Use Of Rosiglitazone Research Articles

The effect of withdrawal of rosiglitazone on treatment pathways, diabetes control and patient outcomes: A retrospective cohort study

AimsTo describe the withdrawal of rosiglitazone and the impact upon glycaemic control; intensification of therapy; and progression to major adverse cardiovascular events (MACE), cancer and mortality. MethodsData were from the Clinical Practice Research Datalink (CPRD), a longitudinal UK database. Rosiglitazone use was profiled from launch (2000) until withdrawal (2010). Patients discontinuing from July 2010 were included in the analysis to ascertain the impact on glycaemic control; therapy intensification; and progression to MACE, death and cancer. For comparison, patients were matched to those maintained on pioglitazone as a control group. ResultsRosiglitazone use peaked in May 2007. Of patients prescribed rosiglitazone at discontinuation 54.1% patients used a dual-therapy regimen; most commonly with metformin (46.7%). 65.1% patients remained at the same stage of the diabetes pathway following discontinuation. 51.7% of patients replaced rosiglitazone with pioglitazone. Patients discontinuing were more likely (HR=2.29), to subsequently intensify therapy than controls. After discontinuation of rosiglitazone there was a significant increase in HbA1c, from a median of 6.9% to 7.3%. In matched analysis, there was a significantly greater increase in HbA1c for rosiglitazone patients (0.33% versus 0.10%). Following discontinuation, crude rates for MACE, cancer and mortality were 8.4, 17.9 and 15.8 pkpy, respectively. None was significantly different in the matched analysis. ConclusionWithdrawal of rosiglitazone was associated with worsening glucose control and subsequent intensification of treatment regimen.

Rosiglitazone may reduce thyroid cancer risk in patients with type 2 diabetes

Background. Whether rosiglitazone use in patients with type 2 diabetes may affect thyroid cancer risk has not been investigated.Methods. The reimbursement databases of all diabetic patients under oral anti-diabetic agents or insulin from 1996 to 2009 were retrieved from the National Health Insurance of Taiwan. An entry date was set at 1 January 2006, and 887,665 patients with type 2 diabetes were followed for thyroid cancer incidence until the end of 2009 for ever-users, never-users, and subgroups of rosiglitazone exposure using tertile cut-offs for time since starting rosiglitazone, duration of therapy, and cumulative dose. Hazard ratios were estimated by Cox regression.Results. There were 103,224 ever-users and 784,441 never-users, with respective numbers of incident thyroid cancer of 84 (0.08%) and 764 (0.10%), and respective incidence of 23.12 and 28.09 per 100,000 person-years. The overall multivariable-adjusted hazard ratio was not significant. However, in dose-response analyses, the adjusted hazard ratios (95% confidence intervals) were significant for the third tertile of duration of therapy (≥ 14 months) and cumulative dose (≥ 1,800 mg) for age ≥ 50 years: 0.53 (0.31–0.89) and 0.50 (0.29–0.87), respectively.Conclusions. This study suggests that rosiglitazone use in patients with type 2 diabetes may reduce the risk of thyroid cancer.

Structure-based identification of novel PPAR gamma ligands

Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor with an important role in the glucose metabolism and a target for type 2 diabetes mellitus therapy. The recent findings relating the use of the receptor full agonist rosiglitazone and the incidence of myocardial infarction raised concerns regarding whether receptor activation can actually be useful for diabetes management. The discovery of MRL-24 and GQ-16, ligands that can partially activate PPARγ and prevent weight gain and fluid retention, showed that a submaximal receptor activation can be a goal in the development of new ligands for PPARγ. Additionally, two previously described receptor antagonists, SR-202 and BADGE, were also shown to improve insulin sensitivity and decrease TNF-α level, revealing that receptor antagonism may also be an approach to pursue. Here, we used a structure-based approach to screen the subset ‘Drugs-Now’ of ZINC database. Fifteen ligands were selected after visual inspection and tested for their ability to bind to PPARγ. A benzoimidazol acetate, a bromobenzyl-thio-tetrazol benzoate and a [[2-[(1,3-dioxoinden-2-ylidene)methyl]phenoxy]methyl]benzoate were identified as PPARγ ligands, with IC50 values smaller than 10μM. Molecular dynamic simulations showed that the residues H323, H449, Y327, Y473, K367 and S289 are key structural elements for the molecular recognition of these ligands and the polar arm of PPARγ binding pocket.

Rosiglitazone use and post-discontinuation glycaemic control in two European countries, 2000–2010

ObjectivesTo evaluate the impact of risk minimisation policies on the use of rosiglitazone-containing products and on glycaemic control among patients in Denmark and the UK.Design, setting and participantsWe used population-based...

Rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

Rosiglitazone improves glycemic control for patients with type 2 diabetes mellitus, but there remains controversy regarding an observed association with cardiovascular hazard. The cardiovascular effects of rosiglitazone for patients with coronary artery disease remain unknown. To examine any association between rosiglitazone use and cardiovascular events among patients with diabetes mellitus and coronary artery disease, we analyzed events among 2368 patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Total mortality, composite death, myocardial infarction, and stroke, and the individual incidence of death, myocardial infarction, stroke, congestive heart failure, and fractures, were compared during 4.5 years of follow-up among patients treated with rosiglitazone versus patients not receiving a thiazolidinedione by use of Cox proportional hazards and Kaplan-Meier analyses that included propensity matching. After multivariable adjustment, among patients treated with rosiglitazone, mortality was similar (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.58-1.18), whereas there was a lower incidence of composite death, myocardial infarction, and stroke (HR, 0.72; 95% CI, 0.55-0.93) and stroke (HR, 0.36; 95% CI, 0.16-0.86) and a higher incidence of fractures (HR, 1.62; 95% CI, 1.05-2.51); the incidence of myocardial infarction (HR, 0.77; 95% CI, 0.54-1.10) and congestive heart failure (HR, 1.22; 95% CI, 0.84-1.82) did not differ significantly. Among propensity-matched patients, rates of major ischemic cardiovascular events and congestive heart failure were not significantly different. Among patients with type 2 diabetes mellitus and coronary artery disease in the BARI 2D trial, neither on-treatment nor propensity-matched analysis supported an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Risk of Bladder Cancer in Diabetic Patients Treated with Rosiglitazone or Pioglitazone: A Nested Case–Control Study

Evidence has emerged that pioglitazone may increase the risk of bladder cancer, but the association has not been confirmed. This potential risk also has not been evaluated in users of rosiglitazone. Using Taiwan’s National Health Insurance Research Database (NHIRD), this large population-based nested case–control study was conducted to explore the relationship between the use of rosiglitazone or pioglitazone and risk of bladder cancer in diabetic patients. We identified 3,412 cases of newly diagnosed bladder cancer and 17,060 controls (1:5 matched by age and sex) among a diabetic patient cohort from the NHIRD.We defined an index date for each case as the date of first hospitalization for bladder cancer. Each control was assigned the index date of their corresponding case. Multivariable conditional logistic regressions were used to estimate the association between exposure (timing and duration) to rosiglitazone or pioglitazone and bladder cancer. We defined rosiglitazone or pioglitazone exposure as ‘‘current’’ if the prescription duration covered the index date or ended at 90 days before, as ‘‘recent’’ if it ended 91–180 days before the index date, or as ‘‘past’’ if the last prescription ended more than 180 days before. Duration of rosiglitazone or pioglitazone use was defined based on the cumulative days of exposure prior to the index date: < 1, 1–2 and ≥ 2 years. Rosiglitazone and pioglitazone use were associated with risk of bladder cancer and the associations were stronger with a longer term of exposure (pioglitazone < 1 year odds ratio [OR] 1.45 [95 % CI 1.12–1.87, p < 0.01], 1–2 years OR 1.74 [95 % CI 1.05–2.90, p = 0.03] and ≥ 2 years OR 2.93 [95 % CI 1.59–5.38, p < 0.01]; rosiglitazone < 1 year OR 0.98 [95 % CI0.82–1.17, p = 0.81], 1–2 years OR 1.78 [95 % CI 1.31–2.39, < 0.01] and ≥ 2 years OR 2.00 [95 % CI 1.37–2.92, p < 0.01]). Long-term exposures to pioglitazone and rosiglitazone were associated with higher odds of bladder cancer, and the highest odds were seen in users with ≥ 2 years of exposure.

Mortality among veterans with type 2 diabetes initiating metformin, sulfonylurea or rosiglitazone monotherapy

Despite oral hypoglycaemic medications being the most commonly used pharmacological treatments for type 2 diabetes, research is limited on their comparative safety, particularly their effects on overall mortality. We compared mortality risk with monotherapy initiation of four oral hypoglycaemic medications in a nationwide cohort of US veterans with type 2 diabetes. We identified new users of oral hypoglycaemic medication monotherapy between 2004 and 2009 who received care for at least 1 year from the Veterans Health Administration.Patients were followed until initial monotherapy discontinuation,addition of another diabetes pharmacotherapy, death or end of follow-up. Mortality HRs were estimated using Cox regression adjusted for potential confounding factors. Among new users of metformin, sulfonylureas and rosiglitazone (185,360 men, 7,812 women), 4,256 (2.2%) died during follow-up. Average duration of medication use ranged from 1.4 to 1.7 years. Significantly higher mortality risk was seen for glibenclamide (known as glyburide in the USA and Canada) (HR 1.38, 95% CI 1.27, 1.50) or glipizide (HR 1.55,95% CI 1.43, 1.67) compared with metformin monotherapy,and for glipizide compared with rosiglitazone (HR 1.27, 95%CI 1.01, 1.59) or glibenclamide monotherapy (HR 1.12, 95%CI 1.02, 1.23). A significant sex–rosiglitazone interaction was seen (p=0.034) compared with metformin monotherapy, with women having a higher HR (HR 4.36, 95% CI 1.34, 14.20)than men (HR 1.19, 95% CI 0.95, 1.49). Significantly higher mortality was associated with glibenclamide, glipizide and rosiglitazone use compared with metformin, and with glipizide use compared with rosiglitazone or glibenclamide. The potential for residual confounding by indication should be considered in interpreting these results.

Potential for cardiac protection with dipeptidyl peptidase-4 inhibitors: The stromal cell-derived factor-1α hypothesis (二肽基肽酶-4抑制剂潜在的心脏保护作用：基质细胞衍生因子-1α假说)

Potential for cardiac protection with dipeptidyl peptidase-4 inhibitors: The stromal cell-derived factor-1α hypothesis (二肽基肽酶-4抑制剂潜在的心脏保护作用：基质细胞衍生因子-1α假说)

Trial update: the Diabetes REduction Approaches with ramipril and rosiglitazone Medications (DREAM) trial

BACKGROUND Diabetes (T2DM) is a worldwide medical and social emergency in the westernized societies. Lifestyle changes, diet and physical activity, have shown a protective effect on the likelihood of developing T2DM and are strongly recommended for primary prevention in people at increased risk for T2DM. However, maintaining adherence to these nonpharmacologic strategies is dishearteningly challenging, and the possible use of drugs to prevent T2DM remains of keen interest. Metformin, glitazones, acarbose and orlistat can reduce the risk of developing T2DM. Recently, post hoc analyses of several clinical studies suggested that ACE-I as well might reduce the risk of T2DM. AIM OF THE STUDY Since none of these trials was designed with this primary end-point, the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) Investigators studied the effects of ramipril or rosiglitazone on the risk of T2DM in a randomized trial designed with T2DM as a primary outcome. METHOD Subjects with fasting impaired plasma glucose levels or impaired glucose tolerance, without cardiovascular disease, were randomly assigned, in a 2-by-2 factorial design, to receive either ramipril (up to 15 mg daily) or placebo and either rosiglitazone or placebo. They were followed for a median of 3 years. RESULTS Rates of the primary end points, T2DM or death, were not significantly lower in the ramipril group than in the placebo group. In contrast to ramipril, the use of rosiglitazone resulted in a significant reduction in T2DM or death. DISCUSSION Disappointingly, 14 participants on rosiglitazone developed non-fatal heart failure, compared with 2 cases in the placebo group, and the group gained 3% (2.2 kg) more in body weight than the placebo group. Moreover, we still do not know whether the effect of rosiglitazone on the incidence of T2DM will persist after drug washout. CONCLUSIONS We believe that the high cost of the drug and the study’s negative cardiovascular and body weight outcomes favour a lifestyle strategy in preventing T2DM.

Do thiazolidinediones still have a role in treatment of type 2 diabetes mellitus?

Thiazolidinediones have been introduced in the treatment of type 2 diabetes mellitus (T2DM) since the late 1990s. Although troglitazone was withdrawn from the market a few years later due to liver toxicity, both rosiglitazone and pioglitazone gained widespread use for T2DM treatment. In 2010, however, due to increased risk of cardiovascular events associated with its use, the European Medicines Agency recommended suspension of rosiglitazone use and the Food and Drug Administration severely restricted its use. Thus pioglitazone is the only thiazolidinedione still significantly employed for treating T2DM and it is the only molecule of this class still listed in the American Diabetes Association-European Association for the Study of Diabetes 2012 Position Statement. However, as for the other thiazolidinediones, use of pioglitazone is itself limited by several side effects, some of them potentially dangerous. This, together with the development of novel therapeutic strategies approved in the last couple of years, has made it questionable whether or not thiazolidinediones (namely pioglitazone) should still be used in the treatment of T2DM. This article will attempt to formulate an answer to this question by critically reviewing the available data on the numerous advantages and the potentially worrying shortcomings of pioglitazone treatment in T2DM.

Rosiglitazone use and associated adverse event rates in Canada between 2004 and 2010

BackgroundWe examined the change in the use of rosiglitazone-containing products (RCPs) Canada-wide between 2004 and 2010 and whether the rates of adverse events in association with RCP therapy in Canadian patients changed in this period to better understand the real world use of RCP medications and as part of a regulatory commitment by GlaxoSmithKline to Health Canada to assess whether there was an impact of a risk communication on cardiac safety.MethodsRCP utilization data were obtained from IMS Brogan’s longitudinal de-identified patient database (known as LRx) that tracks prescription activity using store-based data collection from pharmacies in all Canadian provinces. Adverse events (AEs), serious adverse events (SAEs) and cardiac AEs associated with RCP use in Canadian patients between April 2004 and December 2010 were identified from GlaxoSmithKline’s AE database and, using the LRx data, rates per 100,000 patients were estimated.ResultsA total of 239,184 patients were identified as having received at least one RCP prescription between 2004 and 2010 from the LRx. After excluding those with inconsistent gender or age, only one RCP prescription at the pharmacy, a prescription from a pharmacy that had not consistently reported for the past six years or an unreasonably high number of prescriptions, 180,936 patients remained for the analysis. The number of reports identified from the AE database that occurred between April 2004 and December 2010 was 1,037. The average monthly rates of AEs, SAEs and cardiac AEs decreased by 57%, 43% and 4%, respectively, between the observed periods, April 2004-October 2007 and November 2007-December 2010.ConclusionsThe findings of this analysis demonstrate a significant decrease in RCP use in Canada following a meta-analysis publication suggesting harm, which has been maintained. It is not possible to disentangle whether the continuing decline can be attributed to the meta-analysis, the changes in prescribing guidelines, media attention or a combination of some or all of these factors.

Prescribing pattern of glucose lowering drugs in the United Kingdom in the last decade: a focus on the effects of safety warnings about rosiglitazone

In the last decade, new glucose lowering drugs (GLDs) have been launched, and also several warnings regarding their safety. The cardiovascular safety of thiazolidinediones (TZD) has been questioned. We analyzed the prescription pattern of GLDs from 2000 to November 2009 in the United Kingdom (UK) using the THIN database with special focus on the effects of the safety warnings about rosiglitazone issued in May 2007 and January 2008. Annual prevalence and incidence of GLD prescriptions were measured. For TZD, the monthly prevalence and incidence of prescription were calculated from May 2006 to January 2009. The switching pattern around the FDA alert and the characteristics of subjects starting treatment with TZD before and after the alerts were observed. The prevalence of prescriptions of GLDs increased during the 10 year period, metformin increasing more than three times. Rosiglitazone prevalence showed an increased trend until May 2007, (2.3/1000 person-years) and decreased thereafter (January 2009: 1.1/1000 person-years). The use of pioglitazone increased surpassing rosiglitazone from April 2008 onwards. The incidence of rosiglitazone use decreased sharply after May 2007 (0.8/1000 person-years). The prevalence of use of other therapies remained rather stable from 2000 to 2007 but increased afterwards. After May 2007, rosiglitazone users were increasingly switched to pioglitazone. There was an increased proportion of new users of pioglitazone with cardiovascular risk after the alerts. The prescription of GLDs in the UK has increased in the last decade. For TZDs, it changed after May 2007 as well as the characteristics of the subjects treated with them.

Heart and skeletal muscle insulin resistance but not myocardial blood flow reserve could be related to chronic use of thiazolidione in patients with type-2 diabetes

Heart and skeletal muscle insulin resistance and abnormal myocardial flow reserve (MFR) occurs in patients with type-II diabetes. Improvement of heart and skeletal muscle insulin resistance with rosiglitazone use over 16 weeks have been reported. However, it is not clear whether chronic use of troglitazone can improve heart and skeletal muscle insulin resistance and MFR. Materials and Methods: To test the hypothesis whether effects of troglitazone on heart and skeletal muscle insulin resistance and MFR in patients with type-II diabetes, rest and dipyridamole stress perfusion positron emission tomography (PET) with 13N-ammonia and heart and skeletal muscle 18FDG PET scans under insulin clamping were undertaken before and 12 month after the initiation of troglitazone therapy (400 mg/day) in 23 patients with type-II diabetes. Twenty patients with type-II diabetes without CAD and without medications were served as controls. In controls, any medications were not added from the first PET study and 12 months after the second PET study. Results: Baseline myocardial blood flow (MBF) was comparable before and after the troglitazone group as was the controls. MBF during dipyridamole administration (0.56 mg/min/kg) was not significantly improved in troglitazone group and controls. MFR was not improved in troglitazone group and controls. In troglitazone group, whole body glucose disposal rate (GDR; μmole/min/kg) significantly improved (pre; 19.0 ± 9.55, post; 28.7 ± 15.3, p as did the skeletal muscle glucose utilization rate (SMGU (μmole/min/kg); pre; 20.3 ± 12.0, post; 34.8 ± 10.6, p insulin resistance is implicated in patients with type-II diabetes and impaired MFR is uncoupled with insulin resistance in the whole body and heart and skeletal muscle in patients with type-II diabetes.

Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs

Aims/hypothesisCurrent drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes.MethodsUsing a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999–2008.ResultsThere were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10−5), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%).Conclusions/interpretationHip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.

Blockade of human HERG K+ channels by rosiglitazone, an antidiabetic drug

This study examined the effect of rosiglitazone, an oral antidiabetic drug, on human ether-a-gogo-related gene (HERG) channels expressed in human embryonic kidney (HEK293) cells. Using the whole-cell patch-clamp technique, interaction between rosiglitazone and HERG in HEK293 cells was studied. Rosiglitazone inhibited HERG channels in a concentration-dependent manner, with an IC₅₀ value of 18.8 μM and a Hill coefficient of 1.0. These effects were reversible after wash-out of the drug. The rosiglitazone-induced inhibition of HERG channels was voltagedependent, with a steep increase in inhibition over the voltage range of channel opening. However, inhibition was voltage-independent over the voltage range in which channels are fully activated. Rosiglitazone did not change the steady-state activation or inactivation curves or the activation or deactivation kinetics, implying that rosiglitazone blocks HERG channels predominantly in the open and inactivated state rather than in the closed state. The present study suggests that rosiglitazone blocks HERG channels by binding to activated and inactivated channels, and rosiglitazone use should thus be carefully monitored in patients with pre-existing QT prolongation.

Bone Effects of Rosiglitazone in HIV-Infected Patients With Lipoatrophy

Objectives: Thiazoledinediones increase limb fat in HIV+ patients with lipoatrophy. However, their use in the general population has been associated with bone loss and fracture. We sought to determine the effects of rosiglitazone on bone metabolism in HIV-infected patients. Methods: HIV+ patients with lipoatrophy were randomized to rosiglitazone versus placebo for 48 weeks in a double-blind, placebo-controlled trial. Limb fat, bone mineral density (BMD), bone formation markers (procollagen type 1 amino-terminal propeptide [P1NP], osteocalcin [OC]) and bone resorption markers (C-terminal telopeptide of type I collagen [CTX]) were measured, along with receptor activator for nuclear factor kappa β ligand (RANKL), osteoprotegerin (OPG), and inflammatory cytokines. Results: Seventy-one subjects were randomized to rosiglitazone or placebo: 17% female and 51% white. Total BMD did not change significantly in either group. In the rosiglitazone group, P1NP showed statistically significant decreases at 24 and 48 weeks; however, changes compared to placebo were only significant at 24 weeks. OC decreased significantly in the rosiglitazone group at 24 weeks, but there were no between-group differences. CTX, RANKL, or OPG did not change for either group. Multivariable regression within the rosiglitazone arm showed P1NP changes were inversely associated with limb fat changes, protease inhibitors, and tenofovir use. Conclusion: Rosiglitazone use was associated with decreased bone formation, but it did not alter bone resorption or total BMD. The increase in limb fat that accompanies rosiglitazone use appears to be associated with decreased osteoblast activity. Further studies are needed to determine the effect of thiazoledinediones on bone health in HIV-infected persons.

Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta-analysis

Patients with type 2 diabetes have a 40% increased risk of bladder cancer. Thiazolidinediones, especially pioglitazone, may increase the risk. We conducted a systematic review and meta-analysis to evaluate the risk of bladder cancer among adults with type 2 diabetes taking thiazolidinediones. We searched key biomedical databases (including MEDLINE, Embase and Scopus) and sources of grey literature from inception through March 2012 for published and unpublished studies, without language restrictions. We included randomized controlled trials (RCTs), cohort studies and case-control studies that reported incident bladder cancer among people with type 2 diabetes who ever (v. never) were exposed to pioglitazone (main outcome), rosiglitazone or any thiazolidinedione. Of the 1787 studies identified, we selected 4 RCTs, 5 cohort studies and 1 case-control study. The total number of patients was 2,657,365, of whom 3643 had newly diagnosed bladder cancer, for an overall incidence of 53.1 per 100,000 person-years. The one RCT that reported on pioglitazone use found no significant association with bladder cancer (risk ratio [RR] 2.36, 95% confidence interval [CI] 0.91-6.13). The cohort studies of thiazolidinediones (pooled RR 1.15, 95% CI 1.04-1.26; I(2) = 0%) and of pioglitazone specifically (pooled RR 1.22, 95% CI 1.07-1.39; I(2) = 0%) showed significant associations with bladder cancer. No significant association with bladder cancer was observed in the two RCTs that evaluated rosiglitazone use (pooled RR 0.87, 95% CI 0.34-2.23; I(2) = 0%). The limited evidence available supports the hypothesis that thiazolidinediones, particularly pioglitazone, are associated with an increased risk of bladder cancer among adults with type 2 diabetes.

Pilot study of rosiglitazone as an in vivo probe of paclitaxel exposure

• Paclitaxel and rosiglitazone are primarily metabolized by CYP2C8 and their in vitro metabolism by human liver microsomes is correlated. Probe assays that quantify the in vivo activity of CYP enzymes which are important in drug metabolism have been developed for use in clinical pharmacology research. A probe of CYP2C8 that is easy to administer and interpret may be valuable for individualized dosing of paclitaxel. • This pilot study demonstrates for the first time that there is an in vivo correlation between paclitaxel and rosiglitazone exposure. The finding, that a single rosiglitazone plasma concentration after oral dosing may explain significant variance in paclitaxel exposure, suggests that rosiglitazone may satisfy the requirements of a clinically useful in vivo probe. However, it is acknowledged that there is a need for further studies evaluating the use of rosiglitazone as a CYP2C8 probe and quantifying the relationship, in order to guide dosing of narrow therapeutic index drugs metabolized primarily by CYP2C8, such as paclitaxel. To evaluate the use of rosiglitazone and the erythromycin breath test (ERMBT), as probes of CYP2C8 and CYP3A4, respectively, to explain inter-individual variability in paclitaxel exposure. The concentration of rosiglitazone at 3 h and ERMBT results were included in a regression model to explain the variability in paclitaxel exposure in 14 subjects. Rosiglitazone concentration was significantly correlated with paclitaxel exposure (P= 0.018) while ERMBT had no predictive value (P= 0.47). The correlation between the exposure of rosiglitazone and paclitaxel likely reflects mutual dependence on the activity of CYP2C8. Rosiglitazone or similar agents may have value as in vivo probes of CYP2C8 activity.

Prescribing of Rosiglitazone and Pioglitazone Following Safety Signals

Relevant safety signals in the EU are regularly communicated in so-called 'Direct Healthcare Professional Communications' (DHPCs) or European Medicines Agency (EMA) press releases. Trends of a decrease in the use of rosiglitazone following regulatory safety warnings have been described in the US. In the EU, however, relatively little is known about dispensing patterns following DHPCs or other safety signals such as EMA press releases. The objective of this study was to analyse trends in dispensing patterns of rosiglitazone and pioglitazone following DHPCs and EMA press releases in the EU member state, the Netherlands. Data for this study were obtained from the PHARMO Record Linking System, which includes drug dispensing records from community pharmacies of approximately 2.5 million individuals in the Netherlands. Over the period 1998-2008 an auto-regressive, integrated, moving average model (ARIMA) was fitted. The DHPC letters or EMA press releases were used as determinants. Adjustments were made for publication of certain literature. Stratification was performed for dispensings prescribed by general practitioners (GPs) and those prescribed by specialists. For rosiglitazone, four EMA press releases and two DHPCs were issued; for pioglitazone, one DHPC was issued. The number of rosiglitazone dispensings prescribed by GPs decreased significantly after publication of DHPCs and EMA press releases concerning the risk of macular oedema and risk of fractures (both p-values 0.001). The number of rosiglitazone dispensings decreased statistically significantly after publication of EMA press releases 2 and 3 concerning cardiovascular risks but not for EMA press release 4. Adjustment for certain publications in the literature reduced the effect of communicated safety issues on the proportion of dispensings. Although it is difficult to disentangle the effect of DHPCs and EMA press releases from the effect of reports published in the literature, our results suggest that prescribers may react to such safety communications.

Association of thiazolidinediones with liver cancer and colorectal cancer in type 2 diabetes mellitus

The objective of this nationwide case-control study was to evaluate the risk of specific malignancy in diabetic patients who received thiazolidinediones (TZDs). A total of 606,583 type 2 diabetic patients, age 30 years and above, without a history of cancer were identified from the Taiwan National Health Insurance claims database during the period between January 1 2000 and December 31 2000. As of December 31 2007, patients with incident cancer of liver, colorectal, lung, and urinary bladder were included as cases and up to four age- and sex-matched controls were selected by risk-set sampling. Logistic regression models were applied to estimate the odds ratio (OR) and 95% confidence interval (CI) between TZDs and cancer incidence. A total of 10,741 liver cancer cases, 7,200 colorectal cancer cases, and 70,559 diabetic controls were included. A significantly lower risk of liver cancer incidence was found for any use of rosiglitazone (OR: 0.73, 95% CI: 0.65-0.81) or pioglitazone (OR: 0.83, 95% CI: 0.72-0.95), respectively. The protective effects were stronger for higher cumulative dosage and longer duration. For colorectal cancer, rosiglitazone, but not pioglitazone, was associated with a significantly reduced risk (OR: 0.86; 95% CI: 0.76-0.96). TZDs were not associated with lung and bladder cancer incidence, although a potential increased risk for bladder cancer with pioglitazone use ≥3 years could not be excluded (OR: 1.56; 95% CI: 0.51-4.74). The use of pioglitazone and rosiglitazone is associated with a decreased liver cancer incidence in diabetic patients. The effects on occurrence of specific cancer types may be different for pioglitazone and rosiglitazone.