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

Manuscript

People with type 2 diabetes mellitus,¹ pre-diabetes² and insulin resistance^{3 4} are more likely to develop myocardial infarction and stroke and have also associated metabolic abnormalities, such as lipid abnormalities, hypertension and chronic vascular inflammation, that are themselves significant cardiovascular risk factors.^{5 6}

Pioglitazone is known to improve 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, 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 pre-diabetes or insulin resistance was not 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.^8–14 These trials comprised patients with insulin 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 events, myocardial infarction and stroke) and risks (eg, heart 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 review and meta-analysis of relevant randomised controlled trials to date.

Methods

The current meta-analysis was conducted in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis: the PRISMA Statement.¹⁵

Results

Literature search identified 2956 articles and 2945 were excluded by reviewing topics or abstracts. The literature review identified 11^{8–14 17–20} articles for detailed assessment (see online supplementary figure 1). One study was excluded because the study period was <1 year.¹⁸ Our final primary analysis included 10 articles derived from 9 randomised controlled trials.^{8–14 17 19 20} A total of 12 026 individuals were eligible, with mean age 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 and design of the included trials were summarised in table 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, J-SPIRIT)^{9 10} enrolled only participants with a stroke or transient ischaemic attack, while in the other studies the majority of participants had not experienced a stroke or transient ischaemic attack at the time of study entry. The number of participants ranged from 121 to 5238. The mean study duration was 2.7 years (ranged from 1 to 4.8 years). The assessment of risk of bias is shown in table 2. Three trials had high risks of performance bias and detection bias because they were non-blinded.^{10 11 14}

Discussion

Our 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 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 among 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, significantly reduced new-onset diabetes mellitus. However, pioglitazone use was associated with increased risks of heart failure, bone fracture, 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.^21–23 Since the pathogenesis of atherosclerosis is multifactorial involving dyslipidaemia, 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 effects of pioglitazone use on the triglyceride/high-density lipoprotein-cholesterol ratio correlated with delayed atheroma progression in patients with diabetes.²⁵ Also, cholesterol efflux capacity was inversely associated with the incidence of cardiovascular events in a population-based cohort²⁶ and treatment with pioglitazone for 12 weeks significantly increased the cholesterol efflux capacity.²⁷ In a study using serial (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 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, rosiglitazone, has been associated with an increased risk of 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 failure are the most concerned adverse effects when patients receive thiazolidinedione 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 safety algorithms that triggered dose reduction for excessive 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 of randomised controlled trials showed that treatment with thiazolidinediones resulted in modest bone loss.³¹ One study suggested thiazolidinediones increased bone fracture in women, but not in men,³² while other studies suggest that both sexes are similarly affected.³³ However, the two 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 may play a role in carcinogenesis³⁴ and the risk of cancer is a concern when thiazolidinedione is prescribed. Several studies^{35 36} and a meta-analysis³⁷ reported that 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 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 and the 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 tolerance⁸ and insulin resistance population⁹ 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 treatment probably helped to prevent the development of macrovascular complications.

There are several limitations in this study. First, this meta-analysis was not registered in PROSPERO. Second, the results of this analysis dominated by two trials: IRIS⁹ and PROactive¹⁷ 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} reported composite of myocardial infarction and stroke while others^{11 13 14 17 19} reported non-fatal myocardial infarction, non-fatal stroke and vascular death as major vascular events. Since fatal myocardial infarction and fatal stroke are likely the major components of cardiovascular death, the end points categorised as major cardiovascular events among available trials may not be substantially different. Fourth, the populations and frequency of medication use, especially statins, differed across trials. Since our study was a study-level meta-analysis, the issues mentioned above may not be well-settled. Individual-level pooled analyses of relevant trials could provide additional insights. Finally, TSA showed that the required information sizes were not achieved for most end 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 and 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 risk-benefit profile, treatment with pioglitazone may be a reasonable choice in appropriately selected patients with insulin resistance, pre-diabetes and type 2 diabetes mellitus.