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Original Studies |
Department of Medicine, State University of New York (H.E.L.), Brooklyn, New York 11203; and SmithKline Beecham Pharmaceuticals (J.F.D., R.P., E.B.R., M.I.F.), Collegeville, Pennsylvania
Address all correspondence and requests for reprints to: Harold E. Lebovitz, M.D., Department of Medicine, Division of Endocrinology, State University of New York Health Science Center, 450 Clarkson Avenue, Box 50, Brooklyn, New York 11203. E-mail: hlebovitz{at}attglobal.net
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Thiazolidinediones are insulin-sensitizing agents that act as ligands
for the 
-subtype of the peroxisome proliferator-activated receptor
(PPAR), which is directly involved in the regulation of genes
controlling glucose homeostasis and lipid metabolism
(13, 14, 15, 16). Troglitazone, the first
thiazolidinedione that had been approved for clinical use, was
effective in reducing glycemia in patients with type 2 diabetes
(17, 18), but was also associated with hepatotoxicity and
rare cases of liver failure and death (19, 20, 21, 22). As a
result, frequent monitoring of hepatic function had been required
during troglitazone treatment (19). The U.S.
FDA asked Parke-Davis/Warner-Lambert to remove
troglitazone from the market as of March 22, 2000. The FDA
took this action after its review of recent safety data on
troglitazone, rosiglitazone, and pioglitazone
had demonstrated that troglitazone is more toxic to the
liver than the other two drugs. Data to date show that rosiglitazone
and pioglitazone, both approved in the past year, offer
benefits similar to troglitazone without the same risk
(23).
Rosiglitazone is a potent member of the thiazolidinedione class, with a
binding affinity for PPAR that is approximately 30-fold greater than
that of pioglitazone and 100-fold greater than that of
troglitazone (24, 25, 26). This translates to a
clinical dose that is approximately 1/100th that of
troglitazone (4–8 vs. 400–600 mg) and 1/6th
that of pioglitazone (4–8 vs. 15–45 mg). This
report describes the results of a multicenter study designed to assess
the efficacy and safety of rosiglitazone monotherapy in patients with
type 2 diabetes whose hyperglycemia was inadequately controlled by diet
or an oral antihyperglycemic agent.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Patient population
Patients, 36–81 yr old, with a diagnosis of type 2 diabetes (as defined by the National Diabetes Data Group) (27) were eligible for the study if they had fasting plasma glucose (FPG) between 7.8–16.7 mmol/L, fasting plasma C peptide level greater than 0.26 nmol/L, and a body mass index (BMI) between 22–38 kg/m2 at screening. Patients with angina or cardiac insufficiency (New York Heart Association class III or IV), renal impairment (serum creatinine, >159 µmol/L), hepatic disease [alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, or total bilirubin, >2.5 times the upper limit of the reference range], history of diabetic ketoacidosis, history of chronic insulin use, symptomatic diabetic neuropathy, a serious major illness that would compromise their participation, and women of childbearing potential were excluded from the study.
Study design
The study was divided into three phases: a screening period of up to 14 days (during which patients discontinued all antidiabetic medications), a 4-week single blind placebo baseline period, and a 26-week double blind treatment period. At the end of the screening period, patients were assessed for inclusion in the placebo baseline period. Eligible patients received instruction on a weight maintenance diet during the placebo baseline phase and reinforcement at all subsequent study visits. After completing the baseline period, patients were randomly assigned to receive placebo, 2 mg rosiglitazone twice daily (bd), or 4 mg rosiglitazone bd. Study medications were matched for weight, shape, and color and dispensed in bottles of 40 tablets (enough for 20 days).
All patients were given a complete physical examination at screening and at the end of the treatment period. Interim medical histories, reports of adverse events, and standard laboratory assessments (including clinical chemistry, hematology, and urinalysis) were obtained at each visit. Electrocardiograms were performed at screening, baseline, and weeks 12 and 26 of the double blind treatment period.
Evaluation of efficacy
The primary end point for evaluating effects on glycemic control was the change in hemoglobin A1c (HbA1c) from baseline to 26 weeks in the rosiglitazone treatment groups compared with the placebo group by an intention to treat analysis. Other measures of efficacy were comparisons of rosiglitazone with placebo for changes from baseline to week 26 in FPG, C peptide, immunoreactive insulin, proinsulin, 32–33 split proinsulin, fructosamine, urinary albumin excretion as determined by urinary albumin/creatinine ratio (ACR), and serum lipids. All of the efficacy parameters were measured at two visits during the run-in period, at baseline (the day of randomization), and at five visits during the treatment phase. The proportions of patients who had a reduction in HbA1c of more than 1 percentage point or a reduction in FPG of more than 1.67 mmol/L at week 26 compared with baseline were determined in each treatment group.
Laboratory measurements
HbA1c was measured by high performance liquid chromatography (Variant Bio-Rad Laboratories, Inc., Richmond, CA), with a normal reference range of 4.1–6.5%; the assay was linear up to 17.89%. FPG was measured by the hexokinase method with an Olympus Corp. analyzer (New Hyde Park, NY). Serum total cholesterol and triglycerides were measured by enzymatic methods with the same analyzer. Fructosamine was measured by colorimetric analysis (RoTAG fructosamine assay, Roche, Indianapolis, IN), C peptide was determined by RIA (Diagnostic Products, Los Angeles, CA), immunoreactive insulin was measured by a one-step immunoenzymatic assay (28, 29) (Access Ultrasensitive Immunoassay System, Sanofi Pharmaceuticals, Inc.; normal reference range, 13–61 pmol/L), and proinsulin and 32–33 split proinsulin were determined by time-resolved fluoroimmunoassay linear to at least 400 pmol/L (Delfia, Wallac, Inc., Turku, Finland). Serum high density lipoprotein (HDL) cholesterol was isolated by precipitation and then measured by enzymatic methods with an Olympus Corp. analyzer. Serum low density lipoprotein (LDL) cholesterol was assayed using the Direct LDL Cholesterol Immunoseparation Reagent Kit (Genzyme, Cambridge, MA). Free fatty acids were measured by enzymatic colorimetric analysis (COBAS analyzer, Roche). SmithKline Beecham Clinical Laboratories (Van Nuys, CA) performed all laboratory tests, with the exception of the insulin assays. Insulin samples were assayed at Addenbrooke’s National Health Service Trust (Cambridge, UK).
Statistical analyses
Efficacy analyses were performed for the intention to treat population, defined as all randomized patients who had at least one on-therapy value. In the case of missing data or early withdrawals, the last observation was carried forward to week 26. The safety parameters were assessed based on observed week 26 data without carrying forward the last observation.
Treatment groups were compared using analysis of covariance with terms for baseline, treatment, center, and BMI. Pairwise comparisons to placebo used Dunnett’s multiple comparison procedure to maintain a two-sided 0.05 significance level within each parameter (30, 31) The statistical significance of the within-group change from baseline was tested by a paired t test. ACR was log transformed before analysis of covariance with terms for baseline and treatment. Results in the log scale were back-transformed to provide geometric means and corresponding percent change from baseline. Separate analyses were performed for all patients and for those with microalbuminuria.
Estimates of insulin resistance and ß-cell function were derived from fasting glucose and insulin using the homeostasis model assessment (HOMA), a mathematical model that relates fasting blood glucose and insulin levels to insulin resistance (IR) and ß-cell function (BCF) (32): IR = [fasting insulin (µU/mL) x fasting glucose (mmol/L)]/22.5; and BCF = [20 x fasting insulin (µU/mL)]/fasting glucose (mmol/L) - 3.5]. HOMA estimates of insulin resistance and ß-cell function have been validated by comparison with results of glucose clamp studies (33). Estimates of insulin resistance and ß-cell function were calculated for all patients at baseline and at weeks 4, 8, 12, 18, and 26 using FPG and insulin values obtained at those times. For patients with missing values at week 26, the last observation was carried forward. Statistical analyses were performed on the percentages of change from baseline to week 26 in insulin resistance and in ß-cell function using the SAS statistical package (SAS Institute, Inc., Cary, NC).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 623 patients entered the placebo baseline phase, and 90 patients withdrew before randomization. Five hundred and thirty-three patients were randomized to treatment; 40 (7.5%) withdrew before having a valid, postbaseline data point. Therefore, the intention to treat population (randomized patients with at least 1 valid postbaseline data point) consisted of 493 patients, 472 of whom had no major protocol violations and comprised the efficacy evaluable population.
Three hundred and sixty-five patients (68.4% of those randomized) completed the 26-week study period. One hundred and sixty-eight patients withdrew during double blind treatment: 77 (44%), 46 (26%), and 45 (25%) from the placebo, 2 mg rosiglitazone bd, and 4 mg rosiglitazone bd groups, respectively. Lack of efficacy was the most common reason for withdrawal, reported for 20.5%, 5.1%, and 8.2% of patients in the placebo, 2 mg rosiglitazone bd, and 4 mg rosiglitazone bd groups, respectively.
Baseline characteristics were similar in all three treatment groups
(Table 1
). For the entire intention to
treat population, mean HbA1c and FPG were 8.9%
and 12.49 mmol/L, respectively. The mean BMI was 29.7
kg/m2, and 74% of patients had a BMI of 27
kg/m2 or more. Before entering the study, 27% of
patients had been managed with diet and exercise alone (drug naive),
and 73% had been receiving oral antihyperglycemic agents (primarily
sulfonylureas). The mean duration of diagnosed diabetes
was approximately 5 yr.
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Rosiglitazone (2 and 4 mg bd) decreased mean
HbA1c by 1.2 and 1.5 percentage points,
respectively (P = 0.0001), compared with placebo (Fig. 1A). At 26 weeks, rosiglitazone (2 and 4
mg bd) reduced mean HbA1c from baseline in the
intention to treat population by 0.3 percentage points
(P = 0.0045) and 0.6 percentage points
(P < 0.0001), respectively, whereas placebo treatment
increased mean HbA1c by 0.9 percentage points
(P < 0.0001; Fig. 1B). The proportions of patients
treated with rosiglitazone (2 and 4 mg bd) who achieved a reduction in
HbA1c from baseline of 1 percentage point or more
were 29.5% and 36.1%, respectively, vs. 3.8% for the
placebo-treated population.
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). In placebo-treated patients
previously treated with a single oral antihyperglycemic agent, mean
HbA1c rose progressively from week -6 until week
4 and was stable throughout the remainder of the treatment phase (Fig. 2B). In rosiglitazone-treated patients, both the drug-naive and
previously treated populations exhibited decreases in mean
HbA1c starting at week 8, which were maximal at
18–26 weeks of treatment (Fig. 2, A and B).
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8% and 7%) at 26 weeks
revealed that a greater number of patients achieved target goals in the
rosiglitazone treatment groups than in the placebo group (Table 2). In patients who were above target
HbA1c levels at baseline, less than 2% of
placebo-treated patients achieved these goals, whereas 39.1% and
19.3% of patients treated with 4 mg rosiglitazone bd achieved
HbA1c below 8% and below 7%, respectively.
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If the data including only those patients who actually completed 26 weeks of treatment are analyzed, 26% and 7% of placebo-treated patients, 52% and 26% of those treated with 2 mg rosiglitazone bd, and 65% and 32% of those treated with 4 mg rosiglitazone bd achieved an HbA1c of 8% or less and 7% or less, respectively.
Furthermore, responders were defined based on clinically important
decreases from baseline at week 26 in HbA1c
(
0.7 percentage point decrease) and FPG (1.67 mmol/L decrease). The
difference in the proportions of HbA1c and FPG
responders relative to the placebo group was statistically significant
in both rosiglitazone-treated groups.
In both rosiglitazone-treated groups, mean FPG decreased by treatment
week 4 and reached a nadir by week 12, remaining stable for the
duration of the double blind treatment phase (Fig. 3). At 26 weeks, rosiglitazone (2 and 4
mg bd) produced mean decreases in FPG relative to placebo of 3.22 and
4.22 mmol/L (P = 0.0001), respectively, and mean
decreases from baseline of 2.11 and 3.00 mmol/L (P =
0.0001), respectively (Table 3).
Placebo-treated patients showed a progressive rise in mean FPG from
baseline (week 0) to week 8 of double blind treatment, after which mean
FPG remained stable for the duration of the double blind treatment
period.
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Effects on ß-cell function and insulin resistance
HOMA estimates of ß-cell function and insulin resistance showed
significant mean increases in ß-cell function and reductions in
insulin resistance among rosiglitazone-treated patients. At 26 weeks,
patients treated with 2 and 4 mg rosiglitazone bd showed increases in
estimated ß-cell function of 49.5% and 60.0%, respectively
(P < 0.00001 compared with placebo for both groups),
By contrast, estimated ß-cell function decreased 4.5% in the placebo
group (Fig. 4).
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).
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).
Rosiglitazone (2 mg bd) significantly reduced these parameters from
baseline, but not compared with placebo.
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There was a statistically significant mean decrease from baseline
in urinary ACR in the 4 mg rosiglitazone bd treatment group (Table 5). The 2 mg rosiglitazone bd treatment
group showed a similar decrease. This may be compared with an
insignificant increase from baseline in the placebo group. Analysis of
ACR in the subgroup of patients with microalbuminuria at baseline
showed that both doses of rosiglitazone were associated with reductions
from baseline in ACR, ranging from approximately 39–42%. Relative to
the placebo group, the rosiglitazone treatment groups showed decreases
in ACR of approximately 30% (Table 6).
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). No statistically significant effect
on plasma triglycerides was noted with either dose of rosiglitazone.
Rosiglitazone-treated patients had significant increases in mean body
weight relative to baseline (1.6 and 3.5 kg for 2 and 4 mg
rosiglitazone bd, respectively) and relative to placebo-treated
patients (2.6 and 4.5 kg for 2 and 4 mg rosiglitazone bd,
respectively). This weight gain, however, was coupled with a
statistically significant decrease from baseline in the waist/hip
ratio. Patients classified as treatment responders (0.7 percentage
point reduction in HBA1c from baseline) gained
more weight than nonresponders.
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The proportions of patients with at least one adverse experience during the double blind treatment phase in the rosiglitazone treatment groups (73.1–74.3%) were similar to the proportion in the placebo group (69.9%). The mean decrease in hemoglobin was 6.0 g/L in the 2 mg rosiglitazone bd group and 10.0 g/L in the 4 mg rosiglitazone bd treatment group. Corresponding mean decreases from baseline in hematocrit were 0.8 (P = 0.0001) and 2.1 percentage points (P < 0.0001), respectively. These hematological changes occurred primarily within the first 8–12 weeks of treatment; hemoglobin remained constant during the second 12 weeks of treatment, whereas hematocrit increased slightly. No patients withdrew due to anemia or decreased hemoglobin or hematocrit.
There were no significant changes from baseline in vital signs or electrocardiogram parameters for rosiglitazone-treated patients compared with placebo-treated patients. Thirty-one patients developed edema during the study: 3 in the placebo group, 10 in the 2 mg rosiglitazone bd group, and 18 in the 4 mg rosiglitazone bd group. All cases of edema were mild (25 cases) or moderate (6 cases), and no patient withdrew due to edema. One patient in the 4 mg rosiglitazone bd treatment group had a transient elevation of aminotransferase level of 217 U/L (reference range, 0–48 U/L) at week 4. However, medication was continued, and the aminotransferase level returned to within the reference range by week 8; the patient completed the study.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Achievement of glycemic targets was significantly influenced by prestudy glucose management therapy. Patients previously treated with diet and exercise alone responded better than those who were previously treated with monotherapy. In previously drug-naive patients, 4 mg rosiglitazone bd produced a decrease in mean HbA1c from 8.5% at baseline to 7.5% at 26 weeks. By contrast, patients treated with 4 mg rosiglitazone bd who had previously received a single antihyperglycemic medication achieved a mean HbA1c of 7.9%. These findings provide support for the early use of rosiglitazone in the treatment of patients with type 2 diabetes who are poorly controlled with diet and exercise alone.
The effects of rosiglitazone in decreasing plasma insulin levels,
increasing body weight, increasing plasma LDL and HDL cholesterol, and
lowering plasma free fatty acids are in accord with what is expected
from a potent PPAR agonist (34, 35). Observed
reductions (or lack of increase) in plasma immunoreactive insulin,
proinsulin, split proinsulin, and C peptide after rosiglitazone
treatment reflect a decrease in insulin resistance, which has been
demonstrated in previous studies of thiazolidinediones. Applying the
HOMA model to the fasting plasma glucose and insulin levels in the
trial population confirmed the effect of rosiglitazone in decreasing
insulin resistance. Several recent studies have shown that the HOMA
model provides a valid assessment of changes in insulin resistance in
population-based studies (32, 37, 38). However, this tool
is not yet validated for measuring improvements in ß-cell function by
other independent methods. Therefore, the data that it provides must be
viewed as an intriguing estimate that needs further validation.
The weight gain observed in rosiglitazone-treated patients may be due to a combination of factors: increased adipocyte differentiation potentially leading to alterations in fat mass (39, 40), fluid retention and edema (39, 41), increased appetite, reductions in physical activity (42), and improved glycemic control. The relative contribution of these is unknown, but will be addressed in future studies. It is interesting to note that the increases in weight were accompanied by decreases in the waist to hip ratio from baseline, suggesting that rosiglitazone treatment leads to increased calorie storage in sc adipocytes, which are not associated with increased cardiovascular risk (43). Several studies measuring regional adiposity by computerized tomography suggest that troglitazone, another thiazolidinedione, decreases visceral and increases sc adipose tissue when given to type 2 diabetic patients (44, 45).
Fluid retention and expanded plasma volume may also contribute to the small decreases observed in hemoglobin and hematocrit in the rosiglitazone-treated groups. There was no significant incidence of elevated liver enzymes associated with rosiglitazone therapy. Furthermore, in approximately 3300 patients with type 2 diabetes treated with rosiglitazone for more than 6 months, there was no significant increase in ALT or other liver enzyme levels, which provides additional support for the hepatic safety of rosiglitazone (46).
Studies using data derived from HOMA calculations have suggested that ß-cell function decreases with duration of diabetes in type 2 diabetic patients treated with diet therapy or antihyperglycemic therapy (47, 48, 49). In this 6-month study, HOMA estimates of ß-cell function indicate that rosiglitazone significantly improves ß-cell function. The improvement in ß-cell function is probably secondary to the increased insulin sensitivity and the concomitant decrease in hyperglycemia. It will be important to determine whether the improvement in ß-cell function that occurs with rosiglitazone therapy persists over several years.
Among rosiglitazone-treated patients who had microalbuminuria at baseline, ACR decreased relative to baseline and placebo. Microalbuminuria in diabetic patients is in part related to insufficient glycemic control and may show significant improvement with glycemic control or antihypertensive therapy (50, 51). As only a small percentage of rosiglitazone-treated patients were receiving concomitant antihypertensive therapy (13.7% and 16.5% of the 2 and 4 mg bd groups, respectively), this decrease is probably the result of either improved glycemic control observed with rosiglitazone or a different effect of thiazolidinediones on mesangial cell function (52).
Rosiglitazone is effective monotherapy for type 2 diabetes when used in patients previously treated with diet and exercise or in patients previously treated with antihyperglycemic monotherapy. The demonstrated effectiveness of rosiglitazone in improving glycemic control while decreasing insulin secretion was well tolerated, and there appears to be no sign of hepatotoxicity (53).
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Acknowledgments |
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Footnotes |
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the Health Sciences-East Falls (Philadelphia, PA); Larry B. Ballonoff, M.D., Endocrinology Department, Kaiser-Permanente (Denver, CO); Thomas C. Marbury, M.D., Orlando Clinical Research Center (Orlando, FL); David Morin, R.Ph., M.D., Tri-Cities Medical Research (Bristol, TN); Larry Gilderman, D.O., University Clinical Research Associates, Inc. (Pembroke Pines, FL); Kenneth H. Williams, M.D. (Baltimore, MD); Bernard S. Burke, M.D., Internal Medicine Associates of West Chester/CCA (West Chester, PA); Angelo A. Licata, M.D., Ph.D., Cleveland Clinic Foundation (Cleveland, OH); Thomas W. Littlejohn III, M.D., Piedmont Medical Research Associates Maplewood Family Practice (Winston- Salem, NC); Paresh Dandona, B.Sc., M.B.B.S., D.Phil., Millard Fillmore Health System (Buffalo, NY); Lance W. Kirkegaard, M.D., Puget Sound Medical Research, Clinical Trials Division of Hilltop Research, Inc. (Tacoma, WA); Paul G. Sandall, M.D., Health Research, Inc. (Albuquerque, NM); David A. Podlecki, M.D., Longmont Clinic, PC (Longmont, CO); Jerry Drucker, M.D. (Palm Harbor, FL); Julio Rosenstock, M.D., Dallas Diabetes and Endo Research Center, PA (Dallas, TX); Alan N. Peiris, M.D., University Physicians Practice Group (Johnson City, TN); Randall Gore, M.D., Hilltop Research (Portland OR); R. Eric McAllister, D.Phil., M.D. (Ukiah, CA); Harold E. Lebovitz, M.D., State University of New York Health Science Center (Brooklyn, NY); Rochelle L. Chaiken, M.D., State University of New York Health Science Center (Brooklyn, NY); C. Andrew De Abate, M.D., C. Andrew De Abate Medical Research Center (New Orleans, LA); Howard T. Hinshaw, M.D., Nalle Clinic (Charlotte, NC); Sheldon Berger, M.D., Chicago Center for Clinical Research (Chicago, IL); Marc S. Rendell, M.D., St. Joseph Hospital/Creighton Diabetes Center (Omaha, NE); Barry Goldstein, M.D., Ph.D., Division of Endocrinology and Metabolic Diseases, Thomas Jefferson University (Philadelphia, PA); Lisa B. Johnson, M.D., Turkshead Internal Medicine Group (West Chester, PA); Anne C. Bowen, M.D., Turkshead Internal Medicine Group (West Chester, PA); Daniel Porte, Jr., M.D., V.A. Puget Sound Health Care System (Seattle, WA); and Summer Pek, M.D., University of Michigan Medical Center (Ann Arbor, MI).
Received December 20, 1999.
Revised September 30, 2000.
Accepted October 5, 2000.
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References |
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 K. Wang, Z. Zhou, M. Zhang, L. Fan, F. Forudi, X. Zhou, W. Qu, A. M. Lincoff, A. M. Schmidt, E. J. Topol, et al. Peroxisome Proliferator-Activated Receptor {gamma} Down-Regulates Receptor for Advanced Glycation End Products and Inhibits Smooth Muscle Cell Proliferation in a Diabetic and Nondiabetic Rat Carotid Artery Injury Model J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 37 - 43. [Abstract] [Full Text] [PDF]
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 A. B. Goldfine, S. Crunkhorn, M. Costello, H. Gami, E. J. Landaker, M. Niinobe, K. Yoshikawa, D. Lo, A. Warren, J. Jimenez-Chillaron, et al. Necdin and E2F4 Are Modulated by Rosiglitazone Therapy in Diabetic Human Adipose and Muscle Tissue Diabetes, March 1, 2006; 55(3): 640 - 650. [Abstract] [Full Text] [PDF]
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F. F. Samaha, P. O. Szapary, N. Iqbal, M. M. Williams, L. T. Bloedon, A. Kochar, M. L. Wolfe, and D. J. Rader Effects of Rosiglitazone on Lipids, Adipokines, and Inflammatory Markers in Nondiabetic Patients With Low High-Density Lipoprotein Cholesterol and Metabolic Syndrome Arterioscler Thromb Vasc Biol, March 1, 2006; 26(3): 624 - 630. [Abstract] [Full Text] [PDF]
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 R. Agarwal Anti-inflammatory effects of short-term pioglitazone therapy in men with advanced diabetic nephropathy Am J Physiol Renal Physiol, March 1, 2006; 290(3): F600 - F605. [Abstract] [Full Text] [PDF]
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 S. Guldiken, B. Turgut, M. Demir, E. Arikan, M. Kara, O. Vural, A. Tugrul, and J. Fareed The Effects of Rosiglitazone Treatment on the Fibrinolytic System in Patients with Type 2 Diabetes Mellitus Clinical and Applied Thrombosis/Hemostasis, January 1, 2006; 12(1): 55 - 60. [Abstract] [PDF]
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 C.-Y. Lin, T. Gurlo, L. Haataja, W. A. Hsueh, and P. C. Butler Activation of Peroxisome Proliferator-Activated Receptor-{gamma} by Rosiglitazone Protects Human Islet Cells against Human Islet Amyloid Polypeptide Toxicity by a Phosphatidylinositol 3'-Kinase-Dependent Pathway J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6678 - 6686. [Abstract] [Full Text] [PDF]
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U. Panchapakesan, S. Sumual, C. A. Pollock, and X. Chen PPAR{gamma} agonists exert antifibrotic effects in renal tubular cells exposed to high glucose Am J Physiol Renal Physiol, November 1, 2005; 289(5): F1153 - F1158. [Abstract] [Full Text] [PDF]
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Z. T. Bloomgarden Second World Congress on the Insulin Resistance Syndrome: Hypertension, cardiovascular disease, and treatment approaches Diabetes Care, August 1, 2005; 28(8): 2073 - 2080. [Full Text] [PDF]
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R. B. Goldberg, D. M. Kendall, M. A. Deeg, J. B. Buse, A. J. Zagar, J. A. Pinaire, M. H. Tan, M. A. Khan, A. T. Perez, S. J. Jacober, et al. A Comparison of Lipid and Glycemic Effects of Pioglitazone and Rosiglitazone in Patients With Type 2 Diabetes and Dyslipidemia Diabetes Care, July 1, 2005; 28(7): 1547 - 1554. [Abstract] [Full Text] [PDF]
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C. Patel, K. L Wyne, and D. K McGuire Thiazolidinediones, peripheral oedema and congestive heart failure: what is the evidence? Diabetes and Vascular Disease Research, May 1, 2005; 2(2): 61 - 66. [Abstract] [PDF]
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H. K.R. Karlsson, K. Hallsten, M. Bjornholm, H. Tsuchida, A. V. Chibalin, K. A. Virtanen, O. J. Heinonen, F. Lonnqvist, P. Nuutila, and J. R. Zierath Effects of Metformin and Rosiglitazone Treatment on Insulin Signaling and Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes: A Randomized Controlled Study Diabetes, May 1, 2005; 54(5): 1459 - 1467. [Abstract] [Full Text] [PDF]
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B. Kimmel and S. E. Inzucchi Oral Agents for Type 2 Diabetes: An Update Clin. Diabetes, April 1, 2005; 23(2): 64 - 76. [Abstract] [Full Text] [PDF]
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 A. Y.Y. Cheng and I. G. Fantus Oral antihyperglycemic therapy for type 2 diabetes mellitus Can. Med. Assoc. J., January 18, 2005; 172(2): 213 - 226. [Abstract] [Full Text] [PDF]
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S. A. Smith, L. E. Porter, N. Biswas, and M. I. Freed Rosiglitazone, But Not Glyburide, Reduces Circulating Proinsulin and the Proinsulin:Insulin Ratio in Type 2 Diabetes J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6048 - 6053. [Abstract] [Full Text] [PDF]
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Y. Guan Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome J. Am. Soc. Nephrol., November 1, 2004; 15(11): 2801 - 2815. [Abstract] [Full Text] [PDF]
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 E. Chiquette, G. Ramirez, and R. DeFronzo A Meta-analysis Comparing the Effect of Thiazolidinediones on Cardiovascular Risk Factors Arch Intern Med, October 25, 2004; 164(19): 2097 - 2104. [Abstract] [Full Text] [PDF]
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H. Yki-Jarvinen Thiazolidinediones N. Engl. J. Med., September 9, 2004; 351(11): 1106 - 1118. [Full Text] [PDF]
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S. Y. Honisett, L. Stojanovska, K. Sudhir, B. A. Kingwell, T. Dawood, and P. A. Komesaroff Hormone Therapy Impairs Endothelial Function in Postmenopausal Women with Type 2 Diabetes Mellitus Treated with Rosiglitazone J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4615 - 4619. [Abstract] [Full Text] [PDF]
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L. Normen, J. Frohlich, J. Montaner, M. Harris, T. Elliott, and G. Bondy Combination Therapy With Fenofibrate and Rosiglitazone Paradoxically Lowers Serum HDL Cholesterol Diabetes Care, September 1, 2004; 27(9): 2241 - 2242. [Full Text] [PDF]
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 C M. B Edwards GLP-1: target for a new class of antidiabetic agents? J R Soc Med, June 1, 2004; 97(6): 270 - 274. [Full Text] [PDF]
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 J. Sutinen, K. Kannisto, E. Korsheninnikova, R. M. Fisher, E. Ehrenborg, T. Nyman, A. Virkamaki, T. Funahashi, Y. Matsuzawa, H. Vidal, et al. Effects of rosiglitazone on gene expression in subcutaneous adipose tissue in highly active antiretroviral therapy-associated lipodystrophy Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E941 - E949. [Abstract] [Full Text] [PDF]
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 A. Y. Cheng and I G. Fantus Thiazolidinedione-Induced Congestive Heart Failure Ann. Pharmacother., May 1, 2004; 38(5): 817 - 820. [Abstract] [Full Text] [PDF]
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H. Bays, L. Mandarino, and R. A. DeFronzo 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., February 1, 2004; 89(2): 463 - 478. [Full Text] [PDF]
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A. R. Diani, G. Sawada, B. Wyse, F. T. Murray, and M. Khan Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes Am J Physiol Endocrinol Metab, January 1, 2004; 286(1): E116 - E122. [Abstract] [Full Text]
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M. B. Davidson Is Treatment of Insulin Resistance Beneficial Independent of Glycemia? Diabetes Care, November 1, 2003; 26(11): 3184 - 3186. [Full Text] [PDF]
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 B. K. Skrumsager, K. K. Nielsen, M. Muller, G. Pabst, P. G. Drake, and B. Edsberg Ragaglitazar: The Pharmacokinetics, Pharmacodynamics, and Tolerability of a Novel Dual PPAR{alpha} and {gamma} Agonist in Healthy Subjects and Patients with Type 2 Diabetes J. Clin. Pharmacol., November 1, 2003; 43(11): 1244 - 1256. [Abstract] [Full Text] [PDF]
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V. De Leo, A. la Marca, and F. Petraglia Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome Endocr. Rev., October 1, 2003; 24(5): 633 - 667. [Abstract] [Full Text] [PDF]
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J. P.H. van Wijk, E. J.P. de Koning, E. P. Martens, and T. J. Rabelink Thiazolidinediones and Blood Lipids in Type 2 Diabetes Arterioscler Thromb Vasc Biol, October 1, 2003; 23(10): 1744 - 1749. [Abstract] [Full Text] [PDF]
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V. Fonseca, G. Grunberger, S. Gupta, S. Shen, and J. E. Foley Addition of Nateglinide to Rosiglitazone Monotherapy Suppresses Mealtime Hyperglycemia and Improves Overall Glycemic Control Diabetes Care, June 1, 2003; 26(6): 1685 - 1690. [Abstract] [Full Text] [PDF]
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 J. Tordjman, G. Chauvet, J. Quette, E. G. Beale, C. Forest, and B. Antoine Thiazolidinediones Block Fatty Acid Release by Inducing Glyceroneogenesis in Fat Cells J. Biol. Chem., May 23, 2003; 278(21): 18785 - 18790. [Abstract] [Full Text] [PDF]
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 J. Tuepker, S. M. Haffner, K. Williams, A. S. Greenberg, W. M. Weston, H. Chen, and M. I. Freed Effect of Rosiglitazone Treatment on Nontraditional Markers of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus * Response Circulation, April 29, 2003; 107 (16): e109 - e109. [Full Text] [PDF]
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I. Pavo, G. Jermendy, T. T. Varkonyi, Z. Kerenyi, A. Gyimesi, S. Shoustov, M. Shestakova, M. Herz, D. Johns, B. J. Schluchter, et al. Effect of Pioglitazone Compared with Metformin on Glycemic Control and Indicators of Insulin Sensitivity in Recently Diagnosed Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1637 - 1645. [Abstract] [Full Text] [PDF]
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 F. Zangeneh, Y. C. Kudva, and A. Basu Insulin Sensitizers Mayo Clin. Proc., April 1, 2003; 78(4): 471 - 479. [Abstract] [PDF]
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M. C. Chapelsky, K. Thompson-Culkin, A. K. Miller, M. Sack, R. Blum, and M. I. Freed Pharmacokinetics of Rosiglitazone in Patients with Varying Degrees of Renal Insufficiency J. Clin. Pharmacol., March 1, 2003; 43(3): 252 - 259. [Abstract] [Full Text] [PDF]
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K. A. Virtanen, K. Hallsten, R. Parkkola, T. Janatuinen, F. Lonnqvist, T. Viljanen, T. Ronnemaa, J. Knuuti, R. Huupponen, P. Lonnroth, et al. Differential Effects of Rosiglitazone and Metformin on Adipose Tissue Distribution and Glucose Uptake in Type 2 Diabetic Subjects Diabetes, February 1, 2003; 52(2): 283 - 290. [Abstract] [Full Text] [PDF]
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K. Starkey, A. Heufelder, G. Baker, W. Joba, M. Evans, S. Davies, and M. Ludgate Peroxisome Proliferator-Activated Receptor-{gamma} in Thyroid Eye Disease: Contraindication for Thiazolidinedione Use? J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 55 - 59. [Abstract] [Full Text] [PDF]
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 B. Ljung, K. Bamberg, B. Dahllof, A. Kjellstedt, N. D. Oakes, J. Ostling, L. Svensson, and G. Camejo AZ 242, a novel PPAR{alpha}/{gamma} agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats J. Lipid Res., November 1, 2002; 43(11): 1855 - 1863. [Abstract] [Full Text] [PDF]
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M. St. John Sutton, M. Rendell, P. Dandona, J. F. Dole, K. Murphy, R. Patwardhan, J. Patel, and M. Freed A Comparison of the Effects of Rosiglitazone and Glyburide on Cardiovascular Function and Glycemic Control in Patients With Type 2 Diabetes Diabetes Care, November 1, 2002; 25(11): 2058 - 2064. [Abstract] [Full Text] [PDF]
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G. Viberti, S. E. Kahn, D. A. Greene, W. H. Herman, B. Zinman, R. R. Holman, S. M. Haffner, D. Levy, J. M. Lachin, R. A. Berry, 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, October 1, 2002; 25(10): 1737 - 1743. [Abstract] [Full Text] [PDF]
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S. M. Haffner, A. S. Greenberg, W. M. Weston, H. Chen, K. Williams, and M. I. Freed Effect of Rosiglitazone Treatment on Nontraditional Markers of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus Circulation, August 6, 2002; 106(6): 679 - 684. [Abstract] [Full Text] [PDF]
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 S. E. Inzucchi Oral Antihyperglycemic Therapy for Type 2 Diabetes: Scientific Review JAMA, January 16, 2002; 287(3): 360 - 372. [Abstract] [Full Text] [PDF]
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W. A. Hsueh and R. E. Law PPAR{gamma} and Atherosclerosis: Effects on Cell Growth and Movement Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1891 - 1895. [Abstract] [Full Text] [PDF]
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C. J Bailey and C. Day Review: Thiazolidinediones today The British Journal of Diabetes & Vascular Disease, August 1, 2001; 1(1): 7 - 13. [Abstract] [PDF]
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P. Raskin, M. Rendell, M. C. Riddle, J. F. Dole, M. I. Freed, and J. Rosenstock A Randomized Trial of Rosiglitazone Therapy in Patients With Inadequately Controlled Insulin-Treated Type 2 Diabetes Diabetes Care, July 1, 2001; 24(7): 1226 - 1232. [Abstract] [Full Text] [PDF]
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