Rosiglitazone Users Research Articles

Rosiglitazone has a null association with the risk of prostate cancer in type 2 diabetes patients.

This study investigated the risk of prostate cancer in ever users and never users of rosiglitazone in diabetes patients in Taiwan. The nationwide database of the National Health Insurance was used to enroll male patients who had a new diagnosis of type 2 diabetes mellitus at an age ≥ 25 years from 1999 to 2005.A total of 11,495 ever users and 11,495 never users of rosiglitazone matched on propensity score were selected and they were followed up for the incidence of prostate cancer from January 1, 2006 until December 31, 2011. Cox proportional hazard model incorporated with the inverse probability of treatment weighting using the propensity score was used to estimate hazard ratios. At the end of follow-up, incident cases of prostate cancer were found in 84 never users and 90 ever users of rosiglitazone. The calculated incidence was 173.20 per 100,000 person-years in never users and was 187.59 per 100,000 person-years in ever users. The overall hazard ratio (95% confidence intervals) for ever versus never users was 1.089 (0.808-1.466). The hazard ratios were 0.999 (0.643-1.552) for the first tertile (< 672 mg), 1.147 (0.770-1.709) for the second tertile (672-3584 mg) and 1.116 (0.735-1.695) for the third tertile (> 3584 mg) of cumulative dose. Sensitivity analyses consistently showed a null association between rosiglitazone and prostate cancer risk. Rosiglitazone has a null effect on the risk of prostate cancer.

Rosiglitazone Does Not Affect the Risk of Inflammatory Bowel Disease: A Retrospective Cohort Study in Taiwanese Type 2 Diabetes Patients.

Human studies on the effect of rosiglitazone on inflammatory bowel disease (IBD) are still lacking. We investigated whether rosiglitazone might affect IBD risk by using the reimbursement database of Taiwan's National Health Insurance to enroll a propensity-score-matched cohort of ever users and never users of rosiglitazone. The patients should have been newly diagnosed with diabetes mellitus between 1999 and 2006 and should have been alive on 1 January 2007. We then started to follow the patients from 1 January 2007 until 31 December 2011 for a new diagnosis of IBD. Propensity-score-weighted hazard ratios were estimated with regards to rosiglitazone exposure in terms of ever users versus never users and in terms of cumulative duration and cumulative dose of rosiglitazone therapy for dose-response analyses. The joint effects and interactions between rosiglitazone and risk factors of psoriasis/arthropathies, dorsopathies, and chronic obstructive pulmonary disease/tobacco abuse and the use of metformin were estimated by Cox regression after adjustment for all covariates. A total of 6226 ever users and 6226 never users were identified and the respective numbers of incident IBD were 95 and 111. When we compared the risk of IBD in ever users to that of the never users, the estimated hazard ratio (0.870, 95% confidence interval: 0.661-1.144) was not statistically significant. When cumulative duration and cumulative dose of rosiglitazone therapy were categorized by tertiles and hazard ratios were estimated by comparing the tertiles of rosiglitazone exposure to the never users, none of the hazard ratios reached statistical significance. In secondary analyses, rosiglitazone has a null association with Crohn's disease, but a potential benefit on ulcerative colitis (UC) could not be excluded. However, because of the low incidence of UC, we were not able to perform detailed dose-response analyses for UC. In the joint effect analyses, only the subgroup of psoriasis/arthropathies (-)/rosiglitazone (-) showed a significantly lower risk in comparison to the subgroup of psoriasis/arthropathies (+)/rosiglitazone (-). No interactions between rosiglitazone and the major risk factors or metformin use were observed. We concluded that rosiglitazone has a null effect on the risk of IBD, but the potential benefit on UC awaits further investigation.

Thiazolidinediones were associated with higher risk of cardiovascular events in patients with type 2 diabetes and cirrhosis.

Type 2 diabetes mellitus (T2DM) management in patients with cirrhosis is complicated. No clinical trials have investigated appropriate antidiabetic drug use in these patients. This study compared the risks of all-cause mortality, major adverse cardiovascular events (MACE) and hepatic outcomes between patients with T2DM and cirrhosis using and not using thiazolidinedione (TZD). We selected 1,705 propensity score-matched TZD users and nonusers from a Taiwan National Health Insurance Research Database cohort of T2DM patients with compensated cirrhosis between January 1, 2000, and December 31, 2012 and followed them until December 31, 2013. Cox proportional hazards models with robust sandwich standard error estimates were used to assess risks of investigated outcomes for TZD users. MACE incidence rates during follow-up were 2.14 and 1.30 per 100 patient-years for TZD users and nonusers, respectively (adjusted hazard ratio [aHR] 1.70; 95% confidence interval [CI], 1.32-2.19). On the basis of TZD use, the aHRs (95% CIs) for stroke, ischemic heart disease and heart failure were 1.81 (1.28-2.55), 1.59 (1.03-2.44) and 2.09 (1.22-3.60) respectively. Compared with TZD nonusers, rosiglitazone users had significantly higher aHR [1.67 (1.26-2.20)] and pioglitazone users had no significant difference of aHR [1.12 (0.90-1.64)]. All-cause mortality, hepatocellular carcinoma, decompensated cirrhosis and hepatic failure risks did not differ significantly between TZD users and nonusers. Compared with nonuser, TZD users demonstrated significantly higher MACE risks. Therefore, the risks of cardiovascular complications should be considered when prescribing TZDs to patients with T2DM and cirrhosis.

Comparing the individual effects of metformin and rosiglitazone and their combination in obese women with polycystic ovary syndrome: a randomized controlled trial

To compare the effects of metformin, rosiglitazone, and their combination in obese polycystic ovary syndrome (PCOS) patients with insulin resistance. Prospective randomized controlled trail. Tertiary teaching hospital. Obese Chinese women (body mass index [BMI] ≥25 kg/m2) with insulin resistance who fulfilled the Rotterdam criteria of PCOS. In group 1, 68 patients administered metformin (1,500 mg/day); in group 2, 67 patients administered rosiglitazone (4mg/day); in group 3, 69 patients administered metformin (1,000 mg/day) and rosiglitazone (4 mg/day) for 6 months, all with the same diet and regular exercise lifestyle recommendation. Average menstrual interval, anthropometric measurements, androgen-related parameters, and metabolic features of insulin, carbohydrates, and lipids, with intention-to-treat analysis. The baseline parameters showed no statistically significant differences. After the 6-month treatment, most participants showed an improved menstrual pattern. There were statistically significant decreases in acne scores, weight, BMI, waist circumference, waist-to-hip ratio, and serum testosterone. The metabolic indexes of insulin, carbohydrates, and lipids were improved obviously compared with the baseline in each group. Among the three groups, the patients administered 1,500 mg/day metformin experienced greater reductions in weight. However, the rosiglitazone users (alone or combined with metformin) showed a more notable decline in total cholesterol and triglyceride levels. Considering the benefits of metformin on weight loss, high-dose metformin (1,500 mg/day) along with lifestyle modification should be recommended for obese, insulin-resistant women with PCOS. Rosiglitazone alone or combined with low-dosage metformin plus lifestyle modification should be considered for the women with abnormal lipid profiles. ChiCTR-TRC-13003642 (Chinese Clinical Trial Registry).

2423-PUB: Rosiglitazone Has a Neutral Effect on the Risk of Dementia in Type 2 Diabetes Patients

Background: This study investigated whether rosiglitazone might affect dementia risk. Methods: The Taiwan’s National Health Insurance database was used to enroll a cohort of 1:1 matched-pairs of ever and never users of rosiglitazone based on propensity score from patients with new onset type 2 diabetes during 1999-2006. The patients were alive on January 1, 2007 and were followed-up for dementia until December 31, 2011. Results: A total of 5048 pairs of never users and ever users were identified. The incident case numbers were 127 and 121, respectively. The overall hazard ratio was 0.895 (95% confidence interval: 0.696-1.151) for ever versus never users. The hazard ratios for the first (&amp;lt;12.1 months), second (12.1-25.1 months) and third (&amp;gt;25.1 months) tertiles of cumulative duration were 0.756 (0.509-1.123), 0.964 (0.685-1.357) and 0.949 (0.671-1.341), respectively. When cumulative duration was treated as a continuous variable, the hazard ratio was 1.000 (0.992-1.008). Subgroup analyses conducted in ever users and never users of metformin and in patients whose diabetes was diagnosed during three different periods of time, i.e., 1999-2000, 2001-2003 and 2004-2006, all supported a neutral effect of rosiglitazone. Conclusions: Rosiglitazone has a neutral effect on dementia risk in patients with type 2 diabetes mellitus. Disclosure C. Tseng: None.

Rosiglitazone has a neutral effect on the risk of dementia in type 2 diabetes patients.

This study investigated whether rosiglitazone might increase or reduce dementia risk. Taiwan’s National Health Insurance database was used to enroll a cohort of 1:1 matched-pairs of ever and never users of rosiglitazone based on propensity score from patients with new-onset type 2 diabetes during 1999-2006. The patients were alive on January 1, 2007 and were followed up for dementia until December 31, 2011. A total of 5,048 pairs of never users and ever users were identified. The incident case numbers were 127 and 121, respectively. The adjusted hazard ratio for ever versus never users was 0.895 (95% confidence interval: 0.696-1.151). The adjusted hazard ratios for the first (<12.1 months), second (12.1-25.1 months) and third (>25.1 months) tertiles of cumulative duration of rosiglitazone therapy were 0.756 (0.509-1.123), 0.964 (0.685-1.357) and 0.949 (0.671-1.341), respectively. When cumulative duration was treated as a continuous variable, the adjusted hazard ratio was 1.000 (0.992-1.008). Subgroup analyses conducted in ever users and never users of metformin and in patients diagnosed with diabetes during three different periods of time, i.e., 1999-2000, 2001-2003 and 2004-2006, all supported a neutral effect of rosiglitazone. In conclusion, rosiglitazone does not increase or redcue the risk of dementia.

Disparities in Discontinuing Rosiglitazone Following the 2007 FDA Safety Alert.

Responsiveness to the Food and Drug Administration (FDA) rosiglitazone safety alert, issued on May 21, 2007, has not been examined among vulnerable subpopulations of the elderly. To compare time to discontinuation of rosiglitazone after the safety alert between black and white elderly persons, and across sociodemographic and economic subgroups. A cohort study. Medicare fee-for-service enrollees in 2007 who were established users of rosiglitazone identified from a 20% national sample of pharmacy claims. Outcome of interest was time to discontinuation of rosiglitazone after the May alert. We modeled the number of days following the warning to the end of the days' supply for the last rosiglitazone claim during the study period (May 21, 2007-December 31, 2007) using multivariable proportional hazards models. More than 67% of enrollees discontinued rosiglitazone within six months of the advisory. In adjusted analysis, white enrollees (hazard ratio=0.90; 95% confidence interval, 0.86-0.94) discontinued rosiglitazone later than the comparison group of black enrollees. Enrollees with a history of low personal income also discontinued later than their comparison group (hazard ratio=0.84; 95% confidence interval, 0.81-0.87). There were no observed differences across quintiles of area-level socioeconomic status. White race and a history of low personal income modestly predicted later discontinuation of rosiglitazone after the FDA's safety advisory in 2007. The impact of FDA advisories can vary among sociodemographic groups. Policymakers should continue to monitor whether risk management policies reach their intended populations.

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.

The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies.

BackgroundPatients with type 2 diabetes mellitus (T2DM) are at high risk of heart failure. A summary of the effects of blood glucose-lowering drugs other than glitazones on the risk of heart failure in routine clinical practice is lacking. The objective of this study was to conduct a systematic review and meta-analysis of observational studies on the risk of heart failure when using blood glucose-lowering drugs.MethodsWe systematically identified and reviewed cohort and case–control studies in which the main exposure of interest was noninsulin blood glucose-lowering medications in patients with T2DM. We searched Medline, Embase, and the Cochrane Library to identify publications meeting prespecified eligibility criteria. The quality of included studies was assessed with the Newcastle-Ottawa Scale and the RTI item bank. Results were combined using fixed and random-effects models when at least 3 independent data points were available for a drug-drug comparison.ResultsThe summary relative risk of heart failure in rosiglitazone users versus pioglitazone users (95% CI) was 1.16 (1.05-1.28) (5 cohort studies). Heterogeneity was present (I2 = 66%). For new users (n = 4) the summary relative risk was 1.21 (1.14-1.30) and the heterogeneity was reduced (I2 = 31%);. The summary relative risk for rosiglitazone versus metformin was 1.36 (95% CI, 1.17-1.59) (n = 3). The summary relative risk (95% CI) of heart failure in sulfonylureas users versus metformin users was 1.17 (95% CI, 1.06-1.29) (5 cohort studies; I2 = 24%) and 1.22 (1.02-1.46) when restricted to new users (2 studies).Information on other comparisons was very scarce. Information on dose and duration of treatment effects was lacking for most comparisons. Few studies accounted for disease severity; therefore, confounding by indication might be present in the majority of the within-study comparisons of this meta-analysis.ConclusionsUse of glitazones and sulfonylureas was associated with an increased risk of heart failure compared with metformin use. However, indication bias cannot be ruled out. Ongoing large multidatabase studies will help to evaluate the risk of heart failure in treated patients with diabetes, including those using newer blood glucose-lowering therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2261-14-129) contains supplementary material, which is available to authorized users.

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...

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.

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.

Risk of Death and Cardiovascular Outcomes with Thiazolidinediones: A Study with the General Practice Research Database and Secondary Care Data

ObjectiveTo describe the likely extent of confounding in evaluating the risks of cardiovascular (CV) events and mortality in patients using diabetes medication.MethodsThe General Practice Research Database was used to identify inception cohorts of insulin and different oral antidiabetics. An analysis of bias and incidence of mortality, acute coronary syndrome, stroke and heart failure were analysed in GPRD, Hospital Episode Statistics and death certificates.Results206,940 patients were identified. The bias analysis showed that past thiazolidinedione users had a lower mortality risk compared to past metformin users. There were no differences between past users of rosiglitazone and pioglitazone (adjusted RR of 1.04; 95% CI 0.93–1.18). Current rosiglitazone users had an increased risk of death (adjusted RR 1.20; 95% CI 1.08–1.34) and of hospitalisation for heart failure (adjusted RR of 1.73; 95% CI 1.19–2.51) compared to current pioglitazone users. Risk of mortality was increased two-fold shortly after starting rosiglitazone. Excess risk of death over 3 years with rosiglitazone was 0.3 per 100 in those aged 50–64 years, 2.0 aged 65–74, 3.0 aged 75–84, and 7.0 aged 85+. The cause of death with rosiglitazone was more likely to be due to a disease of the circulatory system.ConclusionsHigher risks for death (overall and due to cardiovascular disease) and heart failure were found for rosiglitazone compared to pioglitazone. These excess risks were largest in patients aged 65 years or older. The European regulatory decision to suspend rosiglitazone is supported by this study.

Use of rosiglitazone and pioglitazone immediately after the cardiovascular risk warnings

Background Meta-analyses of oral hypoglycemic agents (OHAs) revealed that rosiglitazone increased the risk of myocardial infarction (MI) and heart failure (HF) and that pioglitazone increased the risk of HF and decreased the risk of MI. Objective To characterize the change in the pattern of use of OHAs immediately after the publication of these meta-analyses on May 21, 2007. Methods Pharmacy and medical claims data for a managed care organization were analyzed for patients continuously enrolled from January 1, 2005, to November 30, 2007, with at least 1 pharmacy claim for OHA in the 13-month period between November 1, 2006, and November 30, 2007. A 5-month pre-publication period (November 1, 2006, through March 31, 2007) was compared with a 5-month post-publication period (July 1, 2007, through November 30, 2007) using a differences-in-differences multinomial logistic regression. This regression explored discontinuation; continuation with monotherapy or adding another drug; and switching to a drug different from the index monotherapy drug after adjusting for gender, age, type of insurance, past 1-year history of MI or HF, and risk factors for MI and HF in the past 1 year. Results The relative rate of switching to nonindex drug in the postpublication relative to prepublication was 2.64 ( P = .046) for monotherapy rosiglitazone users and 0.72 ( P = .583) for monotherapy pioglitazone users. The differences-in-differences estimate of the rate of switching to nonindex drugs for monotherapy rosiglitazone users was 3.64 ( P = .090) times higher relative to the estimate for monotherapy pioglitazone users. Conclusion The pattern of use differed fundamentally between monotherapy rosiglitazone users and users of all other monotherapy OHAs in the postperiod. Not only were monotherapy rosiglitazone patients switching to non-rosiglitazone drugs at a higher rate, but the rate also was more than 3 times higher than similar switches among monotherapy pioglitazone users in the postperiod relative to the preperiod. This shows that the market response as observed by patient/prescriber decisions to the adverse news was interpreted narrowly to monotherapy rosiglitazone, and there is little or no spillover to the other drugs. Therefore, this study found that there was a differential effect of meta-analyses on the use of the 2 drugs.

The thiazolidinediones rosiglitazone and pioglitazone and the risk of coronary heart disease: A retrospective cohort study using a US health insurance database

Background: The thiazolidinediones (TZDs), including rosiglitazone maleate and pioglitazone hydrochloride, are commonly prescribed in patients with type 2 diabetes mellitus. Although recent meta-analyses suggest there is an increased risk of myocardial infarction (MI) among rosiglitazone users, these findings were not supported by data from other studies. Objective: The goal of this research was to compare the risk of MI, coronary revascularization (CR), and sudden death in patients who began rosiglitazone therapy versus those who began pioglitazone therapy. Methods: This was a retrospective cohort study using information from a large health care database (with data available on ~14 million individuals). All initiators of rosiglitazone or pioglitazone from July 1, 2000, through March 31, 2007, for whom the first dispensing followed ≥6 months of health plan membership and the member's 18th birthday were identified. The propensity score method was used to create matched cohorts of patients in 3 treatment groups: TZD monotherapy, dual therapy (a TZD plus another antidiabetic agent), and TZD therapy with concomitant insulin. Follow-up continued to a change in treatment regimen, defined as regimen switch (ie, the addition of any antidiabetic agent to an existing regimen) or regimen stop (ie, the discontinuation of any component of the therapeutic regimen). Three outcomes that represent coronary heart disease were assessed for this analysis: MI, CR, and sudden death. The proportional hazards model, stratified by therapeutic regimen, was used to estimate hazard ratios (HRs) and 95% CIs of coronary heart disease risk associated with use of rosiglitazone relative to pioglitazone. Results: Among 47,501 matched pairs of rosiglitazone and pioglitazone users, 72,104 (75.9%) were receiving TZD monotherapy, 17,822 (18.8%) were receiving dual therapy, and 5076 (5.3%) were receiving TZD therapy with insulin. Mean follow-up was 9.6 months with regimen switch as the censoring event and 8.4 months with regimen stop as the censoring event. For MI, the HR was 1.35 (95% CI, 1.12–1.62) through regimen switch and 1.41 (95% CI, 1.13–1.75) through regimen stop. For the composite outcome of MI, CR, and/or sudden death, the HR was 1.09 (95% CI, 0.97–1.22) through regimen switch and 1.12 (95% CI, 0.98–1.27) through regimen stop. Conclusions: In this retrospective cohort analysis, MI was more common in users of rosiglitazone than in users of pioglitazone. The incidence of a combined end point of MI, CR, and/or sudden death in patients receiving rosiglitazone was not significantly different from that in patients receiving pioglitazone.

Rosiglitazone and pioglitazone utilization from January 2007 through May 2008 associated with five risk-warning events.

Rosiglitazone was approved by the U.S. Food and Drug Administration (FDA) for type 2 diabetes in 1999. The unique mechanism of action and low risk of hypoglycemia contributed to rapid market uptake of rosiglitazone, but safety concerns became more prominent in 2007. There were 5 major events on 4 calendar days in 2007 regarding safety concerns related to rosiglitazone in certain patients: (1) the May 21, 2007, online release of the rosiglitazone meta-analysis performed by Nissen and Wolski and the FDA safety warning on the same day; (2) the July 30, 2007, conclusion of an FDA advisory committee meeting that rosiglitazone increased cardiac ischemic risk; (3) the August 14, 2007, update of thiazolidinedione (TZD) labels with a black-box warning for heart failure; and (4) the November 14, 2007, update to the warnings and precautions section of the rosiglitazone label for coadministration of nitrate or insulin. To (1) describe TZD (rosiglitazone and pioglitazone) utilization trends from January 1, 2007, continuing through May 2008 amid public announcements of safety concerns and (2) determine the percentage of TZD users who had medical claims indicating increased cardiovascular (CV) risk before and after release (May 21, 2007) of the FDA safety warning and online release of the meta-analysis performed by Nissen and Wolski. A retrospective analysis of pharmacy claims was performed from 9 commercial plans with a combined 9 million eligible members, including a 1.4 million-member cohort from 1 of the plans for which medical claims data were available. We evaluated trends in TZD use for each month for the 17-month period from January 1, 2007, through May 31, 2008, including the percentage of TZD users at increased CV risk. In the trend analysis, for each calendar month of 2007, we calculated mean pharmacy claim counts per day per million members for each of the 2 TZD drugs and for a comparison drug, sitagliptin, a new oral hypoglycemic agent in a different class (dipeptidyl-peptidase-IV inhibitors). For the CV risk analysis, we used the database of integrated medical and pharmacy claims for the 1.4 million-member cohort to identify patients with a current days supply of a TZD on May 20, 2007, December 7, 2007, or May 20, 2008. The medical claims for all identified patients were queried back 2 years from May 20, 2007, December 7, 2007, or May 20, 2008, respectively. Rosiglitazone users at increased CV rsk were defined as those with a medical claim with a primary diagnosis for congestive heart failure (CHF; International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 428.xx or 398.91), those with a current supply of nitrate or insulin therapy, or those with ischemic heart disease, including myocardial infarction (MI; ICD-9-CM codes 410.xx through 414.xx, or surgical procedure codes [36.0x through 36.3x for removal of obstruction and insertion of stents, bypass surgery, and revascularization] in the primary diagnosis field). Pioglitazone users at increased risk were identified from medical claims with a CHF diagnosis code. The average number of claims per day per million members in January 2007 was 97.3 for rosiglitazone and 107.2 for pioglitazone. The average number of claims for rosiglitazone per day per million members began to decrease in May 2007, falling to 41.0 in December 2007, for a total decrease of 58.6% from the February 2007 peak (99.1), and fell further to 31.8 in May 2008. Pioglitazone use increased 8.0% from January to June 2007 (107.2 to 115.8) and remained relatively flat through December 2007 (114.6) and through May 2008 (108.9). Sitagliptin claims increased 5-fold, at a consistent rate, from an average of 8.6 claims per day per million members in January 2007 to 43.4 in December 2007, and continued to increase to 48.7, in May 2008. Of the 5,117 rosiglitazone users on May 20, 2007, 1,296 (25.3%) were identified at increased CV risk versus 590 (22.5%) of 2,621 users on December 7, 2007 (P = 0.006), and 336 (21.8%) of 1,541 users in May 2008 (P = 0.005). Of 6,056 pioglitazone users on May 20, 2007, 170 (2.8%) had a CHF diagnosis versus 160 (2.5%) of 6,275 users on December 7, 2007 (P = 0.376), and 122 of 5,998 users in May 2008 (P = 0.006). Although rosiglitazone utilization per million members declined by more than half in 2007, when CV safety concerns started to emerge, about 1 in 5 rosiglitazone users had elevated CV risk at year-end 2007 and in May 2008. About 3% of pioglitazone users in May 2007 had a diagnosis of CHF in claims history, which declined to 2% in May 2008. Insurers should consider the impact of persistent utilization of TZDs among members with CV risk factors when making formulary decisions.

The cardiovascular safety of rosiglitazone

Background: Thiazolidinediones (rosiglitazone, pioglitazone) influence insulin sensitivity and are used for the treatment of Type 2 diabetes. Rosiglitazone achieves sustained improvements in glycaemic control, whilst having pleiotropic effects on cardiovascular risk factors. However, analysis of cardiovascular outcomes has been controversial. Objectives: Review the cardiovascular safety of rosiglitazone by conducting a literature search. Methods: We conducted a PubMed search and critically reviewed published work on cardiovascular outcome of rosiglitazone, including clinical studies and meta-analyses. Results/conclusion: The meta-analysis by Nissen and Wolski suggested increased cardiovascular risk in users of rosiglitazone, but this was not supported by an interim analysis of the RECORD trial designed to evaluate this, and several other reports failed to shed conclusive light on this issue. The cardiovascular benefits of pioglitazone have also been in doubt due to the failure of the PROactive trial to reach the primary cardiovascular end points, although this study reported a significant reduction in secondary end points. All of this has left diabetes care in some disarray, with weak evidence for adverse cardiovascular effects driving the reduced use of rosiglitazone, an agent that has important sustained effects on glycaemic control.

New use of rosiglitazone decreased following publication of a meta‐analysis suggesting harm

It is uncertain whether meta-analyses lead to changes in prescribing practices. We studied trends in the prescribing of glucose-lowering therapy before and after the publication of a meta-analysis suggesting harm from rosiglitazone. We examined the prescription records of all residents of Ontario, Canada, aged > or = 66 years. For each week between January and December 2007, we identified new users of five categories of glucose-lowering medications: rosiglitazone, pioglitazone, metformin, glibenclamide (glyburide) and insulin. The effect of the meta-analysis was assessed using interventional autoregressive integrated moving-average models. Following the release of the meta-analysis, there was a sudden decline in new users of rosiglitazone (P = 0.01), mirrored by a nearly identical but transient increase in new users of pioglitazone (P < 0.001). There was also a net decline in new users of thiazolidinediones as a class (P < 0.001). The number of new users of other glucose-lowering medications did not change. A highly-publicized meta-analysis regarding rosiglitazone's potential harms led to an abrupt decline in new users of the drug, as well as a transient surge in new use of pioglitazone.

Thiazolidinediones and Fracture Risk in Diabetic Women

Diabetic patients have higher BMD but greater risk for fragility fractures than do nondiabetics. Could diabetes medications account for this finding? In two studies, researchers investigated whether thiazolidinediones (TZDs) were linked to elevated fracture incidence. In the original A Diabetes Outcome Progression Trial (ADOPT) — a comparison of the glucose-controlling effects of rosiglitazone (a TZD), glyburide, and metformin — a relatively high rate of fractures among rosiglitazone users was identified unexpectedly. In a supplementary …