Pioglitazone and the Risk of Myocardial Infarction and Other Major Adverse Cardiac Events: A Meta-Analysis of Randomized, Controlled Trials

Nagajothi, Nagapradeep; Adigopula, Sasikanth; Balamuthusamy, Saravanan; Velazquez-Ceceña, José-Luis E; Raghunathan, Kalpana; Kazemi, Ahmad; Singh, Sarabjeet; Molnár, J.; Khosla, Sandeep; Benatar, Daniel

doi:10.1097/mjt.0b013e318167180c

Cited by 32 publications

(20 citation statements)

References 36 publications

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“…However, neither did pioglitazone show a favorable effect in reducing the risk of stroke, heart failure or AMI. These findings are in agreement with other studies [9,10,19]. …”

Section: Discussionsupporting

confidence: 83%

“…In addition, different TZDs may not share the same vascular effects. Several clinical trials and observational studies have raised the possibility of increased risk of myocardial infarction and cardiovascular mortality among patients on rosiglitazone [6,7,8,9] but not pioglitazone [8,10,11]. Because of the elevated risk of heart disease, the US Food and Drug Administration has informed the public of restrictions in prescribing rosiglitazone-containing medicines, which have already been suspended in Europe.…”

Section: Introductionmentioning

confidence: 99%

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Risk of Stroke with Thiazolidinediones: A Ten-Year Nationwide Population-Based Cohort Study

Sun

Muo

et al. 2013

Cerebrovasc Dis

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Background: Thiazolidinediones (TZDs) - rosiglitazone and pioglitazone - a class of insulin sensitizer for treating type 2 diabetes, have been reported to exhibit neuroprotective effects in preclinical studies and have good effects in the control of blood sugar for diabetic patients with insulin resistance. However, clinical trials and observational studies have raised the possibility of higher stroke risk in patients treated with rosiglitazone. Whether pioglitazone poses similar stroke risk remains uncertain. Most of the studies on cardiovascular effects of TZDs were based on studies in the USA and Europe. The present study aimed to compare the stroke risk among diabetic patients on TZD to those on non-TZD medications in an Asian population. Methods: The study cohort included 15,981 patients with a diagnosis of diabetes without prior stroke, acute myocardial infarction (AMI) or heart failure who were followed from 2001 to 2010. Patients were classified by their prescriptions into rosiglitazone, pioglitazone and non-TZD groups. The study end points included ischemic and hemorrhagic stroke. In view of the reported association of heart failure and AMI with rosiglitazone, these 2 end points were also included in the present study. Cox hazard proportional models were used to estimate the risk of developing the end points. Likelihood ratio test was used to examine the age-drug interactions. Dose-response effects were evaluated by comparing the incidence rates among patients with different cumulative exposures to TZD. Results: During the 10-year follow-up, the rosiglitazone group showed significantly higher risk of ischemic stroke (multivariate adjusted hazard ratio, HR = 1.39; 95% confidence interval, CI = 1.16-1.66) and heart failure (HR = 1.59; 95% CI = 1.18-2.14) than the non-TZD group. The pioglitazone group did not show significant difference from the non-TZD group in ischemic stroke (HR = 0.97; 95% CI = 0.75-1.26) and heart failure (HR = 0.94; 95% CI = 0.59-1.50). The results also showed a significant dose-dependent effect of higher risk of ischemic stroke with increasing dosage of rosiglitazone, while there was no increased risk at any level of pioglitazone dosage. Conclusions: This population-based cohort study shows that rosiglitazone imposes a higher risk of developing stroke or heart failure in this Asian patient population, suggesting the adverse side effects of rosiglitazone across ethnic boundaries. Pioglitazone, on the other hand, does not increase cardiovascular or stroke risk compared to the non-TZD group among diabetic patients without a history of macrovascular disease.

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“…However, neither did pioglitazone show a favorable effect in reducing the risk of stroke, heart failure or AMI. These findings are in agreement with other studies [9,10,19]. …”

Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Risk of Stroke with Thiazolidinediones: A Ten-Year Nationwide Population-Based Cohort Study

Sun

Muo

et al. 2013

Cerebrovasc Dis

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“…It is therefore noteworthy that more attention should be paid to the adverse effect of long-term use of TZDs on the heart of ADPKD patients [39]. Although several studies have confirmed that pioglitazone did not increase the occurrence of cardiovascular events [40], such potential risks cannot be completely excluded, but could perhaps be overcome and minimized by the following measures: (i) strict control of the timing, dose and duration of administration, and avoidance of using the drug in patients with end-stage renal failure or heart failure; (ii) combining the TZD with small doses of the diuretic amiloride (an ENaC inhibitor) to prevent fluid retention; (iii) combining with a V2RA (the diuretic effect may attenuate the adverse effect of rosiglitazone, but attention would need to be paid to its effect on plasma osmotic pressure); and (iv) attempting to use new non-TZD PPAR-γ agonists.…”

Section: Discussionmentioning

confidence: 98%

Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han:SPRD rats

et al. 2010

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Although pioglitazone, a PPAR-gamma (peroxisome-proliferator-activated receptor-gamma) agonist, has been shown to prolong survival in two rapidly progressive pkd1 (polycystic kidney disease 1)-knockout mice models through disparate mechanisms, these studies lacked data on therapeutic potential and long-term safety because of a short observation period. In the present study, we have used another potent PPAR-gamma agonist, rosiglitazone, to treat Han:SPRD rats, a slowly progressive ADPKD (autosomal dominant PKD) animal model, and confirmed that short-term treatment was able to delay the progression of kidney cysts and protect renal function, which may relate to down-regulating the abnormally activated beta-catenin signalling pathway and its anti-inflammatory and anti-fibrosis effects. Long-term administration significantly prolonged the survival of Han:SPRD rats. Moreover, early therapy in rats with normal renal function had a better outcome than delayed therapy, while initiating therapy in rats with mild impaired renal function still protected renal function. The efficacy of rosiglitazone depended on continuous drug administration; withdrawal of the drug caused accelerated deterioration of renal function in effectively treated rats and shortened their survival to an untreated state. Long-term administration led to cardiac enlargement, probably due to rosiglitazone-mediated sodium re-absorption. In conclusion, these results indicate that rosiglitazone was able to effectively delay the progression of kidney disease and protect renal function in Han:SPRD rats, but its adverse effect of inducing cardiac enlargement should also be monitored closely.

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“…A meta-analysis of 12 clinical trials of metformin as monotherapy or combination therapy and of at least 52 weeks in duration indicated that metformin had no significant effect on CV events versus all comparators (odds ratio [OR], 0.937 [95% CI, 0.820-1.070]; P ¼ 0.339), but did reduce CV events compared with placebo or no therapy (OR, 0.794 [95% CI, 0.644-0.979]; P ¼ 0.031) 13 . In a meta-analysis of five trials of pioglitazone versus placebo or active comparators, the relative risk for myocardial infarction (MI) was 0.86 (95% CI, 0.69-1.07; P ¼ 0.17) and for CV mortality was 0.92 (95% CI, 0.73-1.16; P ¼ 0.47), suggesting that pioglitazone at least does not adversely affect CV outcomes 14 . Findings from studies of exenatide showed similar results.…”

Section: Cardiovascular Risk Reductionmentioning

confidence: 98%

A practice-based approach to the 2012 position statement of the American Diabetes Association and the European Association for the Study of Diabetes

Schwartz

2013

Current Medical Research and Opinion

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The position statement on the management of hyperglycemia in patients with type 2 diabetes mellitus issued in 2012 by the American Diabetes Association and the European Association for the Study of Diabetes contains significant improvements over the 2009 version, including an emphasis on patient-centered care, enhanced strategies for lifestyle modification, a focus on comprehensive cardiovascular risk reduction, and increased pharmacotherapy choices. As diabetes management evolves over time, further improvements may be made in future consensus statements, including a focus on prevention and early treatment and improved glycemic control in all patients, including those with comorbidities. These goals will be achievable by waning use of therapies known to cause hypoglycemia and weight gain and the increased use of therapies that do not carry these risks.

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Pioglitazone and the Risk of Myocardial Infarction and Other Major Adverse Cardiac Events: A Meta-Analysis of Randomized, Controlled Trials

Cited by 32 publications

References 36 publications

Risk of Stroke with Thiazolidinediones: A Ten-Year Nationwide Population-Based Cohort Study

Risk of Stroke with Thiazolidinediones: A Ten-Year Nationwide Population-Based Cohort Study

Rosiglitazone attenuates development of polycystic kidney disease and prolongs survival in Han:SPRD rats

A practice-based approach to the 2012 position statement of the American Diabetes Association and the European Association for the Study of Diabetes

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