Thiazolidinedione Group Research Articles

468-P: Use of New Glucose-Lowering Drugs and the Risk of Major Adverse Cardiovascular Events in People with Type 2 Diabetes and Prior Stroke

Background: It remains uncertain whether the use of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and incretin-based drugs is associated with a reduced risk of major adverse cardiovascular events (MACE) compared with that of thiazolidinediones (TZDs) in people with type 2 diabetes and stroke. Objectives: To compare the effectiveness of SGLT2is, incretin-based drugs, and TZDs on MACE in people with type 2 diabetes and prior stroke. Methods: We did a population-based cohort study involving 117,355 individuals who underwent health checkups under the Korean National Health Insurance Service from 2014 to June 2021 and followed up until December 2021. The primary outcome was MACE, defined as a composite of myocardial infarction, ischemic stroke, and all-cause death. We used propensity score weighting for balancing baseline covariates between treatment groups. Weighted cox proportional regression analyses were used to estimate the association of treatments with MACE after adjusting confounders. Results: In a new-user cohort, the incidence rate of MACE was 547, 679, and 625 per 1,000 person-years in the SGLT2i, incretin-based drug, and TZD groups, respectively. Compared with the TZD group, the risk of MACE was significantly reduced in the SGLT2i group (adjusted hazard ratio [HR] 0.87; 95% CI 0.79-0.96) but increased in the incretin-based drug group (adjusted HR 1.11; 95% CI 1.03-1.19). No significant differences were observed in the risk of myocardial infarction and ischemic stroke between the groups. The risk of all-cause death was significantly increased in the incretin-based drug group (adjusted HR 1.14; 95% CI 1.03-1.25) compared with the TZD group. Conclusion: In this population-based study of people with type 2 diabetes and stroke, SGLT2is were associated with a reduced risk of MACE compared with incretin-based drugs and TZDs. Incretin-based drugs were associated with an increased risk of MACE compared with TZDs. Disclosure J.Bae: None. J.Choi: None. N.Kim: None. S.Kim: None.

Comparison of the Effects of Metformin and Thiazolidinediones on Bone Metabolism: A Systematic Review and Meta-Analysis.

Studies have shown that people with diabetes have a high risk of osteoporosis and fractures. The effect of diabetic medications on bone disease cannot be ignored. This meta-analysis aimed to compare the effects of two types of glucose-lowering drugs, metformin and thiazolidinediones (TZD), on bone mineral density and bone metabolism in patients with diabetes mellitus. This systematic review and meta-analysis were prospectively registered on PROSPERO, and the registration number is CRD42022320884. Embase, PubMed, and Cochrane Library databases were searched to identify clinical trials comparing the effects of metformin and thiazolidinediones on bone metabolism in patients with diabetes. The literature was screened by inclusion and exclusion criteria. Two assessors independently assessed the quality of the identified studies and extracted relevant data. Seven studies involving 1656 patients were finally included. Our results showed that the metformin group had a 2.77% (SMD = 2.77, 95%CI [2.11, 3.43]; p < 0.00001) higher bone mineral density (BMD) than the thiazolidinedione group until 52 weeks; however, between 52 and 76 weeks, the metformin group had a 0.83% (SMD = -0.83, 95%CI: [-3.56, -0.45]; p = 0.01) lower BMD. The C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) were decreased by 18.46% (MD = -18.46, 95%CI: [-27.98, -8.94], p = 0.0001) and 9.94% (MD = -9.94, 95%CI: [-16.92, -2.96], p = 0.005) in the metformin group compared with the TZD group.

Effects of Sodium-Glucose Cotransporter-2 Inhibitors and Thiazolidinedione on New-Onset Atrial Fibrillation Risk to Patients with Type 2 Diabetes.

Type 2 diabetes (T2D) is an independent risk factor for the development of atrial fibrillation (AF). Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have recently been shown to decrease the incidence of AF through several mechanisms, including the reduction of atrial dilatation via diuresis and the lowering of body weight. In observational studies of diabetic patients, the use of thiazolidinedione (TZD) was found to have a protective effect on new-onset AF. In this study, we aimed to compare the effect of SGLT-2i and TZD on the risk of AF in patients with T2D. We enrolled 69,122 patients newly prescribed SGLT-2i and 94,262 patients prescribed TZD from January 2014 to December 2018, using the Korean National Health Insurance Service database. We compared new-onset AF events (hospitalizations and outpatient events) in SGLT-2i and TZD groups after having taken medication for greater than 90 days. During a mean follow-up of 1.8 years, 397 (0.72%) new-onset AF events occurred in the SGLT-2i group and 432 (0.79%) events in the TZD group following propensity score matching (each group n = 54,993). The hazard ratio (HR) of AF was 0.918 (95% confidence interval: 0.783-1.076, p = 0.29) in SGLT-2i-treated patients compared with TZD-treated patients. In this study, the risk of new-onset AF is comparable in patients treated with SGLT-2i and TZD in T2D. Either SGLT-2i or TZD would be a reasonable choice for T2D patients who are at risk for AF.

PO-685-03 EFFECT OF SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITOR AND THIAZOLIDINEDIONE ON NEW ONSET ATRIAL FIBRILLATION RISK IN PATIENTS WITH TYPE 2 DIABETES

Type 2 diabetes (T2D) is an independent risk factor for the development of atrial fibrillation (AF). Recently, Sodium-glucose cotransporter-2 inhibitor(SGLT-2i) has been shown to decrease the incidence of AF through several mechanisms including reduction of atrial dilatation via diuresis and lowering body weight. On the other hand, the use of thiazolidinedione (TZD) was found protecting effect on new-onset AF in diabetic patients in observational studies. We aimed to compare the effect on risk of AF with SGLT2 inhibitor and TZD in patients with type 2 diabetes (T2D). We enrolled 69,122 patients who has newly prescribed with SGLT-2i and 94,262 patients prescribed with TZD from January 2014 to December 2018, using the Korean National Health Insurance Service database. We compared new onset AF event (hospitalization and outpatient event) in SGLT-2i and TZD groups after taking medicine more than 90days After propensity score matching (each group n=54,993), 397 (0.72%) of new onset AF events were occured in SGLT-2i group and 432 (0.79%) events in TZD group during a mean follow-up of 1.8 years. The hazard ratio (HR) of AF was 0.918 (95% confidence interval : 0.783-1.076, p = 0.29) in SGLT-2i treated patients compared with TZD-treated patients. In this study, the risk of new onset AF was comparable in patients treated with SGLT-2i and TZD in T2D. Both SGLT-2i and TZD would be a reasonable choice in patients with T2D who are at risk for AF development.

The Effects of Ciglitazone on Enzyme Activities of Carbonic Anhydrase II and Glucose-6- Phosphate Dehydrogenase

Ciglitazone is a compound belonging to the thiazolidinedione (TZD) class and has hypoglycemic effects. Although ciglitazone is not used as a drug, it has been used as a template for the development of other TZD group drugs. Like many TZD group drugs, ciglitazone causes anemia. In this study, the effects of ciglitazone on the enzyme activities of Glucose-6- Phosphate Dehydrogenase (G6PD) and Carbonic Anhydrase II (CA II), which have important functions in maintaining erythrocyte functions and integrity, were investigated in vitro. Pure human erythrocyte CA II and G6PD enzymes were used for activity measurements. Both esterase and hydratase activities were measured for CA II. The result of activity measurements, it was observed that ciglitazone inhibited CA II (IC50 =0.0063 mM for hydratase activity, and IC50 =0.047 mM for esterase activity) and G6PD (IC50 = 0.067 mM) activities. As a result, it was concluded that these enzyme inhibitions may be important in the anemia-causing mechanisms of cigitazone.

Comparative Effects of Sodium-Glucose Cotransporter 2 Inhibitor and Thiazolidinedione Treatment on Risk of Stroke among Patients with Type 2 Diabetes Mellitus.

BackgroundAlthough cardiovascular outcome trials using sodium-glucose cotransporter-2 inhibitors (SGLT-2i) showed a reduction in risk of 3-point major adverse cardiovascular events (MACE), they did not demonstrate beneficial effects on stroke risk. Additionally, meta-analysis showed SGLT-2i potentially had an adverse effect on stroke risk. Contrarily, pioglitazone, a type of thiazolidinedione (TZD), has been shown to reduce recurrent stroke risk. Thus, we aimed to compare the effect of SGLT-2i and TZD on the risk of stroke in type 2 diabetes mellitus (T2DM) patients.MethodsUsing the Korean National Health Insurance Service data, we compared a 1:1 propensity score-matched cohort of patients who used SGLT-2i or TZD from January 2014 to December 2018. The primary outcome was stroke. The secondary outcomes were myocardial infarction (MI), cardiovascular death, 3-point MACE, and heart failure (HF).ResultsAfter propensity-matching, each group included 56,794 patients. Baseline characteristics were well balanced. During the follow-up, 862 patients were newly hospitalized for stroke. The incidence rate of stroke was 4.11 and 4.22 per 1,000 person-years for the TZD and SGLT-2i groups respectively. The hazard ratio (HR) of stroke was 1.054 (95% confidence interval [CI], 0.904 to 1.229) in the SGLT-2i group compared to the TZD group. There was no difference in the risk of MI, cardiovascular death, 3-point MACE between groups. Hospitalization for HF was significantly decreased in SGLT-2i-treated patients (HR, 0.645; 95% CI, 0.466 to 0.893). Results were consistent regardless of prior cardiovascular disease.ConclusionIn this real-world data, the risk of stroke was comparable in T2DM patients treated with SGLT-2i or TZD.

Solvent free synthesis of active 5-benzylidine-1, 3-thiazolidine-2,4-dione derivatives

Present communication describes the attempts made to improve the yields of thiazolidinedione group of derivatives keeping in view of their anti-cancer activity. 5-benzylidine-1,3-thiazolidine-2,4-dione derivatives were the active substrates belonging to α-glucosidase inhibitor classification. These were prepared by the reaction of 4-((Z)-(2,4-dioxothiazolidin-5-ylidene) methyl) benzaldehyde with aromatic/hetero aromatic ketones in the presence of potassium hydroxide and ethanol as solvent. Synthesis of 5-benzylidine-1, 3-thiazolidine-2,4-dione derivatives has been optimized under solvent free condition by screening with different bases in order to achieve the required target (of improving the yields). The solvent free condition has resulted in excellent improvement in yields and reduced the manufacturing cost significantly.

Effect of dipeptidyl peptidase IV inhibitors, thiazolidinedione, and sulfonylurea on osteoporosis in patients with type 2 diabetes: population-based cohort study.

The current study aimed to evaluate the effect of dipeptidyl peptidase IV inhibitors (DPP-IVi), thiazolidinedione (TZD), and sulfonylurea (SU) on osteoporosis in patients with type 2 diabetes. A population-based cohort study was conducted in the Republic of Korea using the Korean National Health Insurance claims database. Data from 2012 to 2017 for patients of 50-99years of age who were prescribed DPP-IVi, TZD, or SU during 2013-2015 were extracted from the database. Based on pre-defined criteria, a total of 381,404 patients were analyzed after inverse probability of treatment weighting. The association between the study drugs and osteoporosis was estimated using Cox proportional hazards models. Data of 220,166 patients who were prescribed DPP-IVi, 18,630 who were prescribed TZD, and 142,608 patients who were prescribed SU were set. In the multivariate-adjusted analysis, the hazard ratio (HR) of osteoporosis in the DPP-IVi group was not significantly different from that of the SU group (HR: 0.97; 95% confidence interval (CI) 0.94-1.00), whereas the HR of osteoporosis in the TZD group was higher (HR: 1.13; 95% CI 1.06-1.20). In the subgroup analysis, the HRs of osteoporosis were higher with pioglitazone (HR: 1.14; 95% CI 1.06-1.23) in the TZD group and with glibenclamides (HR: 1.39; 95% CI 1.09-1.77) in the SU group, whereas drugs with lower HR in the DPP-IVi group were saxagliptin (HR: 0.93; 95% CI 0.87-0.99) and sitagliptin (HR: 0.93; 95% CI 0.89-0.97). DPP-IV inhibitors do not increase the risk of osteoporosis compared with sulfonylureas in patients with type 2 diabetes mellitus, while a weak association was found between thiazolidinediones and increased risk of osteoporosis.

Пиоглитазон – забытый сахароснижающий препарат с доказанными кардиопротективными и нефропротективными свойствами

Considering that type 2 diabetes mellitus is a multicomponent disease and is associated with an extremely high risk of macrovascular complications (myocardial infarction, stroke and death from cardiovascular diseases), at present, much attention is paid to the choice of hypoglycemic drugs, given the individual characteristics of the patient. Preference is given to drugs of those classes that have a positive effect on cardiovascular outcomes. Along with relatively new molecules (inhibitors of the sodium-glucose cotransporter type 2 and agonists of glucagon-like peptide-1 receptors), the well-known drug pioglitazone, which belongs to the thiazolidinediones group, has not left the field of attention of researchers. Importantly, the cardioprotective effect of pioglitazone has been confirmed in several large randomized trials that showed a delay in atherosclerosis and a reduced risk of cardiovascular disease (PERISCOPE, CHICAGO, IRIS and PROactive). As an insulin sensitizer, pioglitazone reduces insulin resistance, has a protective effect on pancreatic β-cells, and also has a beneficial effect on components of insulin resistance syndrome (lowers blood pressure, lipid spectrum parameters) and improves the course of non-alcoholic fatty liver disease. There is evidence of possible side effects (weight gain, fluid retention, fractures), but their severity decreases with decreasing dose of the drug.

Glycaemic control with add-on thiazolidinedione or a sodium-glucose co-transporter-2 inhibitor in patients with type 2 diabetes after the failure of an oral triple antidiabetic regimen: A 24-week, randomized controlled trial.

To evaluate the effectiveness and safety of adding either a sodium-glucose co-transporter-2 inhibitor (SGLT2i) or thiazolidinedione (TZD) in patients with type 2 diabetes (T2D) inadequately controlled with triple therapy. In this prospective, open-label, multicentre, 24-week clinical trial, we randomly assigned 119 patients with T2D who failed to achieve glycaemic control (7% < HbA1c ≤ 10%) with conventional triple oral antidiabetic agents (OADs; metformin, sulphonylurea and dipeptidyl peptide-4 [DPP-4] inhibitor) into two groups who received either an SGLT2i or TZD. The primary endpoint was mean change in HbA1c level between the two groups at 24 weeks. In total, 119 patients were enrolled in the SGLT2i (n = 60) and TZD (n = 59) groups. Mean age of the study subjects was 61.86 years, and the mean duration of T2D was 13.89 years. After 24 weeks, both groups showed significant reductions in HbA1c (from 7.94% ± 0.74% to 6.97% ± 0.84% in the SGLT2i group and from 8.00% ± 0.78% to 7.18% ± 0.98% in the TZD group), without a significant between-group difference (P = .235). A significant body mass index (BMI) reduction was noted in the SGLT2i group, whereas an increase in BMI was noted in the TZD group (-0.79 ± 1.37 vs. 0.92 ± 0.86 kg/m2 , P < .001). Other safety profiles were favourable in both groups. The current study shows that an SGLT2i or TZD could be a valid option as a fourth OAD for treatment of patients with T2D inadequately controlled with a triple combination of OADs.

Metformin monotherapy for adults with type 2 diabetes mellitus.

Metformin monotherapy for adults with type 2 diabetes mellitus.

Clinical outcomes of basal insulin and oral antidiabetic agents as an add-on to dual therapy in patients with type 2 diabetes mellitus

While basal insulin remains the most effective antidiabetic agent and substantially reduces the risk of hypoglycemia, few studies have examined the comparative effect of basal insulin in the real-world setting. This study aimed to assess the outcomes of adding basal insulin compared with thiazolidinediones (TZDs) or dipeptidyl peptidase-4 inhibitors (DPP-4is) as a third antidiabetic agent in patients with type 2 diabetes mellitus (T2DM). A retrospective cohort study involving T2DM was conducted with health administrative data in Taiwan. Patients starting a third antidiabetic agent after receiving a metformin-containing dual combination were identified. The study endpoints included composite major adverse cardiovascular events (MACEs), all-cause mortality, and hypoglycemia. Propensity score matching and Cox modeling were used for analysis. After matching, the basal insulin and TZD groups contained 6,101 and 11,823 patients, respectively, and the basal insulin and DPP-4i groups contained 6,051 and 11,900 patients, respectively. TZDs and DPP-4is were both associated with similar risks of MACEs and hypoglycemia but a lower risk of all-cause mortality than basal insulin (TZDs: HR 0.55, 95% CI 0.38–0.81; DPP-4is: HR 0.56, 95% CI 0.39–0.82). Further studies are needed to elucidate the findings of increased all-cause mortality risk in patients receiving basal insulin, especially those with advanced diabetes.

STUDY OF ACUTE TOXICITY AND POTENTIAL HYPOGLYCEMIC ACTIVITY OF A NEW THIAZOLIDONE (ETHYL ESTER OF 4{(2-ETOXY-2-OXOETHYLIDENE-4-OXO-1-(4-DIFLUORO¬METOXY¬PHENYL-THIAZOLIDINE-2-YLIDENE]HYDRAZONO}-1-METHYLPYRAZOL-3-CARBOXYLIC ACID)

Abstract. Prevalence of diabetes mellitus (DM) is one of the most pressing medical and social challenges in the world. In spite of a large quantity of experimental and clinical studies related to the means and methods of prophylaxis and treatment of DM, goal-oriented synthesis of new compounds with potential hypoglycemic activity, improved pharmacodynamics and pharmacokinetics is prospective. Thiazolidinediones are among the known insulin sensitisers, but their use is not, unfortunately, without adverse events. The search for safe antidiabetic agents from the thiazolidinediones group is continuing. A derivative of a less toxic thiazolidone – ethyl ester of 4{(2-etoxy-2-oxoethylidene-4-oxo-1-(4-difluoro­metoxy­phenylthiazolidine-2-ylidene]hydrazono}-1-methylpyrazol-3-carboxylic acid, synthesized in the laboratory of organic synthesis of Higher State Educational Establishment in Ukraine Bukovinian state medical university under the supervision of prof. M.K. Bratenko, became the subject of this research.Objective - to study the acute toxicity and potential hypoglycemic activity of a new thiazolidone derivative.Material and methods. The acute toxicity of a new investigated compound (IC) was assessed using the V.B. Prozorovsky short-term method, on white sexually mature rates of both sexes, weighing 180-220 g, against a background of intragastric administration in 3% starch suspension on an empty stomach. One-day monitoring of glucose levels in the rats blood was studied after intragastric administration of IC in the dose 1/100 and 1/10 of DL50, (12.8 mg/kbw and 128 mg/kbw, respectively). A medical product from the thiazolidinediones group, Glutazone, with a chemical structure similar to the IC, was used as a reference drug; it was administered to the animals in the dose of 20 mg/kbw (1/100 DL50). The blood glucose level was assessed every 2 hours, using rapid analyzer «OneTouch SelectSimple», before and after IC and Glutazone administration.Results. The absence of animal deaths when the dose 1000 mg/kg was administered suggests that this dose is the maximum tolerated dose (DL0). When IC was administered in wider dose range (1260-2000 mg/kg), decrease of motion activity, loss of appetite, and breathing difficulty were observed. Animal death was observed on the 3d-5th day after administration at DL50 1280±90 mg/kg.One day monitoring of animal blood glucose concentration after administration in the dose of 12.8 mg/kbw had shown the most expressed hypoglycemic effect after single IC administration in the dose of 1/100 DL50 by the sixth, eighth hour, and did not significantly differ in expression and duration of hypoglycemic effect from reference drug (when taken in DL50-equivalent dose). When the dose of IC was increased (128 mg/kg), the hypoglycemic effect took place sooner, was more expressed, and lasted longer. Conclusions. By the toxicological classification of K.K. Sidorov by the DL50 index, the studied compound belongs to the IV toxicity class («low-toxic compounds»). Ethyl ester of 4{(2-etoxy-2-oxoethylidene-4-oxo-1-(4-difluorometoxy­phenylthiazolidine-2-ylidene]hydrazono}-1-methylpyrazol-3-carboxylic acid, when administered in the single dose of 12.8 mg/kg (1/100 DL50), causes mild hypoglycemic effect in rats, similar to the effect of reference drug glutazone (when taken in DL50-equivalent dose). Hypoglycemic activity of the compound after single dose administration into the stomach is dose dependent: when the dose is increased 10-fold (128.6 mg/kg, 1/10 DL50), the hypoglycemic effect happens earlier, is more expressed and prolonged.

Long-term sustainability of glycaemic achievements with second-line antidiabetic therapies in patients with type 2 diabetes: A real-world study.

To inform patients and their carers about both the probability of reducing glycated haemoglobin (HbA1c) to clinically desirable levels and the sustainability of such control over 2 years with major second-line antidiabetic therapies, in individual risk scenarios, with and without third-line intensification. From US Centricity Electronic Medical Records, 163 081 patients with type 2 diabetes aged 18 to 80 years, who had initiated metformin, intensified their treatment with dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs), sulphonylureas (SUs), insulin or thiazolidinediones (TZDs), and continued second-line treatment for ≥6 months, were selected. Treatment groups were balanced with regard to baseline characteristics, and glycaemic achievements were estimated using logistic regression analysis. With HbA1c concentrations of 58-63.9 mmol/mol (7.5-7.9%) at second-line treatment initiation, the adjusted probabilities of achieving HbA1c <53 mmol/mol (<7%) at 6 months were 32%, 38%, 39%, 26% and 38% in the SU, DPP-4 inhibitor, GLP-1RA, insulin and TZD groups, respectively, while with baseline HbA1c concentrations of 64-75 mmol/mol (8-9%), the corresponding probabilities of reducing HbA1c to <58 mmol/mol (<7.5%) were 38%, 44%, 40%, 34% and 42%, respectively. In these baseline HbA1c categories, the adjusted probabilities of sustaining HbA1c achievements over 2 years were higher in the GLP-1RA and TZD groups, compared with the SU and insulin groups (P < .01). With baseline HbA1c concentrations of 75.1-108 mmol/mol (9.1-12%) 38% of patients achieved an HbA1c concentration <58 mmol/mol (<7.5%) at 6 months. The adjusted probability of sustaining this control over 2 years was higher in the incretin and TZD groups (range 62%-75%), while insulin and SUs offered lower chances of sustainable control (range 54%-56%). Patients treated with second-line incretins and TZDs had a significantly higher probability of achieving and sustaining glycaemic control over 2 years without further intensification, compared with those treated with SUs or insulin.

A novel thiazolidinediones ATZD2 rescues memory deficits in a rat model of type 2 diabetes through antioxidant and antiinflammation

Type 2 diabetes (T2DM) has been associated with learning and memory impairment; however, drugs for diabetes could not prevent the development of cognitive decline in T2DM patients. In the present study, compounds derived from thiazolidinediones (TZD), a PPAR-γ agonist, were synthesized by conjuncting the alkyl-substituted benzimidazole group to TZD group (ATZDs). Based on the in vitro evaluation, the neuroprotection of ATZD2 was further investigated using a streptozotocin-induced T2DM rat model. Pharmacokinetic study showed that ATZD2 could pass the blood-brain barrier (BBB) while the rosiglitazone (RSG, the precursor compound of ATZD2) not. Administration of ATZD2 significantly promoted the survival rate and attenuated fasting blood glucose (FBG) levels as compared to RSG treatment in T2DM rats. Furthermore, ATZD2 treatment ameliorated the impairment of learning and memory by Morris water maze test. The beneficial effects of ATZD2 were associated with the down-regulation of hypoxia induced factor-1α, aldose reductase, and Bax expression which are related to T2DM pathology. ATZD2 treatment also attenuated the expression of inflammatory cytokines and restored the balance of redox in the diabetic hippocampus. These effects were more potent as compared with that of RSG at the same dose. The data indicate that ATZD2 may be a potent agent for the treatment of cognitive dysfunction in T2DM.

Effects of thiazolidinedione in patients with active bladder cancer.

To examine the influence of perioperative thiazolidinedione (TZD) on cancer-specific outcomes in patients with diabetes mellitus (DM) undergoing radical cystectomy (RC) for urothelial carcinoma (UC). A retrospective cohort of 173 patients with DM undergoing RC from 2005 to 2010 was identified. Of those, 53 were on TZD treatment at the time of RC, with 33 patients taking pioglitazone. Baseline clinicopathological characteristics, as well as cancer-specific survival (CSS), recurrence-free survival (RFS), and overall survival (OS) were compared between the patients on and off TZD therapy at the time of RC. In subgroup analysis, outcomes in patients specifically taking pioglitazone at the time of RC were compared to those not on a TZD. Baseline clinicopathological characteristics were similar between patients on and off TZD therapy at the time of RC. Overall, the median CSS rate was not reached in either group (P = 0.7). The estimated 5-year CSS was 67.8% in the non-TZD group and 66.3% in the TZD group. On multivariate analysis incorporating patient age, pathological T-staging, and adjuvant chemotherapy, TZD use was found not to be a significant predictor for CSS (hazard ratio 1.20, 95% confidence interval 0.66-2.17; P = 0.5). Additionally, RFS (P= 0.3) and OS (P = 0.2) were also similar between the two groups without adjusting for other variables. Comparison between patients taking pioglitazone vs patients not taking TZD yielded similar CSS (P = 0.2), RFS (P = 0.5), and OS (P= 0.2). CSS, as well as RFS and OS after RC were not compromised in patients on TZD therapy at the time of RC. Additional investigation is warranted in patients with non-muscle-invasive bladder cancer and muscle-invasive bladder cancer undergoing bladder-sparing procedures to assess the safety of using TZD in the setting of active UC.

Toxicological evaluation of subchronic use of pioglitazone in mice.

Pioglitazone (Actos) is one of the most controversial recent oral antidiabetic drugs. It was originally authorized in the European Union in 2000, and approved as an oral monotherapy for overweight second type of diabetic patients in 2002. It belongs to the thiazolidinedione group which some of its members have been withdrawn from the market due to the hepatotoxicity or cardiotoxicity effects. This study investigates sub-chronic use of pioglitazone induced toxicity in mice by the assessment of renal and liver function tests, cardiac enzymes, and some hematological indices with histological changes of liver, kidney, heart, and bladder. 120 albino mice were divided into four groups; 30 in each. The first group (control) received water, second (diabetic) group received alloxan only, while the third and the fourth groups received alloxan with 200 and 400 mg/kg/day of pioglitazone, respectively for 90 days. Prolonged use of pioglitazone induced significant abnormalities of hepatic, renal, and cardiac biomarkers and some hematological indices associated with histopathological changes in the liver, kidney, heart, and bladder that increased based on administered dose. Subchronic use of pioglitazone leads to hepatic, renal, cardiac, hematological, and bladder affection depending on the applied dose.

Evaluation of Protein Kinase Cβ and PPARγ Activity in Diabetic Rats Supplemented with Momordica charantia.

The present study was taken up to compare and evaluate the effect of Momordica charantia supplementation with pioglitazone on PKC-β and PPAR-γ activity in kidneys of diabetic rats. The hypoglycaemic and lipid lowering effect of Momordica charantia were screened in laboratory animal model and its potency was compared with a Thiazolidinedione (TZD) group antidiabetic drug like pioglitazone. Adult healthy albino rats of Wistar strain aged 3-4months, weighing between 170-250gm of either sex were divided into 4 groups; Group 1 (normal controls), Group 2 (diabetic controls), Group 3 (diabetic rats treated with pioglitazone) and Group 4 (diabetic rats treated with bitter melon juice). Type 1 Diabetes was induced in rats by intraperitoneal injection of streptozotocin at a dose of 55 mg/kg body weight, following which glucose levels were estimated by Accu chek- active glucometer on day 0, 7, 14, 21 and 28 days to assess the efficacy of Bitter Melon Juice (BMJ) and pioglitazone. After 28 days of treatment, the rats were sacrificed and blood collected from abdominal vena cava was used for estimation of triglycerides by Glycerol 3 phosphate oxidase phenol aminophenazone method and cholesterol by Cholestrol oxidase phenol aminophenazone method. PKC-β and PPAR-γ were estimated in the dissected kidneys by using double sandwich ELISA based kits on an automated plate reader. BMJ significantly reduced blood glucose levels in group 4 as compared to diabetic controls (p<0.001). Total cholesterol and triglycerides were significantly reduced in both group 3 and 4. In Group 4, there was reduction in PKC-β levels, when compared to Group 3(p=0.004). PPAR-γ levels were increased in both Group 3 and 4, when compared to Group 2. The results suggest that BMJ has hypoglycaemic and lipid lowering effect in diabetic animal models. BMJ increases PPAR-γ activity and decreases PKC-β activity in kidneys of diabetic rats, thereby preventing the complications of diabetes mellitus. Fresh BMJ mimics action of pioglitazone belonging to TZD group thus showing a potential for further research in identifying the active molecules responsible for glucose and lipid lowering action.

Pioglitazone regulates myelin phagocytosis and multiple sclerosis monocytes.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Myeloid phagocytes, including blood monocytes recruited to demyelinating lesions, may play a dual role in MS: on one hand, they might enhance CNS damage after differentiating toward a proinflammatory phenotype; on the other, they promote remyelination and repair through effective phagocytosis of myelin debris. We have previously determined that the retinoid X receptor (RXR) plays an important role in monocyte phagocytosis of myelin. Peroxisome proliferator-activated receptor γ is an RXR binding partner that plays a key role in myeloid cell biology and is targeted by the thiazolidinedione group of antidiabetics such as pioglitazone. Consequently, the purpose of this study was to determine if monocyte functions and differentiation profiles differ in MS patients compared to healthy volunteers (HV) and whether pioglitazone can reverse these differences to promote CNS recovery. Monocytes were isolated from MS patients and HV (n≥36/group), and their ability to phagocytose myelin and modulate inflammation in the presence/absence of 1μmol/L pioglitazone (the invivoachievable concentration) was quantified by flow cytometry, transcriptional profiling, and proteomic assays. MS monocytes display impaired phagocytosis of myelin debris and enhanced proinflammatory differentiation. Pioglitazone treatment causes partial normalization of identified monocyte abnormalities in MS and fully reverses the deficit in myelin phagocytosis. These findings suggest that by inhibiting proinflammatory differentiation of monocytes and enhancing their phagocytosis of myelin, pioglitazone may be a useful adjunct therapy to immunomodulatory agents that target dysregulated adaptive immunity in MS.

The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis.

Thiazolidinediones (TZDs) are associated with an increased risk of fracture but the mechanism is unclear. We sought to determine the effect of TZDs on bone mineral density (BMD) and bone turnover markers. PubMed, EMBASE and Cochrane CENTRAL databases were searched from inception until January 2015 for randomised controlled trials comparing TZDs with metformin, sulfonylureas or placebo, and those reporting changes in BMD and/or bone turnover markers. The primary outcome was percentage change in BMD from baseline and results were pooled with random effects meta-analyses. In all, 18 trials were included in the primary analyses and another two were included in the sensitivity analyses (n = 3,743, 50% women, mean age 56 years, median trial duration 48 weeks). TZDs decreased BMD at the lumbar spine (difference -1.1% [95% CI -1.6, -0.7]; p < 0.0001), total hip (-1.0% [-1.4, -0.6]; p < 0.0001) and forearm (-0.9% [-1.6, -0.3]; p = 0.007). There were statistically non-significant decreases in BMD at the femoral neck (-0.7% [-1.4, 0.0]; p = 0.06) and total body (-0.3% [-0.5, 0.0]; p = 0.08). Five trials (n = 450) showed no statistically significant difference in percentage change in BMD between the TZD group and controls up to 1 year following TZD withdrawal. In 14 trials, the effect of TZD treatment on turnover markers varied considerably between individual studies. Treatment with TZDs results in modest bone loss that may not be reversed 1 year after cessation of treatment.