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Home , Pioglitazone, Rivoglitazone, Tesaglitazar, Voglibose

REVIEW

Favorable cardiovascular effects of : a meta-analysis

Type 2 mellitus is caused by resistance and β cell failure. Pioglitazone and other 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 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: , pioglitazone, cardiovascular complications, non-fatal coronary events, mortality, heart failure

Background only current antidiabetic agents that function Katya Hristova primarily by increasing insulin sensitivity. Type 2 diabetes mellitus (T2DM) is *1 characterized by , β cell ’s cellular actions areUzunova , failure, and microvascular and macrovascular mediated by binding to its , Elena Pavlova Filipova1, complications. There is a two-fold to four- the peroxisome proliferator-activated receptor γ γ fold increased risk of a macrovascular event in gamma (PPAR ) [5]. PPAR is expressed at high Krassimir Boytchev patients with, compared with those without, levels in , where TZDs functions as Kalinov2 & a master regulator of adipocyte differentiation, diabetes [1]. Heart disease was listed as the most 3 frequent and was represented 69.5% of death and at much lower levels in other tissues [6]. The Toni Yonkov Vekov γ 1 cases of people with diabetes [2]. Furthermore, effects of PPAR in adipose tissue are proposed Tchaikapharma High Quality Medicines diabetes mellitus predisposes people to premature to be the main mechanism by which TZD Inc., Science Department, 1 G.M. improves insulin sensitivity. Insulin sensitization Dimitrov Blvd, 1172 Sofia, Bulgaria atherosclerotic coronary artery disease (CAD) – 2New Bulgarian University, Department another leading cause of mortality [3]. Factors appears to be the mechanism whereby TZDs prevent or delay development of T2DM in Informatics, 21 Montevideo Str, 1618 such as diabetes-associated hypertension and Sofia, Bulgaria individuals with prediabetes. TZDs lower 3 dyslipidemia may contribute to the severity of Medical University, Dean of Faculty vascular dysfunction in diabetes. Endothelial hemoglobin A1c potently by around 1% as of Pharmacy, 1 Sv. Kliment Ohriski Str., 5800 Pleven, Bulgaria dysfunction may play a role in the progression monotherapy in T2DM, where they notably do of coronary atherosclerosis and these people are not cause like insulin or insulin *Author for correspondence: at increased risk for cardiac events [4]. secretagogues (i.e., ), and they can [email protected] be used in combination with other antidiabetic Thiazolidinedione drugs (TZDs) are the agents [7]. Pioglitazone is one of the TZDs that

303 Clin. Pract. (2017) 14(5), 303-316 ISSN 2044-9038 Katya Hristova Uzunova REVIEW

have demonstrated significant benefits on both In the present meta-analysis we want to glycemic control and associated cardiovascular demonstrate that pioglitazone is a valuable risk factors including hypertension [8] and option for diabetic patients with potential biochemical markers of risk [9]. cardiovascular benefits. The objective of the meta-analysis was to systematically assess the In the process of atherogenesis and the effect of pioglitazone on mortality and the subsequent increased cardiovascular mortality incidence of cardiovascular complications, using of diabetic patients, endothelial dysfunction is data from the randomized controlled trials of suspected to play an important role. There has pioglitazone in diabetes mellitus. been increasing evidence that TZDs may have some antiatherogenic actions. It was indicated Methods that pioglitazone in contrast to placebo significantly improves endothelial function as „„Study selection well as insulin resistance in patients with newly Published papers and abstracts were diagnosed T2DM and established CAD [10]. identified by a literature search of electronic PROactive results showed that pioglitazone databases that include: PubMed (www.ncbi. reduces incident vascular events in type 2 nlm.nih.gov/pubmed), Medline, Scopus (www. diabetic patients with manifested atherosclerosis scopus.com), PsyInfo, Russian scientific library [11]. (eLIBRARY.ru), sources for unpublished trials are the clinical trials registers, such as www. Measurement of carotid intima-media clinicaltrials.gov, www.clinicaltrialsregister.eu. thickness (IMT) has been validated as a measure Additionally, unpublished materials and results of atherosclerosis and as a strong predictor of of clinical trials were sought through informal cardiovascular events (myocardial infarction and channels and personal communication with stroke). Many human studies noted a reduction researchers who have been working in the in IMT after 12 or 24 weeks of treatment relevant field. We searched for articles published with pioglitazone [12,13] and trough PPARγ in English and Russian languages from 2000 to February 2016. The pre-specified inclusion activation pioglitazone caused an inhibition of criteria used for assessment of studies were: 1. early atherosclerotic process. Data suggested Type of study: epidemiological, controlled and that pioglitazone and other thiazolidinediones blind, randomized; 2. Type of participants: decrease C-reactive protein levels [9], representative group from whole population, microalbuminuria [14], arterial pulse-wave specific strata; 3. Access to the primary source velocity [9], systolic and diastolic blood pressure data; 4. Eligibility of statistical analysis. [8], and increase adiponectin levels [9], each Eligible studies were hard to find because they of which is associated with cardiovascular risk weren’t fully available or weren’t published at reduction. Moreover, PPARγ activation leads to all (publication bias). This meta-analysis is a reduction in blood concentrations of matrix designed to cover all the relevant published and metalloproteinase-9 [15] and soluble CD40 unpublished materials. FIGURE 1 presents ligand [16], both new markers of cardiovascular a flow-diagram which describes the process of risk. screening of identified studies. The therapeutic use of pioglitazone has

been limited in recent years due to concerns Number of published materials Number of materials found over bladder carcinogenicity, the description found in databases - 1521 through other sources - 15 of new risk for fractures and due to increased risk of cardiovascular harm with Number of materials after [17]. Meta-analyses showed increased risk removing of duplicates and materials unrelated to the topic - for myocardial infarction associated with 436 rosiglitazone [18,19]. Different effects of rosiglitazone and pioglitazone on cardiovascular Excluded materials – 112 Number of revised materials – Purpose: not related to study complications suggests that these effects are 451 rather associated with the TZD type. Subgroup objectives

analyses of randomized PROactive Full-text materials included in show that pioglitazone is effective in reducing the the assessment – 339 risk of recurrent stroke: HR 0.53 (95% CI 0.34- 0.85, p=0.009) [20] and recurrent myocardial Revised studies for infarction (MI) and other serious cardiovascular pioglitazone- 144 event in patients with T2DM and previous MI: HR 0.72 (95% CI 0.52 – 0.99, p=0.045) [21], Included studies in meta- although 6% from the group on pioglitazone analysis - 69 have been admitted to hospital with heart failure FIGURE 1. Diagram of the process of source [11]. screening.

304 10.4172/clinical-practice.1000126 Clin. Pract. (2017) 14(5) Favorable cardiovascular effects of pioglitazone: a meta-analysis REVIEW

„„Outcome measures end-points (FIGURE 2) only the PROactive study and one unpublished study, due to the The included various studies, which observed small number of participants, reported for death the effects of pioglitazone no the cardiovascular patients. events, measure different outcomes and very different time intervals. We specified the primary The PROactive (Prospective Pioglitazone outcomes of this meta-analysis: Clinical Trial in Macrovascular Events) study reported that the total mortality in the group • Mortality (total and related to cardiovascular events) of pioglitazone was 177 compared with 186 deaths in the placebo group and suggested that • Non-fatal coronary events (defined as the use of pioglitazone did not influence the myocardial infarction, unstable angina or total mortality. In other studies, different from coronary revascularization) PROactive, the results were more definitive: • Non-fatal heart failure requiring in the group of patients with type 2 diabetes hospitalization. participating in these studies, the total number of reported deaths was 17 and in the group of All studies (TABLE 1), included in the non-users of pioglitazone were 39. From the analysis, were randomized, controlled clinical calculated RR 0.41, 95% CI (0.23 to 0.72) studies. For each study, numbers of patients (FIGURE 2) could be concluded that the use of with events of interest were extracted for each pioglitazone was associated with a significantly treatment group and used to calculate relative reduced risk of mortality. risks. We estimated overall relative risks (RR) and 95% confidence intervals (CIs) for each end When long-term studies were analyzed points using random effect model. separately from short-term, a lower risk of total mortality with the use of pioglitazone were „„Statistical analysis found in both cases, although the number of short-term studies was small and therefore Because statistical heterogeneity was present couldn’t achieve statistical significance. in the results of studies, therefore, the random- effects model was used. In the random-effects In the comparative analysis of pioglitazone model, studies are weighted with the inverse of with other antidiabetic agents, pioglitazone their variance and the heterogeneity parameter. showed lower mortality rates than the groups Forest plots were constructed based on treated with sulfonylureas (RR 0.22 95% CI random-effects models, and between-study (0.05 to 1.03)), placebo (RR 0.16 95% CI heterogeneity was assessed by graphical (0.02 to 1.45)), (RR 0.66 95% CI inspection and with the Higgins I2 statistic, (0.19 to 2.34)), rosiglitazone (RR 0.49 95% which describes the percentage of between- CI (0.04 to 5.36)), glitazars (RR 0.42 95% study variability in effect estimates attributable CI (0.11 to 1.61)) but the overall result did not to true heterogeneity rather than chance. The reached statistical significance(FIGURE 2). Cochran’s Q statistic, a chi-squared (χ2) test of When studies with zero mortality were included heterogeneity and Tau2, estimating the between- in the analysis, there was no statistically study variance, are also presented. The used level significant difference in RR in all groups. of significance was 0.05 and confidence intervals were respectively 95%. Information on causes of death was missing in five of the studies. In other studies participated „„Publication bias 7644 patients, who were pioglitazone users We used funnel and Doi plots to evaluate and in this group were reported 7 deaths due reports for publication bias. In the meta-analysis, to cardiovascular events. However, in the the log of the ratio measure and its standard comparative group with 6106 patients were error are used in funnel plots. A Doi plot (a reported 16 deaths due to cardiovascular events symmetrical mountain-like plot) with Luis (RR 0.35, 95% CI (0.14 to 0.85)). The overall Furuya-Kanamori (LFK) index <|1| indicates random effect relative risk was RR 0.87, 95% CI no asymmetry; LFK index between |1| and |2| (0.62 to 1.23), but with substantial heterogeneity suggests minor asymmetry; and LFK index >|2| (I2=47%) (FIGURE 2). The funnel and Doi suggests major asymmetry. plot in FIGURE 3 were asymmetrical with LFK index >|2|, suggesting gross publication bias. Meta-analysis was performed with R language and Excel macro MetaXL. „„Non-fatal coronary events (defined as myocardial infarction, unstable Results angina or coronary revascularization) „„Mortality PROactive study suggested that pioglitazone Compared to all studies with cardiovascular significantly decrease the number of case with

Clin. Pract. (2017) 14(5) 10.4172/clinical-practice.1000126 305 Katya Hristova Uzunova REVIEW Non-fatal heartNon-fatal failure (P/C)* 209/153 0/0 0/0 30/15 - - - 0/0 - 0/0 - - - 0/0 - 0/0 - - - 0/0 - 0/0 0/0 Non- fatal coronary events (P/C)* 226/286 2/17 0/1 0/0 - - 0/0 0/0 - 0/0 - - 0/0 0/0 - 0/0 - - 0/0 0/0 - 0/0 0/0 Total Total mortality (P/C)* 177/186 0/0 0/0 5/6 0/1 0/0 0/0 0/0 0/1 0/0 0/1 0/0 0/0 0/0 0/1 0/0 0/1 0/0 0/0 0/0 0/1 0/0 0/1 Mortality due to cardiovascular events (P/C)* 127/136 0/0 0/0 5/6 0/0 0/0 0/0 0/0 0/1 0/0 0/0 0/0 0/0 0/0 0/1 0/0 0/0 0/0 0/0 0/0 0/1 0/0 0/0 Number of patients (P/C)* 2605/2633 26/28 23/21 259/259 142/147 329/79 47/11 175/78 176/84 147/147 20/20 6/6 14/16 21/9 28/119 24/24 19/11 24/16 8/8 72/70 21/21 10/10 17/10 Condition DM-2 and non- with high risk of fatal events macrovascular fatal coronaryDM-2 and acute coronary for referred syndrome stenting stent DM-2 with successful implantation dysfunction,DM-2, and systolic Heart (NYHA) Association York New functional Class II/III HF. DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 with overt nephropathy DM-2 DM-2 DM-2 with stable coronary artery disease (CAD) DM-2 -treated DM-2 Drug (control) (placebo) pioglitazone without group (control pioglitazone pioglitazone) without group (control pioglitazone pioglitazone) (glyburide +/-insulin) piogitazone (placebo+insulin) pioglitazone+insulin (placebo) pioglitazone (placebo) pioglitazone (placebo) pioglitazone (placebo) pioglitazone (pioglitazone) (placebo+metformin) pioglitazone+metformin (placebo) pioglitazone (insulin+placebo) insulin+pioglitazone (placebo+diet/ pioglitazone+diet/sulfonylurea sulfonylurea) placebo) (pioglitazone, ragaglitazar (placebo) pioglitazone (placebo) pioglitazone (placebo) pioglitazone or other insulin regimen pioglitazone+initial or other initial insulin regimen (placebo+ medications) pioglitazone (placebo) (placebo) pioglitazone (placebo) pioglitazone (placebo) pioglitazone Study Study duration (weeks) 138 24 24 24 24 26 26 26 24 26 8 8 9 12 12 12 12 12 12 12 12 16 16 , 2002 [43] Author Dormandy, 2005 [12] PROactive 2006 [38] Nishio, 2003 [15] Takagi, 2008 [29] Giles, 2005 [40] Mattoo, 2000 [41] Aronoff, Miyazaki, 2002 [42] Scherbaum and Göke PNFP012 [44] 2010 [45] Truitt, 2004 [46] Negro, Stuart, 2007 [47] 2006 [48] Tooke, Kawamori, 1998 [49] 2004 [50] Saad, Bogacka, 2005 [51] 2004 [52] Wallace, 2006 [53] Katavetin, McMahon, 2005 [54] 2006 [55] Goldstein, 2006 [11] Sourij, Gastaldelli, 2006 [56] Gastaldelli, 2007 [57] Table 1. Studies included in the meta-analysis. 1. Studies Table № as primary complications end points with cardiovascular Studies 1 2 3 4 as secondary complications and studies with other end points end points with cardiovascular Studies 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

306 10.4172/clinical-practice.1000126 Clin. Pract. (2017) 14(5) Favorable cardiovascular effects of pioglitazone: a meta-analysis REVIEW - - 0/0 - 0/0 - - 0/0 2/0 - 0/0 1/0 - - - 0/0 0/0 0/0 - - 1/1 13/12 - 0/0 - 0/2 0/0 - 0/1 0/0 - - 0/0 - 0/0 0/0 - 0/0 - - 0/0 1/0 - 0/0 3/9 - - - 0/0 0/0 0/0 - - 3/8 6/11 - 0/1 - 0/0 0/0 - 0/0 0/0 - - 0/0 0/0 0/0 0/0 0/1 0/0 0/1 0/0 0/0 0/0 0/0 0/0 0/0 1/0 0/0 0/2 1/4 0/0 0/0 0/0 0/0 0/0 0/2 1/6 0/0 0/0 0/0 0/1 0/0 0/0 0/0 0/0 1/2 3/2 0/0 0/0 0/0 0/0 0/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 - 0/0 0/0 0/0 0/0 0/0 0/0 0/1 - 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 - - 0/0 20 379/187 168/160 12/11 373/187 196/99 96/101 12/12 89/84 108/109 121/123 38/37 230/228 146/137 317/313 624/626 13/14 15/15 17/17 91/109 252/251 150/150 1051/1046 28/25 21/22 10/11 22/22 17/17 19/22 58/37 105/100 319/320 597/597 38/39 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 with mild dyslipidemia DM-2 Hyperplasia Adrenal Congenital DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 with microalbuminuria DM-2 with microalbuminuria DM-2 DM-2 disease DM-2 with mild cardiac DM-2 DM-2 DM-2 DM-2 diabetic nephropathy DM-2 with microalbuminuria DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 pioglitazone+metformin/sulfonylurea/ them (placebo) between combination (placebo) pioglitazone+insulin placebo+metformin) pioglitazone+metformin pioglitazone(placebo) pioglitazone+sulfonylurea (placebo+sulfonylurea) placebo) pioglitazone (placebo) pioglitazone (placebo) pioglitazone therapy antidiabetic pioglitazone+other therapy) (+other antidiabetic pioglitazon+metformin glimepiride+metformi glimepiride pioglitazone glimepiride metformin pioglitazone pioglitazone+insulin/metformin glimepiride+insulin/metformin pioglitazone gliclazide+metformin pioglitazone+metformin gliclazide pioglitazone pioglitazone glibenclamide pioglitazone placebo pioglitazone glibenclamide pioglitazone glyburide pioglitazone glyburide pioglitazone glibenclamide pioglitazone diet glimepiride metformin pioglitazone gliclazide metformin pioglitazone glibenclamide pioglitazone pioglitazone placebo pioglitazone basal insulin insulin+pioglitazone metformin sulfonylurea gliclazide+metformin pioglitazon+metformin metformin pioglitazone sulfonylurea+pioglitazone sulfonylurea+metformin metformin pioglitazone glimepiride metformin pioglitazone 16 16 16 16 16 16 23 16 24 26 52 52 72 52 52 52 24 52 52 52 56 52 156 13 12 20 16 52 20 24 32 52 52 52 Martens, 2005 [58] Rosenstock, 2002 59] Einhorn, 2000 [60] Miyazaki, 2001 [61] 2001 [62] Kipnes, Herz, 2003 [63] 2001 [64] Rosenblatt, NCT00151710 [65] 2005 [14] Langenfeld, 2006[66] Umpierrez, 2004 [67] Tan, Yamanouchi2005 [68] 2006 [69] Mazzone, 2006 [70] Perriello, 2005 [71] Matthews, 2005 Charbonnel, [72] 2005 [73] Watanabe, Nakamura, 2004 [74] Nakamura, 2001 [75] 2004 [76] Tan, Jain, 2006 [77] 2010 [78] Giles, 2009 [79] Tolman, Ramachandran, 2004 [80] 2004 [81] Lawrence, Majali,Al 2006 [82] 2005[83] Agarwal, Nakamura, 2001 [75] 2006 [84] Fonseca, 2015 [85] Шаенко, 2003 [86] Pavo, 2004 [87] Hanefeld, Schernthaner 2004 [88] 2005 Yamanouchi [68] 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57

Clin. Pract. (2017) 14(5) 10.4172/clinical-practice.1000126 307 Katya Hristova Uzunova REVIEW 0/0 0/0 - 0/0 - 0/0 0/0 0/0 2/5 2/4 - 0/0 0/0 0/0 - - 0/0 0/0 - 0/0 - - 0/0 0/0 - 0/0 - 0/0 0/0 0/0 10/12 - - 0/0 0/0 0/0 - - 0/0 0/0 - 0/0 - 0/0 0/1 0/0 0/0 0/0 1/2 0/0 0/0 0/0 1/6 2/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/1 0/0 0/0 0/0 - 0/0 0/0 0/0 0/5 1/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 21/21 18/17 28/24 38/40 369/366 45/42 48/48 147/147 572/587 1024/683 67/60 72/358 28/30 31/29 129/136 14/16 17/17 15/15 453/153 24/12 19/16 30/30 DM-2 DM-2 DM-2 DM-2 DM-2 with dyslipidemia DM-2 with metabolic syndrome DM-2 with metabolic syndrome DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 DM-2 with microalbuminuria DM-2 with microalbuminuria DM-2 DM-2 DM-2 2 diabetic nephropathy Type pioglitazone metformin gliclazide metformin pioglitazone metformin pioglitazone diet glimepiride metformin pioglitazone metformin pioglitazone rosiglitazone pioglitazone glimepiride+pioglitazone glimepiride+rosiglitazone metformin+pioglitazone metformin+rosiglitazone (pioglitazone) rivoglitazone metformin+pioglitazone metformin+ tesaglitazar pioglitazone rosiglitazone pioglitazone pioglitazone (placebo) tesaglitazar placebo) (pioglitazone, ragaglitazar secretagogue pioglitazone+metformin/insulin bedtime isophaneinsulin+ metformin/insulin secretagogue pioglitazone voglibose pioglitazone placebo pioglitazone glibenclamide voglibose pioglitazone pioglitazone+sitagliptine pioglitazone+placebo (control) metformin metformin+pioglitazone basal insulin insulin+pioglitazone +metformin sulfonylurea losartan+pioglitazone losartan 12 12 13 16 24 52 52 26 24 24 16 12 12 16 26 12 52 52 24 8 20 52 Lawrence, 2004 [81] Lawrence, Sharma, 2006[89] Ramachandran, 2004 [80] Nagasaka, 2004 [90] 2005 [91] Goldberg, 2005 [92] Derosa, 2006 [93] Derosa, 2010 [45] Truitt, 2006 [94] Kendall, 2007 [95] Bays, Khan, 2002 [96] 2006 [55] Goldstein, 2004 [50] Saad, Aljabri, 2004 [97] 2002 [98] Göke, 2006 [99] Shimizu, Nakamura, 2001 [75] Nakamura, 2004 [74] Rosenstock, 2006 [100] 2006 Wang, 2006 [84] Fonseca, Jin, 2007 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 * (P/C) = Pioglitazone/Control

308 10.4172/clinical-practice.1000126 Clin. Pract. (2017) 14(5) Favorable cardiovascular effects of pioglitazone: a meta-analysis REVIEW

FIGURE 2. Forest plot - all-cause mortality.

( j y y) All-cause Mortality (IVhet Model) LFK index:-6.62 (Major asymmetry) 0.1 0.6 0.2 0.8 0.3 1 0.4 1.2 r 0.5 | 1.4 r e r o o e

0.6 c 1.6 r d - s a Z d 0.7 1.8 | n a 0.8 2 S t 0.9 2.2 1 2.4 1.1 2.6 1.2 2.8 1.3 3

-2 -1 0 1 2 -1 ln RR ln RR

FIGURE 3. Detection of publication bias: funnel plot (left) and Doi plot (right) – all-cause mortality. non-fatal coronary events (FIGURE 4). In the „„Non-fatal heart failure requiring cohort of diabetic patients, information about hospitalization non-fatal coronary events was reported in 40 In PROactive study the use of pioglitazone studies involving 4259 patients on pioglitazone is associated with increased risk of non-fatal and 3989 patients as controls. These studies cases of heart failure (FIGURE 6). Other reported respectively 44 and 50 non-fatal studies that have reported non-fatal heart failure coronary events and calculated risk ratio was requiring hospitalization included 5380 patients RR 0.64, 95% CI (0.44, 0.92). The same data using pioglitazone and 5531 controls. The transformed as the incidence rate per 1000 year number of cases with heart failure was 58 for the pioglitazone group and 39 for the control disclosed that there will be 8.8 cases of non-fatal group. Accordingly, the calculated relative risk coronary events per 1000 years in the group of was RR 1.32, 95% CI (0.88, 1.18). Increased users of pioglitazone and 10.2 cases of non-fatal risk of heart failure was shown when comparing coronary events per 1000 years in the group pioglitazone and placebo (RR 1.30, 95% CI of controls. If all of the studies were analyzed, (1.06, 1.59)) but such increased risk was not including PROactive, the calculated relative established when comparing pioglitazone with glitazars and sulphonylureas (RR 0.43, 95% CI ratio (RR 0.62, 95% CI (0.43, 0.89)) revealed (1.13, 1.39) and RR 0.96, 95% CI (0.48, 1.89), that the use of pioglitazone is associated with respectively). There was moderate heterogeneity significant reduction in risk of non-fatal coronary across the studies for this end point (I2=10%, events but the effect estimates were heterogeneous p=0.35). across the studies, I2=80% (FIGURE 4). There Combination of all studies reported at least was evidence of minor asymmetry in the Doi one case of non-fatal heart failure, without plot (LFK <|2|) (FIGURE 5). PROactive, showed statistically non-significant

Clin. Pract. (2017) 14(5) 10.4172/clinical-practice.1000126 309 Katya Hristova Uzunova REVIEW

difference between group of pioglitazone and non-fatal heart failure (FIGURE 6). Asymmetry controls. The inclusion of PROactive study in of funnel and Doi plots showed evidence of the analysis significantly increased the risk of publication bias (FIGURE 7).

FIGURE 4. Forest plot - non-fatal coronary events

LFK index: -1.49 (Minor asymmetry) Non-Fatal CE (IVhet Model) 0 0,1 0,5 0,15 0,2 1 0,25 0,3 1,5 |Z-score| 0,35 Standard error 0,4 2 0,45 2,5 -1 0 -0,9 -0,8 -0,7 -0,6 -0,5 -0,4 -0,3 ln RR ln RR FIGURE 5. Detection of publication bias: funnel plot (left) and Doi plot (right) – non-fatal coronary events.

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

Non-Fatal HF (IVhet Model) 0 LFK index:-4.64 (Major asymmetry) 0,1 0,5 r 0,2 | e 1 r rr o e 0,3 d 1,5 sc o 0,4 - Z | 2 anda r t 0,5 S 2,5 0,6 3 0 1 0 ln RR ln RR

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

310 10.4172/clinical-practice.1000126 Clin. Pract. (2017) 14(5) Favorable cardiovascular effects of pioglitazone: a meta-analysis REVIEW

Discussion According to Fishman and Tenenbaum the risk Our data support the expectation for reduced of heart failure is a class effect of TZDs, whereas risk (around 60%) of total mortality in the group the ischemic cardiovascular risk is restricted to of pioglitazone (without PROactive study). rosiglitazone but not to pioglitazone [26]. In the comparative analysis of total mortality Observational studies suggest no between users of pioglitazone and users of other increased ischemic heart disease (IHD) risk antidiabetic agents, a similar conclusion was with pioglitazone compared with other made: risk of death in the group of pioglitazone oral hypoglycemic agents [27]. A Taiwan was lower than in groups of sulphonylureas retrospective cohort study of over 473 000 (78%), metformin (34%), rosiglitazone (51%), patients showed that rosiglitazone monotherapy glitazars (58%) and in the placebo group (84%), were at higher risk for any cardiovascular event but the overall result did not reached statistical (hazard ratio [HR] 1.89, 95% CI 1.57, 2.28), significance. The risk of non-fatal coronary myocardial infarction (HR 2.09, 95% CI 1.36, events was decreased between 16% and 60% in 3.24), angina pectoris (HR 1.79, 95% CI the group of pioglitazone. The PROactive study 1.39, 2.30) and transient ischaemic attack (HR found that despite the increased cases of heart 2.57, 95% CI 1.33, 4.96) than those receiving failure in the pioglitazone group, the number metformin monotherapy, but pioglitazone as an of deaths from heart failure was similar in each add-on therapy was found to have a favourable, group. Our findings showed that there was an but nonsignificant, effect on outcome [28]. association (under 50%) between pioglitazone The WellPoint observational study revealed and risk of heart failure. that there was no significant increase in risk Pioglitazone seem to have more favorable of MI (HR 1.04, 95% CI 0.91 – 1.21) [29]. effect on cardiovascular disease. Pioglitazone and Using population-based health care databases metformin are the only glucose- lowering agents in Ontario were found that TZD treatment with RCT data demonstrating a reduction in was associated with a significant increase in the stroke, MI and death in type 2 diabetes [22]. risks of congestive heart failure (CHF), acute A large clinical trial designed to assess the effect myocardial infarction, and all-cause mortality of pioglitazone on ischemic cardiovascular among older persons but this association was outcomes, the Prospective Pioglitazone Clinical significant only with rosiglitazone therapy Trial in Macrovascular Events (PROactive) trial, [30]. One observational study documented proved that pioglitazone significantly reduced that TZDs and metformin were not associated the secondary composite outcome of all- with increased mortality and may improve cause mortality, non-fatal MI and stroke (HR outcomes in older patients with diabetes and 0.84, 95% CI 0.72–0.98) but indicated 11% heart failure [31]. Moreover, only pioglitazone increased chances of congestive heart failure in has been shown to reduce the incidence of major pioglitazone-treated patients [11]. cardiovascular events [11,23]. A meta-analysis of 19 trials also showed As a class, TZDs turn on and off many of the benefit of pioglitazone in regard to the same genes. The function of the target genes cardiovascular events, with an 18% reduced have been mainly concentrated on hepatocytes risk of the composite end point of all cause and adipocytes, which both play a key role in death, MI and stroke [23]. Another meta- systemic lipid metabolism [32]. However, each analysis, comprising randomized controlled PPARγ agonist has its own individual effect to trials, suggested that pioglitazone did not appear stimulate/inhibit the expression of specific genes. to increase the risk of MI (RR 0.86, 95% CI This is particularly relevant to pioglitazone (0.69, 1.07), p=0.17) and the authors didn’t find and rosiglitazone, which have very different statistically significant reduction in stroke and effects on lipid metabolism. Pioglitazone coronary revascularisation compared to control compared with rosiglitazone is associated with [24]. While one meta-analysis of clinical trials found a trend toward elevated risks of myocardial significant improvements in triglycerides, HDL infarction and death from cardiovascular causes cholesterol, LDL particle concentration, and with rosiglitazone [18] other meta-analysis of LDL particle size [33], which may be associated randomized clinical trials stated that there was with their different effect on cardiovascular an increased risk of heart failure compared outcomes. Moreover, thiazolidinediones exert with control for both rosiglitazone (RR 2.18, antiatherogenic effects through a multitude of 95% CI (1.44, 3.32), p=0.0003; 5 studies) and mechanisms, including a decrease in insulin pioglitazone (RR 1.32, 95% CI (1.04, 1.68), resistance, inhibition of atherogenic processes p=0.02; 2 studies), but the risk of cardiovascular in the vascular wall, and a reduction in death was not significantly increased for TZD established and new cardiovascular risk factors. compared with control, nor for rosiglitazone Furthermore, pioglitazone treatment improves and pioglitazone compared with control [25]. chronic vascular inflammation (decrease of

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biomarker hsCRP), which may be associated comorbidities. In this aspect, pioglitazone is with reduced cardiovascular risk [34]. and should remain an important agent within the modern management of type 2 diabetic Conclusions patients, and its clinical use should be consistent In summary, T2DM as a chronic metabolic with the individual patient’s characteristics disorder is associated with a marked increase in since pioglitazone exerts cardioprotective action cardiovascular disease, morbidity and mortality, and has proven to be cost-effective [35-37] in but the majority of published studies do not suggest such an increased risk in pioglitazone- patients with T2DM and macrovascular disease treated patients. Our work shows that [39]. pioglitazone treatment was associated with non-significant decrease in mortality rate and Financial and competing interests reduction of non-fatal cardiovascular events disclosure (defined as myocardial infarction, unstable Tchaikapharma High Quality Medicines angina or coronary revascularization) but a Inc. funded this meta-analysis. KHU and EPF slight risk of non-fatal heart failure was found. are employees of Tchaikapharma High Quality Medicines Inc. The other authors report no Although pioglitazone may also be competing interests. associated with several adverse events, including body weight gain, CHF, peripheral bone Authors’ contributions fractures, the value of pioglitazone as a glucose- The original idea came from TYV. KBK lowering agent (as oral monotherapy, dual assessed the eligibility of the studies and therapy, triple therapy and even combination performed statistical analysis. KHU checked all with insulin) were confirmed, with additive the selected articles for this review and wrote positive effects that may contribute to coronary the article. EPF independently checked data and cerebrovascular protection. and contributed in writing the manuscript. All The goal of diabetes therapy is not only authors revised and provided final approval of glucose lowering, but also protection from its this manuscript.

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