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;40:285–293.)
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.14–16 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.