Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis.

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Term Occurence Count Dictionary
Insulin 5 endocrinologydiseasesdrugs
diabetes mellitus 23 endocrinologydiseases
glucose intolerance 1 endocrinologydiseases
pioglitazone 52 endocrinologydiseasesdrugs
rosiglitazone 1 endocrinologydiseasesdrugs
type 2 diabetes mellitus 9 endocrinologydiseases

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Select Drug Character Offset Drug Term Instance
Insulin 6667 insulin resistance/pre-diabetes and diabetes were analysed separately for cardiovascular outcomes. Insulin resistance was defined as a value of more than 3.0 on the homeostasis model assessment of insulin resistance
Insulin 14601 Pioglitazone; DM, diabetes mellitus; HbA1c, glycated haemoglobin; IGT, impaired glucose tolerance; IRIS, Insulin Resistance Intervention after Stroke; J-SPIRIT, Junteno Stroke Prevention study in Insulin Resistance
Insulin 14692 tolerance; IRIS, Insulin Resistance Intervention after Stroke; J-SPIRIT, Junteno Stroke Prevention study in Insulin Resistance and Impaired glucose Tolerance; PERISCOPE, Pioglitazone Effect on Regression of Intravascular
Insulin 20651 diabetes study; CHICAGO: Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone; IRIS: Insulin Resistance Intervention after Stroke; J-SPIRIT: Juntendo Stroke Prevention study in Insulin Resistance
Insulin 20743 Pioglitazone; IRIS: Insulin Resistance Intervention after Stroke; J-SPIRIT: Juntendo Stroke Prevention study in Insulin Resistance and Impaired glucose Tolerance; PERISCOPE: Pioglitazone Effect on Regression of Intravascular
pioglitazone 480 date (collection): /2017Publication date (epub): 1/2017AbstractObjectivesTo evaluate the effect of pioglitazone in people with insulin resistance, pre-diabetes and type 2 diabetes.Design and settingSystematic review
pioglitazone 967 follow-up.Outcome measuresRelative risk (RR) with 95% CI was used to evaluate the association between pioglitazone and the risk of major adverse cardiovascular events (MACE: composite of non-fatal myocardial infarction,
pioglitazone 1676 to 1.99), oedema (RR, 1.63; CI 1.52 to 1.75) and weight gain (RR 1.60; CI 1.50 to 1.72) increased in pioglitazone group.ConclusionsPioglitazone was associated with reduced risk of MACE in people with insulin resistance,
pioglitazone 2867 microalbuminuria in patients with diabetes mellitus.[5] Furthermore, a prior meta-analysis found that pioglitazone reduced the risk of myocardial infarction, stroke and death compared to control drugs or placebo in
pioglitazone 3032 and death compared to control drugs or placebo in patients with type 2 diabetes mellitus, but whether pioglitazone is beneficial in prevention of cardiovascular diseases among patients with pre-diabetes or insulin resistance
pioglitazone 3272 addressed.[7] Since then, several randomised controlled trials have been published to evaluate the effect of pioglitazone on occurrence of cardiovascular events in various types of patients.[8] These trials comprised patients
pioglitazone 3810 failure, fracture, all-cause mortality, cancer, bladder cancer, oedema, weight gain and hypoglycaemia) of pioglitazone therapy in patients with insulin resistance, pre-diabetes and type 2 diabetes, we conducted a systematic
pioglitazone 4398 Cochrane Central Register of Controlled Trials (1966 to 17 May 2016) using MESH terms and free text: ‘ pioglitazone ’ or ‘actos’ AND ‘diabetes mellitus’ or ‘glucose intolerance’ or ‘prediabetic state’
pioglitazone 5165 pre-diabetes or insulin resistance or type 2 diabetes mellitus; (3) the study included a comparison of pioglitazone with control (eg, placebo or other glucose-lowering agents); (4) total participants and the number of
pioglitazone 7043 (measured in microunits per millilitre) divided by 22.5. The primary end points were the association of pioglitazone therapy (compared with control) with risks for major adverse cardiovascular events (MACE). The definition
pioglitazone 7475 mortality, cancer, bladder cancer, oedema, weight gain and hypoglycaemia. We also analysed the effect of pioglitazone versus placebo on development of diabetes among people with pre-diabetes or insulin resistance, but
pioglitazone 7731 baseline.Relative risk (RR) with 95% CIs was used to estimate the risk of clinical outcomes between the pioglitazone group and the control group. All analyses were based on the intention-to-treat principle. We entered
pioglitazone 7920 intention-to-treat principle. We entered number of participants with events and total number of participants in the pioglitazone and control groups. We pooled data across trials using a fixed-effects model based on Mantel-Haenszel
pioglitazone 9227 required information size was calculated based on the event rate observed in the comparator group and the pioglitazone group. If the Z curve of the cumulative meta-analysis crosses one of the boundaries, no further studies
pioglitazone 10263 61.8±9.0 years, and of whom 36% were women. About 5997 (50%) participants were randomly assigned to the pioglitazone group and 6029 (50%) participants were randomly assigned to the control group. The baseline characteristics
pioglitazone 12994 DM with silent cerebral infarction or carotid artery atherosclerosis or albuminuriaPioglitazone/non- pioglitazone control481/3568.9±7.17.43±0.9/NA24.3±3.3NANANATrialDefinition of primary end point in an original
pioglitazone 13350 active/controlACT NOW[8]Development of diabetesMI+strokeMedian 2.4; mean 2.20/0.2Greater reduction in pioglitazone group with 3.5 mg/dLCHICAGO[19]Absolute change in mean posterior-wall CIMT (carotid intima-media thickness)Non-fatal
pioglitazone 13554 intima-media thickness)Non-fatal MI+non-fatal stroke+cardiovascular death1.5Treatment group difference: ( pioglitazone -glimepiride): −0.32%NAIRIS[9]Any stroke or myocardial infarctionMI+stroke4.8NA−3.0/1.4J-SPIRIT[10]Ischaemic
pioglitazone 14931 Obstruction Prospective Evaluation; MI, myocardial infarction; NA, not available; PROactive, PROspective pioglitazone Clinical Trial In macroVascular Events; PROFIT-J, Primary prevention oF hIgh risk Type 2 diabetes in
pioglitazone 20936 Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation; PROactive: PROspective pioglitazone Clinical Trial In macroVascular Events; PROFIT-J: Primary prevention oF hIgh risk Type 2 diabetes in
pioglitazone 21188 Japan.10.1136/bmjopen-2016-013927.supp1supplementary figureCardiovascular outcomesAmong patients with pre-diabetes or insulin resistance, pioglitazone was associated with lower risks of MACE (2 trials; RR 0.77, 95% CI 0.64 to 0.93; p for heterogeneity=0.44,
pioglitazone 22184 95% CIs estimates for cardiovascular outcomes among patients with pre-diabetes or insulin resistance ( pioglitazone vs control).Figure 2Trial sequential analysis for (A) MACE, (B) myocardial infarction, (C) stroke,
pioglitazone 22696 has been crossed. MACE, major adverse cardiovascular events.Among patients with diabetes mellitus, pioglitazone was associated with a lower risk of MACE (5 trials; RR 0.83, 95% CI 0.72 to 0.97; p for heterogeneity=0.87,
pioglitazone 23066 0.78, 95% CI 0.60 to 1.02; p for heterogeneity=0.90, I[2]=0%) were not significantly different between pioglitazone and comparator groups (figure 3). There was no publication bias in end points of MACE (p=0.88), myocardial
pioglitazone 23688 risk and 95% CIs estimates for cardiovascular outcomes among patients with type 2 diabetes mellitus ( pioglitazone vs control).Figure 4Trial sequential analysis for (A) MACE, (B) myocardial infarction, (C) stroke,
pioglitazone 25704 hypoglycaemia).Figure 5Separate and pooled relative risk and 95% CIs estimates for safety outcomes among all included trials ( pioglitazone vs control).The rate of progression to diabetes was significantly lower in the pioglitazone group than
pioglitazone 25796 trials (pioglitazone vs control).The rate of progression to diabetes was significantly lower in the pioglitazone group than in the placebo group among people with pre-diabetes or insulin resistance (2 trials; RR 0.40,
pioglitazone 26087 meta-analysis including 9 randomised controlled trials with over 120 100 participants found that adding pioglitazone to standard therapy was associated with a 23% risk reduction of MACE among patients with insulin resistance
pioglitazone 26387 diabetes mellitus. The results of our analysis suggest that the cardiovascular event reduction seen with pioglitazone among patients with diabetes mellitus is also seen among patients with insulin resistance or pre-diabetes.
pioglitazone 26513 patients with diabetes mellitus is also seen among patients with insulin resistance or pre-diabetes. Also, pioglitazone use in people with pre-diabetes or insulin resistance, but not having frank diabetes mellitus at baseline,
pioglitazone 26693 having frank diabetes mellitus at baseline, significantly reduced new-onset diabetes mellitus. However, pioglitazone use was associated with increased risks of heart failure, bone fracture, oedema and weight gain.The
pioglitazone 26878 oedema and weight gain.The exact mechanism underlying the cardiovascular risk reduction benefit of pioglitazone is not clear. It would seem unlikely to be simply its hypoglycaemic effect.[21] Since the pathogenesis
pioglitazone 27159 oxidation of lipoprotein and interactions of inflammatory cell,[24] it more likely that the benefit of pioglitazone in cardiovascular event risk reduction is due to its several pleiotropic effects. For instance, favourable
pioglitazone 27290 event risk reduction is due to its several pleiotropic effects. For instance, favourable effects of pioglitazone use on the triglyceride/high-density lipoprotein-cholesterol ratio correlated with delayed atheroma
pioglitazone 27601 associated with the incidence of cardiovascular events in a population-based cohort[26] and treatment with pioglitazone for 12 weeks significantly increased the cholesterol efflux capacity.[27] In a study using serial
pioglitazone 27825 (18)F-fluorodeoxyglucose positron emission tomography imaging to evaluate atherosclerotic plaque inflammation, pioglitazone attenuated atherosclerotic plaque inflammation in patients with impaired glucose tolerance or in patients
pioglitazone 28012 glucose tolerance or in patients with diabetes.[28] However, the observed cardiovascular benefits of pioglitazone cannot be simply explained by a thiazolidinedione ‘class effect’, since another agent in this class,
pioglitazone 28296 cardiovascular events in several meta-analyses.[29][30]There are several safety considerations in use of pioglitazone and we assessed safety outcomes in the present meta-analysis. Fluid retention, weight gain and heart
pioglitazone 28605 compounds. In the current meta-analysis, the risk of heart failure, oedema and weight gain increased in the pioglitazone treatment group. Certain strategies such as excluding patients with a prior heart failure and using
pioglitazone 28880 oedema or weight gain may be helpful to reduce the incidence of heart failure in patients receiving pioglitazone therapy.[9]We found that pioglitazone use was associated with increased risks of bone fracture. A meta-analysis
pioglitazone 28918 to reduce the incidence of heart failure in patients receiving pioglitazone therapy.[9]We found that pioglitazone use was associated with increased risks of bone fracture. A meta-analysis of randomised controlled trials
pioglitazone 29404 included trials in our current analysis, with predominantly with men (> 60% of participants) both showed pioglitazone use substantially increased risk of bone fracture.[9][13]Peroxisome proliferator activated receptor-γ
pioglitazone 29694 when thiazolidinedione is prescribed. Several studies[35][36] and a meta-analysis[37] reported that pioglitazone increased the risk of bladder cancer while other cohort studies[38][39] did not find that pioglitazone
pioglitazone 29797 pioglitazone increased the risk of bladder cancer while other cohort studies[38][39] did not find that pioglitazone increased the risk of bladder cancer or other common cancers. In the analysis of our included trials
pioglitazone 29980 analysis of our included trials that had reported the incidence of any cancer, the risk of cancer in pioglitazone -treated patients was not increased. However, only a few trials reported a cancer end point in our study
pioglitazone 30131 However, only a few trials reported a cancer end point in our study and the risk of cancer when using pioglitazone needs to be further clarified.This meta-analysis suggested that pioglitazone use reduced progression
pioglitazone 30208 risk of cancer when using pioglitazone needs to be further clarified.This meta-analysis suggested that pioglitazone use reduced progression to diabetes mellitus in patients with impaired glucose tolerance[8] and insulin
pioglitazone 30527 mellitus is a major cardiovascular risk factor, avoiding or delaying onset of diabetes mellitus with pioglitazone treatment probably helped to prevent the development of macrovascular complications.There are several
pioglitazone 30912 PROactive[17] trials. The original purpose in some of the included trials was not to investigate the effect of pioglitazone on cardiovascular events. Third, the definition of MACE differed among available trials. Some trials[8][9]
pioglitazone 31926 points.In summary, the current meta-analysis of completed, randomised clinical trials indicates that pioglitazone has beneficial effects in reducing the risk of MACE in people with insulin resistance, pre-diabetes
pioglitazone 32144 type 2 diabetes mellitus. Rates of heart failure, bone fracture, weight gain and oedema increased in pioglitazone -treated patients, while the occurrences of cancer and all-cause mortality did not rise. Weighing the
pioglitazone 32295 occurrences of cancer and all-cause mortality did not rise. Weighing the risk-benefit profile, treatment with pioglitazone may be a reasonable choice in appropriately selected patients with insulin resistance, pre-diabetes
rosiglitazone 28130 cannot be simply explained by a thiazolidinedione ‘class effect’, since another agent in this class, rosiglitazone , has been associated with an increased risk of cardiovascular events in several meta-analyses.[29][30]There
Select Disease Character Offset Disease Term Instance
diabetes mellitus 1812 group.ConclusionsPioglitazone was associated with reduced risk of MACE in people with insulin resistance, pre-diabetes and diabetes mellitus . However, the risks of heart failure, bone fracture, oedema and weight gain were increased.Strengths
diabetes mellitus 2069 studyPioglitazone reduced major adverse cardiovascular events in people with insulin resistance, pre-diabetes and diabetes mellitus (DM).Pioglitazone increased risks of heart failure, oedema and weight gain.Pioglitazone reduced new-onset
diabetes mellitus 2340 people.The results were dominated by two large randomised controlled trials.ManuscriptPeople with type 2 diabetes mellitus ,[1] pre-diabetes[2] and insulin resistance[3][4] are more likely to develop myocardial infarction and
diabetes mellitus 2799 insulin sensitivity, glycaemic control, hypertension, dyslipidaemia and microalbuminuria in patients with diabetes mellitus .[5] Furthermore, a prior meta-analysis found that pioglitazone reduced the risk of myocardial infarction,
diabetes mellitus 3001 myocardial infarction, stroke and death compared to control drugs or placebo in patients with type 2 diabetes mellitus , but whether pioglitazone is beneficial in prevention of cardiovascular diseases among patients with
diabetes mellitus 3512 resistance,[9] pre-diabetes (eg, impaired fasting glucose and/or impaired glucose tolerance)[8][10] or type 2 diabetes mellitus .Therefore, to qualitatively and quantitatively evaluate the overall benefits (eg, major adverse cardiovascular
diabetes mellitus 4436 Trials (1966 to 17 May 2016) using MESH terms and free text: ‘pioglitazone’ or ‘actos’ AND ‘ diabetes mellitus ’ or ‘glucose intolerance’ or ‘prediabetic state’ or ‘impaired glucose tolerance’ or ‘impaired
diabetes mellitus 5107 randomised controlled trial; (2) patients had the history of pre-diabetes or insulin resistance or type 2 diabetes mellitus ; (3) the study included a comparison of pioglitazone with control (eg, placebo or other glucose-lowering
diabetes mellitus 7605 development of diabetes among people with pre-diabetes or insulin resistance, but not having frank diabetes mellitus , at baseline.Relative risk (RR) with 95% CIs was used to estimate the risk of clinical outcomes between
diabetes mellitus 10550 enrolled individuals had a history of insulin resistance, impaired glucose tolerance test or type 2 diabetes mellitus . The studies included participants with or without prior cardiovascular diseases. Two studies (IRIS,
diabetes mellitus 14514 body mass index; CHICAGO, Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone; DM, diabetes mellitus ; HbA1c, glycated haemoglobin; IGT, impaired glucose tolerance; IRIS, Insulin Resistance Intervention
diabetes mellitus 22677 benefit, harm or futility has been crossed. MACE, major adverse cardiovascular events.Among patients with diabetes mellitus , pioglitazone was associated with a lower risk of MACE (5 trials; RR 0.83, 95% CI 0.72 to 0.97; p for
diabetes mellitus 23669 and pooled relative risk and 95% CIs estimates for cardiovascular outcomes among patients with type 2 diabetes mellitus (pioglitazone vs control).Figure 4Trial sequential analysis for (A) MACE, (B) myocardial infarction,
diabetes mellitus 23821 control).Figure 4Trial sequential analysis for (A) MACE, (B) myocardial infarction, (C) stroke, among patients with diabetes mellitus . (A), (B) and (C): the required information size has not been reached and none of the boundaries for
diabetes mellitus 26282 patients with insulin resistance or pre-diabetes and 17% risk reduction of MACE among patients with type 2 diabetes mellitus . The results of our analysis suggest that the cardiovascular event reduction seen with pioglitazone
diabetes mellitus 26420 analysis suggest that the cardiovascular event reduction seen with pioglitazone among patients with diabetes mellitus is also seen among patients with insulin resistance or pre-diabetes. Also, pioglitazone use in people
diabetes mellitus 26602 pre-diabetes. Also, pioglitazone use in people with pre-diabetes or insulin resistance, but not having frank diabetes mellitus at baseline, significantly reduced new-onset diabetes mellitus. However, pioglitazone use was associated
diabetes mellitus 26665 insulin resistance, but not having frank diabetes mellitus at baseline, significantly reduced new-onset diabetes mellitus . However, pioglitazone use was associated with increased risks of heart failure, bone fracture, oedema
diabetes mellitus 30248 needs to be further clarified.This meta-analysis suggested that pioglitazone use reduced progression to diabetes mellitus in patients with impaired glucose tolerance[8] and insulin resistance population[9] which is in consistent
diabetes mellitus 30417 insulin resistance population[9] which is in consistent with findings from a prior study.[40] Since diabetes mellitus is a major cardiovascular risk factor, avoiding or delaying onset of diabetes mellitus with pioglitazone
diabetes mellitus 30504 study.[40] Since diabetes mellitus is a major cardiovascular risk factor, avoiding or delaying onset of diabetes mellitus with pioglitazone treatment probably helped to prevent the development of macrovascular complications.There
diabetes mellitus 32050 beneficial effects in reducing the risk of MACE in people with insulin resistance, pre-diabetes and type 2 diabetes mellitus . Rates of heart failure, bone fracture, weight gain and oedema increased in pioglitazone-treated patients,
diabetes mellitus 32419 reasonable choice in appropriately selected patients with insulin resistance, pre-diabetes and type 2 diabetes mellitus
glucose intolerance 4463 using MESH terms and free text: ‘pioglitazone’ or ‘actos’ AND ‘diabetes mellitus’ or ‘ glucose intolerance ’ or ‘prediabetic state’ or ‘impaired glucose tolerance’ or ‘impaired fasting glucose’
type 2 diabetes mellitus 2333 pre-diabetes people.The results were dominated by two large randomised controlled trials.ManuscriptPeople with type 2 diabetes mellitus ,[1] pre-diabetes[2] and insulin resistance[3][4] are more likely to develop myocardial infarction and
type 2 diabetes mellitus 2994 risk of myocardial infarction, stroke and death compared to control drugs or placebo in patients with type 2 diabetes mellitus , but whether pioglitazone is beneficial in prevention of cardiovascular diseases among patients with
type 2 diabetes mellitus 3505 resistance,[9] pre-diabetes (eg, impaired fasting glucose and/or impaired glucose tolerance)[8][10] or type 2 diabetes mellitus .Therefore, to qualitatively and quantitatively evaluate the overall benefits (eg, major adverse cardiovascular
type 2 diabetes mellitus 5100 randomised controlled trial; (2) patients had the history of pre-diabetes or insulin resistance or type 2 diabetes mellitus ; (3) the study included a comparison of pioglitazone with control (eg, placebo or other glucose-lowering
type 2 diabetes mellitus 10543 1. All enrolled individuals had a history of insulin resistance, impaired glucose tolerance test or type 2 diabetes mellitus . The studies included participants with or without prior cardiovascular diseases. Two studies (IRIS,
type 2 diabetes mellitus 23662 4).Figure 3Separate and pooled relative risk and 95% CIs estimates for cardiovascular outcomes among patients with type 2 diabetes mellitus (pioglitazone vs control).Figure 4Trial sequential analysis for (A) MACE, (B) myocardial infarction,
type 2 diabetes mellitus 26275 patients with insulin resistance or pre-diabetes and 17% risk reduction of MACE among patients with type 2 diabetes mellitus . The results of our analysis suggest that the cardiovascular event reduction seen with pioglitazone
type 2 diabetes mellitus 32043 beneficial effects in reducing the risk of MACE in people with insulin resistance, pre-diabetes and type 2 diabetes mellitus . Rates of heart failure, bone fracture, weight gain and oedema increased in pioglitazone-treated patients,
type 2 diabetes mellitus 32412 be a reasonable choice in appropriately selected patients with insulin resistance, pre-diabetes and type 2 diabetes mellitus

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