Use Of Rosiglitazone Research Articles

Diabetes Pharmacotherapies and Bladder Cancer: A Medicare Epidemiologic Study

ObjectivePatients with type II diabetes have an increased risk of bladder cancer and are commonly treated with thiazolidinediones and angiotensin receptor blockers (ARBs), which have been linked to cancer risk. We explored the relationship between use of one or both of these medication types and incident bladder cancer among diabetic patients (diabetics) enrolled in Medicare.Research Design and MethodsWe constructed both a prevalent and incident retrospective cohort of pharmacologically treated prevalent diabetics enrolled in a Medicare fee-for-service plan using inpatient, outpatient (2003–2011) and prescription (2006–2011) administrative data. The association of incident bladder cancer with exposure to pioglitazone, rosiglitazone and ARBs was studied using muitivariable Cox’s hazard models with time-dependent covariates in each of the two cohorts.ResultsWe identified 1,161,443 prevalent and 320,090 incident pharmacologically treated diabetics, among whom 4433 and 1159, respectively, developed incident bladder cancers. In the prevalent cohort mean age was 75.1 years, mean follow-up time was 38.0 months, 20.2% filled a prescription for pioglitazone during follow-up, 10.4% received rosiglitazone, 31.6% received an ARB and 8.0% received combined therapy with pioglitazone + ARB. We found a positive association between bladder cancer and duration of pioglitazone use in the prevalent cohort (P for trend = 0.008), with ≥24 months of pioglitazone exposure corresponding to a 16% (95% confidence interval 0–35%) increase in the incidence of bladder cancer compared to no use. There was a positive association between bladder cancer and rosiglitazone use for <24 months in the prevalent cohort, but no association with ARB use. There were no significant associations in the incident cohort.ConclusionsWe found that the incidence of bladder cancer increased with duration of pioglitazone use in a prevalent cohort of diabetics aged 65+ years residing in the USA, but not an incident cohort.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0152-4) contains supplementary material, which is available to authorized users.

Rosiglitazone Use and the Risk of Bladder Cancer in Patients With Type 2 Diabetes.

Patients with diabetes have a higher incidence of bladder cancer; however, the association between thiazolidinedione use and bladder cancer risk has been controversial. We aimed to investigate whether pioglitazone or rosiglitazone use is associated with bladder cancer risk in patients with type 2 diabetes mellitus.This nationwide nested case-control study used data set obtained from the Korean National Health Insurance Service National Sample Cohort 2002 to 2013. Among the 47,738 patients with incident diabetes, 85 cases of newly diagnosed bladder cancer and 850 controls (1:10 matched by age, sex, index year, and diabetes diagnosis year) were recruited. Type 2 diabetes mellitus and bladder cancer were diagnosed using the International Statistical Classification of Diseases and Related Health Problems, 10th Revision code.More cases of bladder cancer were diagnosed in men (81.2%), and the stratified age peaked at 70 to 79 years old. Exclusive rosiglitazone use raised the incidence of bladder cancer (odds ratio [OR] = 3.07, 95% confidence interval [CI ] = 1.48-6.37). The risk of bladder cancer started to increase after less than 3 months use (OR = 3.30, 95% CI = 1.02-10.70) and peaked at 3 to 12 months of rosiglitazone use (OR = 4.48, 95% CI = 1.51-13.31). Patients were first exposed to exclusive rosiglitazone within 1 year (OR = 11.74, 95% CI = 2.46-56.12) and those who had consistently used it for 1 year (OR = 4.48 95% CI = 1.51-13.31), had higher risks of bladder cancer compared with nonthiazolidinedione users. Neither pioglitazone use nor exclusive pioglitazone use were associated with an increased incidence of bladder cancer.Rosiglitazone use is associated with an increased risk of incident bladder cancer independent of age and sex in patients with type 2 diabetes mellitus. The highest odds of bladder cancer in rosiglitazone users was seen in those with <1 year of exposure.

Influence of health warnings on the use of rosiglitazone and pioglitazone in an area of Spain: A time-series study.

Background:Throughout 2007 and January 2008, several glitazones health warnings were published on rosiglitazone myocardial infarction risk. The impact of such warnings on glitazones prevalence of utilization has been extensively studied in the United States but only in one European country (England), which has showed different pattern from US studies. The aim of this study is to evaluate the impact of such safety warnings on glitazones utilization in an area of another European country.Methods:We calculated the number of defined daily doses per thousand inhabitants per day of glitazones each month during the period from 2006 to 2008 in a health area of Spain. We analyzed the data graphically and through a segmented regression analysis.Results:Rosiglitazone defined daily doses per thousand inhabitants per day were growing before the safety warnings, after the warnings a change in trend occurred and rosiglitazone utilization showed a downturn slope. Pioglitazone defined daily doses per thousand inhabitants per day were stable before the safety warnings, and a linear growth was observed after the safety warnings. Throughout the study period, rosiglitazone defined daily doses per thousand inhabitants per day were higher than pioglitazone defined daily doses per thousand inhabitants per day until near the end of 2008.Conclusion:Despite the fact that cardiovascular warnings affected rosiglitazone and not pioglitazone, rosiglitazone was more utilized than pioglitazone until near the end of 2008 which is a pattern similar to the one found in another European studies in England, but very different from studies in the United States, where rosiglitazone was less utilized than pioglitazone from the first month after rosiglitazone cardiovascular safety warnings.

Long-Term Treatment with Rosiglitazone Delays Hematopoietic Recovery in Response to Stress

Rosiglitazone is a peroxisome proliferator activated receptor-γ(PPAR-γ) agonist available to improve glucose metabolism in patients with Type 2 diabetes. Recent evidence suggests that therapeutic use of rosiglitazone have caused unwanted hematological side effects, such as anemia, leukopenia, thrombocytopenia, even pancytopenia. However, others reported that pretreatment with rosiglitazone for 5 days could protect against 5-Fu-induced myelotoxity which is FLT3 dependent. Thus, it is still unclear the exact effects of rosiglitazone treatment on homeostatic and stress hematopoiesis. Rosiglitazone is a potent stimulator of adipogenesis, as it can induce adipogenic differentiation both in vitro and in vivo. Recently, it was reported that adipocyte-rich bone marrow(BM) harbored a decreased frequency of progenitor cells. Furthermore, our laboratory and those of other investigators have demonstrated that BADGE, an inhibitor of PPAR-γ signaling pathway, can improved the hematopoietic recovery in response to stress. So we hypothesize that long-term treatment of rosiglitazone may inhibit the hematopoiesis by inducing BM adipogenesis.In this study, we first treated C57BL/6J mice with 37.5mg/kg rosiglitazone for six weeks to examine the long-term effect of rosiglitazone on hematopoiesis in vivo. We found that rosiglitazone treatment does not alter body weight or BM function of normal healthy mice. In response to 5-Fu induced hematopoietic stress, rosiglitazone group mice exhibited delayed recovery of WBC and BMMNC. Furthermore, the frequency and absolute number of GMP and CLP cells in rosiglitazone group was decreased at d14 after 5-Fu. Concomitantly, we found that CFU-GM counts of rosiglitazone group BM were significantly decreased when compared with control group mice, while CFU-GEMM counts revealed no difference. However, we didn't observed any alteration in absolute number of LSK cells between the two groups, although rosiglitazone group mice had increased percentage of LSK. These results indicated that rosiglitazone could maintain the HSC compartment while impair myeloid differentiation from myelosuppressive stress, which may explain the delayed hematopoietic recovery in rosiglitazone group.To answer the question whether the effects of rosiglitazone were directly mediated, in vitro cultures were used. We cultured d3 5-Fu BM cells (BM cells harvested 3 day after 5-FU administration) in the presence of rosiglitazone to detect whether rosiglitazone inhibited hematopoietic progenitor cells in stress condition. Cell proliferation of Lin- cell was unaffected at pharmacologically achievable concentrations of rosiglitazone. However, rosiglitazone at high concentrations (>10μM) significantly inhibit cell proliferation of Lin- cell, which was in agreement with previous reports. To confirm our results, we choose two other TZD drugs to test whether cell proliferation was affected. Similarly, neither troglitazone nor pioglitazone exhibited an inhibition effect on cell proliferation at pharmacologically achievable concentrations. Furthermore, rosiglitazone treatment didn't decrease the numbers of CFU-GM. These data show that rosiglitazone can not directly inhibit cell proliferation or myeloid differentiation of HPC in stress condition.As long-term treatment of rosiglitazone caused a significant increase of BM adipocytes in mice, we speculated that impaired myeloid differentiation in rosiglitazone group mice may be due to enhanced adipogenesis. We found that rosiglitazone promoted the adipogenic differentiation of two stromal cell lines (C3H10T1/2,M2-10B4). In addition, rosiglitazone treated stromal cell lines significantly inhibited cell proliferation and myeloid differentiation of co-cultured Lin- cells.In conclusion, rosiglitazone induced BM adipogenesis can impair the myeloid differentiation of hematopoietic stem cell, which may contribute to a significant delay in hematopoietic recovery after chemotherapeutic stress. Further investigation of the molecular mechanism is warranted and may enable the development of therapies effective for suppressed hematopoiesis induced by TZDs. DisclosuresNo relevant conflicts of interest to declare.

Geographic Variation in Rosiglitazone Use Surrounding FDA Warnings in the Department of Veterans Affairs.

Geographic variation in the use of prescription drugs, particularly those deemed harmful by the FDA, may lead to variation in patient exposure to adverse drug events. One such drug is the glucose-lowering drug rosiglitazone, for which the FDA issued a safety alert on May 21, 2007, following the publication of a meta-analysis that suggested a 43% increase in the risk of myocardial infarction with the use of rosiglitazone. This alert was followed by a black box warning on August 14, 2007, that was updated 3 months later. While large declines have been documented in rosiglitazone use in clinical practice, little is known about how the use of rosiglitazone and other glucose-lowering drugs varied within the Department of Veterans Affairs (VA), surrounding the FDA alerts. Understanding this variation within integrated health care systems is essential to formulating policies that enhance patient protection and quality of care. To document variation in the use of rosiglitazone and other glucose- lowering drugs across 21 Veterans Integrated Service Networks (VISNs). We conducted a retrospective analysis of drug use patterns for all major diabetes drugs in a national cohort of 550,550 veterans with diabetes from 2003 to 2008. This included the time periods when rosiglitazone was added to (November 2003) and removed from (October 2007) the VA national formulary (VANF). We employed multivariable logistic regression models to statistically estimate the association between a patient's location and the patient's odds of using rosiglitazone. Aggregate rosiglitazone use increased monotonically from 7.7%, in the quarter it was added to the VANF (November 4, 2003), to a peak of 15.3% in the quarter when the FDA issued the safety alert. Rosiglitazone use decreased sharply afterwards, reaching 3.4% by the end of the study period (September 30, 2008). The use of pioglitazone, another glucose-lowering drug in the same class as rosiglitazone, was low when the FDA issued the safety alert (0.4%) but increased sharply afterwards, reaching 3.6% by the end of the study period. Insulin use increased monotonically; metformin use remained relatively flat; and sulfonylurea use exhibited a general declining trend throughout the study period. Statistically significant geographic variation was observed in rosiglitazone use throughout the study period. The prevalence range, defined as the range of minimum to maximum use across VISNs was 3.7%-12.4% in the first quarter (January 1 to March 31, 2003); 1.0%-5.5% in the last quarter of study period (July 1 to September 30, 2008); and reached a peak of 9.6%-25.5% in the quarter when the FDA safety alert was issued (April 1 to March 31, 2007). In 5 VISNs, peak rosiglitazone use occurred before the FDA issued the safety alert. The odds ratio of using rosiglitazone in a given VISN varied from 0.55 (95% CI = 0.52-0.59; VISN 10) to 1.58 (95% CI = 1.50-1.66; VISN 15), with VISN 1 being the reference region. The variation was higher in the periods after the FDA issued the safety alert. Much less variation was observed in the use of pioglitazone, metformin, sulfonylurea, and insulin. Our results show statistically significant variation in the way VISNs within the VA responded to the FDA alerts, suggesting a need for mechanisms that disseminate information and guidelines for drug use in a consistent and reliable manner. Further study of regions that adopted ideal practices earlier may provide lessons for regional leadership and practice culture within integrated health care systems.

Rosiglitazone use and associated adverse event rates in Canada: an updated analysis.

BackgroundWe previously reported on the change in the use of rosiglitazone-containing products (RCP) and adverse event reporting rates in Canadian patients between 2004 and 2010. The present study extends this analysis to include the January 2011 to December 2012 time period.MethodsRCP utilization rates were obtained from IMS Health Brogan’s longitudinal de-identified patient database, LRx. GlaxoSmithKline’s global adverse events database was used to extract adverse events (AE), serious adverse events (SAE), and cardiac adverse events (CAE) reported in Canadian patients receiving RCP from April 2004 to December 2012. The patient utilization information from the LRx database was used to estimate rates per 100,000 patients.ResultsAn estimated 182,841 patients were dispensed RCP prescriptions between April 2004 and December 2012. The total number of patients using RCP decreased by 85 % from 2011 to 2012. From its peak use in 2007, the number of patients filling a prescription decreased 97 %. A total of 1069 AEs were reported during the study period, of which 32 AE’s were reported from Jan 2011 to Dec 2012. The average monthly reporting rates of AE’s, SAE’s and CAE’s over 2011–2012 were 10.8/100,000 patients, 9.1/100,000 patients and 5.0/100,000 patients, respectively.ConclusionsThe utilization of RCP in Canada has significantly declined. The significance of the adverse event rate information presented is uncertain and must be evaluated within the context of the well known factors that can influence AE reporting rates, as well as limitations to the methods used to estimate these reporting rates.

Rosiglitazone exerts neuroprotective effects via the suppression of neuronal autophagy and apoptosis in the cortex following traumatic brain injury.

Traumatic brain injury (TBI) is one of the leading causes of mortality and morbidity in adults and children worldwide. Recent studies have demonstrated that both apoptosis and autophagy participate in TBI-induced neuronal cell death and functional loss. The peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist rosiglitazone (RSG) is a well-known anti-inflammatory, which carries out its effects via the activation of PPAR-γ. Previous studies have suggested that RSG may exert neuroprotective effects in animal models of both chronic and acute brain injury; however, whether RSG is involved in autophagic neuronal death following TBI remains to be elucidated. The present study aimed to determine whether RSG carries out its neuroprotective properties via the attenuation of neuronal apoptosis and autophagy, following TBI in a rat model. Furthermore, the role of RSG was investigated with regards to the modulation of inflammation and glutamate excitotoxicity, and the impact of RSG on functional recovery following TBI was determined. The rats were subjected to controlled cortical impact injury, prior to being randomly divided into three groups: A sham-operated group, a TBI group, and an RSG treatment group. The RSG treatment group was intraperitoneally treated with 2 mg/kg RSG immediately after TBI. The results of the present study demonstrated that RSG treatment following TBI significantly reduced neuronal apoptosis and autophagy, and increased functional recovery. These effects were correlated with a decrease in the protein expression levels of tumor necrosis factor α and interleukin-6. However, no significant changes were observed in the protein expression levels of glutamate transporter-1 in the brain cortex. The results of the present study provide in vivo evidence that RSG may exert neuroprotective effects via the inhibition of neuronal apoptosis and autophagy following experimental TBI in rats, and the mechanism underlying these effects may be associated with the anti-inflammatory action of RSG. The present study offers a novel insight into the potential use of RSG as a neuroprotective agent for the treatment of cerebral injuries.

Effects of safety warnings and risk management plan for Thiazolidinediones in Taiwan.

To evaluate changes in thiazolidinedione use and quality of prescription following safety warnings for thiazolidinediones and cardiac risk in 2007, Risk Management Plan (RMP) policy for rosiglitazone in 2010, and warning for pioglitazone and bladder cancer risk in 2010 in Taiwan. We obtained 2003-2011 claims data from Taiwan's National Health Insurance Research Database. Using an interrupted time series design and segmented regression, we estimated changes in monthly prescribing rates for thiazolidinediones among all and prevalent diabetes patients with and without cardiovascular disease history (CV history). We also compared time to prescription of thiazolidinediones among new diabetes patients with CV history before and after each regulatory action using survival analysis. Among prevalent patients with and without CV history, the prescribing rates of rosiglitazone decreased 36.88% and 28.92% after safety warnings in 2007 respectively. Pioglitazone prescriptions increased 13% among patients with CV history, but no changes were detected among patients without CV history. After rosiglitazone's RMP policy in 2010, large reductions in prescriptions were observed in patients with CV history (-101.67%) and those without CV history (-88.04%). Among new diabetes patients with CV history, cardiac safety warnings in 2007 significantly delayed the prescription of rosiglitazone, but no significant change was found for pioglitazone. The Taiwan FDA regulatory actions for thiazolidinediones communicated possible risks of cardiac events and bladder cancer. Different safety regulatory actions had differential impacts on the use of rosiglitazone and pioglitazone and the quality use of these drugs among the high-risk patients.

Effect of pioglitazone medication on the incidence of dementia.

Peroxisome proliferator activated receptor γ-activating drugs show various salutary effects in preclinical models of neurodegenerative disease. The decade-long clinical usage of these drugs as antidiabetics now allows for evaluation of patient-oriented data sources. Using observational data from 2004-2010, we analyzed the association of pioglitazone and incidence of dementia in a prospective cohort study of 145,928 subjects aged ≥60 years who, at baseline, were free of dementia and insulin-dependent diabetes mellitus. We distinguished between nondiabetics, diabetics without pioglitazone, diabetics with prescriptions of <8 calendar quarters of pioglitazone, and diabetics with ≥8 quarters. Cox proportional hazard models explored the relative risk (RR) of dementia incidence dependent on pioglitazone use adjusted for sex, age, use of rosiglitazone or metformin, and cardiovascular comorbidities. Long-term use of pioglitazone was associated with a lower dementia incidence. Relative to nondiabetics, the cumulative long-term use of pioglitazone reduced the dementia risk by 47% (RR = 0.53, p = 0.029). If diabetes patients used pioglitazone <8 quarters, the dementia risk was comparable to those of nondiabetics (RR = 1.16, p = 0.317), and diabetes patients without a pioglitazone treatment had a 23% increase in dementia risk (RR = 1.23, p < 0.001). We did not find evidence for age effects, nor for selection into pioglitazone treatment due to obesity. These findings indicate that pioglitazone treatment is associated with a reduced dementia risk in initially non-insulin-dependent diabetes mellitus patients. Prospective clinical trials are needed to evaluate a possible neuroprotective effect in these patients in an ageing population.

Rosiglitazone treatment and cardiovascular disease in the Veterans Affairs Diabetes Trial.

AimsTo evaluate the relationship between patterns of rosiglitazone use and cardiovascular (CV) outcomes in the Veterans Affairs Diabetes Trial (VADT).MethodsTime-dependent survival analyses, case–control and 1 : 1 propensity matching approaches were used to examine the relationship between patterns of rosiglitazone use and CV outcomes in the VADT, a randomized controlled study that assessed the effect of intensive glycaemic control on CV outcomes in 1791 patients with type 2 diabetes (T2D) whose mean age was 60.4 ± 9 years. Participants were recruited between 1 December 2000 and 31 May 2003, and were followed for 5–7.5 years (median 5.6) with a final visit by 31 May 2008. Rosiglitazone (4 mg and 8 mg daily) was initiated per protocol in both the intensive-therapy and standard-therapy groups. Main outcomes included a composite CV outcome, CV death and myocardial infarction (MI).ResultsBoth daily doses of rosiglitazone were associated with lower risk for the primary composite CV outcome [4 mg: hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.49–0.81 and 8 mg: HR 0.60, 95% CI 0.49–0.75] after adjusting for demographic and clinical covariates. A reduction in CV death was also observed (HR 0.25, p < 0.001, for both 4 and 8 mg/day rosiglitazone); however, the effect on MI was less evident for 8 mg/day and not significant for 4 mg/day.ConclusionsIn older patients with T2D the use of rosiglitazone was associated with decreased risk of the primary CV composite outcome and CV death. Rosiglitazone use did not lead to a higher risk of MI.

How Did Multiple FDA Actions Affect the Utilization and Reimbursed Costs of Thiazolidinediones in US Medicaid?

PurposeThe US Food and Drug Administration (FDA) communicated the potential cardiovascular risk of thiazolidinediones (rosiglitazone and pioglitazone) in 2007 and required a Risk Evaluation and Mitigation Strategy (REMS) for rosiglitazone in 2010. It also communicated in 2010 the potential risk of bladder cancer with pioglitazone use. This study examined the effects of these multiple FDA actions on utilization and reimbursed costs of thiazolidinediones in state Medicaid programs. MethodsState Drug Utilization Data from the Centers for Medicare & Medicaid Services were assessed. An interrupted time series design and segmented linear regression models were used to examine changes in market shares according to both prescription volume and reimbursed costs for rosiglitazone and pioglitazone in the Northeast and Midwest regions of the United States after multiple FDA actions. FindingsCompared with expected rates, there were relative reductions of 65.84% (Northeast region) and 55.09% (Midwest region) in the use of rosiglitazone at 1 year after the 2007 FDA actions for thiazolidinediones and cardiac risk. At the same time, relative increases of 7.30% and 9.28% in the use of pioglitazone were observed in the Northeast and Midwest regions, respectively. Changes in both use and costs of rosiglitazone after the 2010 REMS program could not be estimated because of the already low rates (~1%) before REMS was implemented. One year after the 2010 FDA actions for pioglitazone and its possible association with bladder cancer, relative reductions in pioglitazone use of 21.41% (Northeast region) and 18.12% (Midwest region) were detected. ImplicationsThe Northeast and Midwest regions reported similar patterns of changes after the FDA actions. Use and costs of rosiglitazone were substantially reduced after the 2007 FDA actions for cardiovascular risk, and this drug was rarely used after the 2010 REMS program. Conversely, use and costs of pioglitazone were substantially reduced after the 2010 FDA actions regarding the drug’s possible risk of bladder cancer.

Abstract 356: Effect of Treatment with Rosiglitazone on High-sensitivity Cardiac Troponin Levels Among Patients with Type 2 Diabetes Mellitus

Background: Rosiglitazone has been associated with increased risk of adverse cardiovascular events, including myocardial infarction (MI) and heart failure. However, the impact of rosiglitazone on markers of subclinical myocardial injury, such as high-sensitivity cardiac troponin-T levels (hscTnT), is not known. Objective: Evaluate the impact of intermediate-term treatment with rosiglitazone on hscTnT levels among patients with T2DM with or at high risk for coronary artery disease (CAD). Methods: We measured serum hscTnT levels at baseline and after 6 months of study treatment in a randomized trial comparing rosiglitazone versus placebo in patients with T2DM and risk factors for or prevalent CAD. Multivariable adjusted linear regression analysis was performed to identify variables associated with changes in hsTnT levels from baseline to follow up. Results: The study included 150 participants, of whom 106 had paired baseline and end-of-study blood samples for analysis (53 placebo, 53 rosiglitazone, mean age 56 + 8 years, 42% women; 8.8 years average T2DM duration; 42% insulin treated). Almost all study participants (93%) had elevated hscTnT (≥3 ng/L) at baseline; 23% had hscTnT levels exceeding the diagnostic limit commonly used to diagnose MI (≥14 ng/L). As expected, age, male sex and left ventricular hypertrophy were independently associated with elevated hscTnT levels at baseline. HscTnT levels increased from baseline to follow up within both the placebo and rosiglitazone treated groups (Figure), with no difference between the two groups after 6 months (p =0.73). In multivariable adjusted linear regression analysis, male sex (β = 0.36; p= 0.04), baseline hemoglobin A1c (β= 0.43; p= 0.001) and baseline hscTnT levels (β= -0.69; p &lt;0.0001) were independently associated with an increase in hscTnT from baseline to follow-up. Use of rosiglitazone was not associated with an increase in hscTnT levels in the adjusted model (p = 0.65). Conclusion: There is high prevalence of elevated hscTnT among patients with T2DM with prevalent or clustered risk factors for CAD, exceeding the MI detection limit in almost a quarter of such patients. Rosiglitazone did not impact hscTnT levels, adding to the growing body of literature suggesting that rosiglitazone is not associated with direct myocardial injury.

Peroxisome proliferator-activated receptor-gamma agonists for Alzheimer's disease and amnestic mild cognitive impairment: a systematic review and meta-analysis.

Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly, and close associations between AD and diabetes have been found. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonists, as newly-developed oral hypoglycaemic agents, were evaluated as a possible therapy for AD. We systematically evaluated the efficacy and safety of PPAR-γ agonists in the treatment of AD and amnestic mild cognitive impairment (aMCI), the prodromal stage of AD. A search of the electronic databases PubMed, EMBASE, CINAHL, Cochrane Library and China National Knowledge Infrastructure (until July 2014) was conducted, and included randomized controlled trials. Dichotomous data were expressed as risk ratios (RRs) with 95% confidence intervals (CIs), and continuous data were expressed as mean differences (MD) with 95% CIs. The results were pooled using a random-effects model. Nine eligible studies were identified, with 4,327 participants. Using the Alzheimer's Disease Assessment Scale-Cognitive subscale, pioglitazone was found to be efficacious, especially for patients with comorbid diabetes (MD -3.47, 95% CI -4.40 to -2.54). Rosiglitazone was not efficacious, even for apolipoprotein E (APOE) ε4 non-carriers (MD -0.31, 95% CI -1.12 to 0.51). There was no increase in any adverse events (AEs) or serious AEs compared with placebo. Peripheral edema was the most frequent AE related to PPAR-γ agonist treatment (RR 4.14, 95% CI 2.37-7.23). There is insufficient evidence to support the use of rosiglitazone in aMCI and AD patients in order to improve cognitive performance. Nonetheless, the efficacy of pioglitazone seems to be promising, particularly for patients with comorbid diabetes, however this needs to be further confirmed by well-designed trials with large sample sizes. PPAR-γ agonists such as rosiglitazone and pioglitazone are generally well-tolerated in AD and aMCI patients.

Pioglitazone and bladder cancer risk: a multipopulation pooled, cumulative exposure analysis.

The evidence on the association between pioglitazone use and bladder cancer is contradictory, with many studies subject to allocation bias. The aim of our study was to examine the effect of exposure to pioglitazone on bladder cancer risk internationally across several cohorts. The potential for allocation bias was minimised by focusing on the cumulative effect of pioglitazone as the primary endpoint using a time-dependent approach. Prescription, cancer and mortality data from people with type 2 diabetes were obtained from six populations across the world (British Columbia, Finland, Manchester, Rotterdam, Scotland and the UK Clinical Practice Research Datalink). A discrete time failure analysis using Poisson regression was applied separately to data from each centre to model the effect of cumulative drug exposure on bladder cancer incidence, with time-dependent adjustment for ever use of pioglitazone. These were then pooled using fixed and random effects meta-regression. Data were collated on 1.01 million persons over 5.9 million person-years. There were 3,248 cases of incident bladder cancer, with 117 exposed cases and a median follow-up duration of 4.0 to 7.4 years. Overall, there was no evidence for any association between cumulative exposure to pioglitazone and bladder cancer in men (rate ratio [RR] per 100 days of cumulative exposure, 1.01; 95% CI 0.97, 1.06) or women (RR 1.04; 95% CI 0.97, 1.11) after adjustment for age, calendar year, diabetes duration, smoking and any ever use of pioglitazone. No association was observed between rosiglitazone and bladder cancer in men (RR 1.01; 95% CI 0.98, 1.03) or women (RR 1.00; 95% CI 0.94, 1.07). The cumulative use of pioglitazone or rosiglitazone was not associated with the incidence of bladder cancer in this large, pooled multipopulation analysis.

The impact of pioglitazone on bladder cancer and cardiovascular events.

Type 2 diabetes mellitus (T2DM) is a chronic condition with increasing prevalence and severe complications. Thiazolidinediones have been marketed since 1997 and are effective glucose-lowering drugs, but individual drugs within the class have been linked to serious adverse effects that resulted in the removal of troglitazone from the market, restrictions to rosiglitazone's use, and a warning added to pioglitazone's label. In 2007, a meta-analysis linked rosiglitazone to myocardial infarction (MI). Pioglitazone does not appear to share this risk. To the contrary, pioglitazone may reduce risk for MI. However, retrospective evaluations have increasingly linked pioglitazone to a higher risk of bladder cancer that appears to be time- and dose-dependent. Pioglitazone remains a medication appropriate for consideration in the management of T2DM; however, clinicians and patients should weigh its risks compared with alternatives, with a regular review of risks.

Should we stop prescribing pioglitazone?

We read with interest the paper ‘Thiazolidinediones and associated risk of bladder cancer: a systematic review and meta-analysis’ by Turner et al. [1]. The authors present the results of a meta-analysis including a large number of patients. They concluded that pioglitazone use is associated with a modest but significant increase in the risk of bladder cancer, which further increases with both higher cumulative dose (>28 g) and duration of exposure (>12–24 months). Interestingly, the effect of rosiglitazone on bladder cancer risk was not significant [1]. A few comments might be of interest, based on the results of a recent study (published in August 2013), not included in the meta-analysis [2]. This was an observational follow-up study of patients included in the PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) trial, who had received pioglitazone for 2.6 years. PROactive had shown a modest but significant reduction in the composite of all cause mortality, non-fatal myocardial infarction (MI) and stroke in high cardiovascular disease (CVD) risk type 2 diabetes mellitus (T2DM) patients [3]. After a mean follow-up time of 8.7 years (including the PROactive period), the CVD benefit was lost, since only 13.5% continued on pioglitazone [2]. There was no evidence of increased risk of bladder cancer in these patients (89% of them were at the maximum dose of 45 mg day−1) [2]. Interestingly, no significant between group differences were observed in the percentage of patients reporting any other malignancies, except for prostate malignancy, a finding that needs further confirmation [3]. The leading cause of death in patients with T2DM is CVD [3]. As PROactive has shown, 40 patients would need to be treated for 3 years in order to prevent one first CVD event. In other words, the number needed to treat is approximately 120 per year [3], while the number needed to treat for harm (that is to develop one case of bladder cancer) shown by the meta-analysis was 3408 for ever pioglitazone use, 1119 for >28 g cumulative dose and 1404 for >24 months cumulative duration [1]. On the contrary, rosiglitazone use has been associated with increased risk for MI (although not for CVD or all cause mortality) in an older meta-analysis, showing one additional MI per 52 patients treated for 5 years [4]. These results were confirmed by a comparative meta-analysis, showing a significant increase in the odds of MI, congestive heart failure and death (170 excess MIs, 649 excess cases of heart failure and 431 excess deaths for every 100 000 patients receiving rosiglitazone rather than pioglitazone) [5]. It seems therefore prudent to prescribe an agent that has been shown to protect the cardiovascular system, for at least 3 years, rather than avoid it for the fear of causing bladder cancer, the possibility of which for such a period seems very low (taking into account that the cumulative dose of 28 g stands for a 31 month period of 30 mg day−1, which is the usual pioglitazone dose). This becomes more important in an era when clinicians, the Food and Drug Administration and the European Medicines Agency are very cautious about the effect of any anti-diabetic and anti-obesity drug on the cardiovascular system [6]. New studies are already being conducted to test the effect of other drug categories, such as glucagon-like peptide (GLP)-1 based therapies, on the cardiovascular system [6]. In conclusion, we believe that pioglitazone should continue to be considered a reliable therapeutic option in patients with T2DM for a period of up to 2 years (with a potential extension to 3 years), since its benefit and safety on the cardiovascular system overweigh the potential risk for bladder cancer. Patients at high risk for bladder cancer, such as those with a family history, microscopic haematuria and exposure to carcinogenic substances, should be excluded.

Effect and cardiovascular safety of adding rosiglitazone to insulin therapy in type2 diabetes: A meta-analysis.

Aims/IntroductionRecently, the use of rosiglitazone has been limited or withdrawn from the market as a result of cardiovascular risk. However, theoretically adding rosiglitazone to insulin could help insulin to decrease the glucose level. The present meta-analysis was designed to investigate the effect and safety of adding rosiglitazone to insulin therapy in type 2 diabetes.Materials and MethodsWe searched published and unpublished databases through to March 2012. Randomized controlled trials (RCTs) comparing rosiglitazone in combination with insulin (RSG + INS) vs insulin alone (INS) in type 2 diabetes with outcomes including glycated hemoglobin levels, insulin dose, lipid parameters, blood pressure, edema and cardiovascular adverse events were selected.ResultsNine RCTs with durations of 24–26 weeks involving 1,916 patients were included. The RSG + INS group showed significantly decreased glycated hemoglobin levels by 0.89% (P < 0.00001) with an 8.48-U reduction in daily insulin dose (P <0.00001). However, the risks of hypoglycemia and edema were more frequent in the RSG+INS group (P < 0.0001; P = 0.03, respectively). Total cholesterol level was significantly increased in the RSG+INS group (P < 0.00001), but none of the high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol or triglyceride levels were significantly different between groups. There were no significant differences between groups with regard to the risks of myocardial infarction, heart failure, cardiovascular death or all-cause death.ConclusionsRosiglitazone could help type 2 diabetes patients with poorly controlled glucose with insulin therapy to decrease glucose levels and reduce their daily insulin dose, but at the cost of increased total cholesterol level, hypoglycemia and edema risk. Compared with insulin therapy, adding rosiglitazone to insulin did not increase the risks of myocardial infarction, heart failure, cardiovascular death or all-cause death.

Use of Antidiabetic Drugs in the U.S., 2003–2012

To describe market trends for antidiabetic drugs, focusing on newly approved drugs, concomitant use of antidiabetic drugs, and effects of safety concerns and access restrictions on thiazolidinedione use. Nationally projected data on antidiabetic prescriptions for adults dispensed from U.S. retail pharmacies were extracted from IMS Health Vector One National and Total Patient Tracker for 2003-2012 and from Encuity Research Treatment Answers and Symphony Health Solutions PHAST Prescription Monthly for 2012. Since 2003, the number of adult antidiabetic drug users increased by 42.9% to 18.8 million in 2012. Metformin use increased by 97.0% to 60.4 million prescriptions dispensed in retail pharmacies in 2012. Among antidiabetic drugs newly approved for marketing between 2003 and 2012, the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin had the largest share with 10.5 million prescriptions in 2012. Rosiglitazone use plummeted to <13,000 prescriptions dispensed in retail or mail-order pharmacies in 2012. Concomitancy analyses showed that 44.9% of metformin use was for monotherapy. Between 33.4 and 48.1% of sulfonylurea, DPP-4 inhibitor, thiazolidinedione, and glucagon-like peptide 1 analog use was not accompanied by metformin. The antidiabetic drug market is characterized by steady increases in volume, and newly approved drugs experienced substantial uptake, especially DPP-4 inhibitors. The use of rosiglitazone has been negligible since restrictions were put in place in 2011. Further study is needed to understand why one-third to one-half of other noninsulin antidiabetic drug use was not concomitant with metformin use despite guidelines recommending that metformin be continued when other agents are added to treatment.

Select Articles Published on the Topic of Coronary Heart Disease in 2013

Select Articles Published on the Topic of Coronary Heart Disease in 2013

Utilisation trends of rosiglitazone and pioglitazone in Australia before and after safety warnings

BackgroundA see on cardiovascular diseases and bladder cancer. The changes to the patterns of rosiglitazone and pioglitazone utilisation in Australia following the timing of these various health authority warnings such as the Australian Therapeutic Good Administration (TGA), European Medicines Agency (EMA) press releases or U.S. Food and Drug Administration (FDA) is unknown. This study investigated the utilisation patterns of rosiglitazone and pioglitazone in Australia before and after warnings of major drug authorities.MethodsWe evaluated rosiglitazone and pioglitazone dispensing using the Pharmaceutical Benefit Scheme (PBS) subsidised drug dispensing data for the Australian population from February 2004 to July 2012. The World Health Organisation Anatomic Therapeutic Chemical (ATC)/Defined Daily Dose (DDD) system was used to compare the drug utilisation patterns following the announcements of EMA, FDA, and TGA safety warnings, which first occurred in May 2007. The DDD/1000population/day were examined in a series of time-series regression analysis with the drug safety warnings specified as interventions.ResultsRosiglitazone utilisation increased steadily from 2004 until reaching a peak at 1.96/1000population/day in January 2007. Then rosiglitazone use decreased significantly after the initial EMA press release and FDA warning on cardiovascular risk in May 2007 (with a 15.04% average monthly decline, p-value <0.001), however use did not significantly decrease after the TGA warning or subsequent EMA and FDA warnings. Pioglitazone utilisation proceeded rosiglitazone in September 2008 and remained above 1.5/1000/day during 2009–2010. However, pioglitazone utilisation has slightly declined after the FDA, EMA, and TGA warnings related to bladder cancer.ConclusionsDrug safety warnings were associated with a decrease in rosiglitazone and pioglitazone utilisation in Australia. Rosiglitazone began to decline prior to TGA warnings in December 2007, which suggests that Australian prescribers may have acted in response to scientific evidence or international safety warnings (EMA, FDA), prior to the response of the TGA. Minor effects were observed after bladder cancer warnings on pioglitazone utilisation.