The effects of triple vs. dual and monotherapy with rosiglitazone, glimepiride, and atorvastatin on...

doi: 10.1111/j.1472-8206.2011.00960.x

O R I G I N A L

A R T I C L E

The effects of triple vs. dual andmonotherapy with rosiglitazone, glimepiride,and atorvastatin on lipid profile andglycemic control in type 2 diabetes mellitusrats

Danish Ahmeda*, Manju Sharmab, K.K. Pillaib

aDepartment of Pharmaceutical Sciences, Faculty of Health Medical Sciences, Indigenous and Alternative Systems of

Medicines, Allahabad Agricultural Institute-Deemed University, Allahabad, Uttar Pradesh-211007, IndiabDepartment of Pharmacology, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), New Delhi-110062, India

I N T R O D U C T I O N

Type 2 diabetes is a heterogeneous, progressive disorder

initially characterized by impaired glucose tolerance and

compensatory hyperinsulinaemia and in the late stages,

by severe insulin resistance and impaired b-cell function

[1]. The syndrome is characterized by an imbalanced

interplay between endocrine pancreatic function, insulin

sensitivity of liver, muscle, and adipose tissues, and

neural activity [2] and be an adjunct to hyperglycemia,

dyslipidemia, hypertension, obesity and in the long-term

micro- and macro-vascular complications, leading to

impaired life quality and increased mortality [3]. In

addition, various phenomenon that directly accompany

diabetes mellitus could accelerate atheorgenesis, i.e.,

glycosylation of arterial wall proteins and lipoproteins,

increased per oxidation of lipids [4], micro vascular

disease, abnormalities in platelet functions [5], and

defective [6]. Although hyperglycemia has been impli-

cated as risk factor for diabetes type 2, dyslipidemia far

overweighs all other risk factors. Hence, the importance

of treatment of concomitant lipid abnormalities is that

pharmacologic therapies do not aggravate associated

lipid abnormalities and preferably leads to their improve-

ment [7]. Unfortunately, none of the available drugs for

clinical use has proved sufficiently efficacious in restoring

normal glucose metabolism alone or in combination

therapy as the disease progresses [8].

There are quite a few reasons to do this investigation

namely the diabetes is itself is progressive with deteriora-

tion of glycemic control and lipid profile overtime and

monotherapeutic attempts to achieve and maintain gly-

cemic control and lipid profile often fail in long-term

[9,10]. The assorted combinations of sulfonylureas and

Keywords

atorvastatin,

glimepiride,

rosiglitazone,

streptozotocin,

triple oral therapy

Received 12 August 2010;

revised 26 April 2011;

accepted 20 May 2011

*Correspondence and reprints:

[email protected];

[email protected]

A B S T R A C T

The present study was undertaken to investigate the effects of triple oral therapy and

different combination of rosiglitazone, atorvastatin, and glimepiride on streptozotocin

(STZ)-induced diabetic rats. The various biochemical parameters studied included

glycosylated hemoglobin (A1c), fasting plasma sugar levels, triglycerides, low-density

lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and very

low-density lipoprotein (VLDL) cholesterol in diabetic and normal rats. The present

study demonstrates that atorvastatin could increase the effect of rosiglitazone and

glimepiride and lipid-lowering effect of combination of rosiglitazone and glimepiride

(GLIM). According to our finding, similar results for rosiglitazone plus atorvastatin

were obtained in terms of correcting lipid parameters, whereas the suppressive action

of triple oral therapy of rosiglitazone and glimepiride, and atorvastatin on blood

glucose, total cholesterol, LDL, VLDL, HDL cholesterol, and triglyceride was more

beneficial than that of dual therapy of different combinations and monotherapy.

ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Societe Francaise de Pharmacologie et de TherapeutiqueFundamental & Clinical Pharmacology 1

Fund

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bigunides are commonly used in clinical practice. But his

potent combination is no longer capable to provide control

over the lipid profile that is more or less always associated

with diabetes type 2. The addition of a hypolipidemic drug

and antidiabetic drugs with different mode of action may

show the way to improved glycemic control and better

lipid profile. The co-existence of insulin resistance and

dyslipidemia in type 2 diabetes mellitus supports the

rationale for the use of a combination of insulin sensitizers

and lipid-lowering drugs [11]. These findings impelled us

to design the present study to investigate whether the

assorted combinations of rosiglitazone (ROSI), glimepiride

(GLIM), and ATOR has any beneficial effect on serum

glucose and serum lipid profile on diabetic rats.

M A T E R I A L S A N D M E T H O D S

Reagents and chemicals

Streptozotocin solution was prepared by dissolution in

0.1 M citrate buffer (pH = 4.5). Rosiglitazone (4 mg/kg)

was made in 1% Tween 80 and 0.9% normal saline.

Glimepiride (1 mg/kg) was made in 1% Tween 80 and

0.9% normal saline. Atorvastatin (5 mg/kg) was dis-

persed in 1% methylcellulose.

Streptozotocin was purchased from Sigma Aldrich

(St. Louis, MO, USA). All other chemicals including ethyl

alcohol, trichloro acetic acid, diethyl ether, and citric acid

were purchased from CDH, Mumbai, India. The reagent kit

for glycosylated heamoglobin (A1c) was purchased from

Monozyme India Pvt. Ltd. (Hyderabad, India). The reagent

kit for triglyceride was procured from Reckon diagnostic

(Vadodara, India). The reagent kits for glucose and

cholesterol were obtained from Span diagnostics (Surat,

India). Water used for the solution preparation and

glassware washing was passed through an Easy Pure UF

water purification unit (Thermolyne Barnstead, NH, USA).

Animals

The present study was executed in 2-day-old neonatal rat

pups. Neonatal 2-day-old rat pups weighing 6–10 g of

either sex were obtained along with their respective

mothers from Central Animal House Facility, Jamia

Hamdard, New Delhi. The present study confirms the

guiding principles given by Institutional Animal Ethics

Committee (IAEC), Jamia Hamdard, New Delhi India,

which are in accordance with 173/CPCSEA, Jan 28, 2000.

Induction of diabetes

The cells in n-STZ rats bear a resemblance to insulin

secretory characteristics found in patients with Type 2

diabetes mellitus [12]. This was the reason for choosing

n-STZ model for the induction of type-2 diabetes mellitus

in rats. The 2-day-old neonatal rat pups were injected

with STZ (80 mcg/g) intraperitonial (i.p) using 26 gauge

(5/8 in. long) needle, with extreme care. The injection

spot was the dorsal midpoint between pelvis and ribs

close to the right side of the spine [13]. After 12 weeks of

the STZ injection, blood glucose of the induced rats was

estimated. The rats showing FBG ‡ 200 mg/dL consid-

ered to be diabetic.

Statistical analysis

Data were expressed as the mean ± SEM. For a statistical

analysis of the data, group means were compared by one-

way analysis of variance (ANOVA) followed by Dunnett’s

‘t’test, which was used to identify differences between

groups. P value < 0.05 was considered significant.

Experimental design

The type 2 diabetic rats of 12 weeks of age (induced by

injecting intraperitoneal streptozotocin to 2-day-old

neonatal pups) were randomized into nine groups com-

prising of six animals in each group as discussed later:

Group I: Normal control rats, received citrate buffer

(pH = 4.5) for 21 days (1 mL/kg p.o).

Group II: Diabetic control rats, received STZ (intra-

peritoneally to 2-day-old neonatal pups with single dose

of 80 lg/g, i.p).

Group III: Rosiglitazone-treated diabetic rats, received

rosiglitazone (4 mg/kg p.o) and continued for 21 days.

Group IV: Glimepiride-treated diabetic rats, received

glimepiride (1 mg/kg p.o) and continued for 21 days.

Group V: Atorvastatin-treated diabetic rats, received

atorvastatin (5 mg/kg p.o) and continued for 21 days.

Group VI: Rosiglitazone- and glimepiride-treated dia-

betic rats, received rosiglitazone (4 mg/kg p.o) + glim-

epiride (1 mg/kg p.o) and continued for 21 days.

Group VII: Rosiglitazone- and atorvastatin-treated

diabetic rats, received rosiglitazone (4 mg/kg p.o) +

atorvastatin (5 mg/kg p.o) and continued for 21 days.

Group VIII: Glimepiride- and atorvastatin-treated dia-

betic rats, received glimepiride (1 mg/kg p.o) + ator-

vastatin (5 mg/kg p.o) and continued for 21 days.

Group IX: Rosiglitazone-, glimepiride-, and atorvasta-

tin-treated diabetic rats, received rosiglitazone (4 mg/kg

p.o) + glimepiride (1 mg/kg p.o) + atorvastatin (5 mg/

kg p.o) and continued for 21 days.

The drug treatment was performed with the help of

oral catheter on every morning. At the end of the drug

treatment, all the animals were fasted overnight but

permit free access to water.

2 D. Ahmed et al.

ª 2011 The Authors Fundamental and Clinical Pharmacology ª 2011 Societe Francaise de Pharmacologie et de TherapeutiqueFundamental & Clinical Pharmacology

R E S U L T S

To evaluate the effect of rosiglitazone, glimepiride, and

atorvastatin alone and in assorted combination, in type

2 diabetes mellitus, several biochemical investigations

were performed in all the groups of experimentally

induced diabetic rats for the estimation of blood glucose,

serum cholesterol (Total, low-density lipoprotein (LDL),

very low-density lipoprotein (VLDL), and high-density

lipoprotein [HDL]), serum triglycerides, and glycosylated

hemoglobin levels (Table I). The following pharmacolog-

ical effects were observed.

Glycemic control

The mean blood glucose levels in rats fed on normal diet

(normal control rats, group I) was stable throughout the

experimental period. Conversely, in STZ-treated group

(diabetic control rats, group II), there was a significant

(P < 0.01) increase in the blood glucose levels (Figure 1)

as compared to the normal control (group I) rats. When

STZ-induced diabetic rats were treated with the drugs

rosiglitazone, glimepiride, and atorvastatin alone and in

various combination with groups III, IV, V, VI, VII, and

IX, respectively, for 21 days, it was observed that

lowering in blood glucose levels in the drug-treated

group received triple combination therapy (ROSI+GLI-

M+ATOR, group IX) was maximum as compared to

diabetic control (group II), the groups received the two

drugs therapy (group VI, VII, and VIII), and individual

drug treatment group (group III, IV, and V).

Effect on the levels of glycosylated heamoglobin

(GHb %)

When STZ-induced diabetic rats were treated with the

drugs, rosiglitazone, glimepiride, and atorvastatin, alone

and in combination with groups III, IV, V, VI, VII, VIII,

and IX, respectively, for 21 days, there was a significant

(P < 0.01) lowering in glycosylated hemoglobin

(Figure 2) in the group that received triple combination

therapy (group IX) than the groups received combina-

tion of two drugs (group VI, VII, and VII) and the

individual drug treatment group (group III, IV, and V).

Whereas, there was no significant change in GHb levels

in atorvastatin-treated rats (group V).

Effect on the levels of serum triglycerides levels

(mg/dL)

As shown in the (Figure 3), when STZ-induced diabetic

rats were treated with the drugs, rosiglitazone, glimepi-

ride, and atorvastatin, alone and in combination with

groups III, IV, V, VI, VII, VII, and IX, respectively, for

21 days, there was a significant (P < 0.01) lowering in

serum triglyceride levels in the group that received triple

combination therapy (group IX) as compared to diabetic

control and the groups received the individual drug

treatment (group III, IV, and V), whereas glimepiride

treatment did not affect the serum triglyceride levels as

compared to group II rats.

Effect on the levels of serum total cholesterol

(mg/dL)

As shown in (Figure 4) that when STZ-induced diabetic

rats were treated with the drugs, rosiglitazone, glimepi-

ride, and atorvastatin, alone and in combination with

groups III, IV, V, VI, VII, VIII, and IX, respectively, for

21 days, there was a significant (P < 0.01) lowering in

serum total cholesterol levels (Figure 4) in the group that

received triple combination therapy (group IX) as com-

pared to diabetic control and the group that received the

different combinations (group III, IV, V, VI, VII, and VIII).

Effect on the levels of serum HDL cholesterol

(mg/dL)

It is lucid from the (Figure 5) that when STZ-induced

diabetic rats were treated with the drugs, rosiglitazone,

glimepiride, and atorvastatin, alone and in combination

with groups III, IV, V, VI, VII, VIII, and IX, respectively,

for 21 days, there was a significant (P < 0.01) increase

in serum HDL cholesterol levels in the group that

received triple combination therapy (group IX) as com-

pared to all the different groups.

Effect on the levels of serum LDL cholesterol (mg/dL)

It is apparent from the (Figure 6) that the serum LDL

cholesterol levels of untreated diabetic rats were consid-

erably higher than those in normal rats. The adminis-

tration of triple combination of rosiglitazone, glimepiride,

and atorvastatin resulted in significant decrease in LDL

cholesterol as compared to other groups. Whereas

monotherapy with glimepiride and rosiglitazone treat-

ment did not affect the LDL cholesterol levels as

compared to group II rats.

Effect on the levels of serum VLDL cholesterol

(mg/dL)

The administration of rosiglitazone, glimepiride, and

atorvastatin as triple combination therapy results in

significant decrease in VLDL cholesterol as compared to

other groups. It was observed that there was significant

(P < 0.01) increase in the VLDL cholesterol levels in the

Triple oral therapy of rosiglitazone, glimepiride, and atorvastatin vs. monotherapy on lipid profile and glycemic control 3


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4 D. Ahmed et al.


diabetic control rats (group II) as compared to normal

control rats (Figure 7).

Effect on fasting plasma insulin levels

When Rosiglitazone, glimepiride, and atorvastatin were

administered together as triple oral therapy, there is a

significant decrease in fasting plasma insulin level

clearly depicting the improvement insulin sensitivity.

Conversely no improvement in insulin sensitivity is

detected in any group except in group (VII) received

the rosiglitazone and atorvastatin dual therapy

(Figure 8).

Figure 2 Effect of rosiglitazone, glimepi-

ride and ATOR alone and in combina-

tion as triple oral therapy in addition to

dual oral therapy on glycosylated

hemoglobin (A1c) (%) of normal and

diabetic rats; values are mean ± SEM;

n = 6; *P < 0.05; **P < 0.01;

***P < 0.001; P > 0.05 is considered as

non-significant (ns).




dual oral therapy on fasting blood glu-

cose level (mg/dL) of normal and diabetic

rats; values are mean ± SEM; n = 6;

*P < 0.05; **P < 0.01; ***P < 0.001;

P > 0.05 is considered as non-significant

(ns).




dual oral therapy on triglyceride (mg/dL)

of normal and diabetic rats; values are

mean ± SEM; n = 6; *P < 0.05;

**P < 0.01; ***P < 0.001; P > 0.05 is

considered as non-significant (ns).



Effect on homeostasis model assessment of insulin

resistance (HOMA-IR)

Rosiglitazone+gliempirde+atorvastatin and rosiglitaz-

one+atorvastatin group showed more control on

insulin resistance as compared to unpretentious

control of other groups receiving different combina-

tions or monotherapy over insulin resistance

(Figure 9).




dual oral therapy on high-density lipo-

protein cholesterol (mg/dL) of normal

and diabetic rats; values are mean ±

SEM; n = 6; *P < 0.05; **P < 0.01;

***P < 0.001; P > 0.05 is considered

as non-significant (ns).




dual oral therapy on total cholesterol

(mg/dL) of normal and diabetic rats;

values are mean ± SEM; n = 6;

*P < 0.05; **P < 0.01; ***P < 0.001;


(ns).




dual oral therapy on low-density lipo-

protein cholesterol (mg/dL) of normal

and diabetic rats; values are mean ±

SEM; n = 6; *P < 0.05; **P < 0.01;

***P < 0.001; P > 0.05 is considered as

non-significant (ns).

6 D. Ahmed et al.


Effect on body weight

Rosiglitazone+glimepirde+atorvastatin group showed

gain in body weight as compared to other groups

(Figure 10).

Histologic studies

Animals were sacrificed by an overdose of anesthetic

ether. The heart and pancreas were immediately expur-

gated. Auricle and aortic root of heart and whole




dual oral therapy on fasting plasma

insulin (pM) of normal and diabetic rats;

values are mean ± SEM; n = 6;

*P < 0.05; **P < 0.01; ***P < 0.001;


(ns).




dual oral therapy on homeostasis model

of insulin resistance (HOMA-IR) of nor-

mal and diabetic rats; values are

mean ± SEM; n = 6; *P < 0.05;

**P < 0.01; ***P < 0.001; P > 0.05 is





dual oral therapy on very low-density

lipoprotein cholesterol (mg/dL) of nor-

mal and diabetic rats; values are

mean ± SEM; n = 6; *P < 0.05;

**P < 0.01; ***P < 0.001; P > 0.05 is




pancreas were removed and the remaining tissue of

heart was washed with ice cold 0.9% sodium chloride

solution. The tissues were conserved in buffered 10%

neutral formal and stored at )20 �C until processed [14].

Histopathologic studies on heart and pancreas shows

relative more degree of cardio protection and retardation

of pancreatic degradation with triple oral therapy viz.

rosglitazone+glimepirde+atorvastatin as compared to

double oral therapy of rosiglitazone+glimepirde, rosiglit-

azone+atorvastatin, and glimepiride+atorvastatin as well

as the monotherapy. The section of rat cardiac tissue from

normal control group cardiac muscle exhibits the inter-

calated disks (ID) marking the intercellular junctions

between the myofilaments (Figure 11 NC) The STZ

diabetic group shows hemorrhage (Figure 11 DC). The

cardiac muscle of diabetic rat after treatment with triple

oral therapy shows very less hemorrhage and necrosis

(Figure 11 DCT7) in comparison with other groups. While

section of rat pancreas from normal control group

showed normal pancreatic acini (Figure 12 NC), STZ

diabetes resulted in degenerative and lytic changes in the

islets of Langerhans of the pancreas (Figure 12 DP). Triple

oral therapy-treated rats show marked decreased in

degeneration and normal looking acini and lobules when

compared with STZ diabetes rats in addition to other

groups (Figure 12 PCT7).

D I S C U S S I O N

In the present study, the administration of triple oral

therapy of rosiglitazone, glimepiride, and atorvastatin

demonstrates the decreased blood glucose, triglyceride,

and cholesterol levels in neonatally induced STZ diabetic

rats as compared to double oral therapy of rosiglitaz-

one+glimepirde, rosiglitazone+atorvastatin, glimepi-

ride+atorvastatin, and all the drugs when used as

monotherapy. Lipid-lowering effects of triple oral therapy

were demonstrated clearly in the present investigation

and are consistent with the previous reports. Chu

et al.[15] observed that serum level of total cholesterol,

LDL, and triglyceride was significantly decreased only

after combination therapy of rosiglitazone and atorvast-

atin. Haffner et al.[16] also reported that dyslipidemia

contributes to excess vascular risk while nature and

mechanism of diabetic dyslipidemia differs between two

types of diabetes. According to our findings, similar

results for rosiglitazone and atorvastatin were obtained

in terms of correcting lipid parameters, whereas sup-

pressive action of triple oral therapy, i.e., rosiglitazone,

glimepiride, and atorvastatin on blood glucose level, total

cholesterol, LDL, VLDL, and triglyceride, was more

beneficial than dual oral therapy and monotherapy.

Boyle et al.[17] reported that triglyceride and HDL

cholesterol levels were decreased and total cholesterol

and LDL cholesterol levels were increased with rosiglitaz-

one and are consistent with our fallout that considerably

demonstrated decrease in blood glucose, triglyceride, total

cholesterol, LDL cholesterol, and increase in HDL choles-

terol levels with triple oral therapy. In addition to

improving and maintaining glycaemic control, the rosig-

litazone reduce b-cell stress, improve insulin resistance,

and modify a variety of cardiovascular risk factors,

including the abnormal lipid profile and increased low-

grade inflammation activity associated with type 2 diabe-

tes. The fundamental defects underlying type 2 diabetes

mellitus are insulin resistance and b-cell failure. Rosiglit-

azone offer therapeutic benefits of increasing insulin

sensitivity and preserving b-cell function.

It appears from the observations of the UKPDS that

monotherapy with any oral agent either fails at the outset

Figure 10 Effect of rosiglitazone, glim-

epiride and ATOR alone and in combi-

nation with triple oral therapy in

addition to dual oral therapy on body

weight variation (g) of normal and

diabetic rats; values are mean ± SEM;

n = 6; *P < 0.05; **P < 0.01;

***P < 0.001; P > 0.05 is considered

as non-significant (ns).

8 D. Ahmed et al.


or will fail overtime [18]. It is often necessary to use multiple

drugs for an optimal outcome. The optimal combination

of agents to consider using initially is still unknown.

It is also evident from the earlier reports [19] that

atorvastatin, a HMG Co-A reductase inhibitor, has insulin

sensitivity properties in Zuckar lean fatty rats. Statins are

lipid-lowering agents that specifically, competitively, and

reversibly inhibit HMG-CoA reductase, which is a rate

limiting enzyme in the cholesterol synthesis pathway.

These agents also reduce triglycerides, by upregulating

the hepatic LDL receptor and probably by reducing VLDL

production [20]. In the present study, we utilized

atorvastatin concomitantly with rosiglitazone and glim-

epirde to improve the dyslipidemic profile associated with

insulin resistance. Stains and fibrates may be useful

adjuncts in the treatment of diabetes because in addition

to their lipid-lowering effect, they beneficially influence

thrombogenic and fibrinolytic factors. Dose-dependent

reductions in serum free fatty acid levels have been

observed with rosiglitazone treatment [21]. Certain

studies have raised the interesting possibility that treat-

ment with an HMG-CoA reductase inhibitor may slow the

progression of diabetic nephropathy.

The results of this combination therapy study exem-

plify the underlying principle for using rosiglitazone, and

glimepiride in combination with atorvastatin. Rosiglit-

azone and sulpholyureas exert their effects by different

and complementary modes of action. Rosiglitazone

improves insulin senstitivity and may theoretically

extend the utility of sulphonylurea and statins treatment

delaying secondary failure. A combined, synergistic

approach to blood-glucose lowering therapy, used early

during disease progression, may enable patients to

achieve and uphold glycemic control over the enduring.

Although there are undesirable cardiovascular adverse

events reported with the utilization of rosiglitazone

Figure 11 NC = Photomicrograph of section of cardiac tissue of normal Wistar rats, 150·, cardiac tissue exhibits the intercalated disks

marking the intercellular junctions between the myofilaments. DC = Photomicrograph of section of cardiac tissue of streptozotocin (STZ)-

induced diabetic Wistar Rats, 150·. Myocytes- atrophy that marked by the large, dark nuclei and loss of cross-striations. DCT1 = Photo-

micrograph of section of cardiac tissue of STZ-induced diabetic Wistar Rats treated with rosiglitazone alone for 21 days, 150· show signs of

atrophy. DCT2 = Photomicrograph of section of cardiac tissue of STZ-induced diabetic Wistar Rats treated with glimepiride alone for 21 days,

150· reveals the myocytes degeneration. DCT3 = Photomicrograph of section of cardiac tissue of STZ-induced diabetic Wistar Rats treated

with atorvastatin for 21 days, 150·, reveals the mild atrophy of myocytic filaments. DCT4 = Photomicrograph of section of cardiac tissue of

STZ-induced diabetic Wistar Rats treated with dual oral therapy with rosiglitazone + glimepiride for 21 days, 150·. Less degeneration of

myocytes. DCT5 = Photomicrograph of section of cardiac tissue of STZ-induced diabetic Wistar Rats treated with dual oral therapy with

rosiglitazone + atorvastatin for 21 days, 150·, exhibits the very mild atrophy. DCT6 = Photomicrograph of section of cardiac tissue of STZ-

induced diabetic Wistar Rats treated with dual oral therapy with glimepiride + atorvastatin for 21 days, 150·, showing the less necrotic

portions. DCT7 = Photomicrograph of section of cardiac tissue of STZ-induced diabetic Wistar Rats treated with triple oral therapy with

rosiglitazone + glimepiride + atorvastatin for 21 days, 150·. Myocytes shows normal cross-striations and intercalated disks.



but when we conducted the study, there was no much

evidence about the adverse cardiovascular events re-

ported for the rosiglitazone. Furthermore, the rosiglitaz-

one is still in use in some regions of Asia Pacific for the

treatment of diabetes. We have also fetched the grant for

the conduction of the project work on the combinations

including the pioglitazone as one of the molecule for the

treatment of type 2 diabetes, and the research work is in

its initial stage.

In conclusion, results from the present investigation

advocate that triple oral therapy with rosiglitazone,

glimepiride, and atorvastatin has made encouraging effect

on glycemic control and lipid profile in STZ-induced

diabetes in rats, compared either with dual oral therapy,

i.e., rosiglitazone+glimepirde, rosiglitazone+atorvastatin,

glimepiride+atorvastatin or when all the three drugs used

as monotherapy. The mechanism(s) underlying the

significant effects of triple oral therapy are likely quite

different from any investigation of type 2 diabetes or

metabolic syndrome. This suggests the need for more

studies presenting the mechanism of synergism of three

agents affording greater glycemic control and lipid profile

control than monotherapy with the individual agent.

A C K N O W L E D G E M E N T S

Author Danish Ahmed acknowledges Sigma Aldrich,

India for providing Streptozotocin (STZ). Glimepiride was

a generous gift from Ranbaxy, India. This work was

supported by a grant from University Grant Commission

(UGC) India.

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