The Long-term Effects of Rosiglitazone on Serum Lipid Concentrations and Body Weight

Wan Sub Shim; Mi Young Do; Soo Kyung Kim; Hae Jin Kim; Kyu Yeon Hur; Eun Seok Kang; Chul Woo Ahn; Sung Kil Lim; Hyun Chul Lee; Bong Soo Cha

Clin Endocrinol. 2006;65(4):453-459. 

Summary and Introduction

Summary

Objective: Although rosiglitazone, an insulin sensitizer, is known to have beneficial effects on high density lipoprotein cholesterol (HDL-C) concentrations and low density lipoprotein (LDL) particle size, it has unwanted effects on total cholesterol (TC) and LDL cholesterol (LDL-C) concentrations and body weight in some short-term studies. The aim of this study was to evaluate the long-term effects of rosiglitazone on serum lipid levels and body weight.
Design: Open labelled clinical study.
Patients and Measurements: We prospectively evaluated fasting serum glucose, haemoglobin A1c (HbA1c), lipid profiles and body weight at baseline and every 3 months after the use of rosiglitazone (4 mg/day) for 18 months in 202 type 2 diabetic patients.
Results: TC levels increased maximally at 3 months and decreased thereafter. However, overall, TC levels remained significantly higher at 18 months than those at baseline. LDL-C levels from the 3-month to the 12-month timepoint were significantly higher than those at baseline. However, after 15 months, LDL-C concentrations were not significantly different from basal LDL-C concentrations. HDL-C levels increased after the first 3 months and these levels were maintained. The increment of change in HDL-C was more prominent in patients with low basal HDL-C concentrations than in patients with high basal HDL-C concentrations. Body weight increased after the first 3 months and these levels were maintained.
Conclusions: HDL-C and body weight increased and remained elevated for the duration of the study. There was an initial increase in LDL-C but this attenuated and by the end of the study was not significantly elevated above baseline levels.

Introduction

Thiazolidinediones (TZDs) are oral antihyperglycaemic agents that reduce insulin resistance (IR) in peripheral tissues and decrease hepatic glucose production.[1] TZDs are potent, synthetic ligands for peroxisome proliferator-activated receptor gamma (PPAR-γ), which mediates physiological responses by altering the transcription of genes that regulate glucose and lipid metabolism.[2,3]

TZDs provide many benefits to patients with type 2 diabetes by improving glycaemic control and insulin sensitivity, thereby having the potential to decrease the risk of cardiovascular disease (CVD) associated with IR.[4,5] TZDs are known to increase high density lipoprotein cholesterol (HDL-C) concentrations,[6] low density lipoprotein (LDL) particle size,[7] and LDL cholesterol (LDL-C) resistance to oxidation.[8] In addition, TZDs decrease intima-media thickness[9] and prevent re-stenosis after coronary stent implantations.[10] These nonhypoglycaemic effects of TZD are thought to potentially decrease the risk of CVD. Some studies have reported the unwanted effects of rosiglitazone on the levels of total cholesterol (TC) and LDL-C concentrations[6] and also on body weight.[11] However, these studies are limited because of short-term patient follow-up.[11-13] The long-term effects of TZDs are of particular interest because patients often use these drugs as a continuous therapy. The aim of this study was to evaluate the long-term effects of rosiglitazone on serum lipid levels and body weight in type 2 diabetic patients.

Research Design and Methods

Study Subjects

A total of 202 type 2 diabetic patients who were currently using oral hypoglycaemic agents or insulin treatments and who had added rosiglitazone (4 mg/day) between January 2001 and September 2003 were enrolled in this study at Severance Hospital, Yonsei University Medical Centre. At the beginning of the study, 97% of the patients had used oral hypoglycaemic agents and 3% of the patients had used insulin for their treatment. During the study period, four patients started to use statin and two patients started to use fibrate. However, we included only the data collected from these patients before the statin or fibrate were used. The Ethics Committee of Yonsei University College of Medicine, Seoul, approved this study, and informed consent was obtained from all subjects.

Methods

Height and weight were measured to the nearest 0·1 cm and 0·1 kg, respectively. Subjects were allowed to wear light clothing but were not permitted to wear shoes during measurement. Body mass index (BMI) was calculated as weight (kg) divided by height squared (m2). Blood samples were collected after 12 h of fasting. Fasting glucose level was measured with the glucose oxidase method. Haemoglobin A1c (HbA1c) was analysed by high-performance liquid chromatography (Variant II; Bio-Rad, Hercules, CA, USA; coefficient of variation (CV) = 2·1%). Insulin concentration was measured by immunoradiometric assay (RIABEAD II kit, Abbott, Japan; intra-assay CV = 1·2-1·9%, interassay CV = 1·4-3·3%). Serum TC, HDL-C and triglyceride concentrations were measured using an autoanalyser (Hitachi 7150, Hitachi Ltd, Tokyo, Japan) and an enzymatic colorimetric method. In the cases when triglyceride levels were lower than 4·5 mmol/l, LDL-C concentrations were calculated using the Friedewald formula:[14]

LDL-C = [total cholesterol − HDL-C − triglyceride/5]

Insulin resistance was calculated using the homeostasis model assessment (HOMA) with the following formula:[15]

HOMA-IR = [fasting insulin (µU/ml) × fasting serum glucose (mmol/l)/22·5]

Postprandial glucose concentrations were measured 2 h after a meal. The atherogenic index of plasma (AIP), which negatively correlates well with LDL particle size, was calculated using the following formula:[16]

AIP = log[triglyceride (mmol/l)/HDL-C (mmol/l)]

In the study population, rosiglitazone (4 mg) was added to the treatment regimen of patients who were currently using oral hypoglycaemic agents or insulin.

Fasting glucose, postprandial glucose at 2 h, HbA1c, TC, HDL-C, triglyceride concentration and body weight were measured 3, 6, 9, 12, 15 and 18 months after the addition of rosiglitazone by the methods described above.

During the study period, 99 patients (49%) had no change in their use of hypoglycaemic agents and 53 patients (26%) decreased their use of hypoglycaemic agents. Twenty-eight patients (14%) increased their use of hypoglycaemic agents. Twenty-two patients (11%) increased their use of some hypoglycaemic agents and also decreased their use of some hypoglycaemic agent other than rosiglitazone.

Statistical Analysis

Statistical analyses were performed using SPSS version 11·0 (SPSS Inc, Chicago, IL, USA). All continuous variables were expressed as the mean ± standard deviation except HOMA-IR, which was expressed as median (interquartile range). Insulin, triglyceride and HOMA-IR values were log-transformed to accommodate any skewing of the distribution.

Values measured every 3 months were compared with the values measured at the baseline, 3-month and 6-month timepoints by using a paired t-test. Values measured every 3 months minus the values measured at baseline were compared to each other by using a paired t-test. The patients were divided into two groups classified by basal HDL-C concentration. Cutoff points were chosen according to the ATP-III criteria for metabolic syndrome,[17] for the comparison of HDL-C concentrations, which were measured every 3 months. One group included patients with baseline HDL-C values < 1·03 mmol/l in males and < 1·29 mmol/l in females, while the other group included patients with HDL-C values ≥ 1·03 mmol/l in males and ≥ 1·29 mmol/l in females. The patients were divided into two groups classified into median initial AIP values for comparison of AIP values, which were calculated every 3 months. One group included patients with baseline AIP values ≥ 0·127, while the other group included patients with baseline AIP values < 0·127. These comparisons were made using the independent sample t-test. HDL-C values and AIP values taken every 3 months minus the HDL-C value and AIP values taken at baseline were compared using an independent sample t-test according to the group classification that was determined by the baseline HDL-C and AIP values, respectively. A two-sided value of P < 0·05 was considered to be statistically significant.

Results

Clinical Characteristics of the Subjects

A total of 202 patients (129 males, 73 females) were enrolled in this study. The mean patient age was 53·8 ± 10·3 years, the duration of the diabetes was 5·9 ± 5·6 years, BMI was 25·3 ± 2·9 kg/m2, HOMA-IR was 2·39 (1·28-3·80), the fasting glucose concentration was 8·76 ± 2·77 mmol/l, HbA1c was 7·78 ± 1·53%, TC concentration was 4·66 ± 0·74 mmol/l, triglyceride concentration was 1·70 ± 0·84 mmol/l, HDL-C was 1·14 ± 0·28 mmol/l, and LDL-C was 2·74 ± 0·70 mmol/l.

Change in Body Weight, BMI, Fasting Glucose, Postprandial Glucose, HbA1c and AIP Values After Rosiglitazone Treatment

Rosiglitazone increased body weight and BMI 3 months after the start of treatment, and the effect continued to 18 months. Fasting glucose, postprandial glucose and HbA1c values from the 3-month until the 18-month timepoint after the start of rosiglitazone use were lower than those at baseline. AIPs from the 15-18-month timepoints were significantly lower than those from the baseline to the 3-month timepoints. AIPs at the 15-month timepoint were significantly lower than those at 6 months ( ).

Table 1.  Changes in Body Weight, BMI, Fasting Glucose, PP 2 h Glucose, HbA1cand AIP After Rosiglitazone Treatment

  Baseline 3 months 6 months 9 months 12 months 15 months 18 months
Weight (kg)  68·1 ± 10·5  68·9 ± 10·6*  68·8 ± 10·6*  69·5 ± 10·8*  68·9 ± 9·8*  68·8 ± 9·7*  69·2 ± 9·7*
BMI (kg/m2)  25·1 ± 2·9  25·4 ± 3·0*  25·5 ± 3·0*  25·6 ± 3·0*  25·5 ± 3·0*  25·4 ± 2·9*  25·6 ± 2·9*
Fasting glucose (mmol/l)  8·76 ± 2·77  7·65 ± 2·17*  7·54 ± 2·03*  7·37 ± 1·98*  7·33 ± 1·85*  7·35 ± 1·83*  7·37 ± 2·04*
PP 2 h glucose (mmol/l) 13·00 ± 5·16 10·99 ± 4·22* 11·17 ± 4·02* 10·98 ± 3·97* 10·53 ± 3·83* 10·46 ± 3·85* 10·69 ± 4·03*
HbA1c(%)  7·78 ± 1·53  7·45 ± 1·18*  7·35 ± 1·23*  7·30 ± 1·23*  7·18 ± 1·10*  7·24 ± 1·30*  7·30 ± 1·36*
AIP 0·141 ± 0·257 0·132 ± 0·300 0·124 ± 0·302 0·111 ± 0·277 0·120 ± 0·286 0·065 ± 0·308*†‡ 0·068 ± 0·251*†
TC/HDL-C  4·30 ± 1·10  4·40 ± 1·22*  4·36 ± 1·21  4·23 ± 1·19†‡  4·25 ± 1·23†‡  4·03 ± 1·16*†‡  4·16 ± 1·26†‡
LDL-C/HDL-C  2·55 ± 0·90  2·60 ± 0·90  2·60 ± 0·91  2·50 ± 0·86†‡  2·49 ± 0·89†‡  2·37 ± 0·87*†‡  2·39 ± 0·88†‡

 

Data are expressed as means ± standard deviation.
BMI, body mass index; PP, postprandial; HbA1c, haemoglobin A1c; AIP, atherogenic index of plasma [log (triglyceride/HDL-C)]; TC, total cholesterol; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol.
*P < 0·05 vs. baseline. †P < 0·05 vs. 3rd month. ‡P < 0·05 vs. 6th month.

Change in Lipid Profiles After Rosiglitazone Use

Total cholesterol values from 3 months until 18 months after the beginning of rosiglitazone use were higher than those at baseline. Total cholesterol values from 12 to 18 months after the beginning of rosiglitazone use were significantly lower than those at the 3-month timepoint. Total cholesterol values from 15 to 18 months after the use of rosiglitazone began were significantly lower than those values at 6 months.

LDL-C values of the 3- and 12-month timepoints were higher than those at baseline, but LDL-C values from the 15-month to the 18-month timepoints were not higher than baseline values. LDL-C values from the 12-18-month timepoints were lower than 3- and 6-month values.

HDL-C values from the 3-month to the 18-month timepoints were higher than those at baseline. HDL-C values at the 15-month timepoint were higher than those from the 3- and 6-month timepoints.

Triglyceride values from the 3-month until the 18-month timepoint were not significantly different from those at baseline. However, triglyceride values at the 18-month timepoint were lower than those at the 3-month timepoint (Fig. 1).

Figure 1.

 

Changes in lipid profiles after rosiglitazone usage: (a) total cholesterol; (b) low density lipoprotein cholesterol (LDL-C); (c) high density lipoprotein cholesterol (HDL-C); (d) triglyceride. *P > 0·05 vs. baseline; †P < 0·05 vs. 3rd month; ‡P < 0·05 vs. 6th month.

Changes in Delta Lipid Profiles

Delta TC and LDL-C values, defined as the value at each respective month minus the baseline value, were significantly lower at 12, 15 and 18 months than at the 3-month timepoint. Delta HDL-C values at the 3-month timepoint were significantly lower than those at the 15-month timepoint. Delta triglyceride values at the 3-month timepoint were significantly higher than those at the 18-month timepoint. Delta TC/HDL-C and delta LDL-C/HDL-C ratios at the 3-month timepoints were significantly higher than those at 9, 12, 15 and 18 months ( ).

Table 2.  Delta Values of Lipid Profiles After Rosiglitazone Use

  3 months 6 months 9 months 12 months 15 months 18 months
Delta TC (mmol/l) 0·37 ± 0·67 0·31 ± 0·69  0·28 ± 0·74  0·26 ± 0·73*  0·17 ± 0·76*  0·15 ± 0·75*
Delta LDL-C (mmol/l) 0·25 ± 0·65 0·22 ± 0·67  0·17 ± 0·72  0·12 ± 0·68*  0·09 ± 0·66*  0·07 ± 0·66*
Delta HDL-C (mmol/l) 0·06 ± 0·21 0·06 ± 0·18  0·08 ± 0·21  0·08 ± 0·21  0·11 ± 0·24*  0·08 ± 0·24
Delta triglyceride (mmol/l) 0·12 ± 0·92 0·09 ± 0·98  0·04 ± 1·00  0·11 ± 0·95  0·00 ± 0·99 −0·02 ± 0·90*
Delta TC/HDL-C 0·14 ± 0·81 0·07 ± 0·80 −0·04 ± 0·87* −0·06 ± 0·86* −0·19 ± 0·94* −0·08 ± 0·93*
Delta LDL-C/HDL-C 0·09 ± 0·66 0·07 ± 0·71 −0·02 ± 0·74* −0·07 ± 0·74* −0·12 ± 0·74* −0·12 ± 0·77*

 

Data are expressed as means ± standard deviation.
TC, total cholesterol; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol.
Delta values are defined as the value at each respective month minus the baseline value.
*P < 0·05 vs. 3rd month.

Change in HDL-C Concentrations According to the Baseline HDL-C Concentrations

The baseline HOMA-IR was higher in the group with lower baseline HDL-C values than in the group with higher baseline HDL-C [2·56 (1·39-4·29) vs. 2·25 (1·00-3·26), group 1 vs. group 2, median (interquartile range), respectively, P < 0·05)]. The increment of HDL-C concentrations after the start of rosiglitazone use was more prominent in the group with lower baseline HDL-C values (< 1·03 mmol/l in males and < 1·29 mmol/l in females) than in the group with higher baseline HDL-C values (> 1·03 mmol/l in males and > 1·29 mmol/l in females) ( ).

Table 3.  HDL-C Levels and the Delta HDL-C Values According to Basal HDL-C Levels After Rosiglitazone Use

  Baseline 3 months 6 months 9 months 12 months 15 months 18 months
HDL-C (mmol/l) Group 1 (n = 106) 0·95 ± 0·16*  1·06 ± 0·25* 1·05 ± 0·23* 1·09 ± 0·20* 1·07 ± 0·21* 1·12 ± 0·22* 1·07 ± 0·21*
Group 2 (n = 96) 1·34 ± 0·23  1·33 ± 0·25 1·35 ± 0·26 1·35 ± 0·29 1·38 ± 0·26 1·41 ± 0·32 1·38 ± 0·33
Delta HDL-C (mmol/l) Group1 (n = 106)    0·11 ± 0·18* 0·10 ± 0·15* 0·14 ± 0·15* 0·12 ± 0·17* 0·15 ± 0·18* 0·11 ± 0·15*
Group 2 (n = 96)   −0·01 ± 0·21 0·01 ± 0·20 0·01 ± 0·25 0·04 ± 0·24 0·07 ± 0·28 0·03 ± 0·29

 

HDL-C, high-density lipoprotein cholesterol; Delta HDL-C, the HDL-C value at the respective time minus the HDL-C value at baseline.
Group 1: HDL-C < 1·03 mmol/l in males, < 1·29 mmol/l in females. Group 2: HDL-C ≥ 1·03 mmol/l in males, ≥ 1·29 mmol/l in females.
*P < 0·05 group 1 vs. group 2.

Change in AIP Values According to the Baseline AIP Values

The decrement of AIP values after the start of rosiglitazone use was more prominent in the group with higher baseline AIP values (> 0·127) than in the group with lower baseline AIP values (< 0·127) after 6 months ( ).

Table 4.  AIP Levels and Delta AIP Values with Respect to Basal AIP Levels After Rosiglitazone Use

  Baseline 3 months 6 months 9 months 12 months 15 months 18 months
AIP
  Group 1 −0·060 ± 0·156* −0·054 ± 0·231* −0·045 ± 0·235* −0·035 ± 0·245* −0·031 ± 0·233* −0·105 ± 0·271* −0·052 ± 0·234*
  Group 2  0·346 ± 0·156  0·325 ± 0·238  0·289 ± 0·270  0·261 ± 0·226  0·272 ± 0·254  0·246 ± 0·236  0·198 ± 0·200
Delta AIP
  Group 1    0·010 ± 0·204  0·017 ± 0·206*  0·026 ± 0·227*  0·025 ± 0·223* −0·044 ± 0·261  0·013 ± 0·223*
  Group 2   −0·025 ± 0·240 −0·057 ± 0·261 −0·089 ± 0·247 −0·072 ± 0·233 −0·083 ± 0·231 −0·124 ± 0·200

 

AIP, atherogenic index of plasma [log(triglyceride/HDL-C)]; delta AIP, the AIP value at the respective time minus the AIP value at baseline.
Group 1: AIP < 0·127. Group 2: AIP ≥ 0·127.
*P < 0·05 group 1 vs. group 2.

Discussion

Rosiglitazone not only decreases serum glucose levels but also alters serum lipid levels. As patients with type 2 diabetes have approximately a two- to fourfold increase in the risk of coronary artery disease,[18,19] determining the effects of rosiglitazone on lipid levels in diabetic patients is important. In particular, the long-term effects of rosiglitazone on lipid profiles are of interest because patients often use them as continuous therapy. However, most studies on the effects of rosiglitazone on lipid profiles have been limited by the short duration of follow-up, which is usually terminated within 24 weeks of treatment onset.[13] Only a few studies have looked at the effects of rosiglitazone on lipid profiles for more than a 1-year period.[20,21] The study by Gegick and Altheimer[20] was limited by the relatively small number of patients involved (only 49 patients) and the small number of timepoints (only two sequential datapoints, 3·1 and 12·6 months). The study by Derosa et al.[21] was also limited by the small study size (42 patients) and by the fact that after discontinuation of currently used oral hypoglycaemic agents, glimepiride and rosiglitazone were both administered initially at the beginning of the study rather than adding rosiglitazone to patients currently using oral hypoglycaemic agents. By contrast, our study has the strength of a large study as data were collected from 202 patients. In addition, our dataset was very broad, with lipid profiles measured at 3-month intervals for 18 months. This study design has enabled us to determine the long-term effects of rosiglitazone on lipid profiles.

This study demonstrated that TC levels peaked at 3 months and decreased thereafter, although the levels were still significantly higher at 18 months compared to those at baseline. We also demonstrated that LDL-C levels from the 3-month to the 12-month timepoints were significantly higher than those at baseline, but after 15 months, LDL-C concentrations werenot significantly different from the basal LDL-C concentrations. Furthermore, our results show that TC and LDL-C concentrations at the 3- and 6-month timepoints were higher than those at baseline, which is consistent with the results of a meta-analysis that included 24-week studies.[13] However, our results that show that TC and LDL-C concentrations at the 12-month timepoint were higher than those at baseline are somewhat different from previous results that show no significant difference between 12-month and baseline TC and LDL-C values.[20] A reason for the discrepancy between these two studies is that our study had the statistical power to discriminate small differences in values as we included more patients (202 patients) than the previous study (49 patients).

HDL-C concentrations from the 3-month to the 18-month timepoints were higher than those at baseline in our study. This result is consistent with the results of previous studies.[13] Our results are also consistent with a previous study[19] that showed that HDL-C concentrations 12 months after the start of rosiglitazone use were higher than at baseline.

Rosiglitazone not only can have effects on the lipid concentration but also can alter the lipid profile quality.[22] In this study, we could not directly measure LDL particle diameter. Instead, AIP levels, which negatively correlate well with LDL particle diameter,[16] were significantly lower at the 15- and 18-month timepoints than at baseline and at the 3-month timepoint. This suggests that LDL particle diameters are increased after treatment with rosiglitazone. Our results are consistent with the results of another study that showed a phenotypic change from small, dense to large, buoyant LDL particles.[22] This study shows that the decrement in AIP values after rosiglitazone use was more prominent in the group with higher baseline AIP values than in the group with lower baseline AIP values. These suggest that the phenotypic changes from small, dense to large, buoyant LDL were more prominent in patients with high basal AIP, who have a high risk of CVD.

Our study also shows that the increment in HDL-C concentrations was more prominent in patients with low basal HDL-C concentrations than in patients with high basal HDL-C concentrations. HDL-C concentrations after rosiglitazone treatment were increased to a greater extent in the patients who had an HDL < 0·91 mmol/l at baseline.[20] These results suggest that the increment in HDL-C concentrations caused by rosiglitazone treatment was more prominent in patients with low basal HDL-C who have a high risk of CVD. This study shows that the IR in patients with low basal HDL-C, who subsequently had a greater degree of increase in HDL-C, was greater than in patients with high basal HDL-C concentration. IR appears to underlie the majority of cases of low HDL in humans.[23,24] An improvement in the HOMA index was seen at 9 and 12 months after rosiglitazone use.[25] These sustained improvements in IR, although IR was not measured serially in this study, may be related to sustained increment in HDL-C after rosiglitazone use.

Clinical trials have demonstrated that TZD treatment may be associated with weight gain.[1,26,27] Obesity is associated with IR and contributes to the development of other comorbidities. Optimal body weight maintenance is the mainstay of diabetes treatment. Thus, patients and physicians are concerned about weight gain associated with TZD use. However, the increases in body weight that are linked to TZD use are positively correlated with reductions in HbA1c.[26] Treatment with TZDs improves insulin sensitivity and favourably alters fat distribution in patients with type 2 diabetes.[28] The clinical meaning of weight gain with TZD treatment is uncertain. Possible causes of weight gain with TZD are elimination of glycosuria (retention of calories), fluid retention and fat cell proliferation.[29] Body weight from the 3-month to the 18-month timepoints after starting rosiglitazone treatment were higher than the weights at baseline in our study. However, we found no further change in body weight after 3 months. This is consistent with the results of a study of troglitazone that showed that weight gain stabilized 12-20 weeks after troglitazone treatment with no further change.[26]

Our study had the limitation that no comparison was made with a control group. Another limitation of our study was that six patients used a hypolipidaemic agent, such as statin or fibrate, during the study period. It is possible that the use of such hypolipidaemic drugs can affect the results of this study. However, this study included only data obtained before the use of statin or fibrate, and in addition, only 3% of the study population used statin or fibrate. Therefore, it is unlikely that the results were affected by statin or fibrate use. Finally, this study includes only Korean type 2 diabetic patients, who are lean relative to other populations. More studies are required to determine whether the conclusion of this study can be applied to other populations whose BMI at baseline is much higher than that of this study.

In summary, we have demonstrated the effect of rosiglitazone on the lipid profile, glycaemic control and body weight for 18 months in 202 patients. TC levels peaked at 3 months and decreased thereafter, but remained significantly higher than the levels measured at baseline. LDL-C levels from the 3-month to the 12-month timepoints were higher than at baseline, but LDL-C levels from the 15-month to the 18-month timepoints were not different from baseline. HDL-C levels from the 3-month to the 18-month timepoints were higher than that at baseline. The increase in HDL-C concentrations was more prominent in the group with low basal HDL-C levels than in the group with high basal HDL-C levels. Body weight increased during the study period, but stabilized after 3 months. In conclusion, HDL-C and body weight increased and remained elevated for the duration of the study. There was an initial increase in LDL-C but this attenuated and by the end of the study was not significantly elevated above baseline levels. Overall, the TC/HDL ratio initially increased but then decreased below baseline levels with longer-term treatment with rosiglitazone.


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