Favorable cardiovascular effects of pioglitazone: a meta-analysis

Corresponding Author:

Katya Hristova Uzunova
Tchaikapharma High Quality Medicines
Inc., Science Department
1 G.M. Dimitrov Blvd, 1172 Sofia, Bulgaria
E-mail: k.uzunova.hq@tchaikapharma.com

Abstract

Type 2 diabetes mellitus is caused by insulin resistance and β cell failure. Pioglitazone and other thiazolidinediones are the antidiabetic agents that increase insulin sensitivity, reduce blood glucose and hemoglobin A1c levels, inhibit adipose-tissue lipolysis, decrease microalbuminuria, inhibit inflammation, decrease blood pressure and reduce adverse cardiovascular risk. The objective of this review was systematic evaluation of the effect of pioglitazone on mortality and cardiovascular events in the patients with diabetes mellitus. In the analysis were included randomized, controlled studies after systematic literature search in electronic databases. Risk ratios with 95% confidence intervals (CI) were calculated, using the random effect model. Statistical heterogeneity across all the studies was tested with the I2 statistics. Pioglitazone was associated with statistically significant reduction in non-fatal coronary events (defined as myocardial infarction, unstable angina or coronary revascularization): RR 0.62, 95% CI (0.43, 0.89), but significant heterogeneity was found (p=0.00, I2=80%). Mortality rate was not significantly different between pioglitazone users and non-users (RR 0.87, 95% CI (0.62, 1.23). Overall risk for non-fatal heart failure was slightly increased (RR 1.31, 95% CI (1.17, 1.47)). No significant heterogeneity was found for any of these analysis (I2=47%, p=0.06 and I2=10%, p=0.35). Pioglitazone is and should remain an important agent within the modern management of type 2 diabetic patients, especially in those at elevated cardiovascular risk.

Keywords

type 2 diabetes, pioglitazone, cardiovascular complications, non-fatal coronary events, mortality, heart failure

Background

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance, β cell failure, and microvascular and macrovascular complications. There is a two-fold to fourfold increased risk of a macrovascular event in patients with, compared with those without, diabetes [1]. Heart disease was listed as the most frequent and was represented 69.5% of death cases of people with diabetes [2]. Furthermore, diabetes mellitus predisposes people to premature atherosclerotic coronary artery disease (CAD) – another leading cause of mortality [3]. Factors such as diabetes-associated hypertension and dyslipidemia may contribute to the severity of vascular dysfunction in diabetes. Endothelial dysfunction may play a role in the progression of coronary atherosclerosis and these people are at increased risk for cardiac events [4].

Thiazolidinedione drugs (TZDs) are the only current antidiabetic agents that function primarily by increasing insulin sensitivity. Thiazolidinedione’s cellular actions are mediated by binding to its nuclear receptor, the peroxisome proliferator-activated receptor gamma (PPARγ) [5]. PPARγ is expressed at high levels in adipose tissue, where TZDs functions as a master regulator of adipocyte differentiation, and at much lower levels in other tissues [6]. The effects of PPARγ in adipose tissue are proposed to be the main mechanism by which TZD improves insulin sensitivity. Insulin sensitization appears to be the mechanism whereby TZDs prevent or delay development of T2DM in individuals with prediabetes. TZDs lower hemoglobin A1c potently by around 1% as monotherapy in T2DM, where they notably do not cause hypoglycemia like insulin or insulin secretagogues (i.e., sulfonylureas), and they can be used in combination with other antidiabetic agents [7]. Pioglitazone is one of the TZDs that have demonstrated significant benefits on both glycemic control and associated cardiovascular risk factors including hypertension [8] and biochemical markers of risk [9].

In the process of atherogenesis and the subsequent increased cardiovascular mortality of diabetic patients, endothelial dysfunction is suspected to play an important role. There has been increasing evidence that TZDs may have some antiatherogenic actions. It was indicated that pioglitazone in contrast to placebo significantly improves endothelial function as well as insulin resistance in patients with newly diagnosed T2DM and established CAD [10]. PROactive results showed that pioglitazone reduces incident vascular events in type 2 diabetic patients with manifested atherosclerosis [11].

Measurement of carotid intima-media thickness (IMT) has been validated as a measure of atherosclerosis and as a strong predictor of cardiovascular events (myocardial infarction and stroke). Many human studies noted a reduction in IMT after 12 or 24 weeks of treatment with pioglitazone [12,13] and trough PPARγ activation pioglitazone caused an inhibition of early atherosclerotic process. Data suggested that pioglitazone and other thiazolidinediones decrease C-reactive protein levels [9], microalbuminuria [14], arterial pulse-wave velocity [9], systolic and diastolic blood pressure [8], and increase adiponectin levels [9], each of which is associated with cardiovascular risk reduction. Moreover, PPARγ activation leads to a reduction in blood concentrations of matrix metalloproteinase-9 [15] and soluble CD40 ligand [16], both new markers of cardiovascular risk.

The therapeutic use of pioglitazone has been limited in recent years due to concerns over bladder carcinogenicity, the description of new risk for fractures and due to increased risk of cardiovascular harm with rosiglitazone [17]. Meta-analyses showed increased risk for myocardial infarction associated with rosiglitazone [18,19]. Different effects of rosiglitazone and pioglitazone on cardiovascular complications suggests that these effects are rather associated with the TZD type. Subgroup analyses of randomized clinical trial PROactive show that pioglitazone is effective in reducing the risk of recurrent stroke: HR 0.53 (95% CI 0.34- 0.85, p=0.009) [20] and recurrent myocardial infarction (MI) and other serious cardiovascular event in patients with T2DM and previous MI: HR 0.72 (95% CI 0.52 – 0.99, p=0.045) [21], although 6% from the group on pioglitazone have been admitted to hospital with heart failure [11].

In the present meta-analysis we want to demonstrate that pioglitazone is a valuable option for diabetic patients with potential cardiovascular benefits. The objective of the meta-analysis was to systematically assess the effect of pioglitazone on mortality and the incidence of cardiovascular complications, using data from the randomized controlled trials of pioglitazone in diabetes mellitus.

Methods

Study selection

Published papers and abstracts were identified by a literature search of electronic databases that include: PubMed (www.ncbi. nlm.nih.gov/pubmed), Medline, Scopus (www. scopus.com), PsyInfo, Russian scientific library (eLIBRARY.ru), sources for unpublished trials are the clinical trials registers, such as www. clinicaltrials.gov, www.clinicaltrialsregister.eu. Additionally, unpublished materials and results of clinical trials were sought through informal channels and personal communication with researchers who have been working in the relevant field. We searched for articles published in English and Russian languages from 2000 to February 2016. The pre-specified inclusion criteria used for assessment of studies were: 1. Type of study: epidemiological, controlled and blind, randomized; 2. Type of participants: representative group from whole population, specific strata; 3. Access to the primary source data; 4. Eligibility of statistical analysis. Eligible studies were hard to find because they weren’t fully available or weren’t published at all (publication bias). This meta-analysis is designed to cover all the relevant published and unpublished materials. FIGURE 1 presents a flow-diagram which describes the process of screening of identified studies.

Figure 1. Diagram of the process of source screening.

Outcome measures

The included various studies, which observed the effects of pioglitazone on the cardiovascular events, measure different outcomes and very different time intervals. We specified the primary outcomes of this meta-analysis:

• Mortality (total and related to cardiovascular events)

• Non-fatal coronary events (defined as myocardial infarction, unstable angina or coronary revascularization)

• Non-fatal heart failure requiring hospitalization.

All studies (TABLE 1), included in the analysisn, were randomized, controlled clinical studies. For each study, numbers of patients with events of interest were extracted for each treatment group and used to calculate relative risks. We estimated overall relative risks (RR) and 95% confidence intervals (CIs) for each end points using random effect model.

Table 1. Studies included in the meta-analysis.

Statistical analysis

Because statistical heterogeneity was present in the results of studies, therefore, the randomeffects model was used. In the random-effects model, studies are weighted with the inverse of their variance and the heterogeneity parameter.

Forest plots were constructed based on random-effects models, and between-study heterogeneity was assessed by graphical inspection and with the Higgins I2 statistic, which describes the percentage of betweenstudy variability in effect estimates attributable to true heterogeneity rather than chance. The Cochran’s Q statistic, a chi-squared (χ²) test of heterogeneity and Tau2, estimating the betweenstudy variance, are also presented. The used level of significance was 0.05 and confidence intervals were respectively 95%.

Publication bias

We used funnel and Doi plots to evaluate reports for publication bias. In the meta-analysis, the log of the ratio measure and its standard error are used in funnel plots. A Doi plot (a symmetrical mountain-like plot) with Luis Furuya-Kanamori (LFK) index <|1| indicates no asymmetry; LFK index between |1| and |2| suggests minor asymmetry; and LFK index >|2| suggests major asymmetry.

Meta-analysis was performed with R language and Excel macro MetaXL.

Results

Mortality

Compared to all studies with cardiovascular end-points (FIGURE 2) only the PROactive study and one unpublished study, due to the small number of participants, reported for death patients.

Figure 2. Forest plot - all-cause mortality.

The PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) study reported that the total mortality in the group of pioglitazone was 177 compared with 186 deaths in the placebo group and suggested that the use of pioglitazone did not influence the total mortality. In other studies, different from PROactive, the results were more definitive: in the group of patients with type 2 diabetes participating in these studies, the total number of reported deaths was 17 and in the group of non-users of pioglitazone were 39. From the calculated RR 0.41, 95% CI (0.23 to 0.72) (FIGURE 2) could be concluded that the use of pioglitazone was associated with a significantly reduced risk of mortality.

When long-term studies were analyzed separately from short-term, a lower risk of total mortality with the use of pioglitazone were found in both cases, although the number of short-term studies was small and therefore couldn’t achieve statistical significance.

In the comparative analysis of pioglitazone with other antidiabetic agents, pioglitazone showed lower mortality rates than the groups treated with sulfonylureas (RR 0.22 95% CI (0.05 to 1.03)), placebo (RR 0.16 95% CI (0.02 to 1.45)), metformin (RR 0.66 95% CI (0.19 to 2.34)), rosiglitazone (RR 0.49 95% CI (0.04 to 5.36)), glitazars (RR 0.42 95% CI (0.11 to 1.61)) but the overall result did not reached statistical significance (FIGURE 2). When studies with zero mortality were included in the analysis, there was no statistically significant difference in RR in all groups.

Information on causes of death was missing in five of the studies. In other studies participated 7644 patients, who were pioglitazone users and in this group were reported 7 deaths due to cardiovascular events. However, in the comparative group with 6106 patients were reported 16 deaths due to cardiovascular events (RR 0.35, 95% CI (0.14 to 0.85)). The overall random effect relative risk was RR 0.87, 95% CI (0.62 to 1.23), but with substantial heterogeneity (I2=47%) (FIGURE 2). The funnel and Doi plot in FIGURE 3 were asymmetrical with LFK index >|2|, suggesting gross publication bias.

Figure 3. Detection of publication bias: funnel plot (left) and Doi plot (right) – all-cause mortality.

Non-fatal coronary events (defined as myocardial infarction, unstable angina or coronary revascularization)

PROactive study suggested that pioglitazone significantly decrease the number of case with non-fatal coronary events (FIGURE 4). In the cohort of diabetic patients, information about non-fatal coronary events was reported in 40 studies involving 4259 patients on pioglitazone and 3989 patients as controls. These studies reported respectively 44 and 50 non-fatal coronary events and calculated risk ratio was RR 0.64, 95% CI (0.44, 0.92). The same data transformed as the incidence rate per 1000 year disclosed that there will be 8.8 cases of non-fatal coronary events per 1000 years in the group of users of pioglitazone and 10.2 cases of non-fatal coronary events per 1000 years in the group of controls. If all of the studies were analyzed, including PROactive, the calculated relative ratio (RR 0.62, 95% CI (0.43, 0.89)) revealed that the use of pioglitazone is associated with significant reduction in risk of non-fatal coronary events but the effect estimates were heterogeneous across the studies, I2=80% (FIGURE 4). There was evidence of minor asymmetry in the Doi plot (LFK <|2|) (FIGURE 5).

Figure 4. Forest plot - non-fatal coronary events

Figure 5. Detection of publication bias: funnel plot (left) and Doi plot (right) – non-fatal coronary events.

Non-fatal heart failure requiring hospitalization

In PROactive study the use of pioglitazone is associated with increased risk of non-fatal cases of heart failure (FIGURE 6). Other studies that have reported non-fatal heart failure requiring hospitalization included 5380 patients using pioglitazone and 5531 controls. The number of cases with heart failure was 58 for the pioglitazone group and 39 for the control group. Accordingly, the calculated relative risk was RR 1.32, 95% CI (0.88, 1.18). Increased risk of heart failure was shown when comparing pioglitazone and placebo (RR 1.30, 95% CI (1.06, 1.59)) but such increased risk was not established when comparing pioglitazone with glitazars and sulphonylureas (RR 0.43, 95% CI (1.13, 1.39) and RR 0.96, 95% CI (0.48, 1.89), respectively). There was moderate heterogeneity across the studies for this end point (I2=10%, p=0.35).

Figure 6. Forest plot - non-fatal heart failure.

Combination of all studies reported at least one case of non-fatal heart failure, without PROactive, showed statistically non-significant difference between group of pioglitazone and controls. The inclusion of PROactive study in the analysis significantly increased the risk of non-fatal heart failure (FIGURE 6). Asymmetry of funnel and Doi plots showed evidence of publication bias (FIGURE 7).

Figure 7. Detection of publication bias: funnel plot (left) and Doi plot (right) – non-fatal heart failure.

Discussion

Our data support the expectation for reduced risk (around 60%) of total mortality in the group of pioglitazone (without PROactive study). In the comparative analysis of total mortality between users of pioglitazone and users of other antidiabetic agents, a similar conclusion was made: risk of death in the group of pioglitazone was lower than in groups of sulphonylureas (78%), metformin (34%), rosiglitazone (51%), glitazars (58%) and in the placebo group (84%), but the overall result did not reached statistical significance. The risk of non-fatal coronary events was decreased between 16% and 60% in the group of pioglitazone. The PROactive study found that despite the increased cases of heart failure in the pioglitazone group, the number of deaths from heart failure was similar in each group. Our findings showed that there was an association (under 50%) between pioglitazone and risk of heart failure.

Pioglitazone seem to have more favorable effect on cardiovascular disease. Pioglitazone and metformin are the only glucose- lowering agents with RCT data demonstrating a reduction in stroke, MI and death in type 2 diabetes [22]. A large clinical trial designed to assess the effect of pioglitazone on ischemic cardiovascular outcomes, the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) trial, proved that pioglitazone significantly reduced the secondary composite outcome of allcause mortality, non-fatal MI and stroke (HR 0.84, 95% CI 0.72–0.98) but indicated 11% increased chances of congestive heart failure in pioglitazone-treated patients [11].

A meta-analysis of 19 trials also showed the benefit of pioglitazone in regard to cardiovascular events, with an 18% reduced risk of the composite end point of all cause death, MI and stroke [23]. Another meta-analysis, comprising randomized controlled trials, suggested that pioglitazone did not appear to increase the risk of MI (RR 0.86, 95% CI (0.69, 1.07), p=0.17) and the authors didn’t find statistically significant reduction in stroke and coronary revascularisation compared to control [24]. While one meta-analysis of clinical trials found a trend toward elevated risks of myocardial infarction and death from cardiovascular causes with rosiglitazone [18] other meta-analysis of randomized clinical trials stated that there was an increased risk of heart failure compared with control for both rosiglitazone (RR 2.18, 95% CI (1.44, 3.32), p=0.0003; 5 studies) and pioglitazone (RR 1.32, 95% CI (1.04, 1.68), p=0.02; 2 studies), but the risk of cardiovascular death was not significantly increased for TZD compared with control, nor for rosiglitazone and pioglitazone compared with control [25]. According to Fishman and Tenenbaum the risk of heart failure is a class effect of TZDs, whereas the ischemic cardiovascular risk is restricted to rosiglitazone but not to pioglitazone [26].

Observational studies suggest no increased ischemic heart disease (IHD) risk with pioglitazone compared with other oral hypoglycemic agents [27]. A Taiwan retrospective cohort study of over 473 000 patients showed that rosiglitazone monotherapy were at higher risk for any cardiovascular event (hazard ratio [HR] 1.89, 95% CI 1.57, 2.28), myocardial infarction (HR 2.09, 95% CI 1.36, 3.24), angina pectoris (HR 1.79, 95% CI 1.39, 2.30) and transient ischaemic attack (HR 2.57, 95% CI 1.33, 4.96) than those receiving metformin monotherapy, but pioglitazone as an add-on therapy was found to have a favourable, but nonsignificant, effect on outcome [28]. The WellPoint observational study revealed that there was no significant increase in risk of MI (HR 1.04, 95% CI 0.91 – 1.21) [29]. Using population-based health care databases in Ontario were found that TZD treatment was associated with a significant increase in the risks of congestive heart failure (CHF), acute myocardial infarction, and all-cause mortality among older persons but this association was significant only with rosiglitazone therapy [30]. One observational study documented that TZDs and metformin were not associated with increased mortality and may improve outcomes in older patients with diabetes and heart failure [31]. Moreover, only pioglitazone has been shown to reduce the incidence of major cardiovascular events [11,23].

As a class, TZDs turn on and off many of the same genes. The function of the target genes have been mainly concentrated on hepatocytes and adipocytes, which both play a key role in systemic lipid metabolism [32]. However, each PPARγ agonist has its own individual effect to stimulate/inhibit the expression of specific genes. This is particularly relevant to pioglitazone and rosiglitazone, which have very different effects on lipid metabolism. Pioglitazone compared with rosiglitazone is associated with significant improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle size [33], which may be associated with their different effect on cardiovascular outcomes. Moreover, thiazolidinediones exert antiatherogenic effects through a multitude of mechanisms, including a decrease in insulin resistance, inhibition of atherogenic processes in the vascular wall, and a reduction in established and new cardiovascular risk factors. Furthermore, pioglitazone treatment improves chronic vascular inflammation (decrease of biomarker hsCRP), which may be associated with reduced cardiovascular risk [34].

Conclusions

In summary, T2DM as a chronic metabolic disorder is associated with a marked increase in cardiovascular disease, morbidity and mortality, but the majority of published studies do not suggest such an increased risk in pioglitazonetreated patients. Our work shows that pioglitazone treatment was associated with non-significant decrease in mortality rate and reduction of non-fatal cardiovascular events (defined as myocardial infarction, unstable angina or coronary revascularization) but a slight risk of non-fatal heart failure was found.

Although pioglitazone may also be associated with several adverse events, including body weight gain, CHF, peripheral bone fractures, the value of pioglitazone as a glucoselowering agent (as oral monotherapy, dual therapy, triple therapy and even combination with insulin) were confirmed, with additive positive effects that may contribute to coronary and cerebrovascular protection.

The goal of diabetes therapy is not only glucose lowering, but also protection from its comorbidities. In this aspect, pioglitazone is and should remain an important agent within the modern management of type 2 diabetic patients, and its clinical use should be consistent with the individual patient’s characteristics since pioglitazone exerts cardioprotective action and has proven to be cost-effective [35-37] in patients with T2DM and macrovascular disease [39].

Financial and competing interests disclosure

Tchaikapharma High Quality Medicines Inc. funded this meta-analysis. KHU and EPF are employees of Tchaikapharma High Quality Medicines Inc. The other authors report no competing interests.

Authors’ contributions

The original idea came from TYV. KBK assessed the eligibility of the studies and performed statistical analysis. KHU checked all the selected articles for this review and wrote the article. EPF independently checked data and contributed in writing the manuscript. All authors revised and provided final approval of this manuscript.

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