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Review Article |

A Meta-analysis Comparing the Effect of Thiazolidinediones on Cardiovascular Risk Factors FREE

Elaine Chiquette, PharmD; Gilbert Ramirez, PhD; Ralph DeFronzo, MD
[+] Author Affiliations

Affiliations: University of Texas Health Science Center at San Antonio (Drs Chiquette and DeFronzo); and Des Moines University, Des Moines, Iowa (Dr Ramirez).


Arch Intern Med. 2004;164(19):2097-2104. doi:10.1001/archinte.164.19.2097.
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Published online

Background  In patients with type 2 diabetes mellitus, all therapeutic options should be evaluated for their effect on cardiovascular risk factors, in addition to glycemic control. We conducted a meta-analysis of randomized controlled trials of pioglitazone hydrochloride and rosiglitazone maleate in patients with type 2 diabetes to evaluate their effect on glycemic control, lipids, blood pressure, and weight.

Methods  Randomized controlled trials of patients with type 2 diabetes that compared pioglitazone or rosiglitazone with placebo for 12 weeks were included. Primary analysis was to compare thiazolidinediones with placebo. Secondary analysis was to identify whether treatment with pioglitazone differed from rosiglitazone in any outcomes. We calculated weighted mean differences and 95% confidence intervals.

Results  Twenty-three randomized controlled trials were identified. Both thiazolidinediones demonstrated similar hemoglobin A1c level decreases of 1.0% to 1.5% and similar increases in body weight of approximately 3.0 kg. Pioglitazone significantly lowered triglyceride level (–40 mg/dL [–0.45 mmol/L]; 95% confidence interval [CI], –53 to –26 mg/dL [–0.60 to –0.29 mmol/L]), increased high-density lipoprotein cholesterol (HDL-C) level (+4.6 mg/dL [+0.12 mmol/L]; 95% CI, 3.6 to 5.5 mg/dL [0.09 to 0.14 mmol/L]), and showed neutral effect on low-density lipoprotein cholesterol (LDL-C) and total cholesterol levels. Rosiglitazone significantly increased HDL-C level (+2.7 mg/dL [+0.07 mmol/L]; 95% CI, 2.0 to 3.4 mg/dL [0.05 to 0.09 mmol/L]), but increased LDL-C level (+15 mg/dL [+0.39 mmol/L]; 95% CI, 13 to 17 mg/dL [0.34 to 0.44 mmol/L]), total cholesterol level (+21 mg/dL [+0.54 mmol/L]; 95% CI, 18 to 25 mg/dL [0.47 to 0.65 mmol/L]), and demonstrated neutral effect on triglyceride level (–1.1 mg/dL [–0.12 mmol/L]; 95% CI, –14 to 12 mg/dL [–0.16 to 0.14 mmol/L]). No data were available on pioglitazone and blood pressure. Rosiglitazone had a neutral effect on systolic (–0.7 mm Hg; 95% CI, –2.6 to 1.1 mm Hg) and diastolic (–0.8 mm Hg; 95% CI, –1.8 to 0.3) blood pressure.

Conclusions  Thiazolidinediones have similar effects on glycemic control and body weight. Pioglitazone produced a more favorable lipid profile. Head-to-head comparative trials as well as longer-term cardiovascular outcome studies are needed to determine whether there are differences in efficacy between the 2 thiazolidinediones.

Figures in this Article

Type 2 diabetes mellitus is an increasingly common disease whose prevalence is closely aligned with the growing epidemic of obesity.1 Diabetes affects nearly 16 million Americans and contributes to almost 200 000 deaths a year, primarily from cardiovascular disease (CVD).2 Strategies that improve known cardiovascular risk factors in patients with diabetes are desirable if the increased risk of CVD is to be prevented. Because obesity is an independent risk factor for CVD36 as well as for diabetes,7 one might predict an increase in CVD as the obesity-induced diabetes epidemic spreads.1

The results of the United Kingdom Prospective Diabetes Study (UKPDS) have demonstrated that improved glycemic control, regardless of the pharmacological intervention (metformin, first and second generation sulfonylureas, or insulin) used to achieve the reduction in hemoglobin A1c (HbA1c) level, can significantly reduce microvascular complications but fails to significantly alter the incidence of CVD.8 Since antihypertensive and lipid-lowering therapies have been shown to decrease the incidence ofCVD in patients with type 2 diabetes,9,10 there is a compelling need for anti-diabetic medications that also address the problem of accelerated CVD through their impact on cardiovascular risk factors.

In the late 1990s, the insulin-sensitizing thiazolidinediones were approved for the treatment of type 2 diabetes mellitus in the United States. There are 2 drugs in this class: rosiglitazone maleate (Avandia; GlaxoSmithKline, Research Triangle Park, NC) and pioglitazone hydrochloride (Actos; Takeda Chemical Industries Ltd, Osaka, Japan). We conducted a meta-analysis of randomized controlled trials of pioglitazone and rosiglitazone in patients with type 2 diabetes to evaluate their effect on glycemic control, lipids, blood pressure, and weight.

We identified the citations using a comprehensive search strategy developed by the National Institute for Clinical Excellence for identifying randomized controlled trials pertinent to the thiazolidinediones of interest (rosiglitazone and pioglitazone).11,12 We searched all electronic bibliographic databases from inception to January 2004: MEDLINE, Cochrane Controlled Trials Register, Cochrane database of systematic reviews, and National Health ServiceCentre for Reviews and Dissemination. In addition, we reviewed New Drug Application submissions from rosiglitazone and pioglitazone available on the Food and Drug Administration Web site and abstracts from recent meetings (ie, American Diabetes Association). Reference lists of all relevant articles also were checked. To be included, the citation had to meet the following 6 criteria: (1) was randomized controlled trial (blind or open), (2) enrolled at least 30 adults with type 2 diabetes, (3) evaluated the effect of rosiglitazone maleate (4 or 8 mg) or pioglitazone hydrochloride (30 or 45 mg) in monotherapy or in combination with other antidiabetic medication (eg, sulfonylureas, metformin, or insulin), (4) evaluated the effect of the drug on HbA1c (lipids and weight were collected but were not a requirement for inclusion), (5) had a minimum treatment duration of 12 weeks, and (6) was published in English.

Two reviewers independently performed the screening of studies, selection, validation, data extraction, and the assessment of methodological quality. Disagreements were resolved by consensus. No studies were excluded on the basis of methodological quality.

The primary analysis was to compare of pioglitazone and rosiglitazone with placebo for all outcomes (HbA1c, fasting blood glucose [FBG], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol, triglyceride, systolic and diastolic blood pressure, and weight). The secondary analysis was to identify whether treatment effects with pioglitazone differed from that with rosiglitazone in any outcomes.

We calculated the weighted mean difference (WMD) and 95% confidence interval (CI) for all variables. The treatment effects were calculated as mean changes from baseline for thiazolidinedione treatment minus those of placebo for each outcome. A fixed-effects model approach was used, but in case of heterogeneity, a random-effects model was used. Heterogeneity was diagnosed using the χ2 test at a P≤.10.

To develop parsimonious meta-regression models, we used simple linear regression to identify significant association between clinical outcomes and their baseline values. Analyses were performed with the statistical package Stata (version 6; Stata Corp, College Station, Tex), using the “metan” and “metareg” routines.13 The routine metareg extends a random effects meta-analysis to estimate the extent to which 1 covariate (in this case pioglitazone or rosiglitazone) explains heterogeneity in the treatment effects.13

Twenty-three randomized controlled trials met the inclusion criteria.1436 The design of each trial included is presented in Table 1. More than 3000 subjects were enrolled in 10 randomized controlled trials evaluating pioglitazone and more than 5000 subjects were enrolledin studies evaluating rosiglitazone. The subjects enrolled in the pioglitazone and rosiglitazone trials were of similar age (56.6 vs 57.5 years) and body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) (29.3 vs 29.7). At baseline, subjects in the pioglitazone trials had a slightly higher HbA1c level (9.6% vs 9.2%; P<.05), triglyceride level (245 vs 211 mg/dL [2.77 vs 2.38 mmol/L]; P<.05), LDL-C level (127 vs 121 mg/dL [3.29 vs 3.13 mmol/L]; P≥.05), andslightly lower HDL-C level (43.9 vs 45.1 mg/dL [1.14 vs 1.17 mmol/L]; P≥.05). The median duration of treatment with the study drug was 16 and 26 weeks for pioglitazone and rosiglitazone, respectively. In most trials, subjects who were receiving prior oral antidiabetic medication were required to discontinue theiruse at the beginning of the run-in/washout phase. The median duration of the run-in/washout phase was 6 weeks for pioglitazone and 4 weeks for rosiglitazone. A minority of trials reported a weight maintenance strategy within their protocol.

The linear regression results were not significant between any clinical outcome and their respective baseline. Therefore, these variables were kept out of the meta-regression model.

GLYCEMIC CONTROL

The effects of thiazolidinediones on glycemic control, as measured by HbA1c and fasting blood glucose, are presented in Table 2 and Table 3. Both doses of pioglitazone hydrochloride (30 mg/d and 45 mg/d) when used as monotherapy significantly reduced HbA1c level by –0.99% (95% CI, –1.32 to −0.66) and –1.21% (95% CI, –1.79 to –0.62) compared with placebo. The addition of pioglitazone hydrochloride (30 mg/d)to other antihyperglycemic agents (metformin or sulfonylureas) ledto greater reductions in HbA1c level by –1.16% (95% CI, –1.41 to –0.90) compared with placebo. Only 1 trial used the maximum dose of pioglitazone hydrochloride (45 mg) in combination with sulfonylurea (HbA1c, –1.56%; 95% CI, –1.96 to –1.16). Both doses of rosiglitazone maleate (4 mg/d and 8 mg/d), when used as monotherapy, resulted in significant reductions in HbA1c level by –0.90% (95% CI, –1.42% to –0.38%) and –1.50% (95% CI, –1.75% to –1.24%), respectively, compared with placebo. The combination of rosiglitazone maleate with metformin, with sulfonylureas or with insulin also resulted in greater reductions in HbA1c level compared with placebo at low (4 mg/d) (Δ = –1.05%; 95% CI, –1.19% to –0.90%) and high (8 mg/d) (Δ = –1.26%; 95% CI, –1.48% to –1.04%) doses. In the pioglitazone hydrochloride monotherapy studies (30 mg/d and 45 mg/d combined), fasting plasma glucose (FPG) concentration decreased on average by 51 mg/dL (–2.83 mmol/L) (95% CI, –62 to –39 mg/dL [–3.44 to –2.16 mmol/L). When pioglitazone was added to another antidiabetic agent, FPG concentration fell approximately 47 mg/dL (−2.61 mmol) (95% CI, –55 to –39 mg/dL [–3.05 to –2.16 mmol/L]). Rosiglitazone, as monotherapy, decreased FPG level by 57 mg/dL (–3.16 mmol/L) (95% CI,–89 to –25 mg/dL [–4.94 to –1.39 mmol/L]) when used as combination therapy, rosiglitazone reduced the FPG by 50 mg/dL (–2.78 mmol/L) (95% CI, –55 to –45 mg/dL [–3.05 to –2.50 mmol/L]).

Table Graphic Jump LocationTable 3. Metabolic Effects of Thiazolidinediones*

Overall, the meta-analysis showed a significant reduction in HbA1c and FPG levels for all thiazolidinedione doses whether used as monotherapy or in combination with other antihyperglycemic agents. The mean HbA1c level at baseline was not significantly related to the observed HbA1c level reduction at end of treatment. Mean baseline HbA1c values were similar across studies, with a mean ± SD of 9.3 ± 0.63; the small variability explains why the relationship between baseline and end of treatment values was not significant at the study level, when a stronger relationship has been consistently observed within studies at the individual patient level. The meta-regression found that the drug grouping did not explainthe heterogeneity (P = .84).

LIPIDS EFFECT

While both thiazolidinediones had similar effects on glycemic control, pioglitazone showed a neutral to beneficial impact on serum lipid levels, whereas rosiglitazone increased LDL-C, total cholesterol, and HDL-C levels and had a neutral effect on triglyceride level. The meta-regression found that the drug grouping was a significant predictor of heterogeneity for all lipid effects (P<.001); therefore, the results were presented and analyzed separately. Rosiglitazone, when used as monotherapy or in combination with other antihyperglycemic agents, was associated with a significant increased in LDL-C level (+15 mg/dL [+0.39 mmol/L]; 95% CI, 13 to 18mg/dL [0.34 to 0.47 mmol/L]), whereas pioglitazone showed a neutral effect on LDL-C level (–0.4 mg/dL [–0.01 mmol/L]; 95% CI, –5 to 4 mg/dL [–0.13 to 0.10 mmol/L]). None of the pioglitazone studies showed a significant difference compared with placebo on LDL-C, whereas every rosiglitazone study showed a statistically significant increased in LDL-C level (Figure 1). Rosiglitazone treatment had no significant effect on the fasting plasma triglyceride concentration, whereas pioglitazone therapy significantly decreased the fasting triglyceride level (–40 mg/dL [–0.45 mmol]; 95% CI, –53 to –26 mg/dL [–0.60 to –0.29 mmol/L]). None of the rosiglitazone trials showed a statistically significant change in fasting plasma triglyceride level, whereas 5 of 8 trials with pioglitazone demonstrated a statistically significant reduction in triglyceride level (Figure 2). Both thiazolidinediones significantly increas-ed the HDL-C concentration (pio-glitazone: Δ = +4.55 mg/dL [+0.12 mmol/L] with 95% CI, 3.61 to 5.48 [0.09 to 0.14 mmol/L]; rosiglitazone: Δ = +2.71 mg/dL [+0.07 mmol/L] with 95% CI, 2.01 to 3.42 mg/dL [0.05to 0.09 mmol/L]) (Figure 3). Pioglitazone had no effect on total cholesterol (–0.1 mg/dL [–0.003 mmol/L]; 95% CI, –5 to 5 mg/dL [–0.13 to 0.13 mmol/L]), whereas rosiglitazone significantly increased the total cholesterol (+21.3 mg/dL [0.55 mmol/L]; 95% CI, 17.7 to 24.9 mg/dL [0.46 to 0.64 mmol/L]) (Figure 4). The treatment effects of pioglitazone on fasting plasma triglyceride, LDL-C, and total cholesterol levels were statistically significantly different than those of rosiglitazone (all P<.01).

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Figure 1.

Effect of pioglitazone hydrochloride (P) or rosiglitazone maleate (R) vs placebo on low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes. To convert cholesterol to millimoles per liter, multiply by 0.0259. bid Indicates twice daily; CI, confidence interval; Ins, insulin; Met, metformin; SU, sulfonylureas; WMD, weighted mean difference.

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Figure 2.

Effect of pioglitazone hydrochloride (P) or rosiglitazone maleate (R) vs placebo on triglycerides in patients with type 2 diabetes. To convert triglycerides to millimoles per liter, multiply by 0.0113. bid Indicates twice daily; CI, confidence interval; Ins, insulin; Met, metformin; SU, sulfonylureas; WMD, weighted mean difference.

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Place holder to copy figure label and caption
Figure 3.

Effect of pioglitazone hydrochloride (P) or rosiglitazone maleate (R) vs placebo on high-density lipoprotein cholesterol (HDL-C) in patients with type 2 diabetes. To convert cholesterol to millimoles per liter, multiply by 0.0259. bid Indicates twice daily; CI, confidence interval; Ins, insulin; Met, metformin; SU, sulfonylureas; WMD, weighted mean difference.

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Place holder to copy figure label and caption
Figure 4.

Effect of pioglitazone hydrochloride (P) or rosiglitazone maleate (R) vs placebo on total cholesterol in patients with type 2 diabetes. To convert cholesterol to millimoles per liter, multiply by 0.0259. bid Indicates twice daily; CI, confidence interval; Ins, insulin; Met, metformin; SU, sulfonylureas; WMD, weighted mean difference.

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BLOOD PRESSURE EFFECT

Only 5 trials were included in this outcome analysis. None of the pioglitazone trials reported blood pressure as an outcome. There were no significantdifferences between rosiglitazone and placebo in changes in systolic (–0.7mm Hg; 95% CI, –2.6 to 1.1 mm Hg) or diastolic blood pressure (–0.8mm Hg; 95% CI, –1.8 to 0.3 mm Hg).

WEIGHT EFFECT

Only 11 of 23 trials were included in this outcome analysis, since most trials did not report variance around the weight change value. Within 6 months of initiating therapy with thiazolidinediones, the average weight gain was +2.7 kg (95% CI, 1.8 to 3.7 kg).The studies were heterogeneous (χ2 = 111.47; P<.001), but drug grouping was not a predictor of the heterogeneity (P>.10). Additional analyses were done to examine the contribution of the Japanese trials to the heterogeneity. The Japanese trials57 included subjects with an average BMI of 25, whereas most studies outside of Japan were conducted in obese individuals (BMI = 30 in average for most studies). For Japanese trials only, the average weight gain was +0.73 kg (95% CI, 0.23 to 1.23 kg) and homogeneous (χ2 = 0.67; P<.71), whereas the non-Japanese trials resulted in a +3.3 kg weight gain (95% CI, 2.5 to 4.2 kg) and remained heterogeneous (χ2 = 43.54; P<.001).

Type 2 diabetes mellitus is more than a disease of glucose metabolism, being associated with a number of metabolic abnormalities, including obesity, insulin resistance, hyperinsulinemia, increased waist circumference and visceral adipose tissue, hypertriglyceridemia, low HDL-C level, small dense LDL-C particles, and high blood pressure.37,38 These abnormalities typically occur in clusters as part of the insulin resistance syndrome (the metabolic syndrome), which precede and predict the development of type 2 diabetes.39 Since all of these abnormalities are recognized risk factors for CVD, it is not surprising that individuals with the insulin resistance syndrome, with or without type 2 diabetes, are at increased risk of CVD.4043

Because 80% of patients with type 2 diabetes have the metabolic syndrome,44 its components are appropriate targets to evaluate the benefits of emerging therapies for type 2 diabetes.

The thiazolidinediones represent the newest class of drugs introduced into the United States for the treatment of type 2 diabetes mellitus. In this meta-analysis, we have evaluated the effects of pioglitazone and rosiglitazone on the following components of the insulin resistance syndrome: glycemia, triglycerides, total cholesterol, LDL-C, HDL-C, blood pressure, and body weight. Both thiazolidinediones produced similar decreases in HbA1c level of –1.0% to –1.5% and similar increases in body weight of approximately +3.0 kg. In contrast, pioglitazone had a more favorable effect on the plasma lipid profile, producing a significant reduction in plasma triglyceride levels compared with the neutral effect of rosiglitazone on triglyceride level. Plasma levels of total cholesterol and LDL-C were significantly increased by rosiglitazone, whereas no changes in these lipid fractions were produced by pioglitazone. Plasma HDL-C concentration increased to a similar extent with both agents. The mechanism responsible for these beneficial effects of pioglitazone have yet to be established but may result from its modest agonistic effect on the peroxisome proliferator-activated receptor-α.45 It also remains to be established whether these beneficial effects of pioglitazone on plasma lipid levels are sufficient to lower the risk of CVD. In addition, whether pioglitazone is superior to rosiglitazone in lipid lowering has not been tested in a head-to-head randomized trial.

Although the effect of both thiazolidinediones to increase body weight has raised some concern, many studies have demonstrated an inverse relationship between body weight and HbA1c.25,28,4649 Thus, the greater the increase in body weight, the greater the reduction in HbA1c level. Moreover, despite the weight gain, pioglitazone reduced plasma triglyceride level, raised HDL-C level, and had a neutral effect on total cholesterol and LDL-C levels. Despite increased body weight, rosiglitazone therapy had a neutral effect on diastolic and systolic blood pressure, and both thiazolidinediones have been shown to reduce the blood pressure in hypertensive patients with type 2 diabetes.50,51 The weight gain associated with thiazolidinediones is therefore unlike the weight gain associated with increased caloric intake.52 The later is associated with the development of insulin resistance and deterioration in glycemic control, a worsening of the dyslipidemia, and a rise in blood pressure.53 Moreover, the thiazolidinediones have many in vivo and in vitro beneficial effects on a variety of measures of atherosclerosis52,54,55 and have been shown to slow progression of carotid intimal thickness56,57 and coronary stent restenosis.5860 Nevertheless, the impact of this weight gain over many years can only be answered with long-term follow-up trials.

Finally, this meta-analysis should not be used to judge the ability of either thiazolidinediones to reduce the incidence of cardiovascular events in patients with type 2 diabetes. The long-term effects of pioglitazone and rosiglitazone on cardiovascular morbidity and mortality currently are being evaluated in several large randomized controlled trials: ADOPT (A Diabetes Outcome Progression Trial),61 RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes), and PROACTIVE (Prospective Pioglitazone Clinical Trial in Macrovascular Events).

Correspondence: Ralph DeFronzo, MD, Diabetes Division, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr,San Antonio, TX 78229 (albarado@uthscsa.edu).

Financial Interest: At the time of writing this manuscript, Dr Chiquette was clinical assistant professor at the University of Texas Health Science Center at San Antonio and was employed by Aventis Pharmaceuticals. Aventis manufactures and markets pharmaceuticals related to the treatment of diabetes and its complications. However, Aventis is not involved in the development or marketing of thiazolidinediones. Dr DeFronzo is on several speaker bureaus and has research grants from the following pharmaceutical companies: Takeda, GlaxoSmithKline, Bristol-Myers Squibb, Novartis, Novo Nordisk, Roche, Aventis, and Pfizer.

Accepted for Publication: May 22, 2004.

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Vongthavaravat  VWajchenberg  BLWaitman  JN  et al. 125 Study Group, An international study of the effects of rosiglitazone plus sulphonylurea in patients with type 2 diabetes. Curr Med Res Opin 2002;18456- 461
PubMed Link to Article
Fonseca  VRosenstock  JPatwardhan  RSalzman  A Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000;2831695- 1702
PubMed Link to Article
Moran  EGSalzman  AYan  YPatwardhan  R Rosiglitazone. BRL 49653: A 26-week randomized, double-blind, double-dummy, multicentered study to evaluate the efficacy, safety and tolerability of rosiglitazone when administered to patients with non-insulin dependent diabetes mellitus (NIDDM) who are inadequately controlled on a maximal dose (20-mg/day) of glyburide: report 079 phase IIIA: final clinical report. Excerpt inLord  JPaisley  STaylor  RThe Clinical Effectiveness and Cost-Effectiveness of Rosiglitazone for Type 2 Diabetes Mellitus London, England National Institute for Clinical Excellence August2000;
Lowry  FSBevivino  MVSalzman  AYan  YPatwardhan  R Rosiglitazone: BRL 49653: a 26-week randomized, double-blind, double-dummy, multicenter study to evaluate the efficacy, safety and tolerability of rosiglitazone 4 mg bd when administered to patients with non-insulin dependent diabetes mellitus (NIDDM) who are inadequately controlled on a maintenance dose (2.5g/day) of metformin: report 093 phase IIIA: final clinical report. Excerpt inLord  JPaisley  STaylor  RThe Clinical Effectiveness and Cost-Effectiveness of Rosiglitazone for Type 2 Diabetes Mellitus London, England National Institute for Clinical Excellence August2000;
Hutchman  JSalzman  ABiswas  NPatwardhan  R Rosiglitazone: BRL 49653: a 26-week randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy, safety and tolerability of rosiglitazone when administered once daily to patients with non-insulin dependent diabetes mellitus (NIDDM) who are inadequately controlled on at least half-maximal dose (10 mg/day) of glyburide: report 096 phase IIIA: final clinical report. Excerpt inLord  JPaisley  STaylor  RThe Clinical Effectiveness and Cost-Effectiveness of Rosiglitazone for Type 2 Diabetes Mellitus London, England National Institute for Clinical Excellence August2000;
DeFronzo  RAFerrannini  E Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14173- 194
PubMed Link to Article
Reaven  GM Banting Lecture 1988: role of insulin resistance in human disease. Diabetes 1988;371595- 1607
PubMed Link to Article
Stern  MPWilliams  KHaffner  SM Identification of persons at high risk for type 2 diabetes mellitus: do we need the oral glucose tolerance test? Ann Intern Med 2002;136575- 581
PubMed Link to Article
Kannel  WBMcGee  DL Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham Study. Diabetes Care 1979;2120- 126
PubMed Link to Article
Lakka  HMLaaksonen  DELakka  TA  et al.  The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;2882709- 2716
PubMed Link to Article
Zavaroni  IBonini  LGasparini  P  et al.  Hyperinsulinemia in a normal population as a predictor of non-insulin-dependent diabetes mellitus, hypertension, and coronary heart disease: the Barilla factory revisited. Metabolism 1999;48989- 994
PubMed Link to Article
Isomaa  BAlmgren  PTuomi  T  et al.  Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24683- 689
PubMed Link to Article
Alexander  CMLandsman  PBTeutsch  SMHaffner  SM NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003;521210- 1214
PubMed Link to Article
Wurch  TJunquero  DDelhon  APauwels  J Pharmacological analysis of wild-type alpha, gamma and delta subtypes of the human peroxisome proliferator-activated receptor. Naunyn Schmiedebergs Arch Pharmacol 2002;365133- 140
PubMed Link to Article
Miyazaki  YMahankali  AMatsuda  M  et al.  Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002;872784- 2791
PubMed Link to Article
Miyazaki  YGlass  LTriplitt  C  et al.  Effect of rosiglitazone on glucose and free fatty acid metabolism in type 2 diabetic patients. Diabetologia 2001;442210- 2219
PubMed Link to Article
Miyazaki  YMahankali  AMatsuda  M  et al.  Improved glycemic control and enhanced insulin sensitivity in liver and muscle in type 2 diabetic subjects treated with pioglitazone. Diabetes Care 2001;24710- 719
PubMed Link to Article
Chilcott  JTappenden  PJones  MLWight  JP A systematic review of the effectiveness of pio-glitazone in the treatment of type 2 diabetes mellitus. Clin Ther 2001;231792- 1823
PubMed Link to Article
Scherbaum  WBurkhard  G the German pioglitazone study group. Pioglitazone reduces blood pressure in patients with type 2 diabetes [abstract]. Diabetes 2001;50 ((suppl 2)) A462
Link to Article
Bakris  GLDole  JFPorter  LEHuang  CFreed  M Rosiglitazone improves blood pressure in patients with type 2 diabetes mellitus [abstract] Diabetes 2000;49 ((suppl 1)) A96
Bays  HMandarino  LDeFronzo  RA Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 2004;89463- 478
PubMed Link to Article
Mokdad  AHFord  ESBowman  BA  et al.  Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;28976- 79
PubMed Link to Article
Plutzky  J The potential role of peroxisome proliferator-activated receptors on inflammation in type 2 diabetes mellitus and atherosclerosis. Am J Cardiol 2003;9234J- 41J
PubMed Link to Article
Satoh  NOgawa  YUsui  T  et al.  Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care 2003;262493- 2499
PubMed Link to Article
Takagi  TAkasaka  TYamamuro  A  et al.  Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus: a serial intravascular ultrasound study. J Am Coll Cardiol 2000;361529- 1535
PubMed Link to Article
Koshiyama  HShimono  DKuwamura  NMinamikawa  JNakamura  Y Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 2001;863452- 3456
PubMed Link to Article
Takagi  TYamamuro  ATamita  K  et al.  Pio-glitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus: an intravascular ultrasound scanning study. Am Heart J 2003;146E5
PubMed Link to Article
Takagi  TYamamuro  ATamita  K  et al.  Impact of troglitazone on coronary stent implantation using small stents in patients with type 2 diabetes mellitus. Am J Cardiol 2002;89318- 322
PubMed Link to Article
Osman  AOtero  JBrizolara  A  et al.  Effect of rosiglitazone on restenosis after coronary stenting in patients with type 2 diabetes. Am Heart J 2004;147e23
PubMed Link to Article
Viberti  GKahn  SEGreene  DA  et al.  A Diabetes Outcome Progression Trial (ADOPT): an international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes. Diabetes Care 2002;251737- 1743
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Effect of pioglitazone hydrochloride (P) or rosiglitazone maleate (R) vs placebo on low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes. To convert cholesterol to millimoles per liter, multiply by 0.0259. bid Indicates twice daily; CI, confidence interval; Ins, insulin; Met, metformin; SU, sulfonylureas; WMD, weighted mean difference.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Effect of pioglitazone hydrochloride (P) or rosiglitazone maleate (R) vs placebo on triglycerides in patients with type 2 diabetes. To convert triglycerides to millimoles per liter, multiply by 0.0113. bid Indicates twice daily; CI, confidence interval; Ins, insulin; Met, metformin; SU, sulfonylureas; WMD, weighted mean difference.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Effect of pioglitazone hydrochloride (P) or rosiglitazone maleate (R) vs placebo on high-density lipoprotein cholesterol (HDL-C) in patients with type 2 diabetes. To convert cholesterol to millimoles per liter, multiply by 0.0259. bid Indicates twice daily; CI, confidence interval; Ins, insulin; Met, metformin; SU, sulfonylureas; WMD, weighted mean difference.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Effect of pioglitazone hydrochloride (P) or rosiglitazone maleate (R) vs placebo on total cholesterol in patients with type 2 diabetes. To convert cholesterol to millimoles per liter, multiply by 0.0259. bid Indicates twice daily; CI, confidence interval; Ins, insulin; Met, metformin; SU, sulfonylureas; WMD, weighted mean difference.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 3. Metabolic Effects of Thiazolidinediones*

References

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Mokdad  AHFord  ESBowman  BA  et al.  Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;28976- 79
PubMed Link to Article
UK Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352837- 853
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Collins  RArmitage  JParish  SSleigh  PPeto  RHeart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 individuals with diabetes: a randomised placebo-controlled trial. Lancet 2003;3612005- 2016
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Heart Outcomes Prevention Evaluation Study Investigators, Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355253- 259
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Lord  JPaisley  STaylor  R The Clinical Effectiveness and Cost-effectiveness of Rosiglitazone for Type 2 Diabetes Mellitus.  London, England National Institute for Clinical Excellence August2000;
Chilcott  JWight  JJones  MLTappenden  P The Clinical Effectiveness and Cost-effectiveness of Pioglitazone for Type 2 Diabetes Mellitus.  London, England National Institute for Clinical Excellence March2001;
Bradburn  MJDeeks  JJAltman  DGNewton  HJ sg104: Metan: an alternative meta-analysis command. Newton  HJed.The Stata Technical Bulletin Reprints, Volume 8 College Station, Tex Stata Corp1999;86- 100
Aronoff  SRosenblatt  SBraithwaite  SEgan  JWMathisen  ALSchneider  RLThe Pioglitazone 001 Study Group, Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. Diabetes Care 2000;231605- 1611
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Kaneko  TBaba  SToyota  T Dose finding study of AD-4833 in patients with non-insulin dependent diabetes mellitus (NIDDM) on diet therapy alone: double-blind comparative study on four dosages. Jap J Clin Exp Med 1997;741250- 1277
Kaneko  TBaba  SToyota  T Clinical evaluation of an insulin-resistance improving agent, AD-4833, in patients with non-insulin dependent diabetes mellitus (NIDDM) on diet therapy alone: a placebo controlled double blind clinical study. Jap J Clin Exp Med 1997;741491- 1514
Kaneko  TBaba  SToyota  T Dose finding study of AD-4833 in patients with non-insulin dependent diabetes mellitus (NIDDM) on treatment with a sulfonylurea drug: single blind comparative study on four dosages. Jap J Clin Exp Med 1997;741278- 1306
Einhorn  DRendell  MRosenzweig  JEgan  JWMathisen  ALSchneider  RLThe Pioglitazone 027 Study Group, Pioglitazone hydrochloride in combination with metformin in the treatment of type 2 diabetes mellitus: a randomized, placebo-controlled study. Clin Ther 2000;221395- 1409
PubMed Link to Article
Rosenstock  JEinhorn  DHershon  KGlazer  NBYu  S Efficacy and safety of pioglitazone in type 2 diabetes: a randomised, placebo-controlled study in patients receiving stable insulin therapy. Int J Clin Pract 2002;56251- 257
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Kipnes  MSKrosnick  ARendell  MSEgan  JWMathisen  ALSchneider  RL Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study. Am J Med 2001;11110- 17
PubMed Link to Article
Herz  MJohns  DReviriego  J  et al.  A randomized, double-blind, placebo-controlled, clinical trial of the effects of pioglitazone on glycemic control and dyslipidemia in oral antihyperglycemic medication-naive patients with type 2 diabetes mellitus. Clin Ther 2003;251074- 1095
PubMed Link to Article
Rosenblatt  SMiskin  B Glazer NB, Prince MJ, Robertson KE. The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus. Coron Artery Dis 2001;12413- 423
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Scherbaum  WAGoke  B Metabolic efficacy and safety of once-daily pioglitazone monotherapy in patients with type 2 diabetes: a double-blind, placebo-controlled study. Horm Metab Res 2002;34589- 595
PubMed Link to Article
Raskin  PRendell  MRiddle  MCDole  JFFreed  MIRosenstock  J A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes. Diabetes Care 2001;241226- 1232
PubMed Link to Article
Lebovitz  HEDole  JFPatwardhan  RRappaport  EBFreed  MIThe Rosiglitazone Clinical Trials Study Group, Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001;86280- 288
PubMed Link to Article
Phillips  LSGrunberger  GMiller  EPatwardhan  RRappaport  EBSalzman  AThe Rosiglitazone Clinical Trials Study Group, Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care 2001;24308- 315
PubMed Link to Article
Barnett  AHGrant  PJHitman  GA  et al. Indo-Asian Trial Investigators, Rosiglitazone in type 2 diabetes mellitus: an evaluation in British Indo-Asian patients. Diabet Med 2003;20387- 393
PubMed Link to Article
Patel  JAnderson  RJRappaport  EB Rosiglitazone monotherapy improves glycaemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study. Diabetes Obes Metab 1999;1165- 172
PubMed Link to Article
Xixing  ZChangyu  PGuangwei  L  et al.  Rosiglitazone improves glycemic control in Chinese patients with type 2 diabetes mellitus in combination with sulfonylurea [abstract]. Diabetes 2001;50A135
Link to Article
Gomez-Perez  FJFanghanel-Salmon  GAntonio Barbosa  J  et al.  Efficacy and safety of rosiglitazone plus metformin in Mexicans with type 2 diabetes. Diabetes Metab Res Rev 2002;18127- 134
PubMed Link to Article
Wolffenbuttel  BHGomis  RSquatrito  SJones  NPPatwardhan  RN Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in type 2 diabetic patients. Diabet Med 2000;1740- 47
PubMed Link to Article
Vongthavaravat  VWajchenberg  BLWaitman  JN  et al. 125 Study Group, An international study of the effects of rosiglitazone plus sulphonylurea in patients with type 2 diabetes. Curr Med Res Opin 2002;18456- 461
PubMed Link to Article
Fonseca  VRosenstock  JPatwardhan  RSalzman  A Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000;2831695- 1702
PubMed Link to Article
Moran  EGSalzman  AYan  YPatwardhan  R Rosiglitazone. BRL 49653: A 26-week randomized, double-blind, double-dummy, multicentered study to evaluate the efficacy, safety and tolerability of rosiglitazone when administered to patients with non-insulin dependent diabetes mellitus (NIDDM) who are inadequately controlled on a maximal dose (20-mg/day) of glyburide: report 079 phase IIIA: final clinical report. Excerpt inLord  JPaisley  STaylor  RThe Clinical Effectiveness and Cost-Effectiveness of Rosiglitazone for Type 2 Diabetes Mellitus London, England National Institute for Clinical Excellence August2000;
Lowry  FSBevivino  MVSalzman  AYan  YPatwardhan  R Rosiglitazone: BRL 49653: a 26-week randomized, double-blind, double-dummy, multicenter study to evaluate the efficacy, safety and tolerability of rosiglitazone 4 mg bd when administered to patients with non-insulin dependent diabetes mellitus (NIDDM) who are inadequately controlled on a maintenance dose (2.5g/day) of metformin: report 093 phase IIIA: final clinical report. Excerpt inLord  JPaisley  STaylor  RThe Clinical Effectiveness and Cost-Effectiveness of Rosiglitazone for Type 2 Diabetes Mellitus London, England National Institute for Clinical Excellence August2000;
Hutchman  JSalzman  ABiswas  NPatwardhan  R Rosiglitazone: BRL 49653: a 26-week randomized, double-blind, multicenter, placebo-controlled study to evaluate the efficacy, safety and tolerability of rosiglitazone when administered once daily to patients with non-insulin dependent diabetes mellitus (NIDDM) who are inadequately controlled on at least half-maximal dose (10 mg/day) of glyburide: report 096 phase IIIA: final clinical report. Excerpt inLord  JPaisley  STaylor  RThe Clinical Effectiveness and Cost-Effectiveness of Rosiglitazone for Type 2 Diabetes Mellitus London, England National Institute for Clinical Excellence August2000;
DeFronzo  RAFerrannini  E Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991;14173- 194
PubMed Link to Article
Reaven  GM Banting Lecture 1988: role of insulin resistance in human disease. Diabetes 1988;371595- 1607
PubMed Link to Article
Stern  MPWilliams  KHaffner  SM Identification of persons at high risk for type 2 diabetes mellitus: do we need the oral glucose tolerance test? Ann Intern Med 2002;136575- 581
PubMed Link to Article
Kannel  WBMcGee  DL Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham Study. Diabetes Care 1979;2120- 126
PubMed Link to Article
Lakka  HMLaaksonen  DELakka  TA  et al.  The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;2882709- 2716
PubMed Link to Article
Zavaroni  IBonini  LGasparini  P  et al.  Hyperinsulinemia in a normal population as a predictor of non-insulin-dependent diabetes mellitus, hypertension, and coronary heart disease: the Barilla factory revisited. Metabolism 1999;48989- 994
PubMed Link to Article
Isomaa  BAlmgren  PTuomi  T  et al.  Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24683- 689
PubMed Link to Article
Alexander  CMLandsman  PBTeutsch  SMHaffner  SM NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes 2003;521210- 1214
PubMed Link to Article
Wurch  TJunquero  DDelhon  APauwels  J Pharmacological analysis of wild-type alpha, gamma and delta subtypes of the human peroxisome proliferator-activated receptor. Naunyn Schmiedebergs Arch Pharmacol 2002;365133- 140
PubMed Link to Article
Miyazaki  YMahankali  AMatsuda  M  et al.  Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002;872784- 2791
PubMed Link to Article
Miyazaki  YGlass  LTriplitt  C  et al.  Effect of rosiglitazone on glucose and free fatty acid metabolism in type 2 diabetic patients. Diabetologia 2001;442210- 2219
PubMed Link to Article
Miyazaki  YMahankali  AMatsuda  M  et al.  Improved glycemic control and enhanced insulin sensitivity in liver and muscle in type 2 diabetic subjects treated with pioglitazone. Diabetes Care 2001;24710- 719
PubMed Link to Article
Chilcott  JTappenden  PJones  MLWight  JP A systematic review of the effectiveness of pio-glitazone in the treatment of type 2 diabetes mellitus. Clin Ther 2001;231792- 1823
PubMed Link to Article
Scherbaum  WBurkhard  G the German pioglitazone study group. Pioglitazone reduces blood pressure in patients with type 2 diabetes [abstract]. Diabetes 2001;50 ((suppl 2)) A462
Link to Article
Bakris  GLDole  JFPorter  LEHuang  CFreed  M Rosiglitazone improves blood pressure in patients with type 2 diabetes mellitus [abstract] Diabetes 2000;49 ((suppl 1)) A96
Bays  HMandarino  LDeFronzo  RA Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 2004;89463- 478
PubMed Link to Article
Mokdad  AHFord  ESBowman  BA  et al.  Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003;28976- 79
PubMed Link to Article
Plutzky  J The potential role of peroxisome proliferator-activated receptors on inflammation in type 2 diabetes mellitus and atherosclerosis. Am J Cardiol 2003;9234J- 41J
PubMed Link to Article
Satoh  NOgawa  YUsui  T  et al.  Antiatherogenic effect of pioglitazone in type 2 diabetic patients irrespective of the responsiveness to its antidiabetic effect. Diabetes Care 2003;262493- 2499
PubMed Link to Article
Takagi  TAkasaka  TYamamuro  A  et al.  Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus: a serial intravascular ultrasound study. J Am Coll Cardiol 2000;361529- 1535
PubMed Link to Article
Koshiyama  HShimono  DKuwamura  NMinamikawa  JNakamura  Y Rapid communication: inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 2001;863452- 3456
PubMed Link to Article
Takagi  TYamamuro  ATamita  K  et al.  Pio-glitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with type 2 diabetes mellitus: an intravascular ultrasound scanning study. Am Heart J 2003;146E5
PubMed Link to Article
Takagi  TYamamuro  ATamita  K  et al.  Impact of troglitazone on coronary stent implantation using small stents in patients with type 2 diabetes mellitus. Am J Cardiol 2002;89318- 322
PubMed Link to Article
Osman  AOtero  JBrizolara  A  et al.  Effect of rosiglitazone on restenosis after coronary stenting in patients with type 2 diabetes. Am Heart J 2004;147e23
PubMed Link to Article
Viberti  GKahn  SEGreene  DA  et al.  A Diabetes Outcome Progression Trial (ADOPT): an international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes. Diabetes Care 2002;251737- 1743
PubMed Link to Article

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