Muraglitazar: A dual peroxisome proliferator-activated receptor agonist

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 A_1c (HbA_1c), 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

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 A_1c (HbA_1c) 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.

CHEMISTRY AND PHARMACOLOGY

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_½ was 7.3±4.0 hours with systemic clearance of 3 mL/min·kg.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 T_max of 1 to 6 hours and a mean T_½ 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 18–40 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 C_max in elderly patients to that of young patients was 1.097 (90% CI, 1.004–1.199), and the ratio of the AUC (elderly to young) was 1.257 (90% CI, 1.160–1.361). The ratio of the C_max in women to men was 1.132 (90% CI, 1.036–1.237), and the ratio of the AUC in women to men was 1.086 (90% CI, 1.002–1.176). 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 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 HbA_1c 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 HbA_1c 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

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 HbA_1c 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

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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13. Bristol-Myers Squibb company press release. Phase III and II data for investigational medicine Pargluva (muraglitazar) highlighted in late-breaking presentation at Annual Scientific Sessions of the American Diabetes Association: phase III study showed Pargluva significantly reduced blood glucose versus pioglitazone as an active control in patients with type 2 diabetes; Long-term data from phase II dose-ranging study also presented. Available at: http:// http://www.bms.com/news/press/data/fg_press_release_5661.html . Accessed August 12, 2005.

14. Devasthale V, Chen S, Jeon Y, et al. Design and synthesis of N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4oxazolyl) ethoxy]phenyl]methyl]glycine [muraglitazar/BMS298585], a novel peroxisome proliferative-activated receptor α/γ dual agonist with efficacious glucose and lipid-lowering agent. J Med Chem. 2005;48:2248–2250.

15. Mosqueda-Garcia R, Frost CH, Swaminathan A, Raymond R, Nepal S, Reeves R, et al. Glucose lowering effects of multiple dose admininstation of muraglitazar (BMS-298585), a novel PPAR α/γ dual agonist, in type 2 diabetic patients [abstract]. Presented at: American Diabetes Association 64th Annual Scientific Session; June 4–8, 2004; Orlando, Fla. Abstract 138-OR.

16. Frost CE, Swaminathan A, Raymond R, Nepal S, Gregg R, Reeves R, et al. Lipid lowering effects of multiple dose administration of Muraglitazar (BMS-298585), a novel PPAR α/γ dual agonist, in type 2 diabetic patients [abstract]. Presented at: American Diabetes Association 64th Annual Scientific Session; June 4–8, 2004; Orlando, Fla. Abstract 1988-PO.

17. Harrity T, Chu C, Kunselman L, Ponticiello R, Cap M, Cheng P, et al. Muraglitazar, a novel non-TZD dual PPAR α/γ agonist, improves metabolic abnormalities in obese, severely diabetic db/db mice [abstract]. Presented at: American Diabetes Association 64th Annual Scientific Session; June 4–8, 2004; Orlando, Fla. Abstract 134-OR.

18. Zhou M, Peters A, Cao G, Farrelly D, Harrity T, Cheng P, et al. Muraglitazar, a novel non-TZD PPAR α/γ dual agonist, regulates genes involved in reverse cholesterol transport, stimulates cholesterol efflux, and reduces MCP1 secretion in human THP1 macrophage cells [abstract]. Presented at: American Diabetes Association 64th Annual Scientific Session; June 4–8, 2004; Orlando, Fla. Abstract 640-P.

19. Swaminathan A, Frost CE, Raymond R, Reeves R, Mosqueda-Garcia R. Pharmacokinetics of single doses of the novel PPAR α/γ dual agonist muraglitazar (BMS-298585) in healthy human subjects [abstract]. Presented at: American Diabetes Association 64th Annual Scientific Session; June 4–8, 2004; Orlando, Fla. Abstract 618-P.

20. Moore KT, Turner KC, Swaminathan A, Nepal S, Reeves RA, Mosqueda-Garcia R. Effects of age and gender on the pharmacokinetics of muraglitazar, a novel dual PPAR α/γ agonist under investigation for the treatment of type 2 diabetes [abstract]. Presented at: American Diabetes Association 65th Annual Scientific Session; June 10–14, 2005; San Diego, Calif. Abstract 519-P.

21. Rubin CJ, Mohideen P, Ledeine JM, Belder R, Fiedorek FT. Improvement of glycemic control with muraglitazar, a novel dual PPAR α/γ agonist, in combination with metformin in patients with type 2 diabetes: a double-blind, randomized, pioglitazone-controlled study [abstract]. Presented at: American Diabetes Association 65th Annual Scientific Session; June 10–14, 2005; San Diego, Calif. Abstract 14-OR.

22. Rubin CJ, Mohideen P, Ledeine JM, Belder R, Fiedorek FT. Attainment of A1c goals with muraglitazar, a novel dual PPAR a/g agonist, in combination with metformin in patients with type 2 diabetes: a double-blind, randomized comparison with pioglitazone plus metformin [abstract]. Presented at: American Diabetes Association 65th Annual Scientific Session; June 10–14, 2005; San Diego, Calif. Abstract 2113-PO.

23. Mohideen P, De Pril V, Rubin CJ. Glycemic efficacy and safety of muraglitazar, a novel dual PPAR α/γ agonist, plus glyburide in patients with type 2 diabetes failing sulfonylurea monotherapy: a randomized, double-blind, placebo-controlled study [abstract]. Presented at: American Diabetes Association 65th Annual Scientific Session; June 10–14, 2005; San Diego, Calif. Abstract 518-P.

24. Mohideen P, De Pril V, Rubin CJ. Improvement of diabetic dyslipidemia with muraglitazar, a novel dual PPAR α/γ agonist, plus glyburide in patients with type 2 diabetes failing sulfonylurea monotherapy: a randomized, double-blind, placebo-controlled study [abstract]. Presented at: American Diabetes Association 65th Annual Scientific Session; June 10-14, 2005; San Diego, Calif. Abstract 968-P.

25. Frederich R, Viraswami-Appanna K, Rubin CJ. Effects of long-term therapy (2-year) with Muraglitazar, a novel dual PPAR α/γ agonist, on diabetic dyslipidemia in patients with type 2 diabetes: a double-blind, randomized, parallel-group study [abstract]. Presented at: American Diabetes Association 65th Annual Scientific Session; June 10–14, 2005; San Diego, Calif. Abstract 967-P.

26. Turner KC, Moore KT, Swaminathan A, Nepal S, Reeves RA, Mosqueda-Garcia R. Lack of drug interaction between metformin and muraglitazar, a novel dual PPAR α/γ agonist under investigation for the treatment of type 2 diabetes [abstract]. Presented at: American Diabetes Association 65th Annual Scientific Session; June 10–14, 2005; San Diego, Calif. Abstract 2115-PO.

27. Darbenzio R, Reitberg DP, Swaminathan A, Nepal S, Munsick C, Reeves R, et al. Lack of pharmacokinetic interaction between glyburide and the novel dual PPAR α/γ agonist muraglitazar [abstract]. Presented at: American Diabetes Association 65th Annual Scientific Session; June 10–14, 2005; San Diego, Calif. Abstract 2114-PO.

28. Swaminathan A, Darbenzio R, Munsick C, Turner KC, Moore KT, Nepal S, et al. Statins do not alter the pharmacokinetics of muraglitazar, a novel dual PPAR a/g agonist under investigation for the treatment of type 2 diabetes [abstract]. Presented at: American Diabetes Association 65th Annual Scientific Session; June 10–14, 2005; San Diego, Calif. Abstract 2116-PO.