ORIGINAL RESEARCH ARTICLE
Pharmacokinetics, Safety, and Tolerability of Saroglitazar
(ZYH1), a Predominantly PPARa Agonist with Moderate PPARc
Agonist Activity in Healthy Human Subjects
Rajendra H. Jani•Kevinkumar Kansagra•
Mukul R. Jain•Harilal Patel
Published online: 24 September 2013
? The Author(s) 2013. This article is published with open access at Springerlink.com
Background and Objectives
cardiovascular risk factor associated with type 2 diabetes
mellitus. Saroglitazar (ZYH1) is a novel peroxisome pro-
liferator-activated receptor (PPAR) agonist with predomi-
nant PPARa and moderate PPARc activity. It has been
developed for the treatment of dyslipidaemia and has
favourable effects on glycaemic parameters in type 2 dia-
betes mellitus. The objective of this phase 1 study was to
evaluate the pharmacokinetics, safety and tolerability of
saroglitazar in healthy human subjects.
MethodsThis was a randomized, double-blind, placebo-
controlled, single-centre, phase I study in healthy human
volunteers, and was performed in two parts; part I evalu-
ated single ascending oral doses of saroglitazar (0.125,
0.25, 0.5, 1, 2, 4, 8, 16, 32, 64 and 128 mg) in healthy
subjects, and part II measured the effects of food and sex
on the pharmacokinetics of 1 mg saroglitazar, the human
equivalent efficacy dose derived from pre-clinical studies.
A total of 96 subjects were enrolled in the study, which
included 88 healthy male subjects in part I and 16 healthy
Dyslipidaemia is a major
subjects (8 males from part I of the study and 8 females) in
ResultsSaroglitazar was rapidly and well absorbed across
all doses in the single-dose pharmacokinetic study, with a
median time to the peak plasma concentration (tmax) of less
than 1 h (range 0.63–1 h) under fasting conditions across
the doses studied. The maximum plasma concentration
ranged from 3.98 to 7,461 ng/mL across the dose range.
The area under the plasma concentration–time curve
increased in a dose-related manner. The average terminal
half-life of saroglitazar was 5.6 h. Saroglitazar was not
eliminated via the renal route. There was no effect of sex
on the pharmacokinetics of saroglitazar, except for the
terminal half-life, which was significantly shorter in
females than in males. Food had a small effect on the
pharmacokinetics; however, it was not consistent in males
and females. Single oral doses of saroglitazar up to 128 mg
were well tolerated. No serious adverse events were
reported. Adverse events were generally mild and moderate
in nature. Saroglitazar did not show any clinically relevant
findings in clinical laboratory investigations, physical
examinations, vital signs and electrocardiograms.
Conclusion The highest dose of saroglitazar evaluated in
this study was 128 mg, several times the estimated thera-
peutic doses (1–4 mg). The pharmacokinetics of saroglit-
azar support a once daily dosage schedule. Saroglitazar was
found to be safe and well tolerated in this study.
Cardiovascular disease is the most common underlying
cause of death, accounting for about 50 % of mortality in
type 2 diabetes mellitus (T2DM) [1, 2]. The results of the
ACCORD (Action to Control Cardiovascular risk in
R. H. Jani (&) ? K. Kansagra
Clinical R&D, Zydus Research Centre, Cadila Healthcare
Limited, Sarkhej-Bavla N.H. No. 8A, Moriya, Ahmedabad
382 213, Gujarat, India
M. R. Jain
Pharmacology & Toxicology, Zydus Research Centre, Cadila
Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moriya,
Ahmedabad 382 213, Gujarat, India
Drug Metabolism & Pharmacokinetics, Zydus Research Centre,
Cadila Healthcare Limited, Sarkhej-Bavla N.H. No. 8A, Moriya,
Ahmedabad 382 213, Gujarat, India
Clin Drug Investig (2013) 33:809–816
Disease; Preterax and Diamicron Modified Release Con-
trolled Evaluation) studies showed that intensive glycaemic
control reduced microvascular complications (new or
worsening nephropathy or retinopathy) but not macrovas-
cular complications (cardiovascular death, nonfatal myo-
cardial infarction or nonfatal stroke) [3, 4]. Diabetic
dyslipidaemia is characterized by elevation of serum tri-
glyceride (TG) levels ([150 mg/dL), reduced high-density
lipoprotein (HDL) cholesterol levels (\40 mg/dL in males
and\50 mg/dL in females) and normal or elevated levels of
6]. Low levels of serum HDL cholesterol have been corre-
lated with cardiovascular disease [7–9],andidentification of
agents thatelevateHDL cholesterolindiabetic patients isan
area of active interest. The American Diabetes Association
been well established that dyslipidaemia is a major cardio-
vascular risk factor associated with T2DM .
Thepotential of peroxisome
receptor (PPAR) agonists to reduce the risk of cardiovas-
cular disease in T2DM patients has remained an area of
continuous medical interest. PPARa and PPARc agonists
are approved for lipid and glycaemic control, respectively
[10, 11]. Numerous dual PPAR agonists have been devel-
oped for management of both glycaemic and lipid abnor-
malities in T2DM. However, none of these agents has so
far been successful [11, 12]. Saroglitazar, [(S)-a-ethoxy-4-
ethoxy})-benzenepropanoic acid magnesium salt], is the
first glitazar that has been granted marketing authorization
in India and is indicated for treatment of diabetic dyslip-
idaemia. Saroglitazar is a dual PPAR agonist with pre-
dominant PPARa and moderate PPARc activity . It
was developed with an expectation to achieve optimum
anti-dyslipidaemic and anti-hyperglycaemic effects, while
avoiding peripheral oedema and weight gain. The structural
formula of saroglitazar is given in Fig. 1.
The purpose of this first-in-humans phase 1 study was to
assess the pharmacokinetics, safety and tolerability of sa-
roglitazar in healthy volunteers.
The study was conducted (from 16 June 2005 to
29 November 2005) in accordance with accepted standards
for the protection of subject safety and welfare, and the
principles of the Declaration of Helsinki and its amend-
ments, and was in compliance with Good Clinical Practice.
The study was initiated after obtaining approval from the
Drug Controller General of India (DCGI; no. 12-05/05-
DC, dated 27 May 2005) and an independent ethics com-
mittee (IEC), Aditya, Ahmedabad, Gujarat, India.
2.1 Study Design
This was a randomized, double-blind, placebo-controlled,
single-centre study to evaluate the pharmacokinetics, safety
and tolerability of single ascending oral doses of saroglit-
azar under fasting conditions in healthy subjects. In addi-
tion, the effects of food and sex on the pharmacokinetics of
saroglitazar were also studied.
Eligible healthy subjects (aged 18–45 years, weighing
50–70 kg) with normal medical history, physical exami-
nation, electrocardiogram (ECG) and clinical laboratory
findings were enrolled. Eligible healthy female subjects
were enrolled if they had undergone surgical sterilization
(tubectomy, hysterectomy or tubal ligation). The subjects
had not received any medications within 14 days prior to
the current study and had not participated in any study
within 3 months prior to the current study.
In each cohort, eight subjects were randomized to
receive either saroglitazar or a matching placebo (3:1) by a
sion 9.1, SAS Institute Inc., Cary, NC, USA). Subjects
were admitted to the clinical pharmacology unit on the
evening prior to dosing and were confined until 72 h after
the last dose. The study drugs, saroglitazar (0.125–0.5 mg
oral suspension or 1–128 mg tablets) or the matching
placebo, were administered orally.
The study was divided into two parts: (i) a single-
ascending-dose study; and (ii) a study of the effects of food
2.1.1 Part I: Single-Ascending-Dose Study
Saroglitazar [versus the matching placebo (3:1)] was
studied in 11 cohorts; each cohort comprised eight healthy
male subjects. In the first three cohorts, saroglitazar (0.125,
0.25 and 0.5 mg) or the placebo was administered as an
oral suspension (0.5 mg/mL). In subsequent cohorts, sa-
roglitazar (1, 2, 4, 8, 16, 32, 64 and 128 mg) or a matching
placebo tablet was orally administered. Study drugs were
administered with 240 mL of water after overnight fasting
for at least 10 h (Fig. 2).
Fig. 1 Structural formula of saroglitazar
810R. H. Jani et al.
2.1.2 Part II: Study of the Effects of Food and Sex
The effects of food and sex were studied with the sarog-
litazar 1 mg tablet. The food effect was studied in a
crossover design. A saroglitazar tablet or a matching pla-
cebo (3:1) was administered orally with 240 mL of water
after overnight fasting for at least 10 h. To assess the food
effect, subjects were given a standard high-fat, high-calorie
meal (approximately 800–1,000 calories, of which 150,
250 and 500–600 calories were from protein, carbohydrate
and fat, respectively) 30 min prior to administration of the
Healthy female volunteers (n = 8) were enrolled to
assess the effect of sex on saroglitazar pharmacokinetics.
Of these, two received placebo and six received saroglit-
azar 1 mg. Male and female subjects were analyzed to
assess the effect of sex on saroglitazar pharmacokinetics
under fasting and fed conditions.
2.2 Blood Sampling for Pharmacokinetics
In part I and part II, venous blood samples (7 mL) were
withdrawn in Vacutainers (ethylenediaminetetraacetic acid
[EDTA]) at pre-dose, at 5, 10, 20, 30 and 45 min, and at 1,
2, 4, 6, 8, 12, 24, 48 and 72 h following study drug
administration, and were placed on ice. Plasma was sepa-
rated within 30 min of collection and stored frozen at
-70 ± 5 ?C until analysis.
2.3 Urine Sampling for Pharmacokinetics
Urine samples were collected pre-dose and at intervals of
0–1, 1–3, 3–6, 6–12, 12–24, 24–36, 36–48, 48–60 and
60–72 h following study drug administration. At the end of
the interval, the urine bottles were shaken and weighed,
and aliquots of the samples were stored frozen at
-70 ± 5 ?C until analysis.
Crossover food effect study
217 male subjects
58 failed screening
71 did not report to the
20 female subjects
Saroglitazar suspension in fasting condition.
N=8 randomized but one subject withdrew because of ectopic beats before dosing.
Saroglitazar tablet in fasting condition
N=8 randomized but one subject withdrew informed consent for period I of the crossover food effect study.
Saroglitazar after food intake.
One subject did not report to the facility for period II of the crossover food effect study.
Fig. 2 Study design and subject disposition. The pharmacokinetics of saroglitazar in male and female subjects were compared at 1 mg doses. In
each group, 6 subjects received saroglitazar and 2 received placebo
Pharmacokinetics, Safety and Tolerability of Saroglitazar811
2.4 Safety Assessments
In both parts of the above study, general safety was eval-
uated by the incidence of adverse events (AEs) through
non-leading questions, clinical laboratory investigations
(haematology, biochemistry and urinalysis), vital signs,
physical examinations and 12-lead ECGs. Identification of
the intensity of each AE was performed on the basis of the
Common Terminology Criteria for AEs (v3.0).
2.5 Bioanalytical Methods
Saroglitazar was assayed in plasma and urine, using a
sensitive and specific liquid chromatography–tandem mass
spectrometry method. The assays were validated in accor-
dance with the US Food and Drug Administration (FDA)
Guidance for Bioanalytical Method Validation .
Plasma samples (1 mL) were processed by liquid–liquid
extraction, using a mixture of diethyl ether:dichloro meth-
ane (80:20). Urine samples were processed using solid-
phase extraction (Waters Oasis HLB cartridge, 30 mg,
1 mL). Glimepiride was used as the internal standard for
both plasma and urine assays. Overlapping calibration
curves were prepared in plasma, with ranges of 0.02–10.0,
0.1–30, 1–1,000 and 5–20,000 ng/mL. The calibration
curve range for urine samples was 0.02–10.0 ng/mL.
Chromatographic separation of both plasma and urine
samples was achieved with an ACE C18 analytical column,
using a mobile phase comprising a 70:30 mixture of
ammonium acetate buffer and acetonitrile. Quantitative
measurement of saroglitazar and the internal standard,
glimepiride, were carried out using mass transition (m/
z) values of 440 and 491, respectively. Quality-control
(QC) samples were analyzed with each batch of urine and
plasma samples at low levels (three times the lower limit of
quantification), medium levels (the middle of the concen-
tration range) and high levels (75–90 % of the upper limit
of quantification). Inter-batch and intra-batch QC samples
were within the acceptance limits.
2.6 Pharmacokinetic Data Analysis
The concentration–time data were subjected to non-com-
partmental pharmacokinetic analysis, using WinNonlin
Professional Software, Versions 4.0.1 and 5.0.1 (Pharsight
Corporation, St Louis, MO, USA). The parameters that
were estimated were the maximum plasma concentration
(Cmax), time to reach Cmax(tmax), area under the plasma
concentration–time curve (AUC), AUC from time zero to
the time of the last measurable concentration (AUClast),
AUC from time zero to infinity (AUC?), terminal elimi-
nation half-life (t?b) and percentage of the drug excreted in
2.7 Statistical Analysis
Descriptive statistics (means and standard deviations) were
used for pharmacokinetic and safety analysis. Dose rela-
tionships with Cmax and AUClast were calculated using
correlation and regression analysis.
A total of 96 subjects were enrolled in the study.
In the single-ascending-dose study (part I), 88 healthy
male subjects were recruited and 87 completed the studies.
One subject was withdrawn because of an ectopic beat
before the dosing of saroglitazar 0.125 mg suspension. In
the crossover food-effect study (part II), eight males (who
were part of the single-ascending-dose study) and eight
females participated. One of the eight female subjects
withdrew her consent before dosing in the fasting study
arm (period I); however, she participated in the fed study
arm (period II). One of the eight male subjects did not
report for the fed study arm (period II) [Fig. 2]. For the
food-effect assessment, statistical analysis was performed
using the five male and five female subjects who completed
both study periods.
3.1 Safety and Tolerability
Saroglitazar was safe and well tolerated up to a 128 mg
oral dose during the single-ascending-dose study and also
during the study of the effects of food and sex. There was
no serious AE observed during the study in any treatment
arm. A total of 22 AEs in 11 subjects were reported during
the study, included rash/itching, abdominal pain, nausea,
cough, cold, headache, backache, body pain, calf pain,
fever, malaise, giddiness, dyspepsia and diarrhoea; how-
ever, they were mild to moderate in intensity. None of the
AEs was treatment emergent, and none required any
treatment for resolution. There was no clinically relevant
trend or change observed in clinical laboratory, urinalysis
or ECG findings in the placebo or treatment arms during
the study. There was no consistent pattern or dose depen-
dency observed in the AEs.
3.2 Pharmacokinetics in the Single-Ascending-Dose
Study (Part I)
Saroglitazar was well absorbed after oral administration
under fasting conditions. The absorption was rapid, with a
median tmaxof less than 1 h. The Cmaxvalues were from
3.98 to 7,461 ng/mL across the dose range. The Cmaxand
AUClast values increased in a dose-related manner.
812R. H. Jani et al.
single-ascending-dose study are presented in Table 1. The
results indicated that saroglitazar is well absorbed in
humans. The exposure increased in a predictable manner
with increasing doses (Fig. 3). Saroglitazar concentration–
time curves (mean ± standard error of the mean) after
administration of 0.125, 0.25, 0.50, 1, 2, 4, 8, 16, 32, 64
and 128 mg are shown in Figs. 4 and 5. These show that
the highest dose had an extended length of drug absorption.
The mean elimination half-life of saroglitazar across the
doses was 5.6 h. Saroglitazar was not excreted in urine,
indicating that it has a non-renal route of elimination. No
concentration of saroglitazar was quantifiable in urine
samples in any of the subjects exposed to saroglitazar. Pre-
clinical studies have shown that saroglitazar is mainly
eliminated by the hepatobiliary route . Taken together,
these data indicate that saroglitazar might have a non-renal
route of elimination in humans. On the basis of the half-
life, the drug does not show a potential for accumulation
following once-daily repeat dosing in normal healthy
3.3 Effects of Food and Sex on Saroglitazar
Pharmacokinetics (Part II)
The effects of food and sex on saroglitazar pharmacoki-
netics are presented in Table 2. The effect of sex on
saroglitazar pharmacokinetics was evaluated at the 1 mg
dose level under fasting conditions. The median tmaxwas
approximately 1 h post-dosing for both males and females.
The meanCmaxand AUC values were similar in both
Table 1 Pharmacokinetic parameters (means ± standard deviations) of saroglitazar following a single oral dose of saroglitazar in healthy
Doses (mg)Cmax(ng/mL)tmax(h)AUClast(ng?h/mL) AUC?(ng?h/mL)
3.98 ± 1.140.75 ± 0.25 12.62 ± 3.6713.22 ± 3.540.13 ± 0.07 6.87 ± 3.63
19.56 ± 3.361.17 ± 1.3946.57 ± 14.6849.27 ± 16.170.31 ± 0.143.08 ± 2.52
23.42 ± 6.320.88 ± 0.5655.98 ± 15.33 58.97 ± 17.140.39 ± 0.132.00 ± 0.78
193.16 ± 42.12 1.00 ± 0.52 249.20 ± 104.58253.82 ± 103.970.13 ± 0.035.39 ± 1.33
2 223.18 ± 27.421.21 ± 0.64 726.46 ± 237.14750.57 ± 255.680.06 ± 0.03 14.34 ± 5.68
4 337.07 ± 90.990.71 ± 0.25 806.40 ± 160.4855.96 ± 172.50.26 ± 0.102.93 ± 0.87
8727.27 ± 408.630.85 ± 0.61 1,802.02 ± 1,009.21,937.66 ± 992.96 0.21 ± 0.144.47 ± 2.07
161,548.47 ± 427.290.64 ± 0.243,563.31 ± 1,094.13 3,689.26 ± 1,132.24 0.25 ± 0.09 3.31 ± 1.95
323,740.17 ± 1,180.281.21 ± 0.64 10,352.04 ± 2,217.12 10,479.65 ± 2,206.85 0.20 ± 0.073.84 ± 1.09
645,091.33 ± 1,257.22 1.17 ± 0.6616,958.86 ± 3,648.04 17,419.22 ± 3,736.560.14 ± 0.08 7.23 ± 6.58
128 7,461.17 ± 3,035.091.88 ± 1.66 32,622.68 ± 8,282.7933,385.65 ± 8,137.620.12 ± 0.077.68 ± 4.14
kzfirst-order elimination rate constant associated with the terminal (log-linear) portion of the curve, AUC area under the plasma concentration–
time curve, AUClastAUC from time zero to the time of the last measurable concentration, AUC?AUC from time zero to infinity, Cmaxmaximum
plasma concentration, t?belimination or terminal half-life, tmaxtime to reach Cmax
aThe suspension was used for dosing, N = 6 (N = 5 for the 0.125 mg dose)
02550 75 100125150
R2 = 0.9399 (Cmax)
= 0.9952 (AUClast)
Mean AUClast (ng·h/mL)
Mean Cmax (ng/mL)
Fig. 3 Dose linearity of the
area under the plasma
concentration–time curve from
time zero to the time of the last
(AUClast) and maximum plasma
concentration ( Cmax) as a
function of a single oral dose of
saroglitazar administered to
Pharmacokinetics, Safety and Tolerability of Saroglitazar 813
05 1015 2025 30
Plasma saroglitazar concentration (ng/mL)
Fig. 4 Line plot for mean (±standard error of the mean) concentration–time curves for saroglitazar after administration of 0.125, 0.25, 0.50, 1
and 2 mg doses to healthy, adult, male, human subjects under fasting conditions
05 1015 202530
Plasma saroglitazar concentration (ng/mL)
Fig. 5 Line plot for mean (±standard error of the mean) concentration–time curves for saroglitazar after administration of 4, 8, 16, 32, 64 and
128 mg doses to healthy, adult, male, human subjects under fasting conditions
814 R. H. Jani et al.
sexes. No statistically significant differences in tmax, AUC
andCmax values were found. The t?b was shorter in
females, and this finding was statistically significant as
compared with male subjects under fasting and fed
The effect of food on saroglitazar pharmacokinetics was
evaluated at the 1 mg dose level in male and female sub-
jects. Administration of food had a small effect on the
pharmacokinetics of the drug. In male subjects, there were
no significant changes in overall exposure (AUC); how-
ever, there were significant increases in tmaxand t?b, and a
decrease in Cmax. In females, the only change that was
observed was a significant reduction in AUC under fed
conditions. No other pharmacokinetics parameters were
affected by food.
Saroglitazar is a novel PPAR agonist with predominant
PPARa and moderate PPARc agonist activity. It has been
developed for the treatment of dyslipidaemia and glycae-
mic management in T2DM. PPARs are nuclear receptors,
and hence the effects of saroglitazar are likely to be
mediated by changes in expression of various genes
involved in metabolism.
In this study, the pharmacokinetics, safety and tolera-
bility of saroglitazar were evaluated in healthy human
subjects. Saroglitazar was found to be well absorbed and
showed predictable pharmacokinetic parameters when
evaluated in the single-ascending-dose study. These data
are consistent with high transepithelial permeability of
saroglitazar (162 nm/s) as seen in the well-established
human Caco-2 cell model for intestinal absorption .
Two different types of formulations were used in this
study. Lower doses were formulated in a suspension form,
which provided the required pharmaceutical properties,
including content uniformity. Higher-dose strengths were
prepared in tablet dosage form. Despite a switch in for-
mulation from the suspension (0.125–0.5 mg) to tablets
(1–128 mg), exposure increased in a dose-related and lin-
ear manner. There was no indication of saturation of
exposure, even at the high dose. The elimination half-life in
subjects treated with 2 mg appeared to be prolonged, per-
haps because of slower clearance in these subjects. This
finding could be due to the small sample size and inter-
After oral administration, the saroglitazar parent drug
was not detected (\20 pg/mL, the lower limit of quantifi-
cation) in urine samples, indicating that saroglitazar is not
eliminated via the renal route. Preclinical studies  have
shown that saroglitazar is mainly eliminated by the enter-
ohepatic route. Since kidney function is compromised in
the advanced stage of T2DM, a non-renal route of elimi-
nation may be beneficial. Saroglitazar dose adjustment may
not be required in such patients.
It should be noted that the single-ascending-dose study
results were limited to healthy volunteers who were under
fasting conditions and were not taking other medications.
Also, there were a limited number of patients in the study
of the effects of food and sex, and no correction was made
for body weight differences.
This first-in-humans study with a small number of
healthy volunteers demonstrated that saroglitazar was well
tolerated up to a dose of 128 mg in the single-ascending-
dose study. Because the estimated therapeutic dose, based
on pre-clinical studies, was in the range of 1–4 mg, the
highest tested dose of 128 mg provided a safety margin of
over 32-fold. Therefore, further dose escalation to reach the
maximum tolerated dose (MTD) was not considered.
Table 2 Pharmacokinetic parameters (means ± standard deviations [SDs]) following a single oral dose of saroglitazar 1 mg in healthy subjects
under fasting and fed conditions
6 1.00 ± 0.52
93.16 ± 42.12
249.19 ± 104.58 253.82 ± 103.975.39 ± 1.33
11.78b± 4.775 198.05 ± 36.86202.44 ± 34.99
5 0.90 ± 0.1496.95 ± 23.56 287.97 ± 101.10
297.36 ± 100.12
Fed6 2.38 ± 1.7984.06 ± 40.74
AUC area under the plasma concentration–time curve, AUClastAUC from time zero to the time of the last measurable concentration, AUC?
AUC from time zero to infinity, Cmaxmaximum plasma concentration, t?belimination or terminal half-life, tmaxtime to reach Cmax
aOne male subject did not report during the fed period of the study, and one female subject withdrew her consent during the fasting period of the
study. The means of all available data (n = 5 or 6, as available) are shown in the table
bSignificant (p\0.05) using a paired t test for fed versus fasting for n = 5 subjects: for 5 fasting male subjects, the tmax, Cmaxand t?b
(mean ± SD) values were 1.00 ± 0.59 h, 99.77 ± 43.47 ng/mL and 5.00 ± 1.03 h, respectively. For 5 fed female subjects, the AUClastand
AUC?(mean ± SD) values were 242.31 ± 102.79 ng?h/mL and 252.08 ± 104.82 ng?h/mL
cSignificant (p\0.05) using unpaired t test for males as compared with females
Pharmacokinetics, Safety and Tolerability of Saroglitazar 815
No serious AEs were observed in this study. All AEs that
were observed were mild to moderate in nature. No con-
sistent pattern or dose dependency was observed in the
AEs. No clinically relevant trends or changes were
observed in medical laboratory, urinalysis or ECG values
Saroglitazar was found to be safe and well tolerated in both
males and females in the SAD study. The highest dose
tested in the study (128 mg) was over 32 times higher than
the proposed efficacious dose. Saroglitazar was very well
absorbed orally and has a non-renal route of elimination.
The pharmacokinetics of saroglitazar are supportive of
once daily dosing for this class.
Healthcare Limited, a Zydus Group Company (Ahmedabad, Gujarat,
India). The authors thank Dr Vikram Ramanathan for his contribution
to the discussion and review of the manuscript, and Mr Rahul Gupta
for providing statistical assistance; both are employees of Cadila
Healthcare Limited. All authors are employees of Cadila Healthcare
Limited. This report was prepared by the authors, who had full access
to all data in the study and had final responsibility for the decision to
submit the manuscript for publication.
Part of this work was presented at the 69th Scientific Sessions of
the American Diabetes Association; New Orleans, LA, USA; 5–9
This study was sponsored and funded by Cadila
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medium, provided the original author(s) and the source are credited.
This article is distributed under the terms of the
1. World Health Organization. Diabetes [factsheet no. 312] (2013)
Accessed 23 May 2013.
2. Morrish NJ, Wang SL, Stevens LK, et al. Mortality and causes of
death in the WHO Multinational Study of Vascular Disease in
Diabetes. Diabetologia. 2001;44(Suppl 2):S14–21.
3. Robert GD, Graham TM. Intensive glycemic control in the
ACCORD and ADVANCE trials. N Engl J Med. 2008;358:
4. Sophia Z, Bastiaan EG, Toshiharu N, et al. Combined effects of
routine blood pressure lowering and intensive glucose control on
macrovascular and microvascular outcomes in patients with
type 2 diabetes. Diabetes Care. 2009;32:2068–74.
5. Solano MDP, Goldberg RB. Management of diabetic dyslipide-
mia. Endocrinol Metab Clin N Am. 2005;34:1–25.
6. American Diabetes Association. Dyslipidemia management in
adults with diabetes. Clinical Practice Recommendation 2004.
Diabetes Care. 2004;27 (Suppl. 1):S68–71.
7. American Diabetes Association. Standards of medical care in
diabetes—2013. Diabetes Care. 2013;36:S11–66.
8. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the
secondary prevention of coronary heart disease in men with low
levels of high-density lipoprotein cholesterol; Veterans Affairs
High-Density Lipoprotein Cholesterol Intervention Trial Study
Group. N Engl J Med. 1999;341:410–8.
9. Steiner G. Dyslipoproteinaemias in diabetes. Clin Invest Med.
10. Robert RH, Michael AL, Sunder M, et al. Effects of the dual
peroxisome proliferator-activated receptor-a/c agonist aleglitazar
on risk of cardiovascular disease in patients with type 2 diabetes
(SYNCHRONY). Lancet. 2009;374:126–35.
11. Vamecq J, Latruffe N. Medical significance of peroxisome pro-
liferator-activated receptors. Lancet. 1999;354:141–8.
12. Alexander T, Michael M, Enrique ZF. Dual and pan-peroxisome
proliferator-activated receptors (PPAR) co-agonism. Cardiovasc
13. Agrawal R. The first approved agent in the glitazar class: sa-
roglitazar. Curr Drug Targets. 2013 August 1. [Epub ahead of
14. US Food and Drug Administration. Guidance for bioanalytical
method validation, US Department of Health and Human Ser-
10 Sep 2013.
15. Sonu S. Biliary excretion of ZYH1 in Wistar rats. Ahmedabad:
Cadila Healthcare Ltd.; 2004.
16. Poonam G. Determination of monodirectional permeability of
ZYH1 across Caco2 cell monolayer using LC-MS/MS. Ahme-
dabad: Cadila Healthcare Ltd.; 2011.
816 R. H. Jani et al.