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THE EFFECT OF TROGLITAZONE ON C- REACTIVE PROTEIN IN INDIVIDUALS WITH PREDIABETES: DATA FROM THE DIABETES PREVENTION PROGRAM.

INTRODUCTION

Prediabetes constitutes a major health problem due to its common presence in high proportion of apparently healthy populations leading to considerable health problems associated with overt diabetes (Ligthart et al., 2016). Prediabetes is a condition typically defined as glycemic parameters above normal but below diagnostic criteria for diabetes, according to the centers for disease control and prevention (CDC) 2014 reports, prediabetes affects 37 percent of United States adults aged 20 years or older, the estimates rises to 51 percent in individuals 65 years or older (CDC, 2014). After adjusting for age differences, CDC reported that the percentage of adults aged 20 years or above affected by prediabetes was similar across ethnic lines, about 35 percent for Hispanic whites, 39 percent for non-Hispanic blacks, and 38 percent for Hispanics (CDC, 2014).

Studies have highlighted the role that inflammatory process plays in the pathogenesis of CVD. C-reactive protein (CRP) is a well-established element of the inflammatory response, blood levels of CRP constitute sensitive marker of the inflammatory response to infection and tissue damage. CRP levels have been considered a powerful predictor of the development of CVD as well as in the development and progression of atherosclerosis. Furthermore, elevated CRP levels have been seen in individuals at increased risk for cardiovascular morbidity and mortality and also recognized as a factor in the development and progression of multiple CVDs especially atherosclerosis and CHDs (Willerson et al., 2004; & Laveti et al., 2013). The association between inflammatory and coagulation markers including CRP and fibrinogen is well documented in the literature (Han et al., 2002; Festa & D'Agostino et al., 2000; & Ndumele et al., 2006). Coronary incidents have been shown to increase significantly with an elevated high base line CRP levels. In fact, large studies suggested the strength of the predictive value of CRP for future cardiovascular events to transcend that of conventional markers such as LDL, a classic maker for the prediction of cardiovascular risks (Ridker, Rifai, & Rose et al., 2002; Blake, Ridker, 2003; Ridker, Bassuk, & Toth, 2003). Several reports have suggested a more important role of CRP, beyond its role as only a marker of vascular and cardiovascular inflammation. CRP was considered a mediator in the pathogenesis of atherosclerosis and other CVDs (Blake, Ridker, 2003; Ridker et al., 2003; Ballou et al., 1992; & Pasceri et al., 2000), in addition to its role as a powerful predictive and prognostic biomarker for CVDs (Donald et al., 2006; Folsom et al., 2006; & Packard et al., 2008).

The effect of rosiglitazone and pioglitazone on reducing CRP levels in individuals with type 2 diabetes is well documented in the literature (Pfutzner et al., 2005; Stocker et al., 2007; Agarwal 2006; Davidson et al., 2007; Hartemann-Heurtier et al., 2009; Forst et al., 2008; Marfella et al., 2006; Ogasawara et al., 2009; & Yu et al., 2007). Recent metanalyses evaluated the effect of the two agents on both diabetics and non-diabetic individuals and showed a remarkable decrease in CRP levels (Qayyum & Adomaityte, 2006; Zhao Y. et al., 2010; & Chen et al, 2015). Limited numbers of studies were specifically designed to examine the effects of rosiglitazone and pioglitazone on CRP levels in prediabetic individuals were found (Mohanty et al., 2004; Mizoguchi et al., 2011). In subjects with diabetes, troglitazone was found to lower CRP levels in limited number of small studies (van Tits et al., 2005; Chu et al., 2002). To date, no known studies were found which specifically designed to investigate the effect of troglitazone on CRP, fibrinogen and tPA levels in prediabetic individuals.

This study used the Diabetes Prevention Program Research Group (DPP) study data set to investigate the relationship between troglitazone and CRP, tPA and fibrinogen and insulin resistance in a prediabetic population.

RESEARCH DESIGN AND METHODS

The original DPP was a 27-center randomized clinical trial to determine whether lifestyle modification or select pharmacological therapy would prevent or delay the onset of diabetes in individuals with IGT. The protocol for DPP has been previously documented in previous publications which included the study design, recruitment and measurement methods, and main characteristics of the overall population (Diabetes Prevention Program Research Group (DPP), 1999; and DPP, 2000). Inclusion criteria were age [greater than or equal to] 25 years, fasting serum glucose (FSG) levels between 5.6-7.7 mmol/l before June 1997 and between 5.3-6.9 mmol/l after that date, and BMI of [greater than or equal to] 24 kg/m2 (DPP Research Group, 1999). Our study utilized the data from the DPP. The original study by the DPP group included a total of 3819 prediabetic individuals. Out of the total participants, 585 were assigned to troglitazone.

Our analysis selected a subgroup (n= 3,171) from the original DPP population to analyze tPA and fibrinogen. The total number of participants in this subgroup was determined based on the number of participants with available values for these markers at the end of 1 year from randomization. A total of 291 were in the troglitazone intervention arm (400mg every day), the rest were in the other three interventions including placebo, lifestyle, and metformin (850mg twice a day). The troglitazone arm was discontinued in June 1998 (DPP Research Group, 1999). In this report, we examine the effects of troglitazone on CRP. We also evaluate the effect of changes in selected measures, particularly changes in measures of insulin resistance and glycemia, obesity, and lipid profile; on the changes in this inflammatory marker.

Statistical Analysis

Descriptive analysis at baseline of all variables were generated for each of the four treatment arms. Analysis was performed and presented using SPSS software. Baseline characteristics were reported as means and standard errors. Paired t-tests were conducted to analyze the main effects of troglitazone on CRP. Partial Spearman correlation coefficients and accompanied P values were used to summarize the association between the main dependent variables at baseline with selected independent variables. Partial Spearman correlation was also performed to summarize the association between the changes in CRP levels at 1 year from baseline to understand whether the greater changes in this variable was affected by changes in weight, waist circumference, insulin resistance measures, or hemoglobin A1c (HbA1c). The correlation analysis was shown as unadjusted, followed by adjusted analysis controlling for age, sex, and ethnicity, in attempt to adjust for these potential confounders. Correlation analysis was performed only on the troglitazone intervention arm.

Multiple linear regression was performed to examine whether the changes in CRP levels due to treatment with troglitazone were explained by a weight and waist circumference changes, and changes in measures of glycemia and insulin resistance. The changes from baseline for CRP levels were shown as mean changes and SE, they were also summarized as the percent change from baseline. The percentage is calculated as [(value at 1 year--baseline value) x 100/baseline value] (Haffner et al, 2005). Median percent changes for CRP levels were tested using nonparametric Wilcoxon's test. Fasting insulin levels along with a pretested model were both used as measures for insulin resistance. The homeostasis model assessment for insulin resistance (HOMA- IR). HOMA- IR was calculated using the following formula (Matthews et al., 1985): HOMA-IR= {fasting insulin [micro]]U/ml x fasting glucose (mmol/l)} /22.5

RESULTS

As indicated in Table 1, baseline characteristics for the subgroup selected for the analysis of inflammatory markers includes values for CRP were presented by intervention groups including placebo (n = 956), troglitazone (n = 291), metformin (n = 962), and ILS (n = 962). Values for inflammatory markers were similar in all interventions, women exhibited higher mean values for CRP than men (0.71 for women and 0.32 for men). While the mean values for waist circumferences at run-in visits were the same across interventions, the mean weights at 6 months were lower in the ILs group compared to the average of the means of the three other interventions (87 [+ or -] 0.66 vs. 93 [+ or -] 0.87) (note: weights were taken at 6 months from randomization; waist circumferences were measured at run-in visits which are the visits scheduled after screening visits, prior to randomization). African Americans also showed higher baseline values for CRP compared to males and compared to the overall average.

Table 2 displays baseline correlations for selected variables with CRP, fibrinogen, and tPA in the inflammatory subgroup in the troglitazone intervention, Table 3 presents these baseline correlations values after adjusting for age, sex, and ethnicity. As shown in Table 2, both weight at 6 months and waist circumference at run-in visit along with fasting glucose and HOMA-IR were all significantly and positivity correlated with all three inflammatory and coagulation markers. Mean HbA1c values were also significantly correlated with fibrinogen and tPA, the correlation did not reach statistical significance with CRP. Fibrinogen and CRP showed a strong and significant correlation (r = 0.53, P <0.001). Table 3 provides the outcomes for the partial correlation analysis after adjusting for age, sex, and ethnicity. The adjusted correlational analysis showed similar results as the unadjusted analysis with slight decrease in the correlation coefficient values. Table 4 displays the mean changes from baseline by treatment group for the overall DPP population.

Table 4 illustrates the changes in the mean values of selected anthropometric and metabolic variables resulting from the effect of the different interventions. It appeared that troglitazone significantly reduced the levels of fasting insulin and HOMA-IR at 1 year from baseline, these values reflect on the magnitude of the effect of this agent on insulin resistance.

Troglitazone showed greater reductions compared to metformin in the mean values of both fasting glucose levels (-4.06 vs -3.60, respectively, both P <0.001) and HOMA-IR (-1.22 vs -1.19, respectively, both P <0.001), while ILS exceeded these values. On lipid profile measures, all four interventions significantly reduced triglycerides levels, troglitazone resulted in the highest mean reductions followed by ILS (-27.28 [+ or -] 3.88 vs. -25.78 [+ or -] 2.29, respectively, both P <0.01), while metformin exhibited the lowest mean reductions (-5.34 [+ or -] 2.16, P = 0.01). Troglitazone did increase the C-LDL levels, different from all other interventions which showed a decrease, however this change was statistically insignificant.

Figure 1 shows the mean changes in CRP, all interventions demonstrated statistically significant decrease in CRP levels (P < 0.001), except placebo which failed to reach a statistical significance. Overall, the median percentage change in CRP at 1 year from baseline was -20.00 percent in the troglitazone arm, shown in Figure 2 (p <0.001 for all between group analysis: troglitazone vs. lifestyle, troglitazone vs. metformin, & troglitazone vs. placebo). Due to the differences in CRP levels with sex where women usually report higher baseline CRP values than men, the effect of the interventions was also reported by sex. In women (Figure 4), the median percent change in CRP at 1 year from baseline was -27.08 percent in the troglitazone arm (troglitazone vs. lifestyle: P = 0.854; troglitazone vs. placebo: P <0.001; and troglitazone vs. metformin: P=0.001). In men (Figure 3), troglitazone reported a median percentage change of -4.64 percent in CRP levels (troglitazone vs. lifestyle: P = 0.012; troglitazone vs. placebo: P = 0.012; and troglitazone vs. metformin: P = 0.33).

Troglitazone also showed significant reduction in triglycerides levels exceeding ILS and metformin in this same DPP population (Mokhtar et al., 2017). A close association between CRP and coagulation markers such as tPA and fibrinogen in the DPP population was also documented in that same previous study (Mokhtar et al., 2017). Similar results underscoring the close association between CRP and fibrinogen was shown in previous investigations, these studies suggested similar association between these two variables and with the component of insulin resistance (Festa & D'Agostino et al., 2000; Han et al., 2002; Juhan-Vague et al., 1993; Festa & D'Agostino et al., 2000; & Ndumele et al., 2006).

Table 5 and table 6 presents the results from the partial spearman correlational analyses between the inflammatory and coagulation markers in relation to the changes in HBA1c from baseline to 1 year in each intervention, before and after adjustment for age, sex, and ethnicity.

These results revelaed an inverse relationship between changes in HBA1c and changes in CRP along with other coagulation markers such as fibrinogen and tPA. Even though the magnitude of the correlation coefficients was moderate, and statistically nonsignificant, it may still suggest an association between the teggects of TZDs on glycemic control and their effects on inflammatory and coagulation markers.

Based on the observed results, it seemed like the decreases in the levels of CRP and fibrinogen neither correlated with improvement shown by troglitazone in insulin sensitivity and glycemia, nor with the changes in weight and waist circumference, although the changes in the two latter variables did not meet a statistical significance.

Multiple linear regression analysis was performed to explain whether the effect of troglitazone on CRP could possibly be explained by changes in selected demographic, anthropometric, or metabolic variables. Results from our regression analysis produced statistically nonsignificant models. Therefore, we may assume that our finding regarding the effect of troglitazone on CRP were not affected by changes in these selected metabolic and anthropometric measures.

(Data for placebo, metformin and lifestyle were already published by Haffner et al., 2005, and were reproduced in this analysis).

DISCUSSION

This current study demonstrated a significant decrease in CRP levels due to treatment with troglitazone. The decrease in CRP levels demonstrated by our analysis was significantly greater than the effect of metformin or placebo as presented in the previous DPP study which analyzed the effect of ILS, metformin, and placebo on CRP levels in the same population studied in this present analysis, with the exclusion of troglitazone intervention. Since CRP levels differ according to gender, women always reported higher baseline CRP than men (Festa et al., 2000) in conformity with our analysis. Therefore, we analyzed the effect of troglitazone on CRP by sex in addition to the overall analysis.

Results from our current analysis showed that troglitazone produced a 27.8 percent decrease in the median levels of CRP in females and 14.6 percent in males. Comparable results were reported by Haffner et al. on three other interventions included in the DPP study. Haffner et al. reported a 29 percent and 14 percent reduction in CRP levels for females in ILS and metformin, respectively, and 33 and 7 percent for male in ILS and metformin, respectively. Clearly troglitazone exceeded the results demonstrated by metformin, the only other available insulin sensitizer.

Although CRP serum levels can increase multiple times in response to acute inflammation (Pepys & Baltz, 1983), these levels are maintained at specific range in healthy individuals (Shine, de Beer, & Pepys, 1981). CRP has been considered a sensitive and stable marker for subclinical inflammatory state (Ridker, 2001). Slight elevations in CRP levels may be considered clinically significant; in fact, levels from 0.3 to 1.0 mg/L are clinically considered true elevation (Slade et al., 2003; Kushner et al., 2006; Giles et al., 2008; & Vuong et al., 2014). Accordingly, results from our analysis, although much smaller in value compared to some previous research, may be regarded as clinically significant.

Since the changes produced by the treatment with troglitazone on CRP differ according to the sex and ethnicity of the participants. Therefore, we were able to suggest that sex and ethnicity play a role in the main effect of this agent. The outcome from our analysis regarding CRP agreed with multiple other findings from previous research. In a meta-analysis by Qayyum & Adomaityte, TZDs were shown to reduce CRP levels in both diabetic and nondiabetic individuals, the mean reduction in CRP in diabetic individuals surpassed which is shown in nondiabetics. This meta-analysis included much more diabetic subjects than others. Additionally, the analysis did not specify the percentage of prediabetics among those nondiabetics included (Qayyum & Adomaityte, 2006). Results from a recent meta-analysis, Zhao et al. showed similar results to ours as well. Unlike the previous analysis by Qayyum & Adomaityte, Zhao et al. demonstrated a more pronounced reduction in CRP levels in nondiabetics than in diabetic populations (Zhao et al., 2010). Both meta-analyses failed to specifically identify how many of the nondiabetic individuals have prediabetes. A more recent meta-analysis by Chen et al. published in 2015 which included only patients with diabetes. Still, results from this analysis showed significant reduction by TZDs on CRP levels (Chen et al., 2015). Limited number of studies, all included small number of participants, specifically examined the effect of TZDs on inflammatory markers in prediabetic patients. Mizoguchi et al. studied the effect of treatment with pioglitazone for four months in 56 individuals with impaired glucose tolerance or with diabetes, pioglitazone treated subjects showed a reduction in CRP levels by 0.27 mg/L, which accounted for more than thirty percent reduction from baseline (Mizoguchi et al., 2011). These results demonstrated a much larger reduction when compared to results from our current analysis.

The lack of large studies specifically designed to analyze the effect of TZDs on CRP levels, as in the previously discussed meta-analyses, may give our analysis a distinctive attribute and may give the opportunity for new research to explore this gap, especially since CRP levels were reported to be closely associated with CVD risks (Liuzzo et al. 1994; Thompson et al, 1995; Haverkate et al, 1997; Willerson et al, 2004; Danesh et al. 2000; Ridker et al, 2002; Blake et al., 2003; & Ridker et al., 2003). Several studies have also elucidated on the importance of CRP in the predictions of future CV events and as a prognostic marker. The favorable effects shown by the TZDs on CRP levels, and eventually on the overall cardiovascular risks have been suggested to be independent of their action on glycemia and insulin sensitivity (van Tits et al., 2005). Two major trials, the REVERAL and the PROVE-IT, examined the effect of agents from different therapeutic classes on clinical cardiovascular outcomes through their actions on CRP levels (Ridker et al., 2005; & Nissen et al., 2005).. Moreover, numerous research has gone further suggesting a greater role of CRP beyond its mere role as a marker of vascular and cardiovascular inflammation, to be considered a risk factor involved in the pathogenesis of atherosclerosis and other CVDs (Blake & Ridker, 2003; Ridker et al., 2003; Ballou et al., 1992; & Pasceri et al., 2000).

The design and scope of this current did not allow us to determine the underlying mechanism behind the strong effect produced by troglitazone on inflammatory markers when compared to other interventions, and whether the observed effects were related to the unique characteristics of these agents or simply a function of their ability to lower plasma glucose levels and improve insulin sensitivity. Troglitazone impact on inflammatory markers may be due its unique mechanism of action. TZDS, including troglitazone are strong activators of [PPAR.sub.[gamma]] (Qayyum et al., 2006; & Quinn et al., 2008). [PPAR.sub.[gamma]] ligands were proven to have strong effects on several other inflammatory markers through their ability to inhibit macrophage activation (Hevener et al., 2007; & Odegaard et al., 2007), interfere with smooth muscle proliferation (Ren et al., 201; & Law et al., 1996), and inhibit or downregulate important proinflammatory protein such cytokines and interleukins (Sigrist et al., 2000; & Ruan et al., 2003; & Fidan et al., 2011). All these actions were suggested pathways which may indirectly impact the levels of the inflammatory and coagulation markers studied in this preset analysis, other possibilities could possibly be due to direct actions of the TZDS on [PPAR.sub.[gamma]] (Samaha et al., 2006). Apparently, more in-depth research is needed to explain the mechanisms behind the TZDs action on these markers.

As previously indicated, our study showed marked elevation in the overall mean CRP levels (0.58 [+ or -] 0.03) in prediabetic individuals at baseline compared with healthy individuals, comparable to what was reported in previous research. A previous analysis in the same population studied in this report have reported on the elevated CRP and fibrinogen levels at baseline in ILs, metformin, and placebo arms, with the exclusion of troglitazone (Haffner et al., 2005; McMillan, 1981 Festa & D'Agostino et al., 2000; & Festa & D'Agostino et al., 1999). Our results as well as others may lead to the suggestion that improved vascular function brought by TZDs could possibly be related to their ability to suppress inflammation and coagulation markers, as suggested by previous reporting (Tousoulis et al., 2007; & Gada et al., 2013).

Elevated CRP and fibrinogen levels in African Americans at baseline were also observed by our analysis. This pattern agrees with what was shown in preceding research (Carroll et al., 2009; Lin et al., 2007; & Wee et al., 2008). In fact, different reports considered the elevation in the levels of CRP and fibrinogen among African Americans to be a possible explanation for the increased risk for CVDs in this population (Anuurad et al., 2008). Our findings, regarding the reduction in inflammatory and coagulation markers, further support the assumption that TZDs exerts their benefits on cardiovascular system by reducing these specific inflammatory markers, this extends to such at risk population as the African Americans. African American and Hispanic American are also reported to have higher rates of insulin resistance and obesity than other ethnicities; which elevates the risks for CVDs (Cossrow et al., 2004).

CONCLUSION

The association of prediabetes with CVDs and cardiovascular mortality was demonstrated in multiple research. CRP was shown as a valid marker for CVDs and the associated prognosis. Numerous research has gone further suggesting a greater role of CRP beyond its mere role as a marker of vascular and cardiovascular inflammation, to be considered a risk factor involved in the pathogenesis of atherosclerosis and other CVDs. The decrease in CRP levels demonstrated by our analysis was significantly greater than the effect of metformin or placebo as presented in the previous DPP study which analyzed the effect of ILS, metformin, and placebo on CRP levels in the same population studied in this present analysis, with the exception of troglitazone arm which was not included. The design and scope of this current did not allow us to determine the underlying mechanism behind the strong effect produced by troglitazone on inflammatory markers REFERENCES

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Khalid Mokthar and Elgenaid Hamadain

University of Mississippi Medical Center, Jackson, MS, USA
Table 1 Descriptive baseline characteristics (means [+ or -] standard
errors) in the inflammatory subgroup displayed by interventions

                       Placebo                 Troglitazone

n                      956                     291
Weight *               94 [+ or -] 0.72        95 [+ or -] 1.23
W.Cir **               105 [+ or -] 0.47       105 [+ or -] 0.83
HbAlc                  5.9 [+ or -] 0.02       5.8 [+ or -] 0.03
HOMA-IR                7.0 [+ or -] 0.13       6.8 [+ or -] 0.23
Fasting insulin        26.4 [+ or -] 0.47      25.0 [+ or -] 0.82
  ([micro]u/ml)
Fasting glucose        107.4 [+ or -] 0.25     109.0 [+ or -] 0.46
  (mg/dl)
Triglycerides mg/dL    167.3 [+ or -] 2.97     161.9 [+ or -] 6.2
CLDL mg/Dl             125.1 [+ or -] 1.07     122.4 [+ or -] 1.83
CRP (mg/dL) overall    0.59 [+ or -] 0.02      0.58 [+ or -] 0.05
Males n                311                     110
CRP                    0.31 [+ or -] 0.02      0.37 [+ or -] 0.08
females n              657                     183
CRP                    0.74 [+ or -] 0.03      0.72 [+ or -] 0.05
AA n                   203                     51
CRP                    0.71 [+ or -] 0.10      0.63 [+ or -] 0.10

                       Metformin               Lifestyle

n                      962                     962
Weight *               91 [+ or -] 0.67        87 [+ or -] 0.66
W.Cir **               105 [+ or -] 0.48       105 [+ or -] 0.49
HbAlc                  5.9 [+ or -] 0.02       5.9 [+ or -] 0.02
HOMA-IR                7.2 [+ or -] 0.13       7.0 [+ or -] 0.14
Fasting insulin        27.0 [+ or -] 0.48      26.5 [+ or -] 0.5
  ([micro]u/ml)
Fasting glucose        107.3 [+ or -] 0.25     107.0 [+ or -] 0.24
  (mg/dl)
Triglycerides mg/dL    159.1 [+ or -] 2.91     163.0 [+ or -] 3.1
CLDL mg/Dl             125.1 [+ or -] 1.04     126.2 [+ or -] 1.05
CRP (mg/dL) overall    0.58 [+ or -] 0.02      0.58 [+ or -] 0.02
Males n                345                     318
CRP                    0.31 [+ or -] 0.02      0.33 [+ or -] 0.03
females n              620                     650
CRP                    0.73 [+ or -] 0.03      0.70 [+ or -] 0.03
AA n                   209                     186
CRP                    0.69 [+ or -] 0.10      0.62 [+ or -] 0.10

* measured at 6 months from randomization ** measured at run-in visits
W Cir = Waist circumference

Table 2 Partial spearman correlation coefficients of baseline values
(P-values) of CRP, tPA, and fibrinogen with selected metabolic and
anthropometric variables (troglitazone arm) in the inflammatory
subgroup

        CRP         tPA         Fibr        W
                                            Cir*

CRP                 0.04        0.53        0.25
                    (NS)        (<0.001)    (<0.001)

tPA     0.04                    0.13        0.20
        (NS)                    (0.04)      (0.001)

Fibr    0.53        0.13                    0.31
        (<0.001)    (0.04)                  (<0.001)

        FSG         FSI         HOM         HBA1
                                A-IR        c

CRP     0.22        0.05        0.22        0.07
        (<0.001)    (NS)        (<0.001)    (NS)

tPA     0.22        0.16        0.23        0.12
        (<0.001)    (0.006)     (<0.001)    (0.04)

Fibr    0.16        0.11        0.18        0.22
        (0.006)     (NS)        (0.003)     (<0.001)

        Weight      TRI         CH          CL
        **          G           O           DL

CRP     0.27        0.03        0.02        0.10
        (<0.001)    (NS)        (NS)        (NS)

tPA     0.22        0.13        0.4         0.04
        (<0.001)    (0.03)      (NS)        (NS)

Fibr    0.26        -0.03       0.08        0.10
        (<0.001)    (NS)        (NS)        (NS)

        UCR         UAL         SCr         eGF
        E           B                       R

CRP     0.10        0.17        0.16        0.05
        (NS)        (0.004)     (0.009)     (NS)

tPA     0.09        0.14        0.01        0.01
        (NS)        (0.2)       (NS)        (NS)

Fibr    0.02        0.09        0.16        0.01
        (NS)        (NS)        (0.007)     (NS)

CRP= C-Reactive Protein (mg-dL), Fibr = Fibrinogen, tPA = Tissue
Plasminogen Activator (ng-dL), W Cir = Waist Circumference (cm), FSG=
Fasting Serum Glucose (mg-dL), FSI = Fasting Serum Insulin (micro
units-mL), HOMA-IR = Homeostasis Model Assessment for Insulin
Resistance, HBA1c = Glycosylated Hemoglobin Type A1C (%), TRIG =
Triglycerides (mg-dL), CHO = Total Cholesterol (mg-dL), CLDL = Low
Density Lipoprotein Subfraction (mg-dL), UALB = Urine Albumin (mg-
dL), SCr = Serum Creatinine (mg-dL), eGFR = Estimated Glomerular
Filtration Rate * waist Circumference was measured at run-in visits
per DPP study ** weight was measured at 6 months visits

Table 3 Partial spearman correlation coefficient of baseline (P-
values) for CRP, tPA, and fibrinogen with selected metabolic and
anthropometric variables in the inflammatory subgroup adjusted for
age, sex, and ethnicity

        CRP         tPA         Fibr        W Cir*

CRP                 0.07        0.49        0.29
                    NS)         (<0.001)    (<0.001)

tPA     0.07                    0.17        0.21
        (NS)                    (0.005)     (<0.001)

Fibr    0.49        0.17                    0.35
        (<0.001)    (0.005)                 (<0.001)

        FSG         FSI         HOMA-       HBA1c
                                IR
CRP     0.18        0.05        0.18        0.09
        (0.003)     (NS)        (0.003)     (NS)

tPA     0.24        0.16        0.26        0.12
        (<0.001)    (<0.001)    (<0.001)    (0.05)

Fibr    0.14        0.12        0.15        0.25
        (0.02)      (0.05)      (0.01)      (<0.001)

        Weight **   TRIG        CHOL        CLDL

CRP     0.29        0.06        0.003       -0.001
        (<0.001)    (NS)        (NS)        (NS)

tPA     0.25        0.13        0.17        0.03
        (<0.001)    (0.04)      (0.004)     (NS)

Fibr    0.28        0.003       0.08        0.11
        (<0.001)    (NS)        (NS)        (NS)

        UCRE        UALB        CREA        eGFR

CRP     0.12        0.21        0.02        0.03
        (0.05)      (<0.001)    (NS)        (NS)

tPA     0.08        0.13        0.07        -0.01
        (NS)        (0.03)      (NS)        (NS)

Fibr    0.06        0.11        0.01        0.02
        (NS)        (NS)        (NS)        (NS)

CRP = C-Reactive Protein (mg-dL), Fibr = Fibrinogen, tPA = Tissue
Plasminogen Activator (ng-dL), W Cir = Waist Circumference (cm), FSG=
Fasting Serum Glucose (mg-dL), FSI = Fasting Serum Insulin (micro
units-mL), HOMA-IR = Homeostasis Model Assessment for Insulin
Resistance, HBA1c = Glycosylated Hemoglobin Type A1C (%), TRIG =
Triglycerides (mg-dL), CHOL = Total Cholesterol (mg-dL), CLDL = Low
Density Lipoprotein Subfraction (mg-dL), UALB = Urine Albumin (mg-
dL), SCr = Serum Creatinine (mg-dL), eGFR = Estimated Glomerular
Filtration Rate * waist Circumference was measured at run-in visits
per DPP study ** weight was measured at 6 months visits

Table 4 Mean changes [+ or -] SE (P-values) of selected variables from
baseline for the overall DPP population by interventions

change           Placebo                    Troglitazone

n                962                        527
Weight (a)       0.34 [+ or -] 1.01 (ns)    *** 3.22 [+ or -] 2.33 (ns)

W Cir (b)        -0.97 [+ or -] 0.71        **** -1.61 [+ or -] 1.71
                 (ns)                       (ns)
HbAlc            0.09 [+ or -] 0.01         0.02 [+ or -] 0.02 (ns)

HOMA-IR          0.35 [+ or -] 0.15         -1.22 [+ or -] 0.16
                 (0.02)
Fasting          0.88 [+ or -] 0.53 (ns)    -4.06 [+ or -] 0.58
insulin
([micro]u/ml)
Fasting          0.28 [+ or -] 0.44 (ns)    -4.10 [+ or -] 0.52
glucose
(mg/dl)
Triglycerides    -8.75 [+ or -] 2.34        -27.28 [+ or -] 3.88
mg/dL
CLDL mg/dL       -1.97 [+ or -] 0.78        1.10 [+ or -] 1.07 (ns)
cholesterol      -3.70 [+ or -] 0.85        -2.61 [+ or -] 1.2 (0.03)

change           Metformin               Lifestyle

n                958                     961
Weight (a)       0.22 [+ or -] 0.96      -0.28 [+ or -] 0.9 (ns)
                 (ns)
W Cir (b)        -2.12 [+ or -] 0.67     -6.8 [+ or -] 0.71

HbAlc            0.01 [+ or -] 0.02      -0.09 [+ or -] 0.01
                 (ns)
HOMA-IR          -1.19 [+ or -] 0.12     -1.58 [+ or -] 0.15

Fasting          -3.60 [+ or -] 0.41     -5.24 [+ or -] 0.53
insulin
([micro]u/ml)
Fasting          -4.52 [+ or -] 0.34     -5.29 [+ or -] 0.35
glucose
(mg/dl)
Triglycerides    -5.34 [+ or -] 2.16     -25.78 [+ or -] 2.29
mg/dL            (0.01)
CLDL mg/dL       -4.52 [+ or -] 0.75     -6.13 [+ or -] 0.75
cholesterol      -5.0 [+ or -] 0.82      -9.84 [+ or -] 0.83

All p values are < 0.01 except when indicated in parenthesis(a) weight
differences at 1 year from 6 months after randomization (b) waist
circumference was taken at run-in visits (visits taking place after
screening visit and prior to randomization n number of participants, *
n = 165, ** n = 285, *** n=218, and **** n = 274 W Cir= Waist
Circumference

Table 5 Partial spearman collations of year 1 changes from baseline
(P-values) in the inflammatory and coagulation markers with metabolic
and renal variables (troglitazone intervention) in the inflammatory
subgroup

        CRP        tPA        Fibr       W Cir*     FSG

CRP     1.0        --         0.50       0.04       -0.11
                   0.05       (0.04)     (NS)       (NS)
                   (NS)
tPA     -0.05      1.0        -0.13      0.41       0.52
        (NS)                  (NS)       (NS)       (0.05)
Fibr    0.53       --         1.0        --         -0.23
        (0.04)     0.13                  0.09       (NS)
                   NS)                   (NS)

        FSI        HOMA-IR    HBA1c      Weight **    TRIG

CRP     -0.31      -0.12      -0.22      0.14 (NS)    -0.5
        (NS)       (NS)       (NS)                    (NS)

tPA     0.62       0.55       0.34       0.53         0.08
        (0.01)     (0.04)     (NS)       (0.04)       (NS)
Fibr    -0.31      -0.23      0.34       0.09 (NS)    -0.65
        (NS)       (NS)       NS)                     (0.009)

        CLDL       CREA       eGFR       ACR

CRP     0.5        0.10       -0.07      0.5
        (NS)       (NS)       (NS)       (0.05)

tPA     -0.19      0.54       0.42       0.06
        NS)        (0.04)     (NS)       NS)
Fibr    0.3        0.19       0.06       0.66
        (NS)       (NS)       (NS)       (0.008)

CRP = C/Reactive Protein (mg/dL), Fibr= Fibrinogen, tPA = Tissue
Plasminogen Activator (ng/dL), W Cir = Waist Circumference (cm), FSG=
Fasting Serum Glucose (mg/dL), FSI = Fasting Serum Insulin (micro
units/mL), HOMA/IR = Homeostasis Model Assessment for Insulin
Resistance, HBA1c = Glycosylated Hemoglobin Type A1C (%), TRIG =
Triglycerides (mg/dL), CLDL = Low Density Lipoprotein Subfraction (mg/
dL), UALB = Urine Albumin (mg/dL), SCr = Serum Creatinine (mg/dL)

* waist Circumference was measured at run-in visits per DPP study **
weight was measured at 6 months visits per DPP study

Table 6 Partial spearman correlations of year 1 changes from baseline
(P-values) in the inflammatory and coagulation markers with metabolic
and renal variables (troglitazone intervention) in the inflammatory
subgroup adjusted for age, sex, and ethnicity

        CRP       tPA       Fibr      W         FSG
                                      Cir*

CRP     1.0       0.04      0.3       --        -.22
                  (NS)      (NS)      0.12      (NS)
                                      (NS)

tPA     0.04      1.0       --        0.23      0.49
        (NS)                0.01      (NS)      (NS)
                            (NS)

Fibr    0.3       --        1.0       --        -.33
        (NS)      0.01                0.17      (NS)
                  (NS)                (NS)

        FSI       HOMA-     HBA1c     Weight*   TRIG
                  IR

CRP     -0.36     -0.27     -0.33     0.07      -0.4
        (NS)      (NS)      (NS)      (NS)      (NS)

tPA     0.58      0.5 (NS)  0.49      0.35      0.04
        (0.05)              (NS)      (NS)      (NS)

Fibr    -0.30     -0.33     .037      0.12      -0.59
        (NS)      (NS)      (NS)      (NS)      (0.04)

        CLDL      SCr       eGFR      ACR

CRP     0.4       -0.13     0.27      0.59
        (NS)      (NS)      (NS)      (0.04)

tPA     0.49      -0.69     0.58      0.04
        (NS)      (0.01)    (0.05)    (NS)

Fibr    0.14      0.6       0.27      0.75
        (NS)      (NS)      (NS)      (0.005)

CRP = C/Reactive Protein (mg/dL), Fibr= Fibrinogen, tPA = Tissue
Plasminogen Activator (ng/dL), W Cir = Waist Circumference (cm), FSG=
Fasting Serum Glucose (mg/dL), FSI = Fasting Serum Insulin (micro
units/mL), HOMA-IR = Homeostasis Model Assessment--for Insulin
Resistance, HBA1c = Glycosylated Hemoglobin Type A1C (%), TRIG =
Triglycerides (mg/dL), CLDL = Low Density--Lipoprotein Subfraction
(mg/dL), UALB = Urine Albumin (mg/dL), SCr = Serum Creatinine (mg/dL)

* waist Circumference was measured at run-in visits per DPP study

** weight was measured at 6 months visits per DPP study

Figure 1 presents the mean changes in CRP levels after 1 year of
follow-up. * statistically non-significant (P value is <0.05 for all
other values)

Placebo           0.02* [+ or -] 0.2
Troglitazone      -0.14 [+ or -] 0.04
Metformin         -0.06 [+ or -] 0.02
Lifestyle         -0.13 [+ or -] 0.02

Note: Table made from bar graph.

Figure 2 Median percent change in
overall CRP levels after 1 year of
treatment with troglitazone

CRP- Overall

Placebo         -29.6
Troglita zone   -20
Metfor min      -12.8
Lifestyle         0

Note: Table made from pie chart.

Figure 3 Median percent change in
overall CRP levels in men after 1 year
of treatment with troglitazone

CRP-Men

Troglitazone    4.64
Placebo         5
Metformin      -7
Lifestyle      -33

Troglitazone

Note: Table made from pie chart.

Figure 4 Median percent change in
overall CRP levels in women after 1
year of treatment with troglitazone

Crp-Women

Troglitazone   -27
Placebo        -29
Metformin      -14
Lifestyle       0

Note: Table made from pie chart.
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Author:Mokthar, Khalid; Hamadain, Elgenaid
Publication:Journal of the Mississippi Academy of Sciences
Article Type:Report
Date:Apr 1, 2018
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