Clinical Care/Education/Nutrition

O R I G I N A L

A R T I C L E

A Comparison of Lipid and Glycemic

Effects of Pioglitazone and Rosiglitazone
in Patients With Type 2 Diabetes and
Dyslipidemia
RONALD B. GOLDBERG, MD1
DAVID M. KENDALL, MD2
MARK A. DEEG, MD, PHD 3
JOHN B. BUSE, MD, PHD4
ANTHONY J. ZAGAR, MS5
JANE A. PINAIRE, PHD5

MENG H. TAN, MD5

MEHMOOD A. KHAN, MD6
ALFONSO T. PEREZ, MD7
SCOTT J. JACOBER, DO5
FOR THE GLAI STUDY INVESTIGATORS

OBJECTIVE Published reports suggest that pioglitazone and rosiglitazone have different
effects on lipids in patients with type 2 diabetes. However, these previous studies were either
retrospective chart reviews or clinical trials not rigorously controlled for concomitant glucoseand lipid-lowering therapies. This study examines the lipid and glycemic effects of pioglitazone
and rosiglitazone.
RESEARCH DESIGN AND METHODS We enrolled subjects with a diagnosis of
type 2 diabetes (treated with diet alone or oral monotherapy) and dyslipidemia (not treated with
any lipid-lowering agents). After a 4-week placebo washout period, subjects randomly assigned
to the pioglitazone arm (n 400) were treated with 30 mg once daily for 12 weeks followed by
45 mg once daily for an additional 12 weeks, whereas subjects randomly assigned to rosiglitazone (n 402) were treated with 4 mg once daily followed by 4 mg twice daily for the same
intervals.
RESULTS Triglyceride levels were reduced by 51.9 7.8 mg/dl with pioglitazone, but
were increased by 13.1 7.8 mg/dl with rosiglitazone (P 0.001 between treatments). Additionally, the increase in HDL cholesterol was greater (5.2 0.5 vs. 2.4 0.5 mg/dl; P 0.001)
and the increase in LDL cholesterol was less (12.3 1.6 vs. 21.3 1.6 mg/dl; P 0.001) for
pioglitazone compared with rosiglitazone, respectively. LDL particle concentration was reduced
with pioglitazone and increased with rosiglitazone (P 0.001). LDL particle size increased more
with pioglitazone (P 0.005).
CONCLUSIONS Pioglitazone and rosiglitazone have significantly different effects on
plasma lipids independent of glycemic control or concomitant lipid-lowering or other antihyperglycemic therapy. Pioglitazone compared with rosiglitazone is associated with significant
improvements in triglycerides, HDL cholesterol, LDL particle concentration, and LDL particle
size.
Diabetes Care 28:15471554, 2005

From the 1Division of Endocrinology, Metabolism, and Diabetes, University of Miami School of Medicine,
Miami, Florida; the 2International Diabetes Center, Park Nicollet Institute, Minneapolis, Minnesota; the
3
Division of Endocrinology and Metabolism, Department of Veterans Affairs and the Indiana University
School of Medicine, Indianapolis, Indiana; the 4Divisions of Endocrinology and of General Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina; the 5Lilly Research Laboratories,
Eli Lilly, Indianapolis, Indiana; 6Takeda Pharmaceuticals North America, Lincolnshire, Illinois; and the
7
Takeda Global Research and Development Center, Lincolnshire, Illinois.
Address correspondence and reprint requests to Scott J. Jacober, DO, Lilly Research Laboratories, A
Division of Eli Lilly, Lilly Corporate Center, DC 5116, Indianapolis, IN 46285. E-mail: sjacober@lilly.com.
Received for publication 10 February 2005 and accepted in revised form 31 March 2005.
Abbreviations: CHD, coronary heart disease; CVD, cardiovascular disease; LOCF, last observation carried forward; PAI-1, plasminogen activator inhibitor-1.
A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
factors for many substances.
2005 by the American Diabetes Association.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby
marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

DIABETES CARE, VOLUME 28, NUMBER 7, JULY 2005

wo core metabolic defects contribute to the development of type 2 diabetes: relative insulin insufficiency
and insulin resistance. Approximately
92% of patients with type 2 diabetes demonstrate insulin resistance (1). Even in the
absence of overt hyperglycemia, insulin
resistance is associated with a cluster of
abnormalities that increase the risk for
cardiovascular disease (CVD), including
dyslipidemia, increased expression of inflammatory markers, activation of procoagulants, hemodynamic changes, and
endothelial dysfunction (2,3).
The dyslipidemia associated with insulin resistance and type 2 diabetes is
characterized by elevated triglycerides
and decreased HDL cholesterol (4 6).
Although LDL cholesterol may not be elevated in type 2 diabetes, an increase in
the proportion of small, dense, and potentially more atherogenic LDL cholesterol particles is observed (7). In addition
to LDL cholesterol, elevated triglyceride
levels and reduced HDL cholesterol levels
are both risk factors for coronary heart
disease (CHD) (8 11). Compared with
nondiabetic individuals, patients with
type 2 diabetes have a two- to fourfold
higher risk of CVD, and dyslipidemia is
an important contributor to the increased
risk in this population (12).
By targeting insulin resistance, the
members of the thiazolidinedione class of
oral antihyperglycemic medications possess both a glucose-lowering effect and
the potential to alter lipid/lipoprotein metabolism. Two members of the thiazolidinedione class are currently available
for the treatment of type 2 diabetes: pioglitazone hydrochloride (Actos; Takeda
Pharmaceuticals North America, Lincolnshire, IL) and rosiglitazone maleate
(Avandia; GlaxoSmithKline, Research
Triangle Park, NC).
This study was conceived following
the report of a nonrandomized clinical
comparison of potential differences in
lipid effects among thiazolidinediones
1547

Effects of pioglitazone and rosiglitazone

Figure 1Patient flow through the study.

(13). Since that time, multiple reports

(14 22) have been published suggesting
that pioglitazone has differential effects
on lipid parameters in patients with type
2 diabetes when compared with rosiglitazone. However, these previous studies
were either retrospective chart review
studies, clinical trials not rigorously controlled for concomitant glucose-lowering
and lipid-lowering therapies, or systematic reviews. With the primary objective
to test the hypothesis that pioglitazone
has greater triglyceride-lowering effects
than rosiglitazone, this study reports results from the first multicenter, prospective, randomized, double-blind, parallelgroup comparison of maximally effective
monotherapy doses of pioglitazone and
rosiglitazone in patients with type 2 diabetes and dyslipidemia receiving no concomitant glucose-lowering or lipidlowering therapies.
RESEARCH DESIGN AND
METHODS Subjects eligible for
participation in this clinical trial were
1548

men or women 35 years of age with a

diagnosis of type 2 diabetes (based on
World Health Organization criteria) with
fasting triglyceride levels 150 mg/dl and
600 mg/dl and fasting LDL cholesterol
levels 130 mg/dl. Other inclusion criteria included fasting serum C-peptide levels 1 ng/ml and HbA1c (A1C) values 7
and 11% if nave to previous oral antihyperglycemic therapy or A1C values 7
and 9.5% if previously treated with oral
antihyperglycemic monotherapy.
Subjects were excluded from participation in this study for any of the following: treatment within 60 days of screening
with insulin, systemic glucocorticoid
therapy, combination oral antihyperglycemic therapy, any lipid-lowering agent,
or any weight loss agent; known allergy to
any thiazolidinedione; serum creatinine
176.8 mol/dl (2.0 mg/dl) or 2
dipstick proteinuria at screening; alanine
aminotransferase or aspartate aminotransferase 1.5 times the upper limit of
normal or significant clinical liver disease;
hemoglobin 10.5 g/dl (females) or

11.5 g/dl (males) at screening; abnormal thyrotropin; functional New York

Heart Association Cardiac Disease Class
III or IV, history of CVD, or heart surgery
within 6 months of screening; receiving
renal dialysis or having renal transplant;
current therapy for malignancy other
than basal cell or squamous cell skin cancer; known history of HIV infection; signs
or symptoms of drug or alcohol abuse;
and any condition or situation precluding
adherence to and completion of the protocol. For female subjects, appropriate
birth control was required, and pregnancy, breast-feeding, or the intent to become pregnant during the study period
prohibited participation.
Subjects were enrolled from the U.S.
(78 sites), Puerto Rico (11 sites), Mexico
(4 sites), and Colombia (7 sites). Conducted in accordance with the Declaration of Helsinki guidelines on good
clinical practice, this study was approved
by each investigators institutional ethical
review board.
Screening for eligibility occurred at
visit 1 after written informed consent was
obtained. At visit 2, subjects were randomly assigned to one of the two treatment groups, although active study drug
administration was not initiated until 4
weeks later (visit 3). Randomization occurred in a stratified fashion with four
strata corresponding to previous oral antihyperglycemic treatment (previously
treated or nave) and sex (male or female).
Subjects discontinued any current oral
antihyperglycemic therapy and received
oral placebo therapy throughout the
4-week, single-blind, lead-in period. At
visit 3, subjects received either 30 mg pioglitazone once daily or 4 mg rosiglitazone
once daily for 12 weeks according to the
randomization assigned at visit 2. Qualified personnel provided dietary counseling on the American Heart Association
weight-maintaining Step I diet, and all
subjects were instructed to follow this diet
throughout the entire study. Clinic visits
occurred every 4 weeks following visit 3
through visit 6. At visit 6 and for the final
12 weeks, the doses of pioglitazone and
rosiglitazone were increased to the maximally effective doses (for monotherapy)
of 45 mg once daily (23) or 4 mg twice
daily (24), respectively. Clinic visits occurred every 6 weeks (visits 7 and 8) for
the remainder of the 24-week total study.
DIABETES CARE, VOLUME 28, NUMBER 7, JULY 2005

Goldberg and Associates

Table 1Characteristics and demographics at visit 3 of all randomly assigned subjects beginning active therapy

n
Sex
Male
Female
Age (years)
Race
White
Hispanic
Asian
African
Other
Duration of diabetes (years)
Body weight (kg)
BMI (kg/m2)
A1C (%)
Fasting plasma glucose (mg/dl)
Previous treatment*
Metformin
Insulin secretagogues
Thiazolidinediones
Fasting lipid profile
Total triglycerides (mg/dl)
Total cholesterol (mg/dl)
LDL cholesterol (mg/dl)
HDL cholesterol (mg/dl)
Apolipoprotein B (g/l)
Fasting free fatty acid (mEq/l)
Fasting insulin (U/ml)
Fasting C-peptide (ng/ml)
HOMA
Insulin resistance
-Cell function
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Preexisting CVD or previous MI
Aspartate aminotransferase (units/l)
Alanine aminotransferase (units/l)
Creatine phosphokinase (units/l)
Plasminogen activator inhibitor 1 (ng/ml)
C-reactive protein (mg/l)

Pioglitazone

Rosiglitazone

P value

369

366

199 (53.9)
170 (46.1)
55.9 10.5

201 (54.9)
165 (45.1)
56.3 11.3

239 (64.8)
105 (28.5)
10 (2.7)
9 (2.4)
6 (1.6)
3.9 4.4
93.7 20.6
33.7 12.9
7.6 1.2
180.5 59.7
280 (75.9)
97/212 (45.8)
97/212 (45.8)
18/212 (8.5)

219 (59.8)
118 (32.2)
12 (3.3)
10 (2.7)
7 (1.9)
4.0 4.6
92.5 21.0
32.6 6.6
7.5 1.2
177.3 57.4
274 (74.9)
92/206 (44.7)
95/206 (46.1)
19/206 (9.2)

258.5 159.4
193.4 31.3
106.9 25.4
38.8 10.0
1.05 0.20
0.64 0.28
19.7 19.4
3.9 1.7

239.5 132.6
193.7 33.7
109.0 25.9
39.7 10.3
1.04 0.20
0.62 0.29
17.8 14.3
3.6 1.6

0.079
0.882
0.260
0.211
0.781
0.579
0.132
0.043

8.2 6.4
83.6 125.2
128.4 15.9
78.7 9.3
31 (8.4)
22.0 7.1
27.0 10.7
108.0 85.1
64.2 43.4
7.0 10.1

7.7 7.2
71.1 69.7
129.1 16.4
78.5 8.9
24 (6.6)
21.7 7.5
25.6 10.9
109.6 77.7
59.6 40.4
6.6 7.7

0.386
0.095
0.584
0.765
0.401
0.547
0.063
0.790
0.143
0.580

0.824

0.572
0.842

0.847
0.450
0.122
0.230
0.459
0.797

Data are n (%) or means SD. *Totals of 280 (pioglitazone) and 274 (rosiglitazone) patients reported
previous antidiabetes therapy, but only 212 (pioglitazone) and 206 (rosiglitazone) patients reported the class
of previous antidiabetes therapy. Includes short-acting secretagogues repaglinide and nateglinide. HOMA,
homeostasis model assessment; MI, myocardial infarction.

Analytical methods
The following analyses were performed
by Covance Central Laboratory Services
(Indianapolis, IN): triglycerides, total
cholesterol, and plasma glucose in blood
samples (following at least 10 h of fasting)
using standard enzymatic methods; HDL
and LDL cholesterol (Roche Diagnostics,
Indianapolis, IN) by direct methods; free
DIABETES CARE, VOLUME 28, NUMBER 7, JULY 2005

fatty acid by the Wako enzymatic method

(Wako Chemicals, Richmond, VA); apolipoprotein B by immunoassay (Beckman
IMMAGE Immunochemistry System,
Beckman Instruments, Brea, CA); A1C by
chromatography (Bio-Rad, Hercules,
CA); total insulin by immunoassay (Abbott IMX Microparticle EIA, Abbott Laboratories, Abbott Park, IL); C-peptide by

radioimmunoassay (Adaltis Italia, Rome,

Italy); highly sensitive C-reactive protein
by immunonephelometry (Dade Behring,
Newark, DE); and plasminogen activator
inhibitor-1 (PAI-1) by immunoassay (Asserachrom PAI-1 Antigen EIA, Diagnostica Stago, France). LDL particle size and
concentration were measured using proton nuclear magnetic resonance spectroscopy at LipoScience (Raleigh, NC).
Surrogates of insulin resistance and -cell
function were estimated by homeostasis
model assessments (25). Safety assessments included adverse events, blood
pressure and heart rate, hemoglobin and
hematocrit, liver function, pedal edema,
body weight, and hypoglycemic episodes.
Statistical methods
Data are presented as means SE (or SD
where indicated). Differences between
treatments in demographics and baseline
levels (visit 3) for patients entering active
drug therapy were evaluated using a 2
test for categorical variables or an independent-groups t test for continuous variables. Efficacy analyses were conducted
on subjects providing a baseline measurement and at least one postbaseline measurement. The last-observation-carriedforward (LOCF) change from baseline
level and LOCF actual value were analyzed using a fixed-effects ANCOVA. The
ANCOVA model was composed of terms
for strata, geographic region in which the
investigative site was located (five regions:
Mexico/Puerto-Rico/Colombia, MidAtlantic/Eastern, West/Midwest/Texas,
South/Southeast, and West Coast/
Hawaii), treatment, and baseline value.
The change from baseline to the last observed value was of primary interest, and
the triglycerides change was the primary
efficacy variable. The visit-wise changes
from baseline were also analyzed using
LOCF. LOCF percent change from baseline was also analyzed for the lipid variables. Treatments were compared using
least-square means (26 27).
A mixed-model repeated-measures
analysis was used to confirm the LOCF
triglyceride results. The model used was
comprised of terms for strata, geographic
region, treatment, visit, treatment visit
interaction, baseline value, and visit
baseline level interaction. The covariance
structure was modeled using an unstructured covariance matrix within each treatment. The Kenward-Roger degrees of
freedom were used for the tests. Addition1549

Effects of pioglitazone and rosiglitazone

Figure 2Comparison of fasting triglyceride (A), HDL cholesterol (B), non-HDL cholesterol
(C), LDL cholesterol (D), and mean A1C (E) levels observed during 24 weeks of therapy with
pioglitazone (PIO) and rosiglitazone (ROSI). LDL cholesterol levels were directly measured (not
calculated). Patients were randomly assigned to either 12 weeks of 30 mg/day pioglitazone followed by 12 weeks of 45 mg/day pioglitazone () or 12 weeks of 4 mg/day rosiglitazone once
daily followed by 12 weeks of 4 mg rosiglitazone twice daily (f). Vertical bars represent SE. *P
0.001 between treatment groups; P 0.05 between treatment groups.

ally, the change from baseline triglycerides was analyzed for the subset of
patients who completed the study. SAS
version 8.2 (SAS Institute, Cary, NC) was
used for all analyses. All tests were two
sided, and results were considered statistically significant at P 0.05.
1550

RESULTS Figure 1 summarizes patient flow through the study. Similar numbers of subjects completed therapy for the
pioglitazone and rosiglitazone groups. The
distribution of subjects among the various
withdrawal categories was also similar between treatment groups.

There were no statistically significant

differences between the treatment groups
in respect to demographics, baseline
characteristics, and laboratory measurements with the exception of fasting Cpeptide levels, which were lower in
subjects randomly assigned to rosiglitazone (Table 1).
Figure 2 shows the 24-week time
course for fasting triglycerides, HDL cholesterol, non-HDL cholesterol, LDL cholesterol, and A1C. Baseline and end point
values for each are found in Table 2.
By the first posttherapy visit, triglyceride levels were significantly decreased
with pioglitazone and significantly increased with rosiglitazone compared with
baseline. Differences in triglyceride levels
between treatment groups were significant at every time point (P 0.001) (Fig.
2A). By week 24, triglyceride levels in pioglitazone-treated subjects were significantly reduced by 51.9 7.8 mg/dl
(12.0 3.0%, median of 19.8%) below
baseline (Table 2), whereas triglyceride
levels in rosiglitazone-treated subjects
were elevated by 13.1 7.8 mg/dl
(14.9 3.1%, median of 3.5%) above
baseline (the percent change represents
the mean of the individual percent
changes from baseline). The 95% CI
(based on the ANCOVA model) for the
mean change from baseline to the last observed value was 67.2 to 36.6 mg/dl
in the pioglitazone group and 2.2 to
28.5 mg/dl in the rosiglitazone group.
The mixed-model repeated-measures results for change from baseline triglyceride
level (data not shown) as well as the results from an analysis of study completers
(data not shown) were similar to the
LOCF results.
Both pioglitazone and rosiglitazone
increased HDL cholesterol over time, but
mean changes from baseline to end point
were significantly greater with pioglitazone compared with rosiglitazone, respectively: 5.2 0.5 mg/dl (14.9
1.2%) versus 2.4 0.5 mg/dl (7.8
1.2%) (P 0.001) (Table 2). The differences in HDL cholesterol levels between
treatment groups were significant at every
time point (P 0.001) (Fig. 2B).
Non-HDL cholesterol levels remained relatively constant in pioglitazone-treated subjects but were markedly
increased with rosiglitazone therapy over
the treatment period, such that the differences between treatment groups were significant at every time point (P 0.001)
DIABETES CARE, VOLUME 28, NUMBER 7, JULY 2005

Goldberg and Associates

Table 2Effects of pioglitazone and rosiglitazone on outcome measures for subjects with at
least one postbaseline measurement

n
Triglyceride (mg/dl)
Baseline
Change from baseline
Percent change from baseline
HDL cholesterol (mg/dl)
Baseline
Change from baseline
Percent change from Baseline
Non-HDL cholesterol (mg/dl)
Baseline
Change from baseline
Percent change from baseline
LDL cholesterol (mg/dl)
Baseline
Change from baseline
Percent change from baseline
Total cholesterol (mg/dl)
Baseline
Change from baseline
Percent change from baseline
Total-to-HDL cholesterol ratio
Baseline
Change from baseline
Apolipoprotein B (g/l)
Baseline
Change from baseline
Free fatty acid (mEq/l)
Baseline
Change from baseline
A1C (%)
Baseline
Change from baseline
Fasting plasma glucose (mg/dl)
Baseline
Change from baseline
Fasting insulin (U/ml)
Baseline
Change from baseline
Fasting C-peptide (ng/ml)
Baseline
Change from baseline
HOMA of insulin resistance
Baseline
Change from baseline
HOMA -cells
Baseline
Change from baseline
PAI-1 (ng/ml)
Baseline
Change from baseline
C-reactive protein (mg/l)
Baseline
Change from baseline

Pioglitazone

Rosiglitazone

P value

363

356

257.8 8.2
51.9 7.8*
12.0 3.0*

235.3 6.6
13.1 7.8
14.9 3.1*

0.001
0.001

38.8 0.5
5.2 0.5*
14.9 1.2*

39.8 0.6
2.4 0.5*
7.8 1.2*

0.001
0.001

154.8 1.6
3.6 1.9
3.8 1.3*

153.6 1.6
25.7 2.0*
18.6 1.3*

0.001
0.001

107.1 1.3
12.3 1.6*
15.7 1.9*

109.1 1.4
21.3 1.6*
23.3 1.9*

0.001
0.002

193.6 1.6
8.8 1.9*
5.7 1.0*

193.4 1.8
28.2 1.9*
15.9 1.0*

0.001
0.001

5.3 0.1
0.3 0.1*

5.1 0.1
0.7 0.1*

0.001

1.05 0.01
0.00 0.01

1.04 0.01
0.11 0.01*

0.001

0.64 0.01
0.11 0.02*

0.62 0.02
0.12 0.02*

0.681

7.6 0.1
0.7 0.1*

7.5 0.1
0.6 0.1*

0.129

180.6 3.1
33.2 2.2*

176.5 3.0
36.6 2.2*

0.233

19.7 1.0
4.5 0.5*

17.9 0.8
4.6 0.5*

0.918

3.9 0.1
0.7 0.1*

3.7 0.1
0.7 0.1*

0.652

8.2 0.3
2.8 0.2*

7.8 0.4
3.0 0.2*

0.449

83.8 6.6
8.0 3.5*

71.8 3.7
6.7 3.6

0.780

62.8 2.3
10.4 2.0*

60.0 2.3
11.7 2.0*

0.623

7.0 0.6
2.0 0.3*

6.6 0.4
2.5 0.3*

0.288

Data are means SE. *P 0.05 vs. baseline; change from baseline and percent change from baseline are
least-square means adjusted for baseline level. LDL cholesterol levels were directly measured (not calculated). HOMA, homeostasis model assessment.

DIABETES CARE, VOLUME 28, NUMBER 7, JULY 2005

(Fig. 2C). By week 24, non-HDL cholesterol levels in pioglitazone-treated subjects were 3.6 1.9 mg/dl (3.8 1.3%)
above baseline, whereas levels in rosiglitazone-treated subjects increased 25.7
2.0 mg/dl (18.6 1.3%) above baseline
(P 0.001 between treatments) (Table
2).
Both pioglitazone and rosiglitazone
also increased LDL cholesterol over time,
but mean changes from baseline to end
point were significantly less with pioglitazone compared with rosiglitazone, respectively: 12.3 1.6 mg/dl (15.7
1.9%) versus 21.3 1.6 mg/dl (23.3
1.9%) (P 0.001) (Table 2). The differences in LDL cholesterol levels between
treatment groups were significant at every
time point (P 0.001) except at weeks 4
and 12 (Fig. 2D). Lastly, apolipoprotein B
was unchanged in the pioglitazone group
but significantly increased in the rosiglitazone group (Table 2).
Figure 3 compares the effects of pioglitazone and rosiglitazone on LDL particle concentration and particle size at end
point. These agents had opposing effects
on particle concentration: a significant reduction was observed with pioglitazone,
whereas rosiglitazone therapy resulted in
a significant increase. Both agents increased particle size, but the increase
observed with pioglitazone was significantly greater than that observed with
rosiglitazone.
Both agents significantly improved
glycemic control. Although statistical differences between treatment groups were
observed for A1C values between weeks 4
and 12, these differences are not clinically
significant (Fig. 2E). Furthermore, there
was no difference between agents with respect to A1C or fasting plasma glucose
changes at end point (Table 2). No significant differences were observed between
agents for changes in free fatty acid levels,
PAI-1, C-reactive protein, and indices of
insulin secretion and sensitivity (Table 2).
Mean body weight changes from
baseline were similar for both pioglitazone (2.0 0.2 kg) and rosiglitazone
(1.6 0.2 kg) (P 0.164). Additionally,
no differences between agents were observed with regard to liver function tests
(alanine aminotransferase and aspartate
aminotransferase), creatine phosphokinase, blood pressure and heart rate, hemoglobin and hematocrit, hypoglycemic
episodes, or adverse events including
edema and congestive heart failure.
1551

Effects of pioglitazone and rosiglitazone

Figure 3Comparison of mean LDL particle concentration (A) and particle size (B) at baseline
and end point (24 weeks) for patients treated with pioglitazone (PIO) and rosiglitazone (ROSI).
Vertical bars represent SE.

CONCLUSIONS This prospective, randomized, multicenter, doubleblind clinical trial demonstrates that
pioglitazone and rosiglitazone exert different effects on plasma lipids. Pioglitazone is associated with significant
improvements versus rosiglitazone in triglyceride, HDL cholesterol, non-HDL
cholesterol, and LDL particle concentrations and LDL particle size, despite similar effects on glycemic control and
surrogate measures of insulin resistance.
The different lipid responses to maximal monotherapy doses of pioglitazone
and rosiglitazone observed in this study
are consistent with results from prior, less
well-controlled comparison studies and
the large, randomized, multicenter placebo-controlled trials for pioglitazone
(23,28,29). Additionally, a meta-analysis
of these studies (18) demonstrates results
1552

very similar to those of our study. The

mechanism(s) by which these agents exert differential effects on the lipid profile
are not clearly understood, and studies
are underway to elucidate these mechanisms.
The effects of lipids on cardiovascular
disease are well known. At increased concentrations, LDL cholesterol, total cholesterol, and triglycerides, and HDL
cholesterol at decreased concentrations,
are known to be risk factors for CVD in
the general population (8 11) and in
subjects with type 2 diabetes (34). Although lowering LDL cholesterol is the
primary target according to both the National Cholesterol Education Program
Adult Treatment Panel III (35,36) and
American Diabetes Association guidelines
(12), raising HDL cholesterol is a secondary target, the benefit of which was dem-

onstrated by the Veterans Affairs HighDensity Lipoprotein Cholesterol

Intervention Trial (VA-HIT) study (37),
in which increasing HDL cholesterol and
lowering triglycerides with the fibrate
gemfibrozil decreased cardiovascular
events by 24%. In subjects with hypertriglyceridemia (200 mg/dl), lowering
non-HDL cholesterol to levels 130
mg/dl is recommended for high-risk subjects by the National Cholesterol Education Program Adult Treatment Panel III
(36). In our study, rosiglitazone raised
non-HDL cholesterol levels and pioglitazone did not.
The dyslipidemia of diabetes is usually characterized by a combination of increased triglyceride and decreased HDL
cholesterol levels and, most often, nearnormal LDL cholesterol concentrations
(38). However, insulin resistance with or
without hyperglycemia is associated with
qualitative changes in the composition of
LDL particles shown to be associated with
greater risk for atherosclerosis and cardiovascular disease (39). These changes in
the LDL particles include a decrease in
particle size and a greater density of each
particle concomitant with a relative decrease in the cholesterol content of each
particle (40). It is generally accepted that
the increase in triglyceride levels in type 2
diabetes is in part responsible for these
atherogenic changes in the LDL profile
(5,7,11,41,42).
In the current study, pioglitazone and
rosiglitazone differed significantly with
opposing effects on triglycerides. Although both agents increased HDL cholesterol, pioglitazone increased HDL
cholesterol more. Furthermore, pioglitazone caused a shift from small, dense LDL
particles to larger, more buoyant LDL particles. This change in the size of the particles was accompanied by a decrease in
particle concentration (particle number),
an effect not observed with rosiglitazone.
Rosiglitazone was associated with an increase in LDL particle size as well as an
increase in triglyceride levels and LDL
particle numbers. These observed differences in the lipid effects between pioglitazone and rosiglitazone raise several
mechanistic questions. First, the shift toward larger LDL particles observed with
rosiglitazone therapy cannot be due to effects on triglyceride levels. Secondly, the
increase in LDL by pioglitazone can only
be explained by increases in particle size,
as the measured number of LDL particles
DIABETES CARE, VOLUME 28, NUMBER 7, JULY 2005

Goldberg and Associates

was slightly reduced. The greater increase

in LDL observed with rosiglitazone is the
result of both increases in particle size and
particle number. These observations suggest that previous speculation (43,44)
that differences in lipid effects between
pioglitazone and rosiglitazone might be
due to differential effects on particle size
are no longer tenable.
Finally, in light of the recent guidelines, subjects with diabetes often are prescribed lipid-lowering medication, most
frequently a statin. However, subjects in
this study were not treated with such
therapy. This study was purposely designed to eliminate the confounding influence of concomitant glucose-lowering
and lipid-lowering medications to allow
for a clear assessment of the glycemic and
lipid effects of the two thiazolidinediones.
Simvastatin, when added to either pioglitazone or rosiglitazone, produced similar
mean lipid changes from baseline with
both these thiazolidinediones, suggesting
that differences between these agents
would be preserved with concomitant
statin therapy (45). A current, ongoing
study named COMPLEMENT has been
designed to assess these parameters in
subjects with diabetes who are simultaneously taking a statin (46).
In summary, the current study demonstrates that pioglitazone and rosiglitazone differ in their effects on triglyceride,
HDL cholesterol, non-HDL cholesterol,
and LDL cholesterol particle concentrations and particle size. These differences
were observed despite the finding that
these agents produced similar improvements in many of the nonlipid CHD/CVD
risk factors associated with insulin resistance and type 2 diabetes (A1C, fasting
plasma glucose, fasting insulin levels, homeostasis model assessment of insulin resistance, PAI-1, and C-reactive protein).
Whether these differences in lipid effects
translate into differences for the risk of
CVD is not clear. Although no trials directly comparing the effects of pioglitazone and rosiglitazone on CVD outcomes
are underway, multiple ongoing trials are
evaluating CVD event reduction with either pioglitazone or rosiglitazone (Prospective Pioglitazone Clinical Trial in
Macrovascular Events [PROactive] [47],
Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes [RECORD] [48], and the Rationale
for the Bypass Angioplasty Revascularization Investigation 2 Diabetes [BARI 2D]
DIABETES CARE, VOLUME 28, NUMBER 7, JULY 2005

trial [49]). These studies should provide

insight into the cardiovascular benefits of
the two drugs.
Acknowledgments This study was jointly
funded by Eli Lilly and Takeda Pharmaceuticals North America.
We acknowledge the efforts of Lisa Martin,
Sandra Althouse, Melvin Prince, MD, and Janet Tobian, MD, PhD, without whom this
project could not have reached completion.

11.

12.

13.

14.
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Boyle PJ, King AB, Olansky L, Marchetti
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Buse JB, Tan MH, Prince MJ, Erickson PP:
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Derosa G, Cicero AFG, Gaddi A, Ragonesi
PD, Fogari E, Bertone G, Ciccarelli L, Piccinni MN: Metabolic effects of pioglitazone and rosiglitazone in patients with
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Phillips LS, Grunberger G, Miller E, Patwardhan R, Rappaport EB, Salzman A:
Once- and twice-daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care
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diabetes, mellitus. Coron Artery Dis 12:
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LD, Godin C, Duran S, Hawkins F, Lochnan H, Escobar-Jimenez F, Hardin PA,
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Ther 25:1074 1095, 2003
Patel J, Anderson RJ, Rappaport EB: Rosiglitazone monotherapy improves glycaemic control in patients with type 2
diabetes: a twelve-week, randomized,
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Nolan JJ, Jones NP, Patwardhan R, Deacon LF: Rosiglitazone taken once daily
provides effective glycaemic control in
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Patwardhan R, Freed MI: Rosiglitazone
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33. Lebovitz HE, Dole JF, Patwardhan R, Rappaport EB, Freed MI: Rosiglitazone
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IM, Manley SE, Matthews DR, Holman
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Wittes J: Gemfibrozil for the secondary
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40. Reaven GM, Chen YD, Jeppesen J, Maheux P, Krauss RM: Insulin resistance and
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Taskinen MR: Diabetic dyslipidemia. Atheroscler Suppl 3:4751, 2002
Freed MI, Ratner R, Marcovina SM, Kreider MM, Biswas N, Cohen BR, Brunzell
JD, Rosiglitazone Study 108 investigators:
Effects of rosiglitazone alone and in combination with atorvastatin on the metabolic abnormalities in type 2 diabetes
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Bell DS: Dyslipidemia in type 2 diabetes
and the effect of thiazolidinediones. Endocrinologist 13:496 504, 2003
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Plotkin DJ, Perevozskaya IT, Shah S, Maccubbin DL, Mitchel YB, Tobert JA, Simvastatin/Thiazolidinedione Study Group.
Effects of simvastatin on the lipid profile
and attainment of low-density lipoprotein
cholesterol goals when added to thiazolidinedione therapy in patients with type
2 diabetes mellitus: a multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther 26:379 389, 2004
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aspirus.org/heart_institute/newsletters/
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Massi-Benedetti M, Skene A: The prospective pioglitazone clinical trial in macrovascular events (PROactive): can
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Circulation 107:636 642, 2003

DIABETES CARE, VOLUME 28, NUMBER 7, JULY 2005

- 2 - PL Journal Club August 2005

PL Journal Club August 2005 - 11 -

The following succinct analysis appeared in Prescribers Letter.

DIABETES
Reps will be touting new evidence that pioglitazone (Actos)
improves lipids better than rosiglitazone (Avandia).
Both glitazones reduce A1C equally.
But pioglitazone seems better at lowering triglycerides and
increasing HDL. Pioglitazone LOWERS triglycerides about 9% to 12%...
rosiglitazone can INCREASE triglycerides up to 15%.
Pioglitazone also raises HDL about 12% to 19%...compared to
8% to 19% for rosiglitazone.
Keep this in perspective. Most diabetes patients take statins
or other lipid-lowering drugs, which may negate any differences.
Pio and rosi differ in cost. Pio is about $192 for a months supply
of the 45 mg tabs...rosi is about $175 for a month of the 8 mg tabs.
Keep in mind that lipid levels are only SURROGATE MARKERS...they
dont show if either glitazone is better for long-term OUTCOMES.

(For more on this topic, see Detail-Document #210802 at www.prescribersletter.com.)

Primary Reference Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of
pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547-54.

Discussion Questions

2.

3.

How commonly are pioglitazone and rosiglitazone used in Type 2 diabetes?

Both pioglitazone (Actos) and rosiglitazone (Avandia) are Top 100 Drugs in the U.S.
Over 9 million prescriptions in 2004.

What are the differences between these agents?

There are NO significant differences in glucose-lowering; both lower hemoglobin A1C by 0.5% 1%.
There are NO outcomes studies for diabetes-related endpointscardiovascular diseaserenal diseaseor
microvascular events such as retinopathy.
There is NOT much difference in adverse effectsedemaelevation of liver function tests (LFTs).
Preliminary evidence suggests that there MAY be a difference in serum lipid effects.

What is known about the effects of glitazones on lipids?

Tend to increase HDL cholesterol.
Variable to neutral effects on LDL cholesterol.
Big difference is rosiglitazone tends to increase triglycerides where pioglitazone is more likely to reduce
triglycerides.
This study evaluates the effects of rosiglitazone and pioglitazone on triglycerides, HDL, LDL, and LDL
particle composition and size.

Analysis of new study

4.

PL Journal Club gives you insights and guides you to the discoveries that Prescribers Letter researchers and editors uncover. Each month
we analyze many new studies and help you discover the answers to the hard questions. What are the real advantages and disadvantages
of new therapies? How do they compare with other options? What do prescribers and pharmacists need to know? We look beyond
the headlines and promotional materials to interpret the clinical studies and data. Sometimes the marketing spin doesnt stand up to
scrutiny. Sometimes studies do not really prove what they are reported to prove. PL Journal Club helps guide you to the truth and how to
apply new ndings to patient care.
PL Journal Club builds on Prescribers Letter to provide you with background for your own journal club discussions. We wont bring up
every possible question, but you canin your own journal club. If a question comes up, go to www.prescribersletter.com to nd more
background. As a PL Journal Club participant, you get access to all of Prescribers Letter and you get access to the special PL Journal
Club online tools. Youll be able to communicate with other PL Journal Club participants in many other locations. Plus, youre able to
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Club, then click DISCUSSION FORUM. Feel free to call or email us with suggestions or if we can be of assistance... 209-472-2240 or
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Instructions

Go to www.prescribersletter.com to get materials and use the PL Journal Club tools. PL Journal Club leaders can use the tools to invite
participantssend reminders...get attendance rosters...download interpretations and analyses of studies...etc. Participants can use the tools
to get discussion materials...get advance notice of discussion questions...reference citations...etc. Youll also get great background materials, including Prescribers Letter and Prescribers Letter Detail-Documents. PL Journal Club functions like a typical journal club meeting, except that it is pre-organized for you and you get the expert analysis of important new studies done by the large Prescribers Letter
research and editorial staff. Let the questions serve as a springboard for your discussions. Let your own patient cases shape the discussion.
Each month PL Journal Club gives you two topics that are also covered in Prescribers Letter. Your group might discuss only one or both
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PL Journal Club Contributing Editors:

Overview of current therapy

1.

Welcome to PL Journal Club

What type of study was this and how were the patients selected?
A randomized, double-blind trial of rosiglitazone versus pioglitazone.
Subjects with Type 2 diabetes were screened from the U.S., Mexico, Puerto Rico, and Columbia.
Eligible patients were > 35 years of age, triglycerides between 150 and 600 mg/dL, a C-peptide level >1
ng/mL, and an A1C between 7% 11% (if nave to oral hypoglycemic medications) or between 7%
9.5% (if previously treated with oral hypoglycemic monotherapy).

LEADER NOTES

Rex W. Force, Pharm.D., FCCP, BCPS

Professor, Department of Family Medicine
Associate Professor, Department of Pharmacy
Practice
Director of Research, Grants and Information
Systems
Family Medicine Clinical Research Center
Idaho State Univ.

Mark Graber, M.D.

Research Director,
Division of Emergency Medicine
Associate Professor of Clinical
Surgery and Family Medicine
Univ. of Iowa Hospitals and
Clinics

Brian C. Harrington, M.D., MPH, FAAFP

Past Program Director,
Darnall Family Medicine Residency Program
Fort Hood, TX
Current Teaching Faculty
Southern Colorado Family Medicine Residency
Program
Assistant Clinical Professor
Univ. of Colorado Health Sciences Center

Prescribers Letter Editorial Staff: Editor: Jeff M. Jellin, Pharm.D.; Senior Associate Editor: Karen Davidson, Pharm.D.; Assistant Editors: Kim Palacioz, Pharm.D., Tanveer Khan, Pharm.D., Joseph A. Woelfel, Ph.D., FASCP, R.Ph., Melissa Murn, PA-C, Pharm.D., Kayla
Dotson, Pharm.D., Crystal Amos, B.Sc.Pharm., ACPR; Assistant Editor and Director of Continuing Education: Tony Martin, Pharm.
D., MBA; Associate Clinical Editor: Mark Graber, M.D.; Editorial Project Manager: Timothy Swaim; Editorial Liaison: Karen Wilson;
Editorial Assistant: Tyler Nagata; Database Coordinator: Stephanie Feilzer-Pate; Drug Information Consultants: Neeta OMara, Pharm.D.,
BCPS, Jill E. Allen, Pharm.D., BCPS; Research and Review: Kwabena O.M. Adubofour, M.D., FACP, Thomas Barringer, M.D., FAAFP,
Robert T. Browne, M.D., FAAFP, Matthew Cline, M.D., FAAFP, Sandra Harley Counts, Pharm.D., Rex Force, Pharm.D., BCPS, Joseph
Guglielmo, Pharm.D., Marcia Isakari, M.D., Sheela Kapre, M.D., Adam Kaye, Pharm.D., FASCP, William Kehoe, Pharm.D., MA, FCCP,
BCPS, Ted Lee, M.D., Stanley Leong, Pharm.D., Guey Mark, M.D., John Morozumi, M.D., Kay Niegel, R.Ph., Mike Pastrick, R.Ph., Allen
Shaughnessy, Pharm.D., Tom Simpson, Pharm.D., FCSHP, Sharm Steadman, Pharm.D.
Prescribers Letter Editorial Advisory Board: Jan Basile, M.D., Professor of Medicine, Medical Univ. of South Carolina; Robert E. Bickerton, M.D., FACP, Private Practice; Kevin Brown, M.D., FACOG, Private Practice; David B. Brushwood, J.D., Law Professor, University
of Florida; Narinder Duggal, M.D., BSc (Pharm) CDE, CGP, FRCPC, Univ. of Washington; Col John D. Grabenstein, R.Ph., Ph.D., Deputy
Director for Clinical Operations, US Army Medical Command; Mark A. Graber, M.D., Research Director, Div of Emergency Medicine,
Associate Professor of Clinical Surgery and Family Medicine, University of Iowa Hospitals and Clinics; Col. Jefferson Harman, Jr., M.D.,
Director, Travis Air Force Base Family Practice Residency Program; Arthur Hull Hayes, Jr., M.D., President, MediScience Associates, Inc.,
former Commissioner of the FDA; B. Mark Hess, M.D., FACP, Wright State University; Eric Jackson, Pharm.D., BCPS, Asylum Hill Family Practice Center University of Connecticut; Peter Jacobsen, Ph.D., D.D.S., Professor of Oral Medicine, University of the Pacic, School
of Dentistry; Evan L. Lipkis, M.D., Medical Director, Advanced Center for Total Health Care, Glenbrook Hospital; Stephen L. McKernan,
BS.Pharm., N.D., D.O., FAAFP, Director, Conroe Family Practice Residency Program; Darius Noori, Pharm.D., M.D.; Robert W. Patterson, M.D., FABFP, FAAFP, Family Practice; David E. Rosenthal, M.D., FACP, Abington Memorial Hospital; David Stadtner, M.D., Private
Practice; Kathryn Taubert, Ph.D., American Heart Assoc National Center; Walter Way, M.D., University of Cal at San Francisco; C. Wayne
Weart, Pharm.D., BCPS, Professor and Chair, Medical University of South Carolina; Charles, F. Weiss, M.D., Clinical Professor of Pediatrics, University of South Florida; Craig Williams, Pharm.D., Purdue University.

DISCLOSURE:

Therapeutic Research Center/Prescribers Letter does not receive any commercial support and does not accept any advertising. It is
completely independent and is supported entirely by subscriptions. It is our policy that all editors refrain from having any ties with any organization that could inuence the editorial objectivity of Prescribers Letter or PL Journal Club. Prescribers Letter and PL Journal Club
focus on delivering completely objective, unbiased drug information and advice for the benet of subscribers.

LEADER NOTES

- 10 - PL Journal Club August 2005

PL Journal Club August 2005 - 3 -

References

DIABETES
Chren M. Interactions between physicians and drug company representatives. Am J Med 1999;107:182-3.
Goldberg RB, Kendall DM, Deeg MA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type
2 diabetes and dyslipidemia. Diabetes Care 2005;28:1547-54.
Grandage KK, Slawson DC, Shaughnessy AF. When less is more: a practical approach to searching for evidence-based answers. J Med
Libr Assoc 2002;90:298-304.
Shaughnessy AF, Slawson DC, Bennet JH. Teaching information mastery: evaluating information provided by pharmaceutical
representatives. Fam Med 1995;27:581-5.
Slawson DC, Shaughnessy AF. Obtaining useful information from expert based sources. BMJ 1997;314:947-9.
Slawson DC, Shaughnessy AF, Bennett JH. Becoming a medical information master: feeling good about not knowing everything. J Fam
Pract 1994;38:505-13.
Watkins RS, Kimberly J Jr. What residents dont know about physician-pharmaceutical industry interactions. Acad Med 2004;79:432-7.
Additional Prescribers Letter Resources available at www.prescribersletter.com
Does Actos Improve Lipids Better than Avandia? Pharmacist's Letter/Prescriber's Letter 2005;21:210802.
Worksheet to Evaluate Drug Studies. Pharmacist's Letter/Prescribers Letter 2005;21:210610.
Liver Function Test Scheduling. Pharmacist's Letter/Prescribers Letter 2004;20:200903.

5.

6.

7.

Avandia (Rosiglitazone) Approved For Use With Insulin. Pharmacist's Letter/Prescribers Letter 2003;19:190402.
Relationship Between Industry And Research And Professional Education. Pharmacists Letter/Prescriber's Letter
2001;8:171025.

WOMENS HEALTH
Abraham GE. Nutritional factors in the etiology of the premenstrual tension syndromes. J Reprod Med 1983;28:446-64.
Bertone-Johnson ER, Hankinson SE, Bendich A, et al. Calcium and vitamin D intake and risk of incident premenstrual syndrome. Arch
Intern Med 2005;165:1246-52.
Clinical management guidelines for obstetricians-gynecologists: premenstrual syndrome. ACOG practice bulletin. No. 15. Washington, D.C.:
American College of Obstetricians and Gynecologists, April 2000.

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9.

Dell DL. Premenstrual syndrome, premenstrual dysphoric disorder, and premenstrual exacerbation of another disorder. Clin Obstet
Gynecol 2004;47:568-75.

Fletcher RH, Fletcher SW, Wagner EH. Clinical epidemiology: The essentials. 3rd ed. Baltimore: Williams & Wilkins,1996.

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Friis RH, Sellers TA., Moffitt HL. Epidemiology for public health practice. 3rd ed. Gaithersburg, Maryland: Aspen Publishers, Inc., 2004.

Grady-Weliky TA. Clinical practice. Premenstrual dysphoric disorder. N Engl J Med 2003;348:433-8.
National Osteoporosis Foundation. Prevention: Calcium & Vitamin D. http://www.nof.org/prevention/calcium.htm. (Accessed 7/26/05).
Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual
symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol 1998;179:444-52.
Additional Prescribers Letter Resources available at www.prescribersletter.com
Calcium and Other Supplements for PMS. Pharmacist's Letter/Prescribers Letter 2005;21:210813.

Exclusion criteria included elevated serum creatinine, elevated liver enzymes, recent cardiovascular
disease, combination oral hypoglycemic agents, and treatment for lipid disorders.

How are study groups defined?

4,410 patients screened, 802 patients randomized, 735 received study drug.
Patients were an average age of 55, 54% were male, 60% 65% were white, 30% were Hispanic, BMI
of 33, an A1C of 7.5%, triglycerides of 250 mg/dL, LDL of 108 mg/dL, and < 10 % had pre-existing
cardiovascular disease.
Study groups were well matched at baseline, indicating effective randomization procedures.
Patients received either rosiglitazone 4 mg daily or pioglitazone 30 mg daily for 12 weeks.
Doses were increased to rosiglitazone 4 mg twice daily or pioglitazone 45 mg daily for the final 12 weeks.
Serum lipids were measured every 4 weeks.

What are the strengths and weaknesses of this trial?

Randomized, double -blind trial.
Relatively small study with enough power to detect differences in endpoints.
Evaluated changes in laboratory parameters, NOT clinical outcomes.
Follow-up rates are so-so with about 20% of patients dropping out over the 24-week study period.

How were the study subjects not representative of real world diabetic patients?
Exclusion criteria significantly limit the generalizability of the study to the real world. Criteria included:
o NO other diabetes medications or statins most patients with diabetes do take these.
o any condition or situation precluding adherence to...the protocol. nonadherence occurs in reality
and would result in smaller lipid changes.

How did the drugs work in this trial?

At 24 weeks, both drugs reduced hemoglobin A1C by similar amounts (about 0.7 %).
Rosiglitazone increased HDL by an average of 2.4 mg/dL, increased triglycerides by 13.1 mg/dL, and
increased LDL by 21.3 mg/dL.
Pioglitazone increased HDL by an average of 5.2 mg/dL, decreased triglycerides by 51.9 mg/dL, and
increased LD by 12.3 mg/dL.
LDL particles were larger and less buoyant with pioglitazone.

Were there any significant adverse affects in either group?

NO differences in weight gain, elevation of LFTs, hypoglycemia, edema, or heart failure.

Were there any other design issues that might influence the results?
A MAJOR limitation is that the results do NOT necessarily translate to an outcome we care about.
Altering an intermediate outcome (LDL or blood pressure) does NOT always translate to a reduction in
cardiovascular disease. For example, in the ALLHAT trial, doxazosin lowered blood pressure as well as
chlorthalidone, but doxazosin was associated with new heart failure at an alarming rate.
Screen-failure rate was quite high only 18% of those screened were randomized. This calls into question
the external validity.
Glycemic control was modest at best (A1C of ~7.5% on glitazone monotherapy).
Withdrawal rate was quite high nearly 20%.
Sponsored by the makers of pioglitazone (Takeda).

Calcium and Vitamin D for Reducing Fracture Risk. Pharmacist's Letter/Prescriber's Letter 2005;21:210609.
Calcium and Colorectal Cancer. Pharmacist's Letter/Prescriber's Letter 2005;21:210656.
PMS Guidelines. Pharmacist's Letter/Prescribers Letter 2000;16:160803.
Calcium Salts. Pharmacist's Letter/Prescribers Letter 2000;16:160313.

LEADER NOTES

LEADER NOTES

- 4 - PL Journal Club August 2005

11.

PL Journal Club August 2005 - 9 -

Were the results expressed in terms we care about and can use?

Yes. Treatment resulted in similar reductions in hyperglycemia, but very different changes in good and
bad cholesterol. However, whether this actually affects cardiovascular outcomes is yet to be determined.

How should the new findings change current therapy?

12.

13.

Are the patients studied similar to those you see?

Discuss your patient population.
Study population:
o Generally, patients were young (age 55).
o Recently diagnosed with diabetes (<4 years).
o Both men and women were represented.
o Predominantly white, potentially limiting the application of the results to other patients.

Do the results force you to change your practice? How?

No. But this trial will be used to aggressively market a product.

Results should be interpreted with caution until there are comparisons with cardiovascular disease rates.
Patients with diabetes should still have their comorbid conditions (elevated LDL and blood pressure)
treated aggressively.
Patie nts not reaching goal LDL cholesterol and triglycerides, who are receiving rosiglitazone, should be
evaluated carefully. A trial of pioglitazone may be worthwhile in these cases.

Apply the new findings to the following case

You are a 2nd-year resident attending a noon CME conference sponsored by a local pharmaceutical
representative. Before the CME, the representative takes ten minutes to tell you about one of his drugs, Actos.
He touts that Actos should be chosen over the other thiazolidinedione-class drug, Avandia, because a recent
study proves Actos lowers triglycerides and raises HDL. He states that the same study showed Avandia
actually raised triglycerides.

14.

15.

Ask journal club participants if they can be improperly influenced by pharmaceutical

presentations? What about their peers?
Compare your results to a 1999 survey of medical residents:
o 61% felt they would NOT be influenced.
o Only 16% felt their peers would NOT be influenced.
Are providers naively overconfident in their ability to resist drug company influence?
Some journal club participants may claim that they can remain objective and not allow such
presentations to improperly influence their choice of medications.
The PRIMARY goal of pharmaceutical company representatives is to promote their products and to
change prescription behaviors.
Representatives are often effective regardless of the merits of the information. In order to get providers to
prescribe their drug, companies may focus their appeals upon emotional tugs and logical fallacies.

How can providers sort through a drug companys information to determine what matters for
their practice?
Information must be both VALID and RELEVANT.
VALIDITY relates to the methodology and scientific rigor of a study.
Points that undermine this studys validity:
o No intention-to-treat analysis; many drop-outs from study (Figure 1, pg 1548).

LEADER NOTES

14.

15.

How much daily intake of calcium would you recommend for TZ?

For a calcium calculator www.cdc.gov/powerfulbones/parents/toolbox/calculator.html.

For foods high in calcium www.cdc.gov/powerfulbones/parents/toolbox/list.html.

1200 mg daily of elemental calcium is reasonable .

Current recommendations for persons ages 19 30 are at least 1000 mg/day. The focus of these
recommendations, especially in women, is maintaining bone density (CDC, National Osteoporosis
Foundation, USDA, USDHHS).
Two clinical trials:
o 1200 mg of elemental calcium daily was shown to significantly reduce PMS symptoms in women
already diagnosed with the condition (Thys-Jacobs et al).
o Patients with the highest daily intakes of calcium ( 1283 mg) and vitamin D ( 706 IU) were at
significantly lower risk of developing PMS (Table 2) (Bertone-Johnson el al).
Lower amounts of calcium may be effective, but the evidence suggests that 1000-1200 mg daily or more,
would be a prudent daily intake for the prevention and treatment of PMS.
Vitamin D is important for calcium metabolism and appears to have independent health benefits at higher
doses of at least 700 IU daily.

TZ tells you she had taken calcium carbonate in the past and it caused constipation and
abdominal cramps. What are the choices for calcium supplementation? See Prescribers Letter

Detail-Document #160313 on Calcium Salts.

Calcium carbonate (Tums, Os-Cal, Caltrate, Rolaids, etc)

40% elemental calcium by weight (the most of any form)
Absorption impaired by high gastric pH (antacids)
Usually cheapest form
Calcium citrate (Citracal, etc)
21% elemental calcium by weight
More soluble than calcium carbonate, better for high gastric pH, elderly
May protect against kidney stones
More expensive than calcium carbonate
Calcium phosphate includes tricalcium phosphate and dicalcium phosphate (Posture)
38% and 31% elemental calcium by weight, respectively
Low solubility; similar to calcium carbonate
Calcium gluconate
9% elemental calcium by weight (for oral form)
Preferred for IV treatment of severe hypocalcemia; very soluble
More expensive than calcium carbonate and citrate forms
Calcium glubionate (Neo-Calglucon)
6.5% elemental calcium by weight
Syrup form may be useful in children and the elderly
More expensive
Calcium lactate
13% elemental calcium by weight

16.

Assume that calcium supplements and lifestyle changes have not adequately alleviated her PMS
symptoms. What prescription drugs may be helpful for treating PMS?

The best supporting evidence exists for SSRIs, which should be considered a first-line prescription choice.
Serotonin reuptake inhibitors
Analgesics
NSAIDs
Hormonal contraceptives
Spironolactone
Oral contraceptives but not
progesterone agents alone
Anxiolytics
GnRH agonists

For more content, and to see comments from other PL Journal Clubs on this topic go to
www.prescribersletter.com - click on PL Journal Club - click on DISCUSSION FORUM .
Youll be able to pose your questions to the study author, Dr. Bertone -Johnson.

LEADER NOTES

- 8 - PL Journal Club August 2005

9.

10.

PL Journal Club August 2005 - 5 -

Were there any design issues that might influence results?

The MAJOR limitation of case-control studies is that biases are not well controlled for .
o For example, women who consume large amounts of calcium might have other health habits that
reduce their risk of developing PMS.
o They may have a different personality type or outlook on life that results in better coping mechanisms
and responses to stresses.
o Without randomization, we cannot be certain that women who consume large amounts of calcium or
vitamin D might not be different in some way from those who consume lower amounts of these
nutrients.
Nurses may not be representative of ALL women; therefore, generalizability may be suspect.
Recall biases can be a significant problem; that is, are subjects adequately recalling their health history?
Other limitations:
o PMS may be difficult to diagnose, making correct identification of PMS cases complicated.
o Small proportion of patients reported using calcium supplements, making it difficult to identify the
potential benefit of high-dose calcium supplementation in preventing PMS development.
Were the results expressed in terms we care about? Is the intervention feasible?

Yes. Young women are frequently NOT receiving enough calcium and vitamin D in their diet.
This study demonstrates an association between high levels of calcium intake and subsequent development
of PMS.
Its reasonable to recommend these nutrients in a larger subset of women.
Calcium and vitamin D intake has been associated with a reduction in the risk of osteoporosis and some
cancers. It is extremely unlikely that these products will cause significant adverse effects. Since the cost
of these products is relatively low, it makes sense to recommend an increased intake.

The validity and relevance of this study are low . This study does NOT dictate a practice preference of
pioglitazone over rosiglitazone for patients with diabetes or high triglycerides.

16.

12.

Are the patients studied similar to those you see in clinic?

Discuss your patient population.
Study population:
o A relatively homogeneous population of nurses; this may limit external validity.
Do the results force you to change your practice? How?
Maybe. The results are not earth shattering enough to mandate an immediate change.
Results support potential additional benefits of calcium and vitamin D supplementation. Its reasonable to
use the results from this trial as additional supporting evidence in recommending calcium and vitamin D
supplementation to younger patients. Again, the downside is relatively minimal.

Apply the new findings to the following case

TZ is a 22 year old female, who presents for her annual well woman exam. She is generally healthy, exercises
regularly, and is non-obese. Her mother takes calcium pills for bone health and tells TZ that calcium also used
to help her severe PMS symptoms. TZ denies PMS symptoms, but asks if she should be taking calcium too.
13.

Do you think TZ should pay attention to her calcium intake?

Yes. Calcium intake is critical for bone strength. This is an important period for TZs bone growth.
Women benefit from reaching the highest bone mass possible, which usually peaks during their mid-30s.
This study suggests a role for calcium and vitamin D in preventing PMS.
People should be getting adequate daily calcium intake with their diets. Many people do NOT.
Poor dietary habits have been associated with PMS.
If TZs dietary intake of calcium appears inadequate, and given her mothers history of PMS,
recommending dietary supplementation may be prudent.

LEADER NOTES

What attributes should you consider when evaluating if one drug is better than another?

Shaughnessy and Slawson describe the STEP approach:

Safety long-term or serious side effects
Tolerability best to compare drop out rates, not relative incidence of side effects
Effectiveness may be hard to get good comparative data from drug representatives
Price direct + indirect (extra monitoring costs; extra visits, etc.)

17.

How should the new findings change current therapy?

11.

o Results focused on RELATIVE change, rather than the ABSOLUTE changes in triglycerides.
ABSOLUTE changes were relatively small.
A valid study may not be particularly RELEVANT.
The best information is patient oriented evidence that matters (POEMs). Many studies look at
intermediate endpoints, disease oriented evidence (DOE). For example, small changes in lipid levels may
not have a significant clinical benefit. A change in heart attack rates would be more useful.
Points that affect this studys relevance:
o Looked at intermediate endpoints, NOT clinical outcomes.
o Is not real world. Subjects differed in several ways from typical diabetes patients.

18.

19.

What serious adverse reactions can occur in patients taking pioglitazone or rosiglitazone?
Heart failure. Both can cause fluid retention and edema, which can lead to or exacerbate heart failure,
especially when combined with insulin.
Hepatotoxicity. Association was more prevalent with Rezulin (troglitazone), which eventually led to its
withdrawal in 2000. Newer recommendations on LFT monitoring suggest doing so before starting and then
periodically. Some experts interpret periodically to mean every 3 to 6 months.

What if the company rep states that Actos is the most prescribed thiazolidinedione among
endocrinologists? Does this convince you to prefer Actos?
Prescription volume does NOT necessarily indicate it is the BEST choice.
A top ranking may indicate an aggressive marketing program.
Sometimes companies will sell their product at a competitively low price in order to gain market share and
thus claim it is the number one prescription item in its class.

How much do pioglitazone and rosiglitazone cost?

Approximate retail price for a month supply, as used in the study:

pioglitazone 45 mg once a day = $165 $192
rosiglitazone 8 mg daily (#60 of 4 mg or #30 of 8 mg) = $166 $175

20.

How can providers interact with pharmaceutical representatives in a way that is mutually
respectful and helps the representative be a positive resource for information?
Explain that you need information that is VALID and RELEVANT.
Emphasize the need for POEMs, not DOEs; limit pre-clinical data.
Ask them to provide information that conforms to the STEP approach.

For more content, and to see comments from other PL Journal Clubs on this topic go to
www.prescribersletter.com - click on PL Journal Club - click on DISCUSSION FORUM .
Youll be able to pose your questions to the study author, Dr. Goldberg.

LEADER NOTES