to be capable of changing the relative deficit of GDF15 into an abundance that is thought to contribute to reduce liver fat. Subjects &amp; Methods In the SPIOMET4HEALTH trial, patients with "adolescent PCOS" (age range 12. 0–23.9 years; BMI &amp;lt;35 kg/m 2) will be recruited in seven centers across Europe. A total of 364 patients are expected to engage into a lifestyle intervention, and to receive either placebo, or PIO, or SPIO, or SPIOMET once daily (1: 1: 1: 1 randomization; single tablets; double blinding) for 12 months. Post-treatment follow-up will span 6 months. The primary endpoint is ovulation rate, as judged by a combination of menstrual data and progesterone concentrations in saliva; the analysis will start by testing for superiority between placebo and SPIOMET. Secondary endpoints include pre-treatment, on-treatment and post-treatment measures of androgen excess, body composition and insulin sensitivity, as well as measures of quality of life, and of adherence to treatment. The design of this trial has been endorsed by the European Medicines Agency, as part of a "Paediatric Investigation Plan". Expected Results/Discussion The SPIOMET4HEALTH project is expected to deliver the first results of an international, randomized, double-blind, active-controlled/placebo-controlled trial evaluating the safety, efficacy, and tolerability of the fixed dose combination SPIOMET in adolescent girls and young women with PCOS. Favorable results of this Phase 2 trial may advance SPIOMET into Phase 3. Reference: Ibáñez L, et al. An International Consortium Update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence. Horm Res Paediatr 2017;88: 371-395. Presentation: No date and time listed

Adjudicating Mild Cognitive Impairment Due to Alzheimer’s Disease as a Novel Endpoint Event in the TOMMORROW Prevention Clinical Trial

BackgroundThe onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer’s disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial.MethodsThe TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant’s clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages — independent review, collaborative review, and full committee review — requiring a unanimous decision and ratification by the chair.ResultsOf 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators’ clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80–90% for the remainder of the study.ConclusionsThe adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

Systemic Treatment with Pioglitazone Reverses Vision Loss in Preclinical Glaucoma Models.

Neuroinflammation significantly contributes to the pathophysiology of several neurodegenerative diseases. This is also the case in glaucoma and may be a reason why many patients suffer from progressive vision loss despite maximal reduction in intraocular pressure. Pioglitazone is an agonist of the peroxisome proliferator-activated receptor gamma (PPARγ) whose pleiotrophic activities include modulation of cellular energy metabolism and reduction in inflammation. In this study we employed the DBA2/J mouse model of glaucoma with chronically elevated intraocular pressure to investigate whether oral low-dose pioglitazone treatment preserves retinal ganglion cell (RGC) survival. We then used an inducible glaucoma model in C57BL/6J mice to determine visual function, pattern electroretinographs, and tracking of optokinetic reflex. Our findings demonstrate that pioglitazone treatment does significantly protect RGCs and prevents axonal degeneration in the glaucomatous retina. Furthermore, treatment preserves and partially reverses vision loss in spite of continuously elevated intraocular pressure. These data suggest that pioglitazone may provide treatment benefits for those glaucoma patients experiencing continued vision loss.

Efficacy and safety of standard dose pioglitazone versus low-dose pioglitazone as an add on treatment in type 2 diabetes mellitus: A randomized controlled trial

Background: On June 18, 2013, India banned pioglitazone, a peroxisome proliferation activator gamma agonist, and a popular anti-diabetic drug used in the treatment of type 2 diabetes mellitus (T2DM), but on August 21, 2013, ban was revoked after stiff opposition from diabetologists and pioglitazone was reintroduced to the market again. Aim and Objective: The aim of this study was to assess the efficacy and safety of low-dose pioglitazone compared to standard dose pioglitazone in adults with T2DM. Materials and Methods: After obtaining permission from the Institutional Ethics Committee, 50 patients with T2DM who were not under adequate glycemic control with metformin and glimepiride combination therapy are included in the study. The patients were randomly assigned (1:1) into pioglitazone 7.5 mg group and 15 mg group as an add on treatment to the existing therapy. Results: All the glycemic parameters such as FBS, post prandial blood glucose (PPBS), and hemoglobin (HbA1c) are significantly reduced in both groups from baseline to the end of 12 weeks. FBS reduced from 183.64 ± 20.9 to 152.08 ± 15.2 in the Pioglitazone 7.5 mg group and from 177.32 ± 16.89 to 145.2 ± 11.6 in the pioglitazone 15 mg group (P &lt; 0.05), PPBS was reduced from 260.2 ± 31.09 to 213.8 ± 29.5 and from 256.24 ± 43.72 to 203.52 ± 27.5 (P &lt; 0.05) in 7.5 mg and 15 mg group, respectively. HbA1c was reduced from 8.969 ± 0.88 to 8.508 ± 0.9 in 7.5 mg group (P &lt; 0.05) and in 15 mg group, it was reduced from 8.796 ± 0.79 to 8.19 ± 0.72 (P &lt; 0.05). In the study, Pioglitazone 7.5 mg efficaciously reduced glycemic parameters similar to pioglitazone 15 mg and there was no statistically significant difference between the groups. Three patients reported with pedal edema as adverse effect in pioglitazone 15 mg therapy, whereas only one in 7.5 mg pioglitazone therapy complained of ankle edema. Conclusion: Low-dose pioglitazone offers an attractive alternative option to standard dose pioglitazone as an add on therapy for T2DM due to its effectiveness in reducing glycemic markers and also fewer side effect profile.

Safety and efficacy of pioglitazone for the delay of cognitive impairment in people at risk of Alzheimer's disease (TOMMORROW): a prognostic biomarker study and a phase 3, randomised, double-blind, placebo-controlled trial

The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65-83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85-12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45-1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Takeda and Zinfandel.

Dose-dependent effects of prenatal exposure of pioglitazone, the PPARγ agonist, on the hippocampus development and learning and memory performance of rat offspring

It is known that pioglitazone, defined as a PPARγ agonist, has neuron-protective properties in nervous system disorders. The aim of this study is to investigate the effects of pioglitazone administration at different doses during prenatal period on the neurons, glial cells and learning-memory levels in the hippocampus of rat offspring.Pregnant rats were divided into three groups; Low-Dose Pioglitazone (LDP), High-Dose Pioglitazone (HDP) and control (C) (n = 3). Pregnant rats in the HDP and LDP groups were given pioglitazone at 30 mg/kg and 5 mg/kg doses, respectively, by gavage once a day during their pregnancy. No procedure was applied to the rats in the control group. Morris water tank test was applied to offspring obtained from postnatal 24th to 28th day. The offspring were sacrificed on the 29th postal day and their brain tissues removed. Stereological, histopathological and immunohistochemical techniques were used to analyze brain tissues.As a result of the analysis, it was observed that there were delays in learning and memory, the number of pyramidal neurons decreased, and the density of cells stained with glial fibrillar acidic protein (GFAP) positive increased in the HDP group compared to the other groups (p < 0.05). No significant difference was found between the LDP and control groups in terms of these parameters (p > 0.05).Our results showed that pioglitazone administered in the prenatal period had an effect on the hippocampus development and learning and memory performance of rats, depending on the dose.

A randomized phase 1b cross-over study of the safety of low-dose pioglitazone for treatment of autosomal dominant polycystic kidney disease.

BackgroundAutosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenetic disorders in humans and is characterized by numerous fluid-filled cysts that grow slowly, resulting in end-stage renal disease in the majority of patients. Preclinical studies have indicated that treatment with low-dose thiazolidinediones, such as pioglitazone, decrease cyst growth in rodent models of PKD.MethodsThis Phase 1b cross-over study compared the safety of treatment with a low dose (15 mg) of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone or placebo in PKD patients, with each treatment given for 1 year. The study monitored known side effects of PPAR-γ agonist treatment, including fluid retention and edema. Liver enzymes and risk of hypoglycemia were assessed throughout the study. As a secondary objective, the efficacy of low-dose pioglitazone was followed using a primary assessment of total kidney volume (TKV), blood pressure (BP) and kidney function.ResultsEighteen patients were randomized and 15 completed both arms. Compared with placebo, allocation to pioglitazone resulted in a significant decrease in total body water as assessed by bioimpedance analysis {mean difference 0.16 Ω [95% confidence interval (CI) 0.24–2.96], P = 0.024} and no differences in episodes of heart failure, clinical edema or change in echocardiography. Allocation to pioglitazone led to no difference in the percent change in TKV of −3.5% (95% CI −8.4–1.4, P = 0.14), diastolic BP and microalbumin:creatinine ratio.ConclusionsIn this small pilot trial in people with ADPKD but without diabetes, pioglitazone 15 mg was found to be as safe as placebo. Larger and longer-term randomized trials powered to assess effects on TKV are needed.

Metabolic Profiling of Female Tg2576 Mouse Brains Provides Novel Evidence Supporting Intranasal Low-Dose Pioglitazone for Long-Term Treatment at an Early Stage of Alzheimer's Disease.

Accumulating evidence suggests that disruptions in brain energy metabolism may be a key player in the pathogenesis of Alzheimer’s disease (AD). Pioglitazone (PIO) has been found to exert beneficial effects on metabolic dysfunction in many AD preclinical studies. However, limited success in clinical trials remains an obstacle to its development for the treatment of AD. PIO’s poor brain penetration was often cited as a contributing factor to the lack of clinical benefit. In this study, we prepared PIO-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles and administered them as suspended nanoparticles via nebulization. Preliminary investigation of drug distribution to the brain revealed comparatively reduced systemic exposure after administering PIO nanoparticles via the intranasal route. In vitro, extracellular flux analysis showed significantly raised spare respiratory capacity when cells were treated with low-dose PIO nanoparticles. Tg2576 transgenic mice treated with low-dose PIO nanoparticles over four months exhibited an overall trend of reduced hyperactivity in open field tests but did not show any visible effect on alternation rates in the Y-maze task. Subsequent 1H NMR-based metabolic profiling of their plasma and different brain regions revealed differences in metabolic profiles in the cerebellum, cortex, and hippocampus of Tg2576 mice after long-term PIO treatment, but not in their midbrain and plasma. In particular, the specificity of PIO’s treatment effects on perturbed amino acid metabolism was observed in the cortex of transgenic mice with increases in alanine and N-acetylaspartate levels, supporting the notion that PIO treatment exerts beneficial effects on impaired energy metabolism associated with AD. In conclusion, inhalation exposure to PIO nanoparticles presents an exciting opportunity that this drug could be administered intranasally at a much lower dose while achieving a sufficient level in the brain to elicit metabolic benefits at an early stage of AD but with reduced systemic exposure.

Improved Renoprotection in Diabetes with Combination Therapy of Coccinia indica Leaf Extract and Low-Dose Pioglitazone

Background: The metabolic changes associated with diabetes can lead to nephropathy eventually resulting in end-stage renal disease. Current antidiabetic therapies do not effectively prevent the onset of diabetic kidney diseases as well as progression. Aim: To evaluate the effect of Coccinia indica leaf extract alone and in combination with pioglitazone, an antihyperglycemic agent was used to modulate the progressive kidney damage induced by type 2 diabetes in rats. Hypotheses: Pioglitazone causes severe adverse effects when administered for long-term therapy. The hypotheses in this study is to examine the renoprotective effect of Coccinia indica leaf extract (200 mg/kg p.o.) when co-administered with low-dose pioglitazone (7 mg/kg) in type-2-diabetes-induced nephropathy in rats and simultaneously evaluate the hypoglycemic response as well. Methods: Rats (Males, Sprague Dawley) were kept on a high-fat diet and were given a single dose of streptozotocin (35 mg/kg, i.p.) to induce diabetic nephropathy. Treatment groups received either Coccinia indica leaf extract or pioglitazone or pioglitazone with Coccinia indica extract, fenofibrate, or lisinopril for 7 weeks. Blood glucose, antioxidant status, triglycerides, total cholesterol, creatinine, blood urea nitrogen, and proteinuria levels were estimated and compared with the normal control and disease control (untreated) groups. Results: The untreated diabetic rats showed increased blood glucose levels, lipid profiles, and renal oxidative stress, along with an increase in nephropathy markers such as blood urea nitrogen, creatinine, and proteinuria. Histopathological examination revealed glomerular damage. Combination treatment with Coccinia indica leaf extract and a low dose of pioglitazone normalized the nephropathic markers as well as histopathological changes. Conclusion: Coccinia indica leaf extract when co-administered with a low dose of pioglitazone as antidiabetic therapy showed good glycemic control and a beneficial renoprotective effect. Combination therapy would lower the dose of pioglitazone and also protect kidneys from drug-induced toxicity as observed from normalized nephropathic markers in a diabetic rat model.

Renal cyst growth is attenuated by a combination treatment of tolvaptan and pioglitazone, while pioglitazone treatment alone is not effective

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common monogenic disorders, characterized by the progressive formation of fluid-filled cysts. Tolvaptan is an approved drug for ADPKD patients, but is also associated with multiple side effects. The peroxisome proliferator-activator receptor gamma (PPARγ) agonist pioglitazone slows disease progression in the PCK rat model for PKD. Here, we tested whether a combination treatment of relevant doses of tolvaptan and pioglitazone leads to improved efficacy in an adult-onset PKD mouse model. Tolvaptan indeed slowed PKD progression, but the combination treatment was not more effective than tolvaptan alone. In addition, although pioglitazone raised plasma levels of its surrogate drug marker adiponectin, the drug unexpectedly failed to slow PKD progression. The pioglitazone target PPARγ was expressed at surprisingly low levels in mouse, rat and human kidneys. Other pioglitazone targets were more abundantly expressed, but this pattern was comparable across various species. The data suggest that several potential pharmacokinetic and pharmacodynamic (PK/PD) differences between different species may underlie whether or not pioglitazone is able to slow PKD progression. The ongoing phase II clinical trial with low-dose pioglitazone treatment (NCT02697617) will show whether pioglitazone is a suitable drug candidate for ADPKD treatment.

Low-Dose Pioglitazone does not Increase ROS Production in Chronic Granulomatous Disease Patients with Severe Infection.

We sought to further investigate the efficacy and safety of pioglitazone for chronic granulomatous disease (CGD) patients with severe infection. CGD patients with severe infection were enrolled and treated with pioglitazone for 90 days. The degree of improvement in infection and the changes of dihydrorhodamine-123 (DHR) were used to evaluate the efficacy of pioglitazone. The adverse reaction of pioglitazone was also investigated. We planned to enroll 30 patients at first in the study. However, the study was terminated due to negative results from all 3 enrolled patients. The 3 patients were diagnosed with CGD by clinical characteristics, DHR analysis, and genetics analysis. Mutations were CYBB (c.177C>A; p.C59X) in P1, CYBB (c.1498G>T; p.D500Y) in P2, and NCF2 (c.137T>G; p.M46R) in P3, respectively. The age of onset of the 3 patients was within 2 years after birth. The most common sites of infection were lung, lymph node, skin, and soft tissue, which were experienced in all 3 patients. The age of administration with pioglitazone was 5.2 years, 16 years and 11.1 years, respectively. The 3 patients experienced no improvement in severity of infection and stimulation index of the DHR did not also improve after receiving pioglitazone 10, 45 and 90 days, respectively. No drug-related adverse reaction was found during the period of pioglitazone. Low dose of pioglitazone did not improve the severity of infection and production of ROS in CGD patients with severe infection.

Low-dose pioglitazone can ameliorate learning and memory impairment in a mouse model of dementia by increasing LRP1 expression in the hippocampus

Amyloid-β (Aβ) accumulation in the brain is a pathological feature of Alzheimer’s disease (AD) and enhancing Aβ clearance is a potential therapeutic strategy. Pioglitazone is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist and is widely used to treat type 2 diabetes. We previously reported that low-dose pioglitazone increased the expression of low-density lipoprotein receptor-related protein 1 (LRP1), which upregulates the clearance of Aβ, using human brain microvascular endothelial cells. We investigated whether low-dose pioglitazone can rescue the pathological phenotype and memory impairment in senescence-accelerated mouse prone-8 (SAMP8) mice by increasing LRP1 levels. SAMP8 mice were treated with vehicle or pioglitazone in dosages of 2 or 5 mg/kg/day for 7 weeks. In the water maze test, 2 mg/kg/day of pioglitazone significantly attenuated the increased escape latency in SAMP8 mice (p = 0.026), while 5 mg/kg/day of treatment did not. Compared with vehicle treatment, the hippocampi of SAMP8 mice with 2 mg/kg/day of pioglitazone exhibited fewer Aβ deposits and reduced Aβ1–40 levels, along with elevated LRP1 expression (p = 0.005). Collectively, our results proposed that a new therapeutic application of the PPAR-γ agonist for AD treatment should be considered at a lower dose than the conventional dose used to treat diabetes.

Effects of pioglitazone on mnemonic hippocampal function: A blood oxygen level–dependent functional magnetic resonance imaging study in elderly adults

IntroductionMitochondrial dysfunction is implicated in the pathophysiology of Alzheimer's disease (AD). Accordingly, drugs that positively influence mitochondrial function are being evaluated in delay-of-onset clinical trials with at-risk individuals. Such ongoing clinical research can be advanced by developing a better understanding of how these drugs affect intermediate brain phenotypes associated with both AD risk and pathophysiology. MethodsUsing a randomized, parallel-group, placebo-controlled design in 55 healthy elderly volunteers, we explored the effects of oral, low-dose pioglitazone, a thiazolidinedione with promitochondrial effects, on hippocampal activity measured with functional magnetic resonance imaging during the encoding of novel face–name pairs. ResultsCompared with placebo, 0.6 mg of pioglitazone (but not 2.1 mg, 3.9 mg, or 6.0 mg) administered daily for 14 days was associated with significant increases in right hippocampal activation during encoding of novel face–name pairs at day 7 and day 14, relative to baseline. DiscussionOur exploratory analyses suggest that low-dose pioglitazone has measurable effects on mnemonic brain function associated with AD risk and pathophysiology.

The TOMMORROW study: Design of an Alzheimer's disease delay-of-onset clinical trial

IntroductionAlzheimer's disease (AD) is a continuum with neuropathologies manifesting years before clinical symptoms; thus, AD research is attempting to identify more disease-modifying approaches to test treatments administered before full disease expression. Designing such trials in cognitively normal elderly individuals poses unique challenges. MethodsThe TOMMORROW study was a phase 3 double-blind, parallel-group study designed to support qualification of a novel genetic biomarker risk assignment algorithm (BRAA) and to assess efficacy and safety of low-dose pioglitazone to delay onset of mild cognitive impairment due to AD. Eligible participants were stratified based on the BRAA (using TOMM40 rs 10524523 genotype, Apolipoprotein E genotype, and age), with high-risk individuals receiving low-dose pioglitazone or placebo and low-risk individuals receiving placebo. The primary endpoint was time to the event of mild cognitive impairment due to AD. The primary objectives were to compare the primary endpoint between high- and low-risk placebo groups (for BRAA qualification) and between high-risk pioglitazone and high-risk placebo groups (for pioglitazone efficacy). Approximately 300 individuals were also asked to participate in a volumetric magnetic resonance imaging substudy at selected sites. ResultsThe focus of this paper is on the design of the study; study results will be presented in a separate paper. DiscussionThe design of the TOMMORROW study addressed many key challenges to conducting a dual-objective phase 3 pivotal AD clinical trial in presymptomatic individuals. Experiences from planning and executing the TOMMORROW study may benefit future AD prevention/delay-of-onset trials.

BEHAVIORAL CORRELATES OF COGNITIVELY HEALTHY ADULTS

Data were collected from cognitively healthy subjects enrolled in the TOMMORROW study. This is a Phase 3 clinical trial investigating a biomarker to predict the risk of mild cognitive impairment (MCI). It is also evaluating the efficacy of low-dose pioglitazone in delaying the onset of MCI in subjects who are considered high risk according to the biomarker algorithm. Thousands of cognitively healthy volunteers were screened for this study. We designed a sub-study at our research site in conjunction with this larger study, to create a ‘snapshot’ of the highly functioning senior. Through analysis of the data, certain trends in behavior and lifestyle were identified. 100 charts were randomly chosen for data collection. All of the subjects who completed the baseline visit and qualified with normal cognitive assessments were enrolled in the TOMMORROW study and eligible for the sub-study. The subjects were between ages 65 and 83 years and all determined to be cognitively normal. Charts were reviewed for subjects prior to any type of study intervention. The categories included gender, level of education, employment status, level and type of physical activity, volunteer status, hobbies/interests, sleep satisfaction, and supplement use. Male/female ratio was evenly matched. 82% had an education level of 13 years and above. 72% were unemployed/retired. 68% engaged in moderate (3-4 times/week) or high (5 or more times/week) levels of physical activity; endurance activities (walking/hiking) were most popular at 61%. All subjects reported at least one hobby or interest; friends/family/church were the most common. 75% were satisfied with sleep. The highest utilized supplements were aspirin and multivitamin. This sub-study has given us a valuable profile of the cognitively healthy senior enrolled in the TOMMORROW study. While these patterns of behavior do not indicate causality, they suggest avenues for future research. Much information can be obtained from such a large community-based study, to enhance our knowledge beyond the primary intent of the study. Studying healthy seniors will help us gain a better understanding of those who are ill as well as potential insights into prevention.

Benefits of combination low-dose pioglitazone plus fish oil on aged type 2 diabetes mice

The elderly patients with type 2 diabetes suffer more adverse drug events than young adults due to pharmacokinetic and pharmacodynamic changes associated with aging. Reducing the risks of these medication-related problems are equally important for the clinical care of older type 2 diabetes patients. Pioglitazone is used for treating type 2 diabetes as an oral antidiabetic drug. Despite pioglitazone is used helpful insulin sensitizers, the accumulation of subcutaneous fat is considered a major adverse effect of pioglitazone therapy. We investigated to reduce the adverse effect of pioglitazone by combination with fish oil rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in aged diabetic KK mice. The accumulation of subcutaneous fat associated with high-dose pioglitazone is reduced by fish oil, suppressing lipogenesis and stimulating fatty acid β-oxidation in the liver. Our data suggest that adding fish oil to low-dose pioglitazone results in antidiabetic efficacy similar to that of the high-dose without concomitant body weight gain.