Lipid Lowering Effects of Saroglitazar in Preclinical Models: Potential Synergistic Interaction with Statins
Suresh R. Giri, Akshyaya Rath, Bibhuti Bhoi, Chitrang Trivedi, Pankaj R. Patel and Mukul R. Jain
Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, Gujarat, India. E-mail : [email protected]
Abstract
Effect of Saroglitazar on serum LDL-C and TC in
hApoB100/hCETP double transgenic mice
• Saroglitazar is a novel dual PPARa/g agonist that has shown significant lipid-lowering
and insulin-sensitizing effects with good safety profile in various preclinical models.
Figure 1. Effect of Saroglitazar after 14 days of once daily oral dose
administration in hApoB100/hCETP double transgenic mice.
• In present study, we have evaluated the lipid lowering activity of saroglitazar in hApoB100/
hCETP double transgenic mice, a model that exhibits human-like serum LDL-C and
HDL-C profile. The effect of saroglitazar in combination with statins was evaluated in
high-fat, high-cholesterol (HF-HC) diet-fed golden Syrian hamsters.
-5 0
-6 0
-7 0
-8 0
S a r o g l it a z a r ( 0 . 1 m g /k g )
-1 0
50
-2 0
-3 0
-4 0
-5 0
-6 0
-7 0
S a r o g lit a z a r ( 1 m g /k g )
S a r o g l it a z a r ( 0 . 1 m g /k g )
S a r o g l it a z a r ( 0 . 3 m g /k g )
S a r o g lit a z a r ( 1 m g /k g )
S a r o g lit a z a r ( 3 m g /k g )
S a r o g lit a z a r ( 3 m g /k g )
S a r o g li t a z a r ( 1 0 m g /k g )
S a r o (1 m g /k g )
S a r o ( 1 m g /k g ) + A t o r v a ( 0 .6 2 m g /k g )
S a r o g li t a z a r ( 1 0 m g /k g )
30
S a r o ( 1 m g /k g ) + R o s u v a ( 0 . 6 2 m g /k g )
40
% C h a n g e in s e r u m T C v s C o n t r o l
-4 0
R o s u v a ( 0 .6 2 m g /k g )
S a r o (1 m g /k g )
% C h a n g e in s e ru m L D L -C v s C o n tr o l
-3 0
S a r o g l it a z a r ( 0 . 3 m g /k g )
30
20
10
-1 0
-2 0
-3 0
-4 0
-5 0
S a r o ( 1 m g /k g ) + A t o r v a ( 0 .6 2 m g /k g )
S a r o ( 1 m g /k g ) + R o s u v a ( 0 . 6 2 m g /k g )
LDL-C: 67 % reduction at 1 mg/kg
ED50 dose is 0.11 mg/kg
Effect of Saroglitazar on LDL-C/ HDL-C ratio and serum TG in
hApoB100/hCETP double transgenic mice
Control
-2 0
-3 0
-4 0
-5 0
-6 0
-7 0
-8 0
-9 0
S a r o g l it a z a r ( 0 . 1 m g /k g )
S a r o g l it a z a r ( 0 . 3 m g /k g )
S a r o g li t a z a r ( 1 0 m g /k g )
50
-2 0
-3 0
-4 0
-5 0
-6 0
-7 0
S a r o g l it a z a r ( 0 . 1 m g /k g )
-8 0
S a r o g lit a z a r ( 1 m g /k g )
S a r o g lit a z a r ( 3 m g /k g )
60
S a r o g l it a z a r ( 0 . 3 m g /k g )
S a r o g lit a z a r ( 1 m g /k g )
-9 0
S a r o g lit a z a r ( 3 m g /k g )
S a r o g li t a z a r ( 1 0 m g /k g )
40
30
20
10
-1 0
-2 0
-3 0
-4 0
-5 0
S a r o ( 1 m g /k g ) + A t o r v a ( 0 .6 2 m g /k g )
S a r o ( 1 m g /k g ) + R o s u v a ( 0 . 6 2 m g /k g )
-2 0
TG: 39% reduction at 1 mg/kg
± 5.3*
109.7
86.8
±
6.2*
± 14.8
35.3
± 1.9*
73.1
±
2.8*
52.3
± 5.7*
LDL-C
Total Cholesterol
Triglycerides
31.6 ± 3.3*
66.5 ±
5.1*
42.6 ±
(mg/dL)
(mg/dL)
(mg/dL)
29.9
108.1
±
± 3.7*
10.7
67.0
151.2
±
±
7.7
5.2*
41.6
5.8*
± 4.1*
108.2 ± 14.7
14.8
mg/kg)
42.7 ± 2.9*
83.9in HF-HC
±
5.3*diet fed
68.7 hamster
± 13.4 model.
Table 2. Saroglitazar(0.3
Serum biochemical
parameters
on day-7
-3 0
Saroglitazar(1 mg/kg)
35.3
± 1.9*
Saroglitazar(10 mg/kg)
29.9
± 3.7*
73.1
±
2.8*
±
5.2*
52.3
± 5.7*
Total
Cholesterol
Table
2.Saroglitazar(3
Serum
biochemical
parameters
onLDL-C
day-7
in HF-HC
diet-fed
hamster Triglycerides
model.
Treatment
Group
mg/kg)
31.6 ± 3.3*
66.5 ±
5.1*
42.6 ± 5.8*
60
(mg/dL)
67.0
(mg/dL)
41.6
HF-HC
Control
181.9 ± 13.5
330.2 ±
All values are measured at the end of treatment (14 day), and expressed as mean SEM (n = 6)
± 4.1*
12.7
(mg/dL)
436.8 ± 21.7
* indicates significantly
different as compared to control,
p <0.05 ±
(ANOVA)
Atorvasatin
(0.62 mg/kg)
205.5
19.0
365.5 ±
24.3
414.0 ± 61.3
Table 2. Serum biochemical parameters on day-7 in HF-HC diet fed hamster model.
Rosuvasatin (0.62 mg/kg)
192.4 ± 17.1
359.8 ±
15.6
354.2 ± 21.6
Saroglitazar
(1 mg/kg)
Treatment Group
LDL-C±
199.7
Saro (1 mg/kg) + Atorva (0.62 mg/kg)
105.4
± 14.9*
236.4
±
20.9*
92.0
± 4.7*
229.0
±
11.9*
(mg/dL)
HF-HC Control
181.9
±
Atorvasatin (0.62 mg/kg)
205.5
±
Saro (1 mg/kg) + Rosuva (0.62 mg/kg)
Cholesterol
13.0 Total333.0
±
18.2Triglycerides
280.9 ± 35.1*
(mg/dL)
13.5
330.2
±
19.0
365.5
±
12.7
24.3
All values are measured at the end of treatment (7 day), and expressed as mean SEM (n = 6)
(0.62 mg/kg)
192.4 p±<0.05
17.1
359.8 ±
15.6
* Rosuvasatin
indicates significantly
different as compared to control,
(ANOVA)
(mg/dL)
194.1 ± 19.7*
436.8 ± 21.7
195.6 ± 15.3*
414.0 ± 61.3
354.2 ± 21.6
Saroglitazar (1 mg/kg)
199.7
±
13.0
333.0
±
18.2
280.9 ± 35.1*
Saro (1 mg/kg) + Atorva (0.62 mg/kg)
105.4
± 14.9*
236.4
±
20.9*
194.1 ± 19.7*
Saro (1 mg/kg) + Rosuva (0.62 mg/kg)
92.0
± 4.7*
229.0
±
11.9*
195.6 ± 15.3*
A t o r v a ( 0 .6 2 m g /k g )
R o s u v a ( 0 .6 2 m g /k g )
S a r o (1 m g /k g )
40
S a r o ( 1 m g /k g ) + A t o r v a ( 0 .6 2 m g /k g )
S a r o ( 1 m g /k g ) + R o s u v a ( 0 . 6 2 m g /k g )
20
-2 0
-4 0
-6 0
-8 0
-6 0
LDL-C/HDL-C ratio: 61% reduction at 1 mg/kg
74.1
All values are measured at the end of treatment (7 day), and expressed as mean SEM (n = 6)
* indicates significantly different as compared to control, p <0.05 (ANOVA)
R o s u v a ( 0 .6 2 m g /k g )
S a r o (1 m g /k g )
Triglycerides
(mg/dL)
All values are measured at the end of treatment (14 day), and expressed as mean SEM (n = 6)
Saroglitazar(0.1
mg/kg)
74.1 ±to control,
5.3* p <0.05
109.7(ANOVA)
±
6.2*
86.8 ±
* indicates
significantly
different as compared
Figure 4. Effect of Saroglitazar (alone) and in combination with statin after 7 days of once daily oral dose administration in HF-HC diet-fed hamsters.
-1 0
Total Cholesterol
(mg/dL)
Serum biochemical parameters on day-14 and day-7 in
Control
± 10.7
±
7.7
108.2 ± 14.7
transgenic
mice and 108.1
HF-HC
fed151.2
hamster
model
respectiv
Saroglitazar(10 mg/kg)
-1 0
-4 0
A t h e r o g e n ic d y s lip id e m i a ( T G /H D L r a t io )
-1 0
LDL-C
(mg/dL)
Treatment Group
Treatment Group
Saroglitazar(3
mg/kg)
A t o r v a ( 0 .6 2 m g /k g )
% C h a n g e in s e ru m T G v s C o n tr o l
% C h a n g e in L D L - C / H D L - C r a t io v s C o n t r o l
Figure 2. Effect of Saroglitazar after 14 days of once daily oral dose
administration in hApoB100/hCETP double transgenic mice.
hApoB100/hCETP double transgenic mice.
Table 1. Serum biochemical parameters on day-14 in hApoB100/hCETP double transgenic mi
Saroglitazar(1 mg/kg)
10
Effect of Saroglitazar (alone) and in combination with statin on
serum TG and TG / HDL-C ratio in HF-HC diet fed hamsters
% C h a n g e in s e ru m T G v s C o n tr o l
• The hApoB100/hCETP double transgenic mice and Syrian Golden hamster animals used
in this study were supplied by Animal Research Facility, Zydus Research Centre (ZRC).
day
transgenic
HF-HC
fedonhamster
model respe
Table 1.mice
Serum and
biochemical
parameters
day-14 in
mg/kg)parameters
42.7on day-14
± 2.9*in hApoB100/hCETP
83.9 ±
5.3* double
68.7
± 13.4mice.
Table 1. Saroglitazar(0.3
Serum biochemical
transgenic
Combination of Saroglitazar with atorvastatin and rosuvastatin showed synergistic
42 and 48 % reduction in LDL-C respectively.
TC: 50 % reduction at 1 mg/kg
Serum biochemical parameters on day-14 and day-7 in
Serum transgenic
biochemical
parameters
day-14 and
mice and
HF-HC diet-fedon
hamsters.
Saroglitazar(0.1 mg/kg)
20
-6 0
Materials and Methods
Poster No. : 693-P
-2 0
-9 0
• Overall, these results suggest that Sarogltiazar is an effective therapeutic option for
treatment of dyslipidemia, particularly in combination with statins.
• Serum biochemical parameters were measured using autoanalyser (Cobas c 311 from
Roche Diagnostics) using commercially available kits from Roche Diagnostics,GmbH
D-68298 Mannheim, Germany. The percent reduction was calculated considering the
values on pretreatment (day-0) and treatment day (day-7) for treatment group Vs control.
A t o r v a ( 0 .6 2 m g /k g )
R o s u v a ( 0 .6 2 m g /k g )
-1 0
% C h a n g e in s e r u m T C v s C o n t r o l
% C h a n g e in s e ru m L D L -C v s C o n tr o l
• The HF-HC diet-fed hamsters treated with saroglitazar (1 mg/kg), atorvastatin (0.62 mg/
kg) and rosuvastatin (0.62 mg/kg) once daily for seven days did not show any reduction
in LDL-C when these agents were administered alone. However, co-administration of
saroglitazar (1 mg/kg) with atorvastatin (0.62 mg/kg) or rosuvastatin (0.62 mg/kg) showed
a significant and synergistic LDL-C lowering effect (42 and 48 % reduction respectively).
Similar synergistic effect was also observed in case of serum triglycerides (42 and 53%
reduction) and LDL-C/HDL-C ratio (43 and 49% reduction).
• Golden Syrian hamsters (12-14 week old) were fed normal or HF-HC diet for 14 days.
The animals were selected based on their body weights day-0 serum LDL-C levels
and randomized into various treatment groups (n=6). During next 7 days each animal
was dosed daily (by oral gavage) with vehicle, Saroglitazar (Saro) 1 mg/kg, atorvastatin
(atorva) 0.62 mg/kg, rosuvastatin (rosuva) 0.62 mg/kg, Saro (1 mg/kg) + atorva (0.62
mg/kg) or Saro (1 mg/kg) + Rosuva (0.62 mg/kg). On day 7, animals were bled one-hour
post-dosing and serum was analyzed for TC, TG, LDL-C and HDL-C levels.
Figure 3. Effect of Saroglitazar (alone) and in combination with statin after 7
days of once daily oral dose administration in HF-HC diet-fed hamsters.
A t o r v a ( 0 .6 2 m g /k g )
• Once-daily oral treatment of hApoB100/hCETP double transgenic mice with saroglitazar
for 14 days resulted in dose-dependent reductions in serum LDL-C. The ED50 for LDL-C
lowering effect was found to be 0.11 mg/kg. Once-daily oral treatment with Saroglitazar
(1 mg/kg) for 14 days caused 67% reduction in LDLC, 50 % reduction in total cholesterol
(TC), 39 % reduction in triglycerides (TG) and 61 % reduction in LDL-C/HDL -C ratio as
compared to vehicle treated controls.
• The hApoB100/hCETP double transgenic mice (27-33 week old) were randomized and
grouped (n=6) based on day-0 serum LDL-C levels. The mice were treated with vehicle
or saroglitazar (0.1, 0.3, 1,3 and 10 mg/kg/day) for 14 days by oral gavage. On day-14, at
1 h post dose, blood samples were collected for estimation of non-fasted serum LDL-C,
TC, TG and HDL-C levels.
Effect of Saroglitazar (alone) and in combination with statin
on serum LDL-C and TC in HF-HC diet-fed hamsters
Combination of Saroglitazar with atorvastatin and rosuvastatin showed synergistic
reduction in serum TG and atherogenic dyslipidemia ratio (TG/HDL-C).
Conclusions
• Saroglitazar (1 mg/kg) caused 67% reduction in LDL-C, 50 % reduction in total
cholesterol, 39 % reduction in triglycerides and 61 % reduction in LDL-C/HDL
-C ratio as compared to vehicle treated controls in hApoB100/hCETP double
transgenic mice .
• Co-administration of Saroglitazar with atorvastatin or rosuvastatin in HF-HC
diet-fed hamster model showed a significant and synergistic LDL-C lowering
effect. Similar synergistic effect was also observed in case of serum triglycerides
and atherogenic dyslipidemia ratio (TG/HDL-C).
• Sarogltiazar is an effective therapeutic option for treatment of dyslipidemia,
particularly in combination with statins.
75th Scientific Session - ADA, June 5-9, 2015 • Boston, MA, USA