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 Muraglitazar: A dual peroxisome proliferator-activated recep

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PostSubject: Muraglitazar: A dual peroxisome proliferator-activated recep   Thu Sep 20, 2007 11:34 pm

Muraglitazar: A dual peroxisome proliferator-activated receptor agonist


Source: Formulary

By: Jennifer Kirwin, PharmD, BCPS, Jenny Van Amburgh, PharmD, CDE

Originally published: September 1, 2005



Abstract



Muraglitazar (Bristol-Myers Squibb/Merck) is a new agent under
investigation for the treatment of patients with type 2 diabetes. It
belongs to a novel class of drugs that target the peroxisome
proliferator-activated receptors, both alpha and gamma subtypes.
Available clinical data describe improvements in glycemic parameters
similar to available thiazolidinediones. In addition to improvements in
blood glucose and hemoglobin A1c (HbA1c), muraglitazar treatment is
associated with a substantial reduction in triglycerides (TGs), an
increase in HDL-C, and a modest decrease in LDL-C levels. Safety data
are limited, but in available abstracts, there are reports of
moderately elevated rates of edema, weight gain, and hypoglycemia with
muraglitazar compared with placebo or pioglitazone. When used in
combination with metformin or glyburide, chronic heart failure events
have been reported with muraglitazar. If approved, muraglitazar will
provide a convenient alternative for the treatment of type 2 diabetes.
(Formulary. 2005;40:285293.)



According to the World Health Organization (WHO), the number of people
worldwide with diabetes was estimated in 2000 at 177 million and it is
likely that this number will increase to at least 300 million by 2025.1
In 2002, the prevalence of diabetes in the United States was estimated
to be 18.2 million people (6.3% of the population). Type 2 diabetes
accounts for approximately 90% of all cases of diabetes and is becoming
a problem for children and adolescents, particularly in American
Indians, African-Americans, and Latin-Americans.1,2 Diabetes is also
the sixth-leading cause of death by disease in the United States.3



Type 2 diabetes is characterized by hyperglycemia as a result of
insulin resistance and insulin deficiency. Patients with type 2
diabetes are typically obese and have a type of dyslipidemia that is
characterized by elevated triglycerides (TGs), elevated LDL-C, and
decreased HDL-C.4,5 The morbidity and mortality associated with type 2
diabetes is comprised equally of hyperglycemia, obesity, and
dyslipidemia. Patients with diabetes are at high risk of coronary
events, similar to those without diabetes but with a previous major
coronary event.6



Current treatments for diabetes aim to improve glycemic control and
increase insulin sensitivity to decrease or avoid acute and long-term
complications such as hyper- and hypoglycemia, retinopathy,
nephropathy, neuropathy, and cardiovascular disease. Available oral
treatment options include sulfonylureas, insulin secretagogues
(non-sulfonylureas), biguanides, alpha-glucosidase inhibitors, and
thiazolidinediones. The thiazolidinediones (glitazones) are the newest
oral agents for the treatment of type 2 diabetes and work by targeting
the peroxisome proliferator-activated receptors (PPARs).



PPARs are members of the nuclear receptors supergene family. These
nuclear receptors are ligand-activated transcription factors that
regulate gene expression in response to stimuli in the body. PPARs are
specifically involved in the regulation of lipid and glucose
metabolism, adipocyte differentiation, inflammatory responses, and
cancer.7 There are 3 subtypes of PPARs, designated as alpha, beta, and
gamma, and they are uniquely expressed in adipose tissues; skeletal
muscle; and liver, kidney, and heart tissue.8 PPAR alpha is involved in
the oxidation of fatty acids in the liver, the cellular uptake of fatty
acids, and the control of lipoprotein metabolism. This receptor site
has been of recent interest as a possible contributory factor in the
pathogenesis of dyslipidemia and a target for treatment.7 PPAR beta has
been primarily studied in animal models and its role in humans is still
being determined.7 PPAR gamma has been the most extensively studied
subtype receptor and is involved in glucose and lipid metabolism.8



The glitazones, pioglitazone and rosiglitazone, are highly selective to
PPAR gamma and minimally selective to PPAR alpha. Therefore, these
agents are associated with improvements in insulin sensitivity and
glycemic control and variable alterations in lipid levels. The average
reductions in fasting blood glucose and hemoglobin A1c (HbA1c) with
these agents are between 25 and 50 mg/dL and 1.1% and 1.6%,
respectively.9,10 The lipid-lowering benefits seen when treating with
the glitazones typically consist of an increase in HDL-C, a decrease in
TGs, and a variable effect on LDL-C with reports of either increasing
or no change in the levels.10 The most common adverse drug events
reported with the glitazones are weight gain and edema. An average of
5% to 8% of patients taking pioglitazone and rosiglitazone have
reported mild-to-moderate edema.9 This problem is of special concern in
patients with a history of chronic heart failure (CHF); therefore,
these agents should be avoided in patients with a New York Heart
Association (NYHA) Class III or IV functional status.11



It is now understood that the fibrate class of lipid-lowering agents
(ie, clofibrate, fenofibrate, and gemfibrozil) exert their clinical
effects through activation of PPAR alpha. Prior to the discovery of
PPAR alpha, these agents were developed and marketed without full
understanding of their mechanism of action. On average, fibrates
increase HDL-C by 10% to 20%, decrease TGs by 20% to 50%, and decrease
LDL-C by 5% to 20%.12 The most common adverse drug reactions associated
with these medications are dyspepsia, abdominal pain, and diarrhea.12



Muraglitazar (BMS-298585) is a dual PPAR activator under development
for the treatment of type 2 diabetes. It is a member of a new class of
drugs called the non-thiazolidinedione or the "glitazar" class. If
approved, muraglitazar will be co-marketed by Bristol-Myers Squibb and
Merck.13 Muraglitazar works at both the PPAR gamma as well as PPAR
alpha receptors with preliminary reports showing a decrease in glucose,
TG, and LDL-C levels and an increase in HDL-C levels.1416 The fact
that muraglitazar has potential to improve glycemic control as well as
improve the dyslipidemia associated with type 2 diabetes may translate
to a reduction in the risk of cardiovascular complications associated
with type 2 diabetes.
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PostSubject: Re: Muraglitazar: A dual peroxisome proliferator-activated recep   Thu Sep 20, 2007 11:34 pm

CHEMISTRY AND PHARMACOLOGY





Muraglitazar is a novel, non-thiazolidinedione PPAR alpha/gamma dual
agonist (Figure 1). It is synthesized from oxybenzylglycine and has
shown to have high binding affinity to the PPAR alpha and PPAR gamma
receptors. When compared with rosiglitazone, muraglitazar was found to
have comparable functional activity at PPAR gamma. When compared with
fenofibric acid, a weak PPAR alpha agonist, muraglitazar was found to
be more potent at PPAR alpha.14



In vivo, muraglitazar has demonstrated glucose and TG-lowering effects
in male db/db mice.14 It was also associated with a reduction in both
free fatty acid and insulin levels.14 Devasthale et al suggested that
effects on glucose and insulin levels are mediated through PPAR gamma
while TG-lowering effects are mediated through PPAR alpha.14



The effects of muraglitazar have also been examined in sigma db/db mu
mice, which serve as genetic models of diabetes and obesity.17 After 2
weeks of treatment with muraglitazar 10 mg/kg/d, fasting glucose was
significantly decreased, as was area under the glucose-response curve
following oral glucose challenge.17 In a separate study over 4 weeks,
muraglitazar-treated mice showed lower levels of TGs, free fatty acids,
glucose, and insulin with doses of 0.1 to 30 mg/kg/d. Treatment with a
dose of 30 mg/kg/d was also associated with improved polyuria, as
demonstrated by reduced urine output.17



Muraglitazar may also have a possible effect on atherogenesis by
enhancing reverse cholesterol transport in THP1 macrophage cells. The
agent was also found to inhibit the secretion of MCP1, a
chemoattractant protein, which may translate into a reduction in
macrophage migration into vessel walls.18



Pharmacokinetics. In male rats, muraglitazar was 88%
bioavailable following oral administration of 10 mg/kg. Following
intra-arterial administration of 5 mg/kg, T was 7.34.0 hours with
systemic clearance of 3 mL/minkg.14



The pharmacokinetics of muraglitazar were also evaluated in a
placebo-controlled, single-dose study of healthy subjects. Subjects
were randomly assigned to receive 1 of 6 doses of muraglitazar (0.5,
1.5, 5, 25, 100, or 300 mg). Muraglitazar was rapidly absorbed with a
Tmax of 1 to 6 hours and a mean T of 19 to 27 hours.19



The effects of age and gender on the pharmacokinetics of muraglitazar
were described in abstract form.20 Eighty subjects were enrolled in 1
of 4 groups: young males or females (aged 1840 y) or elderly males or
females (aged ≥65 y). Subjects received 10 mg of muraglitazar by mouth,
and blood samples were collected for 72 hours following the dose. Age
appeared to have little effect, as the ratio of the Cmax in elderly
patients to that of young patients was 1.097 (90% CI, 1.0041.199), and
the ratio of the AUC (elderly to young) was 1.257 (90% CI,
1.1601.361). The ratio of the Cmax in women to men was 1.132 (90% CI,
1.0361.237), and the ratio of the AUC in women to men was 1.086 (90%
CI, 1.0021.176). The authors reported that these factors do not
require dose adjustment.20



CLINICAL TRIALS



Glucose-lowering effects. The glucose-lowering effects of
muraglitazar in patients with type 2 diabetes were described in a
poster presented at the American Diabetes Association (ADA) 2004 Annual
Scientific Session.15 Patients with a fasting serum glucose of 150 to
280 mg/dL were randomized to receive muraglitazar (1.5, 5, or 20 mg),
pioglitazone 45 mg, or placebo by mouth once daily for 28 days. All 38
patients were placed on a standardized, weight-maintaining diet. The
outcome of the study was the mean 24-hour glucose concentration at
7-day intervals, as calculated by averaging several pre- and
post-prandial glucose concentrations in one 24-hour period. Treatment
with muraglitazar was associated with a dose-dependent reduction in
24-hour mean glucose concentrations. In patients treated with 1.5, 5,
and 20 mg of muraglitazar, 24-hour mean glucose was reduced from
baseline by 24 (95% CI, 78 to 30) , 76 (95% CI, 130 to 22), and 100
(95% CI, 154 to 47) mg/dL, respectively. Fasting glucose was also
reduced, and as with 24-hour mean glucose concentrations, this effect
was greater in patients treated with ≥5 mg of muraglitazar. The authors
also noted a non-significant trend towards reduced fasting plasma
insulin levels that did not appear to be dose-related. Comparisons
among various doses of muraglitazar and pioglitazone or placebo were
not made. The authors concluded that muraglitazar therapy was
associated with several favorable effects on glycemic parameters.15







The effects of combination treatment with muraglitazar and metformin
were evaluated in a double-blind, randomized, active-controlled trial
of 1,159 patients with type 2 diabetes uncontrolled on metformin alone
(Table 1).19 In this phase 3 study, patients received treatment with
either muraglitazar 5 mg qd or pioglitazone 30 mg qd in addition to
their stable metformin dose (mean metformin dose 1,851 mg and 1,854 mg
daily in pioglitazone and muraglitazar groups, respectively). At
baseline, mean HbA1c was 8.1% in both groups. After 24 weeks of
treatment, patients taking muraglitazar had a significantly greater
reduction in HbA1c than patients taking pioglitazone (1.14% vs 0.85%,
P<.0001, respectively). Fasting plasma glucose concentrations were
similarly reduced more in the muraglitazar group (44 mg/dL vs 33
mg/dL with pioglitazone).21 More muraglitazar-treated patients met the
HbA1c target of <7% than pioglitazone-treated patients (60% vs 44%
for muraglitazar and pioglitazone groups, respectively, P values not
reported). One-third of muraglitazar-treated patients also had an HbA1c
<6.5%, compared to 23% of pioglitazone-treated patients.22 Based on
these data, it appears muraglitazar 5 mg is more effective than
pioglitazone 30 mg when used to treat patients with uncontrolled type 2
diabetes already taking metformin.



The effects of combination treatment with muraglitazar and glyburide
were evaluated in 583 patients with type 2 diabetes uncontrolled by at
least half-maximal doses of sulfonylureas.23 Patients were randomized
to receive muraglitazar 2.5 or 5 mg or placebo in addition to glyburide
15 mg daily for 24 weeks. Baseline HbA1c ranged from 8% to 8.2%. The
results of the study demonstrated that muraglitazar treatment was
significantly more effective than placebo, with mean changes in HbA1c
from baseline of 1% and 1.2% for muraglitazar 2.5 and 5 mg,
respectively, and +0.2% for placebo-treated patients (P<.001). Based
on these data, the authors concluded that muraglitazar can effectively
improve glucose control when added to glyburide in patients
uncontrolled on sulfonylurea treatment alone.23







Lipid-lowering effects. The lipid-lowering effects of
muraglitazar were examined in a placebo- and active-controlled study in
patients with type 2 diabetes. Subjects were randomly assigned (10 per
group) to receive treatment with muraglitazar (1.5, 5, or 20 mg),
pioglitazone 45 mg, or placebo by mouth once daily for 28 days. All
patients were placed on a standardized, weight-maintaining diet.
Thirty-six patients were enrolled in the study. Baseline values were
not provided, and the authors did not describe concomitant use of
lipid-lowering medications. Muraglitazar treatment was associated with
reductions in TGs: 27% and 51% for the 5-mg and 20-mg doses,
respectively, compared with 12% for pioglitazone. Muraglitazar-treated
groups were also found to have reduced levels of LDL-C from baseline
(range 23.1% to +12.3% for all doses), but these results were not
dose-dependent. Pioglitazone-treated patients had a 1.1% increase in
LDL-C compared to baseline. Improvements in total cholesterol from
baseline were also demonstrated (range 1% to 18.6%) for all doses of
muraglitazar. The authors concluded that muraglitazar treatment
produced improvements in TGs, LDL-C, and total cholesterol that were
numerically better than pioglitazone, though statistical analysis was
not provided.16 The effect of combination treatment with muraglitazar
and glyburide on lipid parameters was also evaluated in the group of
583 patients, reported earlier.23,24 Continued treatment with a statin
was allowed at stable doses. The primary end point was change from
baseline in TGs and HDL-C levels at week 12. At baseline, the 3 groups
had TG levels of 193 to 204 mg/dL, HDL-C levels of 44 mg/dL, and
non-HDL-C levels of 156 to 161 mg/dL. At week 12, the adjusted mean
percentage change from baseline TGs was 3.9%, 26.1%, and +3.2% for
muraglitazar 2.5 and 5 mg and placebo (glyburide alone), respectively
(P<.0001 vs placebo). HDL-C was increased from baseline by 7.4% and
13.7% in patients treated with muraglitazar 2.5 and 5 mg, respectively,
and decreased 0.2% in patients treated with placebo (P<.0001 vs
placebo). Non-HDL-C was decreased by 0.9% and 5.5% in the muraglitazar
2.5 and 5 mg groups, respectively, and increased by 2.2% in the placebo
group. These changes were maintained in assessments at week 24. The
authors concluded that muraglitazar, when taken with glyburide,
produced improvements in lipid parameters in patients with poor
glycemic control on sulfonylureas alone.24



The long-term effects of muraglitazar treatment on lipid parameters
were evaluated in a prospective, randomized, double-blind study of 985
patients with uncontrolled type 2 diabetes treated with diet and
exercise.25 All patients had completed a 24-week short-term therapy
study with doses of muraglitazar ranging from 0.5 to 20 mg qd or 15 mg
PO qd of pioglitazone. In the study, doses of muraglitazar were
titrated upward if HbA1c targets were not reached, and statin therapy
was allowed. Baseline values were not described. In patients who
remained on their initial randomized dose for the entire study
duration, TGs were reduced by 13.2% and 22.4% from baseline with
muraglitazar 1.5 (n=75) and 5 mg qd (n=108), respectively, and reduced
by 12.3% from baseline with pioglitazone 15 mg qd (n=65). HDL-C
increased by 17.2%, 28.9%, and 17.7% from baseline for muraglitazar 1.5
and 5 mg and pioglitazone, respectively. Non-HDL-C was reduced by
11.4%, 11.3%, and 8.8% from baseline for muraglitazar 1.5 and 5 mg, and
pioglitazone, respectively. The authors concluded that muraglitazar
monotherapy may be beneficial in the treatment of dyslipidemia in
patients with type 2 diabetes. Statistical analyses and the percentage
of patients using concomitant statin therapy were not provided.25



ADVERSE EFFECTS



Muraglitazar appears to be generally well tolerated.15,16 In available
abstracts, there are reports of modestly elevated rates of edema,
weight gain, and hypoglycemia with muraglitazar compared with placebo,
but statistical analysis was not provided.24 When used in combination
with metformin or glyburide, CHF-related events were also reported, but
further description was not provided.21,23 This may be more common in
patients with pre-existing cardiac disease.23



In one large trial, rates of edema were reported to be 9.2% with
muraglitazar (in combination with metformin) and 7.2% in patients
treated with pioglitazone (and metformin). Weight gain was also higher
with muraglitazar at 1.4 kg versus 0.6 kg in the pioglitazone group.
Statistical significance was not reported for weight gain or rates of
edema. Of the 4 events related to CHF (3 in muraglitazar-treated
patients, 1 in the pioglitazone group), all recovered with the use of
diuretics or discontinuation of the study drug. Hypoglycemia (defined
as symptoms and fingerstick levels <50 mg/dL) was confirmed in 3
muraglitazar-treated patients and 1 pioglitazone-treated patient.21



In a long-term study, muraglitazar remained well tolerated. The authors
reported that no new concerns emerged during 2 years of treatment.25
Adverse effects on hepatic function were not mentioned in the available
abstracts.



DRUG INTERACTIONS





Formulary considerations



The effect of the concomitant administration of muraglitazar and
metformin was evaluated in an open-label, single-sequence study of
healthy subjects. Thirty-eight subjects were enrolled. Muraglitazar 10
mg and metformin 1,000 mg bid were used for comparison. The
investigators concluded that a single dose of muraglitazar did not
alter the steady-state pharmacokinetics of metformin and vice versa and
that there is no drug interaction between metformin and muraglitazar.26
Data also support a lack of interaction between muraglitazar and
glyburide as demonstrated in an open-label, randomized, cross-over
study of 22 healthy subjects.27 The effect of coadministration of an
80-mg dose of atorvastatin, simvastatin, or pravastatin with
muraglitazar (10 mg with atorvastatin, 20 mg with all others) was
evaluated in 3 separate open-label, randomized, cross-over studies. The
authors reported that no statin altered the pharmacokinetics of
muraglitazar. Muraglitazar treatment was associated with "clinically
insignificant" changes in the metabolites of simvastatin and
atorvastatin (all ≥16%). The authors concluded that there were no
pharmacokinetic interactions between muraglitazar and these 3
statins.28 Information about the adverse effects of concomitant use was
not provided.



DOSING AND ADMINISTRATION



The pharmacokinetic profile of muraglitazar appears consistent with
once-daily administration and all studies reviewed used qd
administration.17



In each issue, the "Focus on" feature reviews a newly approved or
investigational drug of interest to pharmacy and therapeutics committee
members. The column is coordinated by Robert A. Quercia, MS, RPh,
director of Drug Information Services at Hartford Hospital in Hartford,
Conn, and adjunct associate professor, University of Connecticut School
of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, assistant
professor of pharmacy practice, University of Connecticut School of
Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group,
Hartford Hospital.



EDITORS' NOTE: The clinical information provided in "Focus on"
articles is as current as possible. Due to regularly emerging data on
developmental or newly approved drug therapies, articles include
information published or presented and available to the author up until
the time of the manuscript submission.







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