CLINICAL RESEARCH: CLINICAL TRIALS
Anti-Inflammatory Effects of Pioglitazone and/or Simvastatin in High Cardiovascular Risk Patients With Elevated High Sensitivity C-Reactive Protein
The PIOSTAT Study
Markolf Hanefeld, MD, PhD*,*,
Nikolaus Marx, MD ,
Andreas Pfützner, MD, PhD ,
Werner Baurecht, MSc ,
Georg Lübben, MD||,
Efstrathios Karagiannis, MD||,
Ulf Stier, MD* and
Thomas Forst, MD
* GWT, Center for Clinical Studies, Dresden, Germany
University Ulm, Medical Department II, Ulm, Germany
Institute for Clinical Research and Development, Mainz, Germany
Acromion, Frechen, Germany
|| Takeda Pharma, Aachen, Germany
Manuscript received April 11, 2006;
revised manuscript received August 24, 2006,
accepted August 28, 2006.
* Reprint requests and correspondence: Dr. Markolf Hanefeld, Forschungshereich Endokrinologie and Stoffwechsel, Zentrum für Klinische Studien, GWT-TUD mbH, Fiedlerstrasse 34, 01307 Dresden, Germany. (Email: hanefeld{at}gwtonline-zks.de).
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Abstract
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OBJECTIVES: The purpose of this study was to test the safety and efficacy of pioglitazone and simvastatin in combination versus each drug individually in non-diabetic subjects with cardiovascular disease (CVD) and elevated high-sensitivity C-reactive protein (hs-CRP) levels.
BACKGROUND: Low-grade inflammation is a pathogenic factor for atherosclerosis. High-sensitivity CRP, matrix metalloproteinase (MMP)-9, and plasminogen activator inhibitor (PAI)-1 are markers of inflammation. Statins and peroxisome proliferator-activated receptor (PPAR)- agonists lower inflammatory markers and reduce CVD in type 2 diabetes.
METHODS: In a 12-week, prospective, double-blind trial, 125 subjects were randomized to simvastatin or pioglitazone plus placebo or a simvastatin/pioglitazone combination. We tested changes in hs-CRP by analysis of covariance. A subgroup analysis was performed in patients with and without the metabolic syndrome (MetS). The correlation between changes in hs-CRP and homeostasis model assessment (HOMA; a measure of insulin resistance) was calculated with the Spearman's rank test.
RESULTS: At baseline, there were no significant between-group differences. At 12 weeks, pioglitazone and simvastatin monotherapies significantly reduced hs-CRP (3.64 ± 2.42 mg/l to 2.48 ± 1.77 mg/l and 3.26 ± 2.02 mg/l to 2.81 ± 2.11 mg/l) and the combination regimen had an additive effect (from 3.49 ± 1.97 mg/l to 2.06 ± 1.42 mg/l, p < 0.001). For subgroups, the difference between monotherapy and combination therapy was only significant for simvastatin versus simvastatin plus pioglitazone in patients without MetS. Homeostasis model assessment decreased in those receiving pioglitazone, and the correlation between changes in HOMA and hs-CRP was significant (r = 0.43; p < 0.05). The PAI-1 decreased significantly in the pioglitazone groups only, and MMP-9 was also significantly lowered in the pioglitazone groups. No treatment-related serious adverse events occurred in any group.
CONCLUSIONS: Pioglitazone, probably by reducing insulin resistance, has additive anti-inflammatory effects to simvastatin in non-diabetic subjects with CVD and high hs-CRP.
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Abbreviations and Acronyms
| | CVD = cardiovascular disease | | HOMA = homeostasis model assessment | | hs-CRP = high-sensitivity C-reactive protein | | MCP = macrophage chemoattractant protein | | MetS = metabolic syndrome | | MMPs = matrix metalloproteinases | | PAI = plasminogen activator inhibitor | | PPAR = peroxisome proliferator-activated receptor | | TZD = thiazolidinediones |
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In the last decade, low-grade inflammation has been identified as a pivotal pathogenic factor in the development of atherosclerosis. Inflammatory activity has been shown to predict myocardial infarction and stroke in patients with pre-existing cardiovascular disease (CVD). Numerous inflammatory parameters, such as cell adhesion molecules, cytokines, chemokines, and acute phase reactants, have been identified as valuable risk markers for the prediction of cardiovascular events (1,2). The inflammatory phase protein, C-reactive protein (CRP), is associated with an increased risk for CVD and stroke. It is frequently measured in clinical practice and has been investigated extensively in the context of atherosclerosis and vascular complications (3–6). Inflammatory activity is closely connected to the metabolic syndrome (MetS) (7). In addition, matrix-degrading matrix metalloproteinases (MMPs), such as MMP-9, have been implicated in plaque rupture through their capacity to thin the protecting fibrous cap of the plaque, thus rendering it more vulnerable (8). In fact, MMP-9 levels are elevated in patients with unstable plaques (9). Furthermore, peripheral blood levels of MMP-2 and -9 are elevated in patients with acute coronary syndromes (10).
Statins are currently the best known pharmaceutical intervention for CVD. In addition to their low-density lipoprotein (LDL)-cholesterol–lowering effect, statins exert anti-inflammatory actions by stimulating the expression of peroxisome proliferator-activated receptor (PPAR)- (11–13). Further pleiotropic effects are the inhibition of matrix degradation by MMPs and the improvement of endothelial function by the up-regulation of nitric oxide synthesis (14,15).
In recent years, a close inter-relationship between inflammation, insulin resistance, lipid disorders, the MetS, and the development of atherosclerosis has been identified in diabetic and non-diabetic patients. In this context, a new pharmaceutical class of drugs that targets insulin resistance, the thiazolidinediones (TZDs) (PPAR- agonists), are now widely used for the treatment of type 2 diabetes. Besides their beneficial effects on glucose and lipid metabolism, TZDs have pleiotropic and anti-inflammatory properties. Clinical studies have shown that they are able to reduce inflammatory markers, such as CRP, MMP-9, macrophage chemoattractant protein (MCP)-1, and soluble CD40L (16–19). However, of the degree to which the beneficial effects of TZDs might be due to improvements in diabetic control remains an open question. The TZDs inhibit the proliferation of neointimal tissue in patients with and without type 2 diabetes (20). This results in a decrease in the intima media thickness of carotid arteries in those with diabetes (21–23). Results of a recent study of the TZD pioglitazone (24) suggested that it reduces cardiovascular end points in patients with type 2 diabetes mellitus. Currently, it is good clinical practice, according to international guidelines, to treat patients with CVD with statins. There is, nevertheless, only scarce information on the benefits of treatment with TZDs, alone or in combination with statins, in patients with CVD and increased high-sensitivity (hs)-CRP levels. No data differentiating for subjects with and without the MetS have been published from patients with type 2 diabetes and CVD.
In this study, we aimed to investigate the effect of pioglitazone alone versus simvastatin alone versus pioglitazone combined with simvastatin on different markers of low-grade inflammation in non-diabetic people with high cardiovascular risk.
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Methods
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This phase III study was a prospective, double-blind, double-dummy, 3-arm parallel-group trial evaluating the anti-inflammatory effects of pioglitazone and/or simvastatin treatment in patients with increased cardiovascular risk and activated inflammation, defined as a CRP level >1 mg/l.
Study subjects.
A total of 135 patients, ages 30 to 70 years, with CVD (defined as medical history of myocardial infarction; coronary angiography evidence of CVD; unstable angina pectoris; duplex-sonography of cervical or leg vessels with atherosclerotic vascular lesions; or electrocardiographic evidence of ischemia, stroke, transient ischemic attack, or peripheral arterial disease) and/or hypertension (blood pressure >140/90 mm Hg or current treatment with an antihypertensive drug) and with an hs-CRP level in the range of >1.0 mg/l to <10 mg/l, were randomly assigned to treatment with pioglitazone and placebo, simvastatin and placebo, or pioglitazone in combination with simvastatin.
Main exclusion criteria were: previously known or newly detected diabetes mellitus (fasting plasma glucose  126 mg/dl according to the American Diabetes Association and World Health Organization definition) or chronic inflammatory diseases, statin therapy within the last 4 weeks, significant hepatic (alanine aminotransferase >2.5-fold of the gender-specific normal value) or renal (serum creatinine >2 mg/dl) disease, or congestive heart failure (New York Heart Association functional class I to IV).
The MetS was diagnosed according to the American Heart Association/National Heart Lung Blood Institute definition of 3 or more of the following 5 traits: waist circumference 102 cm (men) and 88 cm (women); triglycerides 1.7 mmol/l; high-density lipoprotein (HDL)-cholesterol <1.03 mmol/l (men) and <1.3 mmol/l (women); blood pressure 130/85 mm Hg or treated with antihypertensive medication; or fasting plasma glucose 5.6 mmol/l (25).
Study treatments.
Treatment was started with 30 mg pioglitazone and/or 20 mg simvastatin. After 2 weeks, the pioglitazone dose was increased to 45 mg and the simvastatin dose was increased to 40 mg. The local ethics committee approved the protocol, and all patients provided written informed consent before enrollment in the study.
Assessments.
Insulin, glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, MCP-1, MMP-9, and plasminogen activator inhibitor (PAI)-1 were measured at study entry and after 12 ± 1 weeks of study medication. The hs-CRP was measured after 6 ± 1 weeks and 12 ± 1 weeks to obtain further information about the time course of the anti-inflammatory response. Insulin sensitivity was estimated by homeostasis model assessment (HOMA) at baseline and after 12 weeks of treatment.
All measurements were obtained in the morning after an overnight fast. Patients were asked to refrain from coffee or tea for at least 8 h before each study visit. Blood pressure was measured with the patient in the sitting position for at least 5 min. Height was measured at the first visit, and weight was measured at the first visit and at each subsequent one.
Biochemical parameters.
High-sensitivity CRP was measured by immune turbidometry with latex particles (26).
The intra-assay coefficient of variation was 1.29% and the inter-assay variability was 1.56%. Active PAI-1 antigen was measured with enzyme immunoassay (Technoclone GmbH, Heidelberg, Germany). Real insulin was determined by enzyme-linked immunoabsorbent assay (Anthos Mikrosystem, Krefeld, Germany). Plasma glucose was measured with the glucose dehydrogenase method, cholesterol with the cholesterol oxidase method, HDL-cholesterol with the CHOD-PAP method after precipitation (Dia Sys Diagnostic Systems, Holzheim, Germany), and triglycerides were measured with GPO-PAP (DiaSys Diagnostic Systems). Insulin resistance was calculated from the fasting insulin and glucose values by means of HOMA analysis (HOMA score = insulin [mU/l] x glucose [mmol/l]/22.5).
Statistical analyses.
All statistical analyses were performed with SAS version 8.2 (SAS Institute Inc., Cary, North Carolina). No formal sample size calculation (as for a confirmatory trial) was performed.
All randomized patients who received at least 1 dose of study medication were included in the intention-to-treat analysis of safety and tolerability. All patients with a baseline value and at least 1 post-baseline assessment for hs-CRP  10 mg/l were included in the efficacy analysis.
Data are presented as arithmetic mean ± SD for continuous variables and as the number/proportion of patients for categorical variables. The geometric means for the primary efficacy parameter hs-CRP are also provided. All inferential statistical analyses were performed in an exploratory sense and all p values <0.05 were interpreted as significant.
Treatment groups were compared at baseline using the Student t test for continuous variables and the chi-square test for categorical variables. The statistical evaluation of changes from baseline for the primary parameter was performed with an analysis of covariance (ANCOVA) model with fixed effect factors for treatment group and center and with baseline hs-CRP value as covariate. The natural logarithmic transformation was applied to the hs-CRP values because of their skewed distribution.
The F test was used to test the overall null hypothesis of "no difference between treatment groups." Comparisons between all pairs of means were performed within the ANCOVA model by calculating simultaneous 95% confidence intervals (CIs) of between-group treatment differences for the least square (LS)-means with the Tukey-Kramer procedure. The change from baseline within each treatment group was assessed with 1-sample t tests for the hypothesis of LS-mean = 0.
For changes from baseline of secondary efficacy parameters, 2-sided p values for within-group and between-group treatment differences were calculated, with the t test procedure for paired and independent samples. No transformations were applied to the secondary efficacy parameters.
The relationships between insulin resistance and hs-CRP and between insulin resistance and MMP-9 were assessed with the Spearman's rank-order correlation coefficient.
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Results
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A total of 135 patients were randomized to 1 of 3 treatment groups. Three of these patients did not receive any dose of study medication; thus, 132 patients were included in the intention-to-treat analysis of safety and tolerability. Forty-four patients were treated with pioglitazone plus placebo (pioglitazone monotherapy), 43 patients with simavastatin plus placebo (simvastatin monotherapy), and 45 patients with pioglitazone plus simvastatin (combination). Twenty-two patients (16.7%) discontinued the study prematurely. Seven of the 132 patients were excluded from the efficacy analysis, because they had no hs-CRP value 10 mg/l either at baseline or at least 1 post-baseline. Thus, 125 patients (39 in the pioglitazone monotherapy group, 43 in the simavastatin monotherapy group, and 43 in the pioglitazone and simvastatin combination group) were included in the efficacy analyses.
Demographic data and clinically relevant concomitant medication for patients included in the efficacy analysis are presented in Table 1. All concomitant medications were unchanged throughout the investigation. Treatment groups were comparable with respect to age; gender; presence of CVD, hypertension, and MetS; and antihypertensive and antithrombotic therapy. There were no statistically significant differences between the treatment groups in any baseline parameters.
There were no significant differences in the baseline levels of hs-CRP between the 3 groups. After 12 weeks of treatment, hs-CRP levels were reduced from 3.64 ± 2.42 mg/l to 2.48 ± 1.77 mg/l with pioglitazone monotherapy and from 3.26 ± 2.02 mg/l to 2.81 ± 2.11 mg/l with simvastatin monotherapy (as illustrated in Fig. 1). Combination treatment with pioglitazone and simvastatin resulted in an additive decrease in hs-CRP levels from 3.49 ± 1.97 mg/l to 2.06 ± 1.42 mg/l after 12 weeks.
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Figure 1 Changes in hs-CRP in the 3 Treatment Groups
Percentage changes from baseline (±95% confidence interval) in high sensitivity C-reactive protein (hs-CRP) from baseline to 12 weeks in the 3 treatment groups (solid bar = pioglitazone; open bar = simvastatin; hatched bar = pioglitazone plus simvastatin). All percentages represent 1 subtracted from the antilogs of least square mean differences between baseline and week-12 log-transformed values derived from the analysis of covariance model.
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The exploratory p value related to the F test of testing the global null-hypothesis of equal treatment means for the change from baseline with the log-transformed data was p = 0.0143. Exploratory simultaneous 95% CIs according to Tukey-Kramer for the antilogs of the differences between the LS-means revealed significant differences (i.e., value "1" not included) for the pairwise comparison of simvastatin monotherapy versus pioglitazone plus simvastatin in favor of the combination therapy (antilog of the difference between the LS means resulted in 1.40; 95% CIs ranged from 1.07 to 1.84; p = 0.0103). Statistics for hs-CRP for patients with and without the MetS by treatment group and pertinent results of the ANCOVA for the change from baseline after 12 weeks of treatment are given in Table 2. The percentage reductions in hs-CRP levels in each treatment group are displayed in Figure 1. Decreases in hs-CRP after 6 weeks of treatment were comparable to the decreases after 12 weeks.
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Table 2. Changes in High-Sensitivity C-Reactive Protein (mg/l) in the 3 Treatment Groups Categorized by Patients With and Without the Metabolic Syndrome
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All results for the secondary efficacy parameters are shown in Table 3. The MMP-9 baseline levels were comparable among the 3 groups. At 12 weeks, there was a 13.8% reduction in MMP-9 plasma levels with pioglitazone monotherapy (p = 0.003) and a 13.2% reduction with the pioglitazone and simvastatin combination (p = 0.004) (Fig. 2). In contrast, treatment with simvastatin monotherapy resulted in a 41.5% increase in the levels of MMP-9 (p = 0.019). After 12 weeks of treatment, MMP-9 levels were significantly lower in both pioglitazone groups compared with the simvastatin monotherapy group (p < 0.001).
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Figure 2 Changes in MMP-9, MCP-1, and PAI-1 in the 3 Treatment Groups
Arithmetic mean ± SEM for the relative change from baseline to 12 weeks in matrix metalloproteinase-9 (MMP-9), macrophage chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) in the 3 treatment groups (solid bars = pioglitazone; open bars = simvastatin; hatched bars = pioglitazone plus simvastatin): *p < 0.05 versus baseline; **p < 0.01 versus baseline; ***p < 0.001 versus baseline.
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The MCP-1 levels decreased in the pioglitazone-treated patients (p = 0.052). The PAI-1 levels decreased significantly after treatment with pioglitazone monotherapy (p < 0.001) and after combined treatment with pioglitazone and simvastatin (p = 0.005). There were no significant changes in either MCP- or PAI-1 with simvastatin monotherapy.
Significant improvements in total, LDL, and HDL cholesterol were achieved with treatment with simvastatin monotherapy (p < 0.05) and with combined simvastatin and pioglitazone treatment (p < 0.05), whereas there were small increases in total cholesterol and LDL-cholesterol after treatment with pioglitazone monotherapy. Triglycerides were significantly decreased during combined treatment with pioglitazone and simvastatin only (p < 0.001) (Table 3).
There was a small but significant decrease (p < 0.0001) in fasting plasma glucose levels in the pioglitazone monotherapy group and not in the simvastatin monotherapy group or the pioglitazone and simvastatin combination group. There were no episodes of hypoglycemia.
The HOMA decreased significantly during treatment with pioglitazone as monotherapy (p = 0.003) and in combination with simvastatin (p < 0.001) but remained unchanged during simvastatin monotherapy. The decrease in HOMA correlated with a decrease in MMP-9 (r = 0.47; p < 0.0001), PAI-1 (r = 0.30; p < 0.001), and hs-CRP (r = 0.23; p < 0.05) in the total patient population. In the different treatment groups, the decrease in HOMA correlated significantly with the decrease in hs-CRP in the pioglitazone monotherapy group only (r = 0.43; p = 0.0059) (Fig. 3). This correlation also remained significant when excluding the single point on the extreme left of the figure (Fig. 3). There was no significant correlation between the improvement in hs-CRP and the changes in MCP-1 (r = 0.06; p = 0.5388).
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Figure 3 Correlations of the Changes in HOMA With the Changes of hs-CRP
Changes in homeostasis model assessment (HOMA) versus changes in high-sensitivity C-reactive protein (hs-CRP) after 12 weeks of treatment. R = Spearman's rank correlation coefficient; *p < 0.05 for test of |R| = 0; pioglitazone (filled diamonds), p = 0.0059; simvastatin (open triangles), p = 0.9112; pioglitazone plus simvastatin (filled crosses), p = 0.3848.
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All treatment regimens were well tolerated in general. Treatment with pioglitazone as monotherapy and in combination was associated with a higher incidence of peripheral edema (11.4% and 22.2%, respectively) than simvastatin monotherapy (7.0%; p = 0.7133 vs. pioglitazone monotherapy and p = 0.0695 vs. pioglitazone combination therapy) and with significant increases in body weight and body mass index (p < 0.01) (Table 3). There was only 1 serious adverse event (1 patient in the pioglitazone monotherapy group was hospitalized owing to nephrolithiasis), but it was thought to be unrelated to study medication.
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Discussion
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Key findings.
Our study in non-diabetic patients with CVD and elevated hs-CRP levels is the first to show a significant anti-inflammatory effect of pioglitazone that was comparable to that of 40 mg simvastatin. Furthermore, the combination of pioglitazone plus simvastatin had additive effects on hs-CRP, with a >40% reduction. Patients with the MetS had higher level of hs-CRP, as already known. By subgroup analysis, the additive effect of pioglitazone was only significant for patients without the MetS. Because our patients did not have diabetes, the anti-inflammatory effects of pioglitazone seem to be unrelated to improvements in glycemic control but might be related to improvements in insulin sensitivity. This is supported by the fact that we found a highly significant correlation between improvements in HOMA and reductions in hs-CRP. The effects of pioglitazone on insulin resistance have also been shown in other clinical studies (27,28). A rapid effect of rosiglitazone, another PPAR- agonist, on inflammatory biomarkers has also been shown in healthy non-diabetic subjects, promoting the concept that TZDs also act independently of their metabolic effects on low-grade inflammation (29). Our findings should be clinically relevant if, as suggested, low-grade inflammation is a driving force in the development of vascular complications.
A difference between groups was also observed in relation to MMP-9, an enzyme that is of great importance for plaque stability. Pioglitazone, as monotherapy and in combination, resulted in a significant reduction in MMP-9, whereas simvastatin monotherapy produced a significant increase. None of the treatment regimens had a significant effect on MCP-1. The HOMA was significantly improved with pioglitazone, as expected, whereas simvastatin had no effect. Simvastatin as monotherapy and in combination with pioglitazone gave significant decreases in total cholesterol and LDL-cholesterol along with increases in HDL-cholesterol; this was not observed with pioglitazone monotherapy.
Statins have been shown to reduce cardiovascular events in both primary and secondary prevention trials (30–33). Several studies suggest that the observed clinical benefits of statin therapy might go beyond the reduction of LDL-cholesterol (31–34). Further to the improvement in lipid metabolism, statins reduce low-grade inflammation, which might contribute to their anti-atherosclerotic effects. Data from prospective studies suggest that statin therapy might also prevent CVD by decreasing CRP levels (11,12,35,36). Recently it has been shown that, in patients receiving statins, the reduction of LDL-cholesterol levels resulted in a slowed progression of vascular lesions whereas the additional lowering of hs-CRP-levels caused a regression of atherosclerotic plaques (11,12). In addition, statins have been found to inhibit MMP-9 activity and secretion by macrophages (37), to lower MMP-9 levels in patients with hypercholesterolemia (38,39), and to decrease MMP-1 in human vascular endothelial cells (40). The MMP-9 levels are elevated in patients with unstable plaques, and MMP-2 and -9 levels contribute to acute coronary syndromes by destabilizing the protective fibrous caps of the plaques (7). The MMP-9 levels are also elevated in patients with diabetes mellitus, and treatment with TZDs (e.g., pioglitazone) seems to be effective in reducing the levels of this enzyme (16,19,41). In our study, pioglitazone monotherapy and the combination of pioglitazone with simvastatin resulted in a marked reduction in MMP-9, whereas the use of simvastatin monotherapy for unknown reasons was associated with a significant increase. Although simvastatin had no effect on insulin HOMA, we found a significant correlation between changes in insulin resistance as measured by HOMA and changes in MMP-9 levels.
In recent studies, treatment with TZDs was found to reduce plasma MCP-1 in subjects with and without diabetes (17,19). In this trial, neither simvastatin nor pioglitazone had a significant effect on the levels of MCP-1. Stimulation of PPAR- reduces plasma levels of CRP, MMP-9, MCP-1, and soluble CD40L (16,17,19,42); improves endothelial function (43,44); and reduces the intima media thickness of carotid arteries (21,23). In the recently published PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events) study, treatment with pioglitazone in patients with type 2 diabetes resulted in a significant reduction in death, myocardial infarction, and stroke as aggregated events over a treatment period of 3 years (24). However, it should be noted that a meta-analysis of phase 2 and 3 trials of muraglitazar, a PPAR- - agonist, concluded that mortality and major cardiovascular event rates increased when compared with pioglitazone or placebo (45). It has been suggested that the proinflammatory and atherogenic effects of CRP might be mediated by an increase in PAI-1 (46,47). In this study, we found a significant decrease in plasma PAI-1 after treatment with pioglitazone monotherapy or in combination with simvastatin. Simvastatin monotherapy produced a nonsignificant decrease in PAI-1 levels.
Safety.
Throughout the study, both drugs were well tolerated and there was only 1 severe adverse event registered. Patients receiving pioglitazone showed a modest increase in body weight (mean <2 kg) that didn't occur with simvastatin. It is important to underline the safety of pioglitazone in terms of hypoglycemia (no events were reported), even in people with normal glucose tolerance.
Conclusions.
We found that pioglitazone and simvastatin exerted anti-inflammatory effects in non-diabetic patients with CVD and elevated hs-CRP. Our study is the first to show that combining pioglitazone with simvastatin in non-diabetic patients with increased cardiovascular risk resulted in an additive effect on low-grade inflammation, without a significant increase in serious adverse events. The additive effect of pioglitazone on hs-CRP reduction was only significant for patients without the MetS. Although treatment with each drug in monotherapy significantly improved several risk markers for CVD, only the combination of pioglitazone and simvastatin, with its synergistic effect, seemed to have full anti-inflammatory potency and impact on the whole risk profile of patients with CVD. Prospective efficacy and safety trials are needed to determine whether a TZD and statin combination reduces the incidence of cardiovascular events in patients with high cardiovascular risk and increased low-grade inflammation.
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Footnotes
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This study was sponsored by Takeda. Drs. Lübben and Karagiannis are employees of Takeda.
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References
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