| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Studies |
University of Arkansas for Medical Sciences (V.A.F), Little Rock, Arkansas 72205; and Parke-Davis Pharmaceutical Research Division of Warner-Lambert Company (T.R.V., S.M.H., M.N.G., R.W.W.), Ann Arbor, Michigan 48105
Address all correspondence and requests for reprints to: Thomas R. Valiquett, Clinical Research, Parke-Davis/Warner Lambert Research Division, 2800 Plymouth Road, Ann Arbor, Michigan 48105
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
1.5 ng/mL. Prior oral hypoglycemic therapy was
withdrawn in patients who received it before the study. FSG, HbA1c,
C-peptide, and serum insulin were evaluated at baseline and the end of
the study. Analysis was performed on two subsets of patients based on
prestudy therapy: Patients treated with diet and exercise only before
the study (22% of patients), and those who had been receiving
sulfonylurea therapy (78% of patients). Patients treated with 400 and 600 mg troglitazone had significant decreases from baseline in mean FSG and HbA1c at month 6 compared with placebo-treated patients (FSG: -51 and -60 mg/dL, respectively; HbA1c: -0.7 and -1.1%, respectively). In the diet-only subset, 600 mg troglitazone therapy resulted in a significant (P < 0.05) reduction in HbA1c (-1.35%) and a significant reduction in FSG (-42 mg/dL) compared with placebo. Patients previously treated with sulfonylurea therapy had significant (P < 0.05) decreases in mean FSG with 200–600 mg troglitazone therapy compared with placebo (-48, -61, and -66 mg/dL, respectively). Significant (P < 0.05) decreases in mean HbA1c occurred with 400 and 600 mg troglitazone therapy at month 6 (-0.8 and -1.2%, respectively) compared with placebo in this same subset. Significant (P < 0.05) decreases in tri-glycerides and free fatty acids occurred with troglitazone 400 and 600 mg, and increased high-density lipoprotein occurred with 600 mg troglitazone.
We conclude that troglitazone monotherapy significantly improves HbA1c and fasting serum glucose, while lowering insulin and C-peptide in patients with type 2 diabetes. Troglitazone 600 mg monotherapy is efficacious for patients who are newly diagnosed and have never received pharmacological intervention for diabetes.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Troglitazone (Rezulin) is a new therapeutic agent for the treatment of type 2 diabetes mellitus that reduces insulin resistance by enhancing insulin action in skeletal muscle, liver, and adipose tissue (5, 6). Troglitazone is a thiazolidinedione and is not an insulin secretagogue, nor does it mimic the action of insulin. Although the exact molecular mechanism of action is unknown, it may enhance insulin sensitivity by interacting with peroxisome proliferator-activated receptors to alter gene expression related to key proteins involved in insulin action (5). In patients with mild to moderate type 2 diabetes, troglitazone monotherapy administered for 12 weeks resulted in decreased insulin resistance and improved glycemic control in those who were previously maintained by diet alone or who were inadequately controlled with sulfonylurea therapy (7, 8). The purpose of the present study was to determine the metabolic effects of troglitazone monotherapy over a range of doses in patients with type 2 diabetes who had progressed to moderately uncontrolled levels of fasting glucose in the presence of adequate insulin levels.
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This 6-month, double-blind, placebo-controlled trial was conducted at 21 hospital and outpatient clinics across all regions of the United States and three provinces of Canada. Patients discontinued all pharmacological treatment for diabetes during a 2-week screening period before the 6-month double-blind period. Patients using diet and exercise as their only treatment regimen continued this regimen during screening and throughout the study. Four patients in the Canadian centers were on metformin monotherapy, which was discontinued at screening. Patients were then randomly assigned to receive either troglitazone 100, 200, 400, or 600 mg or matching placebo according to a blocked randomization schedule (block size 5). Blinded study medication was administered once daily with a beverage during breakfast (QAM). The protocol was Institutional Review Board approved, and all patients signed informed consents.
All biochemical measurements were made by Corning-Nichols Lab. (San Juan Capistrano, CA) on blood collected monthly after an overnight fast (water only). Hemoglobin A1c (HbA1c) was measured using automated ion-exchange high performance liquid chromatography (Bio-Rad Variant, Bio-Rad Labs., Hercules, CA), serum glucose by enzymatic (hexokinase) method, insulin by a two-site immunoenzymometric assay (sensitivity 2.5 µU/mL, no cross-reactivity with C-peptide), and C-peptide with a double antibody RIA (sensitivity 0.25 ng/mL).
Patients
Men or women with inadequately controlled type 2 diabetes were
entered into this study. Patients were required to have a fasting serum
glucose (FSG) of >140 mg/dL and an HbA1c of >6.5% (upper limit of
normal reference range), and a fasting C-peptide level of 1.5 ng/mL
was required to insure adequate ß-cell function (0.5–2.0 ng/mL
normal range). Of the 642 subjects screened, 61 (<10%) had a
fasting C-peptide level <1.5 ng/mL. Patients had been treated with
either diet (and exercise) alone (22% of patients) or up to half the
maximum dose of a sulfonylurea (78% of patients). Patients who used
insulin chronically or had a history of ketoacidosis, symptomatic
diabetic neuropathy or retinopathy, or renal disease (serum creatinine
>2 mg/dL) were excluded, as were patients with significant
cardiovascular complications, active cancer, or elevated liver
enzymes.
The 402 patients who were randomized into the double-blind phase were
evenly distributed across treatment groups with respect to age; gender;
race; body mass index; duration of diabetes; and baseline FSG, HbA1c,
and C-peptide (Table 1
). Baseline
glycemic measures were indicative of inadequate glycemic control with
mean FSG and HbA1c, well above the normal range.
|
). FSG levels at screening (first visit) were similar
between the two patient subsets (
200 mg/dL). However, baseline FSG
increased substantially in the 2-week period between screening and
randomization (baseline) for those patients who had discontinued
sulfonylurea therapy (Table 1). This difference in glycemic control at
randomization for these two subsets of patients had a major impact on
the results of the study and are analyzed separately within this
study. Disposition
Of the 402 patients enrolled, 286 (71%) completed 6 months of treatment. A greater percentage of patients completed treatment as the dose of troglitazone increased. Twenty six percent of patients in the placebo group withdrew because of inadequate glycemic control, whereas only 13% of patients treated with 600 mg troglitazone withdrew for the same reason (unacceptable glycemic control as determined by investigator). Twenty one percent, 19%, and 13% of patients treated with 100 mg, 200 mg, and 400 mg troglitazone, respectively, were withdrawn for unacceptable glycemic control.
Efficacy and safety assessments
Changes from baseline in FSG and HbA1c after 6 months of treatment were the primary efficacy end points. In addition, insulin and C-peptide levels were assessed.
A complete physical examination and electrocardiogram were performed at screening and at the end of the study. A standard panel of laboratory parameters (chemistry, hematology, and urinalysis) was monitored on a monthly basis, and treatment-emergent adverse events were reported using a modified COSTART dictionary.
Statistical analyses
An intent-to-treat analysis was performed for all patients randomized into the double-blind study having a baseline measurement and at least one follow-up measurement. Patients withdrawing before the end of the study were included using the last-observation-carried-forward rule.
Summary statistics were calculated for baseline and change from baseline at each month of the double-blind period for each efficacy variable. Baseline was the last available measurement taken before randomization. An analysis of covariance (ANCOVA) was performed to adjust for treatment-group differences at baseline with effects due to treatment, center, and baseline as a covariate. Comparisons between troglitazone groups and placebo were performed using step-down tests for linear trend and Dunnett’s tests (9, 10, 11).
Analysis of two patient subsets was conducted to explore the effect of prestudy antidiabetic therapy on glycemic measures. The first subset consisted of patients who had been on diet therapy only and had never received pharmacological intervention for diabetes before the study. The second subset consisted of patients who had been receiving up to half the maximal dose of an oral antidiabetic agent, mainly sulfonylureas, before entering the study. For each patient subset, the difference in change from baseline in glycemic measures at month 6 between troglitazone and placebo was investigated using ANCOVA with the effect of treatment, center, and baseline as a covariate.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Troglitazone, at doses of 200–600 mg, significantly improved
glycemic control compared with placebo after 6 months of treatment.
When the adjusted mean change from baseline (adjusted for
treatment-group differences at baseline and effect of study center) was
compared with placebo, FSG was reduced by 42 mg/dL, 51 mg/dL, and 60
mg/dL at 200 mg, 400 mg, and 600 mg troglitazone, respectively.
Patients treated with 400 and 600 mg troglitazone had significant
reductions in HbA1c when compared with placebo; the adjusted mean
changes from baseline relative to placebo for 400-mg and 600-mg groups
were -0.7% and -1.1%, respectively. (Fig. 1). Overall, 40% and 42% of patients
treated with 400 mg and 600 mg troglitazone, respectively, reached a
level of HbA1c 
8%.
|
Glycemic control: analysis by prestudy therapy
At the initial screening visit, mean FSG values for patients who
withdrew from sulfonylurea therapy and those on diet-only prestudy were
virtually identical (Table 1). When patients withdrew from sulfonylurea
therapy following screening, glycemic control deteriorated over the
2-week period between screening and baseline, skewing the mean baseline
FSG upward by 41 mg/dL in this subset of patients (represents 78% of
all patients). In contrast, mean FSG remained virtually unchanged from
screening to baseline (+3 mg/dL) in diet-only patients (200.3 mg/dL and
201.2 mg/dL, respectively). Figure 2A illustrates the deterioration
of glycemic control experienced by patients when sulfonylurea therapy
was removed following screening.
|
Both HbA1c and FSG showed significant improvement
(P < 0.05) at the 600-mg dose of troglitazone for
patients who were on diet-only prestudy therapy before the study (Fig. 3A and B). Statistical significance was
achieved at the 600-mg dose despite the low number of patients (15, 16, 17, 18, 19)
per treatment group (Table 2). Sixty
seven percent of the patients treated with 600 mg troglitazone achieved
an HbA1c 8% compared with 44% of placebo-treated patients. Forty
percent of patients treated with 600 mg troglitazone achieved the
American Diabetes Association target goal (12) for HbA1c of <7%
compared with 17% of placebo-treated patients.
|
|
Patients treated with sulfonylureas prestudy showed significant
(P < 0.05) reductions in FSG and HbA1c compared with
placebo at the 400-and 600-mg dose of troglitazone (Table 2).
However, the declines in HbA1c did not reach baseline levels because of
the dramatic increase in FSG following withdrawal of sulfonylurea
therapy at the screening visit. It is important to note that the
magnitude of the difference from placebo in HbA1c at month 6 was
similar for the diet-treated and sulfonylurea-treated patient subsets
at the 600-mg dose of troglitazone.
Fasting insulin and C-peptide
As expected, when therapy with an insulin secretagogue is
discontinued, insulin declines, as was observed for those patients on
sulfonylurea therapy prestudy (Table 3). These patients treated with
placebo showed a median reduction in insulin of 11% in response to the
withdrawal of the secretagogue. The degree of insulin reduction
attributable to troglitazone was confounded by the withdrawal of the
insulin secretagogue. However, a true pharmacological effect could be
observed for that subset of patients who never received sulfonylurea
therapy. These patients had mean reductions from baseline in insulin of
20% (400 mg) and 25% (600 mg) and in C-peptide of 36% for patients
treated with 400 and 600 mg troglitazone. This reduction in circulating
insulin and C-peptide, coupled with the reduction in FSG, suggests
improved insulin-mediated peripheral glucose utilization.
|
Patients treated with troglitazone 200–600 mg showed
significant (P < 0.05) reductions in mean
triglycerides compared with placebo; these reductions represent a
15–23% decrease in triglycerides from baseline (Table 4). Mean levels of free fatty acids
(FFAs) also decreased significantly (P < 0.05) for
patients treated with 400 and 600 mg troglitazone; patients treated
with 600 mg had a 35% decrease in FFAs. An improvement in mean
high-density lipoprotein (HDL) (an increase) occurred in patients
treated with 200 and 600 mg troglitazone; patients treated with 600 mg
troglitazone had a significant (P < 0.01) increase in
mean HDL compared with placebo, and a 12% increase compared with
baseline. Low-density lipoprotein (LDL) increased at month 6 for
troglitazone-treated patients. These increases were significantly
different from placebo (P < 0.05) for patients treated
with 100–600 mg troglitazone. However, there were no changes in
apolipoprotein B in patients treated with troglitazone or placebo
|
Troglitazone was well tolerated throughout the study, with an
adverse event profile similar to that of placebo. Overall, 75% of
placebo-treated and 75% of troglitazone-treated patients reported one
or more adverse events, with the comparable percentages at all
troglitazone doses. The most frequently occurring adverse events were
infection, pain, and headache for both placebo- and
troglitazone-treated patients overall (Table 5). Serious adverse events occurred in
4% of placebo-treated patients and 4% of troglitazone-treated
patients; none were considered by the investigator to be related to
troglitazone. There were no clinically significant changes in physical
examination, or electrocardiogram for troglitazone-treated patients. No
clinically significant changes from baseline in weight were observed
(-8 lb, -5 lb, -3 lb, 0 lb, and 1 lb for placebo, 100 mg, 200
mg, 400 mg, and 600 mg troglitazone, respectively); changes in weight
correlated with changes in glycemic control.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The differences in these two populations became clear on withdrawal of sulfonylurea therapy over the 2-week period between the screening visit and the baseline visit. Patients previously treated with sulfonylurea therapy prestudy showed a dramatic increase of 41 mg/dL FSG (mean) from screening, whereas patients treated with diet only prestudy showed virtually no change over this 2-week period. Therefore, patients in these two subgroups began the study at two very different levels of glycemic control, which ultimately impacted the study outcome.
Following 6 months of troglitazone treatment, the magnitude of reductions in FSG were similar for both the diet-only and sulfonylurea prestudy subgroups (-48 mg/dL and -33 mg/dL at 600 mg troglitazone, respectively). However, absolute levels of glycemic control relative to prestudy levels were improved only for the diet pretreated patients. Diet-only pretreated patients also demonstrated a more rapid rate of FSG reduction. This, coupled with the lower level of HbA1c when troglitazone was initiated in this patient group, was possibly because of comparatively better insulin responsiveness to glucose because of lower glucose levels and higher levels of circulating insulin (14, 15). Indeed, at the start of treatment (randomization), insulin levels were found to be lower in the patients in which sulfonylurea was withdrawn compared with those pretreated with diet.
These results suggest that when insulin levels are reduced by withdrawal of sulfonylurea therapy, the efficacy of troglitazone is delayed. Troglitazone is an insulin action enhancing agent and requires the presence of insulin to manifest its glucose lowering effects. Previous studies of troglitazone have confirmed a high correlation between circulating insulin concentrations and glucose reduction (16).
The results of this study have important implications in the use of troglitazone based on the progression of type 2 diabetes and the presence or absence of other antidiabetes therapy. Hyperglycemia associated with type 2 diabetes likely results from a combination of peripheral tissue insulin resistance and defective ß-cell insulin secretory response to glucose. The duration of diabetes as it relates to ß-cell reserve and responsiveness to glucose may be central in determining the degree to which patients will respond to troglitazone monotherapy and which patients will require the maintenance of an insulin secretagogue in combination with troglitazone. Results of a large study of troglitazone monotherapy and in combination with maximum dose sulfonylurea in patients in later stages of diabetes in poor glycemic control showed that patients who had troglitazone added to existing sulfonylurea without a period of sulfonylurea withdrawal experienced significant, absolute improvements in glycemic measures compared with baseline, and a large proportion of patients achieved American Diabetes Association treatment target goals of HbA1c <7% (17). The effectiveness of troglitazone monotherapy being better without a sulfonylurea washout period suggests that in the present study the withdrawal of sulfonylurea delayed glycemic response to troglitazone.
In this study, a dose-dependent lowering of plasma FFAs and triglycerides in troglitazone-treated patients is consistent with a primary effect of the drug to suppress lipolysis (18). The lowering of circulating FFAs can be expected to enhance the effect of insulin to suppress hepatic glucose production and further stimulate peripheral glucose utilization (19, 20) Apolipoprotein B, a highly atherogenic component of LDL, did not change nor did circulating very-low-density lipoprotein, indicative of a shift in total cholesterol from smaller to larger, less atherogenic particle size (21). These results are consistent with another troglitazone study showing significant shifts in LDL particle size from small and dense to large, buoyant, less atherogenic particles (22).
In summary, troglitazone monotherapy is safe and effective oral therapy for patients with type 2 diabetes in whom diet therapy has failed.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Troglitazone Study Group: Thomas Blevins, Austin, Texas; Joshua
Cohen, Washington, District of Columbia; Keith Dawson, Vancouver,
British Columbia, Canada; Neal Friedman, Albuquerque, New Mexico;
Hertzel Gerstein, Hamilton, Ontario, Canada; Barry Goldstein,
Philadelphia, Pennsylvania; Barry Gumbiner, Rochester, New York;
Jennifer Hone, Wheatridge, Colorado; Willa Hsueh, Los Angeles,
California; David Kelly, Pittsburgh, Pennsylvania; K. Jean Lucas,
Atlanta, Georgia; Frank Maggiacomo, Providence, Rhode Island; William
Mitchell, Albuquerque, New Mexico; Jerrold Olefsky, San Diego,
Californ; Ann Peters, Los Angeles, California; Sanford Plevin, Palm
Harbor, Florida; Kenneth Polonsky, Chicago, Illinois; Stuart Ross,
Calgary, Alberta, Canada; Sherwyn Schwartz, San Antonio, Texas;
Gerald Shulman, New Haven, Connecticut; Richard Sims, Birmingham,
Alabama; James Snyder, Las Vegas, Nevada; Ruenrudee Suwannasri, St.
Louis, Missouri.
Received December 18, 1997.
Revised March 5, 1998.
Revised June 3, 1998.
Accepted June 9, 1998.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  X. Ruan, F. Zheng, and Y. Guan PPARs and the kidney in metabolic syndrome Am J Physiol Renal Physiol, May 1, 2008; 294(5): F1032 - F1047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. K. McGuire and S. E. Inzucchi New Drugs for the Treatment of Diabetes Mellitus: Part I: Thiazolidinediones and Their Evolving Cardiovascular Implications Circulation, January 22, 2008; 117(3): 440 - 449. [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Christensen, B. Meibohm, E. V. Capparelli, P. Velasquez-Mieyer, G. A. Burghen, and W. V. Tamborlane Single- and Multiple-Dose Pharmacokinetics of Pioglitazone in Adolescents With Type 2 Diabetes J. Clin. Pharmacol., October 1, 2005; 45(10): 1137 - 1144. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 Y. Miyazaki, A. Mahankali, E. Wajcberg, M. Bajaj, L. J. Mandarino, and R. A. DeFronzo Effect of Pioglitazone on Circulating Adipocytokine Levels and Insulin Sensitivity in Type 2 Diabetic Patients J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4312 - 4319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Strowig, M. L. Aviles-Santa, and P. Raskin Improved Glycemic Control Without Weight Gain Using Triple Therapy in Type 2 Diabetes Diabetes Care, July 1, 2004; 27(7): 1577 - 1583. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 K. M. Ogilvie, R. Saladin, T. R. Nagy, M. S. Urcan, R. A. Heyman, and M. D. Leibowitz Activation of the Retinoid X Receptor Suppresses Appetite in the Rat Endocrinology, February 1, 2004; 145(2): 565 - 573. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Davidson Is Treatment of Insulin Resistance Beneficial Independent of Glycemia? Diabetes Care, November 1, 2003; 26(11): 3184 - 3186. [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 E. H. Koh, M.-S. Kim, J.-Y. Park, H. S. Kim, J.-Y. Youn, H.-S. Park, J. H. Youn, and K.-U. Lee Peroxisome Proliferator-Activated Receptor (PPAR)-{alpha} Activation Prevents Diabetes in OLETF Rats: Comparison With PPAR-{gamma} Activation Diabetes, September 1, 2003; 52(9): 2331 - 2337. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 R. L. Barbieri Metformin for the Treatment of Polycystic Ovary Syndrome Obstet. Gynecol., April 1, 2003; 101(4): 785 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Strowig, M. L. Aviles-Santa, and P. Raskin Comparison of Insulin Monotherapy and Combination Therapy With Insulin and Metformin or Insulin and Troglitazone in Type 2 Diabetes Diabetes Care, October 1, 2002; 25(10): 1691 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Miyazaki, A. Mahankali, M. Matsuda, S. Mahankali, J. Hardies, K. Cusi, L. J. Mandarino, and R. A. DeFronzo Effect of Pioglitazone on Abdominal Fat Distribution and Insulin Sensitivity in Type 2 Diabetic Patients J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2784 - 2791. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Miyazaki, M. Matsuda, and R. A. DeFronzo Dose-Response Effect of Pioglitazone on Insulin Sensitivity and Insulin Secretion in Type 2 Diabetes Diabetes Care, March 1, 2002; 25(3): 517 - 523. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. E. Inzucchi Oral Antihyperglycemic Therapy for Type 2 Diabetes: Scientific Review JAMA, January 16, 2002; 287(3): 360 - 372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Miyazaki, A. Mahankali, M. Matsuda, L. Glass, S. Mahankali, E. Ferrannini, K. Cusi, L. J. Mandarino, and R. A. DeFronzo Improved Glycemic Control and Enhanced Insulin Sensitivity in Type 2 Diabetic Subjects Treated With Pioglitazone Diabetes Care, April 1, 2001; 24(4): 710 - 719. [Abstract] [Full Text]
|
|
|
|
 |
|
 E. Arioglu, J. Duncan-Morin, N. Sebring, K. I. Rother, N. Gottlieb, J. Lieberman, D. Herion, D. E. Kleiner, J. Reynolds, A. Premkumar, et al. Efficacy and Safety of Troglitazone in the Treatment of Lipodystrophy Syndromes Ann Intern Med, August 15, 2000; 133(4): 263 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. DeFronzo Pharmacologic Therapy for Type 2 Diabetes Mellitus Ann Intern Med, August 17, 1999; 131(4): 281 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. I. Misbin The Ethics of Clinical Research Ann Intern Med, February 2, 1999; 130(3): 241 - 241. [Full Text] [PDF]
|
|
|
|
|
|
R. I. Misbin Comment on the Ethics of Placebo-Controlled Trials in Patients with Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 823 - 823. [Full Text]
|
|
|
|
|
|
V. Fonseca Ethics of Placebo-Controlled Trials in Patients with Type 2 Diabetes Mellitus--Authors' Response J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 823a - 824. [Full Text]
|
|
|
|
|
|
Y. Guan, Y. Zhang, A. Schneider, L. Davis, R. M. Breyer, and M. D. Breyer Peroxisome proliferator-activated receptor-gamma activity is associated with renal microvasculature Am J Physiol Renal Physiol, December 1, 2001; 281(6): F1036 - F1046. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
